1 Left Atrial Appendage (LAA) and Stroke Kenneth C. Huber, MD, FACC CEO, Saint Luke’s Cardiovascular Consultants Co-Executive Medical Director, Saint Luke’s Mid America Heart Institute Professor of Medicine, UMKC School of Medicine Kenneth C. Huber, MD, FACC Disclosure WATCHMAN Advisory Board – Boston Scientific WATCHMAN Professional Training Event - Proctor Learning Objectives • At the conclusion of this session, the learner should be able to: – Identify the role the Left Atrial Appendage (LAA) plays in stroke risk for patients with Atrial Fibrillation – Review data on LAA closure as an alternative to oral anticoagulants for stroke prevention in patients with Atrial Fibrillation – Develop strategies to incorporate LAA closure into contemporary clinical practice LAA and Stroke • Role of LAA in embolic stroke is in setting of patients with ATRIAL FIBRILLATION (AF) Atrial Fibrillation An Epidemic Savelieva, et al. Clin Cardiol 2008;31 5 Million 10 Million Distribution of AF by Age Over 50% of AF occurs in the 6% of the population ≥ 75 years of age WM Feinberg, et al. Arch Int Med 1995;155:469-73
22
Embed
Disclosure Left Atrial Appendage (LAA) and Stroke · Left Atrial Appendage (LAA) and Stroke Kenneth C. Huber, MD, FACC EO, Saint Luke’s ardiovascular onsultants Co-Executive Medical
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
1
Left Atrial Appendage (LAA) and Stroke
Kenneth C. Huber, MD, FACC CEO, Saint Luke’s Cardiovascular Consultants
Co-Executive Medical Director, Saint Luke’s Mid America Heart Institute
Professor of Medicine, UMKC School of Medicine
Kenneth C. Huber, MD, FACC
Disclosure
WATCHMAN Advisory Board – Boston Scientific
WATCHMAN Professional Training Event - Proctor
Learning Objectives
• At the conclusion of this session, the learner should be able to:
– Identify the role the Left Atrial Appendage (LAA) plays in stroke risk for patients with Atrial Fibrillation
– Review data on LAA closure as an alternative to oral anticoagulants for stroke prevention in patients with Atrial Fibrillation
– Develop strategies to incorporate LAA closure into contemporary clinical practice
LAA and Stroke
• Role of LAA in embolic stroke is in setting of patients with ATRIAL FIBRILLATION (AF)
Atrial Fibrillation An Epidemic
Savelieva, et al. Clin Cardiol 2008;31
5 Million
10 Million
Distribution of AF by Age
Over 50% of AF occurs in the 6% of the population ≥ 75 years of age
WM Feinberg, et al. Arch Int Med 1995;155:469-73
2
Atrial Fibrillation Stroke Risk • AF increases the risk of stroke 5-fold (5-6% annual risk)
• AF is responsible for 15-20% of all strokes
D.R. Holmes. Seminars in Neurology. 2010;30:528 Heart Disease and Stroke Statistical Update: 2009 Circulation, 1-27-09
Stroke 1991;22(18)
0%
10%
20%
30%
40%
50–59 60–69 70–79 80–89
% A
F S
tro
ke
s
Age (years)
• 800,000 strokes/yr in U.S. = 100,000 AF strokes/yr
Functional Impact of AF-Related Stroke
CATASTROPHIC
60% 30%
10%
DR Holmes. Seminars in Neurology 2010;30:528 HT Tu et al. Cerebrovascular Disease 2010;30(4):389
Death or Severe
Disability
50% = Hemiparesis 19% = Aphasia 26% = Dependent ADL 26% = Nursing Homes Generally occlude large intracranial arteries
No Disability/ Transient
Mod Dis
Atrial Fibrillation - Stroke
Pathophysiology
Linking-Diastolic Function, Left Atrial Size, and LAA Size and Function
Atrial Fibrillation as a Systemic Vascular Disease
