Prediction of the warfarin maintenance dose after completion of the 10 mg initiation nomogram: do we really need genotyping?

Summary.  Introduction : Initiation of warfarin therapy is complicated by its narrow therapeutic index and inter-patient dose-effect variability. A '10-mg nomogram' warfarin initiation protocol permits safe therapeutic anticoagulation in outpatients started on warfarin. We aimed to develop a safe and effective warfarin maintenance dose prediction tool in these patients. Methods : Baseline potential predictor variables were collected on a retrospective cohort of outpatients initiated on warfarin for venous thromboembolism treatment. The primary outcome was the warfarin maintenance dose, defined as mean warfarin dose over the last 10 days of the first month of warfarin treatment. Univariate and multivariate analyses were performed to determine which baseline variables were warfarin maintenance dose predictors. An independent cohort of patients validated the derived warfarin maintenance dose prediction rule. Results : Patient's age and weight, cumulative dose of warfarin over the first week of induction and international normalized ratio (INR) on days 3, 5 and 8 were statistically significant predictors of the warfarin maintenance dose. Our final prediction rule reads: maintenance dose (in mg) = 2.5 + 10% of the first week cumulative dose - INR value at day 8 + 1.5 if INR was below 2.0 at day 5. In the validation cohort, the predicted dose was strongly correlated with the actual maintenance dose ( r  = 0.88, P  < 0.0001). The mean difference between observed and predicted dose was not clinically significant: −0.1 ± 1.1 mg. Conclusion : In outpatients initiated on warfarin using a '10-mg nomogram', a simple prediction rule can accurately predict warfarin maintenance dose. Prospective studies employing the rule are indicated.     

Predicting warfarin maintenance dose in patients with venous thromboembolism based on the response to a standardized warfarin initiation nomogram

Summary. Background: Polymorphisms in the VKORC1 and CYP2C9 genes influence warfarin requirements. It has been suggested that dosing algorithms incorporating them might outperform usual care. Standardized warfarin initiation nomograms are safe and effective and patients’ responses to them could be used to predict warfarin requirements without the need for genetic testing. Objectives: To develop a model to predict warfarin dose requirements based on the response to a standard nomogram without using genetic testing. Patients/methods: We included 363 outpatients with acute venous thromboembolism who were started on treatment using a standardized warfarin nomogram and achieved a stable maintenance warfarin dose defined as a dose prescribed twice consecutively after two consecutive INR measurements between 2.0 and 3.0. Linear regression was used to derive equations predicting the maintenance dose and models were validated using non‐parametric bootstrapping and tested in an independent cohort. Results: Three models were constructed for patients completing the nomogram until day 3 (warfarin dose (mg week^?1) = Exp [2.737 + 1.896(INR₃^?1)?0.008(Age)]; R²_adj = 0.462), day 5 (warfarin dose (mg week^?1) = Exp[2.261 + 2.412(INR₃^?1) ?0.285(ΔINR_5?3)]; R²_adj = 0.603) and day 8 (warfarin dose (mg week^?1) = Exp[1.574 + 1.788(INR₈^?1) + 0.024(cumulated warfarin dose until nomogram day 7)]; R²_adj = 0.643), where Exp is the exponential function; INR₃ and INR₈ are the INR on days 3 or 8 of the nomogram, and ΔINR_5?3 is the difference in the INR on days 5 and 3. All models were internally and externally validated and were accurate to within 25% of the actual dose in >60% of patients. Conclusion: Maintenance warfarin dose can be accurately predicted using individual response to a standard warfarin initiation nomogram without the need for costly genetic testing.     

