Literature Review

Combination of Rivaroxaban and Aspirin Improves Cardiovascular Outcomes

Although the combination increases the risk of major bleeding, its net clinical benefit is greater than that of aspirin.


 

Compared with aspirin alone, a regimen of rivaroxaban plus aspirin is associated with better cardiovascular outcomes among patients with stable atherosclerotic vascular disease, according to research published August 27 in the New England Journal of Medicine. Although the combination increases the risk of major bleeding events, it has greater net clinical benefit than aspirin alone, said the investigators.

John W. Eikelboom, MBBS
“Even small improvements in the effectiveness of treatments that prevent stroke and heart attack are important, because cardiovascular disease is very common,” said John W. Eikelboom, MBBS, Associate Professor of Hematology and Thromboembolism at McMaster University in Hamilton, Canada. The treatment effect in the current study was “unexpectedly large,” he added.

COMPASS: An International Trial

“Efforts to improve aspirin have focused primarily on combining aspirin with another antiplatelet drug or replacing aspirin with another antiplatelet drug, but this [tactic] has had only limited success,” said Dr. Eikelboom. He and his colleagues conducted the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, a double-blind study to evaluate whether rivaroxaban, a selective direct factor Xa inhibitor, either alone or in combination with aspirin, would be more effective than aspirin alone for secondary cardiovascular prevention.

The study took place at 602 centers in 33 countries. Eligible patients met the criteria for coronary artery disease, peripheral arterial disease, or both. Among the exclusion criteria were high bleeding risk, recent stroke or previous hemorrhagic or lacunar stroke, severe heart failure, and advanced stable kidney disease. During a run-in phase, participants received a rivaroxaban-matched placebo twice daily and aspirin (100 mg/day). Participants who adhered to this regimen were randomized in equal groups to rivaroxaban (2.5 mg bid) plus aspirin (100 mg/day), rivaroxaban (5 mg bid) plus placebo once daily, or aspirin (100 mg/day) plus placebo twice daily.

The primary efficacy outcome was the composite of cardiovascular death, stroke, or myocardial infarction. The main safety outcome was a modification of the International Society on Thrombosis and Hemostasis criteria for major bleeding. The investigators intended to continue the trial until at least 2,200 participants had a confirmed primary efficacy outcome. They planned formal interim analyses of efficacy for when 50% and 75% of primary efficacy events had occurred.

Study Was Stopped Early for Efficacy

The investigators enrolled 27,395 participants into the trial. The population’s mean age was 68.2, and 22.0% of participants were women. The mean systolic blood pressure was 136 mm Hg, the mean diastolic blood pressure was 78 mm Hg, and the mean total cholesterol level was 4.2 mmol/L. Having observed a consistent difference in the primary efficacy outcome in favor of rivaroxaban plus aspirin, the independent data and safety monitoring board recommended early termination of the study at the first formal interim analysis for efficacy.

The rate of primary outcome events was 4.1% (379 patients) in the rivaroxaban-plus-aspirin group, 4.9% (448 patients) in the rivaroxaban group, and 5.4% (496 patients) in the aspirin group. Compared with aspirin alone, rivaroxaban plus aspirin reduced the risk of the primary outcome by 24%. Rivaroxaban alone reduced the risk of the primary outcome by 10%, compared with aspirin alone, but this result was not statistically significant.

The rate of major bleeding events was 3.1% (288 patients) in the rivaroxaban-plus-aspirin group and 1.9% (170 patients) in the aspirin-alone group. Compared with aspirin alone, rivaroxaban plus aspirin increased the risk of major bleeding by 70%. Most of the excess major bleeding occurred in the gastrointestinal tract. The researchers saw no significant between-group difference in the rates of fatal bleeding, intracranial bleeding, or symptomatic bleeding into a critical organ. The rate of serious adverse events was 7.9% (721 patients) in the rivaroxaban-plus-aspirin group, 7.7% (702 patients) in the rivaroxaban group, and 7.3% (662 patients) in the aspirin group.

The risk of the net-clinical-benefit outcome (ie, a composite of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ) was 20% lower with rivaroxaban plus aspirin than with aspirin alone. The risk of the net-clinical-benefit outcome was not significantly lower with rivaroxaban alone than with aspirin alone.

Could Practice Guidelines Change?

Although the rate of stroke was lower among patients receiving rivaroxaban plus aspirin than among patients receiving aspirin alone, the researchers found no statistically significant difference between groups in the rate of myocardial infarction, said Eugene Braunwald, MD, Professor of Cardiovascular Medicine at Brigham and Women’s Hospital in Boston, in an accompanying editorial. Nevertheless, “this trial represents an important step forward in thrombocardiology, and it is likely to change practice guidelines,” he added.

Future clinical investigation in this field could pursue several paths. For example, a head-to-head comparison between aspirin plus a second antiplatelet drug and a low dose of a factor Xa inhibitor could be of great interest, said Dr. Braunwald. “Perhaps substituting a P2Y12 inhibitor or thrombin-receptor antagonist for aspirin, together with a very low dose of a factor Xa inhibitor, might lead to even greater efficacy by reducing myocardial infarction,” he added. Also, different subgroups of patients with stable ischemic heart disease may respond differently to these various drug combinations, and these different responses could enable a personalized approach to patients with stable ischemic heart disease, he concluded.

Erik Greb

Suggested Reading

Braunwald E. An important step for thrombocardiology. N Engl J Med. 2017 Aug 27 [Epub ahead of print].

Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017 Aug 27 [Epub ahead of print].

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