Update on Atrial Fibrillation Clinical Trials - Ohio-ACC...Martinez C, et al. Therapy Persistence in...
Transcript of Update on Atrial Fibrillation Clinical Trials - Ohio-ACC...Martinez C, et al. Therapy Persistence in...
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Update on Atrial Fibrillation Clinical Trials
Sreedhar Billakanty MD FHRS Ohio ACC-Spring Summit
March 28th, 2018
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Disclosures
• Honorarium Bristol-Myers Squibb (Apixaban) Janssen (Rivaroxaban)
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Objectives
• A.Fib and Heart Failure clinical trials (CASTLE AF, PABA CHF)
• Watchman device approval (alternative to anticoagulation, PROTECT AF and PREVAIL)
• Persistent A.Fib ablation trials (Converge and AMAZE trials)
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Olmsted County study
Pro
ject
ed
nu
mb
er
of
pers
on
s w
ith
AF
(mill
ions
)
2000
Year
2005 2010 2015 2020 20302025 2035 2040 2045 20500
16
14
10
6
2
12
8
5.1
15.915.2
14.3
13.1
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10.2
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7.7
5.96.7
4 5.1
12.111.711.1
10.39.4
8.47.5
6.8
5.66.1
4Miyasaka Y, et al. Circulation (2006) 114: 119
A.fib Prevalence
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Heart Rhythm 2015 12, 2332-2343DOI: (10.1016/j.hrthm.2015.06.038)
Metabolic syndrome-Conundrum
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Classification
• Paroxysmal AF – Self-terminating or with intervention < 7 days
• Persistent AF – Sustained >7 days
• Long-standing persistent AF – Continuous ≥1 year
• Permanent AF – Cease further attempts to restore and/or maintain sinus rhythm by
patient (and physician)
• NonValvular AF • absence of rheumatic mitral stenosis, a mechanical or
bioprosthetic heart valve, or mitral valve repair
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Thromboembolism • Stroke: 4.5× ↑risk • Microemboli: ↓cognitive function
Mortality • 2× ↑risk independent
of comorbid CV disease • Sudden death in HF and HCM
Hospitalizations • Most common arrhythmia
requiring hospitalization • 2-3× ↑risk for hospitalization
Impaired hemodynamics • Loss of atrial kick • Irregular ventricular contractions • Heart failure • Tachycardia-induced
cardiomyopathy
• ↓Quality of life • Palpitations, dyspnea, fatigue, ↓exercise tolerance
Van Gelder IC et al. Europace. 2006;8:943-9; Narayan SM et al. Lancet. 1997;350:943-50. Wattigney WA et al. Circulation. 2003;108:711-6. Wyse DG et al. Circulation. 2004;109:3089-95.
• Health care burden • Estimated US cost burden: 15.7
billion
The Consequences of AF
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Strategies for Rhythm Control in Patients with Paroxysmal and persistent AF
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‹#›‹#›
A.fib ablation Indications
• Failed / intolerant to AA class Ic / III drug (s) • Symptomatic paroxysmal A.fib (class IA,
“useful”) • Symptomatic persistent A.fib (class IIA,
“reasonable”) • Symptomatic longstanding persistent (>1 year)
(class IIB, may be)
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‹#›‹#›
A.fib ablation Indications
• Symptomatic paroxysmal / persistent AF, can not tolerate or failed AA drug(s)
• Reasonable initial strategy in some patients
• Need to assess procedural risks and outcomes
• Does not obviate the need for anticoagulation
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‹#›‹#›
CASTLE-AF trial
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• Multicenter, open-label, randomized, controlled trial
• Catheter ablation (N=179) • Medical therapy (N=184) • Median follow-up: 37.8 months • Primary Outcome: Death or hospitalization
for heart failure
CASTLE AF
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• CHF: NYHA I 11%, NYHA II 58%, NYHA III 29%, NYHA IV 2%
• Ischemic 40%, non-ischemic 60%, LVEF 32.5% • AF: paroxysmal 30%, persistent 70%, long-
standing persistent 28% • LA diameter 48mm • Devices: CRT-D 27%, ICD 73%, • Medications: History of amiodarone use 57%
CASTLE AF
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Primary Endpoint
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Primary Endpoint
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Primary Endpoint
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• Primary Outcomes • Death or hospitalization for heart failure • 51 (28.5%) vs. 82 (44.6%); HR 0.62 (95% CI 0.43-0.87); p = 0.007
• Secondary Outcomes • Death • 24 (13.4%) vs. 46 (25.0%); HR 0.53 (95% CI 0.32-0.86) p = 0.01
• Heart failure hospitalization • 37 (20.7%) vs. 66 (35.9%); HR 0.56 (95% CI 0.37-0.83); p = 0.004
• Cardiovascular death • 20 (11.2%) vs. 41 (22.3%); HR 0.49 (95% CI 0.29-0.84); p = 0.009
CASTLE AF
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PABA-CHF: Study Design
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Prospective, randomized, controlled trial
Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing Khan MN et al. N Engl J Med. 2008;359:1778-85.
