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

Strengths and Limitations

A key strength of the present study is that, unlike most reports in the literature, it is a real-world study that includes individuals on long-acting VKA phenprocoumon independently of their indication, which leads to a greater generalizability of the results for this patient group. Furthermore, outcome events were adjudicated by a clinical events committee, guaranteeing a high quality of outcome assessment. Finally, to ascertain the association between active substances with adverse health outcome, the analysis was based on the number of active substances rather than the number of drugs.

The study has potential limitations: (1) Data are shown for baseline medication use only. However, subjects with polypharmacy and several chronic medical conditions do not tend to change the number of medications substantially.[39] (2) Unmeasured confounding variables (eg, alcohol abuse, genetic factors, or dietary vitamin K intake) might have influenced the associations. Nevertheless, adjustment for a broad range of clinical conditions was conducted. (3) No information was available on the adherence to pharmacologic drug treatment. Then again, unlike in prescription databases, the self-reported data source (ie, prescription drug plan) is more likely to reflect the actual drug intake by patients. (4) The data set does not include over-the-counter products (eg, ibuprofen, acetylsalicylic acid), herbal remedies (eg, ginseng, Ginkgo biloba extract, garlic tablets, ginger), vitamins or dietary supplements (eg, fish oil tablets, cod liver oil), potentially leading to an underestimation of the results.

In conclusion, anticoagulated patients with polypharmacy show a significantly increased risk of bleeding, hospitalizations, and all-cause mortality. These results suggest that additional medication intake in such patients should be critically reviewed by physicians, and they highlight the importance of initiating investigations aimed at reducing multiple medication intake. Due to steadily increasing prescription rates of DOACs and the high prevalence of polypharmacy, future studies are needed to provide scientific evidence on the causal relationship between polypharmacy and hemorrhagic complications, and to understand the molecular mechanisms and potential mediators involved in this relationship.