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Dr. Imran Ahmed DM (Cardiology) Kolkata, India
Prevalence and Incidence rates are alarmingly high - Increasing
HF hospitalizations - Increasing HF-attributable deaths - Spiraling
cost of HF-care Worldwide 23 million people affected Prevalence
increases with age (6-10% in > 65 yrs)
Heart Failure in the U.S - A Growing Public Health Problem.
Approximately 5 million patients in this country have HF (1.5 2% of
population) Over 550,000 patients are diagnosed with HF for the
first time each year Primary reason for 12 to 15 million office
visits and 6.5 million hospital days each year In 2001, nearly
53,000 patients died of HF as a primary cause
HF is a complex clinical syndrome that can result from any
structural or functional cardiac disorder that impairs the ability
of the ventricle to fill with or eject blood [ACC focused update
2009]
Stages of Heart Failure At Risk for Heart Failure: STAGE A High
risk for developing HF STAGE B Asymptomatic LV dysfunction Heart
Failure: STAGE C Past or current symptoms of HF STAGE D Refractory
/ End-stage HF
Stages of Heart Failure Designed to emphasize preventability of
HF Designed to recognize the progressive nature of LV
dysfunction
Stages of Heart Failure COMPLEMENT, DO NOT REPLACE NYHA CLASSES
NYHA Classes - shift back/forth in individual patient (in response
to Rx and/or progression of disease) Stages - progress in one
direction due to cardiac remodeling
Heart Failure as a Progressive Disorder Principal manifestation
of progression change in the geometry and structure of the LV
chamber dilation and/or hypertrophy becomes more spherical The
collective process referred to as cardiac remodeling
Outcomes of Cardiac Remodeling Patients die before developing
symptoms (in Stage A or B) Patients develop symptoms controlled by
treatment Patients die of progressive/refractory HF *Sudden death
can interrupt this course at any time
Refractory Heart Failure - Definition Persistence of symptoms
that limit daily life (functional class III or IV of the New York
Heart Association [NYHA]) despite optimal previous treatment with
drugs of proven efficacy for the condition, i.e. ACE inhibitors,
angiotensin II receptor antagonists (ARB), diuretics, digoxin,
beta-blockers and nitrate-hydralazine (esp. in blacks) [Nohria A,
JAMA 2002;287:628-40 and D. Feldman, Clin. Cardiol. 2008;31, 7,
297301]
Terminal Heart Failure Terminal HF is the last step in
refractory HF, where there is a very poor response to all forms of
treatment (by definition, heart transplantation is no longer
indicated), with serious deterioration of quality of life - both
physical and emotional, frequent hospitalization and life
expectancy less than 6 months. [Rev Esp Cardiol
2004;57(9):869-83]
Refractory Heart Failure - Definition Corresponds to stage D
heart failure - refers to patients with advanced structural heart
disease and severe signs of HF at rest who are candidates in the
absence of contraindications for other specialized interventions
such as heart transplantation ventricular remodeling implantation
of mechanical assistance devices intravenous inotropic drugs
Interventional Heart Failure Therapy Term coined by Daniel
Burkhoff (2007) Vicious cycle of refractory HF - - progressive
cardiovascular remodeling - deterioration of renal function -
decreased exercise tolerance [Burkhoff D. SIS 2007
Yearbook;13:65-75]
Need for Interventional HF Therapy Even on max pharma therapy
most patients exhibit - disease progression - repeated
hospitalizations - ultimately succumb to their disease Evidence
indicates that additional neurohormonal blockade may be detrimental
The limit of neurohormonal and cytokine blockade in CHF may be
reached Heart transplantation as a final treatment option also
limited by the small number of donor hearts. [Mann DL. (RENEWAL).
