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Trial Summary PROTECT AF

Title: WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation
Trial Sponsor: Atritech
Year Presented: 2009
Year Published: 2009, 2013, 2014
Topic(s): Arrhythmias, Afib, General Cardiology, Interventional Cardiology, Prevention/Vascular, Cardiac Rhythm Management, Anticoagulation Management
Summary Posted: 11/16/2014
Writer: Anthony A. Bavry, M.D., M.P.H., F.A.C.C.
Author Disclosure:   CONSULTING FEES/HONORARIA: American College of Cardiology Cardiosource(SIGNIFICANT), Boehringer Ingelheim(MODEST) RESEARCH/RESEARCH GRANTS: Novartis Pharmaceuticals(MODEST), Gilead(SIGNIFICANT), Eli Lilly(MODEST)
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Reviewer Disclosure: CONSULTING FEES/HONORARIA: Elsevier Practice Update Cardiology(MODEST) RESEARCH/RESEARCH GRANTS: Astra Zeneca(SIGNIFICANT), Ethicon(SIGNIFICANT), Eisai(SIGNIFICANT), FlowCo(NONE), Amarin(SIGNIFICANT), Roche(SIGNIFICANT), Sanofi Aventis(SIGNIFICANT), PLx Pharma(NONE), Bristol Myers Squibb(SIGNIFICANT), The Medicines Company(SIGNIFICANT), Takeda(NONE), Medtronic(SIGNIFICANT) OTHER FINANCIAL BENEFIT: Belvoir Publications(SIGNIFICANT), Journal of Invasive Cardiology(SIGNIFICANT), Clinical Cardiology(NONE), WebMD(SIGNIFICANT), Slack Publications/Cardiology Research Foundation(SIGNIFICANT), Medscape Cardiology(NONE), Regado Biosciences(NONE)

Description:

The goal of the trial was to evaluate left atrial appendage closure compared with warfarin in patients with nonvalvular atrial fibrillation.

Hypothesis:

Left atrial appendage closure would be noninferior to warfarin therapy in preventing adverse ischemic events.

Drugs/Procedures Used:

Patients with nonvalvular atrial fibrillation and at least one risk factor were randomized to left atrial appendage closure with the WATCHMAN device followed by discontinuation of warfarin after 45 days (n = 463) versus continued warfarin therapy (n = 244).

Concomitant Medications:

In the device arm, patients were treated with warfarin for 45 days, aspirin and clopidogrel until 6 months, then lifelong aspirin.

Patients in the warfarin arm received this study medication for the duration of the study.

Principal Findings:

Overall, 707 patients were randomized. Baseline characteristics were well matched between the groups. The mean age was 72 years, 30% were women, and the mean ejection fraction was 57%. Approximately two-thirds of the patients had a CHADS2 score of 1 or 2. In the device group, 87% of patients discontinued warfarin at 45 days.

The primary efficacy outcome, cardiovascular death, stroke, or systemic embolism, was 3.0 events per 100 patient-years in the device group versus 4.9 events per 100 patient-years in the control group (p for noninferiority >0.99). All strokes were 2.3 events per 100 patient-years versus 3.2 events per 100 patient-years (p = 0.99 for noninferiority), respectively. There was one hemorrhagic stroke in the device group versus six in the warfarin group (p > 0.99 for noninferiority).

At a mean of 2.3 years, the primary efficacy outcome occurred at a rate of 3 events per 100 patient-years in the device group versus 4.3 events per 100 patient-years in the control group (p for noninferiority >0.99).

At a mean of 3.8 years, the primary efficacy outcome occurred at a rate of 2.3 events per 100 patient-years in the device group versus 3.8 events per 100 patient-years in the control group (this met criteria for both noninferiority and superiority). Ischemic stroke: 1.4 events per 100 patient-years in the device group versus 1.1 events per 100 patient-years in the warfarin group (did not meet criteria for noninferiority). Hemorrhagic stroke: 0.2 events per 100 patient-years in the device group versus 1.1 events per 100 patient-years in the warfarin group (met criteria for both noninferiority and superiority). Cardiovascular and all-cause mortality was also lower in the device versus the warfarin group.

The primary composite safety outcome was 7.4 events per 100 patient-years in the device group versus 4.4 events per 100 patient-years in the control group. This was primarily related to complications (pericardial effusions) at the time of device implant.

At a mean of 2.3 years, the primary safety outcome occurred at a rate of 5.5 events per 100 patient-years in the device group versus 3.6 events per 100 patient-years in the control group.

At a mean of 3.8 years, the primary efficacy outcome occurred at a rate of 3.6 events per 100 patient-years in the device group versus 3.1 events per 100 patient-years in the control group (this met criteria for noninferiority).

Interpretation:

Among patients with nonvalvular atrial fibrillation, the use of the WATCHMAN device for left atrial appendage ligation is feasible. This device demonstrated a noninferior rate of cardiovascular death, stroke, or systemic embolism, compared with warfarin alone, which was sustained to 4 years of follow-up. The rate of all strokes (ischemic or hemorrhagic) was noninferior between the groups, and there were significantly less hemorrhagic strokes in the device group. Adverse outcomes were higher in the device group due to a high occurrence of pericardial effusion.

The procedural (and long-term) safety of this device will need to be balanced against the reduction in hemorrhagic strokes afforded from discontinuation of warfarin. It is also possible that this device may prove to reduce ischemic strokes; however, long-term follow-up will be needed to assess this. Left atrial appendage closure did not appear to be associated with a reduction in ischemic strokes compared with warfarin therapy.

Conditions:

  • Arrhythmias / Atrial fibrillation / Anticoagulation
  • Prevention/Primary

Therapies:

  • Anticoagulant / Warfarin

Study Design:

Randomized. Parallel.
Patients Screened: 4,998
Patients Enrolled: 707
Mean Follow Up: 16 months; follow-up to 4 years
Mean Patient Age: 72 years
Female: 30%
Mean Ejection Fraction: 57%

Primary Endpoints:

Primary efficacy endpoint defined as:
  • Ischemic or hemorrhagic stroke, cardiovascular death, or systemic embolization
Primary safety endpoint defined as:
  • Device embolization that required retrieval, pericardial effusion that required intervention, intracranial or gastrointestinal bleeding, or any bleeding that required transfusion

Patient Population:

  • Patients with nonvalvular atrial fibrillation at least 18 years of age
  • CHADS2 score of at least 1

Exclusions:

  • Contraindication to long-term warfarin therapy
  • New York Heart Association class IV heart failure
  • Presence or repair of an atrial septal defect
  • Planned ablation procedure for atrial fibrillation
  • Symptomatic carotid disease
  • Left ventricular ejection fraction <30%
  • Left atrial appendage thrombus

References:

Reddy VY, Sievert H, Halperin J, et al., PROTECT AF Steering Committee and Investigators. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA 2014;312:1988-98.

Reddy VY, Doshi SK, Siever H, et al. Percutaneous Left Atrial Appendage Closure for Stroke Prophylaxis in Patients with Atrial Fibrillation: 2.3 Year Follow-Up of the PROTECT AF Trial. Circulation 2013;Jan 16:[Epub ahead of print].

Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374:534-42.

Randomized Prospective Trial of Percutaneous Left Atrial Appendage Closure Versus Warfarin for Stroke Prevention in Atrial Fibrillation (PROTECT AF). Presented by Dr. David Holmes at ACC.09/i2, Orlando, FL, March 2009.

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