ASN DIALYSIS CURRICULUM ASN DIALYSIS ADVISORY GROUP
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Embed
ASN DIALYSIS ADVISORY GROUP · Death in Hemodialysis Patients. Patrick Pun, ... • Chronic ECFV excess/ vascular access ... The way potassium is removed on dialysis is via diffusion
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Transcript
ASN DIALYSIS CURRICULUM
ASN DIALYSIS ADVISORY GROUP
This image cannot currently be displayed
The Challenge of Sudden Cardiac Death in Hemodialysis Patients
Patrick Pun MD MHS
Division of Nephrology
Department of Medicine
Duke University
2
This image cannot currently be displayed
Learning Objectives
Describe the epidemic of sudden cardiac death (SCD) among CKD (and particularly ESKD) patients
Describe unique risk factors which may explain the high risk of SCD in hemodialysis patients
Describe what we know about SCD prevention and management in hemodialysis patients
This image cannot currently be displayed
Sudden Death is the Leading Cause of Death in Dialysis Patients
AMICHF
ArrhythmiaSCA
Other cardiac
CVA
Infection
WithdrawalMalignancy
All other
USRDS ADR 2011
261
SCD
Prevalent Dialysis Patients 2007-2009
This image cannot currently be displayed
The risk of SCD in ESKD-HD is 20x greater than the general population
18942
73
125
241
0
5
10
15
20
25
30
Gen Pop CVD CKD3-4 CKD 5 ND ESRD-HD
Eve
nts
100
0 p
t-ye
ars
Pun et al Kidney Int 2009 Sep76(6)652-8
N=19440
11 increase risk per 10 mlmin GFR decline
Duke catheterization database
Presenter
Presentation Notes
The relative risk of SCD is remarkably higher in HD pts compared to other populations In the gen pop the risk of SCA is about 2 events per 1000 pt years In patients with CV risk factors the rate doubles and using the Duke Catherization database we found that the rate incrementally increases with kidney disease and concurrent CAD patients with CKD stage 3 and 4 here and pt with advanced CKD 5 but not on dialysis here Notice however the marked increase in SCA events among patients receiving RRT HD nearly doubles
This image cannot currently be displayed
Risk of Sudden Cardiac Death after Dialysis InitiationPD vs HD
What is also clear is that the risk of SCD increases in relationship to the number of years on dialysis Again data from the USRDS showing the increasing cumulative probability of SCD with each passing month on HD
USRDS ADR 2011 6
This image cannot currently be displayed
Why is the SCD rate so high Possible explanations
Misclassification
Same disease as general population just worse
Novel risk factors New Disease
Presenter
Presentation Notes
We can posit several possible explanations why the SCD rate is so high in HD First is it possible that we are and grossly overestimating the SCD rate and counting events are not true SCD Can the increased SCD rate be understood in the context of what we know about the same disease in the GP just much worse Or really is a Is more of a novel disease with novel risk factors13
This image cannot currently be displayed
SCD Traditional Definitions
bullWitnessed cardiac arrest - Within an hour of symptom onset
bullUnwitnessed death- Unexpected- Patient known to be well in the last 24 hours- No other clear non-cardiac cause of death
bullOut of hospital occurrence of unanticipated non-traumatic cardiac death
bullUsually due to ventricular tachyarrhythmia
bullDoes this apply to dialysis patients
This image cannot currently be displayed
Probably not just due to misclassification Some assurances
Registrydeath certificate data prone to misclassification
363 HD patients with witnessed outpt SCD
bull Sensitivity of registry definition 70-83
bull Specificity of registry definition 90
SCD rate is consistent across data sources
bull In clinical trials [HEMO trial 4D trial]
bull In prospective HD cohorts [CHOICE cohort]
Increased rate of SCD unlikely due to just misclassfication
Pun et al Clin J Am Soc Nephrol 2012 Jan7(1)116-22Herzog et al Kidney Int 2011 Sep80(6)572-86
It is generally understood that SCD requires two main ingredients Structural heart disease and acute arrhythmic trigger In the GP cardiomyopathy with decreased LVEF is by far the most power powerful predictor of SCD risk and acute ischemia is most often the acute arrhtyhmic trigger Conventional CHD-related factors produce both ischemic cardiomyopathy and triggers for SCD Whether or not this is the same process we are seeing in chronic kidney disease patients is in question 13
This image cannot currently be displayed
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Bleyer Kidney Int 2006 Jun69(12)2268-73Yamada Clin J Am Soc Nephrol 2010 Oct5(10)1793-8Mangrum et al Heart Rhythm 2005 2(5)S41 Park et al J Am Soc Nephrol 2012 Oct23(10)1725-34
01020304050607080
WFU (n=88) UVA(n=31)
Perc
ent o
f SC
D
EF
lt35
EF
gt35
EF
gt35
EF
lt35
bull Only 7 Systolic Dysfunction in CRiC
bull 5 in incident HD cohort
bull Increased SCA risk cannot be explained by SD IHD disease alone
Presenter
Presentation Notes
What do we see when we look at underlying cardiac dz in CKD pts with SCD In both a case series of SCD victims from WFU and from UVA the the prevalene of low EF was quite small with 70 of patients without any evidence of systolic dysfunction Also in the CRiC study (observational cohort of pts with moderate CKD) the reported prevalence of systolic dysfuntion is only 7 and a large study of incident dialysis patients also showed that systolic dysfunction is also low at 5 This complicates the paradigm of low EF being the strongest predictor of SCD risk Therefore it seems apparaent that the increased SCA risk in CKD pts canrsquot be fully explained by systolic dysfunction and conventional IHD alone 131313
This image cannot currently be displayed
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
Left Ventricular Hypertrophybull56 of HD pts without CADbullEtiologic associations with
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
The Challenge of Sudden Cardiac Death in Hemodialysis Patients
Patrick Pun MD MHS
Division of Nephrology
Department of Medicine
Duke University
2
This image cannot currently be displayed
Learning Objectives
Describe the epidemic of sudden cardiac death (SCD) among CKD (and particularly ESKD) patients
Describe unique risk factors which may explain the high risk of SCD in hemodialysis patients
Describe what we know about SCD prevention and management in hemodialysis patients
This image cannot currently be displayed
Sudden Death is the Leading Cause of Death in Dialysis Patients
AMICHF
ArrhythmiaSCA
Other cardiac
CVA
Infection
WithdrawalMalignancy
All other
USRDS ADR 2011
261
SCD
Prevalent Dialysis Patients 2007-2009
This image cannot currently be displayed
The risk of SCD in ESKD-HD is 20x greater than the general population
18942
73
125
241
0
5
10
15
20
25
30
Gen Pop CVD CKD3-4 CKD 5 ND ESRD-HD
Eve
nts
100
0 p
t-ye
ars
Pun et al Kidney Int 2009 Sep76(6)652-8
N=19440
11 increase risk per 10 mlmin GFR decline
Duke catheterization database
Presenter
Presentation Notes
