Pharmacogenetic association study of warfarin safety endpoints in Puerto Ricans

Abstract

Objective: This study was intended to determine the incidence rate of warfarin-related adverse events (e.g., bleeding) in Puerto Ricans and whether a genetic association between warfarin pharmacogenes and any of these adverse events was observed over the initiation period (i.e., the first 90 days of therapy).

Methods: We conducted an observational, retrospective cohort study of pharmacogenetic association in 122 warfarin-treated, male, Puerto Rican patients (69.9 +/- 9.6 years) from the Veterans Affair Caribbean Healthcare System (VACHS) who consented to participate. Genotyping was performed using the CYP2C9 and VKORC1 assays by Luminex. Event-free survival curves were estimated using the Kaplan-Meier method and analyzed by log-rank test. Cox regression models were constructed and hazard ratios (HR) calculated.

Results: Carriers of functional CYP2C9 and VKORC1 polymorphisms demonstrated a higher incidence rate of multiple adverse events (i.e., 5.2 vs. 1.0 cases per 100 patient-months; RR = 4.8, p = 0.12) than did wild types. A significant association was observed between multiple adverse events and carrier status (HR = 2.5; 95% CI: 1.0-6.3, p = 0.04). However, no significant associations between genotypes and individual outcomes over the first 90 days of therapy were found.

Conclusion: The association of CYP2C9 and VKORC1 genotypes and risks for adverse events due to exposure to warfarin was examined for the first time in Puerto Ricans. Despite a lack of association with individual events in this study population, our findings revealed a potential utility of genotyping for the prevention of multiple adverse events during warfarin therapy.

Figures

Figure 1

The effect of genotypes on time to primary/secondary events. Kaplan–Meier plots (A–C) represent the lack of association for the attainment of the first major bleeding episode (plot A), first above-range INR (INR>4, plot B), and first “non-severe” bleeding event (plot C) among participants after the initiation of standard warfarin therapy (age-adjusted fixed-dose scheme). The statistic in each panel represents the log-rank p-value for testing the equality of survival function. NNH (Number Needed to Harm).

Figure 2

The effect of carrier status on time to multiple adverse events. The Kaplan–Meier plot represents the marginal association of genotypes with multiple adverse events among participants after the initiation of standard warfarin therapy (age-adjusted fixed-dose scheme). The statistic represents the log-rank p-value for testing the equality of survival function. NNH (Number Needed to Harm).