Three-Year Major Bleeding Risk Same With Watchman or Warfarin

Marlene Busko

December 11, 2015

LA JOLLA, CA — Patients with atrial fibrillation (AF) who received a left atrial appendage closure device (Watchman, Boston Scientific) or stayed on long-term warfarin therapy had similar rates of major bleeding during a mean follow-up of 3.1 years, in pooled analysis of two randomized clinical trials[1]. However, patients who received the device and were able to stop taking warfarin and clopidogrel at 6 months had lower rates of major bleeding from then onward, compared with patients receiving long-term warfarin.

Dr Matthew J Price (Scripps Clinic, La Jolla, CA) and colleagues analyzed bleeding safety data from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation (PROTECT-AF) trial and the follow-up Prospective Randomized Evaluation of the Watchman LAA Closure Device In Patients with Atrial Fibrillation Versus Long Term Warfarin Therapy (PREVAIL) trial, and their findings are published online November 25, 2015 in JACC: Cardiovascular Interventions.

"The favorable effect of [left atrial appendage] closure on long-term bleeding [beyond the procedural period, particularly once adjunctive pharmacotherapy was discontinued] should be considered when selecting a stroke-prevention strategy for patients with nonvalvular AF," Price and colleagues conclude.

However, the finding that the overall risk of bleeding was the same with the device or with long-term warfarin is "disturbing," Dr John A Bittl (Munroe Regional Medical Center, Ocala, FL) writes in an accompanying editorial[2]. "Most cardiologists would have expected reduced bleeding in the patients who were randomized to the device as compared with patients treated with continuous anticoagulation," he clarified to heartwire from Medscape.

Moreover, excluding periprocedural events when evaluating a device is  "questionable," according to Bittl.

He agrees that the cautionary memo issued by the Centers for Medicare & Medicaid Services (CMS) is warranted.

Although the device was approved by the US Food and Drug Administration (FDA) in March (after a lengthy process), in November the CMS issued a memo proposing that "the evidence is sufficient to determine percutaneous left atrial appendage closure therapy using an implanted device is not reasonable and necessary." It is gathering public comment before coming to a decision of whether to cover this device, which is expected in February.

"I would have to agree with Dr John Mandrola that the CMS has got this right," Bittl said.

Is There Less Bleeding?

"Differences in bleeding outcomes between mechanical closure and long-term warfarin therapy could help inform the selection of the appropriate management strategy for stroke prevention in patients with AF," Price and colleagues write.

They analyzed pooled data from PROTECT-AF and PREVAIL from 732 patients who received transcatheter left atrial appendage closure and 382 patients who received long-term warfarin therapy to compare major bleeding (defined as bleeding that was life-threatening or resulted in hospitalization, prolonged hospitalization, substantial disability, or death).

The trials enrolled patients with AF who were eligible for warfarin. Patients who received the device continued on warfarin and aspirin, and at 6 weeks after the procedure, transesophageal echocardiography was performed to see if the left atrial appendage was adequately sealed. If it was, they discontinued warfarin and were treated with aspirin and clopidogrel for 6 months and then indefinite aspirin therapy.

Overall, about 11% of patients in both groups experienced a major bleed.

However, in patients who received the device, 48% of the major bleeding occurred within the first 7 days after randomization (during the periprocedural period), whereas all bleeding in the other patients occurred later.

The patients who successfully received the device and were able to stop all anticoagulant and antiplatelet therapy at 6 months had a lower rate of bleeding between 6 months and 3.1 years, compared with the patients on long-term warfarin therapy.

Major Bleeding Rates, Left Atrial Appendage Closure vs Long-Term Warfarin

Time LAA closure, n/N (%) Long-term warfarin, n/N (%) Rate ratio (95%CI) P
Entire study 79/732 (10.8) 43/382 (11.3) 0.96 (0.66–1.40) .84
>7 d postrandomization–3.1 y 40/682 (5.9) 43/381 (11.3) 0.49 (0.32–0.75) .001
>6 mo postrandomization–3.1 y 19/601 (3.2) 35/360 (9.7) 0.28 (0.16–0.49) <0.001
LAA=left atrial appendage

The post hoc analysis that excluded the periprocedural period is an "artificial analysis," Bittl pointed out. "These analyses were post hoc and therefore are exploratory and hypothesis-generating," the authors admit.

"But there's good news in all this that needs further investigation, [which] is that there is a significant 52% reduction in cardiovascular mortality and a borderline 27% reduction in patients who had been randomized to the Watchman device," Bittl added.

"I think it is important that the Watchman device has been approved and is available for clinical use because there will be a small subset of patients for whom it will be helpful."

Ironically, the device name implies that the device is standing by, watching over the patient, but "now the CMS is playing the role of the watchman and keeping an eye on the safety and efficacy of the device as it gets released into clinical practice," he noted.

Potential Future Research Directions

This analysis does not address the comparative risk of bleeding with novel oral anticoagulants, which have been associated with similar or lower rates of all-cause bleeding compared with warfarin, Price and colleagues write.

A perspective that accompanies the article adds: "Whether a shorter period of postprocedural warfarin or dual antiplatelet therapy could reduce nonprocedural bleeding and improve the postprocedural risk profile of [left atrial appendage] closure deserves further evaluation."

The study was funded by Boston Scientific. Price reports having received consulting and proctoring fees from Boston Scientific, St Jude, and WL Gore; disclosures for the coauthors are listed in the article. Dr Bittl has no relevant financial relationships.

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