WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation - PROTECT-AF

Contribution To Literature:

The PROTECT-AF trial showed that left atrial appendage closure is noninferior to warfarin therapy alone in preventing cardiovascular death, stroke, or systemic embolism among patients with nonvalvular atrial fibrillation.

Description:

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

Study Design

  • Randomized
  • Parallel

Patients Screened: 4,998
Patients Enrolled: 707
Mean Follow Up: 16 months; intended follow-up to 5 years
Mean Patient Age: 72 years
Female: 30%
Mean Ejection Fraction: 57%

Patient Populations:

  • 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

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

Drug/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 in 3% per 100 patient-years in the device group versus 4.3% per 100 patient-years in the control group (p for noninferiority >0.99).

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 in 5.5% per 100 patient-years in the device group versus 3.6% per 100 patient-years in the control group.

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 5 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.

Pooled meta-analysis of PREVAIL and PROTECT-AF at 5 years: Cardiovascular death, stroke, or systemic embolism occurred in 2.8% of the device group versus 3.4% of the warfarin group (p = 0.27). Major bleeding or nonprocedure-related bleeding occurred in 1.7% of the device group versus 3.6% of the warfarin group (p = 0.0003).

References:

Reddy VK, Doshi S, Kar S, et al., on behalf of the PREVAIL and PROTECT-AF Investigators. Left Atrial Appendage Closure: 5-Year Outcomes of the PREVAIL and PROTECT-AF Trials. J Am Coll Cardiol 2017;Nov 2:[Epub ahead of print].

Editorial Comment: Saw J. Long-Term Results With Left Atrial Appendage Closure: Watching the Watchman. J Am Coll Cardiol 2017;Nov 2:[Epub ahead of print].

Presented by Dr. Vivek Y. Reddy at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2017), Denver, CO, November 2, 2017.

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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