Half-Dose DOACs Cut Bleeding, Thrombus Risk Post-Watchman LAA Closure

October 15, 2021

In a potential case of "less is more," an antithrombotic regimen with only short-term antiplatelets and long-term reliance on direct oral anticoagulants (DOACs) — but at half the standard dosages — led to an almost 90% drop in risk of thromboembolic and major bleeding events after transcatheter left-atrial appendage (LAA) closure, in an observational study.

Meanwhile, the long-term half-dose DOAC regimen in patients with a history of atrial fibrillation (AF) and LAA closure seemed to shield against device-related thrombosis (DRT) at least as well as a standard oral anticoagulation (OAC) regimen with long-term antiplatelets.

The novel half-dose DOAC regimen, given initially with antiplatelets but continued indefinitely, had been occasionally but successfully used in practice as an alternative to full-dose OAC and antiplatelets in patients with nonvalvular AF, Domenico G. Della Rocca, MD, Texas Cardiac Arrhythmia Institute at St. David's Medical Center, Austin, told theheart.org | Medscape Cardiology.

The experience inspired the current prospective study, launched at three centers toward the end of 2014, that compared patients implanted with Watchman (Boston Scientific) LAA closure devices who were put on the half-dose or a standard regimen.

The results, published October 13 in JACC: Cardiovascular Interventions with Della Rocca as lead author, "confirmed what we were thinking," he said, "that what makes the atrium prone to develop a thrombus on the device is not the device itself, but activation of coagulation related to remodeling of the left atrium."  

Della Rocca referred to evidence that LAA occlusion may trigger activation of the coagulation cascade without much platelet activation, especially, perhaps, in patients with an AF-related myopathy that promotes thrombogenic conditions in the atrium.

That would help explain the limitations of antiplatelet agents in this setting as well as suggest that the half-dose regimen's efficacy may well extend to patients implanted with other transcatheter LAA closure devices, such as the Amplatzer Amulet (Abbott), he proposed, although that has yet to be studied.  

Meanwhile, Della Rocca said, the current study suggests that OAC given indefinitely at half the standard dosage provides antithrombotic protection without raising — and perhaps while cutting — the risk for major bleeding complications.

They Made Sense at the Time

Although antiplatelet agents alone don't prevent thromboembolic stroke in AF, they were empirically selected as the antithrombotic backup in the early days of transcatheter LAA closure after it became clear the devices wouldn't be enough, observed Jonathan P. Piccini, MD, MHS, Duke University Medical Center, Durham, North Carolina, who wasn't part of the current report.

"Maybe that made sense at the time the studies were designed," but the field has since learned much more about the limitations of both antiplatelets and the closure devices, he told theheart.org | Medscape Cardiology. The closure devices "have been super helpful for patients, but there are still challenges: formation of thrombus on the device; the need for some antiplatelet therapy, which predisposes to bleeding; and a residual risk of thromboembolic events," Piccini said.

"What's great about the half-dose DOAC is that it appears to win on each of those major challenges in patients with an occluder."

All of the study's 555 patients with successful Watchman implantation were initially put on OAC along with antiplatelets. But about 36% of the cohort received OAC in the form of a DOAC at half the standard dosage, maintained over the long term but accompanied for the first 45 days by 81 mg aspirin.

The remainder were put on standard management initially featuring either a DOAC or warfarin plus dual antiplatelet therapy (DAPT); OAC was withdrawn after 6 months and the patient continued on aspirin only. That group saw almost 10 times the risk of the primary endpoint — DRT, thromboembolic events, or major bleeding — compared with those on the half-dose regimen.

"These results are intriguing and suggest that [half-dose DOAC] might be an effective long-term prevention against DRT with a minimum of bleeding issues, and that this regimen is superior to an antiplatelet-based strategy," states Jens Erik Nielsen-Kudsk, MD, DMSc, Aarhus University Hospital, Aarhus, Denmark, in an editorial accompanying the Della Rocca report.

"Although the results are remarkable and with potential important clinical implications, there are also important limitations to consider," Nielsen-Kudsk writes. They include its observational nature, encouraging bias from possible selection of low-risk cases for half-dose DOACs, and the exclusion of patients with renal failure, which can predispose to DRT.

Half-Dose Factor Xa Inhibitors

Of the entire cohort — who had a history of nonvalvular AF and stroke risk factors earning a CHADS2 score ≥2 or CHA2DS2-VASc score ≥3 but no indication for long-term antiplatelet therapy — 357 went on the standard regimen and 198 the half-dose DOAC regimen, at their physicians' discretion.

Of those taking half doses, 174 took apixaban (Eliquis) 2.5 mg twice daily and 24 rivaroxaban (Xarelto) 10 mg/day. Baseline characteristics were similar between the two groups, the report states.

Over a median follow-up of 13 months, 2.1% of overall population developed DRT, all of whom were in the standard-care group (3.4% standard dose vs 0% half-dose, P = .009).

The composite primary endpoint consisted of DRT, thromboembolic events (ischemic stroke, transient ischemic attack, or peripheral thromboembolism), and major bleeding events (severe or life-threatening bleeding or moderate bleeding). It occurred in 9.5% and 1% of patients in the standard-care and half-dose groups, respectively, for a hazard ratio of 9.8 (95% CI, 2.3 - 40.7, P = .002).

Thromboembolic events developed in 3.1% and 0.5% of standard-care and half-dose patients, respectively (P = .046) and major bleeding in 3.9% and 0.5%, respectively (P = .04).

"This is really exciting," Piccini said. DOACs may be state-of-the-art for OAC today, but other novel oral anticoagulants, including the factor XI inhibitors, are on the horizon for thromboembolic protection, at least for some patients.

"The concept of treating stroke risk with just one intervention may become a thing of the past," he said. Soon it may be that for any individual patient, the most appropriate antithrombotic therapy will be combination of measures that most minimizes the stroke risk. "And with this study, it looks like the first chapter of that story may very well be half-dose DOAC plus a left-atrial appendage occlusion device for some patients."

Della Rocca has a co-leadership role in the ongoing FADE-DRT trial, a randomized comparison of patients receiving Watchman FLX devices plus standard antithrombotic therapy, a half-dose DOAC regimen, or a strategy of antithrombotics guided by genetic markers of clopidogrel resistance.

Della Rocca has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Piccini has disclosed support from the National Heart, Lung, and Blood Institute and research grants from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips; and serving as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, Myokardia, Nocturnal Product Development, Sanofi, Philips, and Up-to-Date.

Nielsen-Kudsk discloses receiving a research grant from Novo Nordic Research Foundation and serving as an investigator and proctor for Abbott and Boston Scientific.

JACC: Cardiovascular Interventions. Published online October 13, 2021. Abstract, Editorial

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