The influence of ethnicity on warfarin dosage requirement

BACKGROUND: The optimal dose of warfarin varies among individuals, and the prediction of a maintenance dose is difficult. Ethnicity has been reported to influence warfarin dosing. OBJECTIVE: To quantitate the influence of ethnicity on warfarin dose requirement. METHODS: We conducted a retrospective cohort study at a university anticoagulation clinic to evaluate the influence of ethnicity on warfarin dose. Inclusion criteria included age > or = 18 years, target international normalized ratio (INR) 2-3, and warfarin management within the clinic for > or = 3 months with a minimum of 5 clinic visits. We collected clinical and demographic data including age, gender, weight, ethnicity, disease states, concomitant medications, indication, weekly warfarin dosage, and INR. To assess potential confounders, multivariate, repeated-measures regression analysis was used to identify and adjust for variables that may influence the maintenance dose of warfarin. RESULTS: Of the 345 patients who met the inclusion criteria, 27% were Asian American, 6% Hispanic, 54% white, and 14% African American. The adjusted mean (95% CI) weekly warfarin doses for patients with an INR goal of 2 to 3 were Asian Americans 24 mg (21 to 27), Hispanics 31 mg (25 to 37), whites 36 mg (34 to 39), and African Americans 43 mg (39 to 47) (p < 0.001). Additional factors found to influence warfarin dose requirement included age, weight, concomitant use of amiodarone, and diagnosis of venous thromboembolism. CONCLUSIONS: Warfarin dose requirements vary across ethnic groups even when adjusted for confounding factors, suggesting that genetic variation contributes to interpatient variability.     

Pharmacodynamic optimization of warfarin therapy II

A pharmacodynamic (E(max)) model for optimizing warfarin initiation had previously been reported. This study assessed the validity of this model, adjusted further for age in both the initial cohort and another cohort distinct from that used for the formulation of the model. Thirty-one patients undergoing oral anticoagulation for mainly cardiac indications were recruited from Kuala Lumpur. Thirty-four patients undergoing oral anticoagulation for deep vein thrombosis were recruited from Cambridge. They were studied for their anticoagulant response to the initiation of warfarin. The former were intuitively dosed after a 2-day loading of 10 mg warfarin/d. The latter all were commenced on warfarin via a standard 4-day induction protocol of Fennerty et al that allows early estimation of the required maintenance dose. The actual maintenance doses in both cohorts were compared with their predicted doses on the initiation of therapy that was calculated both from this model and from the induction protocol of Fennerty et al. The third day's international normalized ratio and age combination was additive in terms of their influence on the maintenance dose. The predictive model in both cohorts returned similar results and explained at least two thirds of the interindividual variability in warfarin maintenance dose requirements, whereas the induction protocol of Fennerty et al explained only one third of this interindividual variability. Use of this model in the form of the included nomogram should be able to decrease both the occurrence of either under- or overanticoagulation as well as the time taken to initiate treatment and decide the correct maintenance dose during the initiation of oral anticoagulation with warfarin in hospitals. A prospective evaluation of the nomogram is recommended.     

Duration of anticoagulant therapy after initial idiopathic venous thromboembolism

OBJECTIVE: To review the literature investigating the duration of oral anticoagulant therapy following a first event of idiopathic venous thromboembolism (VTE). DATA SOURCE: MEDLINE (1967-April 2003) and bibliographic searches of the English-language literature pertaining to the duration of oral anticoagulant therapy following a first event of idiopathic VTE was conducted. Search terms included venous thromboembolism, anticoagulation, duration of treatment, warfarin, and idiopathic. STUDY SELECTION AND DATA EXTRACTION:The results of all trials and meta-analyses that were obtained are reviewed and critiqued.DATA SYNTHESIS: The risk of recurrent VTE following a first idiopathic event is similar to the risk in patients with a permanent risk factor. Conventional-intensity oral anticoagulant therapy reduces this risk by 80-90%, but at an annual risk of bleeding of approximately 2-3%. According to the PREVENT trial, low-intensity anticoagulation also affords protection against VTE recurrence, but at a lower risk of bleeding. Older trials indicated that longer therapy was superior to shorter therapy; however, data from recent trials have demonstrated that the benefit was maintained only while receiving therapy. CONCLUSIONS: Patients with a first episode of idiopathic proximal VTE should be considered for indefinite anticoagulant therapy. The appropriate intensity of anticoagulation is still controversial; however, it appears that low-intensity treatment would be appropriate in most patients. For patients who will not continue therapy indefinitely, there does not appear to be any long-term benefit to extending the duration of therapy from 3 to 6 months.     