N = 81 with symptomatic, drug-resistant AF; LVEF ≤40%; NYHA Class II or III HF
Primary outcome: Composite of ejection fraction, 6-minute walk distance, and Minnesota Living with Heart Failure score at 6 months
Pulmonary-vein isolation (n = 41)
Atrioventricular-node ablation with biventricular pacing (n = 40)
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Randomized trial of NYHA Class II or III CHF & EF <40% to PVI or AVN + BiV
Khan MN et al. N Engl J Med. 2008;359:1778-85.
PABA-CHF: Composite Primary Endpoints at 6 Months
20
Months
AVN + BiV
6-Minute walk
Dis
tanc
e (m
)
3 60
360
340
320
300
280
260
0
PVI
P < 0.001
MLHF score*
Sco
re*
Months0 6
100
80
60
40
20
0
P < 0.001
PVI AVN + BiV
AVN + BiVE
ject
ion
fract
ion
(%)
P < 0.001
Ejection fraction
Months3 60
37
35
33
31
29
27
25
0
PVI
*↓Score = ↑QoL
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WATCHMAN device data
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360
300
280
260
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Adherence to Anticoagulation Remains a Challenge
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Martinez C, et al. Therapy Persistence in Newly Diagnosed Non-Valvular Atrial Fibrillation Treated with Warfarin or NOAC. A Cohort Study. Thromb Haemost. 2015 Dec 22;115(1):31-9. doi: 10.1160/TH15-04-0350.
~30% of NOAC patients stop taking any drug at 2 years
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Nitinol Frame • Conforms to LAA anatomy to reduce
embolization risk • 10 active fixation anchors - designed to engage
tissue for stability
Proximal Face • Minimizes surface area facing the left atrium to
reduce post-implant thrombus formation • 160 micron membrane PET cap designed to
block emboli and promote healing
Anchors
160 Micron Membrane
WATCHMAN™ LAAC Closure Device
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SH
-535
15-A
B M
AR
2015
Fixation anchors engage LAA wall
Optimal Device Position
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SH 286002 AE NOV 2017
WATCHMAN™ - Most Studied LAAC Device Only one proven with long-term data from randomized trials and multi-center registries
Key Trials N HighlightsPROTECT AF1 (2005-2008) 707 Prospective, randomized 2:1, non-inferiority trial of LAA closure vs. warfarin.
CAP2
(2008-2010) 566 Prospective registry allowing continued access to the WATCHMAN Device and gain further information prior to PMA approval.
PREVAIL3
(2010-2012) 407 Prospective, randomized 2:1, non-inferiority trial to collect additional information on the WATCHMAN Device.
CAP2 (2012-2014) 579 Prospective registry allowing continued access to the WATCHMAN Device
prior to PMA approval.
