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Highlights from

European Society of Cardiology

Congress 2018

Munich 25-29 August 2018

COMMANDER HF: Rivaroxaban does not reduce deaths compared with placebo in chronic heart failure with reduced EF

Take-home messages
  • Rivaroxaban (2.5 mg twice daily) demonstrated no clinical benefit versus placebo in the primary endpoint (composite of death from any cause, myocardial infarction or stroke)
  • A small statistically significant difference in stroke was observed in patients on rivaroxaban versus placebo
  • The safety profile of rivaroxaban was consistent with other trials of rivaroxaban
“We had enrolled a very high-risk population and this might be a reason why the trial didn’t work because in this specific population, heart failure deaths were more frequent than deaths mediated by anti-thrombotic events.”

Professor Faiez Zannad
Université de Lorraine, France

Low-dose rivaroxaban failed to show a statistically significant difference versus placebo in reducing the composite risk of all-cause mortality, heart attack and stroke in patients with chronic heart failure with reduced ejection fraction (HFrEF) according to the COMMANDER HF trial (NCT01877915).

“The primary outcome was neutral and the drug was not effective at reducing all-cause mortality, myocardial infarction or stroke (composite endpoint),” said Professor Faiez Zannad, co-investigator of the trial from the Université de Lorraine, France.

Furthermore, there was no significant difference in all-cause mortality between trial arms (21.8% and 22.1% in rivaroxaban and placebo respectively; hazard ratio (HR): 0.98; 95% CI, 0.87-1.10).

“Myocardial infarction was less frequent with rivaroxaban but this did not reach statistical significance (HR: 0.83, 95% CI, 0.63–1.08, p=0.17); however it did for stroke, with fewer in the rivaroxaban group (2%) than in placebo (3%; HR: 0.66; 95% CI, 0.47-0.95).”

Despite the remarkable progress in treating HFrEF, sudden worsening of the symptoms of heart failure is serious and is associated with high rates of hospitalisation and death, the professor explained.

“Trials in worsening HFrEF of a large number of therapies targeting a variety of mechanisms have failed so far to improve outcome, so we still have an unmet medical need,” Professor Zannad highlighted. “Trials of warfarin, for example, have been inconclusive and it is associated with an increase in bleeding complications.”

The activation of thrombin-related pathways is thought to contribute to these poor outcomes, so the researchers hypothesised that treatment with the factor Xa inhibitor, rivaroxaban, could reduce thrombin generation and improve outcomes for patients with worsening chronic HFrEF and underlying coronary artery disease (CAD). “New oral anticoagulants are safer and act on thrombin, which may contribute to disease progression by inducing inflammation, endothelial dysfunction, and microthrombi, all mechanisms in worsening HF.”

In light of this, the COMMANDER HF trial was designed to test the hypothesis that, low-dose rivaroxaban added to antiplatelet agents could reduce the risk of death from CV events and would be associated with lower rates of all-cause mortality, myocardial infarction and stroke, compared with placebo. “COMMANDER HF was not just another trial of oral anticoagulation in heart failure. The aim was to interfere with disease processes that rely on thrombin using a targeted antithrombin drug,” asserted Professor Zannad.

Data from a total of 5,022 patients were randomised 1:1 in the phase 3, prospective, double-blind trial to receive rivaroxaban at 2.5 mg twice daily or placebo in addition to standard care after treatment for an episode of worsening heart failure. The primary efficacy outcome was the composite of all-cause mortality, myocardial infarction or stroke, while the principal safety outcome was major bleeding.

Reporting the results at the ESC Congress 2018, Professor Zannad said that the primary endpoint occurred in 626 (25.0%) of 2,507 patients treated with rivaroxaban compared with 658 (26.2%) of 2,515 patients treated with placebo over a median follow-up of 21.1 months (HR: 0.94; 95% CI, 0.84-1.05; p=0.27).

“Safety was extremely good and findings were consistent with other trials of low-dose rivaroxaban at 2.5 mg with neutral findings and a placebo-like effect,” he added. The principal safety outcome occurred in 18 patients who took rivaroxaban and in 23 who took placebo (HR: 0.80; 95% CI, 0.43-1.49; p=0.48).

Offering some explanation for the findings, Professor Zannad said: “We had enrolled a very high-risk population and this might be a reason why the trial didn’t work because in this specific population, heart failure deaths were more frequent than deaths mediated by anti-thrombotic events.”

“Our initial hypothesis that heart failure post-hospitalisation may be influenced by thrombin has not been proven here, but on the contrary, we have shown that other anti-coagulant trials should not be conducted in this population because heart failure events are not influenced by anti-thrombotic agents,” concluded Professor Zannad.

Results were published in the New England Journal of Medicine, 27 August 2018.

Based on Zannad F, Anker, S et al. Rivaroxaban in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease. Presented on Monday, 27 August 2018

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