Long-term treatment with warfarin in Chinese population

OBJECTIVE: To estimate the incidence of and risks for bleeding and thromboembolic events after warfarin anticoagulation. We also explored the dosage and international normalized ratio (INR) among Chinese patients during long-term warfarin therapy. METHODS: The population in this retrospective study consisted of inpatients of the only medical center for northern Taipei City, whose initial course of warfarin therapy continued for more than four weeks. Enrollment began in June 1995 and ended in February 1996. Follow-up was completed in March 1998. Relevant data were collected by chart review. The rate of events was calculated using the Kaplan-Meier method, and risk factors were identified by the Cox proportional hazard model. RESULTS: During the study period, 226 patients were identified. The total follow-up time was 248.7 patient-years. Sixty-one patients (27.0%) received anticoagulation for mechanical prosthetic valve, but their duration of therapy accounted for 48.6% of the total patient-years of follow-up. The starting dosage (mean +/- SD) was 3.4+/-1.4 mg/d (range 1.3-10); the maintenance dosage was 3.1+/-1.2 mg/d (range 1.2-7.7). There were 1060 dosing adjustments and 3398 INR measurements collected for these patients. The independent determinants of maintenance dosage were age, body weight, and indication of mechanical prosthetic valve. The INR was 1.9+/-0.5 (range 1.0-3.7). The cumulative probabilities for hemorrhage at 12, 24, and 34 months were 24.5%, 32.3%, and 38.4%, respectively. The corresponding figures for thromboembolism were 8.5%, 10.7%, and 10.7%, respectively. Three hemorrhages were fatal. After adjusting for other patient characteristics, increasing age was the only independent risk factor identified for bleeding. CONCLUSIONS: Antithrombotic efficacy seemed to be maintained, although the mean INR was 1.9. Even so, the substantial incidence of bleeding, especially fatal bleeding, remains a concern. Low-intensity anticoagulation might be needed for Chinese patients during long-term warfarin therapy.     

Ximelagatran for treatment of venous thromboembolism

Acute venous thromboembolism including asymptomatic and symptomatic pulmonary embolism without respiratory or cardiac failure is currently treated for 6 months, initially with subcutaneous low-molecular-weight heparin followed by oral anticoagulation. The main drawback of oral anticoagulation is caused by severe bleeding complications. Oral Ximelagatran has shown to be as effective and safe for the initial treatment of acute deep venous thrombosis compared to subcutaneous low-molecular-weight heparin followed by oral warfarin over a period of 4 weeks. Currently, oral ximelagatran is investigated versus subcutaneous low-molecular-weight heparin and oral warfarin over 6 months to demonstrate an almost equal efficacy and safety. The study is performed on a double blind and double dummy basis. Six months after oral anticoagulation of patients with acute deep venous thrombosis, recurrent venous thromboembolism may occur in up to 25% within 2 years. Ximelagatran is currently investigated versus placebo to demonstrate a reduced recurrence rate of venous thromboembolism over a period of 18 months.     

Decreased warfarin effect after initiation of high-protein, low-carbohydrate diets

