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Low-dose rivaroxaban reduces thromboembolic events in certain patients with HF
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CHICAGO — In a post hoc analysis of the COMMANDER HF trial, treatment with low-dose rivaroxaban reduced risk for thromboembolic events in patients with worsening of chronic HF, reduced ejection fraction, CAD and sinus rhythm.
“However, confirmation of these results by a prospective trial is required in order to establish a role for low-dose rivaroxaban in treating HF patients,” Barry H. Greenberg, MD, director of the Advanced Heart Failure Treatment Program and professor of medicine at UC San Diego Health, who presented the new post hoc analysis data, said during a presentation at the American Heart Association Scientific Sessions.
Overall, 14.3% of this population experienced a thromboembolic event during a median follow-up of 19.6 months. The predefined composite endpoint for this post hoc analysis — MI, ischemic stroke, sudden/unwitnessed death, pulmonary embolism or symptomatic deep vein thrombosis — occurred in 13.1% of patients assigned rivaroxaban (Xarelto, Bayer/Janssen) compared with 15.5% assigned placebo (HR = 0.83; 95% CI, 0.72-0.96).
Low-dose rivaroxaban also reduced risk for MI and ischemic stroke, when examined separately from the composite outcome. MI occurred in 3.9% of the rivaroxaban group vs. 4.7% of the placebo group (HR = 0.83; 95% CI, 0.63-1.08) and ischemic stroke in 1.6% vs. 2.5%, respectively (HR = 0.64; 95% CI, 0.43-0.95). The results also showed reduction in risk for sudden/unwitnessed death (7.6% vs. 8.5%; HR = 0.88; 95% CI, 0.73-1.07) and symptomatic DVT (0.2% vs. 0.3%; HR = 0.71; 95% CI, 0.23-2.24). Risk for PE, which occurred in a small number of patients, was similar at 0.4% in both treatment groups (HR = 1.24; 95% CI, 0.51-2.99).
“These findings support the possibility that low-dose rivaroxaban may reduce the risk of thromboembolic events in HF patients,” Greenberg said.
Findings in context
Previous research from the ATLAS ACS 2-TIMI 51 and COMPASS trials showed benefit of rivaroxaban 2.5 mg twice daily in addition to antiplatelet agents for reduction in risk for CV death, MI and stroke. Although ATLAS ACS 2-TIMI 51 focused on patients with MI and unstable angina and COMPASS focused on those with stable coronary and/or peripheral disease, both trials also included patients with HF, Greenberg said.
As previously reported by Cardiology Today , in the overall COMMANDER HF trial, results of which were presented at the European Society of Cardiology Congress in Munich, low-dose rivaroxaban failed to improve the primary outcome or the secondary efficacy outcome of CV mortality and HF hospitalization. The primary outcome was driven by mortality, a large proportion of which was due to worsening HF, Greenberg said during a presentation. Testing for homogeneity between the three components of the primary outcome suggested that risk varied, and there were numerical advantages of rivaroxaban vs. placebo for MI and stroke.
“The findings [of the overall COMMANDER HF trial] suggest that the ... primary composite [endpoint] was driven by events that were not influenced by rivaroxaban 2.5 mg twice daily,” he said. “Therefore, we postulated that low-dose rivaroxaban would be superior to placebo in reducing the risk of thromboembolic events in this population.”
Freek W.A. Verheugt, MD, professor of cardiology at the Heart-Lung Centre of the University Medical Centre in Nijmegen, the Netherlands, and chair of cardiology at Onze Lieve Vrouwe Gasthuis in Amsterdam, discussed findings of the post hoc analysis during a presentation at the AHA Scientific Sessions.
“Although COMMANDER HF did not meet its primary endpoint, oral anticoagulation did prevent ischemic endpoints — stroke and MI,” Verheugt said. “This underscores the long-term benefit of oral anticoagulation in chronic ischemic heart disease, as found in the old post-MI trials with vitamin K antagonists, and in modern times in the COMPASS and COMMANDER HF trials.”
Greenberg noted several limitations of the trial, including the post hoc analysis design and nonadjudicated endpoints. Additionally, this trial enrolled patients with reduced EF and the effect of rivaroxaban on thromboembolic events in the HF with reduced EF population is unknown, Greenberg said. – by Katie Kalvaitis
Reference:
Greenberg BH, et al. LBS.05 – Late Breaking Clinical Trials: Hot News in HF. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.
Disclosures: The COMMANDER HF study was supported by Janssen. Greenberg reports he received research support from Janssen, serves on speakers bureaus for Otsuka and has consulted for Bayer, Cellular Dynamics, Ionis, Mesoblast, Novartis and Zensun. Verheugt reports he receives research support or is a principal investigator for Bayer HealthCare, Boehringer Ingelheim, Eli Lilly and Roche; is a consultant for Bayer HealthCare, Daiichi Sankyo, Eli Lilly and Merck; receives honoraria from Bayer HealthCare, Daiichi Sankyo, Eli Lilly and Merck; and is on the data safety monitoring boards for the ENTRUST AF-PCI, ENVISAGE TAVI-AF and FRAIL trials.
Perspective
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James L. Januzzi Jr., MD
COMMANDER HF was a large multicenter trial looking at the randomized use of the so-called "vascular" dose of rivaroxaban 2.5 mg twice a day in patients with reduced EF and HF from ischemic heart disease. The primary hypothesis of the original COMMANDER HF study was that treatment with low-dose direct oral anticoagulant therapy would improve HF outcomes; this is because some data suggested the complications of HF might be driven by other subclinical or clinical ischemic heart disease events. The primary results of COMMANDER HF were disappointing. There was some degree of heterogeneity across regions, where in the United States, in North America, there was actually a reduction in the primary endpoint of CV death and HF hospitalization; however, in other regions we did not see this.
The goal of the ancillary study was to examine whether treatment with rivaroxaban in fact did as the researchers expected it to do — which was to reduce ischemic complications, MI, stroke and ischemic death. What they found was that, in fact, it did. It’s not surprising that treatment with rivaroxaban reduced these ischemic complications. However, when looking at whether or not that mediated the primary outcome of the trial, they found that a substantial percentage of the outcomes in COMMANDER HF were apparently unaffected by this benefit to reduce ischemic complications. This argues the primary hypothesis, that ischemic events might drive HF events, was probably incorrect. Although we can indeed prevent ischemic complications from coronary disease and cerebrovascular disease with low-dose rivaroxaban, this may not make a dent in the considerable risk that these patients with HF have.
One important postscript is that these results actually support the primary result of the COMPASS study, which showed reduction of these events in patients with more stable disease. But, in patients with HF, their risk is so high that treatment with rivaroxaban isn’t going to benefit their HF outcomes necessarily.
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