Researchers develop frailty index, offer guidance for DOAC choices

Using a claims-based frailty index (CFI), researchers have successfully developed guidance for choosing DOAC treatment versus warfarin in older patients with atrial fibrillation (AFib).

“We found that apixaban was associated with a 32% relative reduction in the hazard of the composite end point of death, ischemic stroke, or major bleeding compared with warfarin in the overall population and consistent relative reductions of 27% to 39% across frailty subgroups. Although dabigatran and rivaroxaban were not associated with a lower hazard of the composite end point than warfarin in the overall population, we found a 12% to 19% relative reduction in the hazard for the non-frail subgroup and little or no reduction for the prefrail and frail subgroups,” concluded wrote Dae Hun Kim, MD, MPH, ScD, of Brigham and Women’s Hospital, Harvard Medical School, Hebrew SeniorLife, and Beth Israel Deaconess Medical Center, Boston, and colleagues. They published their results in the Annals of Internal Medicine.

“The safety profile of DOACs may be particularly desirable for older adults with frailty, who are at high risk for falls and drug-related adverse events. Currently, decisions about anticoagulant therapy are mainly driven by risk assessment models for ischemic stroke and major bleeding without consideration of frailty. 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 AFib,” they added.

Thus, Kim and fellow researchers undertook this retrospective, observational study to assess outcomes in Medicare beneficiaries with AFib by frailty level after they initiated DOAC therapy with dabigatran, rivaroxaban, or apixaban, compared with warfarin.

Patients were grouped into three cohorts:

  • Dabigatran versus warfarin (n=81,863 and 256,722, respectively)
  • Rivaroxaban versus warfarin (n=185,011 and 228,028)
  • Apixaban versus warfarin (n=227,478 and 206,031)

Frailty was measured using a CFI comprised of 93 variables that are defined in codes for diagnosis, health services, and durable medical equipment use in the year before treatment initiation.

“The CFI has been validated against gait speed, grip strength, frailty phenotype, deficit-accumulation frailty index, and severe disability,” noted Kim and colleagues.

Dabigatran and rivaroxaban initiators were younger than warfarin initiators and healthier, with lower mean claims-based frailty index (CFI) and CHA2DS2-VASc scores, lower mean comorbidity score, and a lower prevalence of comorbidities. Apixaban initiators were older (mean age: 77.3 years); had higher mean CFI, CHA2DS2-VASc, HAS-BLED, and mean comorbidity scores; and a higher prevalence of comorbidities and medication use. These patients also had the highest number of ED visits and hospitalizations, and the lowest use of home health and skilled-nursing facility services.

The primary end point was a composite of death, ischemic stroke, or major bleeding by frailty level. Secondary endpoints included these outcomes individually, as well as major gastrointestinal and intracranial bleeding.

Dabigatran Versus Warfarin

Researchers first compared dabigatran with warfarin. After a median follow-up of 72 days, the rate of the composite end point per 1,000 person-years was 63.5 for dabigatran initiators and 65.6 for warfarin initiators (HR: 0.98 95% CI: 0.92-1.05). Kim et all found evidence of heterogeneity by frailty level on the hazard ratio scale (P for heterogeneity=0.027) but not according to the rate difference (RD) scale (P for heterogeneity=0.23).

Further, in patients in the non-frail subgroup, dabigatran was associated with a lower rate of the composite end point compared with warfarin (HR: 0.81; 95% CI: 0.68-0.97). The same was not true in the prefrail or frail groups.

For the secondary endpoints, dabigatran initiators had:

  • Lower rates of ischemic stroke (HR: 0.72; 95% CI: 0.58-0.89; RD: −2.1; 95% CI: −3.5 to −0.8) and intracranial bleeding (HR: 0.43; 95% CI: 0.33-0.53; RD: −4.9 (95% CI: −6.2 to −3.6).
  • Similar rates of death HR: 1.03; 95% CI: 0.93-1.13; RD: 0.4; 95% CI: −2.5 to 3.4) and major bleeding (HR: 0.97; 95% CI: 0.88-1.07; RD: −1.7; 95% CI: −4.6 to 1.3).
  • A higher rate of major gastrointestinal bleeding (HR: 1.44; 95% CI: 1.27-1.63; RD: 6.3; 95% CI: 4.0-8.7).

Kim and colleagues found no statistically significant evidence for heterogeneity according to frailty on either the HR or RD scales.