Circulation 2004;109:1594-1602]
Basis of Interventional HF Therapies Strengthening of cardiac
contraction with cardiac contractility modulation Modification of
ht rate with vagal nv stimulation Reduction of ventricular size
with surgical ventricular restoration renal perfusion with targeted
renal therapy fluid overload with ultrafiltration Improving cardiac
output with continuous aortic flow augmentation (orqis) Reverse
remodeling with ventricular assist devices [Burkhoff D. SIS 2007
Yearbook;13:65-75]
Use of electrical pulse generators to deliver an electric
current to cardiac tissue ICDs & CRTs are the most important
device-based treatment currently FDA approved for use in CHF ICDs
shown to reduce mortality CRT shown to reduce symptoms and
mortality Newer types under investigation - Cardiac Contractility
Modulators (CCM) - Vagal Nerve Stimulation
Targets of Electrical HF Therapy Increased risk of ventricular
arrhythmias Sudden death Intraventricular dyssynchrony Impaired
cardiac contractility Unregulated sympathetic tone
Implantable Cardioverter Defibrillator Secondary prevention
survivors of VF - documented haemodynamically unstable VT and/or VT
with syncope, a LVEF of 40%, on optimal medical therapy, and with
an expectation of survival with good functional status for 1 yr
[ESC 2008, Class of recommendation I, level of evidence A]
[Meta-analysis of AVID, CASH and CIDS studies. Eur Heart J
2000;21:20712078]
Implantable Cardioverter Defibrillator Primary prevention is
recommended to reduce mortality in patients with non-ischemic
dilated cardiomyopathy or ischemic LV dysfunction due to prior MI
who are at least 40 days post-MI, have an LVEF 35%, in NYHA
functional class II or III, receiving optimal medical therapy, and
who have a reasonable expectation of survival with good functional
status for 1 year [ESC 2008, Class of recommendation I, ICMP -
level of evidence A DCM - level of evidence B]
ICD The Gender Bias! ICD therapy for the primary prevention of
sudden cardiac death may not provide a mortality benefit to women
with heart failure A recent meta-analysis of 5 large, RCTs
including 934 women with HF revealed that primary prophylaxis with
ICDs did not significantly decrease all-cause mortality (HR, 1.01;
95% CI, 0.76-1.33) Future guideline recommendations for the use of
ICDs in women is of ongoing interest [Ghanbari H, Arch Intern
Med.2009;169(16):1500-1506]
Cardiac Resynchronization Therapy
CRT - Recommendations
CRT - Issues Impact on symptoms and exercise tolerance All RCTs
have confirmed a significant alleviation of symptoms and increase
in exercise capacity conferred by CRT. On average, NYHA function
class decreased by 0.50.8 points The 6 min walk distance increased
by 20% Peak oxygen consumption increased by 1015% The functional
benefits and quality of life improvements were sustained 1. Cleland
JG. The effect of cardiac resynchronization on morbidity and
mortality in heart failure. N Engl J Med 2005;352:15391549 2. Linde
C, MUSTIC study. J Am Coll Cardiol 2002;40:111118. 3. Cleland JG,
The CArdiac REsynchronization-Heart Failure (CARE-HF) trial
extension phase. Eur Heart J 2006;27:19281932.
CRT - Issues Impact of CRT on morbidity In the COMPANION trial,
CRT with or without an ICD, lowered the combined endpoint of
all-cause mortality and rehospitalization for HF by 3540%, mainly
driven by the 76% lower rate of hospitalizations. In CARE-HF, CRT-P
lowered the proportion of unplanned hospitalizations for worsening
HF by 52%, and of unplanned hospitalizations for major
cardiovascular events by 39%. 1. Bristow MR,
Cardiac-resynchronization therapy with or without an implantable
defibrillator in advanced chronic heart failure. N Engl J Med
2004;350:21402150. 2. Cleland JG, The effect of cardiac
resynchronization on morbidity and mortality in heart failure. N
Engl J Med 2005;352:15391549.
