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Pharmacogenetics of Anticoagulation and Clinical Events in Warfarin-Treated Patients: A Register-Based Cohort Study with Biobank Data and National Health Registries in Finland

Authors Vuorinen AL, Lehto M, Niemi M, Harno K, Pajula J, van Gils M, Lähteenmäki J

Received 29 October 2020

Accepted for publication 19 January 2021

Published 8 March 2021 Volume 2021:13 Pages 183—195


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Irene Petersen

Anna-Leena Vuorinen,1 Mika Lehto,2,3 Mikko Niemi,4,5 Kari Harno,6 Juha Pajula,1 Mark van Gils,1 Jaakko Lähteenmäki7

1VTT Technical Research Centre of Finland, Tampere, Finland; 2Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland; 3University of Helsinki, Helsinki, Finland; 4Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland; 5Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland; 6Department of Health and Social Management, University of Eastern Finland, Kuopio, Finland; 7VTT Technical Research Centre of Finland, Espoo, Finland

Correspondence: Anna-Leena Vuorinen
VTT Technical Research Centre of Finland, P.O. Box 1300, Tampere, 33101, Finland
Tel +358 40 8485966
Email [email protected]

Purpose: To assess the association between VKORC1 and CYP2C9 variants and the incidence of adverse drug reactions in warfarin-treated patients in a real-world setting.
Materials and Methods: This was a register-based cohort study (PreMed) linking data from Finnish biobanks, national health registries and patient records between January 1st 2007 and June 30th 2018. The inclusion criteria were: 1) ≥ 18 years of age, 2) CYP2C9 and VKORC1 genotype information available, 3) a diagnosis of a cardiovascular disease, 4) at least one warfarin purchase, 5) regular INR tests. Eligible individuals were divided into two warfarin sensitivity groups; normal responders, and sensitive and highly sensitive responders based on their VKORC1 and CYP2C9 genotypes. The incidences of clinical events were compared between the groups using Cox regression models.
Results: The cohort consisted of 2508 participants (45% women, mean age of 69 years), of whom 65% were categorized as normal responders and 35% sensitive or highly sensitive responders. Compared to normal responders, sensitive and highly sensitive responders had fewer INR tests below 2 (median: 33.3% vs 43.8%, 95% CI: − 13.3%, − 10.0%) and more above 3 (median: 18.2% vs 6.7%, 95% Cl: 8.3%, 10.8%). The incidence (per 100 patient-years) of bleeding outcomes was 5.4 for normal responders and 5.6 for the sensitive and highly sensitive responder group (HR=1.03, 95% CI: 0.74, 1.44). The incidence of thromboembolic outcomes was 4.9 and 7.8, respectively (HR=1.48, 95% CI: 1.08, 2.03).
Conclusion: In a real-world setting, genetically sensitive and highly sensitive responders to warfarin had more high INR tests and required a lower daily dose of warfarin than normal responders. However, the risk for bleeding events was not increased in sensitive and highly sensitive responders. Interestingly, the risk of thromboembolic outcomes was lower in normal responders compared to the sensitive and highly sensitive responders.
Trial Registration: NCT04001166.

Keywords: pharmacogenomics, warfarin, bleeding, INR, CYP2C9, VKORC1

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