Apixaban Preferable to Rivaroxaban in AF?

March 11, 2020

Apixaban may be safer and more effective than rivaroxaban for treating nonvalvular atrial fibrillation (AF), a new observational study suggests.

The study, one of the largest to compare the two drugs to date, found that in routine care, rates of ischemic stroke or systemic embolism and bleeding were lower for adults with AF who were prescribed apixaban than for those prescribed rivaroxaban.

"We propensity-matched patients receiving the different medications on many different baseline characteristics, which increases the reliability of our results," lead author Michael Fralick, MD, told Medscape Medical News.

Fralick is an assistant professor in the Department of Medicine, University of Toronto, Canada, and is affiliated faculty in the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Massachusetts.

The study was published online in Annals of Internal Medicine on March 10.

However, two outside experts who reviewed the study for Medscape Medical News urged caution in drawing any conclusions from observational data.

"I am disappointed in the Annals journal allowing such a clear conclusion of one drug being better than another. I do not see such a clear finding and don't think the data they have can get anywhere near that conclusion," Manesh Patel, MD, commented.

Patel is chief of the Division of Cardiology and the Division of Clinical Pharmacology at Duke University School of Medicine, Durham, North Carolina. He headed up the original ROCKET-AF randomized trial of rivaroxaban.

John Eikelboom, MBBS, associate professor, Division of Hematology and Thromboembolism, McMaster University, Hamilton, Ontario, Canada, added: "It may well be true that apixaban is safer and more effective than rivaroxaban for stroke prevention in atrial fibrillation, but observational studies are clearly not the way to address this issue. Seeing yet another observational study on this topic, I think we should be asking ourselves why some leading medical journals continue to publish studies that cannot be trusted because their results are readily explained by confounding."

Commonly Prescribed

Fralick noted that apixaban and rivaroxaban are the two most commonly prescribed direct oral anticoagulants for the prevention of stroke in AF patients.

Both agents showed benefits over warfarin in large-scale, randomized registration trials. No randomized controlled trials have directly compared the two drugs, although such a trial is now underway.

"Until we know the results of the randomized trial, we have to make decisions as to which agent to use on the basis of observational and indirect comparisons. Several such studies have been done previously and have suggested a benefit of apixaban over rivaroxaban," Fralick said.

"Our study is one of the largest observational comparisons of these two agents to date," he said.

For the study, the researchers used data from a large US insurance claims database to identify patients newly prescribed either apixaban or rivaroxaban for AF. Using propensity scoring, they matched 39,351 patients who were prescribed apixaban with the same number of patients who were prescribed rivaroxaban.

The mean age of the patients was 69 years, and 40% were women. The mean follow-up was 288 days for new apixaban users and 291 days for new rivaroxaban users.

The incidence rate of ischemic stroke or systemic embolism was 6.6 per 1000 person-years for those prescribed apixaban, compared with 8.0 per 1000 person-years for those prescribed rivaroxaban (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.68 – 0.98).

For patients prescribed apixaban, the rate of gastrointestinal bleeding or intracranial hemorrhage was also lower (12.9 per 1000 person-years) compared with those prescribed rivaroxaban (21.9 per 1000 person-years). This corresponds to an HR of 0.58 (95% CI, 0.52 – 0.66).

The authors report that the findings were robust across several subgroups and sensitivity analyses, including a population restricted to patients older than 70 years.

The study also included a negative control and found that the rate of heart failure hospitalization was similar for patients prescribed apixaban and those prescribed rivaroxaban (HR, 1.00).

"This finding provides reassurance that our analyses were internally valid but, of course, does not guarantee it because the risk factors for heart failure and our study outcomes may differ," they comment.

Because of the large sample of patients included in the study, the researchers were able to assess the rate of potential rare adverse events. Recent case reports suggest that rivaroxaban might be associated with hepatitis and leukocytoclastic vasculitis, they note.

"Similar to the clinical trial literature, we determined that hepatitis occurs relatively commonly in this patient population (about 12 cases per 1000 person-years); however, we did not identify a higher rate for patients prescribed rivaroxaban," they state.

They also assessed the rate of vasculitis and determined it to be low (about 1 per 1000 person-years), and although a slightly lower rate was found for apixaban, the confidence intervals are wide and include the possibility of null effect, they say.

Fralick says the mechanism behind the results may have to do with the pharmacokinetics of the two drugs. "Apixaban seems to produce a more stable anticoagulation compared with rivaroxaban. That may have something to do with the fact it is given twice daily, whereas rivaroxaban is given once a day. Apixaban seems to have hit the sweet spot of anticoagulation," he commented.

In their article, the researchers cite a randomized study of healthy participants in which apixaban 5 mg twice daily was associated with more consistent and stable anti–factor Xa activity (higher trough and lower peak anti–factor Xa activity) compared with rivaroxaban 20 mg once daily.

"The lower peak anti–factor Xa levels in patients receiving apixaban might account for the lower rates of major bleeding, whereas the higher trough levels may explain the lower rates of stroke and systemic embolism," they suggest.

"These proposed mechanisms are supported further by a recent study of patients with nonvalvular atrial fibrillation that showed lower peak prothrombin time (a measure associated with anticoagulant activity) and higher trough prothrombin time with apixaban compared with rivaroxaban," they add.

"Until we have randomized data comparing the different agents, I would say that there is mounting evidence (including our current study) that apixaban is safer and more effective than rivaroxaban," Fralick concluded.

He said he uses apixaban as his first-choice anticoagulant for AF patients, "the exception being patients who say they would much prefer a once-daily dosage to keep compliant, and then I would prescribe rivaroxaban."

Unadjusted Stroke Rates Equal

In his critique of the study, Patel pointed out that it is a retrospective observational analysis and that the investigators could not determine why one agent was chosen by a physician for one set of patients rather than other patients.

"When they just show the raw rates of observed stroke or systemic embolism in the paper, there is no difference. The rate of stroke with rivaroxaban is 7.27 and with apixaban is 7.21. They then perform a variety of statistical analysis to control for the differences they see in patients (they can't control for the unmeasured differences that they don't have, such as renal function, hemoglobin, left ventricular ejection fraction) and conclude one is better than another," he notes.

Patel is also skeptical of the value of the "negative control" ― the risk for heart failure ― saying, "Depending on the underlying condition (atrial fibrillation), this rate may not be the same, and they don't have information on underlying left ventricular ejection fraction.

"Unfortunately, this study is not conclusive. We need randomized data, and until then, another conclusion could be that clinicians in practice are identifying the right patients to give the different agents to based on their clinical acumen (given the similar stroke rates)," he said.

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital. Fralick has disclosed no relevant financial relationships. Patel has received research funding to support the ROCKET AF trial and consultant/advisory board fees from Janssen and Bayer. Eikelboom has received consulting fees and/or honoraria and grant support from Astra-Zeneca, Bayer Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Pfizer, Janssen, Sanofi-Aventis, and Servier.

Ann Intern Med. Published online March 10, 2020. Abstract

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