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

Anna-Leena Vuorinen, Mika Lehto, Mikko Niemi, Kari Harno, Juha Pajula, Mark van Gils, Jaakko Lähteenmäki, Anna-Leena Vuorinen, Mika Lehto, Mikko Niemi, Kari Harno, Juha Pajula, Mark van Gils, Jaakko Lähteenmäki

Abstract

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: CYP2C9; INR; VKORC1; bleeding; pharmacogenomics; warfarin.

Conflict of interest statement

Dr Juha Pajula, Dr Mark Van Gils, and Mr Jaakko Lahteenmaki reports grant from Business Finland, grants from Oy Karl Fazer AB, grants from Novartis Finland Oy, grants from Pfizer Oy, grants from Roche Diagnostics Oy, grants from Avaintec Oy, grants from Crown CRO Oy, grants from Mediconsult Oy, grants from Biobank Cooperative Finland, outside the submitted work. The authors declare that they have no other competing interests in this work.

© 2021 Vuorinen et al.

Figures

Figure 1
Figure 1
Participant recruitment and eligibility.
Figure 2
Figure 2
Cumulative incidence of bleeding events.
Figure 3
Figure 3
Cumulative incidence of thromboembolic events.

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