The relative risk of SCD is remarkably higher in HD pts compared to other populations In the gen pop the risk of SCA is about 2 events per 1000 pt years In patients with CV risk factors the rate doubles and using the Duke Catherization database we found that the rate incrementally increases with kidney disease and concurrent CAD patients with CKD stage 3 and 4 here and pt with advanced CKD 5 but not on dialysis here Notice however the marked increase in SCA events among patients receiving RRT HD nearly doubles
This image cannot currently be displayed
Risk of Sudden Cardiac Death after Dialysis InitiationPD vs HD
What is also clear is that the risk of SCD increases in relationship to the number of years on dialysis Again data from the USRDS showing the increasing cumulative probability of SCD with each passing month on HD
USRDS ADR 2011 6
This image cannot currently be displayed
Why is the SCD rate so high Possible explanations
Misclassification
Same disease as general population just worse
Novel risk factors New Disease
Presenter
Presentation Notes
We can posit several possible explanations why the SCD rate is so high in HD First is it possible that we are and grossly overestimating the SCD rate and counting events are not true SCD Can the increased SCD rate be understood in the context of what we know about the same disease in the GP just much worse Or really is a Is more of a novel disease with novel risk factors13
This image cannot currently be displayed
SCD Traditional Definitions
bullWitnessed cardiac arrest - Within an hour of symptom onset
bullUnwitnessed death- Unexpected- Patient known to be well in the last 24 hours- No other clear non-cardiac cause of death
bullOut of hospital occurrence of unanticipated non-traumatic cardiac death
bullUsually due to ventricular tachyarrhythmia
bullDoes this apply to dialysis patients
This image cannot currently be displayed
Probably not just due to misclassification Some assurances
Registrydeath certificate data prone to misclassification
363 HD patients with witnessed outpt SCD
bull Sensitivity of registry definition 70-83
bull Specificity of registry definition 90
SCD rate is consistent across data sources
bull In clinical trials [HEMO trial 4D trial]
bull In prospective HD cohorts [CHOICE cohort]
Increased rate of SCD unlikely due to just misclassfication
Pun et al Clin J Am Soc Nephrol 2012 Jan7(1)116-22Herzog et al Kidney Int 2011 Sep80(6)572-86
It is generally understood that SCD requires two main ingredients Structural heart disease and acute arrhythmic trigger In the GP cardiomyopathy with decreased LVEF is by far the most power powerful predictor of SCD risk and acute ischemia is most often the acute arrhtyhmic trigger Conventional CHD-related factors produce both ischemic cardiomyopathy and triggers for SCD Whether or not this is the same process we are seeing in chronic kidney disease patients is in question 13
This image cannot currently be displayed
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Bleyer Kidney Int 2006 Jun69(12)2268-73Yamada Clin J Am Soc Nephrol 2010 Oct5(10)1793-8Mangrum et al Heart Rhythm 2005 2(5)S41 Park et al J Am Soc Nephrol 2012 Oct23(10)1725-34
01020304050607080
WFU (n=88) UVA(n=31)
Perc
ent o
f SC
D
EF
lt35
EF
gt35
EF
gt35
EF
lt35
bull Only 7 Systolic Dysfunction in CRiC
bull 5 in incident HD cohort
bull Increased SCA risk cannot be explained by SD IHD disease alone
Presenter
Presentation Notes
What do we see when we look at underlying cardiac dz in CKD pts with SCD In both a case series of SCD victims from WFU and from UVA the the prevalene of low EF was quite small with 70 of patients without any evidence of systolic dysfunction Also in the CRiC study (observational cohort of pts with moderate CKD) the reported prevalence of systolic dysfuntion is only 7 and a large study of incident dialysis patients also showed that systolic dysfunction is also low at 5 This complicates the paradigm of low EF being the strongest predictor of SCD risk Therefore it seems apparaent that the increased SCA risk in CKD pts canrsquot be fully explained by systolic dysfunction and conventional IHD alone 131313
This image cannot currently be displayed
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
Left Ventricular Hypertrophybull56 of HD pts without CADbullEtiologic associations with
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Learning Objectives
Describe the epidemic of sudden cardiac death (SCD) among CKD (and particularly ESKD) patients
Describe unique risk factors which may explain the high risk of SCD in hemodialysis patients
Describe what we know about SCD prevention and management in hemodialysis patients
This image cannot currently be displayed
Sudden Death is the Leading Cause of Death in Dialysis Patients
AMICHF
ArrhythmiaSCA
Other cardiac
CVA
Infection
WithdrawalMalignancy
All other
USRDS ADR 2011
261
SCD
Prevalent Dialysis Patients 2007-2009
This image cannot currently be displayed
The risk of SCD in ESKD-HD is 20x greater than the general population
18942
73
125
241
0
5
10
15
20
25
30
Gen Pop CVD CKD3-4 CKD 5 ND ESRD-HD
Eve
nts
100
0 p
t-ye
ars
Pun et al Kidney Int 2009 Sep76(6)652-8
N=19440
11 increase risk per 10 mlmin GFR decline
Duke catheterization database
Presenter
Presentation Notes
The relative risk of SCD is remarkably higher in HD pts compared to other populations In the gen pop the risk of SCA is about 2 events per 1000 pt years In patients with CV risk factors the rate doubles and using the Duke Catherization database we found that the rate incrementally increases with kidney disease and concurrent CAD patients with CKD stage 3 and 4 here and pt with advanced CKD 5 but not on dialysis here Notice however the marked increase in SCA events among patients receiving RRT HD nearly doubles
This image cannot currently be displayed
Risk of Sudden Cardiac Death after Dialysis InitiationPD vs HD
What is also clear is that the risk of SCD increases in relationship to the number of years on dialysis Again data from the USRDS showing the increasing cumulative probability of SCD with each passing month on HD
USRDS ADR 2011 6
This image cannot currently be displayed
Why is the SCD rate so high Possible explanations
Misclassification
Same disease as general population just worse
Novel risk factors New Disease
Presenter
Presentation Notes
We can posit several possible explanations why the SCD rate is so high in HD First is it possible that we are and grossly overestimating the SCD rate and counting events are not true SCD Can the increased SCD rate be understood in the context of what we know about the same disease in the GP just much worse Or really is a Is more of a novel disease with novel risk factors13
This image cannot currently be displayed
SCD Traditional Definitions
bullWitnessed cardiac arrest - Within an hour of symptom onset
bullUnwitnessed death- Unexpected- Patient known to be well in the last 24 hours- No other clear non-cardiac cause of death
bullOut of hospital occurrence of unanticipated non-traumatic cardiac death
bullUsually due to ventricular tachyarrhythmia
bullDoes this apply to dialysis patients
This image cannot currently be displayed
Probably not just due to misclassification Some assurances