CRT - Issues Impact of CRT on mortality In COMPANION, CRT-D
showed a significant decrease in all- cause mortality (RR
reduction: 36%; P = 0.003), while the 24% RR reduction with CRT-P
was nearly significant (P =0.059). In CARE-HF, (only CRT-P), a 36%
RR reduction in the risk of death (P , 0.002) was observed after a
mean follow-up time of 29 months. In the CARE-HF extension study, a
RR reduction of 40% (P = 0.0001) was observed, mainly due to
HF-related deaths 1. Bristow MR, Cardiac-resynchronization therapy
with or without an implantable defibrillator in advanced chronic
heart failure. N Engl J Med 2004;350:21402150. 2. Cleland JG, The
effect of cardiac resynchronization on morbidity and mortality in
heart failure. N Engl J Med 2005;352:15391549. 3. Cleland JG, The
CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension
phase. Eur Heart J 2006;27:19281932
CRT - Issues Impact of CRT on cardiac function & structure
All RCTs have consistently shown up to 15% absolute reduction in
LVEDD and up to 6% increase in LVEF following CRT The effect was
significantly greater in patients with non- ischaemic than in those
with ischaemic heart disease. These observations provide consistent
evidence of a substantial, progressive, and sustained reverse
remodelling effect conferred by CRT. 1. Gervais R. Surface
electrocardiogram to predict outcome in candidates for cardiac
resynchronization therapy: a subanalysis of the CARE-HF trial. Eur
J Heart Fail 2009;11:699705
CRT - Issues Ambulatory patients in NYHA class IV COMPANION
enrolled 217 NYHA class IV patients termed ambulatory patients
Patients with no scheduled or unscheduled admissions for HF during
the last month and with a life expectancy of 6 months. Time to
all-cause mortality or first all-cause hospitalization was
significantly improved by both CRT-P and CRT-D vs OMT No
significant benefit was observed on all-cause mortality. Data
support the use of CRT to improve morbidity (but not mortality) in
ambulatory class IV patients. 1. Lindenfeld J. Effects of cardiac
resynchronization therapy with or without a defibrillator on
survival and hospitalizations in patients with New York Heart
Association class IV heart failure. Circulation
2007;115:204212
CRT - Issues QRS morphology: LBBB vs RBBB Favourable outcome in
CARE-HF was defined as freedom from death or major cardiovascular
event Baseline typical LBBB pattern predicted a favourable outcome.
By multivariable analysis, prolonged PR interval and right bundle
branch block (RBBB) were the only predictors of non- favourable
outcome. 1. Gervais R. Surface electrocardiogram to predict outcome
in candidates for cardiac resynchronization therapy: a subanalysis
of the CARE-HF trial. Eur J Heart Fail 2009;11:699705.
CRT - Issues CRT-D in patients with an indication for an ICD
MIRACLE ICD and a large meta-analysis support the choice of a CRT-D
in patients in NYHA class III/IV, with LVEF of 35%, QRS of 120 ms
with a conventional indication for an ICD 1. Abraham WT. Effects of
cardiac resynchronization on disease progression in patients with
left ventricular systolic dysfunction, an indication for an
implantable cardioverter-defibrillator, and mildly symptomatic
chronic heart failure. Circulation 2004;110:28642868. 2. Lam SK,
Owen A. Combined resynchronisation and implantable defibrillator
therapy in left ventricular dysfunction: Bayesian network
meta-analysis of randomised controlled trials. Br Med J
2007;335:925
CRT - Beyond Current Guidelines CRT in Patients With Narrow QRS
Complex CONQUEST (Congestive Heart Failure and QRS Duration:
Establishing Prognosis) study, with 3,000 HF patients, showed that
42% of the patients had a QRS duration < 120 ms Echo studies
have shown that 40% - 50% of HF patients with a narrow QRS complex
may also exhibit LV dyssynchrony Echo predictors of response to CRT
(small studies) - septal to lateral or opposing segment delay of 65
ms - standard deviation of time to peak tissue velocity >32 ms
1. Abraham J. Is echocardiographic assessment of dyssynchrony
useful to select candidates for cardiac resynchronization therapy?
Circulation: Cardiovascular Imaging. 2008; 1: 79-85. 2. Bommel V.
