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Bleeding events attributable to concurrent use of warfarin and other medications in high-risk elderly: meta-analysis and Italian population-based investigation

  • Pharmacoepidemiology and Prescription
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Abstract

Purpose

The aim of this study was to estimate the proportion of bleedings that occurred among warfarin users attributable to the concomitant use of other medications. A general approach for measuring the impact of the prescriptive inappropriateness on drug adverse outcomes at the population level is described.

Methods

A meta-analysis was conducted to obtain summary relative risks of bleeding associated with concurrent use of warfarin and other medications compared to warfarin use alone. A population-based investigation was performed, in an Italian cohort of cardiopathic patients aged 65 years or older, to estimate the prevalence of concurrent users of warfarin and other medicaments. The population attributable fraction was computed by combining data on summary relative risks and prevalence of concurrent users.

Results

Concomitant use of warfarin and cotrimoxazole, amiodarone, quinolones, macrolides, platelet aggregation inhibitors, SSRIs, NSAIDs, and lipid-lowering agents was associated with an increased risk of bleeding. The corresponding attributable fractions were 3% (95% CI 2 to 4%), 21% (1 to 41%), 21% (17 to 25%), 9% (8 to 10%), 14% (12 to 16%), 6% (5 to 8%), 10% (1 to 20%), and 8% (0 to 18%), respectively.

Conclusions

More than half of bleeding events occurring among frail elderly using warfarin are attributable to a concomitant use of warfarin with certain drugs. Because some of these drugs appear to be essential for the treatment/prevention of cardiovascular conditions, and their concomitant use with warfarin could be acceptable in some cases, proper INR-monitoring and warfarin dose adjustments are requested.

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Acknowledgements

I-GrADE members: Nera Agabiti, Claudia Bartolini, Roberto Bernabei, Alessandra Bettiol, Stefano Bonassi, Achille Patrizio Caputi, Silvia Cascini, Alessandro Chinellato, Francesco Cipriani, Giovanni Corrao, Marina Davoli, Massimo Fini, Rosa Gini, Francesco Giorgianni, Ursula Kirchmayer, Francesco Lapi, Niccolò Lombardi, Ersilia Lucenteforte, Alessandro Mugelli, Graziano Onder, Federico Rea, Giuseppe Roberto, Chiara Sorge, Michele Tari, Gianluca Trifirò, Alfredo Vannacci, Davide Liborio Vetrano, Cristiana Vitale.

Funding

This study was funded by a research grant from AIFA—the Italian Medicines Agency—(project AIFA FARM9LBBBL), Rome, Italy. Data analyses were performed at the Laboratory of Healthcare Research & Pharmacoepidemiology, Dept. of Statistics and Quantitative Methods, University of Milano-Bicocca with grants from the Italian Ministry for University and Research (‘Fondo d’ Ateneo per la Ricerca’ portion, year 2015).

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Authors and Affiliations

  1. Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca, Via Bicocca degli Arcimboldi 8, Edificio U7, Milan, 20126, Italy

    Rosanna Irene Comoretto, Federico Rea & Giovanni Corrao

  2. Department of Neurosciences, Psychology, Drug Research and Children’s Health, University of Florence, Florence, Italy

    Ersilia Lucenteforte & Alessandro Mugelli

  3. Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy

    Gianluca Trifirò

  4. Department of Epidemiology, Lazio Regional Health Service, Rome, Italy

    Silvia Cascini

  5. Epidemiology Unit, Regional Agency for Healthcare Services of Tuscany, Florence, Italy

    Giuseppe Roberto

  6. Treviso Local Health Unit, Treviso, Italy

    Alessandro Chinellato

  7. Pharmacology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Salerno, Italy

    Amelia Filippelli

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  1. Rosanna Irene Comoretto
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on behalf of the Italian Group for Appropriate Drug prescription in the Elderly (I-GrADE)

Contributions

GC generated the study idea. GC and RIC wrote the final manuscript. RIC and FR performed the data analysis. EL, GT, SC, GR, and AC extracted the data and authorized their utilization. AM and AF assisted in interpreting the results under clinical prospective. All authors assisted the results interpretation and manuscript revision. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Rosanna Irene Comoretto.

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Conflict of interests

EL received research support from the Italian Agency of Drug (AIFA) that is not related to this study. AM received research support from the Italian Agency of Drug (AIFA), the Italian Ministry for University and Research (MIUR), Gilead, and Menarini. In the last 2 years, he received personal fees as speaker/consultant from Menarini Group, IBSA, Molteni, Angelini and Pfizer Alliance. None of these is related to this study. GT leads an academic pharmacoepidemiology team which runs project that are sponsored by pharmaceutical companies and that are not related to the topic of the paper. GC received research support from European Community (EC), European Medicine Agency (EMA), Italian Agency of Drug (AIFA), High Health Institute (ISS), Ministry for Health, and University and Research. He took part to a variety of projects that were funded by pharmaceutical companies (i.e., Novartis, GSK, Roche, AMGEN, and BMS). He also received honoraria as member of Advisory Board from Roche. None of these is related to this study. RIC, FR, LS, SC, GR, AC, and AF declare that they have no conflict of interest.

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Comoretto, R.I., Rea, F., Lucenteforte, E. et al. Bleeding events attributable to concurrent use of warfarin and other medications in high-risk elderly: meta-analysis and Italian population-based investigation. Eur J Clin Pharmacol 74, 1061–1070 (2018). https://doi.org/10.1007/s00228-018-2467-8

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