Registrydeath certificate data prone to misclassification
363 HD patients with witnessed outpt SCD
bull Sensitivity of registry definition 70-83
bull Specificity of registry definition 90
SCD rate is consistent across data sources
bull In clinical trials [HEMO trial 4D trial]
bull In prospective HD cohorts [CHOICE cohort]
Increased rate of SCD unlikely due to just misclassfication
Pun et al Clin J Am Soc Nephrol 2012 Jan7(1)116-22Herzog et al Kidney Int 2011 Sep80(6)572-86
It is generally understood that SCD requires two main ingredients Structural heart disease and acute arrhythmic trigger In the GP cardiomyopathy with decreased LVEF is by far the most power powerful predictor of SCD risk and acute ischemia is most often the acute arrhtyhmic trigger Conventional CHD-related factors produce both ischemic cardiomyopathy and triggers for SCD Whether or not this is the same process we are seeing in chronic kidney disease patients is in question 13
This image cannot currently be displayed
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Bleyer Kidney Int 2006 Jun69(12)2268-73Yamada Clin J Am Soc Nephrol 2010 Oct5(10)1793-8Mangrum et al Heart Rhythm 2005 2(5)S41 Park et al J Am Soc Nephrol 2012 Oct23(10)1725-34
01020304050607080
WFU (n=88) UVA(n=31)
Perc
ent o
f SC
D
EF
lt35
EF
gt35
EF
gt35
EF
lt35
bull Only 7 Systolic Dysfunction in CRiC
bull 5 in incident HD cohort
bull Increased SCA risk cannot be explained by SD IHD disease alone
Presenter
Presentation Notes
What do we see when we look at underlying cardiac dz in CKD pts with SCD In both a case series of SCD victims from WFU and from UVA the the prevalene of low EF was quite small with 70 of patients without any evidence of systolic dysfunction Also in the CRiC study (observational cohort of pts with moderate CKD) the reported prevalence of systolic dysfuntion is only 7 and a large study of incident dialysis patients also showed that systolic dysfunction is also low at 5 This complicates the paradigm of low EF being the strongest predictor of SCD risk Therefore it seems apparaent that the increased SCA risk in CKD pts canrsquot be fully explained by systolic dysfunction and conventional IHD alone 131313
This image cannot currently be displayed
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
Left Ventricular Hypertrophybull56 of HD pts without CADbullEtiologic associations with
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Sudden Death is the Leading Cause of Death in Dialysis Patients
AMICHF
ArrhythmiaSCA
Other cardiac
CVA
Infection
WithdrawalMalignancy
All other
USRDS ADR 2011
261
SCD
Prevalent Dialysis Patients 2007-2009
This image cannot currently be displayed
The risk of SCD in ESKD-HD is 20x greater than the general population
18942
73
125
241
0
5
10
15
20
25
30
Gen Pop CVD CKD3-4 CKD 5 ND ESRD-HD
Eve
nts
100
0 p
t-ye
ars
Pun et al Kidney Int 2009 Sep76(6)652-8
N=19440
11 increase risk per 10 mlmin GFR decline
Duke catheterization database
Presenter
Presentation Notes
The relative risk of SCD is remarkably higher in HD pts compared to other populations In the gen pop the risk of SCA is about 2 events per 1000 pt years In patients with CV risk factors the rate doubles and using the Duke Catherization database we found that the rate incrementally increases with kidney disease and concurrent CAD patients with CKD stage 3 and 4 here and pt with advanced CKD 5 but not on dialysis here Notice however the marked increase in SCA events among patients receiving RRT HD nearly doubles
This image cannot currently be displayed
Risk of Sudden Cardiac Death after Dialysis InitiationPD vs HD
What is also clear is that the risk of SCD increases in relationship to the number of years on dialysis Again data from the USRDS showing the increasing cumulative probability of SCD with each passing month on HD
USRDS ADR 2011 6
This image cannot currently be displayed
Why is the SCD rate so high Possible explanations
Misclassification
Same disease as general population just worse
Novel risk factors New Disease
Presenter
Presentation Notes
We can posit several possible explanations why the SCD rate is so high in HD First is it possible that we are and grossly overestimating the SCD rate and counting events are not true SCD Can the increased SCD rate be understood in the context of what we know about the same disease in the GP just much worse Or really is a Is more of a novel disease with novel risk factors13
This image cannot currently be displayed
SCD Traditional Definitions
bullWitnessed cardiac arrest - Within an hour of symptom onset
bullUnwitnessed death- Unexpected- Patient known to be well in the last 24 hours- No other clear non-cardiac cause of death
bullOut of hospital occurrence of unanticipated non-traumatic cardiac death
bullUsually due to ventricular tachyarrhythmia
bullDoes this apply to dialysis patients
This image cannot currently be displayed
Probably not just due to misclassification Some assurances
Registrydeath certificate data prone to misclassification
363 HD patients with witnessed outpt SCD
bull Sensitivity of registry definition 70-83
bull Specificity of registry definition 90
SCD rate is consistent across data sources
bull In clinical trials [HEMO trial 4D trial]
bull In prospective HD cohorts [CHOICE cohort]
Increased rate of SCD unlikely due to just misclassfication
Pun et al Clin J Am Soc Nephrol 2012 Jan7(1)116-22Herzog et al Kidney Int 2011 Sep80(6)572-86
It is generally understood that SCD requires two main ingredients Structural heart disease and acute arrhythmic trigger In the GP cardiomyopathy with decreased LVEF is by far the most power powerful predictor of SCD risk and acute ischemia is most often the acute arrhtyhmic trigger Conventional CHD-related factors produce both ischemic cardiomyopathy and triggers for SCD Whether or not this is the same process we are seeing in chronic kidney disease patients is in question 13
This image cannot currently be displayed
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Bleyer Kidney Int 2006 Jun69(12)2268-73Yamada Clin J Am Soc Nephrol 2010 Oct5(10)1793-8Mangrum et al Heart Rhythm 2005 2(5)S41 Park et al J Am Soc Nephrol 2012 Oct23(10)1725-34
01020304050607080
WFU (n=88) UVA(n=31)
Perc
ent o
f SC
D
EF
lt35
EF
gt35
EF
gt35
EF
lt35
bull Only 7 Systolic Dysfunction in CRiC
bull 5 in incident HD cohort
bull Increased SCA risk cannot be explained by SD IHD disease alone
Presenter
Presentation Notes
What do we see when we look at underlying cardiac dz in CKD pts with SCD In both a case series of SCD victims from WFU and from UVA the the prevalene of low EF was quite small with 70 of patients without any evidence of systolic dysfunction Also in the CRiC study (observational cohort of pts with moderate CKD) the reported prevalence of systolic dysfuntion is only 7 and a large study of incident dialysis patients also showed that systolic dysfunction is also low at 5 This complicates the paradigm of low EF being the strongest predictor of SCD risk Therefore it seems apparaent that the increased SCA risk in CKD pts canrsquot be fully explained by systolic dysfunction and conventional IHD alone 131313
