Prevalent aetiologies of non-therapeutic warfarin anticoagulation in a network of pharmacist-managed anticoagulation clinics

What is known and objective: There is wide inter‐patient and intra‐patient variability in the pharmacodynamic profile of warfarin. To determine the prevailing aetiologies of non‐therapeutic warfarin anticoagulation episodes among patients currently enrolled in an outpatient anticoagulation clinic and compare the relative frequency in which they occur compared to therapeutic anticoagulation regimens. Methods: Prospective, observational cohort study set within three pharmacist‐managed anticoagulation clinics in a community outpatient health system. Patients were included, if they were seen for an office visit during the 6‐month period from September 2006 to March 2007 and evaluated for the presence or absence of 12 investigational factors linked to non‐therapeutic anticoagulation results. Multivariate stepwise logistic regression performed to assess predictive value of each factor. Results: A total of 5817 patient‐visits were documented producing 2886 (49·6%) non‐therapeutic and 2931 (50·4%) therapeutic International Normalized Ratio (INR) readings. The most prevalent aetiologies linked to non‐therapeutic INR results included change in dietary vitamin K intake (16·9%, OR 6·4), non‐compliance (15·0%, OR 4·9), and initiation of anticoagulant therapy (9·9%, OR 2·3). The factor with the highest predictive value of non‐therapeutic INR results was a change in health status (OR 9·5) despite its lower rate of frequency (4·9%). Despite identification of many causative factors in this study, 40·2% of non‐therapeutic INR readings had no known aetiology. In the end, the lack of any study factor was a greater predictor of therapeutic anticoagulation (86·2%), than the presence of a study factor was for predicting non‐therapeutic INR values (51·4%). What is new and conclusion: Change in health status was the strongest predictor of non‐therapeutic INR levels out of the investigational factors evaluated. Our study demonstrated that there are many aetiologies for non‐therapeutic INR values that were not explained by our investigational factors.     

Search for predictors of nontherapeutic INR results with warfarin therapy

BACKGROUND: The effectiveness and safety of warfarin require maintaining an international normalized ratio (INR) within the therapeutic range. OBJECTIVE: To identify predictors of nontherapeutic INR results in patients receiving warfarin. METHODS: A retrospective study was conducted using 350 ambulatory care patients from a broad geographic region, all receiving long-term warfarin therapy and followed in a tertiary-care cardiology clinic. Possible predictors of nontherapeutic INR results (gender, age, body weight, body mass index, height, race, tobacco use, alcohol use, warfarin dose, therapeutic indication, regimen intensity, INR monitoring frequency/category, interacting medications, adverse events) were assessed with logistic regression models. Subset analysis involved 146 patients concurrently monitored with capillary whole blood INR (CoaguChek). RESULTS: As measured on venous specimens, 52% (182/350) of the patients had subtherapeutic INR results and 13% (44/350) had supratherapeutic INR results despite frequent (< or =4 wk) monitoring in 75% of the patients. Due to the small sample size, supratherapeutic INR results could not be further analyzed. Of 19 predictors tested, only daily warfarin dose (p < 0.02) and regimen intensity (p < 0.03) were significant independent and additive predictors of subtherapeutic results. Patients on the high-intensity regimen (INR 2.5-3.5) and receiving warfarin < or =6 mg/day had >50% risk of having subtherapeutic INR results. Subtherapeutic CoaguChek results were independent predictors of subtherapeutic venipuncture INR results in the subset (p = 0.001). CONCLUSIONS: In the absence of readily identifiable predictors, only higher warfarin dosing and/or more frequent monitoring (possibly with point-of-care/home monitoring devices) may minimize the time that INRs are subtherapeutic, especially in patients receiving low-dose and/or high-intensity anticoagulation therapy.     

