Physicians' Academy for Cardiovascular Education

Polypharmacy is associated with higher rates of adverse clinical outcomes in AF patients

Jaspers Focks J et al., BMJ 2016

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

Jaspers Focks J, Brouwer MA, Wojdyla DM, et al.
BMJ 2016;353:i2868


Polypharmacy, generally defined as the use of five or more concomitant drug treatments, is related to having several comorbidities [1,2]. Polypharmacy increases the risk of death and more bleeding complications and moreover, may alter the response to specific therapies due to more drug interactions, like anticoagulation for atrial fibrillation (AF) patients [3,4]. These disadvantages may influence clinical decision making and can lead to under-treatment, particularly in older AF patients, which, in turn, contributes to increased adverse outcomes [5-7].
For patients with AF, apixaban has been shown to be more effective and safer than warfarin [8,9]. Although there are data supporting that the apixaban benefit compared with warfarin was irrespective of age [10], the effect of polypharmacy specifically is not known, since there are older patients without comorbidities, and younger patients with comorbidities.

In this post hoc analysis of the ARISTOTLE trial (comparing apixaban with warfarin for reduction of stroke and other thromboembolic events (SSE) in AF), the association between the number of drugs used and the extent of comorbidity and adverse outcomes was evaluated, in 18,201 AF patients, with a median follow-up of 1.8 years. Moreover, the relative treatment effect of apixaban versus warfarin was assessed in relation to the number of concomitant drug treatments. Patients were categorised as using 0-5, 6-8 and ≥9 concomitant drugs.  

Main results

  • The median number of drug treatments used was 6 (IQR: 5-9) and polypharmacy was present in 13,932 (76.5%) patients.   
  • 53% (2385/4474) of patients enrolled in North America used ≥9 drugs, compared with 10-21% for the other regions.  
  • The median number of represented drug classes increased from 2 (IQR: 2-3) to 5 (IQR: 4-5), for patients using 0-5 drugs and ≥9 or more drugs, respectively.
  • Event rates for the primary SSE efficacy endpoint: 1.29 per 100 patient years (PY) for patients using 0-5 drugs, 1.57 per 100 PY for those using ≥9 drugs (P<0.001).
  • There was a 2-fold increased risk for all-cause death for patients using ≥9 compared with those using 0-5 concomitant drugs (P<0.001).
  • Using 0-5 drugs as a reference group, the risk of major bleeding was adjusted HR for 6-8 drugs: 1.24; 95% CI: 1.04 - 1.49, adjusted HR for ≥9 drugs: 1.72; 95% CI: 1.41 - 2.10.
  • Event rates for the net benefit outcome (combined endpoint of SSE, major bleeding, and all-cause death): 5.24 per 100 PY for 0-5 drugs, 6.59 per 100 PY for 6-8 drugs, 8.92 per 100 PY for ≥9 drugs (P<0.001).
  • For the primary efficacy outcome, risk reductions of apixaban vs. warfarin were consistent, irrespective of the number of concomitant drugs used (P interaction = 0.82).
  • Relative risk reductions for apixaban vs. warfarin regarding major bleeding decreased with increasing number of concomitant drugs (P interaction=0.017), with absolute rate reductions per 100 PY of 1.28 for 0-5 drugs, 0.82 for 6-8 drugs and 0.66 for ≥9 drugs.


In the ARISTOTLE trial population, polypharmacy was common and associated with higher comorbidity, higher mortality, and higher event rates of thromboembolic complications and major bleeding. Apixaban was more effective than, and at least as safe as warfarin, regardless of the number of drugs taken, however the benefit with apixaban compared to warfarin on major bleeding decreased with higher number of concomitant drugs.
Find this article online at BMJ


1. Jyrkkä J, Enlund H, Korhonen MJ, et al. Patterns of drug use and factors associated with polypharmacy and excessive polypharmacy in elderly persons: results of the Kuopio 75+ study: a cross-sectional analysis. Drugs Aging 2009;26:493-503.
2. Gnjidic D, Hilmer SN, Blyth FM, et al. Polypharmacy cutoff and outcomes: five or more medicines were used to identify community dwelling older men at risk of different adverse outcomes. J Clin Epidemiol 2012;65:989-95.
3. Nieuwlaat R, Olsson SB, Lip GYH, et al. Euro Heart Survey Investigators Euro Heart Survey on Atrial Fibrillation. Guideline-adherent antithrombotic treatment is associated with improved outcomes compared with undertreatment in high-risk patients with atrial fibrillation. Am Heart J 007;153:1006-12.
4. Scowcroft AC, Lee S, Mant J. Thromboprophylaxis of elderly patients with AF in the UK: an analysis using the General Practice Research Database (GPRD) 2000-2009. Heart 2013;99:127-32.
5. Proietti M, Raparelli V, Olshansky B, et al. Polypharmacy and major adverse events in atrial fibrillation: observations from the AFFIRM trial. Clin Res Cardiol 2016;105:412-20.
6. Piccini JP, Hellkamp AS, Washam JB, et al. Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Circulation 2016;133:352-60.
7. Leiss W, Méan M, Limacher A, et al. Polypharmacy is associated with an increased risk of bleeding in elderly patients with venous thromboembolism. J Gen Intern Med 2015;30:17-24.
8. Connolly SJ, Eikelboom J, Joyner C, et al. AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17.
9. Granger CB, Alexander JH, McMurray JJV, et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
10. Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J 2014;35:1864-72.