Diabetes May Boost Benefits of COMPASS Dual Antithrombotic Approach

Among patients with stable CAD or PAD, those with diabetes appear to derive greater absolute benefits from a combination of low-dose rivaroxaban (Xarelto; Bayer/Janssen) and aspirin compared with aspirin alone, a prespecified analysis of the COMPASS trial shows.

Though diabetes status did not significantly influence treatment effects, patients with versus without the condition had numerically greater reductions in a number of adverse clinical outcomes, including MACE (CV death, MI, or stroke) and all-cause death, according to Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA).

The increase in major bleeding seen with the addition of rivaroxaban, however, was no greater in patients with diabetes, he reported during the virtual American College of Cardiology (ACC) 2020 Scientific Session. The findings were published simultaneously online in Circulation.

Bhatt noted that neither fatal nor intracranial bleeding was increased with the addition of rivaroxaban and that net clinical benefit—which takes into account irreversible ischemic and bleeding outcomes—favored dual therapy, regardless of diabetes status.

“Use of dual pathway inhibition with low-dose rivaroxaban plus aspirin is particularly attractive in high-risk patients, such as those with diabetes,” Bhatt concluded.

Dual Pathway Inhibition in Diabetes

Prior data, including those from the REACH registry, have shown that polyvascular disease and diabetes are powerful drivers of ischemic risk, Bhatt said. One strategy for addressing that risk is dual pathway inhibition with an anticoagulant and an antiplatelet.

That was tested in the COMPASS trial, which enrolled 27,395 patients with stable CAD or PAD, or both, and showed that combining rivaroxaban 2.5 mg (the vascular dose) twice daily plus aspirin 100 mg once daily reduced MACE and mortality, while increasing ISTH major bleeding, compared with aspirin alone. In this new analysis, the investigators focused on the 6,922 patients with diabetes at baseline and 11,356 without diabetes.

Diabetes status did not significantly influence any of the outcomes examined (P = NS for interaction for all), although—stemming from their overall higher risk of adverse outcomes—patients with diabetes had numerically greater absolute reductions in adverse clinical outcomes. ISTH major bleeding was increased with dual pathway inhibition to a similar extent in patients with and without diabetes.

Within the diabetes group, the benefits of low-dose rivaroxaban plus aspirin did not vary significantly based on the presence or absence of prior ischemic events, revascularization, or both, “suggesting that the benefits of dual pathway inhibition are not predicated on a history of prior ischemic events or revascularization per se, but rather on the presence of atherosclerosis,” Bhatt said.

‘Could Be a Very Valuable Therapy’

A panel discussion after Bhatt’s presentation revolved around the place of dual pathway inhibition with low-dose rivaroxaban and aspirin in the secondary prevention toolbox for patients with stable vascular disease and multiple risk factors. Which agent to add next is something physicians ponder all the time, Bhatt said, and “in that patient that has multiple things that are out of whack . . . I usually focus on the number that is most out of kilter and try to remember not to forget everything else.”

The challenge with adding low-dose rivaroxaban to aspirin is that there is no single test that would prompt it, he pointed out. “Basically the doctor has to remember to do it. And there, what I would do in that patient—who typically would be on aspirin in this stable setting—is see: are they at low bleeding risk? Are they still at high ischemic risk despite control of all their other risk factors? And if the answer is yes, again making sure they are at low bleeding risk, I would add this vascular dose of rivaroxaban.”

I hope [this study] helps get rivaroxaban at this vascular dose used more often. Deepak Bhatt

Session moderator B. Hadley Wilson, MD (Sanger Heart and Vascular Institute, Charlotte, NC), asked Bhatt whether these results in the diabetes subgroup would have an impact on adoption of dual pathway inhibition, which hasn’t gained a lot of traction, at least in the cardiology community.

Bhatt said the PAD and vascular medicine communities have started using it, adding that the potential pool of patients who would be eligible in the stable CAD population is substantial.

“I realize in terms of just initiating new therapies, incrementally adding more therapies, financial cost of therapies, you know that’s not going to happen, at least while [rivaroxaban is] a branded drug. Once it goes generic then that might be a different story,” Bhatt said. Bleeding risk remains a consideration as well, he continued, “so I do think it’s important to identify patients that are at really high ischemic risk and focus these sorts of therapies that have bleeding hazard, that have financial cost, on those that are most likely to derive large absolute risk reductions.”

That would include patients with diabetes, Bhatt indicated. “I hope [this study] helps get rivaroxaban at this vascular dose used more often.”

Speaking with TCTMD, Wilson predicted the study “will, I think, further highlight that [this approach] does have an important role in these patients with diabetes and vascular disease, and that we need to really look at this and think about this with our patients in this higher-risk category. This could be a very valuable therapy to help reduce these complications in this higher-risk group.”

The analysis “may really bring front and center to the cardiology community the importance of this dual therapy,” not only for patients with diabetes but also perhaps for those who have vascular disease but lower levels of overall risk, he added.

The bleeding risk associated with adding low-dose rivaroxaban is a consideration, though the benefits in terms of reductions in ischemic risks outweigh that concern, Wilson said.

This study, he said, “will help cardiovascular clinicians throughout the world rethink the value of this dual therapy—rivaroxaban low dose and aspirin—in these patients.”