Researchers suggest off label use of direct oral anticoagulants for LV thrombi needs more study

Treatment with direct oral anticoagulants (DOACs) carried a greater risk of stroke or systemic embolism (SSE) versus warfarin, challenging “the assumption of DOAC equivalence,” researchers reported.

In a multicenter study of anticoagulation strategies for left ventricular (LV) thrombi, a higher risk of SSE was significantly associated with DOAC treatment versus warfarin in a univariable analysis (hazard ratio 2.71, 95% CI 1.31-5.57, P=0.01), according to Austin A. Robinson, MD, of the University of Virginia Health System in Charlottesville, Virginia, and co-authors.

Prior SSE was also significantly associated with SSE (HR 2.13, 95% CI 1.22-3.72, P=0.01), they reported in JAMA Cardiology.

The findings held up in multivariable analysis, with a higher SSE risk for anticoagulation with DOAC versus warfarin (HR 2.64, 95% CI 1.28 to 5.43, P=0.01). Once again, prior SSE also remained significantly associated with SSE (HR 2.07, 95% CI 1.17 to 3.66, P=0.01).

“These results challenge the assumption of DOAC equivalence with warfarin for LV thrombi and highlight the need for prospective randomized clinical trials to determine the most effective treatment strategies for LV thrombi,” the authors wrote.

Robinson and co-authors also noted that among the “412 patients treated with an oral anticoagulant…43.9% used an off-label DOAC for at least part of their treatment course.”

Indeed, the “ease of dosing and lack of requirement for dietary restrictions or daily monitoring, combined with the strength of data in atrial fibrillation and venous thromboembolic disease, makes the off-label use of DOACs tempting,” pointed out Ann Marie Navar MD, PhD, of the Duke Clinical Research Institute in Durham, N.C., and Roxana Mehran, MD, of the Icahn School of Medicine at Mount Sinai in New York City, in an editor’s note accompanying the study.

They highlighted that a “signal for harm…persisted despite multiple analytic approaches to adjust for confounding by treatment selection and across multiple subgroups, including by causative mechanism of cardiomyopathy and comorbid atrial fibrillation.”

However, they also called for caution when interpreting the results. First, “the signal for excess stroke emerged late, long after the generally accepted window of time needed for anticoagulation,” adding that the delay may be due to “late sequelae, unresolved left ventricular thrombi, or an artifact of a nonrandomized study design.”

While Robinson’s group conducted the research at only a trio of centers, Navar and Mehran acknowledged that “this study begs for better understanding of the off-label use of DOACS and prompts a call for larger studies to further evaluate this observation.”

The current study was part of the Retrospective Evaluation of DOACs and Vascular Endpoints of Left Ventricular Thrombi (RED VELVT) observational study.

The authors retrospectively identified 514 patients (279 men; mean age 58.4 years; majority white) with echocardiogram-diagnosed LV thrombi at three academic medical centers. Patients were treated from October 2013 to March 2019. Baseline clinical and imaging information was recorded, along with duration and timing of anticoagulation regimens.

In the study cohort, 300 patients received warfarin and 185 received a DOAC, with apixaban topping the list (n=150), followed by rivaroxaban (Xarelto), and dabigatran (Pradaxa). However, 64 patients switched treatment between these groups, leaving 236 warfarin-only patients and 121 DOAC-only patients.

The authors reported the most common cause of switching therapy from warfarin to a DOAC was convenience (19.2%), while the most common cause of switching therapy from a DOAC to warfarin was cost (31.6%).

Embolic events were assigned as a composite outcome of clinically documented SSE, and patients who had not experienced an SSE by medical record review were contacted by telephone for final ascertainment of events. Median follow-up was 351 days.

The authors found that for a combined end point of death or SSE, treatment with a DOAC versus warfarin was significantly tied to one or the other (HR 1.55, 95% CI 1.05-2.30, P=0.03) in an unadjusted Cox proportional hazards regression model.

Robinson’s group offered some possible reasons for the higher rate of vascular events with DOAC treatment, such as the possibility that different classes of DOACs possess differing levels of effectiveness for LV thrombi treatment.

Study limitations include its retrospective nature and lack of randomization, as well as the absence of information on dosing, adherence to DOACs, or time therapeutic range for warfarin treatment.

Still, the authors noted that the current results offered more data than other retrospective studies addressing DOACs for LV thrombus, including a 2019 single-center study by Robinson and colleagues.

“None [of the previous studies] has allowed for assessment of robust differences between DOACs and warfarin because they were limited to a single-center design, small numbers of patients…shorter follow-up period…and, most important, very few SSE events” at no more than five, they wrote. “By contrast, the present study is the largest and only multicenter study to date…evaluating the use of DOACs to reduce embolic events in LV thrombi.”

  1. Anticoagulation with direct oral anticoagulants (DOACs) was associated with a higher risk of ischemic stroke and systemic emboli compared with standard-of-care warfarin.

  2. Off-label use of DOACs for left ventricular thrombi should be prescribed with caution until clinical trial data comparing their use to warfarin is available.

Shalmali Pal, Contributing Writer, BreakingMED™

The study was funded by NIH.

Robinson reported grants from the NIH. Co-authors reported support from, or relationships with, Medtronic, Siemens Healthineers, American Heart Association, Siemens Healthcare, and Heart Flow.

Navar and Mehran reported serving as JAMA Cardiology associate editors.

Navar reported support from, or relationships with, NIH, Amarin, Amgen, Regeneron, Janssen, and Sanofi, Novo Nordisk, Esperion, BI, Pfizer, Esperion, Novartis, The Medicines Company, and AstraZeneca.

Mehran reported support from, or relationships with AstraZeneca, Medtronic, Janssen, Bayer, Beth Israel Deaconess, CSL Behring, DSI, Novartis Pharmaceuticals, OrbusNeich, Novartis, Sanofi/ Regeneron, Boston Scientific, Sanofi, Medscape/WebMD, Roivant Services, Siemens Medical Solutions Boston Scientific, Janssen Scientific Affairs, and Medtelligence (Janssen Scientific Affairs), Abbott, Bristol-Myers Squibb, Abiomed, The Medicines Company, Idorsia Pharmaceuticals, Regeneron Pharmaceuticals, and Spectranetics/Philips/Volcano Corp.

Cat ID: 102

Topic ID: 74,102,730,102,206,308,745,914,192,925