Device Description

The WATCHMAN (Boston Scientific Corp., Maple Grove, Minnesota) left atrial appendage closure (LAAC) technology is a percutaneously delivered permanent cardiac implant placed in the LAA. The WATCHMAN device consists of 3 components: the WATCHMAN LAAC device, the WATCHMAN delivery system, and the WATCHMAN access system. The WATCHMAN LAAC device is a self-expanding nitinol structure covered by a porous polyethylene terephthalate membrane on the proximal face. The closure device is available in 5 sizes, ranging from 21 to 33 mm in diameter. The access and delivery systems allow for femoral venous access and provide a means to cross into the left atrium through the interatrial septum. The device is designed to be permanently implanted at or slightly distal to the ostium of the LAA to trap potential emboli before they can exit the LAA.

Studies to Support the Premarket Approval Application

A premarket approval (PMA) application of this device containing the results of the Embolic Protection in Patients With Atrial Fibrillation (PROTECT AF) pivotal study was previously reviewed by the US Food and Drug Administration (FDA) and was presented to the Circulatory System Devices Panel on April 23, 2009. During the deliberations, the panel largely believed that short-term efficacy had been demonstrated by the data available from the PROTECT AF trial. However, because of the lack of available long-term data and concerns about the periprocedural risks associated with device placement, the FDA issued a “not approvable” letter. Subsequently, the FDA worked interactively with the sponsor on the design of a new trial to gather additional safety and effectiveness data on the WATCHMAN device and to address the concerns discussed by the panel. In July 2010, the FDA conditionally approved the Patients With Atrial Fibrillation Versus Long-Term Warfarin Therapy (PREVAIL) trial, which is a prospective, randomized, controlled, multicenter clinical trial that uses a Bayesian design. The FDA recognized that although the existing data from PROTECT AF were not adequate to provide a reasonable assurance of device safety and effectiveness, there was value in the information captured in the PROTECT AF trial. Therefore, the PREVAIL study was designed to borrow strength from PROTECT AF by incorporating a portion of the PROTECT AF data into a Bayesian statistical analysis plan while simultaneously addressing the limitations of the PROTECT AF study. In addition to new data collected in PREVAIL, continued follow-up of PROTECT AF subjects was collected to provide critical insights into long-term device safety and effectiveness. The results of PREVAIL, continued access (CAP) registry of the PROTECT AF study, and additional long-term follow-up data from PROTECT AF have been reviewed by the FDA under PMA application, which was the subject of the 2013 advisory panel meeting. See Table 1 for a summary of clinical studies in WATCHMAN program used to support safety and efficacy in the panel meeting.

Studies to Support the Premarket Approval Application

A premarket approval (PMA) application of this device containing the results of the Embolic Protection in Patients With Atrial Fibrillation (PROTECT AF) pivotal study was previously reviewed by the US Food and Drug Administration (FDA) and was presented to the Circulatory System Devices Panel on April 23, 2009. During the deliberations, the panel largely believed that short-term efficacy had been demonstrated by the data available from the PROTECT AF trial. However, because of the lack of available long-term data and concerns about the periprocedural risks associated with device placement, the FDA issued a “not approvable” letter. Subsequently, the FDA worked interactively with the sponsor on the design of a new trial to gather additional safety and effectiveness data on the WATCHMAN device and to address the concerns discussed by the panel. In July 2010, the FDA conditionally approved the Patients With Atrial Fibrillation Versus Long-Term Warfarin Therapy (PREVAIL) trial, which is a prospective, randomized, controlled, multicenter clinical trial that uses a Bayesian design. The FDA recognized that although the existing data from PROTECT AF were not adequate to provide a reasonable assurance of device safety and effectiveness, there was value in the information captured in the PROTECT AF trial. Therefore, the PREVAIL study was designed to borrow strength from PROTECT AF by incorporating a portion of the PROTECT AF data into a Bayesian statistical analysis plan while simultaneously addressing the limitations of the PROTECT AF study. In addition to new data collected in PREVAIL, continued follow-up of PROTECT AF subjects was collected to provide critical insights into long-term device safety and effectiveness. The results of PREVAIL, continued access (CAP) registry of the PROTECT AF study, and additional long-term follow-up data from PROTECT AF have been reviewed by the FDA under PMA application, which was the subject of the 2013 advisory panel meeting. See Table 1 for a summary of clinical studies in WATCHMAN program used to support safety and efficacy in the panel meeting.

