Influence of Kidney Transplant Status on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage.
ABSTRACT: STUDY DESIGN:To assess whether warfarin dose requirement, anticoagulation control, and risk of hemorrhage differ in kidney transplant recipients (KTRs) compared with patients without kidney transplants (non-KTRs). DESIGN:Analysis of data from the Warfarin Pharmacogenetics Cohort, a prospective cohort of first-time warfarin users followed at two anticoagulation clinics. SETTING:Two outpatient anticoagulation clinics at two large, academic, tertiary care hospitals. PATIENTS:Adults aged 20 years or older starting warfarin for anticoagulation with a therapeutic international normalized ratio (INR) goal of 2-3 who were KTRs (n=65) or non-KTRs (n=1630). MEASUREMENTS AND MAIN RESULTS:Warfarin dose requirement, anticoagulation control, and risk of hemorrhage were assessed in each group. KTRs required an approximately 20% lower warfarin dose (4.7 vs 5.6 mg/day, p=0.0005) compared with non-KTRs. Genetic variants had similar effects on dose in both groups. Mean percentage of time in therapeutic range (PTTR) was similar among KTRs and non-KTRs. Although the proportion of patients achieving good anticoagulation control (PTTR ? 60%) was low in both groups, it was similar among KTRs and non-KTRs. KTRs had a higher risk of major hemorrhage (hazard ratio 2.1, p=0.0081), but this difference was not statistically significant after controlling for kidney function, clinical, and genetic factors. CONCLUSION:KTRs initiating warfarin require lower doses and closer monitoring to optimize anticoagulation therapy. Additional studies are needed to confirm these findings.
Project description: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.
Project description:OBJECTIVE:We assessed the influence of age on warfarin dose, percentage time in target range (PTTR), and risk of major hemorrhage. DESIGN:Warfarin users recruited into a large prospective inception cohort study were categorized into three age groups: young (younger than 50 yrs), middle aged (50-70 yrs), and elderly (older than 70 yrs). The influence of age on warfarin dose and PTTR was assessed using regression analysis; risk of major hemorrhage was assessed using proportional hazards analysis. Models were adjusted for demographic, clinical, and genetic factors. SETTING:Two outpatient anticoagulation clinics. PARTICIPANTS:A total of 1498 anticoagulated patients. OUTCOMES:Warfarin dose (mg/day), PTTR, major hemorrhage. RESULTS:Of the 1498 patients, 22.8% were young, 44.1% were middle aged, and 33.1% were elderly. After accounting for clinical and genetic factors, compared with young warfarin users, warfarin dose requirements were 10.6% lower among the middle aged and an additional 10.6% lower for the elderly. Compared with young patients, middle-aged and elderly patients spent more time in target international normalized ratio (INR) range (p<0.0001), despite having fewer INR assessments (p<0.0001). Compared with young warfarin users, absolute risk of hemorrhage was marginally higher among the middle aged (p=0.08) and significantly higher among the elderly (p=0.016). Compared with young warfarin users, after adjustment, the relative risk of hemorrhage increased by 31% for each age category (p=0.026). CONCLUSIONS:In a real-world setting, despite achieving better anticoagulation control, elderly patients had a higher risk of major hemorrhagic events. As the population ages and the candidacy for oral anticoagulation increases, strategies that mitigate the elevated risk of hemorrhage need to be identified.
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.
Project description:Candidates for chronic warfarin therapy often have co-morbid conditions, such as heart failure, with reduced left ventricular ejection fraction. Previous reports have demonstrated an increased risk of over-anticoagulation due to reduced warfarin dose requirement in patients with decompensated heart failure. However, the influence of left ventricular systolic dysfunction (LVSD), defined as left ventricular ejection fraction <40%, on warfarin response has not been evaluated. Here, we assess the influence of LVSD on warfarin dose, anticoagulation control (percent time in target range), and risk of over-anticoagulation (international normalized ratio >4) and major hemorrhage. Of the 1,354 patients included in this prospective cohort study, 214 patients (16%) had LVSD. Patients with LVSD required 11% lower warfarin dose compared with those without LVSD (p <0.001) using multivariate linear regression analyses. Using multivariate Cox proportional hazards model, patients with LVSD experienced similar levels of anticoagulation control (percent time in target range: 51% vs 53% p = 0.15), risk of over-anticoagulation (international normalized ratio >4; hazard ratio 1.01, 95% confidence interval 0.82 to 1.25; p = 0.91), and risk of major hemorrhage (hazard ratio 1.11; 95% confidence interval 0.70 to 1.74; p = 0.66). Addition of LVSD variable in the model increased the variability explained from 35% to 36% for warfarin dose prediction. In conclusion, our results demonstrate that patients with LVSD require lower doses of warfarin. Whether warfarin dosing algorithms incorporating LVSD in determining initial doses improves outcomes needs to be evaluated.