EWOLUTION (2013-2015)4* 1025 Prospective registry allowing all patients receiving a WATCHMAN Device at
participating centers in Europe, Middle East and Russia
Total patients >3,000 ~9,000 Patient-Years of Follow-up
1 Reddy, et al. JAMA. 2014 ;312(19): 1988-1998. 2 Reddy VY et al. Circulation. 2011; 123:417-424. 3 Holmes et al., JACC 2014,;4(1): 1-11. 4Boersma, L. V. A., et al. CCI (2015); 88(3): 460-465.
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SH 286002 AE NOV 2017
Patient Level Meta-Analysis PROTECT AF, PREVAIL 5 Years
HR p-value
Efficacy 0.82 0.3
All stroke or SE 0.96 0.9
Ischemic stroke or SE 1.7 0.08
Hemorrhagic stroke 0.2 0.0022
Ischemic stroke or SE >7 days 1.4 0.3
Disabling/Fatal Stroke (MRS change of ≥2) 0.45 0.03
Non-Disabling Stroke 1.38 0.35
CV/unexplained death 0.59 0.03
All-cause death 0.73 0.04
Major bleed, all 0.91 0.6
Major bleeding, non procedure-related 0.48 0.0003
0.01 1 10Favors WATCHMAN ! " Favors warfarin
Hazard Ratio (95% CI)
Sou
rce:
. R
eddy
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, et a
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Year
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SH 286002 AE NOV 2017
Patient Level Meta-Analysis PROTECT AF, PREVAIL 5 Years
HR p-value
Efficacy 0.82 0.3
All stroke or SE 0.96 0.9
Ischemic stroke or SE 1.7 0.08
Hemorrhagic stroke 0.2 0.0022
Ischemic stroke or SE >7 days 1.4 0.3
Disabling/Fatal Stroke (MRS change of ≥2) 0.45 0.03
Non-Disabling Stroke 1.38 0.35
CV/unexplained death 0.59 0.03
All-cause death 0.73 0.04
Major bleed, all 0.91 0.6
Major bleeding, non procedure-related 0.48 0.0003
0.01 1 10Favors WATCHMAN ! " Favors warfarin
Hazard Ratio (95% CI)
Sou
rce:
. R
eddy
VY,
Dos
hi S
K, K
ar S
, et a
l. 5-
Year
Out
com
es A
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trial
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rom
the
PR
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nd
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ls. J
. Am
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. 201
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ss
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SH 286002 AE NOV 2017
Warfarin Cessation with WATCHMAN
92% 99%45 Days
92% of patients were able to discontinue warfarin after 45 days, with 99% able to discontinue after 1 year3
1. Reddy, VY et al. Circulation. 2011;123:417-424. 2 WATCHMAN FDA Panel Sponsor Presentation. Oct 2014.. 3 Holmes, DR et al. JACC 2014; 64(1):1-12.
WATCHMAN Enables Patients to Discontinue Long-term OAC
92%92%
99%
1 Year
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SH 286002 AE NOV 2017
WATCHMAN is the most studied LAAC Device with Long-term Clinical Data
Results
Safety WATCHMAN procedure is safe 95% implant success; ~4% complication rates1
Primary Efficacy
WATCHMAN comparable to warfarin 18% reduction in events (p=0.27)2
Stroke WATCHMAN comparable to warfarin
55% reduction in disabling/fatal stroke (p=0.03)*, largely driven by
80% reduction in hemorrhagic stroke (p=0.003)2
Mortality WATCHMAN statistically significant to warfarin
27% reduction in all-cause mortality (p=0.04)2
41% reduction in CV/unexplained mortality (p=0.03)2
Major Bleeding
WATCHMAN statistically significant to warfarin post-
procedure72% reduction after 6-months (p=0.001)3
WarfarinCessation
WATCHMAN allows the majority of patients to discontinue
warfarin92% of patients discontinue after 45-days; 99% of patients discontinue after 1 year4
1. WATCHMAN FDA Panel Sponsor Presentation. Oct 2014.; 2 Reddy VY et al. JACC. 2017; In Press; 3. Price, M. J., V. Y. Reddy, et al. JACC: CV Interv 2015; 8(15): 1925-1932; 4. Holmes, DR et al. JACC 2014; 64(1): 1-12; 6.
