Cautions Raised Against Off-Label DOACs to Clear Left Ventricular Thrombi

April 28, 2020

The newer class of oral anticoagulants that have been supplanting the traditional mainstay warfarin for a variety of indications may be inferior for at least one use — getting rid of left ventricular (LV) thrombus to reduce thromboembolic risk.

In a retrospective, three-center experience of more than 500 patients with LV thrombi, the adjusted risk for stroke or systemic embolism was more than doubled in those treated with a direct oral anticoagulant (DOAC) compared with warfarin.

The guidelines prefer using warfarin over DOACs in that setting, though without a lot of supporting clinical trial evidence, and none of the DOACs are approved for treatment of LV thrombi. Still, 44% of patients in the study who received an OAC were given one of the newer agents off-label for at least part of their treatment course.

The study, even with its limitations, argues against the apparently common assumption that DOACs are at least as effective and safe as warfarin for indications beyond those for which they are approved, such as stroke reduction in atrial fibrillation (AF) or treatment of deep-vein thrombosis (DVT), concludes a report published April 22 in JAMA Cardiology.

"This isn't the definitive word on it, but intuitively I didn't think there'd be a difference between warfarin and the DOACs. I thought if anything, if we saw a difference, it would be in favor of DOACs, so we were shocked," lead author Austin A. Robinson, MD, University of Virginia Health System, Charlottesville, Virginia, told theheart.org | Medscape Cardiology.

The findings underscore the need for high-quality randomized trials to explore whether, for this indication, there should be a major role for the DOACs, he said, referring to the factor Xa inhibitors rivaroxaban (Xarelto, Bayer), apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), and edoxaban (Savaysa, Daiichi Sankyo) and the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim).

But, for now, "there's already an established standard for the treatment of LV thrombi, and that's warfarin. So in practice I think it raises the bar for using DOACs off-label for LV thrombi," Robinson said.

"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 off-label use of DOACs tempting," observes an accompanying editorial.

"Nonetheless, 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," agree Ann Marie Navar, MD, PhD, Duke Clinical Research Institute, Durham, North Carolina, and Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York City. The study also "provides compelling evidence that such a trial is overdue."

Meanwhile, they write, "patients should be made aware that DOACs are not US Food and Drug Administration-approved for left ventricular thrombi and clinicians should be cautious in prescribing DOACs for off-label indications."

Of the study's 514 patients with LV thrombi by echocardiography who were seen between 2013 and 2019 at three tertiary care medical centers, the report notes, 300 were treated with warfarin and 185 received a DOAC off label.

Of those, 236 patients received warfarin only, 121 received only a DOAC, and 64 at some point crossed over from one type of treatment to the other. In addition, 93 patients received either a parenteral anticoagulant or no anticoagulant.

"The most common cause of switching therapy from warfarin to a DOAC was convenience," the report notes, "whereas the most common cause of switching therapy from a DOAC to warfarin was cost."

Apixaban was the DOAC of choice three-fourths of the time, rivaroxaban was number two, and only nine patients received dabigatran; edoxaban wasn't widely available at the time.

There were 36 ischemic strokes and 18 systemic emboli during a median follow-up of 351 days, for an event rate of 0.065 per patient-year. The adjusted risk was significantly increased in patients taking a DOAC, at a hazard ratio (HR) of 2.64 (95% confidence interval [CI], 1.28 - 5.43; P = .01).

A prior stroke or systemic embolic event was a predictor of such events on OAC, HR 2.07 (95% CI, 1.17 - 3.66; P = .01), but demographics, body mass index, history of AF or DVT, antiplatelet therapy, LV ejection fraction, thrombus shape, and thrombus mobility were not predictive.

The report did not compare bleeding events.

Follow-up echocardiograms were obtained in 69.3% of patients, and 62.3% overall had a second follow-up echo. Of the 356 patients with at least one follow-up echocardiogram, 65% showed LV thrombus resolution. Thrombus resolution wasn't associated with choice of OAC agent; the adjusted HR for a DOAC vs warfarin was 1.08 (95% CI, 0.78 - 1.50; P = .64).

Robinson and his colleagues propose a few explanations for the finding of greater stroke or systemic embolism risk on DOACs. One, he said in an interview, is the possibility that the DOACs were actually more effective at dissolving LV thrombi, but in a way — especially for certain shapes of thrombus — that makes embolism more likely. If anticoagulation dissolves the stalk faster than the thicker head of the thrombus, "that could facilitate embolization. So maybe paradoxically, really effective anticoagulation can be worse for LV thrombi," Robinson said.

Another possibility: warfarin and the DOACs all vary in their anticoagulant properties, and patients with LV thrombi tend to have other vascular risk factors, he noted. So, "it could be that the stroke and emboli we're seeing aren't even from the LV thrombus, that they're unrelated, coming from some other source in the vasculature that's differentially suppressed by warfarin vs the DOACs."

That would make LV thrombus a marker not only of cardiac risk, "but also of vascular risk for having stroke. And that risk for stroke or systemic embolism persists and isn't necessarily tied to the thrombus that is or was in the left ventricle," he said. "Maybe it's more than what you see on the echo."

Supporting that view, 8.7% of patients in whom thrombus was resolved at a follow-up echocardiogram experienced a stroke or systemic embolic event within the next 30 days.

Also, the event curves showing a significant advantage for DOACs vs warfarin over the long term didn't actually start to separate substantially until several months after the thrombus was first detected. 

The findings, therefore, "should be interpreted with caution," write Navar and Mehran. "The signal for excess stroke emerged late, long after the generally accepted window of time needed for anticoagulation. Whether these are late sequelae, unresolved left ventricular thrombi, or an artifact of a nonrandomized study design cannot be known, especially in this study of only 3 centers."

Robinson reported no relevant financial relationships; disclosures for the other authors are in the report. Navar discloses receiving grants and personal fees from Amarin, Amgen, Regeneron, Janssen, and Sanofi; and personal fees from Novo Nordisk, Esperion, Boehringer Ingelheim, Pfizer, Esperion, Novartis, The Medicines Company, and AstraZeneca. Mehran discloses receiving grants/research institutional funding from AstraZeneca, Medtronic, Janssen, Bayer, Beth Israel Deaconess, CSL Behring, Daiichi Sankyo, Novartis Pharmaceuticals, OrbusNeich, Novartis, Sanofi/ Regeneron, and Boston Scientific; personal fees from Sanofi, Medscape/WebMD, Roivant Sciences, Siemens Medical Solutions Boston Scientific, Janssen Scientific Affairs, and Medtelligence (Janssen Scientific Affairs); grants, personal fees, and other support from Abbott; grants and other support from Bristol-Myers Squibb; and personal fees to her spouse from Abiomed and The Medicines Company; having consulting relationships with Idorsia Pharmaceuticals Ltd, Regeneron Pharmaceuticals, and Spectranetics/Philips/Volcano; serving on a data safety and monitoring board for Watermark Research Partners; and holding equity in Claret Medical and Elixir Medical.

JAMA Cardiol 2020. Published online April 22. ReportEditorial 

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