OBJECTIVE: To report 2 cases of decreased international normalized ratio (INR) after initiation of a high-protein, low-carbohydrate diet. CASE SUMMARIES: Case 1. A 67-year-old white woman had been receiving warfarin for 3 years for venous thromboembolism. After initiation of a high-protein, low-carbohydrate diet, the patient required a 22.2% increase (from 45 to 57.5 mg/wk) in warfarin dose. Her INR remained in the therapeutic range on this dose for 8 weeks. When the patient stopped the high-protein, low-carbohydrate diet, a decrease back to the original warfarin dose was required to return to a therapeutic INR. Case 2. A 58-year-old white man had been receiving warfarin for 8 years for a cerebrovascular accident. Initiation of a high-protein, low-carbohydrate diet resulted in a 30% increase (from 26.25 to 37.5 mg/wk) in warfarin dose. His warfarin dose was reduced to the original dose after he stopped the high-protein, low-carbohydrate diet. DISCUSSION: The Naranjo probability scale indicated a possible adverse effect between warfarin and high-protein diets. High-protein diets have been shown to increase serum albumin levels. This may result in more warfarin binding to serum albumin, thereby decreasing the anticoagulant effect of warfarin. The increase of albumin occurs rapidly after initiation of a high-protein diet and appears to promptly affect anticoagulation therapy with warfarin. CONCLUSIONS: These cases indicate a significant interaction between high-protein, low-carbohydrate diets and warfarin therapy. Patients receiving warfarin therapy should be educated on and monitored for the potential interaction that occurs with warfarin therapy and high-protein, low-carbohydrate diets.     

The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.

BACKGROUND: Heparins and warfarin are currently used as venous thromboembolism (VTE) prophylaxis in surgery. Inhibition of factor (F) Xa provides a specific mechanism of anticoagulation and the potential for an improved benefit-risk profile. OBJECTIVES: To evaluate the safety and efficacy of apixaban, a potent, direct, oral inhibitor of FXa, in patients following total knee replacement (TKR), and to investigate dose-response relationships. PATIENTS/METHODS: A total of 1238 patients were randomized to one of six double-blind apixaban doses [5, 10 or 20 mg day(-1) administered as a single (q.d.) or a twice-daily divided dose (b.i.d.)], enoxaparin (30 mg b.i.d.) or open-label warfarin (titrated to an International Normalized Ratio of 1.8-3.0). Treatment lasted 10-14 days, commencing 12-24 h after surgery with apixaban or enoxaparin, and on the evening of surgery with warfarin. The primary efficacy outcome was a composite of VTE (mandatory venography) and all-cause mortality during treatment. The primary safety outcome was major bleeding. RESULTS: A total of 1217 patients were eligible for safety and 856 patients for efficacy analysis. All apixaban groups had lower primary efficacy event rates than either comparator. The primary outcome rate decreased with increasing apixaban dose (P = 0.09 with q.d./b.i.d. regimens combined, P = 0.19 for q.d. and P = 0.13 for b.i.d. dosing).A significant dose-related increase in the incidence of total adjudicated bleeding events was noted in the q.d. (P = 0.01) and b.i.d. (P = 0.02) apixaban groups; there was no difference between q.d. and b.i.d. regimens. CONCLUSIONS: Apixaban in doses of 2.5 mg b.i.d. or 5 mg q.d. has a promising benefit-risk profile compared with the current standards of care following TKR.     

Dabigatran for the prevention and treatment of thromboembolic disorders

Dabigatran, an oral direct thrombin inhibitor, was the first of a new class of drugs referred to as non-vitamin K oral anticoagulants. Dabigatran is better than warfarin for stroke prevention in non-valvular atrial fibrillation (dose of 150 mg twice a day), non-inferior to enoxaparin for venous thromboembolism prevention after orthopedic surgery and non-inferior to warfarin in preventing recurrence after acute venous thromboembolism. The safety profile is similar to standard anticoagulants, with significant reduction observed in intracranial hemorrhage. Other advantages include a rapid onset of action and a predictable pharmacokinetic profile, allowing a fixed-dose regimen without the need for routine anticoagulation monitoring. In the event of bleeding, general support measures are recommended and if severe, the use of non-specific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa must be considered. A specific reversal agent (idarucizumab) is in development.     

