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Quality of anticoagulation control and hemorrhage risk among African American and European American warfarin users.

ABSTRACT: OBJECTIVE:We evaluated whether percent time in target range (PTTR), risk of over-anticoagulation [international normalized ratio (INR)>4], and risk of hemorrhage differ by race. As PTTR is a strong predictor of hemorrhage risk, we also determined the influence of PTTR on the risk of hemorrhage by race. PARTICIPANTS AND METHODS:Among 1326 warfarin users, PTTR was calculated as the percentage of interpolated INR values within the target range of 2.0-3.0. PTTR was also categorized as poor (PTTR<60%), good (60?PTTR<70%), or excellent (PTTR?70%) anticoagulation control. Over-anticoagulation was defined as INR more than 4 and major hemorrhages included serious, life-threatening, and fatal bleeding episodes. Logistic regression and survival analyses were carried out to evaluate the association of race with PTTR (?60 vs. <60) and major hemorrhages, respectively. RESULTS:Compared with African Americans, European Americans had higher PTTR (57.6 vs. 49.1%; P<0.0001) and were more likely to attain 60?PTTR<70% (22.9 vs. 13.1%; P<0.001) or PTTR of at least 70% (26.9 vs. 18.2%; P=0.001). Older (>65 years) patients without venous thromboembolism indication and chronic kidney disease were more likely to attain PTTR of at least 60%. After accounting for clinical and genetic factors, and PTTR, African Americans had a higher risk of hemorrhage [hazard ratio (HR)=1.58; 95% confidence interval (CI): 1.04-2.41; P=0.034]. Patients with 60?PTTR<70% (HR=0.62; 95% CI: 0.38-1.02; P=0.058) and PTTR of at least 70% (HR=0.27; 95% CI: 0.15-0.49; P<0.001) had a lower risk of hemorrhage compared with those with PTTR less than 60%. CONCLUSION:Despite the provision of warfarin management through anticoagulation clinics, African Americans achieve a lower overall PTTR and have a significantly higher risk of hemorrhage. Personalized medicine interventions tailored to African American warfarin users need to be developed.

SUBMITTER: Limdi NA

PROVIDER: S-EPMC5657532 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Quality of anticoagulation control and hemorrhage risk among African American and European American warfarin users.

Limdi Nita A NA Brown Todd M TM Shendre Aditi A Liu Nianjun N Hill Charles E CE Beasley Timothy M TM

Pharmacogenetics and genomics 20171001 10

<h4>Objective</h4>We evaluated whether percent time in target range (PTTR), risk of over-anticoagulation [international normalized ratio (INR)>4], and risk of hemorrhage differ by race. As PTTR is a strong predictor of hemorrhage risk, we also determined the influence of PTTR on the risk of hemorrhage by race.<h4>Participants and methods</h4>Among 1326 warfarin users, PTTR was calculated as the percentage of interpolated INR values within the target range of 2.0-3.0. PTTR was also categorized as ...[more]

PMID: 28806200

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Project description:BACKGROUND: Cytochrome P4502C9 (CYP2C9) plays a vital role in drug metabolism. There has been an increased effort to identify polymorphisms within the gene and determine their clinical consequences. However, most of these efforts have focused on populations of European descent. Herein we report the influence of CYP2C9 genotype on warfarin dose among European American and African American patients. We also identify two new mutations; one in the coding region and one in the non-coding region of the CYP2C9 gene. METHODS: Patients (?20 years of age) are enrolled after obtaining medical, lifestyle and concomitant medication history. Changes in International Normalized Ratio (INR), warfarin dose, co-medications, diet, physical activity and the occurrence of complications are documented. CYP2C9 genotype was determined using PCR-RFLP and pyrosequencing. Differences in genotype frequencies and HWE assumptions were assessed using ?(2) statistics and exact tests. The genotype dose association was evaluated using multivariable linear regression. RESULTS: This report includes 490 patients (mean age 60.6 ± 15.6, 51.3% men). African American patients comprise 48.9% of the cohort with mean follow-up of 13.5 (±10.6) months. Both the CYP2C9 *2 and *3 allele were more frequent in European Americans (11.24%, 5.1%) compared to African Americans (1.1% and 1.8%). CYP2C9 *5 (0.9%), *6 (0.4%), and *11 (1.1%) variants were only observed in African Americans. The variant genotype is more frequent among European Americans compared to African Americans (29.8% vs. 9.73%, p<0.0001). Warfarin dose was significantly related to CYP2C9 genotype (p<0.0001) both in univariate and multivariate analyses. Multivariable race-specific analyses highlight the contribution of CYP2C9 genotype among European American but not among African American patients. CONCLUSION: The variant CYP2C9 genotype is more frequent among European Americans compared to African Americans. Among African Americans the variant genotype frequency is higher than previously reported. CYP2C9 genotype predicts warfarin dose in European Americans, but not in African Americans.

Project description:Previous studies in patients with atrial fibrillation showed that a history of heart failure (HF) could negatively impact anticoagulation quality, as measured by the average time in therapeutic range (TTR). Whether additional markers of HF severity are associated with TTR has not been investigated thoroughly. We aimed to examine the potential role of HF severity in the quality of warfarin control in patients with HF with reduced ejection fraction. Data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial were used to investigate the association between TTR and HF severity. Multivariable logistic regression models were used to examine the association of markers of HF severity, including New York Heart Association (NYHA) class, Minnesota Living with HF (MLWHF) score, and frequency of HF hospitalization, with TTR ?70% (high TTR). We included 1,067 participants (high TTR, N?=?413; low TTR, N?=?654) in the analysis. In unadjusted analysis, patients with a high TTR were older and less likely to have had strokes or receive other antiplatelet agents. Those patients also had lower NYHA class, better MLWHF scores, greater 6-minute walk distance, and lower frequency of HF hospitalizations. Multivariable analysis showed that NYHA class III and/or IV (Odds ratio [OR] 0.68 [95% confidence intervals [CIs] 0.49 to 0.94]), each 10-point increase in MLWHF score (i.e., worse health-related quality of life) (OR 0.92 [0.86 to 0.99]), and higher number of HF hospitalization per year (OR0.45 [0.30 to 0.67]) were associated with decreased likelihood of having high TTR. In HF patients with systolic dysfunction, NYHA class III and/or IV, poor health-related quality of life, and a higher rate of HF hospitalization were independently associated with suboptimal quality of warfarin anticoagulation control. These results affirm the need to assess the new approaches, such as direct oral anticoagulants, to prevent thromboembolism in this patient population.

Project description: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.

Dataset Information

Quality of anticoagulation control and hemorrhage risk among African American and European American warfarin users.

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Quality of anticoagulation control and hemorrhage risk among African American and European American warfarin users.

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