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Rivaroxaban Plus Aspirin Nearly Halves Ischemic Stroke Risk

Compared with aspirin alone, the dual therapy prevented mild and severe strokes and reduced risk, regardless of patients’ stroke history.


LOS ANGELES—Combined treatment with a low dosage of the anticoagulant rivaroxaban plus aspirin cut the incidence of ischemic strokes nearly in half, compared with aspirin alone, in a multicenter, randomized trial of more than 27,000 patients with stable atherosclerotic vascular disease.

This dramatic reduction in ischemic strokes, as well as a 42% reduction in all-cause strokes, by adding low-dose rivaroxaban (Xarelto) occurred without a significant increase in hemorrhagic strokes, but with a small increase in total major bleeding events such as gastrointestinal bleeds, said Mike Sharma, MD, at the International Stroke Conference 2018.

Mike Sharma, MD

“There was a consistent effect across all strata of stroke risk,” Dr. Sharma said. Among patients with a prior stroke, rivaroxaban plus aspirin provided the greatest benefit, with no increase in intracranial hemorrhages, Dr. Sharma said.

“We think these results will fundamentally change how we approach stroke prevention,” said Dr. Sharma, a stroke neurologist in the Population Health Research Institute of McMaster University in Hamilton, Ontario.

An Analysis of Data From COMPASS

Dr. Sharma reported results from a secondary analysis of data collected in the COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease) trial, which enrolled 27,395 patients with stable coronary or peripheral artery disease at 602 centers in 33 countries.

The primary outcome of the trial, reported in 2017, was the combined rate of cardiovascular death, myocardial infarction, or stroke during an average of 23 months of follow-up. Patients received rivaroxaban plus aspirin (ie, 2.5 mg of rivaroxaban twice daily plus 100 mg of aspirin once daily), aspirin alone (ie, 100 mg of aspirin daily), or rivaroxaban alone (ie, 5.0 mg of rivaroxaban twice daily). A primary outcome event occurred in 4.1% of patients treated with rivaroxaban plus aspirin, 4.9% of patients who received rivaroxaban alone, and 5.4% of patients who received aspirin alone—a statistically significant 24% relative risk reduction in the combined treatment group, compared with aspirin only. The rivaroxaban only–treated patients did not significantly differ from the control patients who received only aspirin. The rate of major bleeds in patients treated with rivaroxaban plus aspirin was 1.2% greater, compared with aspirin only, but the rate of nonfatal symptomatic intracranial hemorrhages was identical in the two treatment groups.

The present study focused on various measures of stroke. The rate of all strokes was 42% lower among the patients treated with rivaroxaban plus aspirin, compared with the aspirin-alone patients, and the rate of ischemic strokes was 49% lower with the dual therapy, compared with aspirin only. Both differences were statistically significant. In contrast, the rivaroxaban-alone regimen did not significantly reduce all-cause strokes. It did significantly reduce ischemic strokes, compared with aspirin only, but it also significantly increased hemorrhagic strokes, compared with aspirin only, an adverse effect not caused by the combination of low-dose rivaroxaban plus aspirin.

Benefit in High-Risk Patients

Rivaroxaban plus aspirin surpassed aspirin alone for preventing mild and severe strokes and for preventing strokes in patients with a history of a prior stroke and in those without a prior stroke. The stroke reduction produced by rivaroxaban plus aspirin was greatest in the highest risk patients—those with a prior stroke. On the combined regimen, these patients had an average stroke incidence of 0.7% per year, compared with an annual 3.4% rate among the patients on aspirin only. This 2.7% absolute reduction by using rivaroxaban plus aspirin translated into a number needed to treat of 37 patients with a history of stroke to prevent one new stroke per year.

The 2017 report of the main COMPASS results included a net clinical benefit analysis that factored together the primary end point events and major bleeding events. The net rate of all these events was 4.7% with rivaroxaban plus aspirin and 5.9% with aspirin only, a statistically significant 20% relative risk reduction for all adverse outcomes with dual therapy. Researchers are assessing the cost-effectiveness of adding rivaroxaban, Dr. Sharma said.

Rivaroxaban received FDA marketing approval in 2011 for preventing deep vein thrombosis and preventing stroke in patients with atrial fibrillation at dosages higher than those used in COMPASS. The approved rivaroxaban dosage is 10 mg/day for preventing deep vein thrombosis, and 20 mg/day for preventing stroke in patients with atrial fibrillation. The 2.5-mg formulation of rivaroxaban that was given twice daily had the best safety and efficacy in COMPASS, but it is not available now on the US market, although it is available in Europe. Johnson & Johnson, which markets rivaroxaban globally with Bayer, submitted an application to the FDA in December 2017 for marketing approval of the 2.5-mg formulation in twice-daily dosing for use as in the COMPASS trial.

COMPASS was sponsored by Bayer, and Dr. Sharma has been a consultant or adviser to Bayer.

—Mitchel L. Zoler

Suggested Reading

Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330.

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