Arterial Stiffness Microvascular Dysfunction Diastolic Dysfunction LA Enlargement
Neurohormonal (Ang II, TGF B) Tissue Factors (CTGF, MMPs) Vascular/Hemostatic (PDGF,
Endothelin-1) Oxidative/Inflammation (CRP)
Genetic/Telomere
Risk Factor Risk Marker
Modifier
Atrial Fibrillation
Hypertension
Obesity
Sleep Apnea
Sedentary Lifestyle
Thrombosis/Embolization
Electrical Fibrillation
Insufficient contraction of LAA
Stagnant blood flow
Thrombosis / clot formation
Thromboembolism
Stroke
Johnson, Eur J Cardiothoracic Surg 2000;17
Left Atrial Appendage Thrombosis
3
LAA – Culprit Location of Thrombi in Left Atrium
0
20
40
60
80
100
Sto
dd
ard
: J
AC
C, '9
5
Ma
nn
ing
: C
irc
, '9
4
Ab
erg
: A
cta
Me
d S
ca
n, '6
9
Ts
ai:
JF
MA
, '9
0
Kle
in:
Int
J C
ard
Im
ag
: '9
3
Ma
nn
ing
: C
irc
, '9
4
Kle
in:
Cir
c,
'94
Le
un
g: J
AC
C, '9
4
Ha
rt:
Str
ok
e, '9
4
To
tal
Left Atrial Appendage Left Atrium
Blackshear et al., Ann Thoracic Surg, 1996;61:755
Location
Fre
quency (
%) 90%
in
LAA
LAA Anatomy: Thrombi Haven
• LA: mostly smooth and “vein like” derived from sinus venosus
• LAA: derived from the embryonic/ primordial muscular atrium
January, CT. et al.. JACC. 2014; doi: 10.1016/j.jacc.2014.03.022
Stroke Prevention: Medical Therapy: Oral Anticoagulants
Cornerstone of Therapy: Warfarin
Hart et al. Ann Int Med 1999;131:492-501
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
Aggregate
100% 50% 0 -50% -100%
Warfarin Better Control Better (placebo)
Reduction of all-cause mortality
RRR 26%
Reduction of stroke
RRR 62%
6
-5
-
-4
-
-3
-
-2
-
-1
INR
Over-a
nti-
coagula
ted
Under-a
nti-
coagula
ted
Therapeutic
Range
INR >3
doubles
incidence of
intracranial
hemorrhage
INR < 2
increases
stroke risk
70%
Oake N, et al. Can Med Assoc J. 2007:176(11);1589−1594 Budnitz, et al. Annals of Internal Medicine. 2007:147(11); 229 Baker WL, J. Manag Care Pharm 2009 Walker et al. Heart Rhythm Society 2008
Majority of Patients at High Stroke Risk, All Eligible for Anti-coagulation
0%
10%
20%
30%
40%
50%
0 1 2 3 4 5 6-9
PROTECT AF
CHA2DS2-VASc Score ≥22
93%
0%
10%
20%
30%
40%
50%
0 1 2 3 4 5 6-9
High Risk1
CAP PREVAIL CAP2
Patients (%)
CHA2DS2-VASc Score
96% 100% 100%
Anticoagulation Eligible1
Source: Holmes, DR et al. JACC 2015. In Press. 1. AHA/ACC/HRS Guidelines (2014).
14
Majority of Patients in the Trial were at Moderate to High Bleeding Risk1
1. Estimated HAS BLED score. Labile INR and liver function were not collected and given a score of zero Source: Holmes DR, et al. Holmes, DR et al. JACC 2015;
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 1-2 3+
PROTECT AF
CAP
PREVAIL
CAP2
Patients (%)
HAS BLED* Score
Warfarin Time in Therapeutic Range (TTR) for Control Groups
Study Warfarin Control Group Mean TTR
PROTECT AF 70%
PREVAIL 68%
RE-LY1 (Dabigatran) 64%
ARISTOTLE2 (Apixaban) 62%
ROCKET AF3 (Rivaroxaban) 55%
1. Cannoly SJ et al. NEJM 2009 2. Granger CB et al. NEJM 2011
3. Patel MR et al. NEJM 2011
Implant Success & Warfarin Cessation
Study 45-day 12-month
PROTECT AF 87% >93%
CAP 96% >96%
PREVAIL 92% >99%
Implant success defined as deployment and release of the device into the left atrial appendage
Warfarin Cessation PREVAIL Implant Success
No difference between new and
experienced operators Experienced Operators
• n=26 • 96%
New Operators • n=24
• 93% p = 0.28
PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424. PREVAIL: Holmes, DR et al. JACC 2014; 64(1):1-12.
