Less MI, Stroke on Rivaroxaban in Sinus-Rhythm Heart Failure: Post Hoc COMMANDER HF

November 13, 2018

CHICAGO — Treatment with a thrombin-suppressing direct oral anticoagulant (DOAC) probably didn't stem the progression of heart failure (HF) in the COMMANDER HF trial, but it could well have cut patients' risk for thromboembolic events, say researchers based on a post hoc look at the trial.

The new analysis saw a 17% reduction in risk (P = .013) for a thromboembolic composite end point over a median 21 months in its patients with HF and in sinus rhythm who took low-dose rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals), compared with placebo, both on top of aspirin.

The benefit was driven by numerical reductions in two of the composite's components, myocardial infarction (MI) and stroke, the latter of which reached significance on its own.

The post hoc result contrasts with previously reported neutral outcomes for the primary efficacy end point, all-cause mortality, MI, and stroke; and secondary outcomes of cardiovascular (CV) mortality and HF hospitalization in the trial, which entered mostly high-risk patients with recent symptom exacerbation.

Together, the findings suggest that the primary end point was unaffected by DOAC treatment because mortality in the trial "was driven by events that were not influenced by rivaroxaban," despite the drug's beneficial effect on MI and stroke, proposed Barry Greenberg, MD, University of California, San Diego, La Jolla.

"Thromboembolic events, while not the major source of morbidity and mortality in COMMANDER HF, occurred commonly during follow-up," Greenberg observed. But rivaroxaban's preventive effect was likely "masked by the preponderance of events related to worsening heart failure," he said when presenting the post hoc analysis here at the American Heart Association Scientific Sessions 2018.

"I think we studied the wrong population here, in that we looked at worsening heart failure, where there's so much else going on that outcomes are heart-failure-driven. We really almost missed that signal," Greenberg told theheart.org | Medscape Cardiology.

With COMMANDER HF and analyses of HF subgroups in the ATLAS ACS-2 TIMI 51 and COMPASS trials, "there's a pattern that emerges," he said. "That is, there are background thromboembolic events, and those are favorably affected by low-dose rivaroxaban."

Those other trials had included patients with recent MI or unstable angina, and patients with chronic stable coronary artery disease (CAD) or peripheral vascular disease, respectively.

"Post hoc analyses cannot be paradigm-changers. This is promising, but still needs refinement, as further studies will need to be done," observed Biykem Bozkurt, MD, PhD, DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, for theheart.org | Medscape Cardiology.

"Without that, I'm not sure people will be able to initiate it solely for the indication of heart failure and reduction in thromboembolic events," said Bozkurt, who wasn't involved in COMMANDER HF.

Also not with the trial, James L. Januzzi Jr, MD, Massachusetts General Hospital, Boston, agreed that it "adds another piece of understanding regarding the role of rivaroxaban at the low dose, the vascular dose, for reducing ischemic complications in people with coronary artery disease."

Januzzi agreed when interviewed that in COMMANDER HF, HF in some patients was so severe that a reduction in ischemic events on rivaroxaban "would not be that beneficial. But it doesn't mean that there weren't patients, particularly those in the less-severe ranges of heart failure, who probably did benefit because their ischemic heart disease was the more predominant issue."

So based on the accumulated trial evidence, he said, "I think it's necessary to take a step back and ask how we can we individualize the care of patients." The message isn't that low-dose rivaroxaban doesn't help in ischemic HF; rather, he said, it's incumbent on researchers to pin down which of those patients should and should not get rivaroxaban.

"It may very well be as simple as looking at their NTproBNP," he said, referring to the biomarker N-terminal pro-B-type natriuretic peptide, which can predict poor prognosis from HF progression. "And if it's above a certain value, their heart failure risk is so high, you wouldn't treat them with rivaroxaban."

But, "if the NT-proBNP is low, it says your heart failure risk is relatively contained, and you are vulnerable to ischemic heart disease events."

COMMANDER HF, as presented in August at the European Society of Cardiology Congress 2018 and published in the New England Journal of Medicine, had randomly assigned 5022 patients with recent exacerbation of chronic HF, CAD, a left ventricular ejection fraction of 40% or less, and elevated natriuretic peptides but no atrial fibrillation (AF) to receive rivaroxaban 2.5 mg twice daily or placebo on top of standard care. About half were in New York Heart Association functional class 3 or 4.

