Rivaroxaban plus standard therapy reduces thromboembolic events in HF, CAD patients

Five milligrams of rivaroxaban per day added to a patient’s standard therapy for heart failure (HF) and coronary artery disease (CAD) could reduce that patient’s risk of future thromboembolic events, researchers reported in JAMA Cardiology April 24.

Rivaroxaban, an oral anticoagulant, has been a fixture in cardiology departments across the U.S. since it was first approved by the FDA in 2011. Low doses of the drug improved survival outcomes in patients with acute coronary syndrome in the ATLAS ACS 2-TIMI 51 study and in stable patients with chronic atherosclerotic CV disease in the COMPASS trial.

It was another study that caught first author Barry Greenberg, MD, and colleagues’ attention, though—the COMMANDER HF trial, which enrolled a similar patient population but found low-dose rivaroxaban failed to reduce the risk of all-cause mortality, MI or stroke among participants.

Since COMMANDER HF was the only trial of the three that required patients to have had a recent episode of worsening HF accompanied by CAD and normal sinus rhythm, the authors suggested the studies’ conflicting results might be owed to the fact that many of the deaths in the COMMANDER HF trial were associated with pump failure and weren’t amenable to antithrombotic therapy.

“Regardless, there is evidence that patients with HF and CAD are at increased risk for atherothrombotic events, and it is possible that an effect of rivaroxaban on thromboembolic events in the COMMANDER HF trial might have been masked by pump failure deaths that drove the primary outcome,” Greenberg, of the University of California, San Diego, and co-authors wrote. “Thus, for this post hoc analysis, we defined an outcome that was more specific to thromboembolic events.”

The primary outcome of Greenberg et al.’s study was a thromboembolic composite of MI, ischemic stroke, sudden or unwitnessed death, symptomatic pulmonary embolism, or symptomatic deep venous thrombosis. They retrospectively analyzed 5,022 patients in the COMMANDER HF trial, all of whom had been discharged from a hospital or outpatient clinic after treatment for worsening HF.

Participants in the study were randomized 1:1 to either receive 2.5 mg of oral rivaroxaban twice daily or a placebo in addition to their standard therapy.

Greenberg’s team found that over an average follow-up of 20 months, fewer patients assigned to rivaroxaban had a thromboembolic event including sudden or unwitnessed deaths—13.1% compared to 15.5% of patients taking the placebo. When sudden and unwitnessed deaths were excluded, the results remained significant, with 6.1% of the rivaroxaban group experiencing an event versus 7.6% of the placebo group.

The authors said their findings confirmed that while thromboembolic events weren’t the major driver of the study’s endpoint, they do occur frequently in these patients. Either way, rivaroxaban showed promise in reducing the prevalence of those events.

In a linked JAMA editorial, Marvin A. Konstam, MD, of the CardioVascular Center at Tufts Medical Center in Boston, said that despite strong rationale and research dating back more than six decades, the medical community still struggles to find sufficient evidence to drive clinical practice when it comes to antithrombotics and HF.

“Greenberg et al. should be commended for reporting important new clues toward solving the mystery of the role of antithrombotic therapy in HF,” he wrote. “Their analysis also displays the complexity of estimating net clinical benefit for a finding with important reduction in nonfatal morbidity in which potential for harm also exists.

“The present analysis could represent a turning point toward the elusive clinical trial design that will yield the mystery’s ultimate solution.”