Final Watchman Trial Analyses Encourage Experts, but Caveats Remain

November 03, 2017

DENVER, CO — Five-year outcomes using the Watchman (Boston Scientific) left atrial appendage (LAA) occluder were "comparable" to those using standard oral anticoagulation (OAC) with warfarin, researchers say, in a combined patient-level analysis of two related trials, PROTECT-AF and PREVAIL[1].

That might suggest an advantage for the LAA-closure device overall in patients with nonvalvular atrial fibrillation (AF) who would otherwise be on lifelong OAC, but the findings aren't so clear-cut. For example, a Watchman-related trend toward more ischemic strokes was countered, to some extent, by a significant drop in hemorrhagic stroke.

That suggests more realistically that Watchman and possibly other LAA-closure devices will be better options in some patients but not others.

Although some have long decried any overall positive interpretation of either trial and the utility and promise of Watchman itself, the prevailing view here at TCT 2017, where the 5-year meta-analysis was presented and scrutinized, was more measured.

Dr Saibal Kar

The device therapy "provides stroke prevention in nonvalvular atrial-fibrillation patients to a similar degree as oral anticoagulation. And by minimizing major bleeding, particularly hemorrhagic stroke, left atrial appendage closure results in less disability or death in comparison to warfarin," according to Dr Saibal Kar (Cedars-Sinai Medical Center, Los Angeles, CA).

"We feel that for patients who are poor candidates for long-term oral anticoagulation, with emphasis on long-term, left atrial appendage closure is a reasonable strategy for stroke prevention," said Kar during presentation of the meta-analysis here to coincide with its publication in the Journal of the American College of Cardiology.

Patients who received Watchman in the trial also took warfarin for the next 45 days, followed by dual-antiplatelet therapy out to 6 months; thereafter they took aspirin as the only antithrombotic.

"There may be a slightly lower ischemic-stroke rate with warfarin anticoagulation," Dr Gregg W Stone (Columbia University, New York) said from the dais after Kar's presentation. "That being said, I believe that left atrial appendage occlusion with the Watchman is now the viable and clearly safe approach for patients with any sort of contraindications or strong anxiety toward oral anticoagulation."

Others on the panel agreed. "The overall message, I think, is that for the patients who enrolled in these trials, the device seems to be quite worthwhile," said Dr Stephen G Ellis (Cleveland Clinic, OH).

"I think the analysis is complex, I think that's a challenge for the community to wrap their heads around," observed Dr Ori Ben-Yehuda (Cardiology Research Foundation, New York, NY). "And obviously the context of a randomized clinical trial may not be the same as what we'll see in postmarketing experiences. So I think we need further studies."

Still, he added, "I think patients are very interested in this; they don't want blood thinners, and the hemorrhagic-stroke reduction is very compelling. As a clinician I would definitely have this as an option."

For patients who are "poor candidates for long-term oral anticoagulation," said Dr Ajay J Kirtane (New York-Presbyterian/Columbia University Medical Center) on a query from | Medscape Cardiology, he'd agree that "this is an effective therapy in preventing those strokes that arise from the atrial appendage."

Limiting it to patients with increased bleeding risk or who for some other reason can't take OAC is a "fair and conservative interpretation" of the trials, "until we gain greater confidence and real-world experience and digest these data," said Dr C Michael Gibson (Beth Israel Deaconess Medical Center, Boston, MA) in an interview.

In patients with AF and a history of bleeding on OAC, using Watchman, "I think, is a no brainer. The patients all want it. The physicians all want it, it's a very easy decision to make," Dr Robert J Sommer (New York-Presbyterian/Columbia University Medical Center) said from the panel.

"But you get into other groups who may potentially be interested in the device, particularly younger patients who are very active, don't want to be on anticoagulation—I think these ischemic-stroke rates in the device [that] are trending up is a problem."

Kar said, "We do agree that this is not a first-line therapy, that those people who cannot, those who will not, and those who shall not take long-term anticoagulation are the people who should have this device."

Follow-up Completed

"At 5 years, the data look the same," Dr Vivek Y Reddy (Mount Sinai Hospital, New York, NY), lead author on the new Watchman publication, said in an interview. The new combined analysis of PROTECT-AF and PREVAIL, the smaller latter study designed to be interpreted along with the former, represents the last of several prospectively ordained looks at their results.

"The overall stroke rate was similar, which addressed the hypothesis that local therapy worked reasonably well compared with systemic therapy," Reddy said. Although ischemic strokes increased on the Watchman, he acknowledged, the device prevented the far more serious intracranial bleeds that are a feared OAC complication.

He seemed to agree with panelists and others about the appropriate patients for Watchman. "The mean age of our patients is like 76 or 77. The vast majority of these patients have already had a bleeding episode, although there are some patients who haven't had one and for various reasons they want to do it—either lifestyle reasons or because of a fall risk or something like that."

PROTECT-AF first entered patients in 2008, when it was a different world for oral anticoagulation, and the treatment choice was limited vitamin-K antagonists like warfarin. The Watchman's journey has been followed in the pages of | Medscape Cardiology from those earliest days, which covered the first report of PROTECT-AF results in 2009, through multiple reviews by the FDA before it gained market approval in 2015. It has also included point-counterpoint commentaries over the trials' stroke rates and statistical analyses.