CRT Beyond Current Guidelines . JACC; 56:10, 2010 Aug 31,75462
CRT in Narrow QRS Complex CRT in Patients With Narrow QRS
Complex CONQUEST (Congestive Heart Failure and QRS Duration:
Establishing Prognosis) study, with 3,000 HF patients, showed that
42% of the patients had a QRS duration < 120 ms Echo studies
have shown that 40% - 50% of HF patients with a narrow QRS complex
may also exhibit LV dyssynchrony Echo predictors of response to CRT
(small studies) - septal to lateral or opposing segment delay of 65
ms - standard deviation of time to peak tissue velocity >32 ms 1
VO2 2 NYHA
CRT in Patients With Narrow QRS Complex ESTEEM-CRT &
RethinQ Trials - no improvement in primary endpoints peak Vo2 or
LVEF - significant improvement in 2 endpoint of NYHA class
Limitations of ESTEEM-CRT and RethinQ - included few patients with
limited follow-up (up to 6 months) - did not focus on
rehospitalization and long-term survival Results from ESTEEM-CRT
& RethinQ make the expansion of CRT to HF pts with narrow QRS
complex currently unlikely Ongoing Echo-CRT trial with speckle
tracking will determine whether CRT is an effective Rx modality in
this specific group 1. Leon AR. Evaluation of CRT in Narrow QRS
Patients With Mechanical Dyssynchrony From a Multicenter Study
(ESTEEM-CRT). Paper presented at Heart Rhythm Society Congress; May
15, 2008; SanFrancisco, CA 2. Beshai JF. RethinQ. N Engl J Med
2007;357:246171
CRT - Beyond Current Guidelines CRT in patients with mild heart
failure MIRACLE ICD II trial - 186 patients in NYHA class II with
LVEF 130 ms and a Class I indication for an ICD At 6 months of
follow-up, patients in the CRT-ON group had a greater reduction in
LV diastolic & systolic volumes (p< 0.05) and significant
improvement in NYHA class (p=0.05) Similar results reported by the
CONTAK-CD trial, with significant reductions in LV dimensions
CRT - Beyond Current Guidelines CRT in patients with mild heart
failure Results of CONTAK-CD and MIRACLE ICD II showed that LV
reverse remodeling was a better predictor of long-term survival
than clinical improvement Effect - 2 large clinical trials were
conducted to investigate whether CRT could prevent or attenuate
disease progression and induce LV reverse remodeling in mild heart
failure - The REVERSE (Resynchronization Reverses Remodeling in
Systolic Left Ventricular Dysfunction) [J Am Coll Cardiol
2009;54:18371846] - The MADIT-CRT (Multicenter Automatic
Defibrillator Implantation Trial with Cardiac Resynchronization
Therapy) [Circulation 2010 10.1161/CIRCULATIONAHA.110.955039]
CRM6-4403-0810 2010 Boston Scientific. All rights reserved. 40
MADIT-CRT Main Inclusion Criteria Ischemic heart disease (NYHA
Class I or II) or non- ischemic heart disease (NYHA Class II) for
at least three months prior to entry Optimal pharmacologic therapy
Beta blockers, ACE/ARB, and statins (ischemic patients) unless not
tolerated or contraindicated Left ventricular ejection fraction 30%
QRS duration 130 ms Sinus rhythm
CRM6-4403-0810 2010 Boston Scientific. All rights reserved. 41
MADIT-CRT Results The primary endpoint was a composite of death
from any cause and non-fatal HF-related adverse events. Mean
follow-up of 2.4 years Results showed that CRT-D was associated
with a 34% reduction in the relative risk of the primary endpoint
Benefit attributable primarily to a 41% decrease in HF-related
adverse It was subsequently discovered and validated that in the
LBBB subgroup, patients received substantial benefit from CRT-D.
Non-LBBB patients did not show evidence of benefit. The LBBB
sub-group made up approximately 70% of the total MADIT-CRT
population. 3% mortality in both groups 34% 57%
CRM6-4403-0810 2010 Boston Scientific. All rights reserved.
MADIT-CRT Results of Minor Endpoints 42
REVERSE Trial Inclusion criteria (N =610) - patients treated
with an optimal medical regimen - NYHA function class I or II and
NSR - LVEF 40%, QRS duration 120 ms, LVEDD55 mm - All patients had
a history of HF symptoms Method - implantation of a CRT-D (85%) or
CRT-P (15%) and compared between activated (CRT-ON) vs CRT-OFF
Primary endpoint was the percentage of clinically worsened
patients, ascertained by the use of a composite endpoint. Secondary
endpoint was echocardiographic change in LV end-systolic volume
index [Linde C. REVERSE trial. J Am Coll Cardiol
2008;52:18341843]
After 12 months, no significant difference observed in the
primary endpoint However, a significant degree of reverse LV
remodelling was observed among patients on CRT, manifested by
decreases in the LVESVi (p < 0.0001) and LVEDV, and an increase
in LVEF(p < 0.0001) Significant reverse remodelling linked to
reduced HF morbidity indicates that CRT may potentially modify
disease progression in mild HF patients.