This image cannot currently be displayed
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
Left Ventricular Hypertrophybull56 of HD pts without CADbullEtiologic associations with
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
The risk of SCD in ESKD-HD is 20x greater than the general population
18942
73
125
241
0
5
10
15
20
25
30
Gen Pop CVD CKD3-4 CKD 5 ND ESRD-HD
Eve
nts
100
0 p
t-ye
ars
Pun et al Kidney Int 2009 Sep76(6)652-8
N=19440
11 increase risk per 10 mlmin GFR decline
Duke catheterization database
Presenter
Presentation Notes
The relative risk of SCD is remarkably higher in HD pts compared to other populations In the gen pop the risk of SCA is about 2 events per 1000 pt years In patients with CV risk factors the rate doubles and using the Duke Catherization database we found that the rate incrementally increases with kidney disease and concurrent CAD patients with CKD stage 3 and 4 here and pt with advanced CKD 5 but not on dialysis here Notice however the marked increase in SCA events among patients receiving RRT HD nearly doubles
This image cannot currently be displayed
Risk of Sudden Cardiac Death after Dialysis InitiationPD vs HD
What is also clear is that the risk of SCD increases in relationship to the number of years on dialysis Again data from the USRDS showing the increasing cumulative probability of SCD with each passing month on HD
USRDS ADR 2011 6
This image cannot currently be displayed
Why is the SCD rate so high Possible explanations
Misclassification
Same disease as general population just worse
Novel risk factors New Disease
Presenter
Presentation Notes
We can posit several possible explanations why the SCD rate is so high in HD First is it possible that we are and grossly overestimating the SCD rate and counting events are not true SCD Can the increased SCD rate be understood in the context of what we know about the same disease in the GP just much worse Or really is a Is more of a novel disease with novel risk factors13
This image cannot currently be displayed
SCD Traditional Definitions
bullWitnessed cardiac arrest - Within an hour of symptom onset
bullUnwitnessed death- Unexpected- Patient known to be well in the last 24 hours- No other clear non-cardiac cause of death
bullOut of hospital occurrence of unanticipated non-traumatic cardiac death
bullUsually due to ventricular tachyarrhythmia
bullDoes this apply to dialysis patients
This image cannot currently be displayed
Probably not just due to misclassification Some assurances
Registrydeath certificate data prone to misclassification
363 HD patients with witnessed outpt SCD
bull Sensitivity of registry definition 70-83
bull Specificity of registry definition 90
SCD rate is consistent across data sources
bull In clinical trials [HEMO trial 4D trial]
bull In prospective HD cohorts [CHOICE cohort]
Increased rate of SCD unlikely due to just misclassfication
Pun et al Clin J Am Soc Nephrol 2012 Jan7(1)116-22Herzog et al Kidney Int 2011 Sep80(6)572-86
It is generally understood that SCD requires two main ingredients Structural heart disease and acute arrhythmic trigger In the GP cardiomyopathy with decreased LVEF is by far the most power powerful predictor of SCD risk and acute ischemia is most often the acute arrhtyhmic trigger Conventional CHD-related factors produce both ischemic cardiomyopathy and triggers for SCD Whether or not this is the same process we are seeing in chronic kidney disease patients is in question 13
This image cannot currently be displayed
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Bleyer Kidney Int 2006 Jun69(12)2268-73Yamada Clin J Am Soc Nephrol 2010 Oct5(10)1793-8Mangrum et al Heart Rhythm 2005 2(5)S41 Park et al J Am Soc Nephrol 2012 Oct23(10)1725-34
01020304050607080
WFU (n=88) UVA(n=31)
Perc
ent o
f SC
D
EF
lt35
EF
gt35
EF
gt35
EF
lt35
bull Only 7 Systolic Dysfunction in CRiC
bull 5 in incident HD cohort
bull Increased SCA risk cannot be explained by SD IHD disease alone
Presenter
Presentation Notes
What do we see when we look at underlying cardiac dz in CKD pts with SCD In both a case series of SCD victims from WFU and from UVA the the prevalene of low EF was quite small with 70 of patients without any evidence of systolic dysfunction Also in the CRiC study (observational cohort of pts with moderate CKD) the reported prevalence of systolic dysfuntion is only 7 and a large study of incident dialysis patients also showed that systolic dysfunction is also low at 5 This complicates the paradigm of low EF being the strongest predictor of SCD risk Therefore it seems apparaent that the increased SCA risk in CKD pts canrsquot be fully explained by systolic dysfunction and conventional IHD alone 131313
This image cannot currently be displayed
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
Left Ventricular Hypertrophybull56 of HD pts without CADbullEtiologic associations with
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Risk of Sudden Cardiac Death after Dialysis InitiationPD vs HD
What is also clear is that the risk of SCD increases in relationship to the number of years on dialysis Again data from the USRDS showing the increasing cumulative probability of SCD with each passing month on HD
USRDS ADR 2011 6
This image cannot currently be displayed
Why is the SCD rate so high Possible explanations
Misclassification
Same disease as general population just worse
Novel risk factors New Disease
Presenter
Presentation Notes
We can posit several possible explanations why the SCD rate is so high in HD First is it possible that we are and grossly overestimating the SCD rate and counting events are not true SCD Can the increased SCD rate be understood in the context of what we know about the same disease in the GP just much worse Or really is a Is more of a novel disease with novel risk factors13
This image cannot currently be displayed
SCD Traditional Definitions
bullWitnessed cardiac arrest - Within an hour of symptom onset
bullUnwitnessed death- Unexpected- Patient known to be well in the last 24 hours- No other clear non-cardiac cause of death
bullOut of hospital occurrence of unanticipated non-traumatic cardiac death
bullUsually due to ventricular tachyarrhythmia
bullDoes this apply to dialysis patients
This image cannot currently be displayed
Probably not just due to misclassification Some assurances
Registrydeath certificate data prone to misclassification
363 HD patients with witnessed outpt SCD
bull Sensitivity of registry definition 70-83
bull Specificity of registry definition 90
SCD rate is consistent across data sources
bull In clinical trials [HEMO trial 4D trial]
bull In prospective HD cohorts [CHOICE cohort]
Increased rate of SCD unlikely due to just misclassfication
Pun et al Clin J Am Soc Nephrol 2012 Jan7(1)116-22Herzog et al Kidney Int 2011 Sep80(6)572-86
It is generally understood that SCD requires two main ingredients Structural heart disease and acute arrhythmic trigger In the GP cardiomyopathy with decreased LVEF is by far the most power powerful predictor of SCD risk and acute ischemia is most often the acute arrhtyhmic trigger Conventional CHD-related factors produce both ischemic cardiomyopathy and triggers for SCD Whether or not this is the same process we are seeing in chronic kidney disease patients is in question 13