Efficacy and safety of intravenous phytonadione (vitamin K1) in patients on long-term oral anticoagulant therapy

OBJECTIVES: To determine the safety and efficacy of intravenously administered phytonadione (vitamin K1) in patients on routine oral warfarin anticoagulation. PATIENTS AND METHODS: This retrospective cohort study comprised adults who were taking warfarin, were not bleeding, and received intravenous phytonadione anticoagulation therapy before a diagnostic or therapeutic procedure between September 1, 1994, and March 31, 1996. The main outcome measures were adverse reactions to intravenously administered phytonadione, prothrombin-international normalized ratio time values, the incidence of bleeding and thrombosis after the procedure, and the time between the procedure and return to anticoagulation after resumption of warfarin treatment. RESULTS: Two (1.9%) of the 105 patients studied had suspected adverse reactions to intravenous phytonadione (dyspnea and chest tightness during infusion in both). For the 82 patients who underwent a procedure, the median time from phytonadione to procedure onset was 27 hours (range, 0.7-147 hours), which was significantly less for patients receiving an initial phytonadione dose of more than 1 mg (P=.009). None had thromboembolism after surgery, although 2 (2.4%) of the 82 patients had procedure-associated major bleeding. For the 60 patients resuming warfarin therapy after a procedure, the median time to return to therapeutic anticoagulation was 4.1 days (range, 0.8-31.7 days) and was unaffected by the phytonadione dosage. CONCLUSIONS: Intravenous phytonadione appears to be safe and is effective for semiurgent correction of long-term oral anticoagulation therapy before surgery. In small doses, it does not prolong the patient's time to return to therapeutic anticoagulation.     

Anticoagulation in elective surgery.

Several categories of patients may be receiving anticoagulation therapy and require surgery. Many patients take cardioprotective aspirin or warfarin for atrial fibrillation, the presence of a mechanical heart valve, prior thromboembolism, a documented left ventricular thrombus, or a history of venous thromboembolism with or without a pulmonary embolism. Inpatients may be receiving injectable forms of anticoagulation to reduce risk of deep venous thrombosis or for other conditions, such as atrial fibrillation. Patients receiving any type of anticoagulation present a problem when they require surgery because the interruption of anticoagulant therapy increases their risk of thromboembolism and stroke (Schanbacher & Bennett, 2000). Rational decisions regarding the appropriateness of perioperative anticoagulation depend on individual patient factors and can only be made when the risk of perioperative thromboembolism is balanced against the risk of perioperative bleeding.     

Crossover Comparison of Rizatriptan 5 mg and 10 mg Versus Sumatriptan 25 mg and 50 mg in Migraine

Rizatriptan is a selective 5-HT_1B/1D receptor agonist with rapid oral absorption and early onset of action in the acute treatment of migraine. This double-blind, placebo-controlled, crossover study compared rizatriptan 5 mg versus sumatriptan 25 mg, and rizatriptan 10 mg versus sumatriptan 50 mg. A total of 1329 patients were allocated to one of five groups for treatment of two attacks: rizatriptan 5 mg/sumatriptan 25 mg; sumatriptan 25 mg/rizatriptan 5 mg; rizatriptan 10 mg/sumatriptan 50 mg; sumatriptan 50 mg/rizatriptan 10 mg; placebo/placebo. For each attack, patients rated headache severity, presence of associated symptoms, and functional disability prior to dosing and at intervals through 4 hours thereafter. Patients also rated their satisfaction with medication. Rizatriptan 5 mg and 10 mg provided faster relief of headache pain and greater relief of migraine symptoms than the 25-mg and 50-mg doses of sumatriptan, respectively. The response to rizatriptan was better than sumatriptan on additional measures including functional disability and satisfaction with medication. All active treatments were highly effective compared to placebo and acted as early as 30 minutes after dosing. All active treatments were well-tolerated and showed comparable safety profiles.     

Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor.

BACKGROUND: The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. METHODS: In this double-blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up. RESULTS: Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) - 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months (rate difference of 3.6% per patient-year; 95% CI - 3.8, 11.0). There were no major bleeds in either group. CONCLUSION: Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.     

