PROTECT AF: Longer Follow-up Provides Clarity on Watchman vs. Warfarin for A-fib

Updated, long-term data from the PROTECT AF trial lend support to the idea that percutaneous closure of the left atrial appendage (LAA) is as good as warfarin at preventing stroke in patients with atrial fibrillation (A-fib), according to a paper published online January 16, 2013, ahead of print in Circulation.

PROTECT AF, first published in August 2009 in the Lancet, randomized patients with nonvalvular A-fib to percutaneous LAA closure with the Watchman device (Atritech, Plymouth, MN; n = 463) or ongoing warfarin treatment alone (n = 244). Although the device was found at 1,050 patient-years of follow-up to be noninferior to warfarin in terms of preventing stroke, systemic embolism, and cardiovascular death, its use was accompanied by a higher risk of complications, mostly pericardial effusion and procedural stroke.

The current analysis by Vivek Y. Reddy, MD, of the Mount Sinai School of Medicine (New York, NY), and colleagues extends follow-up by 50% over the Lancet paper, to a total of 1,588 patient-years. Mean follow-up was 2.3 ± 1.1 years, and 469 patients (66.3%) completed at least 2 years of monitoring.

Teasing Out Influences on Efficacy, Safety

Based on intent-to-treat, the Watchman device again proved noninferior for the primary composite efficacy endpoint (stroke, systemic embolism, and cardiovascular or unexplained death) and led to an increase in the primary composite safety outcome (procedure-related events and major bleeding; table 1).

Table 1. PROTECT AF at 1,588 Patient-Years: Annual Event Rates

 

^a Probability of noninferiority > 0.999.

Efficacy in the intention-to-treat population was consistent regardless of patient age, sex, and morphology of A-fib and LAA.

Per-protocol analysis showed fewer efficacy events with the Watchman than with warfarin alone (2.3% vs. 4.1% per year; probability of superiority = 0.955), as did an analysis excluding events occurring on the day of deployment. Watchman patients who completed warfarin and clopidogrel therapy and were only taking aspirin after device implementation also held an advantage over the warfarin-alone group.

In addition, per-protocol analysis found that the risk of adverse safety events, mainly bleeding, was lower for Watchman than warfarin alone (1.5% vs. 3.6% per year; RR 0.42; 95% CI 0.22-0.87). Watchman patients who were on aspirin alone after completing warfarin and clopidogrel were at a similarly reduced risk of adverse safety events.

Watchman also benefitted patients more than warfarin when the functional impact of adverse events was considered in terms of disability (defined as an increase in modified Rankin score of 2 points or more) or death (RR 0.41; 95% CI 0.22-0.82 for intention-to-treat and RR 0.33; 95% CI 0.16- 0.71 for per-protocol).

Among the 19% of patients with previous stroke or TIA at the time of enrollment, those treated with warfarin experienced higher risk of recurrent stroke. Annual rates were 5.3% in patients assigned to LAA closure and 8.2% in those assigned to ongoing warfarin (RR 0.64; 95% CI 0.24-1.74; probability of noninferiority = 0.987).

A Longer Horizon

Dr. Reddy told TCTMD in a telephone interview that the earlier Lancet paper was based on “relatively short-term data. . . . Now we know that even long term the device works as well as [warfarin].” Five-year data are forthcoming, he reported.

In a telephone interview with TCTMD, Ziyad M. Hijazi, MD, MPH, of Rush University Medical Center (Chicago, IL), agreed that the updated PROTECT AF results add useful information. Longer follow-up has confirmed that the Watchman device is “definitely” noninferior to warfarin alone. “People before were [crediting the device’s apparent benefit to the fact] that many patients were still on warfarin at 45 days and on antiplatelet therapy for 6 months,” he explained.

Also important, Dr. Hijazi stressed, is that even patients with prior stroke who received warfarin still faced the possibility of recurrence. “We’re giving the wrong medication to these patients, the wrong therapy. We ought to eliminate the source of the clots, which is the appendage,” he advised.

Dr. Reddy concurred, noting, “If you’ve had a stroke, not only does that not preclude you from having the device, it actually seems to be the same if not better in terms of benefit.”

Room to Grow

Moreover, “[l]ooking beyond the technical issues related to the Watchman device, these data suggest that the concept of ‘local’ LAA closure is a scientifically valid approach to decrease stroke in [A-fib] patients,” the study authors conclude, noting that complications associated with the device had “less long-term impact than adverse events in patients assigned to warfarin.”

Meanwhile, the field continues to evolve. A US Food and Drug Administration (FDA) advisory panel initially recommended approval of the Watchman after findings from PROTECT AF were presented in March 2009 at the American College of Cardiology (ACC) Annual Scientific Session/i2 Summit; but 1 year later, the agency asked Atritech to confirm the device’s safety and efficacy by conducting a new randomized trial.

Results from that trial, PREVAIL, are slated to be presented March 2013 at the ACC Annual Scientific Session in San Francisco, CA, Dr. Reddy reported, adding, “The data will end up getting submitted to the FDA, and hopefully later this year, the FDA will act.”

Through PREVAIL, the FDA wanted to better understand how growing experience with LAA closure would affect outcomes, especially for new operators, he explained. The arrival of new anticoagulants on the market, such as dabigatran and rivaroxaban, may also have played a role in the agency’s reluctance.

Dr. Hijazi reported that the Watchman is “popular” in Europe, where it has already received CE Mark approval. “Many institutions in Europe use it routinely, even for more lax indications,” he commented.

In the United States, physicians have turned to the FDA-approved Lariat suture delivery device (Sentre Heart, Redwood City, CA) for off-label use, he said. “I am one of those people. . . . [Y]ou can only get [the Watchman] at one of a few investigative sites. If you’re not [at such a site], you cannot help your patients, so [we have been] bringing in these patients and closing their appendage with the Lariat.” Thus far, close to 1,200 cases have been performed in this country, he added, “with excellent results.”

 

 

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Sources:1. Reddy VY, Doshi SK, Sievert 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;Epub ahead of print.

 

2. 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;374:534-542.

 

 

 

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