Thromboembolic Events in Users of Warfarin Treated with Different Skeletal Muscle Relaxants
Charles E. Leonard,
Colleen M. Brensinger,
Warren B. Bilker,
Samantha E. Soprano,
Neil Dhopeshwarkar,
Todd E. H. Hecht,
Scott E. Kasner,
Edith A. Nutescu,
Anne Holbrook,
Matthew Carr,
Darren M. Ashcroft,
Cheng Chen,
Sean Hennessy
Affiliations
Charles E. Leonard
Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Colleen M. Brensinger
Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Warren B. Bilker
Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Samantha E. Soprano
Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Neil Dhopeshwarkar
Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Todd E. H. Hecht
Division of General Internal Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Scott E. Kasner
Division of Vascular Neurology, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Edith A. Nutescu
Department of Pharmacy Practice and Center for Pharmacoepidemiology and Pharmacoeconomic Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA
Anne Holbrook
Division of Clinical Pharmacology and Toxicology, Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada
Matthew Carr
Center for Pharmacoepidemiology and Drug Safety, Division of Pharmacy & Optometry, School of Health Sciences, University of Manchester, Manchester M13, UK
Darren M. Ashcroft
Center for Pharmacoepidemiology and Drug Safety, Division of Pharmacy & Optometry, School of Health Sciences, University of Manchester, Manchester M13, UK
Cheng Chen
Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Sean Hennessy
Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Background and Objectives: Warfarin and a skeletal muscle relaxant are co-treatments in nearly a quarter-million annual United States (US) office visits. Despite international calls to minimize patient harm arising from anticoagulant drug interactions, scant data exist on clinical outcomes in real-world populations. We examined effects of concomitant use of warfarin and individual muscle relaxants on rates of hospitalization for thromboembolism among economically disadvantaged persons. Materials and Methods: Using 1999–2012 administrative data of four US state Medicaid programs, we conducted 16 retrospective self-controlled case series studies: half included concomitant users of warfarin + one of eight muscle relaxants; half included concomitant users of an inhaled corticosteroid (ICS) + one of eight muscle relaxants. The ICS analyses served as negative control comparisons. In each study, we calculated incidence rate ratios (IRRs) comparing thromboembolism rates in the co-exposed versus warfarin/ICS-only exposed person-time, adjusting for time-varying confounders. Results: Among ~70 million persons, we identified 8693 warfarin-treated subjects who concomitantly used a muscle relaxant, were hospitalized for thromboembolism, and met all other inclusion criteria. Time-varying confounder-adjusted IRRs ranged from 0.31 (95% confidence interval: 0.13–0.77) for metaxalone to 3.44 (95% confidence interval: 1.53–7.78) for tizanidine. The tizanidine finding was robust after quantitatively adjusting for negative control ICS findings, and in numerous prespecified secondary analyses. Conclusions: We identified a potential >3-fold increase in the rate of hospitalized thromboembolism in concomitant users of warfarin + tizanidine vs. warfarin alone. Alternative explanations for this finding include confounding by indication, a native effect of tizanidine, or chance.
