Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial

Abstract

Objective To determine whether the treatment effect of apixaban versus warfarin differs with increasing numbers of concomitant drugs used by patients with atrial fibrillation.Design Post hoc analysis performed in 2015 of results from ARISTOTLE (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation)—a multicentre, double blind, double dummy trial that started in 2006 and ended in 2011.Participants 18 201 ARISTOTLE trial participants.Interventions In the ARISTOTLE trial, patients were randomised to either 5 mg apixaban twice daily (n=9120) or warfarin (target international normalised ratio range 2.0-3.0; n=9081). In the post hoc analysis, patients were divided into groups according to the number of concomitant drug treatments used at baseline (0-5, 6-8, ≥9 drugs) with a median follow-up of 1.8 years. Main outcome measures Clinical outcomes and treatment effects of apixaban versus warfarin (adjusted for age, sex, and country).Results Each patient used a median of six drugs (interquartile range 5-9); polypharmacy (≥5 drugs) was seen in 13 932 (76.5%) patients. Greater numbers of concomitant drugs were used in older patients, women, and patients in the United States. The number of comorbidities increased across groups of increasing numbers of drugs (0-5, 6-8, ≥9 drugs), as did the proportions of patients treated with drugs that interact with warfarin or apixaban. Mortality also rose significantly with the number of drug treatments (P<0.001), as did rates of stroke or systemic embolism (1.29, 1.48, and 1.57 per 100 patient years, for 0-5, 6-8, and ≥9 drugs, respectively) and major bleeding (1.91, 2.46, and 3.88 per 100 patient years, respectively). Relative risk reductions in stroke or systemic embolism for apixaban versus warfarin were consistent, regardless of the number of concomitant drugs (Pinteraction=0.82). A smaller reduction in major bleeding was seen with apixaban versus warfarin with increasing numbers of concomitant drugs (Pinteraction=0.017). Patients with interacting (potentiating) drugs for warfarin or apixaban had similar outcomes and consistent treatment effects of apixaban versus warfarin.Conclusions In the ARISTOTLE trial, three quarters of patients had polypharmacy; this subgroup had an increased comorbidity, more interacting drugs, increased mortality, and higher rates of thromboembolic and bleeding complications. In terms of a potential differential response to anticoagulation therapy in patients with atrial fibrillation and polypharmacy, apixaban was more effective than warfarin, and is at least just as safe.Trial registration ARISTOTLE trial, ClinicalTrials.gov NCT00412984.

Risk–Benefit Profile of Direct-Acting Oral Anticoagulants in Established Therapeutic Indications: An Overview of Systematic Reviews and Observational Studies

“…With regard to renal injury, fewer data exist; a meta-analysis of ten RCTs found no differences in the risk of renal failure (compared with VKAs), although rivaroxaban showed a trend for increased risk and an increased risk of creatinine elevation (RR 1.25, 95 % CI 1.08–1.45; I 2  = 0 %) [25]The impact of polypharmacy and drug–drug interactionsPost-analyses of ROCKET-AF (rivaroxaban) and ARISTOTLE (apixaban) revealed that two-thirds and three-quarters of patients had polypharmacy, respectively. This subgroup had a higher risk of bleeding but not stroke (rivaroxaban), increased mortality, and higher rates of thromboembolic and bleeding complications (apixaban) [105, 106]. The precise magnitude and impact of drug–drug interactions requires database analysis in the near future, when the use of DOACs reaches a plateau [94]The need for measuring anticoagulant activityAt the time of approval, no need for INR monitoring was promoted as a key advantage favoring DOACs over VKAs.…”

Relevance of Polypharmacy for Clinical Outcome in Patients Receiving Vitamin K Antagonists

“…Vitamin K antagonists (VKAs) are known to interact with various prescription and over‐the‐counter medicines and increase the risk of bleeding, which makes it important to closely monitor VKA‐treated patients on multiple medications . In this context, anticoagulated subjects with polypharmacy often have an unpredictable dose‐response relationship to oral anticoagulation, in which polypharmacy was shown to be a risk indicator for cardiac death and anticoagulation‐related events such as bleeding and thromboembolic events . In the context of direct‐acting oral anticoagulants (DOACs), data from the ROCKET‐AF, ARISTOTLE, and Hokusai‐VTE trials suggested that DOACs are more effective than and at least as safe as warfarin, regardless of the number of drugs taken .…”

“…In this context, anticoagulated subjects with polypharmacy often have an unpredictable dose‐response relationship to oral anticoagulation, in which polypharmacy was shown to be a risk indicator for cardiac death and anticoagulation‐related events such as bleeding and thromboembolic events . In the context of direct‐acting oral anticoagulants (DOACs), data from the ROCKET‐AF, ARISTOTLE, and Hokusai‐VTE trials suggested that DOACs are more effective than and at least as safe as warfarin, regardless of the number of drugs taken . However, due to different pharmacokinetic properties of phenprocoumon and warfarin, the clinical outcome of patients receiving long‐acting VKA phenprocoumon might vary from recent reports with warfarin.…”

Assessing medication burden and polypharmacy: finding the perfect measure

“…Indeed, recent work has been focused on generating evidence about the effectiveness of polypharmacy among older adults with multimorbidity and geriatric syndromes including frailty, falls, and functional impairment. Post hoc analysis of the apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial showed that patients with atrial fibrillation treated with apixaban had consistently lower major bleeding rates compared with warfarin treatment, although the magnitude of benefit decreased with the increasing polypharmacy exposure [11]. In community-dwelling older men with ischemic heart disease, greater adherence to optimal therapy was associated with lower risk of institutionalization and mortality, stratified according to presence of geriatric syndromes [12].…”