Inferences from MADIT-CRT & REVERSE MADIT-CRT & REVERSE
demonstrated reduced morbidity No significant improvement seen in
NYHA I class pts at baseline (18% of pts in REVERSE & 15% pts
in MADIT-CRT) Improvement primarily in pts with QRS 150 ms and/or
typical LBBB. In MADIT-CRT, women with LBBB demonstrated a
particularly favourable response. Survival advantage is not
established. In MADIT-CRT the extent of reverse remodelling was
concordant with & predictive of improved clinical outcomes [ESC
guidelines . Focussed update. European Heart Journal (2010) 31,
267787]
Electrical Therapy for CHF Cardiac Contractility Modulation
(CCM) Therapy Mech. - To enhance the strength of cardiac muscular
contraction, non-excitatory electrical signals are delivered during
the absolute refractory period of the cardiac cycle The CCM signals
delivered by OPTIMIZERdevice is via 3 cardiac leads (1 right atrial
and 2 right ventricular septal)
Cardiac Contractility Modulation Therapy The OPTIMIZER system
was studied in the FIX-CHF-4 trial - enrolled 164 subjects;
ineligible for CRT; EF 8weeks) home inotropic therapy as
destination therapy in patients of advanced heart failure or as
BTT. Int J Cardiol. 2005;99(1):47-50.
Continous Inotropic Support Continuous intravenous infusion of
a positive inotropic agent may be considered for palliation of
symptoms in patients with refractory end-stage HF (ACC Class IIb /
Level of Evidence: C) The use of continuous IV support to allow
hospital discharge should be distinguished from the intermittent
administration of infusions of such agents to patients who have
been successfully weaned from inotropic support Intermittent
outpatient infusions of vasoactive drugs such as nesiritide or
positive inotropic drugs have not shown to improve symptoms or
survival in patients with advanced HF 1. Jessup M. 2009 Focused
Update: ACCF/AHA Guidelines for the Diagnosis and Management of
Heart Failure in Adults: Developed in Collaboration With the
International Society of Heart and Lung Transplantation.
Circulation. 2009;119(14):1977-2016..
Interventional Fluid Removal Decompensated HF is comlicated by
sodium and fluid retention Limitations of loop diuretics have led
to the development of interventional approaches to fluid removal
such as - Interventional vasodilatation - Ultrafiltration
Interventional Vasodilatation A novel technique that aims to
target the kidneys directly, with drugs administered directly into
the renal arteries One approach called Targeted Renal Therapy (TRT)
can be achieved with the Benephit Renal Infusion System A
bifurcated femoral catheter that can be advanced through the
ascending aorta and into the renal arteries This catheter can then
be used to deliver vasodilators directly into the renal arteries in
attempts to improve renal perfusion & GFR thus limiting the
systemic effects of the medication
Interventional Ultrafiltration Ultrafiltration is currently a
class IIa recommendation by the ACC/AHA guidelines and is indicated
for patients with refractory congestion not responding to medical
therapy One type of ultrafiltration device, the Aquadex system
consists of a peripheral venous access catheter, a disposable 0.12
m2 polysulphone filter circuit and a console unit
The Aquadex Ultrafiltration System Can be used by a trained
cardiologist, does not require a nephrologist or use of a dialysis
unit Can remove fluid at a max rate of 500 mL/h for up to 8 hours
Compared to intravenous diuretic therapy, the Aquadex system
resulted in greater weight loss, net fluid loss, decreased
frequency of hypokalemia at 48 hours, and with reduced heart
failure rehospitalizations at 90 days 1. Wertman B. Ultrafiltration
for the management of acute decompensated heart failure. J Cardiac
Fail. 2008;14(9):754-759
Treatment of Valvular Disease HF leads to enlargement of the
mitral annulus, displacement of the papillary muscles, and
tethering of the mitral valve Benefit of treating functional MR in
HF is not well established - class IIb recommendation according to
the ACC/AHA guideline Despite lack of evidence surgical correction
of functional MR is sometimes performed in patients with end-stage
HF Minimally invasive tech for the treatment of MR have also been