Project description:BACKGROUND AND OBJECTIVES:Dosing algorithms for warfarin incorporate clinical and genetic factors but may not account for the numerous comorbidities affecting patients who start warfarin while hospitalized. We aimed to determine whether these algorithms perform differently when warfarin is initiated for inpatients compared with outpatients. PATIENTS AND METHODS:We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial who were randomized to either pharmacogenetically or clinically guided warfarin dosing algorithms. Clinicians and participants were blinded to dose during the first 28 days. We compared groups, based on location at the time of the first warfarin dose request, in relation to the following outcomes: percentage of time in the therapeutic international normalized ratio (INR) range (PTTR) during the first 4 weeks, time to first therapeutic INR, time to maintenance dose, and the difference between predicted and observed maintenance doses. RESULTS:A total of 527 participants started warfarin as inpatients and 488 as outpatients. There was no difference in PTTR based on location: 43.2 % for inpatient versus 47.4 % for outpatient initiation [mean adjusted difference -2.2 %; 95 % confidence interval (CI) -5.9 to 1.6]. Similarly, there were no differences in time to first therapeutic INR [hazard ratio (HR) 1.06; 95 % CI 0.91-1.24] or to maintenance dose (HR 0.96; 95 % CI 0.81-1.14). There was no evidence of interaction between study intervention (pharmacogenetically vs. clinically guided therapy) and location of initiation for these main outcomes. The difference between predicted and observed maintenance doses was similar for both locations. CONCLUSION:The warfarin dosing algorithms performed similarly for subjects who initiated warfarin as inpatients and outpatients, regardless of whether dosing was pharmacogenetically or clinically guided.
Project description:<h4>Background</h4>Although multiple reports have documented the influence of CYP2C9 and VKORC1 variants on warfarin dose, risk of over-anticoagulation and hemorrhage, their influence on anticoagulation maintenance and individual proportion of time spent in target INR range (PPTR) is limited. Moreover the potential benefit of genotype-guided dosing implemented after initiation of therapy in a racially diverse population has not been explored. Herein we present the influence of CYP2C9 and VKORC1 C1173T on warfarin response during the first 30 days of therapy.<h4>Methods</h4>Warfarin dose was empirically determined in 250 African Americans 271 European Americans. The influence of CYP2C9 and VKORC1 on rate of INR increase, anticoagulation maintenance, risk of over-anticoagulation, and change in dose over 30 days was evaluated after adjustment for socio-demographic, lifestyle and clinical factors. Possession of variant VKORC1 (+/- variant CYP2C9) genotype was associated with a more rapid attainment of target INR and higher frequency of dose adjustments. Patients possessing variant genotypes spent less time in target range. However adjustment for rate of INR increase rendered the association non-significant. European Americans (but not African Americans) possessing variant VKORC1 (+/- variant CYP2C9) genotype had a higher risk of over-anticoagulation. Neither CYP2C9 nor VKORC1 influenced the risk of minor hemorrhage. CYP2C9 and VKORC1 explained 6.3% of the variance in dose change over the first 30 days of therapy demonstrating that the usefulness of genotype-guided dosing may extend beyond first day of therapy.<h4>Conclusion</h4>The benefit of genotype-based dose prediction may extend beyond first few days of therapy. Whether genotype-guided dosing will decrease the risk of over-anticoagulation, improve anticoagulation control and most importantly improve outcomes for chronic warfarin users remains to be proven.
Project description:INTRODUCTION:Warfarin is the most commonly prescribed oral anticoagulant in sub-Saharan Africa and requires ongoing monitoring. The burden of both infectious diseases and non-communicable diseases is high and medicines used to treat comorbidities may interact with warfarin. We describe service provision, patient characteristics, and anticoagulation control at selected anticoagulation clinics in Uganda and South Africa. METHODS:We evaluated two outpatient anticoagulation services in Kampala, Uganda and three in Cape Town, South Africa between 1 January and 31 July 2018. We collected information from key staff members about the clinics' service provision and extracted demographic and clinical data from a sample of patients' clinic records. We calculated time in therapeutic range (TTR) over the most recent 3-month period using the Rosendaal interpolation method. RESULTS:We included three tertiary level, one secondary level and one primary level anticoagulation service, seeing between 30 and 800 patients per month. Care was rendered by nurses, medical officers, and specialists. All healthcare facilities had on-site pharmacies; laboratory INR testing was off-site at two. Three clinics used warfarin dose-adjustment protocols; these were not validated for local use. We reviewed 229 patient clinical records. Most common indications for warfarin were venous thrombo-embolism in 112/229 (49%), atrial fibrillation in 74/229 (32%) and valvular heart disease in 30/229 (13%). Patients were generally followed up monthly. HIV prevalence was 20% and 5% at Ugandan and South African clinics respectively. Cardiovascular comorbidity predominated. Furosemide, paracetamol, enalapril, simvastatin, and tramadol were the most common concomitant drugs. Anticoagulation control was poor at all included clinics with median TTR of 41% (interquartile range 14% to 69%). CONCLUSIONS:TTR was suboptimal at all included sites, despite frequent patient follow-up. Strategies to improve INR control in sub-Saharan patients taking warfarin are needed. Locally validated warfarin dosing algorithms in Uganda and South Africa may improve INR control.
