In stable atherosclerosis, a combination of aspirin plus rivaroxaban provided a similar relative degree of benefit on coronary, cerebrovascular and peripheral endpoints in patients with and without diabetes, a prespecified analysis of the COMPASS trial has shown. It also noted that, given their higher baseline risk, the absolute benefits appeared greater in those with diabetes, including a three-fold greater reduction in all-cause mortality.
The findings were outlined in a virtual presentation by Deepak L. Bhatt, MD, of Brigham and Women’s Hospital Heart and Vascular Center, and a professor of medicine at Harvard Medical School, Boston, at the American College of Cardiology/World Congress of Cardiology’s virtual scientific sessions (ACC.20/WCC Virtual) which was originally scheduled to take place March 28–30 in Chicago. The data were also simultaneously published online in Circulation.
“Diabetes with atherosclerosis either with or without ischemic events is associated with an extremely high rate of cardiovascular death, MI or stroke over just four years. One potential way to address this cardiovascular risk, this residual risk, is with dual pathway inhibition—that is, combining antiplatelet therapy with anticoagulation,” Bhatt explained on a video link. “This concept was tested in the COMPASS trial.”
The main COMPASS (Cardiovascular outcomes for people using anticoagulation strategies) trial demonstrated that aspirin plus rivaroxaban 2.5mg twice daily was superior to aspirin plus rivaroxaban placebo in reducing ischemic events in 27,395 patients with coronary artery disease (CAD) and/or peripheral arterial disease (PAD). The study found a significant reduction in cardiovascular death with dual pathway inhibition, as well as lower all-cause mortality.
In the present prespecified analysis of COMPASS, investigators analyzed the results of rivaroxaban plus aspirin versus aspirin alone in the subgroups of patients with or without diabetes mellitus at baseline.
The primary efficacy endpoint was the composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke. Secondary endpoints included all-cause mortality and all major vascular events (CV death, MI, stroke or major adverse limb events, including amputation). The primary safety endpoint was a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria for major bleeding. There was also a prespecified net clinical benefit of CV death, MI, stroke, fatal bleeding and symptomatic bleeding into a critical organ.
In the overall trial, there were 10,341 patients with diabetes and 17,054 without diabetes. The COMPASS diabetes subanalysis found a consistent and similar relative risk reduction for benefit of rivaroxaban plus aspirin (n=9,152) versus placebo plus aspirin (n=9,126) in patients both with (n=6,922) and without (n=11,356) diabetes for the primary efficacy endpoint (hazard ratio [HR] 0.74, p=0.002, and HR 0.77, p=0.005, respectively, pinteraction=0.77) and all-cause mortality (HR 0.81, p=0.05 and HR 0.84, p=0.09, respectively, pinteraction=0.82). Although the absolute risk reductions (ARR) appeared numerically larger in patients with versus without diabetes, both subgroups derived similar benefit (2.3% vs. 1.4% for the primary efficacy endpoint at three years, pinteraction<0.0001; 1.9% vs. 0.6% for all-cause mortality, pinteraction=0.02; 2.7% vs. 1.7% for major vascular events, pinteraction<0.0001). Because the bleeding hazards were similar among patients with and without diabetes, the prespecified net benefit for rivaroxaban appeared particularly favorable among patients with diabetes (2.7% vs. 1.0%, pinteraction=0.001).
Bhatt also outlined that the findings on the primary outcome of CV death, MI or stroke in those with and without diabetes, either with or without prior ischemic events or with or without revascularization “demonstrated a consistent benefit across all these subgroups of subgroups, with interaction p values that aren’t significant, 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.”
He acknowledged that the diabetes subgroup was not specifically powered to efficacy or safety, but pointed out that the analysis was prespecified “with sufficient power to show a significant reduction in the primary endpoint in the overall trial in [those] with or without diabetes.”
He also pointed that because the trial was stopped early by the data safety monitoring board (DSMB), subgroup analyses were further limited. However, he said, “The independent DSMB felt that the trial needed to be stopped due to overwhelming efficacy, including a reduction in all-cause mortality in the overall trial.”
In conclusion, Bhatt told the conference: “Low-dose rivaroxaban plus aspirin reduced major adverse cardiovascular events in stable atherosclerosis, irrespective of the presence or absence of diabetes, although the absolute risk reductions were numerically larger with diabetes, including a three-fold greater reduction in all-cause mortality. As in the overall [COMPASS] trial, there was a significant increase in major bleeding, but not in fatal or intracranial bleeding. The net clinical benefit when examining irreversible outcomes appeared numerically greater in those with diabetes. Use of dual pathway inhibition with low-dose rivaroxaban plus aspirin is particularly attractive in high-risk patients, such as those with diabetes.”