Determination of kinetic parameters for prothrombin complex activity during initiation of anticoagulation

Objective: A prospective determination of the kinetic parameters of prothrombin complex activity (PCA) during initiation of anticoagulation in seven adult patients (4 males and 3 females, age 62·9±5·8 years, mean±SD) receiving anticoagulant therapy with warfarin. Method: All excluding one patient received a fixed daily dose of 5 mg warfarin over an initial 3 days. Three successive daily doses of warfarin were recorded, together with the corresponding PCA. The kinetic parameters for elimination of PCA during the initiation of anticoagulation were estimated from the log PCA–time plot with a 1-compartment model. Results: The mean elimination rate constant ( k _p) of PCA was 0·377 day⁻¹ (range 0·242–0·588 day⁻¹) during initiation of anticoagulation. The coefficient of variation in k _p was about 28%, indicating the considerable inter-individual differences in PCA response to warfarin. The mean plasma half-life of PCA was 1·96 days. There were no significant relationships (by simple regression analysis) between k _p and cumulative warfarin doses per kg of body weight or age during initiation of anticoagulation. Conclusion: The results suggest that for a 50% reduction of PCA, one would need about 2 days after initiation of anticoagulation.     

Danazol increases the anticoagulant effect of warfarin.

OBJECTIVE: To report two cases demonstrating an interaction between danazol and warfarin, resulting in the potentiation of warfarin's effect and bleeding complications. DATA SOURCES: Case reports, review articles, and studies identified by MEDLINE. STUDY SELECTION: All published English-language reports involving danazol and warfarin interactions were reviewed. DATA SYNTHESIS: Danazol, a synthetic testosterone derivative, is used in the treatment of endometriosis, fibrocystic breast disease, menorrhagia protein C deficiency, and hemophilia. We describe two cases including an interaction between danazol and warfarin, resulting in bleeding complications. There are at least two other reported cases of this interaction. This interaction may be attributable to several mechanisms. Danazol may inhibit the metabolism of warfarin and/or it may have a direct effect on the coagulation and fibrinolytic systems. CONCLUSIONS: Based on this report and other published cases, clinicians must be aware that danazol may increase the anticoagulant effect of warfarin. Patients receiving warfarin who are prescribed danazol must be monitored closely to prevent excessive anticoagulation and subsequent bleeding. Studies are needed to determine the frequency of this interaction and its underlying mechanisms.     

Crossover comparison of rizatriptan 5 mg and 10 mg versus sumatriptan 25 mg and 50 mg in migraine. Rizatriptan Protocol 046 Study Group

Rizatriptan is a selective 5-HT1B/1D receptor agonist with rapid oral absorption and early onset of action in the acute treatment of migraine. This double-blind, placebo-controlled, crossover study compared rizatriptan 5 mg versus sumatriptan 25 mg, and rizatriptan 10 mg versus sumatriptan 50 mg. A total of 1329 patients were allocated to one of five groups for treatment of two attacks: rizatriptan 5 mg/sumatriptan 25 mg; sumatriptan 25 mg/rizatriptan 5 mg; rizatriptan 10 mg/sumatriptan 50 mg; sumatriptan 50 mg/rizatriptan 10 mg; placebo/placebo. For each attack, patients rated headache severity, presence of associated symptoms, and functional disability prior to dosing and at intervals through 4 hours thereafter. Patients also rated their satisfaction with medication. Rizatriptan 5 mg and 10 mg provided faster relief of headache pain and greater relief of migraine symptoms than the 25-mg and 50-mg doses of sumatriptan, respectively. The response to rizatriptan was better than sumatriptan on additional measures including functional disability and satisfaction with medication. All active treatments were highly effective compared to placebo and acted as early as 30 minutes after dosing. All active treatments were well-tolerated and showed comparable safety profiles.     