This image cannot currently be displayed
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Bleyer Kidney Int 2006 Jun69(12)2268-73Yamada Clin J Am Soc Nephrol 2010 Oct5(10)1793-8Mangrum et al Heart Rhythm 2005 2(5)S41 Park et al J Am Soc Nephrol 2012 Oct23(10)1725-34
01020304050607080
WFU (n=88) UVA(n=31)
Perc
ent o
f SC
D
EF
lt35
EF
gt35
EF
gt35
EF
lt35
bull Only 7 Systolic Dysfunction in CRiC
bull 5 in incident HD cohort
bull Increased SCA risk cannot be explained by SD IHD disease alone
Presenter
Presentation Notes
What do we see when we look at underlying cardiac dz in CKD pts with SCD In both a case series of SCD victims from WFU and from UVA the the prevalene of low EF was quite small with 70 of patients without any evidence of systolic dysfunction Also in the CRiC study (observational cohort of pts with moderate CKD) the reported prevalence of systolic dysfuntion is only 7 and a large study of incident dialysis patients also showed that systolic dysfunction is also low at 5 This complicates the paradigm of low EF being the strongest predictor of SCD risk Therefore it seems apparaent that the increased SCA risk in CKD pts canrsquot be fully explained by systolic dysfunction and conventional IHD alone 131313
This image cannot currently be displayed
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
Left Ventricular Hypertrophybull56 of HD pts without CADbullEtiologic associations with
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Why is the SCD rate so high Possible explanations
Misclassification
Same disease as general population just worse
Novel risk factors New Disease
Presenter
Presentation Notes
We can posit several possible explanations why the SCD rate is so high in HD First is it possible that we are and grossly overestimating the SCD rate and counting events are not true SCD Can the increased SCD rate be understood in the context of what we know about the same disease in the GP just much worse Or really is a Is more of a novel disease with novel risk factors13
This image cannot currently be displayed
SCD Traditional Definitions
bullWitnessed cardiac arrest - Within an hour of symptom onset
bullUnwitnessed death- Unexpected- Patient known to be well in the last 24 hours- No other clear non-cardiac cause of death
bullOut of hospital occurrence of unanticipated non-traumatic cardiac death
bullUsually due to ventricular tachyarrhythmia
bullDoes this apply to dialysis patients
This image cannot currently be displayed
Probably not just due to misclassification Some assurances
Registrydeath certificate data prone to misclassification
363 HD patients with witnessed outpt SCD
bull Sensitivity of registry definition 70-83
bull Specificity of registry definition 90
SCD rate is consistent across data sources
bull In clinical trials [HEMO trial 4D trial]
bull In prospective HD cohorts [CHOICE cohort]
Increased rate of SCD unlikely due to just misclassfication
Pun et al Clin J Am Soc Nephrol 2012 Jan7(1)116-22Herzog et al Kidney Int 2011 Sep80(6)572-86
It is generally understood that SCD requires two main ingredients Structural heart disease and acute arrhythmic trigger In the GP cardiomyopathy with decreased LVEF is by far the most power powerful predictor of SCD risk and acute ischemia is most often the acute arrhtyhmic trigger Conventional CHD-related factors produce both ischemic cardiomyopathy and triggers for SCD Whether or not this is the same process we are seeing in chronic kidney disease patients is in question 13
This image cannot currently be displayed
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Bleyer Kidney Int 2006 Jun69(12)2268-73Yamada Clin J Am Soc Nephrol 2010 Oct5(10)1793-8Mangrum et al Heart Rhythm 2005 2(5)S41 Park et al J Am Soc Nephrol 2012 Oct23(10)1725-34
01020304050607080
WFU (n=88) UVA(n=31)
Perc
ent o
f SC
D
EF
lt35
EF
gt35
EF
gt35
EF
lt35
bull Only 7 Systolic Dysfunction in CRiC
bull 5 in incident HD cohort
bull Increased SCA risk cannot be explained by SD IHD disease alone
Presenter
Presentation Notes
What do we see when we look at underlying cardiac dz in CKD pts with SCD In both a case series of SCD victims from WFU and from UVA the the prevalene of low EF was quite small with 70 of patients without any evidence of systolic dysfunction Also in the CRiC study (observational cohort of pts with moderate CKD) the reported prevalence of systolic dysfuntion is only 7 and a large study of incident dialysis patients also showed that systolic dysfunction is also low at 5 This complicates the paradigm of low EF being the strongest predictor of SCD risk Therefore it seems apparaent that the increased SCA risk in CKD pts canrsquot be fully explained by systolic dysfunction and conventional IHD alone 131313
This image cannot currently be displayed
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
Left Ventricular Hypertrophybull56 of HD pts without CADbullEtiologic associations with
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
It is generally understood that SCD requires two main ingredients Structural heart disease and acute arrhythmic trigger In the GP cardiomyopathy with decreased LVEF is by far the most power powerful predictor of SCD risk and acute ischemia is most often the acute arrhtyhmic trigger Conventional CHD-related factors produce both ischemic cardiomyopathy and triggers for SCD Whether or not this is the same process we are seeing in chronic kidney disease patients is in question 13
This image cannot currently be displayed
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Bleyer Kidney Int 2006 Jun69(12)2268-73Yamada Clin J Am Soc Nephrol 2010 Oct5(10)1793-8Mangrum et al Heart Rhythm 2005 2(5)S41 Park et al J Am Soc Nephrol 2012 Oct23(10)1725-34
01020304050607080
WFU (n=88) UVA(n=31)
Perc
ent o
f SC
D
EF
lt35
EF
gt35
EF
gt35
EF
lt35
bull Only 7 Systolic Dysfunction in CRiC
bull 5 in incident HD cohort
bull Increased SCA risk cannot be explained by SD IHD disease alone
Presenter
Presentation Notes
What do we see when we look at underlying cardiac dz in CKD pts with SCD In both a case series of SCD victims from WFU and from UVA the the prevalene of low EF was quite small with 70 of patients without any evidence of systolic dysfunction Also in the CRiC study (observational cohort of pts with moderate CKD) the reported prevalence of systolic dysfuntion is only 7 and a large study of incident dialysis patients also showed that systolic dysfunction is also low at 5 This complicates the paradigm of low EF being the strongest predictor of SCD risk Therefore it seems apparaent that the increased SCA risk in CKD pts canrsquot be fully explained by systolic dysfunction and conventional IHD alone 131313
This image cannot currently be displayed
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
Left Ventricular Hypertrophybull56 of HD pts without CADbullEtiologic associations with
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
