DOAC Don’ts: New Review Clarifies When Not to Use Direct Oral Anticoagulants

The advent of the non-vitamin K antagonist, fixed-dose direct oral anticoagulants (DOACs) was welcomed by patients and doctors alike, both for dispensing with the routine INR monitoring needed with warfarin and for offering an edge in terms of efficacy or safety in certain settings. But as a new state-of-the-art review points out, there are specific scenarios in which DOACs have never proved beneficial or may actually be more dangerous.

“The goal [of the paper] was by no means to be anti-DOAC,” senior author Behnood Bikdeli, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “There’s a large portion of people either with A-fib who require anticoagulation or with VTE, and potentially even for some other indication, who would truly benefit from DOACs, because in many scenarios, they're at least as effective and not infrequently they are safer. Without question, they're more convenient for patients and for clinicians. So there's a lot of good that they do, but that doesn't mean that they get carte blanche for every single condition, every single indication.”

This review, Bikdeli continued, aims to pinpoint not only the scenarios where the evidence supports the use of a DOAC, but also those where a DOAC has been found to be ineffective or harmful. A third section details the situations or indications that urgently need more research.

The paper, led by Antoine Bejjani, MD (Brigham and Women’s Hospital), was published online ahead of the January 23, 2024, issue of the Journal of the American College of Cardiology.

Dos and Don’ts for DOACs

Randomized clinical trials, backed up by subsequent professional guidelines, support using DOACs for stroke prevention in patients with atrial fibrillation (AF), including those who have had a recent ACS or PCI. They are also indicated for AF and many types of concomitant valve disease—with some notable exceptions. Similarly, DOACs are recommended for acute and extended-duration management in patients with venous thromboembolism, as well as for patients with cancer-associated thrombosis. Also, the COMPASS trial supported a role for low-intensity rivaroxaban in patients with stable atherosclerotic CVD, and the VOYAGER PAD trial showed that the DOAC had benefits in patients who’d had a recent peripheral-artery revascularization.

But as the review carefully spells out, DOACs have come up short in other medical settings, including mechanical heart valves, rheumatic AF, TAVI, embolic stroke of undetermined cause (ESUS), left ventricular assist devices, heart failure with reduced LV systolic function without AF, and thrombotic antiphospholipid syndrome (APS). Indeed, this last condition was the focus of a meta-analysis, published earlier this month by many of the same investigators, indicating that DOACs increase the risk of adverse events in patients with thrombotic APS.

That inspired this more comprehensive review, said Bikdeli. The multidisciplinary team assembled to conduct it, he said, identified the areas above where there is at least some evidence, including randomized trials, pointing to the potential for inefficacy or harm with DOACs.

For the situations where DOACs are contraindicated, a dedicated section of the review paper offers up what’s known about the mechanisms driving the lack of efficacy and potential hazards, Bikdeli noted.

A third section of the document seeks to illuminate the areas where the benefit of DOACs remains uncertain, typically due to a lack of dedicated trials, small trial sizes, or inconclusive results. These include left ventricular thrombus, catheter-associated DVT, cerebral venous sinus thrombosis, and splanchnic vein thrombosis. Of these, Bikdeli told TCTMD, he suspects LV thrombus is an area where DOACs may yet prove beneficial. Small trials have suggested a benefit to DOAC use in LV thrombus and an American Heart Association statement has offered “cautious” support. He himself is a senior investigator for REWARF-STEMI, which is comparing warfarin versus rivaroxaban for LV thrombus after STEMI; results will be released later this spring.

Bikdeli also highlighted the need for more research into the role of DOACs in catheter-induced DVT, an area where, to the best of his knowledge, no trials are currently underway but the population of patients at risk is large.

A Terrific Resource

Commenting on the paper for TCTMD, Jan Steffel, MD (University Heart Center Zurich, Switzerland), called it a “terrific document . . . . It’s from a large group of real experts in this field, and I think it adds quite a lot to our understanding and our practical management of patients.”

Steffel was the lead author of the 2021 European Heart Rhythm Association practical guide on the use of DOACs in patients with AF. This, he said, was an attempt to answer practical questions about anticoagulant usage and dosage in everyday scenarios—a patient with declining kidney function, for instance, or one scheduled for PCI or TAVI.

This new JACC review, he said, “is taking exactly the opposite approach. They are saying: when should we not be using these? And I think this is just as important. Here we're really talking about the don’ts.”

Here we're really talking about the don’ts. Jan Steffel

In particular, said Steffel, the excellent graphics summarizing the evidence in a quick glance, as well as a decision-tree graphic for all scenarios, will be very useful to practicing physicians uncertain of whether a DOAC can be used in a given setting. “And, what they really point out quite well is the areas of uncertainty and ambiguity,” he added.

Also made clear are the areas where new trials are urgently needed, even as the drugs themselves are coming off patent. These decisions, Steffel said, “affect a lot of patients. . . . It is up to us as a medical and scientific community to not let these patients be left behind. We need to continue to invest in research [to learn] how to treat them best.”

Bikdeli, too, urged physicians to keep their patients in mind when digesting this review. “We also have to empower patients with this information,” he said. “If it's somebody with bread-and-butter, high-risk A-fib or bread-and-butter venous thrombosis, I think in many cases it's a no-brainer: all in all, so long as patients are able to afford DOACs, they provide an equally safe, potentially safer option with similar efficacy, and in some cases superior efficacy. But if there are those more nuanced cases, or if it's a case with a red flag, as we have in the paper, in most of those, the DOAC should be excluded. And if it's one of those that are kind of gray areas, at the very least, I suggest that my colleagues discuss the uncertainty with their patients.”

It may be that patients, once informed of the lack of evidence, may still chose to take a DOAC because of the potential benefits. “That's completely reasonable,” said Bikdeli. “But one of the challenges, in my humble perspective, is some colleagues are unaware of the uncertainty we outlined in this paper. And because of that, they do not share it with the patients. The patients are in the dark.”