Rivaroxaban Versus Warfarin

The next comparison was between rivaroxaban and warfarin. After a median follow-up of 82 days, the rate of the composite end point per 1,000 person-years was 77.8 in rivaroxaban initiators, compared with 83.7 for warfarin initiators (HR: 0.98; 95% CI: 0.94-1.02; RD: −5.9; 95% CI: −9.4 to −2.4).

In measuring HRs, they found that rivaroxaban was associated with a lower rate of the composite end point compared with warfarin in the non-frail subgroup but not the prefrail or frail subgroup (P for heterogeneity=0.026).

RD scale measurements showed that rivaroxaban was associated with fewer composite events in the non-frail and frail subgroups (P for heterogeneity=0.040).

In secondary endpoints, rivaroxaban initiators had:

  • Lower mortality rates (HR: 0.91; 95% CI: 0.86-0.97; RD: −5.7; 95% CI: −8.2 to −3.2).
  • Lower ischemic stroke rates (HR: 0.71; 955 CI: 0.61-0.83 RD: −2.6; 95% CI: −3.6 to −1.5).
  • Lower intracranial bleeding rates (HR: 0.62; 95 %CI: 0.53-0.72; RD: −3.6; 95% CI: −4.7 to −2.5).
  • Higher rates of major bleeding (HR: 1.09; 95% CI: 1.03-1.17; RD: 1.4; 95% CI: −1.0 to 3.8).
  • Higher rates of major gastrointestinal bleeding (HR: 1.40; 95% CI: 1.29-1.52; RD: 6.2; 95% CI: 4.4-8.1).

“There was statistically significant evidence for heterogeneity by frailty for major bleeding and major gastrointestinal bleeding on both the HR and RD scales. The positive association between rivaroxaban and bleeding events seemed stronger for the prefrail subgroup. No statistically significant heterogeneity was found for death, ischemic stroke, and intracranial bleeding,” wrote researchers.

Apixaban Initiators Versus Warfarin

Finally, Kim et al compared apixaban initiators with warfarin. After a median follow-up of 84 days, the rate of the composite endpoint per 1,000 person-years was 60.1 versus 92.3, respectively. They noted that the beneficial association with apixaban was consistent across all frailty subgroups on the HR scale (P for heterogeneity=0.080) but was greater on the RD scale for the frail subgroup (P for heterogeneity˂0.001).

For secondary endpoints, apixaban initiators had:

  • Lower rates of death (HR: 0.82; 95% CI: 0.77-0.88; RD: −10.3; 95% CI: −13.2 to −7.3).
  • Lower rates of ischemic stroke (HR: 0.63; 95% CI: 0.54-0.74; RD: −4.0; 95% CI: −5.3 to −2.7).
  • Lower rates of major bleeding (HR: 0.51; 95% CI: 0.46-0.55; RD: −19.3; 95% CI: −21.7 to −17.0).
  • Lower rates of major gastrointestinal bleeding (HR: 0.52; 95% CI: 0.46-0.58; RD: −10.6; 95% CI: −12.3 to −8.8).
  • Lower rates of intracranial bleeding (HR: 0.51; 95% CI: 0.43-0.60; RD: −5.1; 95% CI: −6.3 to −3.8).

The researchers noted: “The associations were consistent across frailty subgroups on the HR scale, but RD estimates were greater as frailty increased (P for heterogeneity˂0.05 for all secondary endpoint).

“In conclusion, our study provides evidence to guide the choice of a DOAC versus warfarin for older adults with AFib. Only apixaban was consistently associated with lower rates of the composite end point of death, ischemic stroke, and major bleeding than warfarin across all frailty levels. Our novel approach to evaluating heterogeneity of the emulated effectiveness of drug therapy using a CFI can be extended to claims-based pharmacoepidemiologic studies to generate evidence that is unavailable from clinical trials,” concluded Kim and fellow researchers.

Study limitations include the inability to measure clinical variables that affect the efficacy and safety of oral anticoagulant use, unmeasured confounding, and short duration of all follow-ups.

  1. Researcher provides evidence to guide the choice of a DOAC versus warfarin for older adults with AFib.

  2. Only apixaban was consistently associated with lower rates of the composite end point of death, ischemic stroke, and major bleeding than warfarin across all frailty levels.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was funded by the National Institute on Aging.

Kim reported grants from the National Institutes of Health during the conduct of the study, and personal fees from Alosa Health outside the submitted work.

Cat ID: 913

Topic ID: 74,913,282,494,730,913,255,925