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

Lisa Eggebrecht, MSc; Markus Nagler, Dipl-Psych; Sebastian Göbel, MD; Heidrun Lamparter, Dipl-Psych; Karsten Keller, MD; Bianca Wagner, MPharm; Marina Panova-Noeva, MD, MSc, PhD; Vincent ten Cate, MSc; Christoph Bickel, MD; Michael Lauterbach, MD; Christine Espinola-Klein, MD; Roland Hardt, MD; Thomas Münzel, MD; Jürgen H. Prochaska, MD; Philipp S. Wild, MD, MSc


J Am Geriatr Soc. 2019;67(3):463-470. 

In This Article

Abstract and Introduction


Background: Although polypharmacy is associated with a negative clinical outcome in various settings and commonly observed in patients receiving oral anticoagulation therapy, evidence on the relevance for the clinical outcome of anticoagulated patients is currently limited. The aim of the study was to investigate the effect of polypharmacy on the clinical outcomes among patients taking phenprocoumon.

Design: Prospective cohort study.

Setting: Regular medical care.

Participants: Information on 2011 individuals receiving vitamin K antagonists was available for analysis from the prospective multicenter thrombEVAL study.

Measurements: Data were obtained from clinical visits, computer-assisted interviews, and laboratory measurements. Information on clinical outcome was obtained during a 3-year follow-up period and subsequently validated via medical records.

Results: The prevalence of polypharmacy (five drugs or more) was 84.1% (n = 1691). Quality of anticoagulation therapy assessed by time in therapeutic range was lower in individuals on five to eight drugs and nine drugs or more (70.7% and 64.7%, respectively) compared with subjects without polypharmacy (73.4%). In addition, a significantly higher variability of international normalized ratio measurements was found in the presence of polypharmacy. The cumulative incidence of bleeding, hospitalization, and all-cause mortality, but not for thromboembolic events, increased across groups of medication. In adjusted Cox regression analysis, polypharmacy is an independent risk factor for bleeding (hazard ratio [HR]≥ 9 drugs vs 1–4 drugs = 1.62; 95% confidence interval [CI] = 1.04–2.52; p = .033); hospitalization (HR≥ 9 drugs vs 1–4 drugs = 1.60; 95% CI = 1.26–2.03; p < .001; and all-cause mortality (HR≥ 9 drugs vs 1–4 drugs = 2.16; 95% CI = 1.43–3.27; p < .001) in a dose-dependent relationship. Per additional drug, bleeding risk was increased by 4%.

Conclusions: Polypharmacy influences the quality of anticoagulation therapy and translates into an elevated risk of adverse events in anticoagulated patients. This suggests that additional medication intake in such patients should be critically reviewed by physicians, and it highlights the importance of initiating investigations aimed at reducing multiple medication intake.


Demographic changes with increasing life expectancy will lead to a growing number of patients with multiple chronic conditions in the near future.[1] Multimorbidity is commonly accompanied by the use of multiple drugs in a single patient, a condition known as polypharmacy,[2] most often defined as a constant intake of more than four drugs by a patient. It is increasingly prevalent in daily clinical practice.[3–5] Unfortunately, polypharmacy was described as associated with a higher risk of adverse drug reactions, drug-drug interactions, poor adherence to medical therapy, lower quality of life, and a higher frequency of hospitalization.[6,7]

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.[8] 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.[9,10] 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.[10–12] 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. There have not yet been any studies investigating the association between polypharmacy, quality of oral anticoagulation therapy, and clinical outcome in subjects taking phenprocoumon.

Therefore, the aim of this analysis was to evaluate the impact of polypharmacy on the quality of anticoagulation therapy and subsequent clinical outcome in patients receiving the long-acting VKA phenprocoumon.