Apixaban May Be Best DOAC for Frail, Older Patients With AF

In older patients with atrial fibrillation (AF), apixaban seems to improve outcomes relative to warfarin regardless of frailty status, whereas other direct oral anticoagulants (DOACs) appear beneficial only in nonfrail individuals, suggest the results of a Medicare claims-based analysis.

Apixaban (Eliquis; Bristol-Myers Squibb) was associated with a lower risk of a composite of death, ischemic stroke, or major bleeding in an overall comparison versus warfarin, as well as in the nonfrail, prefrail, and frail subgroups. There also were lower risks associated with the DOAC across secondary outcomes that included the individual components of the composite endpoint, major GI bleeding, and intracranial bleeding, with differences between groups enhanced in frail patients.

These broad apparent benefits were not seen with dabigatran (Pradaxa; Boehringer Ingelheim) or rivaroxaban (Xarelto; Bayer/Janssen), Dae Hyun Kim, MD, ScD (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA), and colleagues report.

The study, published online July 19, 2021, ahead of print in the Annals of Internal Medicine, “really confirmed the way a lot of physicians are prescribing these drugs,” Kim told TCTMD. Apixaban is the most commonly prescribed DOAC in recent years, especially for older patients, because bleeding risk is lower compared with the other agents in its class, he noted. “This gives some additional support to the way physicians are prescribing DOACs in patients with advanced age.”

John Dodson, MD (NYU Langone Health, New York, NY), who focuses on geriatric cardiology, said even though the findings don’t represent the final word on the subject, they do support an advantage for apixaban over other DOACs in older patients with frailty, adding that “it kind of tracks with our clinical experience.”

The investigators suggest that apixaban is safer than dabigatran and rivaroxaban because its renal clearance—and, thus, plasma drug concentration and bleeding risk—is lower, and Dodson said that’s a plausible hypothesis. “I can say certainly as a practicing cardiologist, in my older patients, I use pretty much exclusively apixaban because of the renal clearance issue,” he commented. “I think a lot of other cardiologists feel the same way about apixaban.”

The Impact of Frailty

In pivotal trials, the DOACs have been shown to be at least as effective as warfarin, with generally lower risks of major bleeding. They are also more convenient than warfarin in that they don’t require regular blood testing to check anticoagulation levels and have fewer interactions with food and other drugs.

“Currently, decisions about anticoagulant therapy are mainly driven by risk-assessment models for ischemic stroke and major bleeding without consideration of frailty,” Kim et al write. “Because of the poor representation of older adults with frailty and the lack of frailty assessment in clinical trials, the role of frailty in the choice between a DOAC and warfarin is uncertain, and anticoagulant use remains suboptimal in frail patients with AF.”

To see how frailty influences the comparison between DOACs and warfarin, the researchers performed a propensity score-matched analysis of fee-for-service Medicare claims data. The study included beneficiaries 65 and older who initiated dabigatran, rivaroxaban, apixaban, or warfarin for AF between 2010 and 2017. Mean age was 76 to 77, and roughly half of the patients were women. Frailty level was defined using a validated claims-based index.

This gives some additional support to the way physicians are prescribing DOACs in patients with advanced age. Dae Hyun Kim

Kim et al performed three separate analyses—each DOAC versus warfarin—in different cohorts meant to emulate the clinical trials. Median follow-up was relatively short, ranging from 72 to 84 days across the three comparisons. The number of patients was 158,730 in the dabigatran analysis, 275,944 in the rivaroxaban analysis, and 218,738 in the apixaban analysis.

Overall, only apixaban was associated with a lower rate of the composite of death, ischemic stroke, or major bleeding (60.1 vs 92.3 per 1,000 person-years; HR 0.68; 95% CI 0.65-0.72). The differences between the DOAC and warfarin groups did not reach significance for dabigatran (63.5 vs 65.6 per 1,000 person-years; HR 0.98; 95% CI 0.92-1.05) or rivaroxaban (77.8 vs 83.7 per 1,000 person-years; HR 0.98; 95% CI 0.94-1.02).

Frailty status came into play, however. Apixaban was associated with improved outcomes in the nonfrail, prefrail, and frail subsets, whereas a lower risk of the composite endpoint was seen only in the nonfrail patients for dabigatran (HR 0.81; 95% CI 0.68-0.97) and rivaroxaban (HR 0.88; 95% CI 0.77-0.99).

Apixaban was associated with lower rates of a variety of secondary outcomes as well, with results generally consistent across frailty groups. Dabigatran was associated with lower risks of ischemic stroke and intracranial bleeding and a higher risk of major GI bleeding versus warfarin, with no evidence that frailty influenced the findings. For rivaroxaban, associations with greater risks of major bleeding and major GI bleeding relative to warfarin appeared stronger in prefrail patients.

Incorporating Frailty Into Decision-Making

“This really confirms the current prescribing patterns of DOACs for older patients, especially [those with] advanced age and medical complexity, [in] that apixaban appears to be associated with lower clinical events across the frailty spectrum in older patients compared to warfarin but that dabigatran and rivaroxaban were only associated with lower events in the nonfrail subgroup,” Kim said.

However, he cautioned against comparing the DOACs based on these data since they were all analyzed separately against warfarin in different patient cohorts, which resulted in varying event rates in the comparator arm. “If the event rate is different in the reference group, then we really need to be careful not to make that conclusion prematurely,” Kim said, referring to any superiority of apixaban. Nevertheless, he added, the study “essentially supports use of apixaban in the really frail, older patient population.”

The question then is: how should clinicians be assessing frailty in everyday practice to guide treatment decisions?

Kim and Dodson both pointed out that there are validated tools to assess frailty but also noted that they aren’t used consistently in practice and that there isn’t agreement on the optimal approach in the first place. Most prescribing physicians, Kim said, use an “eyeball test” to size up a patient’s level of frailty.

The technique used in the current study—which takes into account healthcare use, diagnoses, and procedure codes in claims data to estimate frailty level—can be used in future studies to look at how this metric influences comparisons of different therapies, potentially guiding decision-making, Kim said.

For now, he said, “any assessment is better than no assessment, and it should be used more often especially before making a treatment decision.”

As for whether frailty should be assessed by physicians prescribing oral anticoagulants, Dodson said, “My argument is that we should be, but we still need to generate evidence about how that might change our recommendations.”

He said he envisions having a frailty assessment built into electronic health records 5 to 10 years in the future, which would overcome the challenges with administering existing evaluations, which can be time-consuming and difficult to in daily practice. “If you can have some way—which they’ve done in this paper—of having a claims-based assessment of frailty and a score that’s been validated, that’s a real advance,” Dodson said.