For those getting rivaroxaban vs control subjects, the hazard ratio (HR) for the primary end point of death, MI, or stroke was 0.94 (95% CI, 0.84 - 1.05), which was driven by a significant mortality reduction.

The rivaroxaban group did not show an elevated risk for the primary safety end point of "fatal bleeding or bleeding into a critical space with potential for permanent disability," which was HR 0.80 (95% CI, 0.43 - 1.49). But their HR for major bleeding by International Society on Thrombosis and Haemostasis criteria was 1.68 (95% CI, 1.18 - 2.39).

The post hoc analysis looked at a composite thromboembolic-event end point that included MI, ischemic stroke, sudden or unwitnessed death, pulmonary embolism, or symptomatic deep venous thrombosis. All of the component end points had been prespecified in the protocol, Greenberg said.

The 17% drop in that composite end point for the 2507 rivaroxaban recipients, compared compared the 2515 who received placebo, was significant at P = .013.

Hazard Ratios for Thromboembolic Events in COMMANDER HF Post Hoc Analysis, Rivaroxaban vs Placebo
End Points HR (95% CI)
Composite end point* 0.83 (0.72–0.96)
MI 0.83 (0.63–1.08)
Ischemic stroke 0.64 (0.43–0.95)
Sudden or unwitnessed death 0.88 (0.73–1.07)
Symptomatic PE 1.24 (0.51–2.99)
Symptomatic DVT 0.71 (0.23–2.24)
*MI, ischemic stroke, sudden or unwitnessed death, pulmonary embolism (PE), or symptomatic deep venous thrombosis (DVT)


As invited discussant after Greenberg's presentation, Freek W.A. Verheugt, MD, Onze Lieve Vrouwe Gasthuis, Amsterdam, explained the biochemistry and plaque-rupture underpinnings he sees for the observed rivaroxaban benefit in COMMANDER HF.

Plaque rupture promotes production of prothrombin and then thrombin, the latter of which "is the strongest platelet activator in biology," he said.

"So anticoagulant therapy is also indirectly an antiplatelet drug. Therefore, I think, anticoagulation is also effective for the prevention and treatment of coronary thrombosis."

Verheugt also proposed that some ischemic strokes in the study might have been caused by atrial thrombi in patients with undisclosed AF, the risk for which could potentially have been lowered by rivaroxaban.

"The dose of rivaroxaban used in the study was, I think, too low to ensure that it really could prevent embolic stroke from the left atrial appendage," Verheugt said. "But the reduction was clear."

When interviewed, Bozkurt agreed that some patients in the study could have had undisclosed AF or been susceptible to new AF during the follow-up, and therefore rivaroxaban might have lowered their risk for cardiogenic ischemic stroke.

But also, she said — consistent which Verheugt's proposal — reductions in MI and stroke but not DVT or PE suggest, hypothetically, that much of the benefit was less related to prevention of venous thromboembolic events and more to an effect on the arterial bed that averts thrombosis associated with unstable plaques.

Janssen funded COMMANDER HF. Greenberg discloses receiving research support from Janssen, serving on a speakers bureau for Otsuka and as a consultant or advisory board member for Bayer, Novartis, Mesoblast, Zensun, Ionis, and Cellular Dynamics. Verheugt discloses receiving research support from Bayer Healthcare, Boehringer Ingelheim, Eli Lilly, and Roche; serving as a consultant to and receiving honoraria from Bayer Healthcare, Eli Lillyi, Daiichi-Sankyo, and Merck. Januzzi has reported receiving research grants and other research support from Roche Diagnostics, Singulex, Abbott, Prevencio, Cleveland Heart Labs, Boehringer Ingelheim, Janssen, AbbVie, and Alere; and serving as a consultant or on an advisory board for Roche Diagnostics, Corvidia, Abbott, Critical Diagnostics, and MyoKardia. Bozkurt discloses serving as a consultant or on an advisory board for Bayer Health Care, Lantheus Imaging, and LivaNova USA.

American Heart Association (AHA) Scientific Sessions 2018. Abstract 19574. Presented November 11, 2018.

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