It is generally understood that SCD requires two main ingredients Structural heart disease and acute arrhythmic trigger In the GP cardiomyopathy with decreased LVEF is by far the most power powerful predictor of SCD risk and acute ischemia is most often the acute arrhtyhmic trigger Conventional CHD-related factors produce both ischemic cardiomyopathy and triggers for SCD Whether or not this is the same process we are seeing in chronic kidney disease patients is in question 13
This image cannot currently be displayed
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Bleyer Kidney Int 2006 Jun69(12)2268-73Yamada Clin J Am Soc Nephrol 2010 Oct5(10)1793-8Mangrum et al Heart Rhythm 2005 2(5)S41 Park et al J Am Soc Nephrol 2012 Oct23(10)1725-34
01020304050607080
WFU (n=88) UVA(n=31)
Perc
ent o
f SC
D
EF
lt35
EF
gt35
EF
gt35
EF
lt35
bull Only 7 Systolic Dysfunction in CRiC
bull 5 in incident HD cohort
bull Increased SCA risk cannot be explained by SD IHD disease alone
Presenter
Presentation Notes
What do we see when we look at underlying cardiac dz in CKD pts with SCD In both a case series of SCD victims from WFU and from UVA the the prevalene of low EF was quite small with 70 of patients without any evidence of systolic dysfunction Also in the CRiC study (observational cohort of pts with moderate CKD) the reported prevalence of systolic dysfuntion is only 7 and a large study of incident dialysis patients also showed that systolic dysfunction is also low at 5 This complicates the paradigm of low EF being the strongest predictor of SCD risk Therefore it seems apparaent that the increased SCA risk in CKD pts canrsquot be fully explained by systolic dysfunction and conventional IHD alone 131313
This image cannot currently be displayed
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
Left Ventricular Hypertrophybull56 of HD pts without CADbullEtiologic associations with
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
It is generally understood that SCD requires two main ingredients Structural heart disease and acute arrhythmic trigger In the GP cardiomyopathy with decreased LVEF is by far the most power powerful predictor of SCD risk and acute ischemia is most often the acute arrhtyhmic trigger Conventional CHD-related factors produce both ischemic cardiomyopathy and triggers for SCD Whether or not this is the same process we are seeing in chronic kidney disease patients is in question 13
This image cannot currently be displayed
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Bleyer Kidney Int 2006 Jun69(12)2268-73Yamada Clin J Am Soc Nephrol 2010 Oct5(10)1793-8Mangrum et al Heart Rhythm 2005 2(5)S41 Park et al J Am Soc Nephrol 2012 Oct23(10)1725-34
01020304050607080
WFU (n=88) UVA(n=31)
Perc
ent o
f SC
D
EF
lt35
EF
gt35
EF
gt35
EF
lt35
bull Only 7 Systolic Dysfunction in CRiC
bull 5 in incident HD cohort
bull Increased SCA risk cannot be explained by SD IHD disease alone
Presenter
Presentation Notes
What do we see when we look at underlying cardiac dz in CKD pts with SCD In both a case series of SCD victims from WFU and from UVA the the prevalene of low EF was quite small with 70 of patients without any evidence of systolic dysfunction Also in the CRiC study (observational cohort of pts with moderate CKD) the reported prevalence of systolic dysfuntion is only 7 and a large study of incident dialysis patients also showed that systolic dysfunction is also low at 5 This complicates the paradigm of low EF being the strongest predictor of SCD risk Therefore it seems apparaent that the increased SCA risk in CKD pts canrsquot be fully explained by systolic dysfunction and conventional IHD alone 131313
This image cannot currently be displayed
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
Left Ventricular Hypertrophybull56 of HD pts without CADbullEtiologic associations with
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Bleyer Kidney Int 2006 Jun69(12)2268-73Yamada Clin J Am Soc Nephrol 2010 Oct5(10)1793-8Mangrum et al Heart Rhythm 2005 2(5)S41 Park et al J Am Soc Nephrol 2012 Oct23(10)1725-34
01020304050607080
WFU (n=88) UVA(n=31)
Perc
ent o
f SC
D
EF
lt35
EF
gt35
EF
gt35
EF
lt35
bull Only 7 Systolic Dysfunction in CRiC
bull 5 in incident HD cohort
bull Increased SCA risk cannot be explained by SD IHD disease alone
Presenter
Presentation Notes
What do we see when we look at underlying cardiac dz in CKD pts with SCD In both a case series of SCD victims from WFU and from UVA the the prevalene of low EF was quite small with 70 of patients without any evidence of systolic dysfunction Also in the CRiC study (observational cohort of pts with moderate CKD) the reported prevalence of systolic dysfuntion is only 7 and a large study of incident dialysis patients also showed that systolic dysfunction is also low at 5 This complicates the paradigm of low EF being the strongest predictor of SCD risk Therefore it seems apparaent that the increased SCA risk in CKD pts canrsquot be fully explained by systolic dysfunction and conventional IHD alone 131313
This image cannot currently be displayed
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
Left Ventricular Hypertrophybull56 of HD pts without CADbullEtiologic associations with
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
bullLVMIgt125 gm2 = 30 increased risk of death at 5 yrs
bullLVH= Increased rate of arrhythmias
bull Increased myocardial fibrosis with diffuse subendocardialenhancement
Meier et al Nephron 2001 Mar87(3)199-214Silverberg et al KI 1989Ayus et al JASN 2005Mark PB et al Kidney International (2006) 69 1839ndash1845
Presenter
Presentation Notes
First LVH is highly prevalent in ESRD patients An increase in LV mass is seen in up to 56 HD pts who do not have CHD There are etiologic associations with chronic (ECFV) excess and increased demand of AVF pressure loading and HTN Anemia secondary hyperparathyroidism (SHPT) Aluminum toxicity In fact LVH has emerged as a powerful predictor of cardiac mortality Having a LVMIgt125 is associated with a 30 increased 5 yr mortality (50 vs 20 Silverberg)ndash Whehter or not this is due to sudden death is uncertain but in the general population LVH has been associated with an increased rate of arrhythmias likely due to decreased myocardial reserve and ischemia tolerance and increased myocardial fibrosis 13
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Foley et al NEJM 2011 365 1099
Mortality and CV events on Days of the Dialysis Week
32000 US HD patients
Rat
e pe
r 10
0 pt
yea
rs
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Hemodialysis as an acute trigger for SCD
Potentially due to rapid shifts in
bull Potassium
bull Calcium
bull Fluid
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Role of Serum Potassium in SCA
Study of 500 witnessed peridialytic SCA vs 1600 matched controls
Risk linked to extremes of serum potassium (K)
Lowest risk at K ~ 50
Pun et al Kidney Int 2011 Jan79(2)218-27
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Role of Dialysate Potassium in SCA
Use of low potassium diaysate (lt2 meqL) was associated with a two-fold increase in risk of SCA
