The Role of Rivaroxaban in Stable Cardiovascular Disease

One in four deaths every year are the result of a cardiovascular event.

Despite best and evidence-based practices, up to 10% of patients who survive have a recurrent event annually.

Traditionally aspirin has been used for secondary prevention of these events and has been shown to reduce major cardiovascular events by as much as 19% and death from cardiovascular causes by 9%. Warfarin, with and without aspirin, was found to be superior to aspirin monotherapy in the secondary prevention of myocardial infarctions, but the bleeding risk associated with long-term use outwieghted the prospective clinical benefit.

Research has indicated that novel oral anticoagulants such as rivaroxaban (Xarelto, Janssen) cause less bleeding compared to warfarin. As a result, these newer agents have been studied for a variety of indications, including those where warfarin had been previously shown to be beneficial but risky.

A recent study revealed that rivaroxaban in combination with aspirin had significantly fewer cardiovascular events compared to aspirin alone. The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) study was a double-blind-double dummy randomized, international trial published in The New England Journal of Medicine that evaluated the effect of rivaroxaban with or without aspirin for the prevention of cardiofascular events in patients with stable atherosclerotic vascular disease who had just underwent coronary-artery bypass graft surgery.

The study researchers randomly assigned more than 27,000 patients to receive rivaroxaban 2.5 mg twice daily with aspirin 100 mg daily, rivaroxaban 5 mg twice daily with aspirin-matched placebo, or aspirin 100 mg daily with rivaroxaban-matched placebo. Patients were monitored at 1 month, 6 months, and every 6 months thereafter for an average of almost 2 years (23 months).

The combination of rivaroxaban and aspirin resulted in significantly fewer primary outcome events including cardiovascular death, stroke, and myocardial infarctions compared to aspirin alone (4.1% vs. 5.4%; HR 0.76, P <0.001). There was no difference seen between rivaroxaban and aspirin monotherapy (P=0.12). The combination also resulted in significantly fewer secondary outcomes including ischemic stroke, myocardial infarction, acute limb ischemia, death from coronary heart disease, cardiovascular-related death, death from any cause, and cardiovascular-related hospitalization compared to aspirin monotherapy. The addition of rivaroxaban to aspirin did not reduce other outcomes such as myocardial infarction or heart failure. The differences in outcomes were evident throughout the trial, but became most noticable after almost a year of therapy.

Unfortunately, bleeding was more common in the rivaroxaban-aspirin group compared to aspirin alone including major bleeding (3.1% vs. 1.9 %; HR 1.7, P <0.001), minor bleeding (9.2% vs. 5.5%; HR 1.7, P <0.001), and bleeding requiring transfusion (1% vs. 0.5%; HR 1.97, P <0.001). The most common site of major bleeding was the gastrointestinal tract. Promising was the fact that there did not appear to be a difference in the incidence of fatal bleeding (0.2% vs. 0.1%; HR 1.49, p=0.32), intracranial bleeding (p=0.77), or bleeding into another major organ (P=0.14). The authors also evaluated net-clinical benefit of the primary outcome compared to major bleeding and found a the benefit of combination therapy outweighed the risk of bleeding better than aspirin alone (P <0.001).

Whether rivaroxaban will become standard of care in the secondary prevention of cardiovascular events is still to be determined. Although the study allowed for blood pressure control and statin therapy, the specifics of those therapies were not documented nor considered when evaluating outcomes. Further studies that integrate and evaluate all secondary prevention measures to determine the full extent and role that rivaroxaban may have are needed. Still, it represents a promising addition to our current approach and may benefit thousands of patients who suffer from cardiovascular events each year.

References

1. Centers for Diseases Control and Prevention. Available online: https://www.cdc.gov/heartdisease/facts.htm

2. Eikelboom JW, Connolly SJ, Dagenais GR, et al. Rivaroxaban with or without asprin in stable cardiovascular disease. N Engl J Med. 2017;377:1319-1330