Project description:In patients with kidney impairment, warfarin, a drug metabolized primarily by the cytochrome P-450 system, is initiated at similar doses and managed similarly as in the general medical population. Unfortunately, few data exist to guide dose adjustment in patients with decreased kidney function. Here, we determine the degree of warfarin dose reduction associated with kidney impairment and make recommendations for warfarin dosing.Cross-sectional analysis.Long-term warfarin users followed up at anticoagulation clinics (n = 980); 708 participants from the University of Alabama (UAB) and 272 participants from the University of Chicago (UIC).No/mild (estimated glomerular filtration rate [eGFR] ? 60 mL/min/1.73 m(2)), moderate (eGFR, 30-59 mL/min/1.73 m(2)), and severe (eGFR < 30 mL/min/1.73 m(2)) kidney impairment; CYP2C9 and VKORC1 genotype; age; race; sex; body mass; sociodemographic factors; smoking status; alcohol; vitamin K intake; comorbid conditions (eg, congestive heart failure); and drug interactions (eg, amiodarone and statins).Warfarin dose (milligrams per day) was evaluated using linear regression after adjustment for clinical, demographic, and genetic factors.Prevalences of moderate (31.8% and 27.6%) and severe kidney impairment (8.9% and 6.6%) were similar in the UAB and UIC cohorts. Warfarin dose requirements were significantly lower in patients with moderate and severe kidney impairment compared with those with no/mild kidney impairment in the UAB (P < 0.001) and UIC (P < 0.001) cohorts. Compared with patients with no/mild kidney impairment, patients with moderate kidney impairment required 9.5% lower doses (P < 0.001) and patients with severe kidney impairment required 19% lower doses (P < 0.001).No measurement of warfarin, serum albumin, vitamin K, and coagulation factors; no evaluation of other markers (eg, cystatin).Moderate and severe kidney impairment were associated with a reduction in warfarin dose requirements.
Project description:Anticoagulation clinics were initially developed to provide safe and effective care for warfarin-treated patients with atrial fibrillation, venous thromboembolism, and mechanical valve replacement. Traditionally, these patients required ongoing laboratory monitoring and warfarin dose adjustment by expert providers. With the introduction of direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, and edoxaban), many have questioned the need for anticoagulation clinic. However, we think that the growing number of oral anticoagulant choices creates an urgent need for expanding the traditional role of the anticoagulation clinic. We outline 3 key purposes that a reimagined anticoagulation clinic would serve: (1) to assist patients and clinicians with selecting the most appropriate drug and dose from a growing list of anticoagulant options (including warfarin), (2) to help patients minimize the risk of serious bleeding complications with careful long-term monitoring and peri-procedural management, and (3) to encourage ongoing adherence to these life-saving medications. We also describe how repurposing anticoagulation clinics as broader medication safety clinics would promote safe and effective care across a range of cardiovascular conditions for high-risk medications (eg, spironolactone, amiodarone). Finally, we highlight a few existing health systems that are overcoming key challenges to implementing a reimagined anticoagulation or medication safety clinic structure.
Project description:Although management of warfarin is challenging for patients with chronic kidney disease (CKD), no prospective studies have compared response to warfarin among patients with minimal, moderate, and severe CKD. This secondary analysis of a prospective cohort of 578 patients evaluated the influence of kidney function on warfarin dosage, anticoagulation control, and risk for hemorrhagic complications. We adjusted all multivariable regression and proportional hazard analyses for clinical and genetic factors. Patients with severe CKD (estimated GFR <30 ml/min per 1.73 kg/m2) required significantly lower warfarin dosages (P = 0.0002), spent less time with their international normalized ratio within the target range (P = 0.049), and were at a higher risk for overanticoagulation (international normalized ratio >4; P = 0.052), compared with patients with no, mild, or moderate CKD. Patients with severe CKD had a risk for major hemorrhage more than double that of patients with lesser degrees of renal dysfunction (hazard ratio 2.4, 95% confidence interval 1.1 to 5.3). In conclusion, patients with reduced kidney function require lower dosages of warfarin, have poorer control of anticoagulation, and are at a higher risk for major hemorrhage. These observations suggest that warfarin may need to be initiated at a lower dosage and monitored more closely in patients with moderate or severe CKD compared with the general population. Diminished renal function may have implications for a larger proportion of warfarin users than previously estimated.