Successful anticoagulation with dalteparin in a patient with mechanical heart valves

BACKGROUND: Standard thromboprophylaxis of patients with mechanical heart valves is achieved using warfarin. In certain patients this may be very difficult; thus, alternative pharmacotherapy must be used. OBJECTIVE: To report a case of a patient who successfully used dalteparin, a low-molecular-weight heparin, for anticoagulation. CASE SUMMARY: A 58-year-old white woman with mechanical aortic and mitral heart valves initially received warfarin for anticoagulation. Thromboprophylaxis was very challenging. Her international normalized ratios (INRs) were erratic and occasionally responded paradoxically to changes in dose. Finally, she experienced a left hemispheric stroke when her INR was extremely subtherapeutic. Subsequently, despite best efforts, her INR again was subtherapeutic; warfarin was discontinued and dalteparin was initiated with daily self-administered subcutaneous injections of 16 000 units. No complications have arisen since initiation of the new pharmacotherapy approximately 18 months ago. DISCUSSION: The use of low-molecular-weight heparin for the treatment and prevention of venous thromboembolism is well described. There are few reports of its use for thromboprophylaxis of patients with mechanical heart valves. Our patient has been managed successfully with dalteparin. CONCLUSIONS: Dalteparin was effectively and safely used for the thromboprophylaxis of a patient with mechanical heart valves whose anticoagulation was previously difficult to manage with warfarin. Dalteparin deserves further study in patients who are unable to tolerate warfarin.     

Risk of post‐thrombotic syndrome after subtherapeutic warfarin anticoagulation for a first unprovoked deep vein thrombosis: results from the REVERSE study

Summary. Background: Risk factors for post‐thrombotic syndrome (PTS) remain poorly understood. Objectives: In this multinational multicenter study, we evaluated whether subtherapeutic warfarin anticoagulation was associated with the development of PTS. Methods: Patients with a first unprovoked deep venous thrombosis (DVT) received standard anticoagulation for 5–7 months and were then assessed for PTS. The time in the therapeutic range was calculated from the international normalized ratio (INR) data. An INR below 2, more than 20% of the time, was considered as subtherapeutic anticoagulation. Results: Of the 349 patients enrolled, 97 (28%) developed PTS. The overall frequency of PTS in patients with subtherapeutic anticoagulation was 33.5%, compared with 21.6% in those with an INR below two for ≤ 20% of the time (P = 0.01). During the first 3 months of therapy, the odds ratio (OR) for developing PTS if a patient had subtherapeutic anticoagulation was 1.78 (95% confidence interval [CI] 1.10–2.87). After adjusting for confounding variables, the OR was 1.84 (95% CI 1.13–3.01). Corresponding ORs for the full period of anticoagulation were 1.83 (95% CI 1.14–3.00) [crude] and 1.88 (95% CI 1.15–3.07) [adjusted]. Conclusion: Subtherapeutic warfarin anticoagulation after a first unprovoked DVT was significantly associated with the development of PTS.     

The use of letter communication for patients enrolled in a pharmacist managed anticoagulation clinic

What is known and Objective: It is unknown how letter communication vs. telephone communication compares in terms of affecting outcomes in patients followed in a busy anticoagulation clinic. This study was performed to determine if sending letters to communicate laboratory results and future appointments with patients enrolled in a pharmacy managed anticoagulation clinic is an effective alternative to telephone communication. Methods: A retrospective review of quality assurance data currently collected at our facility was performed. Data were analyzed 4 months before and 4 months after the implementation of the letter notification. Data on percent international normalized ratio (INR) in therapeutic range, missed laboratory draw frequency and major bleeding events were collected daily, compiled monthly and then compared between the telephone and letter groups. Results: There was no statistical difference in the percentage of INRs that were within goal range before and after letter initiation. There was a slight increase in the percentage of INR laboratory draws that were missed after the implementation of the letters (23% vs. 26%, P = 0·002). There were more major bleeding events after letter initiation, but this did not reach statistical significance. Approximately 80% of the patients received letters as the method of communication in the letter group. What is new and Conclusion: The use of letters to notify warfarin patients with laboratory results is an effective method of communication without adversely affecting patient outcomes .     