The Word on Watchman Today

In the PROTECT-AF and PREVAIL studies, the 732 LAA-closure patients, compared with the 382 controls who received warfarin, showed a nonsignificant difference (P=0.87) in a composite of stroke, systemic embolism, or cardiovascular or unexplained death, the primary end point.

They also showed a trend toward greater risk of ischemic stroke or systemic embolism (P=0.08) as an individual end point, but significantly less hemorrhagic stroke (P=0.0022), disabling stroke (P=0.027), cardiovascular or unexplained death (P=0.027), and all-cause mortality (P=0.035).

Risks of major bleeding events were about the same (P=0.60) overall, but it was 52% lower (P=0.0003) for Watchman patients after major bleeding related to the device's implantation procedure were excluded.

PROTECT-AF and PREVAIL at 5 years: Watchman vs Warfarin

End points HR (95% CI) P
Stroke, systemic embolism, or CV death 0.82 (0.58–1.17) 0.27
All strokes or systemic embolism 0.96 (0.60–1.54) 0.87
Ischemic stroke/systemic embolism 1.71 (0.94–3.11) 0.08
Hemorrhagic stroke 0.20 (0.07–0.56) 0.0022
Disabling stroke 0.41 (0.19–0.90) 0.027
Nondisabling stroke 1.79 (0.85–3.77) 0.13
CV or unexplained death 0.59 (0.37–0.94) 0.027
Death from any cause 0.73 (0.54–0.98) 0.035
Any major bleeding 0.91 (0.64–1.29) 0.60
Non–procedure-related major bleeding 0.48 (0.32–0.71) 0.0003

"The reduction in disabling strokes with Watchman serves as a reminder of the differential functional impact of ischemic and hemorrhagic strokes," writes Dr Jacqueline Saw (Vancouver General Hospital, BC) in an editorial accompanying the meta-analysis[2].

Intracranial hemorrhage is a small but daunting accepted OAC risk, "and it is reassuring to observe dramatic reduction with LAA closure," she writes.

"Reduction of cardiovascular and all-cause mortality is a remarkable feat with this device therapy and emphasizes one of the key benefits with LAA closure, which is reduction of major bleeding and associated complications with lifelong OAC administration."

LAA Not the Only Source of Embolism

In clinical practice, it may not be prudent to give up on OAC and antiplatelets entirely in patients with Watchman or any other LAA occluder, some observed.

"There's clearly this issue of benefit from long-term anticoagulation that goes beyond just the left atrial appendage," said Dr Robert W Yeh (Beth Israel Deaconess Medical Center, Boston, MA) a media briefing on the Watchman data.

"So I think it's unrealistic for us to expect that a left atrial appendage occlusion device is going to decrease stroke to the exact same extent as a systemic therapy that decreases stroke, not just in the left atrial appendage but from other sources," he said.

"That is why I think there's growing interest from us and many others about adding an additional, probably smaller dose of an anticoagulant that might address those alternative strokes, in combination with the device."

Kar discloses receiving research grants from and served as a consultant for Abbott Vascular and Boston Scientific, serving on an advisory board for left atrial appendage closure, and serving as a proctor for Boston Scientific. Reddy discloses research grant support from or consulting for Abbott, Biosense Webster, and Boston Scientific. Disclosures for the coauthors are listed in the paper. Stone reports fees or honoraria for consulting or speaking from Matrizyme, Ablative Solutions, Claret, Sirtex, Vascular Dynamics, Miracor, Neovasc, V-wave, Backbeat Medical, Valfix, Therox, and Reva; and equity interest in Qool Therapeutics, Caliber, Aria, Biostar, Medfocus, Micardia, Cagent, Spectrawave, and Guided Delivery Systems. Ellis discloses grant or research support from Abbott Vascular and Boston Scientific; and fees or honoraria from consulting or speaking from the same two companies and Medtronic. Ben-Yehuda discloses fees or honoraria for consulting or speaking from Cardiovalve. Kirtane discloses receiving grant or research support from Abbott Vascular, Abiomed, Boston Scientific; Medtronic, Philips, CSI, Cathworks, Siemens, and ReCor Medical. Gibson reports receiving grant or research support from Angel Medical, Bayer, CSL Behring, Ikaria, Janssen, Johnson & Johnson, and Portola; and fees or honoraria for consulting or speaking from Bayer, the Medicines Company, Boston Clinical Research Institute, CRF, Eli Lilly, Gilead Sciences, Novo Nordisk, Pfizer, and WebMD. Sommer reports receiving grant or research support from AstraZeneca and fees or honoraria for consulting or speaking from Boston Scientific, WL Gore, and St Jude Medical. Saw reports receiving grant support from AstraZeneca, Abbott Vascular, St Jude Medical, Boston Scientific, and Servier; speaker honoraria from AstraZeneca, St Jude Medical, Boston Scientific, and Sunovion; consultancy and advisory board honoraria from AstraZeneca, St Jude Medical, and Abbott Vascular); and proctorship honoraria from St Jude Medical and Boston Scientific. Yeh reports receiving grant or research support from Abiomed and Boston Scientific; and fees or honoraria for consulting or speaking from Abbott Vascular, Boston Scientific, and Medtronic.

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