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Very long-term outcome after initially successful catheter ablation of atrial fibrillation
Heart Rhythm Volume 11, Issue 5, Pages 771-776 (May 2014)
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Heart Rhythm 2014 11, 771-776DOI: (10.1016/j.hrthm.2014.02.003)
445 patients, 66+/- 34 months f/up
16% at 5 years, 30% at 10 years VLR: Very late recurrence
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Heart Rhythm 2014 11, 771-776DOI: (10.1016/j.hrthm.2014.02.003)
445 patients, 66+/- 34 months f/up
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Confidential ! For Internal Educational Use Only ! Not for Distribution. 13Feb2017
AtriCure Randomized Pivotal Study
VAL-1200
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Confidential – For Internal Education Use Only – Not for Distribution34
Control ArmStandalone Endocardial Ablation Procedure
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Confidential – For Internal Education Use Only – Not for Distribution35
Study ProcedureConvergent Procedure• Treatment Arm • Convergent Procedure
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Confidential – For Internal Education Use Only – Not for Distribution36
Study Design
❖ Randomized 2:1 (convergent procedure versus standard ablation) multi-center, prospective, open label pivotal study
❖ 27 US Sites, 3 OUS sites
❖ 153 patients
❖ Initial Post procedure follow-up: 12 months
❖ 3 month Blanking Period
❖ Long-term follow-up 18 months with annual phone follow-up for 5 years
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Confidential – For Internal Education Use Only – Not for Distribution37
Study Primary Efficacy Endpoint
Primary Efficacy Endpoint Recurrent atrial fibrillation / flutter
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Confidential – For Internal Education Use Only – Not for Distribution38
Study Safety Endpoints
Primary Safety Endpoint 30 day procedure related adverse events
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Left Atrial Appendage Ligation with the LARIAT® Suture Delivery System as Adjunctive Therapy to
Pulmonary Vein Isolation for Persistent or Longstanding Persistent Atrial Fibrillation
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LARIAT Procedure
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amaze Protocol OverviewPrincipal Purpose Evaluate freedom from AF
Patient Population
Persistent or longstanding persistent AF (< 3 yrs continuous AF) planned for catheter ablation
Investigational Tx LARIAT LAA ligation followed by PVI catheter ablation (4 weeks)
Control Tx PVI catheter ablation without LAA ligation
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SH 286002 AE NOV 2017
ASAP-TOO (NCT02928497):Overview
Study Objective Evaluate LAA Closure with WATCHMAN in NVAF patients deemed not suitable for oral anti-coagulation therapy
Study DesignProspective, multi-center Randomized 2:1 (Watchman vs Control) Considering Group Sequential Design
Primary Endpoint
Effectiveness Endpoint Time to first occurrence of ischemic stroke or systemic embolism
Safety Endpoint 7-day rate of all-cause death, ischemic stroke, systemic embolism, or device- or procedure- related events requiring open cardiac surgery or major endovascular intervention
Patient Population 888
Number of Sites 100 global sites
Follow-up*• 45 Day with TEE • 6,18 month phone visit • 12 month with TEE • Bi-annually for years 2-5
• Brain imaging required at baseline if prior stroke or TIA Holmes et al. AHJ 2017; in press
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SH 286002 AE NOV 2017
Oral Anticoagulation is Standard of Care, but Not Ideal for All NCDR Pinnacle Registry
Warfarin• Bleeding risk• Daily regimen • High non-adherence rates• Regular INR monitoring • Food and drug interaction issues• Complicates surgical procedures
Novel Oral Anticoagulants• Bleeding risk• Daily or 2x/daily regimen • High non-adherence rates• Complicates surgical procedures• Limited reversal agents • High cost
1. Hsu, J et al. JAMA Cardiol. Published online March 16, 2016. doi:10.1001/jamacardio.2015.0374
Use of OACs in AF Patients peaks at ~50%,use declines with increasing risk
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Heart Rhythm 2017 14, 763-782DOI: (10.1016/j.hrthm.2017.01.032)
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Ablation is salvation
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