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 trialLiterature - 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) , which is associated with polypharmacy, adverse events, and frailty potentially altering response to anticoagulation . 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 .
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.