Dataset Information

Race-Specific Influence of CYP4F2 on Dose and Risk of Hemorrhage Among Warfarin Users.

ABSTRACT: OBJECTIVE:The p.V433M in cytochrome P450 4F2 (rs2108622, CYP4F2*3) is associated with a higher warfarin dose and lower risk of hemorrhage among European Americans. We evaluate the influence of CYP4F2*3 on warfarin dose, time to target international normalized ratio (INR), and stable dose, proportion of time spent in target range (PTTR), as well as the risk of overanticoagulation and hemorrhage among European and African Americans. DESIGN:CYP4F2*3 was genotyped in 1238 patients initiated on warfarin in a prospective inception cohort. Multivariable linear regression was used to assess warfarin dose and PTTR; proportional hazards analysis was performed to evaluate time to target INR and stable dose, overanticoagulation, and hemorrhage. SETTING:Two outpatient anticoagulation clinics. PARTICIPANTS:A total of 1238 anticoagulated patients. OUTCOMES:Warfarin dose (mg/day), time to target INR and stable dose, PTTR, overanticoagulation (INR more than 4), and major hemorrhage. RESULTS:Minor allele frequency for the CYP4F2*3 variant was 30.3% among European Americans and 8.4% among African Americans. CYP4F2*3 was associated with higher dose among European Americans but not African Americans. Compared to CYP4F2*1/*1, *1/*3 was associated with a statistically nonsignificant increase in dose (4.5%, p=0.22) and *3/*3 was associated with a statistically significant increase in dose (13.2%, p=0.02). CYP4F2 genotype did not influence time to target INR, time to stable dose, or PTTR in either race group. CYP4F2*3/*3 was associated with a 31% lower risk of over anticoagulation (p=0.06). Incidence of hemorrhage was lower among participants with CYP4F2 *3/*3 compared with *1/*3 or *1/*1 (incidence rate ratio = 0.45, 95% confidence interval 0.14-1.11, p=0.09). After controlling for covariates, CYP4F2 *3/*3 was associated with a 52% lower risk of hemorrhage, although this was not statistically significant (p=0.24). CONCLUSION:Possession of CYP4F2*3 variant influences warfarin dose among European Americans but not African Americans. The CYP4F2-dose, CYP4F2-overanticoagulation, and CYP4F2-hemorrhage association follows a recessive pattern with possession of CYP4F2*3/*3 genotype likely demonstrating a protective effect. These findings need further confirmation.

SUBMITTER: Shendre A

PROVIDER: S-EPMC4803610 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Race-Specific Influence of CYP4F2 on Dose and Risk of Hemorrhage Among Warfarin Users.

Shendre Aditi A Brown Todd M TM Liu Nianjun N Hill Charles E CE Beasley T Mark TM Nickerson Deborah A DA Limdi Nita A NA

Pharmacotherapy 20160314 3

<h4>Objective</h4>The p.V433M in cytochrome P450 4F2 (rs2108622, CYP4F2*3) is associated with a higher warfarin dose and lower risk of hemorrhage among European Americans. We evaluate the influence of CYP4F2*3 on warfarin dose, time to target international normalized ratio (INR), and stable dose, proportion of time spent in target range (PTTR), as well as the risk of overanticoagulation and hemorrhage among European and African Americans.<h4>Design</h4>CYP4F2*3 was genotyped in 1238 patients ini ...[more]

PMID: 26877068

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Project description:BackgroundAnticoagulation management is difficult in chronic kidney disease, with frequent supratherapeutic international normalized ratios (INRs ≥ 4) increasing hemorrhagic risk. We evaluated whether the interaction of INR and lower estimated glomerular filtration rate (eGFR) increases hemorrhage risk and whether patients with lower eGFRs experience slower anticoagulation reversal.Study designProspective cohort study.Setting & participantsWarfarin pharmacogenetics cohort (1,273 long-term warfarin users); warfarin reversal cohort (74 warfarin users admitted with INRs ≥ 4).PredictoreGFR, INR as time-dependent covariate, and their interaction in the pharmacogenetics cohort; eGFR in the reversal cohort.Outcomes & measurementsIn the pharmacogenetics cohort, hemorrhagic (serious, life-threatening, and fatal bleeding) risk was assessed using proportional hazards regression. In the reversal cohort, anticoagulation reversal was assessed from changes in INR, warfarin and metabolite concentrations, clotting factors (II, VII, IX, and X), and PIVKA-II (protein induced by vitamin K absence or antagonist II) levels at presentation and after reversal, using linear regression and path analysis.ResultsIn the pharmacogenetics cohort, 454 (35.7%) had eGFRs < 60 mL/min/1.73 m(2). There were 137 hemorrhages in 119 patients over 1,802 person-years of follow-up (incidence rate, 7.6 [95% CI, 6.4-8.9]/100 person-years). Patients with lower eGFRs had a higher frequency of INR ≥ 4 (P<0.001). Risk of hemorrhage was affected significantly by eGFR-INR interaction. At INR<4, there was no difference in hemorrhage risk by eGFR (all P ≥ 0.4). At INR≥4, patients with eGFRs of 30 to 44 and < 30 mL/min/1.73 m(2) had 2.2-fold (95% CI, 0.8-6.1; P=0.1) and 5.8-fold (95% CI, 2.9-11.4; P<0.001) higher hemorrhage risks, respectively, versus those with eGFRs ≥ 60 mL/min/1.73 m(2). In the reversal cohort, 35 (47%) had eGFRs < 45 mL/min/1.73 m(2). Patients with eGFRs < 45 mL/min/1.73 m(2) experienced slower anticoagulation reversal as assessed by INR (P=0.04) and PIVKA-II level (P=0.008) than those with eGFRs ≥ 45 mL/min/1.73 m(2).LimitationsLimited sample size in the reversal cohort, unavailability of antibiotic use and urine albumin data.ConclusionsPatients with lower eGFRs have differentially higher hemorrhage risk at INR ≥ 4. Moreover, because the INR reversal rate is slower, hemorrhage risk is prolonged.

Dataset Information

Race-Specific Influence of CYP4F2 on Dose and Risk of Hemorrhage Among Warfarin Users.

Publications

Race-Specific Influence of CYP4F2 on Dose and Risk of Hemorrhage Among Warfarin Users.

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