Vascular dose of rivaroxaban added to aspirin reduces risk of ischemic events in patients with diabetes and atherosclerosis
Low-dose rivaroxaban plus aspirin reduced the risk of major cardiovascular events in patients with stable atherosclerosis, irrespective of the presence or absence of diabetes.
In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) Diabetes trial, a substudy of the parent COMPASS trial, the absolute reduction in the risk of achieving the primary efficacy endpoint, a composite of cardiovascular death, myocardial infarction (MI), or stroke, was numerically larger in the patients with diabetes than in those without diabetes, said Deepak L. Bhatt, MD, MPH, from Brigham and Women’s Hospital, Boston.
Data from the Reduction of Atherothrombosis for Continued Health (REACH) registry show that, compared with having risk factors alone, the presence of established atherosclerosis raises the risk of future cardiovascular events, and a history of ischemic events raises the risk even more. “The REACH registry taught us that polyvascular disease (ie, concomitant coronary artery disease and peripheral arterial disease or cerebrovascular disease) is a powerful driver of ischemic risk, as is diabetes mellitus,” said Dr. Bhatt.
COMPASS Diabetes tested a strategy of the combination of antiplatelet therapy and anticoagulation in 6,922 patients with diabetes and 11,356 patients without diabetes who were enrolled in the parent COMPASS trial, which included 27,395 patients. In the study, patients were randomly assigned to rivaroxaban at a dosage of 2.5 mg twice daily plus aspirin, 100 mg/day, or placebo plus aspirin.
A significantly lower rate of the primary end point was observed with dual therapy versus placebo plus aspirin both in patients with diabetes (hazard ratio [HR] 0.74; P = .002) and in those without diabetes (HR 0.77, P = .005). The interaction P value was not significant (P = .77), “implying that the benefits of rivaroxaban plus aspirin were similar and consistent in those with and without diabetes,” said Dr. Bhatt. “However, due to the much greater absolute risk that patients with diabetes faced, their absolute risk reduction was numerically larger, 2.3%, vs 1.4% [at 3 years].”
Rate of death from any cause demonstrated a similar pattern, with consistent benefits to dual therapy versus controls in those with diabetes (HR 0.81; P = .05) and without diabetes (HR 0.84; P = .09), with a P value for interaction of .82). As with the primary endpoint, the numerical absolute risk reduction was larger in those with versus without diabetes (1.9%, versus 0.6%), constituting a threefold greater reduction in mortality in the subgroup with diabetes.
On the endpoint of major vascular events, which encompassed CV death, MI, stroke, major adverse limb events, and major vascular amputation, the risk reduction with dual therapy was significant in those both with diabetes and without diabetes, with an HR of approximately 0.73 or 0.74 in both these subgroups, with an interaction P value that was not significant (P = .88). The absolute risk reduction was again numerically larger in those with versus without diabetes, 2.7% versus 1.7%.
As in the overall COMPASS trial, there was a significant increase in major bleeding with dual therapy versus monotherapy in patients with diabetes (HR 1.7; P = .0006) and without diabetes (HR 1.69; P < .0001). There was no significant increase detected in the rates of intercranial or fatal bleeding either in those with or without diabetes.
The net clinical benefit, an end point that combines cardiovascular death, MI, stroke, fatal bleeding, or symptomatic bleeding into a critical organ, favored dual therapy in patients with and without diabetes, though the absolute risk reduction was again numerically larger in patients with diabetes versus those without diabetes (2.7% versus 1.0%).
“Subgroup analysis indicated that the benefit of dual pathway inhibition on the primary end point was not predicated on a history of ischemic events or revascularization, but rather on the presence of atherosclerosis,” said Dr. Bhatt.
The diabetes subgroup was not specifically powered for safety or efficacy, Dr. Bhatt noted as a limitation, and early stopping of the trial further limited the power of subgroup analysis, “but the independent Data Safety Monitoring Board felt that the trial needed to be stopped due to overwhelming efficacy, including a reduction in all-cause mortality in the overall trial.”
Putting the data in context, Dr. Bhatt said that he wouldn’t add rivaroxaban to aspirin in patients who have had bleeding episodes on aspirin alone or other regimens more intensive than aspirin monotherapy.
“In patients that haven’t bled before, in particular if they’ve been exposed to more intense antithrombotic therapy, say dual antiplatelet therapy, I think those sorts of patients are good candidates for this vascular dose of rivaroxaban,” he said, cautioning that “there’s no free lunch” in that no antithrombotic regimen that has been shown to reduce the risk of ischemic events has been free of an increase in the incidence of major bleeding.
“The two haven't been successfully divorced,” he said. “So I think there needs to be careful patient assessment when initiating these forms of more potent, prolonged antithrombotic therapy and reassessment over time.”
COMPASS Diabetes is published in: Bhatt DL, Eikelboom JW Connolly SJ. The role of combination antiplatelet and anticoagulation therapy in diabetes and cardiovascular disease: insights from the COMPASS trial. Circulation 28 Mar 2020. doi:10.1161/CIRCULATIONAHA.120.046448. The REACH registry is published in: Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010; 304(12):1350-1357. doi:10.1001/jama.2010.1322. COMPASS was funded by Bayer. Dr. Bhatt has disclosed the following financial interests: Consultant Fees/Honoraria: Elsevier Practice Update Cardiology, Medtelligence/WebMD, MJH Life Sciences, WebMD; Officer, Director, Trustee, or Other Fiduciary Role: TobeSoft; Other: Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Journal of Invasive Cardiology, Medscape Cardiology, Merck & Co., Inc., PhaseBio, PLx Pharma, Regado Biosciences, Slack Publications/Cardiology Research Foundation Research/Research Grants Abbott, Afimmune, Amarin, Amgen Inc., Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Inc, Bristol Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly and Company, Ethicon, FlowCo, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, Novo Nordisk Inc., Pfizer Inc, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, The Medicines Company.