Comparisons Between Oral Anticoagulants Among Older Nonvalvular Atrial Fibrillation Patients

Steven Deitelzweig, MD; Allison Keshishian, MPH; Xiaoyan Li, PhD; Amiee Kang, MPH; Amol D. Dhamane, MS; Xuemei Luo, PhD; Neeraja Balachander, MD, PhD; Lisa Rosenblatt, MD, MPH; Jack Mardekian, PhD; Xianying Pan, MS; Anagha Nadkarni, PhD; Manuela Di Fusco, MS; Alessandra B. Garcia Reeves, MS; Huseyin Yuce, PhD; Gregory Y. H. Lip, MD


J Am Geriatr Soc. 2019;67(8):1662-1671. 

In This Article

Abstract and Introduction


Objectives: Older adult patients are underrepresented in clinical trials comparing non–vitamin K antagonist oral anticoagulants (NOACs) and warfarin. This subgroup analysis of the ARISTOPHANES study used multiple data sources to compare the risk of stroke/systemic embolism (SE) and major bleeding (MB) among very old patients with nonvalvular atrial fibrillation (NVAF) prescribed NOACs or warfarin.

Design: Retrospective observational study.

Setting: The Centers for Medicare & Medicaid Services and three US commercial claims databases.

Participants: A total of 88 582 very old (aged ≥80 y) NVAF patients newly initiating apixaban, dabigatran, rivaroxaban, or warfarin from January 1, 2013, to September 30, 2015.

Measurements: In each database, six 1:1 propensity score matched (PSM) cohorts were created for each drug comparison. Patient cohorts were pooled from all four databases after PSM. Cox proportional hazards models were used to estimate hazard ratios (HRs) of stroke/SE and MB.

Results: The patients in the six matched cohorts had a mean follow-up time of 7 to 9 months. Compared with warfarin, apixaban (HR = .58; 95% confidence interval [CI] = .49-.69), dabigatran (HR = .77; 95% CI = .60-.99), and rivaroxaban (HR = .74; 95% CI = .65-.85) were associated with lower risks of stroke/SE. For MB, apixaban (HR = .60; 95% CI = .54-.67) was associated with a lower risk; dabigatran (HR = .92; 95% CI = .78-1.07) was associated with a similar risk, and rivaroxaban (HR = 1.16; 95% CI = 1.07-1.24) was associated with a higher risk compared with warfarin. Apixaban was associated with a lower risk of stroke/SE and MB compared with dabigatran (stroke/SE: HR = .65; 95% CI = .47-.89; MB: HR = .60; 95% CI = .49-.73) and rivaroxaban (stroke/SE: HR = .72; 95% CI = .59-.86; MB: HR = .50; 95% CI = .45-.55). Dabigatran was associated with a lower risk of MB (HR = .77; 95% CI = .67-.90) compared with rivaroxaban.

Conclusion: Among very old NVAF patients, NOACs were associated with lower rates of stroke/SE and varying rates of MB compared with warfarin.


The presence of atrial fibrillation (AF) is an independent risk factor for stroke, and the percentage of stroke events that could be attributed to AF increases significantly with age.[1] The stroke and major bleeding (MB) risk stratification schemas, CHA2DS2-VASc and HAS-BLED, consider age as a risk factor for stroke/thromboembolism and MB, respectively, in patients with AF.[2,3]

Clinical evidence favors treatment with oral anticoagulants (OACs) to prevent stroke/systemic embolism (SE) in very old adults given that the benefits are considered to outweigh the risk of MB.[4,5] Randomized clinical trials (RCTs) demonstrated that non–vitamin K antagonist oral anticoagulants (NOACs), including apixaban, dabigatran, edoxaban, and rivaroxaban, have a lower frequency of stroke/SE and a noninferior risk of MB compared with conventional therapy, such as vitamin K antagonists (VKAs), among patients aged 75 years and older.[6–8]

The 2018 European Heart Rhythm Association Practical Guide suggests that use of NOACs rather than VKA led to a larger risk reduction among older patients[9] due to the higher risk for stroke/SE and MB in this population. A systematic review among AF patients (aged 65 y or older) comparing NOACs with VKAs suggested that NOACs have favorable results for hemorrhagic stroke and intracranial hemorrhage (ICH).[10] Using the Fit-for-the-Aged (FORTA) classification and Delphi process, warfarin, dabigatran, edoxaban, and rivaroxaban were labeled B (beneficial; safely and effectively treat AF), and apixaban was labeled A (absolutely; most beneficial risk-benefit ratio) for the treatment of AF in patients aged 65 years or older.[11]

Although OACs are recommended for patients with AF and a high CHA2DS2-VASc score, it was consistently reported that less than 50% of patients aged 80 to 89 years are treated with OACs, with reasons pertaining to safety concerns rather than related to efficacy, such as fear of bleeding, perceived harm greater than benefit, poor health, and geriatric syndromes.[12] Moreover, the financial burden and health plan restrictions related to the prescription of NOACs might also serve as potential barriers to treatment. More than 50% of the nonvalvular atrial fibrillation (NVAF) patients are 80 years or older, yet only one-third of the patients enrolled in the four landmark NVAF trials of the NOACs were 75 years of age or older.[13] As the older adult US population increases, this becomes an increasingly important group to study.

This analysis of older patients (aged ≥80 y) in the ARISTOPHANES (Anticoagulants for Reduction in Stroke: Observational Pooled analysis on Health Outcomes and Experience of Patients [NCT03087487]) study aimed to provide complementary information for this underrepresented population by evaluating and comparing the rates of stroke/SE and MB among NVAF patients newly prescribed apixaban, dabigatran, rivaroxaban, or warfarin.