DOAC treatment safe and effective in AF despite multi-morbidity

Outcomes of Apixaban versus warfarin in patients with atrial fibrillation and multi-morbidity: Insights from the ARISTOTLE trial

Literature - Alexander KP, Brouwer MA, Mulder H et al. - American Heart Journal 2018; S0002-8703(18)30296-5

Introduction and methods

Patients aged ≥70 years with atrial fibrillation (AF) often have multi-morbidity (≥3 comorbid conditions) [1], which is associated with polypharmacy, adverse events, and frailty potentially altering response to anticoagulation [2]. This post-hoc analysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial assessed the association between multi-morbidity and both efficacy and safety of apixaban compared with warfarin in older patients with AF.

The multicenter, double-blind ARISTOTLE trial compared apixaban with warfarin in 16,800 patients (aged ≥55 years old) with documented AF or atrial flutter with ≥1 risk factor for thromboembolism between 2006 and 2011, with a median follow-up of 1.8 years (IQR: 1.3-2.3). Eligible patients were randomized to receive apixaban 5 mg twice daily or dose-adjusted warfarin with a target INR of 2.0-3.0. A reduced dose of apixaban 2.5 mg twice daily was used for those patients with ≥2 of the following criteria at baseline: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.

Patients were divided into groups based on the number of comorbidities: 0-2 (no multi-morbidity [36%]), 3-5 (moderate multi-morbidity [51%]) and ≥6 (high multi-morbidity [13%]). The primary efficacy outcome was stroke or systemic embolism (SE) and the primary safety outcome was major bleeding according to the International Society on Thrombosis and Hemostasis (ISTH) criteria [3].

Main results

Multi-morbidity and clinical outcomes

  • AF patients with high or moderate multi-morbidity experienced significantly more stroke/SE or ischemic stroke, compared to patients without multi-morbidity, with HRs up to 2.04 for death in the high multi-morbidity group. The HR for MI with high multi-morbidity differed about 2-fold from the HR with moderate multi-morbidity (HR: 3.15 vs. 1.55), and a similar difference was seen for death (HR: 3.56 vs. 1.66).
  • In AF patients with high or moderate multi-morbidity more major bleedings, major/CRNM bleedings were observed, compared to patients without multi-morbidity, with HRs up to 1.89 for major bleedings with high multi-morbidity.
  • Concerning the net benefit endpoints, high and moderate multi-morbidity resulted in more strokes/SE/major bleeding (HR adj: 1.92, 95%CI: 1.59-2.31, P<0.0001 and HR adj: 1.42, 95%CI: 1.24-1.64, P<0.0001, respectively) and strokes/SE/major bleedings/death (HR adj: 2.657, 95%CI: 2.323-3.039, P<0.0001 and HR adj: 1.546, 95%CI: 1.391-1.718, P<0.0001) in patients with AF, compared to those without multi-morbidity.

Multi-morbidity and effect of apixaban

  • There were no interactions between multi-morbidity group and treatment effects, with a favorable profile of apixaban as compared with warfarin.
  • The risk of major bleeding increased by 14% for every increase of one co-morbidity (HR adj 1.14, 95%CI: 1.09-1.18, P<00001). The HR for major bleeding with apixaban vs. warfarin remained significant in favor of apixaban at each selected co-morbidity level.
  • There was no significant interaction between co-morbidity as a continuous variable and treatment effect (P-interaction=0.10) with a benefit of apixaban, compared with warfarin across the different numbers of comorbidities.
  • There was no interaction between polypharmacy and multi-morbidity for the outcome of major bleeding (P-interaction=0.30).


In this post-hoc analysis of the ARISTOTLE trial, multi-morbidity was associated with an increased risk of stroke/SE, death, and major bleeding, however, efficacy and safety of apixaban compared with warfarin were preserved in older AF patients with multi-morbidity. These data support the use of apixaban for stroke prevention in AF among vulnerable patients with multi-morbidity. Further research is needed into the safety and efficacy of apixaban in the most complex AF patients.


1. Chamberlain AM, Alonso A, Gersh BJ, et al. Multimorbidity and the risk of hospitalization and death in atrial fibrillation” A population-based study. Am Heart J 2017;185:74-84

2. Pilotto A, Gallina P, Copetti M, et al. Warfarin treatment and all-cause mortality in community

dwelling older adults with atrial fibrillation: a retrospective observational study. J Am Geriatr Soc


3. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic

medicinal products in non-surgical patients. J Thromb Haemost 2005;3(4):692-694

Find this article online at Am Heart J

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