A case of sulphasalazine potentiating the hypoprothombinemic effect of warfarin resulting in bleeding

What is known and Objective: One case report demonstrated warfarin resistance associated with sulphasalazine therapy. Our objective is to report on a case of warfarin potentiation rather than resistance, associated with sulphasalazine therapy. Case summary: The patient was taking warfarin for two mechanical heart valves and was prescribed sulphasalazine for inflammatory bowel disease. He had stable international normalized ratios (INRs) before sulphasalazine administration. Approximately 3 weeks after starting sulphasalazine, he presented to the anticoagulation clinic with bruising and an INR of 6·1. The sulphasalazine was stopped, and the warfarin was held for 3 days; then the previous dose was resumed. Three weeks later, the INR returned to a therapeutic level. What is new and Conclusion: This is the first case of sulphasalazine potentiating the effect of warfarin. Sulphasalazine may potentiate the hypoprothombinemic effect of warfarin.     

No increased bleeding events with continuation of oral anticoagulation therapy for patients undergoing cardiac device procedure

Background: Switching warfarin for heparin has been a practice for managing periprocedural anticoagulation in high‐risk patients undergoing device‐related procedures. We sought to investigate whether continuation of warfarin sodium therapy without heparin bridging is safe and, when it is continued, the optimal international normalized ratio (INR) without increased bleeding risk at time of device‐related procedure. Methods and Results: We retrospectively studied 766 consecutive patients taking warfarin long term who underwent device‐related procedures. Patients were grouped by treatment: discontinued warfarin (?warfarin, n = 243), no interruption of warfarin (+warfarin, n = 324), and discontinued warfarin with heparin bridging (+heparin, n = 199). The study primary endpoint was systemic bleeding or formation of moderate or severe pocket hematoma within 30 days of the procedure. Thirty‐one (4%) patients had bleeding events, including pocket hematoma in 29 patients. The bleeding events occurred more often for +heparin (7.0%) than ?warfarin (2.1%) or +warfarin (3.7%, P = 0.029). For +warfarin group, INR of 2.0–2.5 at time of procedure did not increase bleeding risk compared with INR less than 1.5 (3.7% vs 3.4%; P = 0.72), but INR greater than 2.5 increased the bleeding risk (10.0% vs 3.4%; P = 0.029). Concomitant aspirin use with warfarin significantly increased bleeding risk than warfarin alone (5.6% vs 1.4%, P = 0.02). Median length of hospitalization was significantly shorter for +warfarin than +heparin (1 vs 6 days; P < 0.001). Conclusion: Continuation of oral anticoagulation therapy with an INR level of <2.5 does not impose increased risk of bleeding for device‐related procedures, although precaution is necessary to avoid supratherapeutic anticoagulation levels. (PACE 2011; 34:868–874)     

Miconazole and nystatin used as topical antifungal drugs interact equally strongly with warfarin

What is known and Objective: Medline search disclosed 10 case reports of interactions between oral anticoagulants and miconazole oral gel, but none so far between nystatin solution and anticoagulants. We report on change in anticoagulant activity with use of different topical antifungal drugs, miconazole oral gel and vaginal suppositories, and nystatin solution. Methods: We conducted a retrospective study that included 43 patients on stable anticoagulation before the introduction of topical antifungal drugs. Miconazole oral gel was prescribed for 32 patients, nystatin solution for eight patients and miconazole vaginal suppositories for three patients. Results and Discussion: Nineteen (44·2%) of the patients reported bleeding complications and some of these were severe. Fifteen of 32 who used miconazole oral gel and four of 8 of those who used nystatin solution were affected. Before use of the antifungal drugs, the mean weekly warfarin dose in the nystatin group was 14·5 mg, and after antifungal drugs, 9 mg, P = 0·038, while the mean international normalized ratio (INR) before antifungal drugs was 2·5 (range 1·9–3·5) and afterwards it was 10·6 (range 4·5–19·3), P = 0·0001. In the miconazole oral gel group the mean weekly warfarin dose was 15·7 mg, and after 10·8 mg, P = 0·008, while the mean INR before antifungal drugs was 2·44 (range 1·92–3·18) and afterwards it was 8·8 (range 4·9–16·9), P < 0·0001. What is new and Conclusion: Miconazole oral gel and topically applied nystatin solution have equally strong effects on warfarin activity and can provoke major bleeding. Prospective evaluation of this effect is called for. However, based on our results the warfarin dose adjustment appears necessary when the anticoagulant is used concomitantly with those topical antifungals.     

华法林抗凝治疗中药师干预对治疗效果及安全性的影响

目的探讨在华法林抗凝治疗中药师干预对治疗效果及用药安全性的影响。方法选择2017年1月至2017年12月服用华法林进行抗凝治疗的86例患者为对照组,以2018年1月至2018年12月由临床药师参与指导华法林抗凝治疗的86例患者为观察组。比较两组患者的治疗效果。结果观察组达到稳态时间、INR达标时间短于对照组,出院时INR达标率高于对照组(P<0.05)。观察组平均TTR大于对照组,且观察组在TTR<58%范围内的患者占比少于对照组,在TTR>70%范围内患者的占比多于对照组(P<0.05)。观察组血栓及出血总发生率均低于对照组,抗凝知识评分高于对照组(P<0.05)。结论临床药师参与华法林抗凝治疗的指导可以显著提高抗凝质量和安全性,改善患者对抗凝知识的知晓情况。     

Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin

What is known and Objectives: Testing for cytochrome P450‐2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles is recommended by the FDA for dosing of warfarin. However, dose prediction models derived from data obtained in one population may not be applicable to another. We therefore studied the impact of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dose requirement in Malaysia. Methods: Patients who were attending clinics at our hospital and prescribed warfarin with stabilized INR levels of 2–4 were selected. DNA was extracted from blood samples and subsequently genotyped for CYP2C9*1, *2, *3, VKORC1 (G‐1639A) and VKORC1 C1173T. Linear regression modelling using age, CYP2C9 and VKORC1 genotypes, sex, weight and height was undertaken to define a warfarin dosing algorithm. An initial model was developed using data from one cohort of patients and validated using data from a second cohort. Results and Discussion: A model which included age and variants of CYP2C9 and VKORC1 account for about 37% of the variability in warfarin dose required to achieve INR of 2–4. Among the parameters evaluated, only VKORC1 (G‐1639A) and (C1173T) alleles, and age correlated with warfarin dose at 6 month. The mean dose predicted using the algorithm derived from cohort 1 was lower than the actual dose for cohort 2 (3·30 mg, SD 0·84 vs. 3·45 mg, SD 1·42). There was no relationship between INR values and the dose taken by the patients. Race, sex, weight and height did not correlate with dose. What is new and Conclusion: This study identifies factors which affect warfarin dosing in the Malaysia population. However, our best model does not account sufficiently for the variability in dose requirements for it to be used in dose prediction for the individual patient. Other important influential factors affecting warfarin dose requirement remain to be identified.     

Warfarin for atrial fibrillation in community‐based practise

Summary. Background: Previous studies of anticoagulation for atrial fibrillation (AF) have predominantly occurred in academic settings or randomized trials, limiting their generalizability.Objective: To describe the management of patients with AF anticoagulated with warfarin in community‐based practise.Methods: We enrolled 3396 patients from 101 community‐based practises in 38 states. Data included demographics, comorbidities, and International Normalized Ratio (INR) values. Outcomes included time in therapeutic INR range (TTR), stroke, and major hemorrhage.Results: The mean TTR was 66.5%, but varied widely among patients: 37% had TTR above 75%, while 34% had TTR below 60%. The yearly rates of major hemorrhage and stroke were 1.90 per 100 person‐years and 1.00 per 100 person‐years. Four percent of patients (n = 127) were intentionally targeted to a lower INR, and spent 42.7% of time with an INR below 2.0, compared to 18.8% for patients with a 2.0–3.0 range (P < 0.001). Mean TTR for new warfarin users (57.5%) remained below that of prevalent users through the first six months. Patients with interruptions of warfarin therapy had lower TTR than all others (61.6% vs. 67.2%, P < 0.001), which corrected after deleting low peri‐procedural INR values (67.0% vs. 67.4%, P = 0.73).Conclusions: Anticoagulation control varies widely among patients taking warfarin for AF. TTR is affected by new warfarin use, procedural interruptions, and INR target range. In this community‐based cohort of predominantly prevalent warfarin users, rates of hemorrhage and stroke were low. The risk versus benefit of a lower INR target range to offset bleeding risk remains uncertain.     

Can warfarin randomized trials be reproduced in 'real life'? Adherence to warfarin guidelines for intensity of anticoagulation in a university-based warfarin clinic

BACKGROUND: Subjects in clinical trials may benefit from the increased attention and specific focus of the trial, thereby limiting the external validity of clinical trial results to clinical practice. Our study evaluated adherence to guidelines for intensity of anticoagulation in a large, university-based warfarin clinic to assess the generalizability of randomized clinical trials of warfarin efficacy to clinical practice. METHODS: We reviewed anticoagulation clinic records of 480 patients observed for up to 2 years to determine the amount of time anticoagulation was within the recommended therapeutic range. RESULTS: The most common indication for warfarin use was atrial arrhythmia (51.5%). Overall, anticoagulation was within the intended international normalized ratio (INR) target range on 57.8% of treatment days. Nontherapeutic treatment days were due more commonly to subtherapeutic INR values (27.6+/-25.7%) than supratherapeutic INR values (14.9+/-17.0%). This pattern was seen across all warfarin indications. CONCLUSION: These data are comparable to those reported from large randomized trials and thus support the generalizability of clinical trials of long-term warfarin anticoagulation to clinical practice.     

Bosentan and warfarin interaction

OBJECTIVE: To report a case of decreased international normalized ratio (INR) in a patient receiving warfarin and bosentan. CASE SUMMARY: A 35-year-old African American woman with a history of primary pulmonary hypertension managed with warfarin, diltiazem, and hydrochlorothiazide was initiated on bosentan therapy. The patient's INR had been stable and within therapeutic range (goal 2.0-3.0) for the previous 3 months with warfarin 27.5 mg/wk, but became subtherapeutic after 10 days of bosentan therapy. Addition of over-the-counter medications, herbal products, vitamins, or dietary changes was denied. The INR remained subtherapeutic for 5 weeks despite weekly warfarin dose increases. After these 5 weeks of dosage increases, the INR became supratherapeutic for 3 weeks, resulting in a subsequent dosage decrease. The resultant warfarin dose required to maintain a therapeutic INR was 45 mg/wk, a 63.6% dosage increase after the initiation of bosentan. DISCUSSION: This case shows that a clinically significant interaction between bosentan and warfarin may exist. An objective causality assessment revealed that the interaction was probable. Although the possibility of this interaction has been noted, no previously documented occurrence of this interaction has been identified. CONCLUSIONS: Bosentan may significantly decrease the anticoagulant properties of warfarin. The INR should be monitored more frequently when bosentan is initiated, adjusted, or discontinued in patients taking warfarin.     

CYP4F2 gene polymorphism as a contributor to warfarin maintenance dose in Japanese subjects

What is known and Objective: Polymorphisms in the gene encoding CYP4F2 may partly explain the variability in warfarin maintenance dose by altering the metabolism of vitamin K. To determine the genetic factors that cause large inter‐patient variability in warfarin efficacy, we investigated the relationship between serum warfarin concentration and CYP4F2 V433M (1347C>T, rs2108622) polymorphism in Japanese subjects. Methods: Gene variations in VKORC1, CYP2C9 and CYP4F2 were analysed in 126 Japanese patients treated with warfarin. The daily dosage of warfarin, concentration of S‐ and R‐warfarin in plasma, and prothrombin time international normalized ratio (PT‐INR) was used as the pharmacokinetic and pharmacodynamic indices. Results and Discussion: The maintenance dose of warfarin was larger in the CYP4F2 1347 CT genotype group (3·59 ± 1·80 mg/day, P = 0·027) than in the CYP4F2 CC genotype group (2·88 ± 1·00 mg/day). CYP4F2 1347C>T polymorphism significantly affected serum R‐warfarin concentration when the VKORC1‐1639 genotypes are AG and GG. What is new and Conclusion: Although a significant inter‐patient difference in warfarin maintenance dose was observed between the CYP4F2 CC and CT genotypes, serum S‐warfarin concentration was not significantly different between them. An effect of CYP4F2 V433M polymorphism on warfarin maintenance dose was observed but was relatively small when compared to the effects of CYP2C9 and VKOR polymorphism.     

Optimization of inpatient warfarin therapy: impact of daily consultation by a pharmacist-managed anticoagulation service

OBJECTIVE: To determine the effect of daily consultation by a team of hospital pharmacists on the accuracy and rapidity of optimizing warfarin therapy. DESIGN: Comparison of a historical control cohort with a prospective cohort matched for treatment indication. SETTING: A 400-bed university teaching hospital. PATIENTS: Sixty consecutive patients hospitalized in 1992 and starting warfarin for the first time, with anticoagulation therapy managed by physicians, were compared with 60 patients matched for warfarin indication hospitalized in 1995, but with anticoagulation therapy managed with pharmacy consultation. RESULTS: Pharmacist management of initial warfarin therapy resulted in a significant reduction in the length of hospitalization compared with physician dosing, from 9.5 +/- 5.6 days to 6.8 +/- 4.4 days (p = 0.009). The number of patients and patient-days with international normalized ratio (INR) values >3.5 were reduced by pharmacist dosing from 37 patients and 142 days to 16 patients and 29 days, respectively (p < 0.001). Similarly, the number of patients and patient-days with INR >6.0 were reduced from 20 patients and 50 days to two patients and six days, respectively (p < 0.001). There were six documented bleeding complications in 1992 compared with one in 1995 (p = 0.11). The mean INR at discharge was significantly lower in the pharmacy surveillance group, 2.6 +/- 0.58, compared with the physician cohort, 3.3 +/- 2.1 (p = 0.07). Readmissions after discharge due to bleeding or recurrent thrombosis were reduced from five (at 1 mo) and 10 (at 3 mo) to two and five readmissions, respectively, by pharmacist intervention (p = 0.43). The number of patients with concurrently prescribed drugs known to significantly interact with warfarin was significantly lower (6 vs. 13; p = 0.02) in the pharmacy surveillance group. CONCLUSIONS: Among patients starting warfarin for the first time, daily consultation by a pharmacist significantly decreased the length of hospital stay and the number of patients who received excessive anticoagulation therapy. These findings translate into improved quality of care and potentially significant cost savings.     

Comparison of ‘time within therapeutic INR range’ with ‘percentage INR within therapeutic range’ for assessing long‐term anticoagulation control in children: a rebuttal

See also Biss TT, Avery PJ, Walsh PM, Kamali F. Comparison of `time within therapeutic INR range' with 'percentage INR within therapeutic range' for assessing long‐term anticoagulation control in children. J Thromb Haemost 2011; 9 : 1090–2; Biss TT, Avery PJ, Walsh PM, Kamali F. Comparison of time within therapeutic INR range with percentage INR within therapeutic range for assessing long‐term anticoagulation control in children: reply to a rebuttal. This issue, pp 2332–3.     

