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


This study aimed at assessing the consequences of polypharmacy for anticoagulation-specific and nonspecific outcome among participants with oral anticoagulation treatment. To our knowledge, this is the first study investigating the impact of polypharmacy on the quality of anticoagulation therapy and subsequent clinical outcome of patients receiving the long-acting VKA phenprocoumon. In this prospective study of a real-life sample of individuals on oral anticoagulants, 84% of participants were taking five or more medications including their oral anticoagulant. The quality of oral anticoagulation therapy, assessed by TTR and variability of INR measurements, declined with a higher number of drugs. Polypharmacy was related to higher rates of adverse clinical outcomes. Finally, the data demonstrate that polypharmacy was associated with clinically relevant bleeding, hospitalization, and all-cause mortality independent of age, sex, and clinical profile, but not with thrombotic or thromboembolic events.

In general, it is difficult to compare present results with findings of previous studies due to varying classifications of polypharmacy applied in the literature.[21–23] Thus far, there is no consensus definition for polypharmacy, despite an increasing frequency of this condition in clinical practice.[23–25] Previous evidence on the occurrence of polypharmacy among anticoagulated subjects is rare.[26] The prevalence of polypharmacy in the current sample is far higher than rates reported for population-based cohorts (ranging from 4% to 42%).[24,27,28] Despite the challenges faced in comparing polypharmacy investigations, it is clear that polypharmacy is highly prevalent in anticoagulated subjects. This highlights that particular attention should be paid to anticoagulated subjects with polypharmacy who in turn could potentially benefit from more intensive and adequate anticoagulation monitoring.

Prior studies investigated the effect of polypharmacy on a range of health outcomes including falls, adverse drug events, hospitalization, and measures of cognition.[6,29,30] Fewer studies, however, have specifically examined the influence on safety and efficacy end points in oral anticoagulation therapy. In the present analysis on individuals with predominantly phenprocoumon treatment, a high number of drug substances was independently associated with bleeding events, hospitalization, and all-cause mortality. This main finding is in line with previous observations on other anticoagulants.[9–11,31] Focks et al performed a post hoc analysis in the ARISTOTLE trial and argued that polypharmacy is associated with a higher risk of major bleeding (HR = 1.72 for ≥9 vs 0–5 medications; 95% CI = 1.41-2.01; p < .0001).[10]

Atrial fibrillation patients are more commonly affected by traditional cardiovascular risk factors and concomitant diseases than participants with other indications for oral anticoagulation therapy (ie, prosthetic heart valves) and hence exhibit a different pattern of drug use.[11,21] Interestingly, patients using four or more medications and who were managed by professional anticoagulation clinics did not experience an elevated risk of major bleeding.[21] Additionally, in the current analysis the number of co-medications was not statistically related significantly to the incidence and risk of thromboembolic events. This finding is likely due to limitations of sample sizes to detect differences in infrequent outcomes (eg, thromboembolism). Of note, the occurrence of venous embolism (ie, pulmonary embolism and deep vein thrombosis) was higher among subjects on low drug use. Similar to the present data, various reports have demonstrated that polypharmacy is not associated with systemic embolism or stroke,[9,11] leaving the exact pathologic mechanism to be revealed.[32]

The association between polypharmacy and mortality was also shown by several prior studies[2,9,11,33] but not all.[22,34,35] Importantly, in the present data HRs were higher when comparing the category of one to four drugs to nine or more drugs than to five to eight drugs, which supports a dose-response relationship between polypharmacy and adverse health outcomes.

TTR is known to be a major determinant of efficacy and safety of VKA treatment[36] and is stated to be much lower in the class of nine or more medications compared with the group without polypharmacy in the present analysis. On one hand, this could, at least in part, explain the higher bleeding risk. On the other hand, it should be noted that subjects with high drug use spend a higher proportion both in above but also below the therapeutic target range than patients with low drug use. Thus higher variability of INR measurements in the presence of polypharmacy, which is likely to be caused by drug-drug interactions, might be indicative for the increased bleeding risk. Other reasons for more variable INR measures in the polypharmacy group could be more frequent medication changes, poor adherence, or malignancy.

It cannot be disregarded that a higher drug intake is accompanied by more adverse clinical conditions,[31,37] which makes the assumption plausible that a larger number of co-medications is simply an indicator of higher comorbidity and mortality.[2,38] Because subjects on severe polypharmacy were older and sicker, the observed association between marked polypharmacy, hemorrhagic events, and all-cause mortality could theoretically at least partly be explained by potential uncontrolled confounders, such as unknown present diseases, acute infections, changes in VKA dosing, or genetic factors. However, in the current analysis, this association was still observed after adjustment for the CCI that covers 19 major disease categories weighted according to their prognostic impact on patient survival.[20]