Mean Predialysis serum K was in the normal range (49 meqL)
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The way potassium is removed on dialysis is via diffusion down a concentration gradient ie exposure of the serum to a low potassium dialysate bath This figure shows the relationship of low K dialysate and SCA As shown in Panel B The solid bar shows the of SCA patients exposed to low potassium dialysate (defined as lt2 meqL) during the last dialysis treatment hashed bar depicts control patients Nearly 20 of SCA pts were exposed to low potassium baths at the time of the event as compared to 11 controls As shown in Panel A the increased use of low potassium dialsate could not be justified by higher pre-dialysis serum potassium among case patients as the mean predialysis k was 49 (as shown here) and there was no difference between the groups 13----- Meeting Notes (9111 2347) -----13Remind people what low dialysate potassium does
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Difference in risk between low and high K dialysate decreases as serum K increases
No indication of benefit for low K dialysate at any level of serum K
Pun et al Kidney Int 2011 Jan79(2)218-27
Presenter
Presentation Notes
The observation of increased risk with low K dialysate and with elevated pt K begs the question whether or not low K may actually be beneficial for these pts The curves to the right examine the CA probability by predialysis serum K for patients who were prescribed low K baths (red) vs non-low K baths As shown here the difference in risk between low and high K dialysate is greatest at low serum K and decreases as serum K increases However from this analysis we did not see any indication of benefit for low K dialysate even among patients with high serum potassium
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Ca 2+ mmolL gradient
Calcium Low Calcium Dialysate Associates With Increased risk of SCD
Pun et Al Clin J Am Soc Nephrol 2013 May8(5)797-803
Pro
babi
lity
of S
udde
n D
eath
Matched Case Control Study of 2100 patients
bull 50 Increase in SCA risk with dialysate calcium lt25 meqL
bull Risk rises incrementally with increasing serum dialysate gradient
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
HD Exposure
Odds Ratio
1L Fluid Removal on HD
51
15L Fluid Removal on HD
116
2L Fluid Removal on HD
262
Burton JO et al Clin J Am Soc Nephrol (2009) 4 914-920
bull Hemodialysis procedure can reduce myocardial
blood flow even in absence of significant CAD
bull A myocardial ldquostunrdquo may be detected from
echocardiogram regional wall motion abnormalities
(RWMAs)
bull RWMAs present in 50-64 of patients and
associated with poor outcomes
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Cardiomyopathy
Arrhythmic Triggers
SCAMalignant
ArrhythmiasConventional CHD-related Risk Factors
Unique CKD- related Risk factors
LVH
AnemiaCaPhosPTH
Uremia
Inflammation Malnutrition
Autonomic Instability
Volume shifts
Electrolyte shifts
Dialysis Reactions
Unique CKD-related Risk factors
ESKD-HDpatients
CKD
Patients
SCA in CKD A complex interplay of traditional and CKD-related risk factors
Presenter
Presentation Notes
There are also other unique CKD-specific CA triggers which may contribute to susceptibility to arrest
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Management of SCD
Prevent Sudden Cardiac Arrest
bullMedical therapies to treat underlying cardiac disease
bullReduce exposure to triggers
Improve survival following SCA
bullDefibrillation
Presenter
Presentation Notes
So there are Two fundamental approaches to manage SCA risk First is treating and preventing underlying cardiac disease reduce exposure to triggers which wersquove already talked about germane to HD pts Second is to improve survival after a SCA occurs and defibrillators have been pivotal in this regard What do we know about the efficacy of these treatments in HD patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention Beta Blockers
bull Beta Blockers shown to be helpful for prevention in pts with minimal or no CKD
bull Poor Implementation Only 24 of dialysis patients with CAD or prior MI are on beta blockers
bull Only one randomized trial of beta-blockers in ESRD
bull 114 pts with DCM randomized to Carvedilol or placebo
bull Significant survival advantage non significant reduction (24) in SCD
Cice JACC 2003 411438-44
Presenter
Presentation Notes
What about medical therapies for cardiomyopathy BBL have been shown to be helpful in preventing SCD in post MI pts with minimal or no CKD We also know that there is poor implementation of BBL-- only 24 of dialysis patients with documented CAD or prior MI are on BBL There is only one RCT I know of using BBL which enrolled 114 pts with DCM to carvedillol or placebo and as you can see here resulted in significant improvement in survival and and 24 reduction in SCD although non-significant 1313 So what do we know about emd114 pts 23 class III mean EF 2613SCD risk decreased by 24 but not statistically significant
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Medical Therapies for SCD Prevention PhosphorusSHPT
Observational study of 12833 HD patients
bull6 increase in SCD per 1 mgdl increase in Phos
bull7 increase in SCD per 10 mgdl increase is CaxPhos product
bull20 increase with phos gt65
bull6 increase with PTHgt495
PTH
Ganesh et Al JASN 2001
Hyperphosphatemia can provoke vascular calcification endothelial dysfunction and atherosclerosis
Presenter
Presentation Notes
Tie in for CKD BMD
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Benefit in ESRD not clearly known for
bull Statins
bull 4D AURORA studies negative
bull SHARP Reduction in coronary revascularization cardiac events seen only in 23 pts with predialysis CKD not in 13 pts with ESRD
bull ACEIARB
bull Antiplatelet agents
bull Vitamin D
Other Medical Therapies for SCD Prevention
Presenter
Presentation Notes
Statin- SHARP STUDY showed nonsignificant
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Implantable Cardioverter Defibrillators in HD patients
Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17
Herzog et al Kidney Int 2005 Aug68(2)818-25
No ESRD patients included in any randomized trialsbull Secondary prevention ICD (ICD after cardiac arrest)
bull Two retrospective studies show benefit ICD after cardiac arrest compared to patients with cardiac arrest and no ICDbull HR 086 (95 CI 081-091) bull Subject to indication bias
bull Primary prevention (prophylactic ICD)bull No data on mortality benefit in ESRD compared to controlsbull Increased mortality risk of complications in ESRD
compared to non-ESRD ICD recipients
Agarwal et al Heart Rhythm 2009 Nov6(11)1565-71
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Diminishing Benefit of Primary ICD with CKD
Pun et al Am J Kidney Dis 2014 Feb 8epub ahead of print
Meta-analysis of 3 randomized controlled trialsbull 2867 patients
bull 363 with eGFRlt60 no HD patients
bull Diminishing survival benefit of ICD vs no ICD with lower eGFR
Presenter
Presentation Notes
