Results of a large-scale observational study show that among patients aged 65 or older with atrial fibrillation, treatment with rivaroxaban compared with apixaban was associated with a significantly increased risk of major ischemic or hemorrhagic events.
The study was published online December 21 in the Journal of the American Medical Association.
The authors, led by Wayne Ray, PhD, Vanderbilt University School of Medicine, Nashville, Tennessee, note that although previous retrospective cohort studies have examined the comparative effectiveness of rivaroxaban and apixaban in atrial fibrillation, the current study "makes 3 distinct contributions to the evidence needed to guide clinical practice."
First, with more than 580,000 new users of rivaroxaban or apixaban, the current study is larger than previous studies, which enables more precise quantification of the occurrence of infrequent but clinically important events, such as fatal extracranial bleeding.
Second, in contrast to other studies, this study included a comparison of reduced doses of the two drugs, which showed an even larger benefit of apixaban; and thirdly, the primary study outcome was an integrated measure of the major benefits and harms of anticoagulation for patients with atrial fibrillation.
"Our results, along with those from previous observational studies and pharmacokinetic data on the drugs, suggest that apixaban should be the anticoagulant of choice for atrial fibrillation," Ray told theheart.org | Medscape Cardiology.
The authors explain that rivaroxaban and apixaban, both factor Xa inhibitors, now account for nearly all direct oral anticoagulant prescriptions for AF and are prescribed more frequently than warfarin. Two other direct oral anticoagulants are available ― dabigatran and edoxaban ― but are not widely used, Ray noted.
"Four years ago, we had a four-horse race in terms of new oral anticoagulants for AF, then it became a two-horse race between rivaroxaban and apixaban. Now it appears that apixaban has won the race," he commented.
However, Manesh Patel, MD, Duke University, Durham, North Carolina, who was the lead investigator in the ROCKET AF pivotal study of rivaroxaban vs warfarin, said he was surprised that this study was published in JAMA.
"There are clearly many unmeasured variables, and the unadjusted rates of almost every event (stroke and hemorrhages) were less with rivaroxaban, but only after adjustment is apixaban found to have lower rates," he told theheart.org | Medscape Cardiology.
Patel also pointed out that the reduced dose of apixaban was studied in only around 500 patients in randomized trials but was being used in 23% of Medicare patients in this study, suggesting that it is being used off-label in many patients "with higher observed event rates, but after adjustment somehow this leads to substantially better outcomes but no change in observed mortality."
"For me, this study just doesn't pass the sniff test," he added.
Still, authors of an accompanying editorial seem more satisfied that the results begin to suggest an advantage for apixaban.
Enrico G. Ferro, MD, Dhruv S. Kazi, MD, and Peter J. Zimetbaum, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts, say that although observational analyses are susceptible to confounding, "the robustness of the study findings to numerous sensitivity analyses is reassuring."
They note that these findings add to a body of literature suggesting that apixaban is associated with lower bleeding risk and possibly greater thromboembolic protection compared with rivaroxaban.
They point out that the first signal of the possible superiority of apixaban came from the pivotal trials that compared each of the drugs to warfarin. Rivaroxaban was found to be noninferior to warfarin in preventing stroke or systemic embolism with no significant differences in major bleeding or mortality, whereas apixaban was more effective than warfarin in preventing stroke or systemic embolism and significantly reduced major bleeding and all-cause mortality.
The editorialists conclude that: "The report by Ray et al represents the largest and most contemporary evidence from clinical settings on the differential effectiveness and safety associated with apixaban and rivaroxaban, adding that these investigators may have provided "reasonable assurance" that apixaban is more effective and safer than rivaroxaban for patients with atrial fibrillation.
The study included 581,451 Medicare beneficiaries with atrial fibrillation who initiated treatment between 2013 and 2018 with either apixaban (60.9%) or rivaroxaban (39.1%) and were followed for up to 4 years.
The primary outcome was a composite of major ischemic (stroke, systemic embolism) and hemorrhagic (intracerebral hemorrhage, other intracranial bleeding, or fatal extracranial bleeding) events.
After adjusting for baseline differences, patients who received rivaroxaban had a higher risk of the primary outcome (16.1/1000 person-years) than those on apixaban (13.4/1000 person-years), giving a hazard ratio (HR) of 1.18 (95% CI, 1.12 – 1.24) over a median follow-up of 174 days.
The rivaroxaban group had increased risk for both major ischemic events and major hemorrhagic events.
The increased risk with rivaroxaban was seen in both ischemic stroke (HR, 1.12) and hemorrhagic stroke (1.48), as well as nonfatal extracranial bleeding (HR, 2.07) and all-cause mortality (HR, 1.06).
The authors conclude that for 1000 patient-years of treatment, patients who received rivaroxaban had 2.7 additional strokes and 21.1 additional nonfatal bleeding events compared with patients who received apixaban.
Reduced doses of the drugs were taken by 23% of cohort. In this group, there was an even larger difference in the primary outcome between the two drugs (adjusted rate of 27.4 per 1000 person-years for rivaroxaban vs 21.0 per 1000 person-years for apixaban; HR, 1.28).
Pharmacokinetics Is Key
Ray suggested that the better results with apixaban could be explained by pharmacokinetic differences between the two drugs.
"The effects of these drugs are determined by their levels in the blood. At the optimum level there is good stroke prevention activity without much of an increase in bleeding. But this a very delicate balance and stable blood levels are crucial in this situation," he said.
"Rivaroxaban is given just once a day, and levels fluctuate a lot more than apixaban, which is dosed twice a day," he added. "Rivaroxaban produces higher highs at which bleeding risk is increased, and lower lows at which the stroke prevention effect is less than desired."
He believes the larger difference in the low-dose comparison reflects the sensitivity of the population taking the low doses of these medications.
"The low doses are used in the very elderly and frail patients and those with very low body mass or impaired kidney function. This population is extremely sensitive to blood levels of these drugs, so these patients are particularly susceptible to the effects of over- or under-coagulation."
Ray noted that this large study adds to previous smaller observational studies also suggesting lower events rates with apixaban vs rivaroxaban.
"There has been a trend in favor of apixaban before this study because of the more stable blood levels and the previous data suggesting that rivaroxaban causes more bleeding than apixaban. But our study provides more information and because of its large size has been able to look at the most serious type of bleeding, which the previous observational studies weren't able to do," he explained.
Asked for a comment on the study, a spokesperson from Johnson & Johnson, which markets rivaroxaban as Xarelto in the US, said: "Retrospective studies as such have limitations. Only prospective head-to-head clinical trials can directly compare the safety and efficacy of individual medicines. No such trial has been conducted for apixaban and rivaroxaban."
The spokesperson added: "Xarelto is the most studied factor Xa oral anticoagulant in the world with a proven efficacy and safety profile. All anticoagulants, or blood thinners, carry the risk of bleeding and the prescribing information for Xarelto has always warned of these risks."
The study was supported by a grant from the National Heart, Lung, and Blood Institute (NHLBI). Ray reported receiving grants from the NHLBI during the conduct of the study. The editorialists report no disclosures.
JAMA. Published online December 21. Abstract, Editorial
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Cite this: Rivaroxaban Tied to Higher Bleeding, Events vs Apixaban in AF - Medscape - Dec 22, 2021.