A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data

BACKGROUND: Rapid genetic screening for cytochrome P450 (CYP) 2C9 variants may play a role in improving the efficacy and safety of warfarin in individuals with CYP2C9 variants. The feasibility of prospective CYP2C9 model-based warfarin dosing has not yet been assessed.OBJECTIVES: To evaluate the feasibility of applying a CYP2C9 gene-based warfarin dosing model in clinical practice.DESIGN: Prospective, randomized, single-blinded clinical pilot trial.SETTING: Large multispecialty group practice.PATIENTS: Candidates were recruited from a list of clinic patients eligible for warfarin initiation. This included patients with newly diagnosed thromboembolic disease or atrial arrhythmia, as well as patients anticipating elective valvuloplasty or arthroplasty. Patients who previously received warfarin were excluded.Interventions: Subjects were randomized to receive either 1) a standard initiation dose of 5 mg warfarin/day, or 2) rapid CYP2C9 genotyping and an initiation dose determined using parameters estimated from a previously published multivariate model [including age, body size, co-morbidity (e.g., diabetes), clinical indication (e.g., valvuloplasty) and CYP2C9 genotype].MEASUREMENTS: Primary outcome measurements were patient willingness to participate, physician willingness to refer, sample processing time, ability to administer calculated dosage and adequacy of follow-up.LIMITATIONS: This pilot trial was designed to assess the feasibility of model-based warfarin dosing. Power was insufficient for statistical comparison of adverse event rates.RESULTS: Forty-three of 117 patients had no prior warfarin treatment and were eligible. Five declined to participate. Twenty patients were randomized to a standard initiation dose of 5 mg daily. Eighteen patients were randomized to model-based dosing. All but one participant received the assigned initiation dose. Blood draw to dosage calculation time (including genotyping) required approximately 4 hours. Six adverse events occurred within the standard dosing group, and two adverse events occurred within the model-based dosing group.CONCLUSIONS: Prospective application of a multivariate CYP2C9 gene-based warfarin dosing model is feasible.     

Ximelagatran: an oral direct thrombin inhibitor

OBJECTIVE: To present the chemistry, pharmacology, and pharmacokinetics of ximelagatran, an oral direct thrombin inhibitor (DTI), and to review available comparative clinical trial data evaluating its efficacy and safety relative to other antithrombotic agents in the prevention and treatment of thromboembolism. DATA SOURCES: A search of the PubMed and Cochrane databases (1995-August 2004), supplemented by a manual search of article bibliographies, conference abstracts, and data on file from the manufacturer, was conducted. Key search terms were ximelagatran, melagatran, H376/95, and direct thrombin inhibitors. STUDY SELECTION AND DATA EXTRACTION: Pertinent information from available clinical trials, including study design, patient demographics, dosing regimens, anticoagulant comparators, methods for evaluating effectiveness, treatment outcomes, adverse events, and pharmacokinetic and pharmacodynamic evaluations, was extracted. DATA SYNTHESIS: Ximelagatran is an orally administered DTI under development for use in the treatment of venous thromboembolism (VTE), long-term prevention of a second VTE event, stroke secondary to atrial fibrillation, prevention of VTE after orthopedic procedures, and recurrent ischemic events after acute myocardial infarction. CONCLUSIONS: Ximelagatran, in twice-daily doses of 24 or 36 mg, is an alternative to low-molecular-weight heparins or warfarin in thromboprophylaxis following orthopedic knee replacement, atrial fibrillation, or initial treatment of VTE. Improved outcomes versus placebo were seen in the long-term prevention of VTE in patients who completed an initial 6 months of treatment. Liver-related effects need further clarification.     

Controversies in pulmonary embolism and deep venous thrombosis

The diagnosis of venous thromboembolic disease, and pulmonary embolism in particular, remains problematic. Physicians should strongly consider empiric anticoagulation if the best available diagnostic tests are inconclusive, because treatment is usually safe and successful. Twice-daily subcutaneous low-molecular-weight heparin, dosed without monitoring, may eventually replace standard heparin for most treatment of venous thromboembolism, but it is not yet labeled for the treatment of pulmonary embolism. Deep venous thromboembolism and pulmonary embolism should be treated with anticoagulants rather than inferior vena cava filters, even in oncology patients, unless anticoagulation is contraindicated; if so, when the contraindication remits, anticoagulation should be employed. The most effective prophylaxis of venous thromboembolism in at-risk patients should be used, with prolonged duration if evidence from clinical trials supports efficacy and safety. Low-dose warfarin should be used to prevent venous thrombosis and indwelling central venous catheter thrombosis in patients with cancer.