p = 0.04
Endpoints
“Primary effectiveness endpoint captures the events that would also be considered significant safety events (i.e., stroke, death and systemic embolism)”
Key Procedural Safety Events PROTECT AF vs. CAP/PREVAIL
*Overall embolization rate across studies is 0.5%
WATCHMAN Clinical Trial
Efficacy
Long-term PROTECT AF Primary Efficacy
CAP PREVAIL
PAF
RRR 39%
Hemorrhagic Stroke RRR 85%
PROTECT AF: Final Primary Efficacy Events Favor WATCHMAN
Event Rate (per 100 pt-yrs)
Rate Ratio
Posterior Probabilities
WATCHMAN Control Non-
inferiority Superiority
Primary Efficacy 2.3 3.7 0.61 >99.9% 95.4%
Stroke (all) 1.5 2.2 0.68 99.9% 83%
Ischemic 1.3 1.1 1.2 78% 15%
Hemorrhagic 0.2 1.1 0.15 >99.9% 99%
Systemic Embolism
0.2 0.0 NA NA NA
Death (CV & Unexplained)
1.0 2.3 0.4 >99.9% 98.9%
PROTECT AF: 5 Year Mortality WATCHMAN vs. Warfarin
V. Reddy, H. Sievert, J. Halperin et al. JAMA 2014;312:1988
RRR 60% RRR 34%
All Cause Mortality Relative Reduction (vs warfarin) In Context
-35%
-30%
-25%
-20%
-15%
-10%
-5%
0%
% R
R in
All
-Cau
se M
ort
alit
y
Dabigatran 110
Dabigatran 150
Rivaroxaban
Apixaban
WATCHMAN 4 yrs
P=0.051
P=0.13 (NS)
P=0.047
PROTECT AF4 RE-LY1 ROCKET-AF2 ARISTOTLE3
1Connolly, S. NEJM 2009; 361:1139-1151 – 2 yrs f-up 2Patel, M. NEJM 2011; 365:883-891 – 1.9 yrs f-up, ITT 3Granger, C NEJM 2011; 365:981-992 – 1.8 yrs f-up 4Reddy, V. LBCT HRS 2012 – 4 yrs f-up.
P=0.15 (NS)
P=0.0379
ENGAGE-AF
RRR 14%
RRR 34%
16
Meta-Analysis Shows Comparable Primary Efficacy Results to Warfarin
Holmes, DR et al. JACC 2015
HR p-value
Efficacy 0.79 0.22
All stroke or SE 1.02 0.94
Ischemic stroke or SE 1.95 0.05
Hemorrhagic stroke 0.22 0.004
Ischemic stroke or SE >7 days 1.56 0.21
CV/unexplained death 0.48 0.006
All-cause death 0.73 0.07
Major bleed, all 1.00 0.98
Major bleeding, non procedure-related 0.51 0.002
0.01 0.1 1 10
Favors WATCHMAN Favors warfarin
Hazard Ratio (95% CI)
Stroke Severity in PROTECT AF/PREVAIL
• Disabling stroke defined as MRS change of 2 or more or death
• Similar results if defined as absolute MRS > 2
V.Reddy et al, FDA Panel Presentation, October 2014
0.0%
0.4%
0.8%
1.2%
1.6%
2.0%
Non-Disabling Stroke Disabling/Fatal Stroke
Warfarin WATCHMAN
RRR 56%
PROTECT AF & PREVAIL Meta-analysis: WATCHMAN Strokes Are Less Disabling
Disabling Strokes p-value
WATCHMAN Warfarin
All Strokes 27% 61% 0.009
Ischemic Only Strokes 19% 33% 0.43
Based on stroke with MRS change of 2 or more or cause of death related to stroke
Stroke Severity in LAAC vs NOAC Trials Non-Disabling vs. Disabling Fatal Strokes
0%
20%
40%
60%
80%
100%
Warfarin WATCHMAN Warfarin NOACs
Non-disablingStroke
Disabling/FatalStroke
V.Reddy et al, manuscript in preparation
PROTECT/PREVAIL RELY/ROCKET/ENGAGE/ARISTOTLE
RRR 56%
50
60
70
80
90
100
0 7
Time (months)
Free of Major
Bleeding Event
(%)
6 6046 1808 45
Time (days)
Warfarin
+Aspirin
Warfarin
+Aspirin
Aspirin+ Clopidogrel
Aspirin
WATCHMAN Warfarin
71% Relative Reduction
In Major Bleeding
after cessation of anti-thrombotics
HR = 0.29
p<0.001
WATCHMAN Device Arm
Drug Protocol
PROTECT AF/PREVAIL Pooled Analysis: Less Bleeding with WATCHMANTM Device 6 Months Post-Implant
bleeding: Serious bleeding event that required intervention or hospitalization according to adjudication committee
