Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial.
OBJECTIVE
To determine whether the treatment effect of apixaban versus warfarin differs with increasing numbers of concomitant drugs used by patients with atrial fibrillation.


METHODS
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.


METHODS
18 201 ARISTOTLE trial participants.


METHODS
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.


METHODS
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.
Department of Cardiology, Radboud University Nijmegen Medical Centre, PO box 9101, 6500 HB Nijmegen, Netherlands Jeroen.Jaspersfocks@radboudumc.nl.
Jeroen
J
Jaspers Focks
Department of Cardiology, Radboud University Nijmegen Medical Centre, PO box 9101, 6500 HB Nijmegen, Netherlands.
Marc A
MA
Brouwer
Duke Clinical Research Institute, Durham, NC, USA.
Daniel M
DM
Wojdyla
Duke Clinical Research Institute, Durham, NC, USA.
Laine
L
Thomas
Duke Clinical Research Institute, Durham, NC, USA.
Renato D
RD
Lopes
Duke Heart Center, Duke University Medical Center, Durham, NC, USA.
Jeffrey B
JB
Washam
Department of Cardiology, Universidad de La Frontera, Temuco, Chile.
Fernando
F
Lanas
Department of Pharmacology and Clinical Research, St John's Medical College and Research Institute, Bangalore, India.
Denis
D
Xavier
Department of Medicine, Hospital Unit West, Herning, Denmark.
Steen
S
Husted
Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Upsala University, Uppsala, Sweden.
Lars
L
Wallentin
Duke Clinical Research Institute, Durham, NC, USA.
John H
JH
Alexander
Duke Clinical Research Institute, Durham, NC, USA.
Christopher B
CB
Granger
Department of Cardiology, Radboud University Nijmegen Medical Centre, PO box 9101, 6500 HB Nijmegen, Netherlands.
Freek W A
FW
Verheugt
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000188:drug therapy*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D019338:Polypharmacy; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects; D012307:Risk Factors; D020521:Stroke / Q000517:prevention & control; D013923:Thromboembolism / Q000517:prevention & control; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000925:Anticoagulants; D065692:Cytochrome P-450 CYP3A Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin