Optimal initial dose adjustment of warfarin in orthopedic patients.

BACKGROUND: Warfarin sodium is commonly prescribed for the prophylaxis and treatment of venous thromboembolism. Dosing algorithms have not been widely adopted because they require a fixed initial warfarin dose (eg, 5 mg) and are not tailored to other factors that may affect the international normalized ratio (INR). OBJECTIVE: To develop an algorithm that could predict a therapeutic warfarin dose based on drug interactions, INR response after the initial warfarin doses, and other clinical factors. METHODS: We used stepwise regression to quantify the relationship between these factors in patients beginning prophylactic warfarin therapy immediately prior to joint replacement. In the derivation cohort (n = 271), we separately modeled the therapeutic dose after 2 and 3 initial doses. We prospectively validated these 2 models in an independent cohort (n = 105). RESULTS: About half of the therapeutic dose variability was predictable after 3 days of therapy: R2 was 53% in the derivation cohort and 42% in the validation cohort. INR response after 3 warfarin doses (INR3) inversely correlated with therapeutic dose (p < 0.001). Intraoperative blood loss transiently, but significantly, elevated the postoperative INR values. Other significant (p < 0.03) predictors were the first and second warfarin doses (+7% and +6%, respectively, per 1 mg), and statin use (-15.0%). The model derived after 2 warfarin doses explained 32% of the variability in therapeutic dose. CONCLUSIONS: We developed and validated algorithms that estimate therapeutic warfarin doses based on clinical factors and INR response available after 2-3 days of warfarin therapy. The algorithms are implemented online at www.WarfarinDosing.org.

Genetic-based dosing in orthopedic patients beginning warfarin therapy.

High variability in drug response and a narrow therapeutic index complicate warfarin therapy initiation. No existing algorithm provides recommendations on refining the initial warfarin dose based on genetic variables, clinical data, and international normalized ratio (INR) values. Our goal was to develop such an algorithm. We studied 92 patients undergoing primary or revision total hip or knee replacement. From each patient we collected a blood sample, clinical variables, current medications, and preoperative and postoperative laboratory values. We genotyped for polymorphisms in the cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase (VKORC1) genes. Using stepwise regression, we developed a model for refining the warfarin dose after the third warfarin dose. The algorithm explained four fifths of the variability in therapeutic dose (R(2)(adj) of 79%). Significant (P > .05) predictors were INR value after 3 doses (47% reduction per 0.25-unit rise), first warfarin dose (+7% per 1 mg), CYP2C9*3 and CYP2C9*2 genotype (-38% and -17% per allele), estimated blood loss (interacting with INR(3)), smoking status (+20% in current smokers), and VKORC1 (-11% per copy of haplotype A). If validated, this model should provide a safer, more effective process for initiating warfarin therapy.

Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype.

Cytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C9*2 and CYP2C9*3) reduce the clearance of warfarin, increase the risk of bleeding, and prolong the time to stable dosing. Whether prospective use of a retrospectively developed algorithm that incorporates CYP2C9 genotype and nongenetic factors can ameliorate the propensity to bleeding and delay in achieving a stable warfarin dose is unknown. We initiated warfarin therapy in 48 orthopedic patients tailored to the following variables: CYP2C9 genotype, age, weight, height, gender, race, and use of simvastatin or amiodarone. By using pharmacogenetics-based dosing, patients with a CYP2C9 variant achieved a stable, therapeutic warfarin dose without excessive delay. However compared to those without a CYP2C9 variant, patients with a variant continued to be at increased risk (hazard ratio 3.6, 95% confidence interval 1.4-9.5, p = 0.01) for an adverse outcome (principally INR > 4), despite pharmacogenetics-based dosing. There was a linear relationship (R(2) = 0.42, p < 0.001) between the pharmacogenetics-predicted warfarin doses and the warfarin maintenance doses, prospectively validating the dosing algorithm. Prospective, perioperative pharmacogenetics-based dosing of warfarin is feasible; however, further evaluation in a randomized, controlled study is recommended.

Effect of warfarin nonadherence on control of the International Normalized Ratio.

OBJECTIVE: The frequency and causes of ab- errant International Normalized Ratios (INRs) in warfarin recipients and the percentage explainable by warfarin nonadherence were studied. METHODS: The medical records of patients whose warfarin therapy was monitored by a telephone-based anticoagulation service in a Midwestern urban hospital between March 2000 and March 2001 were reviewed for causes of out-of-range INRs, the percentage of out-of-range INRs attributable to warfarin nonadherence, and demographic and clinical variables predictive of nonadherence. RESULTS: Data from 347 patients were studied. The cohort yielded 4305 INRs, of which 1002 (23%) were out of range (lower than 1.8 or higher than 3.4). Thirty-six percent of the out-of-range INRs were due to warfarin or dietary nonadherence, 9% were due to medical systems problems (including drug interactions), 18% were due to a change in clinical status, and 38% were idiopathic. Age younger than 65 years, age greater than 80 years, and living closer to the laboratory were predictive of warfarin nonadherence. CONCLUSION: Warfarin nonadherence was the most common cause of explainable aberrant INRs in patients taking warfarin. Age younger than 65 years, age greater than 80 years, and living close to the laboratory were predictive of warfarin nonadherence.

Warfarin dose reduction vs watchful waiting for mild elevations in the international normalized ratio.

BACKGROUND: Whether clinicians should decrease the warfarin dose in response to a mild, asymptomatic elevation in the international normalized ratio (INR) is unknown. OBJECTIVES: The study objectives were as follows: (1) to evaluate the safety of an anticoagulation service (ACS) policy advocating that the warfarin dose not be changed for isolated, asymptomatic INRs of < or = 3.4; (2) to compare the dosing strategies of an ACS and primary care providers (PCPs); and (3) to quantify the relationship between reduction of the warfarin dose and the subsequent fall in the INR. DESIGN AND SETTING: Randomized controlled study of health maintenance organization outpatients who were receiving warfarin. PATIENTS: We identified 231 patients with a target INR of 2.5 and an isolated, asymptomatic INR between 3.2 and 3.4. Our ACS monitored 103 of the patients; PCPs monitored the remaining 128 patients. MEASUREMENTS: From all 231 patients, we obtained INRs and warfarin dosing history. From the 103 ACS enrollees, we also recorded adverse events. RESULTS: One ACS patient had epistaxis in the 30 days after the elevated INR. Twenty-three percent of ACS enrollees and 47% of PCP patients reduced their warfarin dose (p < 0.001). The median follow-up INRs were similar in both cohorts: 2.7 in the ACS enrollees and 2.6 in the PCP patients. However, in a subgroup analysis of 190 patients who presented with an INR of 3.2 or 3.3, ACS enrollees were more likely to have a follow-up INR in the range of 2 to 3 (p = 0.03). The median follow-up INR was 2.7 in 148 patients who maintained their warfarin dose, 2.5 in 77 patients who decreased their dose by 1 to 20%, and 1.7 in 6 patients who decreased their dose by 21 to 43% (p < 0.001). CONCLUSIONS: These findings support maintaining the same warfarin dose in asymptomatic patients with an INR of < or = 3.3, and reducing the dose for patients who have a greater INR or an increased risk of hemorrhage. Warfarin dose reductions > 20% should be avoided for mildly elevated INRs.

Substitution of generic warfarin for Coumadin in an HMO setting.

BACKGROUND: Substitution of generic warfarin for Coumadin presents safety concerns due to warfarin's narrow therapeutic index and because a prior generic formulation was removed from the US market after it was associated with adverse events. OBJECTIVE: To determine whether a health maintenance organization (HMO) can add generic warfarin to its formulary without adversely affecting warfarin management or increasing adverse events. DESIGN: In a prospective, observational study, an HMO that formerly dispensed only Coumadin added a generic warfarin preparation (Barr Laboratories, Pomona, NY) to its formulary. SETTING: An anticoagulation service (ACS) affiliated with an HMO that was based in St. Louis, MO. PARTICIPANTS: The cohort consisted of 182 enrollees in the ACS as of May 1, 1999. At the start of the study, these participants were taking Coumadin; by October 31, 2000, all had switched to Barr warfarin. MEASUREMENTS AND MAIN RESULTS: We collected data 8 months prior to and 10 months after the introduction of generic warfarin for the following endpoints: international normalized ratio (INR) control, frequency of INR monitoring, number of dose changes, and rate of thrombotic and hemorrhagic events. Statistical process control charts were used to differentiate between random variation in the endpoints and changes due to different warfarin formulations, and we used the Wilcoxon signed-rank test to look for a change in any endpoint after patients changed to generic warfarin. No significant differences were found in any endpoint. CONCLUSIONS: Substitution of Barr warfarin for Coumadin did not significantly affect INR control, warfarin management, or adverse events. Our findings suggest that HMOs can safely substitute at least 1 generic formulation of warfarin without extra monitoring.