Another landmark study in favor of primary prevention ICDs- the MADIT 2 study-- They found an overall 30 reduction in mortality benefit of ICDs vs conventional therapy in pts with ICM and decreased EF Again no dialysis patients but look at the benefit of ICD among different subgroups with decreased eGFR Although underpowered with only 80 pts in this subgroup there was no significant benefit either for all-cause mortality or SCD in patients with GFR lt35 It seems clear that benefit of ICDs in pts with advanced renal dz is not the same as those without renal dz
This image cannot currently be displayed
Why might primary ICDs not be beneficial
bull Increased defibrillation thresholds in CKD and ESRD pts compared to normal
bull ESRD patients not having ldquoshockablerdquo events 38 of ICD recipients on dialysis still die of arrhythmia
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Wase J Interv Card Electrophysiol 2004 Dec11(3)199-204Charytan et al Am J Kidney Dis 2011 Sep58(3)409-17Drew et al Am J Kidney Dis 2011 Sep58(3)494-496
Presenter
Presentation Notes
Why might ICDs not be effective in HD pts First 13Second competing risks may outweigh benefits The annual incidence of hellip13Specific to HD pts vascular access compromise is of particular concern given the importance of stable permanent dialysis access and the association of dialysis catheters with poor outcomes A recent case series of 43 HD pts with ICDrsquos showed that 62 developed central venous stenosis ipsilateral to the device and 48 of these patients were permanently catheter dependent as a result 131313 General population Device infection about 07 annually Explantation for malfunction lt2 annually1313Of these 43 patients 34 (79) underwent imaging of the central veins 21 of the 34 patients (62) had demonstrable central vein stenoses 17 of which were ipsilateral to the cardiac device The mean number of accesses including access present at the time of device insertion was 39 1113092 27 for patients with versus 28 1113092 23 for those without central stenoses Of patients without devices 297 of 547 (54) underwent imaging of central veins and 94 of the 297 (32) had an identified central stenosis (P 1113094 0001 compared with those with imaging) Ten of 21 (48) patients with a cardiac device and central vein stenosis were deemed catheter dependent after device insertion
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
Treat Cardiomyopathy
bullAssess at baseline and q3yrs (2005 KDOQI guideline)
bullUse beta-blocker for dilated cardiomyopathy EF lt35
bullControl SHPT and phosphorus
bullUnclear if other proven therapeutic interventions will also be beneficial in dialysis patients
Reduce and monitor triggers
bullAvoid low potassium and low calcium dialysate
bullReview and adjust prescription dialysis regularly in response to laboratory data
bullReduce IDWGavoid large volume shifts
bullMore frequentlonger dialysis sessions
Presenter
Presentation Notes
Pulling it together How can we rise to meet the challenge of SCA in HD pts given what we know today First I think it is reasonable that we should make an effort to treat cardiomyopathy The KDOQI guidelines suggest that ECHOcardiogram should be performed at baseline and every 3 yrs following There is evidence to support BBL for pts with with dilated CM and EFlt35 but it is unclear if other proven therapeutic interventions will also be beneficial in HD pt Second we should make an effort to reduce and monitor for triggers for SCA If possible we should avoid very low potassium and low calcium dialysate be cognizant of potential interactions with QT prolonging medications Should Review and adjust HD prescriptions regularly in response to labs Direct efforts towards reducing IDWGlarge volume shifts and consider frequent longer dialysis sessions
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
Rising to the Challenge of SCD in Hemodialysis Patients
ICDsbullNo evidence to support prophylactic primary ICDs in dialysis patients
bull Counsel patients regarding likelihood of decreased benefits and increased risks compared to general population
bullConsider ICDs for secondary prevention
bullCoordinated care bt nephrologists and EP
Presenter
Presentation Notes
Regarding ICDs I think there is evidence to support the use of secondary prevention ICDs very unclear benefit with primary ICDs and there is a definite need for greater coordinationa and communication between nephrologists and EP given the potential complications of ICDs 13
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances
Underlying cardiac disease in CKD SCD is rarely traditional ischemic cardiomyopathy with systolic dysfunction
Differences in Structural Heart Disease LVH and Diffuse Myocardial Scarring are more Common
SCD Acute Triggers SCD and Arrhythmias occur most frequently on the first hemodialysis day of the week
Hemodialysis as an acute trigger for SCD
Role of Serum Potassium in SCA
Role of Dialysate Potassium in SCA
Potassium Homeostasis and Risk of SCA Low [K ] bath for High Pt [K]
Slide Number 18
Amount and Rate of Fluid Removal During HD Associates With Myocardial ldquoStunningrdquo
Slide Number 20
Management of SCD
Medical Therapies for SCD Prevention Beta Blockers
Medical Therapies for SCD Prevention PhosphorusSHPT
Other Medical Therapies for SCD Prevention
Implantable Cardioverter Defibrillators in HD patients
Diminishing Benefit of Primary ICD with CKD
Why might primary ICDs not be beneficial
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
Rising to the Challenge of SCD in Hemodialysis Patients
This image cannot currently be displayed
We need
bullLarge cohort studies assessing risk factors with carefully adjudicated endpoints
bull Clinical variables
bull Dialysis variables
bull CardiacEP variables
bull Biomarkers
bullRCT
bull Beta blockers
bull Potassium management
bull ICDs (ICD2 trial wearable ICD subQ ICD)
Rising to the Challenge of SCD in Hemodialysis Patients
Presenter
Presentation Notes
As far where we go from here from a research standpoint I think we really need to start from the beginningndash we need large cohort studies which assess risk factors with carefuly adjudicated endpointsndash we need to better understand the relationship between traditional clinical variables cardiacelectrophysiologic variables and traditional and novel biomarkers with SCA risk and whether or not any of these can serve as effective risk stratification tools From a therapy standpoint we also need to start from the beginningndash BBL trials of intensive potassiumcalcium management and of course ICDs including some of the newer less invasive defibrillation devices such as wearable ICDs and other leadless iCDs to avoid problems with vascular access) 13----- Meeting Notes (9111 1732) -----13RCT of potassium and calcium management
Slide Number 1
Slide Number 2
Learning Objectives
Sudden Death is the Leading Cause of Death in Dialysis Patients
The risk of SCD in ESKD-HD is 20x greater than the general population
Risk of Sudden Cardiac Death after Dialysis Initiation PD vs HD
Why is the SCD rate so high Possible explanations
SCD Traditional Definitions
Probably not just due to misclassification Some assurances