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PREVAIL

Prospective Randomized Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients With Atrial Fibrillation Versus Long-Term Warfarin Therapy

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Year of Publication: 2014

Authors: David R. Holmes JR, MD, Saibal Kar, ..., Vivek Y. Reddy

Journal: Journal of the American College of Cardiology

Citation: J Am Coll Cardiol 2014;64:1-12

Link: https://doi.org/10.1016/j.jacc.2014.04.029

PDF: https://www.jacc.org/doi/epdf/10.1016/j.jacc.2014.04.023

Clinical Question

In patients with nonvalvular atrial fibrillation (NVAF) at high risk for stroke, is left atrial appendage (LAA) occlusion with the Watchman device a safe and effective alternative to long-term warfarin therapy?

Bottom Line

In patients with NVAF, LAA occlusion with the Watchman device was noninferior to warfarin for preventing ischemic stroke or systemic embolism occurring more than 7 days after the procedure. It did not meet the noninferiority criteria for the composite endpoint of stroke, systemic embolism, and cardiovascular death, partly due to a very low event rate in the warfarin group. However, the procedural safety of the device improved significantly compared with the prior PROTECT AF trial, making it a reasonable alternative to warfarin for stroke prevention in appropriate patients.

        Major Points
        PREVAIL was a randomized trial comparing the Watchman LAA closure device against chronic warfarin therapy in 407 patients with NVAF and a CHADS2 score ≥2 (or 1 with other risk factors). 
The trial had two co-primary efficacy endpoints analyzed at 18 months. 
First Efficacy Endpoint (stroke, systemic embolism, CV/unexplained death): Noninferiority was NOT achieved. The event rate was 6.4% in the device group vs. 6.3% in the warfarin group (Rate Ratio 1.07; 95% CrI: 0.57 to 1.89). 
Second Efficacy Endpoint (ischemic stroke or systemic embolism >7 days post-procedure): Noninferiority WAS achieved. 
The primary safety endpoint was met, with the rate of early adverse safety events in the device arm (2.2%) being significantly lower than in the previous PROTECT AF trial and meeting the pre-specified performance goal. 

      

Design

Study Type: Prospective, multicenter, randomized clinical trial with a Bayesian design.

Randomization: 1

Blinding: Unblinded. Participants and clinicians were not masked to treatment assignment.

Enrollment Period: Not specified in the document; trial enrolled 407 patients.

Follow-up Duration: 18 months for the primary analysis.

Centers: Up to 50 sites.

Countries: United States

Sample Size: 407

Analysis: Bayesian analysis using historical data from the PROTECT AF trial as a prior distribution.

Inclusion Criteria

Patients with nonvalvular atrial fibrillation (paroxysmal, persistent, or permanent).
CHADS2 score ≥2, OR
CHADS2 score of 1 with at least one additional risk factor (female age ≥75, LVEF <35%, age 65-74 with diabetes or coronary disease, or age ≥65 with congestive heart failure).

Exclusion Criteria

Requirement for long-term anticoagulation for reasons other than atrial fibrillation.
Contraindication to warfarin or aspirin.
Previous stroke/TIA within 90 days of enrollment.
Symptomatic carotid disease.
Indication for clopidogrel therapy.

Baseline Characteristics

Characteristic	Control	Active
Age, yrs	74.9 ± 7.2	74.0 ± 7.4
Female	25.4%	32.3%
CHADS2 score (continuous)	2.6 ± 1.0	2.6 ± 1.0
History of hypertension	97.1%	88.5%
Previous TIA/ischemic stroke	28.3%	27.5%
LVEF%	56.0 ± 9.8	55.4 ± 10.0
CHA2DS2-VASc score (continuous)	3.9 ± 1.2	3.8 ± 1.2

Arms

Field	Control	Watchman Device
Intervention	Chronic warfarin therapy with a target international normalized ratio (INR) between 2.0 and 3.0.	Implantation of the Watchman LAA occlusion device, followed by a 45-day course of warfarin and aspirin. If TEE showed adequate LAA seal at 45 days, warfarin was stopped and clopidogrel plus aspirin was given until 6 months, followed by lifelong aspirin alone.
Duration	Lifelong	Lifelong implant with a defined post-procedural medication regimen.

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
The first co-primary efficacy endpoint was a composite of stroke (ischemic or hemorrhagic), systemic embolism, and cardiovascular/unexplained death at 18 months.	Primary	0.063 (18-month event rate)	0.064 (18-month event rate)	1.07	Noninferiority NOT achieved
Second co-primary endpoint: Ischemic stroke or systemic embolism >7 days post-randomization	Secondary	0.0200 (18-month event rate)	0.0253 (18-month event rate)	Risk Difference 0.0053 (95% CrI: -0.0190 to 0.0273)	Noninferiority Achieved
Primary safety endpoint (composite of all-cause death, ischemic stroke, SE, or device/procedure event requiring major intervention within 7 days)	Adverse		2.2% (6/269)	Met pre-specified performance goal
All 7-day procedural complications (composite)	Adverse		4.2%	Significantly lower than PROTECT AF (p=0.004)	0.004
Pericardial effusion requiring surgery	Adverse		0.4%	Significantly lower than PROTECT AF (p=0.027)	0.03

Subgroup Analysis

Not discussed in the document.

Criticisms

The trial population was required to be candidates for long-term warfarin, so results do not apply to patients with contraindications to anticoagulation.
The Watchman device was not compared against new oral anticoagulants (NOACs).
The clinical significance of the loss of LAA mechanical function after occlusion is unknown.
The low overall event rate, particularly in the over-performing warfarin control arm, provided limited statistical power to establish noninferiority for the primary efficacy endpoint.

Funding

Atritech/Boston Scientific

Based on: PREVAIL (Journal of the American College of Cardiology, 2014)