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Factor Xa inhibitor failed in reducing mortality among heart failure patients without AF

Dr. Joseph Delano Fule Robles
30 Aug 2018
Prof Faiez Zannad photo from the European Society of Cardiology

The factor Xa inhibitor rivaroxaban failed in reducing the risk of death, MI or stroke as compared with placebo among patients with worsening chronic heart failure (HF) and underlying coronary artery disease (CAD) without atrial fibrillation (AF), according to results of the COMMANDER HF trial reported at the European Society of Cardiology (ESC) Congress 2018.

The study among 2,507 HF patients given rivaroxaban 2.5 mg twice daily showed no significant difference in the occurrence of the composite primary endpoint of all-cause mortality, MI or stroke vs those who received placebo (n=2,515) after a median follow-up period of 21.1 months (25.0 percent vs 26.2 percent; hazard ratio [HR], 0.94; 95 percent confidence interval [CI], 0.84 to 1.05; p=0.27). [N Engl J Med 2018, doi: 10.1056/NEJMoa1808848]

The study, with participants from 628 sites in 28 countries, also showed no significant difference in all-cause mortality between the rivaroxaban and placebo groups (21.8 percent vs 22.1 percent; HR, 0.98; 95 percent CI, 0.87 to 1.10).  

Using low-dose rivaroxaban, the COMMANDER HF trial tested whether the antithrombin agent can reduce thrombin generation with resultant lowering of rates of death and cardiovascular events in patients with chronic HF with reduced ejection fraction (≤ 40 percent), CAD and no AF.

“COMMANDER HF is not just another trial of oral anticoagulation in HF. The aim is to interfere with a disease process that rely on thrombin using a targeted antithrombin drug,” explained investigator Professor Faiez Zannad of the University of Lorraine, Nancy, France.

There was no significant difference in the principal safety outcome of fatal bleeding or bleeding into a critical space with a potential for causing permanent disability between the rivaroxaban and placebo groups (0.7 percent vs 0.9 percent; HR, 0.80; 95 percent CI, 0.43 to 1.49; p=0.48).

Patients who received rivaroxaban had a significantly higher risk of major bleeding, as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria, vs placebo (HR, 1.68; 95 percent CI 1.18 to 2.39; p=0.003).

Serious adverse events were reported in 15.2 percent of patients in the rivaroxaban group vs 14.3 percent in the placebo group. The rate of discontinuation of the trial regimen because of an adverse event was higher in the rivaroxaban vs placebo group (7.1 vs 5.8 percent).

“The most likely reason for the failure of low-dose rivaroxaban to improve cardiovascular outcomes in the current trial is that thrombin-mediated events are not the major driver of HF-related events in patients with recent hospitalization for HF. Whether a higher dose of rivaroxaban could have led to a more favourable result is unknown,” Zannad concluded.

“Results of the COMMANDER HF trial suggest that oral anticoagulation is not indicated in HF in the absence of AF,” said discussant Dr Jean-Claude Tardiff of Montreal Heart Institute, Canada.

Rivaroxaban is an oral direct factor Xa inhibitor that reduces thrombin generation. In doses of 1020 mg daily, this agent is approved for a variety of indications, including the treatment and prevention of venous thromboembolism and the prevention of stroke or systemic embolism in patients with AF. [N Engl J Med 2012;366:1287-1297; N Engl J Med 2010;363:2499-2510; N Engl J Med 2011;365:883-891]

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