Direct and indirect costs of management of long‐term warfarin therapy in Canada

Summary. Background: Comparisons of overall costs and resource utilization associated with anticoagulation management are important as new alternatives to warfarin are introduced. The aim of the present study was to assess total costs of warfarin‐based anticoagulation in different health care models. Methods: Physician‐ or pharmacist‐managed hospital‐ or community‐based anticoagulation clinics in five Canadian provinces were asked to provide itemized information on costs for staff, laboratory, hardware and overheads associated with warfarin management. At each site, cohorts of patients were provided with diaries and participants prospectively entered all costs for warfarin medication and associated health professional contacts, travel to the laboratory, required assistance and time lost from work by patient or caregiver over 3 months. All costs were calculated for a 3‐month period. Results: Data from 429 patients at 15 sites were evaluated. The cost from the Ministry of Health perspective ranged from $108 to $199 per 3 months in the different settings, the patient costs were $40–$80 and the total societal costs ranged from $188–$244. Sensitivity analyses with typical blood test intervals, the most prescribed strength of warfarin and dispensing fee from another province increased these estimates to $230–$302. When reimbursement for unemployed caregivers was also entered the total cost was $308–$503 per 3 months. Conclusions: The total cost for warfarin‐based anticoagulation amounted to at least 10 times the lowest cost for the drug. The costs provided should be useful for comparisons with newer drugs without requirement for routine laboratory monitoring and dose adjustments.     

Comparison of time within therapeutic INR range with percentage INR within therapeutic range for assessing long‐term anticoagulation control in children: reply to a rebuttal

See also Biss TT, Avery PJ, Walsh PM, Kamali F. Comparison of ‘time within therapeutic INR range’ with ‘percentage INR within therapeutic range’ for assessing long‐term anticoagulation control in children. J Thromb Haemost 2011; 9 : 1090–2; Jones S, Monagle P, Newall F. Comparison of ‘time within therapeutic INR range’ with ‘percentage INR within therapeutic range’ for assessing long‐term anticoagulation control in children: a rebuttal. This issue, pp 2331–2.     

Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching

OBJECTIVE: Our objective was to examine possible changes in the effectiveness of warfarin after a nationwide generic substitution of formulations in 1998. METHODS: In the computerized records of a health maintenance organization database, we identified 975 patients who took warfarin continuously over two 6-month periods, before (period 1) and after (period 2) the generic switch. In this sample we performed a retrospective, between-period paired comparison of warfarin doses dispensed and international normalized ratio (INR) levels maintained, as well as of the apparent warfarin sensitivity index (calculated as INR/Warfarin dose [in milligrams per day]). RESULTS: Overall, for period 2, doses were 26.5% higher and INR 4.2% lower, with a 14.7% reduction in warfarin sensitivity index (P <.001). The findings were strongest in the 61 of 975 patients (6.3%) dispensed the lowest maintenance doses (<1.0 mg/d), with minimal change at greater than 3 mg/d. In 94 other patients (9.6%) in whom doses were unchanged, INR (median with 5th and 95th percentiles) dropped to subtherapeutic levels, from 2.2 (1.8, 3.0) to 1.7 (1.3, 1.8) (P <.001). There were no adverse events, expressed as no change in hospital admissions. Apparent warfarin sensitivity was reduced in period 2 by 15% to 20% (P <.001) across all period 1 INR levels. CONCLUSION: Because a general unidirectional change in INR response per unit warfarin dose cannot be explained by biologic mechanisms or confounding, we conclude that slightly reduced bioavailability (within the acceptable bioequivalence range) of the new formulation led to overestimated period 2 doses and reduced apparent warfarin sensitivity in all patient subgroups (by period 1 dose or INR), which was most prominent in those individuals with the lowest maintenance dose requirements.