Low-dose rivaroxaban benefits despite increased bleeding
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 in all-cause strokes by adding low-dose rivaroxaban(Xarelto) occurred without any significant increase in hemorrhagic strokes but with a small increase in total major bleeding events, such as gastrointestinal bleeds, Mike Sharma, MD, said at the International Stroke Conference, sponsored by the American Heart Association.
“There was a consistent effect across all strata of stroke risk. For patients who had a prior stroke, it’s pretty clear to use rivaroxaban plus aspirin because it had a big benefit” with no increase in intracranial hemorrhages, Dr. Sharma said in a video interview.
“We think these results will fundamentally change how we approach stroke prevention,” added Dr. Sharma, a stroke neurologist in the Population Health Research Institute of McMaster University in Hamilton, Ont.
The results he reported came 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, MI, or stroke during an average 23 months of follow-up, which occurred in 4.1% of patients treated with 2.5 mg rivaroxaban twice daily plus 100 mg aspirin once daily, 4.9% of patients who received 5.0 mg rivaroxaban twice daily, and 5.4% in patients who received 100 mg aspirin daily, 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 (N Engl J Med. 2017 Oct 5;377[14]:1319-30). The main results showed a 1.2% increase in the rate of major bleeds in patients treated with rivaroxaban plus aspirin, compared with aspirin only, but the rate of nonfatal symptomatic intracranial hemorrhages was identical in the two treatment groups.
The new results Dr. Sharma reported at the conference 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 ischemic strokes were 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.
Rivaroxaban plus aspirin surpassed aspirin alone for preventing both mild and severe strokes and for preventing strokes both in patients with a history of a prior stroke and in those who never had 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, a 2.7% absolute reduction by using rivaroxaban plus aspirin that 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 endpoint 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. This net clinical benefit suggests that adding rivaroxaban has a cost-effective benefit. Assessment of rivaroxaban’s cost benefit in COMPASS is in process, Dr. Sharma said.
Rivaroxaban received Food and Drug Administration marketing approval in 2011 for preventing deep vein thrombosis and preventing stroke in patients with atrial fibrillation at dosages higher than what was used in COMPASS. The approved rivaroxaban dosage for preventing deep vein thrombosis is 10 mg/day, and 20 mg/day for preventing stroke in atrial fibrillation patients. 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 U.S. market, although it is available in Europe. Johnson & Johnson, which markets rivaroxaban globally with Bayer, submitted an application to the FDA in December 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, the company that markets rivaroxaban in collaboration with Johnson & Johnson. Dr. Sharma has been a consultant or adviser to Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, and Daiichi-Sankyo.
SOURCE: Sharma M et al. ISC 2018, Abstract LB7.