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Abstract
Aim: Although several genetic and nongenetic factors are associated with warfarin dose, approximately 40% of variability remains unexplained. An as yet unexplored factor is medication adherence. Here, we investigate the influence of adherence on response to warfarin and on pharmacogenetic analyses of association. Patients & methods: A total of 311 patients starting warfarin were followed-up prospectively, and adherence was measured at 1, 8 and 26 weeks. The association between adherence and warfarin response was tested, and the additional proportion of variability in response explained by adherence was assessed. Results: Significant associations were found between adherence and achievement of stable dose and time taken to achieve it, with nonadherers taking longer. Adjusting for adherence increased the proportion of explained variability in treatment response by up to 8%. Conclusion: Given the significant contribution of adherence to drug response, we recommend that consideration is given to the value of assessing adherence when designing future pharmacogenetic studies of warfarin and other drugs.
Original submitted 19 July 2012; Revision submitted 26 November 2012
Author contributions
M Pirmohamed, PR Williamson and DA Hughes were involved in conception and design of the study; AL Jorgensen and PR Williamson planned and undertook the statistical analysis; AL Jorgensen monitored the data; AL Jorgensen wrote the manuscript; PR Williamson, M Pirmohamed and DA Hughes reviewed and provided comments on the manuscript; CH Toh facilitated patient identification and quality assurance of the coagulation-based laboratory tests; and A Hanson and D van Eker recruited the patients, designed the case report form and validated the patient data. All authors have approved the final version of the manuscript.
Acknowledgements
The authors are grateful to all the clinicians, nurses, pharmacists and patients who were involved in the study. The authors would also like to thank the Wellcome Trust Sanger Institute for genotyping. The authors would also like to thank the other members of the UK prospective study on warfarin pharmacogenetics for their input into the whole program.
Financial & competing interests disclosure
The authors thank the UK Department of Health for funding the study. M Pirmohamed is a NIHR Senior Investigator. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.