Addressing the Limitations of PROTECT AF Through the PREVAIL Study

During the 2009 FDA meeting, the following major concerns were raised by the panel members—(1) patient population: PROTECT AF permitted enrollment of low-risk subjects, and 34% of device subjects had a CHADS ₂ score of only 1. Professional society guidelines available at the time of PROTECT AF indicated that these patients could be adequately treated with aspirin rather than necessarily requiring oral anticoagulation therapy. The PREVAIL study addressed this limitation by enrolling the higher CHADS ₂ risk patients compared with PROTECT AF (2.2 ± 1.2 vs 2.6 ± 1.0). (2) Adjunctive antiplatelet therapy: PROTECT AF allowed subjects in both treatment groups to be on long-term aspirin and/or clopidogrel therapy at the discretion of the treating physician. This made it difficult to assess the contribution of the use of concomitant antiplatelet drugs to the end point ischemic and bleeding complications. The PREVAIL study excluded subjects with an indication for long-term clopidogrel therapy to avoid this potential confounding issue. (3) Acute safety events: in PROTECT AF, a majority (56%) of primary safety events in the device group occurred on the day of the procedure, and there was no prespecified hypothesis test for procedural safety. So PREVAIL included a co-primary end point with a prespecified hypothesis to evaluate the rate of major procedure-related events occurring between the time of randomization and within 7 days of the procedure.

Efficacy Assessment

Fundamentally, both the PREVAIL and PROTECT AF trials were designed to compare 2 treatment strategies: WATCHMAN device implantation, 45 days of warfarin plus 81 mg aspirin through 45 days postimplantation, followed by aspirin 325 mg plus clopidogrel 75 mg through 6 months’ postimplantation, followed by indefinite use of aspirin 325 mg versus long-term warfarin therapy. The clinical question linked to the performance of the WATCHMAN device is whether the study data support stopping warfarin after satisfactory implantation of the device.

PREVAIL Study

Within 41 US sites, PREVAIL included 269 subjects randomized to the device group and 138 subjects randomized to the control group ( Table 1 ). The study population was predominately men (∼70%) and overwhelmingly Caucasian (∼94%). There were 3 coprimary end points in this study, and a formal statistical hypothesis was prospectively established for each end point. The primary analysis was intent-to-treat and was performed once all subjects had reached at least 6-month follow-up. In an attempt to incorporate PROTECT AF data, yet avoid overly influencing the trial results, the FDA and the sponsor agreed to use previous data in the analyses with a discounting weight of 50%. This means that the number of events and exposure time observed in PROTECT AF were downweighted by 50% when using them as previous information in the final analysis of event rates.

The PREVAIL-only end point events and event rates (sponsor and FDA analyses) are listed in Table 2 . The WATCHMAN device failed to meet the noninferiority criterion for the first primary end point (18-month rate of stroke, systemic embolism, and cardiovascular or unexplained death). The 18-month event rate was 0.064 for the device group and 0.063 for the control group, and the 18-month rate ratio was 1.07 with a 95% credible interval of 0.57 to 1.89. The upper bound of the 95% credible interval for the 18-month rate ratio (1.89) is not lower than the noninferiority margin of 1.75. Thus, the noninferiority criterion “was not met” for the first primary end point based on the prespecified hypothesis. Several panel members expressed ongoing concerns about the results of the first primary end point of PREVAIL. Other panel members were swayed by the totality of data and believed that the totality of the data was favorable or reasonable. Overall, there was a mixed response, but the panel was mostly in favor of using the totality of the data instead of just looking that PREVAIL did not meet the first primary end point. Overall, the panel members believed that the distribution of the data was acceptable.

Table 2

PREVAIL-only endpoint events and event rates (sponsor and FDA analyses)

Dataset Date	Endpoint Event	WATCHMAN		Control
		N Events/Total Pt-yrs	Rate (95% CI ∗ )	N Events/Total Pt-yrs	Rate (95% CI ∗ )
January 2013	Stroke-Ischemic	5/257.1	1.94 (0.63, 4.54)	1/140.1	0.71 (0.02, 3.98)
	Stroke-Hemorrhagic	1/259.0	0.39 (0.01, 2.15)	0/140.8	0.00 (0.00, 2.62)
	Systemic Embolism	1/259.6	0.39 (0.01, 2.15)	0/140.8	0.00 (0.00, 2.62)
	Death (Cardiovascular or Unexplained)	7/259.7	2.70 (1.08, 5.55)	3/140.8	2.13 (0.44, 6.23)
June 2014	Stroke-Ischemic	13/564.9	2.30 (1.23, 3.94)	1/298.1	0.34 (0.01, 1.87)
	Stroke-Hemorrhagic	2/577.3	0.35 (0.04, 1.25)	2/300.1	0.67 (0.08, 2.41)
	Systemic Embolism	1/576.9	0.17 (0.004, 0.97)	0/300.2	0.00 (0.00, 1.23)
	Death (Cardiovascular or Unexplained)	8/578.1	1.38 (0.60, 2.73)	6/300.2	2.00 (0.73, 4.35)

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