Association of DOACs with adverse outcomes in older patients with AF across frailty subgroups

Frailty and Clinical Outcomes of Direct Oral Anticoagulants Versus Warfarin in Older Adults With Atrial Fibrillation

Literature - Kim DH, Pawar A, Gagne JJ et al. - Annals of Internal Medicine 2021, doi:10.7326/M20-7141

Introduction and methods

Aim of the study

Direct oral anticoagulants (DOACs) have a good safety profile and may therefore be especially suited for older adults with frailty [1]. Choices for anticoagulant therapy (DOACs or warfarin) though are largely driven by risk assessment models for stroke and major bleeding [2-5] and frailty is not taken into account. It is unclear what the role of frailty is when choosing the type of anticoagulant therapy, and anticoagulants are underused in frail patients with AF [6,7]. Therefore, in this study, it was examined how frailty affected the effectiveness of a DOAC (dabigatran, rivaroxaban, or apixaban) on outcomes in older patients with AF.

Study design

This retrospective observational, 1:1 propensity score-matched study used Medicare data of prescription drug use and clinical events in older adults (≥65 years) with AF (including those with frailty). 3 Cohorts were created of AF patients who filled a prescription for 1 of the 3 DOACs or warfarin from the approval date: dabigatran (n=81,863) vs. warfarin (n=256,722), rivaroxaban (n=185,011) vs. warfarin (n=228,028), and apixaban (n=222,478) vs. warfarin (n=206,031). Frailty was measured using a validated claims-based frailty index (CFI) [8-11] (range from 0 to 1) consisting of 93 variables. Nonfrailty was defines as CFI<0.15 prefrailty as CFI of 0.15 to 0.24 and frailty as CFI ≥0.25.

Primary outcome

The primary outcomes was a composite end point of death, ischemic stroke, or major bleeding. Follow-up started the day after initiating the index drug and continued until a study outcome, disenrollment from Medicare, end of the study period, discontinuation of use of the index drug, switch to different anticoagulant, admission to nursing facility, enrollment in hospice care, initiation of dialysis or kidney transplantation.

Main results

Dabigatran versus warfarin

  • Over a median follow up of 72 days (IQR 33-143 days) rate of the composite end point per 1000 person-years was 63.5 for dabigatran users and 65.6 for warfarin users (HR 0.98, 95%CI: 0.92-1.05).
  • Dabigatran was associated with a lower rate of the composite end point than warfarin for the nonfrail group (HR 0.81, 95%CI: 0.68-0.97), but not for the prefrail or frail group (P for heterogeneity=0.027).
  • Dabigatran initiators had lower rates of ischemic stroke (HR 0.72, 95%CI: 0.58-0.89) and intracranial bleeding (HR 0.42, 95%CI: 0.33-0.53), similar rates of death and major bleeding and higher rate of major gastrointestinal bleeding (HR 1.44, 95%CI:1.27-1.63). There was no heterogeneity by frail status.

Rivaroxaban versus warfarin

  • Over a median follow-up of 82 days (IQR 33-156 days), rate of the composite end point per 1000 person-years was 77.8 for rivaroxaban users and 83.7 for warfarin users (HR 0.98, 95%CI: 0.94-1.02).
  • Rivaroxaban was associated with lower composite events than warfarin in the nonfrail group (HR 0.88, 95%CI:0.77-0.99), but not for the prefrail or frail group (P for heterogeneity=0.026).
  • Rivaroxaban initiators had lower rates of death (HR 0.91, 95%CI:0.86-0.97), ischemic stroke (HR 0.71, 95%CI: 0.61-0.83) and intracranial bleeding (HR 0.62, 95%CI:0.53-0.72) and higher rates of major bleeding (HR 1.09, 95%CI: 1.03-1.17) and major gastrointestinal bleeding (HR 1.40, 95%CI:1.29-1.52). There was heterogeneity by frailty status for major bleeding and major gastrointestinal bleeding.

Apixaban versus warfarin

  • Over a median follow-up of 84 days (IQR 33 to 157 days), the rate of the composite end point per 1000 person-years was 60.1 for apixaban users and 92.3 for warfarin users (HR 0.68, 95%CI:0.65-0.72).
  • This association was consistent across frailty subgroups (P for heterogeneity=0.080).
  • Apixaban initiators had lower rates of death (HR 0.82, 95%CI: 0.77-0.88), ischemic stroke (HR 0.63, 95%CI:0.54-0.74), major bleeding (HR 0.51, 95%CI:0.46-0.55), major gastrointestinal bleeding (HR 0.52, 95%CI:0.46-0.58) and intracranial bleeding (HR 0.51, 95%CI: 0.43-0.60). The associations were consistent across frailty subgroups.


This study using real-world data showed that the DOACs dabigatran and rivaroxaban were associated with lower rates of the composite end point compared to placebo in older patients with AF only in the non-frail group. Apixaban initiators had lower rates of the composite end point across all frailty subgroups.


1. Steffel J, Verhamme P, Potpara TS, et al; ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39:1330- 93. [PMID: 29562325] doi:10.1093/eurheartj/ehy136

2. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation. Chest. 2010;137:263-72. [PMID: 19762550] doi:10.1378/chest.091584

3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J. 2012;33:1500-10. [PMID: 22246443] doi:10.1093/eurheartj/ehr488

4. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093-100. [PMID: 20299623] doi:10.1378/chest.10-0134

5. Lip GY, Frison L, Halperin JL, et al. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR,Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol. 2011;57:173-80. [PMID: 21111555] doi:10.1016/j.jacc.2010.09.024

6. Perera V, Bajorek BV, Matthews S, et al. The impact of frailty on the utilisation of antithrombotic therapy in older patients with atrial fibrillation. Age Ageing. 2009;38:156-62. [PMID: 19151165] doi:10.1093/ageing/afn293

7. Lefebvre MC, St-Onge M, Glazer-Cavanagh M, et al. The effect of bleeding risk and frailty status on anticoagulation patterns in octogenarians with atrial fibrillation: the FRAIL-AF study. Can J Cardiol. 2016;32:169-76. [PMID: 26277091] doi:10.1016/j.cjca.2015 05.012

8. Kim DH, Schneeweiss S, Glynn RJ, et al. Measuring frailty in Medicare data: development and validation of a claims-based frailty index. J Gerontol A Biol Sci Med Sci. 2018;73:980-7.[PMID: 29244057] doi:10.1093/gerona/glx229

9. Kim DH, Glynn RJ, Avorn J, et al. Validation of a claims-based frailty index against physical performance and adverse health outcomes in the Health and Retirement Study. J Gerontol A Biol Sci Med Sci. 2019;74:1271-6. [PMID: 30165612] doi:10.1093/gerona/gly197

10. Kim DH, Patorno E, Pawar A, et al. Measuring frailty in administrative claims data: comparative performance of four claims-based frailty measures in the U.S. Medicare data. J Gerontol A Biol Sci Med Sci. 2020;75:1120-5. [PMID: 31566201] doi:10.1093/gerona/glz224

11. Gautam N, Bessette L, Pawar A, et al. Updating International Classification of Diseases Ninth Revision to Tenth Revision of a claims-based frailty index. J Gerontol A Biol Sci Med Sci. 2020. [PMID: 32529241] doi:10.1093/gerona/glaa150

Find this article online at Annals of Internal Medicine

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free