Price, MJ. Avoidance of Major Bleeding with WATCHMAN Left Atrial Appendage Closure Compared with Long-Term Oral Anticoagulation : Pooled Analysis of the PROTECT-AF and PREVAIL RCTs. TCT 2014 (abstract)
PROTECT AF: Quality of Life
Alli O, JACC 2008
*p<0.005
17
Economic Analysis: Cost Effectiveness WATCHMAN vs. NOACs vs Warfarin
• Patient level Markov micro-simulation decision analytic model
• 0.5% had device related serious adverse events not resolved at 3 months
18
ASAP Registry Contraindicated Pts (n=150): WATCHMAN ASA/Clop x 6 mo
7.3%
1.5%
0
1
2
3
4
5
6
7
8
Expected, based on CHADS2 Score
Observed Rate in ASAP
• CHADS2 = 2.8 ±1.2
• Prior CVA/TIA in 41%
• Follow up: 16.5 months
V. Reddy et al. JACC 2013;61:2551
ASAP Registry Long-term (5 year) Outcomes
D. Sharma et al. JACC 2016
WATCHMANTM Device Reduces Ischemic Stroke Over No Therapy
* Imputation based on published rate with adjustment for CHA2DS2-VASc score (3.0); Olesen JB. Thromb Haemost (2011)
0
1
2
3
4
5
6
7
8
PROTECT AF PREVAIL Only CAP
Imputed IschemicStroke Rate*
ObservedWATCHMAN IschemicStroke RateIs
chem
ic S
tro
ke R
isk
(Ev
ents
/100
Pat
ien
t-Ye
ars)
79% Relative Reduction
67% Relative Reduction
83% Relative Reduction
Baseline CHA2DS2-VASc = 3.4
Baseline CHA2DS2-VASc = 3.8
Baseline CHA2DS2-VASc = 3.9
FDA Oct 2014 Panel Sponsor Presentation. Hanzel G, et al. TCT 2014 (abstract)
Preventing Stroke in Non-Valvular AF Imputed Benefit of Different Strategies (vs. Control)
Strategies to Incorporate LAA Closure into Clinical Practice
19
FDA Approval 3/20/2015 WATCHMAN Device Patient Selection
Indications for Use The WATCHMAN Device is indicated to
reduce the risk of thromboembolism from
the left atrial appendage in patients with
non-valvular atrial fibrillation who:
•Have an appropriate rationale to seek a
non-pharmacologic alternative to warfarin,
taking into account the safety and
effectiveness of the device compared to
warfarin.
NOT a broad replacement for oral anticoagulation
• Effective 2/20/2016: CMS National Coverage Determination (NCD)
• Medicare coverage “when specific conditions are met”
• 124 page document
CMS “Conditions” • Eligible patients must have CHADS2 score ≥2 or
CHA2DS2-VASc score ≥3
• There must be documented evidence of a formal shared decision interaction between patients and an independent, non-interventional physician
• Patients must be suitable for short-term warfarin, but deemed unable to take long-term OAC
CMS “Conditions” • The procedure must be performed in a hospital with an
established structural heart disease or EP program
• The procedure must be performed by an interventional cardiologist or electrophysiologist, meeting following criteria:
– trained by manufacturer
– ≥ 25 interventional cardiac procedures involving transseptal punctures through an intact septum
– Continues to perform ≥25 interventional cardiac procedures involving transseptal punctures through an intact septum, with at least 12 being LAAC over a two year period
• Patients must be enrolled in a prospective national registry
Frequently Asked Questions About CMS “Conditions”
• Who is this “independent, non-interventional physician” involved in this shared decision process?
• What is this “evidence-based decision tool” that is to be used in the formal shared decision making interaction with the patient?
• What is the prospective national registry that we need to enroll our patients into?