developed (Mitra clip) & may provide additional treatment
options
Tissue Transplantation Tissue transplantation uses living cells
or tissue to restore cardiac pump function It includes - cellular
therapy - stem cell therapy - heart transplant
Cellular Cardiomyoplasty Cellular therapy or cellular
cardiomyoplasty is an investigational approach to the treatment of
ischemic cardiomyopathy Transplanted cell include - fetal and
neonatal cardiomyocytes; - skeletal myoblasts - vascular
endothelial cells; - bone marrow-derived stem cells -
cardiac-derived stem cells; - embryonic stem cells Methods of
delivering stem include - injection during an invasive procedure
(CABG / VAD) - injection directly into the coronary arteries, -
injection directly into the myocardium with the use of
transcutaneous endoventricular catheters such as MyoCath
Cellular Cardiomyoplasty & Stem Cells Cellular
cardiomyoplasty remains a promising interventional approach for the
treatment of ischemic cardiomyopathy and has been associated with
modest improvements in LV function in several human studies Future
research is necessary to optimize selection of cell source, cell
culture technique, method of cell delivery, and also to determine
the long-term clinical benefit of therapy Stem cell therapy is also
promising; however, their use is currently limited by scientific
(increased arrhythmia) and ethical concerns (MAGIC trial,
2009)
Human Heart Transplant (HHT) Allogeneic HHT is a therapeutic
option for patients with refractory end-stage HF, who have failed
other options According to the 2009 update on heart disease and
stroke from the AHA and Stroke Statistics Subcommittee, the 5-year
survival after HHT is 72.3% for males and 67.4% for females Despite
success, heart transplant is limited by the number of hearts
available for transplant each year This limitation in resources
reinforces the need for the development of other interventional
therapies for the treatment of end-stage heart failure.
Palliative Care Palliative care describes a multidisciplinary
approach to patient care that targets both the symptomatic and
psychosocial issues associated with a disease Being recognized as
an essential aspect of HF therapy because of the extreme physical
and emotional symptoms that patients with HF experience Although
the ultimate goal of interventional heart failure therapy is to
prolong life and reduce symptoms, many of these therapies are
associated with unique emotional complications that should be
addressed with the principals of palliative care described by
Goodlin in his state-of-the-art review article 1. Goodlin SJ.
Palliative care in congestive heart failure. J Am Coll Cardiol.
2009;54(5):386-396
Self Care Self-care is defined as a naturalistic
decision-making process involving the choice of behaviors that
maintain - physiologic stability (self-care maintenance) - response
to symptoms when it occurs (self-care management) Self-care
maintenance includes adhering to LSMs such as taking prescribed
medications, eating a low-sodium diet, restricting fluid intake,
exercising and by recognizing signs of worsening HF Self-care
management includes - reducing sodium or fluid intake, taking an
extra dose of diuretic, or seeking medical help Chronicle
(Medtronic), an implantable continuous hemodynamic monitor (ICHM)
measures & stores information for outpatient monitoring 1.
Bourge RC. Randomized controlled trial of an implantable continuous
hemodynamic monitor in patients with advanced heart failure: the
COMPASS- HF study. J Am Coll Cardiol. 2008;51(11):1073-1079
Conclusions and Future The treatment options for patients with
refractory end-stage heart failure are currently limited At this
advanced stage, the goals of treatment frequently change from
prolonging life to hospice / end-of-life care The role of
interventional therapy promises additional treatment options to
these patients Currently available interventional options include
heart transplant, interventional medical therapy, VADs, TAHs.
Future treatment options include the interventional treatment of
mitral valve disease, cellular and stem cell therapy, and use of
next generation VADs or TAHs & ambulatory monitoring
devices