Apixaban Appears Safer, More Effective Than Rivaroxaban in Medicare Study

When older adults with atrial fibrillation (AF) are starting on a direct oral anticoagulant (DOAC) for stroke prevention, they may be better off with apixaban than rivaroxaban.

In a study of claims data from more than 580,000 Medicare beneficiaries, new users of rivaroxaban (Xarelto; Bayer/Janssen) had greater risks of a range of adverse outcomes—including major ischemic and hemorrhagic events—compared with those started on apixaban (Eliquis; Bristol Myers Squibb). Researchers led by Wayne Ray, PhD (Vanderbilt University School of Medicine, Nashville, TN), report their results in the December 21, 2021, issue of JAMA.

Asked about his confidence that the findings represent a true difference between the DOACs, and not due to the types of patients receiving each drug, Ray pointed out that before adjustment, apixaban-treated patients were actually the higher-risk group. If statistical measures to account for those differences weren’t successful, he said, “our thinking is that we may actually be underestimating the comparative benefits of apixaban, because for whatever reason in practice the higher-risk patients seem to be starting apixaban rather than rivaroxaban.”

Overall, “the findings of our study offer pretty compelling evidence that apixaban is the better drug,” Ray commented.

Placing the results in the context of prior research, Peter Zimetbaum, MD (Beth Israel Deaconess Medical Center, Boston, MA), who co-authored an editorial for the paper, had a similar take.

“There’s a fair amount of compelling evidence at this point that apixaban is probably safer than rivaroxaban from a bleeding perspective,” Zimetbaum told TCTMD, adding that this new analysis is a particularly well-done observational study. “Whether or not the efficacy data for stroke prevention is that compelling is less clear, but I’m fairly convinced that the bleeding risk with rivaroxaban is a little higher than it is with apixaban,” he said.

And that plays into Zimetbaum’s clinical decision-making. “I really view this as, in my practice, something where I think mostly about bleeding risk as opposed to efficacy in the average-risk AF patient,” he said, “and I would favor apixaban, particularly if there’s a history of GI bleeding.”

Greater Ischemic, Bleeding Risks With Rivaroxaban

DOACs have taken over from warfarin as the preferred anticoagulation choice for stroke prevention in AF, but questions remain about the comparative safety and efficacy of the various agents in the class, which have not been tested head-to-head in RCTs. The two most commonly prescribed DOACs are apixaban and rivaroxaban, and multiple observational studies—including one from March 2018 and October 2021—have indicated that outcomes might be better with apixaban.

This new analysis adds to those prior studies in multiple ways, Ray said, pointing to the very large number of patients, allowing the investigators to examine differences in lower-frequency events like fatal extracranial bleeding; the use of a primary outcome combining major ischemic and hemorrhagic events to better judge the relative benefits and risks of the two drugs; and the inclusion of patients receiving reduced doses of the anticoagulants.

For the study, the investigators looked at claims data on 581,451 Medicare beneficiaries 65 or older (mean age 77 years; 50.2% women) who started on one of the two DOACs between January 2013 and November 2018; in all, 61% received apixaban. Roughly a quarter of the patients (23.1%) were given a reduced dose.

The primary outcome was a composite of major ischemic events (stroke and systemic embolism) and hemorrhagic events (intracerebral hemorrhage, other intracranial bleeding, and fatal extracranial bleeding). Through a median follow-up of about 6 months, the rate was higher with rivaroxaban versus apixaban (16.1 vs 13.4 per 1,000 person-years; HR 1.18; 95% CI 1.12-1.24). As for the individual components of the endpoint, rivaroxaban was associated both with more major ischemic events (8.6 vs 7.6 per 1,000 person-years; HR 1.12; 95% CI 1.04-1.20) and with more major hemorrhagic events (7.5 vs 5.9 per 1,000 person-years; HR 1.26; 95% CI 1.16-1.36).

Other key outcomes favored apixaban, as well, including hemorrhagic stroke, ischemic stroke, fatal and nonfatal extracranial bleeding, GI bleeding, fatal ischemic/hemorrhagic events, and total mortality.

Risks of the primary outcome and of major hemorrhagic events were greater with rivaroxaban than with apixaban regardless of whether patients were taking a standard or reduced anticoagulant dose. And in patients on a reduced dose—but not a standard dose—rivaroxaban carried a higher risk of major ischemic events.

Making the Choice

In their editorial, Zimetbaum and colleagues Enrico Ferro, MD, and Dhruv Kazi, MD (Beth Israel Deaconess Medical Center), note that in the absence of head-to-head trials, which are unlikely at this point, the choice of one DOAC over another comes down to clinician preference, local practices, and insurance coverage.

To that last consideration, Zimetbaum told TCTMD that payers in New England have begun asking their patients to switch from apixaban to rivaroxaban despite increasing evidence that apixaban carries a lower risk of bleeding.

“The reason for that, presumably, is that the costs for the insurer have become much better for rivaroxaban than apixaban,” he said. “So then the question is: how do we feel about doing that as clinicians? And I think in some cases, not great. Certainly for me in my practice, for patients that I feel have a significant bleeding risk, particularly a GI bleeding risk, I’m going to be very reluctant to let that happen without an argument.”

He added that for patients with a moderate stroke risk and a bleeding risk that is not that high, it’s “probably an acceptable trade-off” to put patients on rivaroxaban to save on cost. But for patients with a high bleeding risk, he said, “I’m going to be concerned about that.”