COMMANDER HF Quashes Oral Anticoagulation Hopes in Sinus Rhythm Heart Failure

August 27, 2018

MUNICH — Long-term oral anticoagulation (OAC) with rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) had no apparent effect on risk for death, myocardial infarction (MI), or stroke in a large randomized trial of patients with a recent episode of worsening heart failure (HF).

Nor was there a significant difference in a primary safety endpoint reflecting fatal or serious bleeding, although less critical bleeding considered manageable was significantly more common with the factor Xa inhibitor than with placebo.

In the trial, called COMMANDER HF, rivaroxaban was given at 2.5 mg twice daily, a far lower dosage than that used for stroke prevention in patients with atrial fibrillation (AF). Entry to the trial required that its patients with HF also have coronary disease and a low ejection fraction but be free of AF.

Randomized therapy was given on top of standard management, which included daily aspirin in more than 90% of patients in both groups; they included 35% of the total who started the trial on dual antiplatelet therapy.

The trial tested whether blocking possible thrombin-mediated mechanisms of HF progression, including inflammation, endothelial dysfunction, and thrombosis, would improve clinical outcomes in patients with HF in sinus rhythm, which has been called the heart failure thrombin hypothesis, observed Faiez Zannad, MD, PhD, Centre Hospitalier Universitaire de Nancy, France.

"This is not the first time that, in worsening heart failure, pathophysiology doesn't fit with the clinical trial evidence," Zannad told theheart.org | Medscape Cardiology, referring to a long list of trials that were inconclusive or failed to show an OAC clinical benefit in HF. They include WASH, HELAS, WATCH, and WARCEF, performed in the era of vitamin K antagonists, which are remotely indirect inhibitors of thrombin, as the only OAC option.

In the era of novel oral anticoagulants, there have been secondary indications in trials not specially about HF, including COMPASS and ATLAS ACS 2-TIMI 51, that more proximal inhibitors of thrombin production, like rivaroxaban, might stem HF progression, Zannad said.

But the results of COMMANDER HF are solid and unambiguous in showing a lesser role, if any, for thrombin in HF progression. "We have closed that door, the hypothesis was proven wrong," he said. "Thrombin inhibition — anticoagulation — doesn't seem to be effective in patients with worsening heart failure."

Indeed, pump failure and related hospitalizations drove outcomes in the trial, he said, not prevention of thromboembolic events.

Although a post hoc analysis suggested a reduction in strokes with rivaroxaban, Zannad said when interviewed, COMMANDER HF highlights the predominance of pump failure and other nonthrombotic aspects of the HF syndrome, and the small role of thrombosis, as drivers of progressive HF.

Zannad presented the trial, with more than 5000 patients, here at the European Society of Cardiology (ESC) Congress 2018 to coincide with its formal publication in the New England Journal of Medicine, with him as lead author.

In an interview, Michael Böhm, MD, University Saarland, Homburg/Saar, Germany, agreed that COMMANDER HF, with which he wasn't involved, definitively showed that progression of HF per se, in contrast to AF-related thromboembolism in patients with HF, is not closely tied to thrombin. "This trial clearly refutes the hypothesis," he said.

"The lack of benefit of rivaroxaban in COMMANDER HF is certainly consistent with the results of prior randomized trials, said Jean-Claude Tardif, MD, from the Montreal Heart Institute, Quebec, Canada, as invited discussant after Zannad's presentation.

The trial, he said, suggests that "the vast majority of events in heart failure patients are deaths and heart failure hospitalization. These appear not to be related to thrombin generation, and hence not affected by anticoagulation."

The accumulated evidence from this and previous trials, Tardif said, "lead me to state that oral anticoagulation therapy is not  indicated in heart failure patients in the absence of atrial fibrillation."

Interviewed, Zannad agreed with that statement with the qualification that it may not apply to patients with chronic, stable HF, who in COMPASS may have benefitted from rivaroxaban's protection against recurrent MI and stroke.

COMMANDER HF randomly assigned 5022 patients with recent exacerbation of chronic HF, a left ventricular ejection fraction (LVEF) of 40% or less (mean, 34%), coronary artery disease, and elevated natriuretic peptides who were AF-free to receive rivaroxaban 2.5 mg twice daily or placebo on top of standard care. The trial was carried out at 628 sites in 32 countries.

Clarifying the nature of patients entered into the trial, Zannad said about 90% of them had been recently hospitalized with acute decompensated HF and the remainder managed with intravenous diuretics in clinic without hospitalization. About half were in New York Heart Association functional class III to IV.

The primary efficacy endpoint occurred in 25% of those assigned to rivaroxaban and in 26.2% of those getting placebo (P = .27) over a median follow-up of 21 months. Nor were there significant differences in mortality or rate of MI. But treatment with the factor Xa inhibitor seemed to cut the risk for stroke in an exploratory analysis.

Table. Hazard Ratios for Outcomes in COMMANDER HF, Rivaroxaban vs Placebo Groups

Endpoints Hazard Ratio (95% Confidence Interval)
Primary efficacy outcomea 0.94 (0.84 - 1.05)
Composite principal safety outcomeb 0.80 (0.43 - 1.49)
ISTH-defined major bleedingc 1.68 (1.18 - 2.39)
Stroked 0.66 (0.47 - 0.95)

aDeath, MI, stroke.

bFatal bleeding or bleeding into a critical space with potential for permanent disability.

cHemoglobin decrease ≥2 g/L; transfusion of ≥2 units packed red cells or whole blood; bleeding at critical site; fatal bleeding per definition of the International Society on Thrombosis and Haemostasis.

dExploratory (not prespecified).

ISTH = International Society on Thrombosis and Haemostasis.

 

The principal safety outcome, defined as fatal bleeding or bleeding into a critical space with potential for permanent disability, occurred in 18 and 23 patients, respectively (P = .48).

That category of bleeding complications consisted of more severe, perhaps fatal or debilitating, events was uncommon and was not significantly increased among patients in either group, Zannad pointed out.

A secondary category of bleeding complications, he said, showed significantly increased risk in the rivaroxaban group. But those bleeds tended to be minor, easily manageable by drug withdrawal or transfusions, and without long-term consequences.

"So the message is really clear, that the patients bled [on rivaroxaban] more than on placebo, but these were minor bleeds that you can work out," Zannad said.

Still, those minor bleeds, he said, were a warning that any efforts to raise the rivaroxaban dosage in patients like those in COMMANDER HF, in hopes of improving HF outcomes, would probably lead to worse bleeding complications.

COMMANDER HF was funded by Janssen. Zannad discloses receiving fees from Janssen, Bayer, Novartis, Boston Scientific, ResMed, Amgen, CVRx, Quantum Genomics, General Electric, Boehringer Ingelheim, AstraZeneca, Vifor Fresenius, and Cardior. Tardif discloses receiving research contracts from Amarin, AstraZeneca, Dalcor, Esperion, Ionis, Pfizer, Sanofi, and Servier and consulting for, receiving royalties from, or having ownership interest in DalCor, Pfizer, and Servier. Boehm discloses receiving research support from or being on an advisory board for Bayer, Boehringer Ingelheim, Medtronic, Novartis, Pfizer, Servier, St Jude Medical, and Vifor and speaking for Amgen, Bayer, Boehringer Ingelheim, Berlin-Chemie, Daiichi-Sankyo, Medtronic, Merck, Novartis, Pfizer, ResMed, Servier, St Jude Medical, and Vifor.

European Society of Cardiology (ESC) Congress 2018.

N Engl J Med. August 27, 2018. Full text

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