Clinical Scenarios: Potential Candidates
• CHA2DS2-VASc ≥ 3 AND Deemed unable to take long term OAC
• History of Major Bleeding: on OAC
– GI/GU
– Intracranial
– ENT
• High risk for major bleeding: Not on OAC
– HAS-BLED ≥ 3 (6% risk/yr)
– Frailty/Fall Risk
– CKD, Liver disease
– Inflammatory Bowel Disease
– Malignancy (Chemotherapy)
– Seizure disorder)
20
Clinical Scenarios: Potential Candidates
• Non-adherence/Non-compliance
– Frailty/Dementia
– Cost
– Choice/Refusal
• Polypharmacy
– Triple therapy – ACS/Vascular disease
• Occupation/Lifestyle
– High risk of trauma
Clinical Scenarios: Not Candidates
• CHA2DS2-VASc 0, 1, or 2 (for Medicare pts)
• No issues with OAC
• Other reason to be on OAC
– Valvular AF/Prosthetic valve
– DVT
– Hypercoagulable state
• LAA anatomy
– Size/shape
– Thrombus/sludge
• Vascular access issues
• Anesthesia risks
Clinical Scenarios: Contraindications
• Absolute contraindication to OAC or DAPT
– Post Implant: 6 weeks OAC 6 months DAPT
– Time for endothelialization
ASAP-TOO Trial • WATCHMAN (DAPT x 3 mo, ASA x 12 mo) • Medical Therapy (no Tx, ASA alone, DAPT
can be considered) • 2:1 randomization
MAHI Shared Clinical Decision Process
• Goal: Educate patient and family on the risks vs benefits of the three different scenarios
Shared Clinical Decision Process 1. Discuss personal risk of stroke
– CHA2DS2-VASC score: % risk/year
2. Discuss benefits of 3 treatment options
– RRR minor if any
↓60-70% (Class IA)
Non-inferior/Imputed placebo (↓70%)
3. Discuss Personalized relative risks of OAC; both warfarin & NOACS
– Quantify if possible (HAS-BLED) variable threshold
– Individual assessment of risk/benefit centered around pharmacotherapy issues
4. Discuss the risks of procedure
– Risks (procedural/device embolization/device related thrombosis)
1
2
3
21
Cardiovascular / Unexplained Death (includes CV deaths preceded by stroke)
Non-fatal Hemorrhagic Stroke
Non-fatal Ischemic Stroke /
Systemic Embolism
Event-free
WATCHMAN N=1000
Warfarin N=1000
200
400
600
800
1000
200
400
600
800
1000
N=1000; Each circle represents a single patient (N=1) with WATCHMAN or warfarin followed through five years
WATCHMAN Comparable to Warfarin for Primary Efficacy
Cardiovascular / Unexplained Death (includes CV deaths preceded by stroke)
Non-fatal Hemorrhagic Stroke
Non-fatal Ischemic Stroke /
Systemic Embolism
Event-free
WATCHMAN Warfarin
100
200
300
400
500
100
200
300
400
500
Zoomed in to show N=500 of 1000 patients for each study arm; Each circle represents a single patient (N=1) with WATCHMAN or warfarin followed through five years
CV Death Lower with WATCHMAN vs. Warfarin
Cardiovascular / Unexplained Death (includes CV deaths preceded by stroke)
Non-fatal Hemorrhagic Stroke
Non-fatal Ischemic Stroke /
Systemic Embolism
Event-free
WATCHMAN Warfarin
100
200
300
400
500
100
200
300
400
500
Zoomed in to show N=500 of 1000 patients for each study arm; Each circle represents a single patient (N=1) with WATCHMAN or warfarin followed through five years
Hemorrhagic Stroke Lower with WATCHMAN vs. Warfarin
Ischemic Stroke/SE Lower with Warfarin vs. WATCHMAN
Cardiovascular / Unexplained Death (includes CV deaths preceded by stroke)
Non-fatal Hemorrhagic Stroke
Non-fatal Ischemic Stroke /
Systemic Embolism
Event-free
Zoomed in to show N=500 of 1000 patients for each study arm; Each circle represents a single patient (N=1) with WATCHMAN or warfarin followed through five years
WATCHMAN Performs Better than Warfarin for Major Bleeding
WATCHMAN and Warfarin Reduce Ischemic Stroke vs. No Therapy
22
Conclusions
Conclusions
• The LAA plays a significant role in stroke risk in patients with AF
• CHA2DS2-VASc score is current goal standard but has significant limitations
– Assessment of risk is key to understanding relative benefits of different treatment options
• Oral anticoagulation is the primary therapy of choice and should be prescribed in virtually all patients
– Warfarin is cornerstone but problematic
– Is NOAC better but not perfect with major benefit due to decreased ICH; similar for non-cranial bleeding
Conclusions • Significant Under treatment
– Unprotected 5,000,000 x 0.4 = 2,000,000 patients
• LAA closure with WATCHMAN has been well studied as currently the only device approved by FDA as an alternative to OAC
• Post FDA approval and CMS clarification on payment, appropriate case selection using a robust, shared, clinical decision making process should identify patients that will benefit
OAC Patient…
$$$
Did I take my medicine?
Joints hurt! Need NSAID
Will the cruiseship doctor know what Rivaroxaban is???