Lars Frison

Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score.

OBJECTIVES The purpose of this study was to investigate predictors of bleeding in a cohort of anticoagulated patients and to evaluate the predictive value of several bleeding risk stratification schemas. BACKGROUND The risk of bleeding during antithrombotic therapy in patients with atrial fibrillation (AF) is not homogeneous, and several clinical risk factors have been incorporated into clinical bleeding risk stratification schemas. Current risk stratification schemas for bleeding during anticoagulation therapy have been based on complex scoring systems that are difficult to apply in clinical practice, and few have been derived and validated in AF cohorts. METHODS We investigated predictors of bleeding in a cohort of 7,329 patients with AF participating in the SPORTIF (Stroke Prevention Using an ORal Thrombin Inhibitor in Atrial Fibrillation) III and V clinical trials and evaluated the predictive value of several risk stratification schemas by multivariate analysis. Patients were anticoagulated orally with either adjusted-dose warfarin (target international normalized ratio 2 to 3) or fixed-dose ximelagatran 36 mg twice daily. Major bleeding was centrally adjudicated, and concurrent aspirin therapy was allowed in patients with clinical atherosclerosis. RESULTS By multivariate analyses, significant predictors of bleeding were concurrent aspirin use (hazard ratio [HR]: 2.10; 95% confidence interval [CI]: 1.59 to 2.77; p < 0.001); renal impairment (HR: 1.98; 95% CI: 1.42 to 2.76; p < 0.001); age 75 years or older (HR: 1.63; 95% CI: 1.23 to 2.17; p = 0.0008); diabetes (HR: 1.47; 95% CI: 1.10 to 1.97; p = 0.009), and heart failure or left ventricular dysfunction (HR: 1.32; 95% CI: 1.01 to 1.73; p = 0.041). Of the tested schemas, the new HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score performed best, with a stepwise increase in rates of major bleeding with increasing HAS-BLED score (p(trend) <0.0001). The c statistic for bleeding varied between 0.50 and 0.67 in the overall entire cohort and 0.68 among patients naive to warfarin at baseline (n = 769). CONCLUSIONS This analysis identifies diabetes and heart failure or left ventricular dysfunction as potential risk factors for bleeding in AF beyond those previously recognized. Of the contemporary bleeding risk stratification schemas, the new HAS-BLED scheme offers useful predictive capacity for bleeding over previously published schemas and may be simpler to apply.

Identifying Patients at High Risk for Stroke Despite Anticoagulation A Comparison of Contemporary Stroke Risk Stratification Schemes in an Anticoagulated Atrial Fibrillation Cohort

Background and Purpose— The risk of stroke in patients with atrial fibrillation (AF) is not homogeneous, and various clinical risk factors have informed the development of stroke risk stratification schemes (RSS). Among anticoagulated cohorts, the emphasis should be on the identification of patients who remain at high risk for stroke despite anticoagulation. Methods— We investigated predictors of thromboembolism (TE) risk in an anticoagulated AF clinical trial cohort (n=7329 subjects) and tested the predictive value of contemporary RSS in this cohort: CHADS2, Framingham, NICE 2006, American College of Cardiology/American Heart Association/European Society of Cardiology 2006, the 8th American College of Chest Physicians guidelines and the CHA2DS2-VASc schemes. Results— On multivariate analysis, significant predictors of TE were stroke/TIA (hazard ratio [HR], 2.24; P<0.001), age 75 years or older (HR, 1.77; P=0.0002), coronary artery disease (HR, 1.52; P=0.0047), and smoking (HR, 2.10; P=0.0005), whereas reported alcohol use (HR, 0.70; P=0.02) was protective. Comparison of contemporary RSS demonstrated variable classification of AF patients into risk strata, although c-statistics for TE were broadly similar among the RSS tested and varied between 0.575 (NICE 2006) and 0.647 (CHA2DS2-VASc). CHA2DS2-VASc classified 94.2% as being at high risk, whereas most other RSS categorized two-thirds as being at high risk. Of the 184 TE events, 181 (98.4%) occurred in patients identified as being at high risk by the CHA2DS2-VASc schema. There was a stepwise increase in TE with increasing CHA2DS2-VASc score (Ptrend<0.0001), which had the highest HR (3.75) among the tested schemes. The negative predictive value (ie, the percent categorized as “not high risk” actually being free from TE) for CHA2DS2-VASc was 99.5%. Conclusion— Coronary artery disease and smoking are additional risk factors for TE in anticoagulated AF patients, whereas alcohol use appears protective. Of the contemporary stroke RSS, the CHA2DS2-VASc scheme correctly identified the greatest proportion of AF patients at high risk, despite the similar predictive ability of most RSS evidenced by the c-statistic.

Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial

BACKGROUND Heparins substantially reduce the risk of thromboembolic complications after total hip or knee replacement. However, they can be given only by injection and have several other drawbacks. We did a multicentre, randomised, double-blind study to examine the dose-response relation of subcutaneous melagatran, a direct thrombin inhibitor, followed by oral ximelagatran as thromboprophylaxis after total hip or knee replacement. We aimed to compare the efficacy and safety with that of dalteparin. METHODS Of 1900 patients, 1495 were assigned to four dose categories of subcutaneous melagatran from just before surgery (1.00 mg, 1.50 mg, 2.25 mg, or 3.00 mg twice daily) followed from the day after surgery by oral ximelagatran (8 mg, 12 mg, 18 mg, or 24 mg twice daily). 381 patients were assigned subcutaneous dalteparin 5000 IU once daily, from the evening before surgery. Bilateral venography was done at 7-10 days, and clinically suspected venous thromboembolism (VTE) was confirmed radiologically. The primary endpoint was the rate of deep-vein thrombosis and pulmonary embolism (PE). Analyses were by intention to treat. FINDINGS 1876 patients underwent total replacement of hip (n=1270) or knee (n=606); evaluable venograms were obtained in 1473 (79%). Four patients without evaluable venograms had PE. Overall, a significant dose-dependent decrease in VTE was seen with melagatran/ximelagatran (lowest to highest group: 111 [37.8%], 70 [24.1%], 71 [23.7%], and 43 [15.1%]; p=0.0001); there were also significant relations for both total hip and total knee replacement individually. The frequency of VTE was significantly lower with the highest dose of melagatran/ximelagatran than with dalteparin (15.1% vs 28.2%, p<0.0001). There were no reoperations due to bleeding and no critical organ bleeding. Excessive surgical bleeding was uncommon but more frequent in the highest dose group. INTERPRETATION This sequential therapy was effective and safe in patients undergoing major joint replacement surgery. The findings should be confirmed in a large phase III trial.

A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I

Summary.  This randomized, controlled, multicentre study evaluated the efficacy and tolerability of the oral direct thrombin inhibitor ximelagatran, compared with a low‐molecular‐weight heparin (dalteparin) followed by warfarin, in the treatment of deep vein thrombosis (DVT) of the lower extremity. Patients with acute DVT received oral ximelagatran (24, 36, 48 or 60 mg twice daily) or dalteparin and warfarin for 2 weeks. Evaluation of paired venograms from 295 of 350 patients showed regression of the thrombus in 69% of patients treated with ximelagatran and 69% of patients treated with dalteparin and warfarin. Progression was observed in 8% and 3% of patients, respectively. Changes in thrombus size according to the Marder score were similar in all groups. Treatment discontinuation due to bleeding occurred in two patients receiving ximelagatran (24‐ and 36‐mg groups) and in two patients receiving dalteparin and warfarin. Reduction in pain, edema and circumference of the affected leg was similar in all groups. Oral ximelagatran appears to be a promising alternative to current anticoagulant therapy to limit the progression of acute DVT, and it seems to possess a wide therapeutic window.

Influence of Age on the Pharmacokinetics and Pharmacodynamics of Ximelagatran, an Oral Direct Thrombin Inhibitor

AbstractObjective: To investigate the influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran. Study design: This was an open-label, randomised, 3 × 3 crossover study with 4 study days, separated by washout periods of 7 days. Subjects: Subjects comprised 6 healthy young men (aged 20–27 years) and 12 healthy older men and women (aged 56–70 years). Methods: All subjects received a 2mg intravenous infusion of melagatran over 10 minutes followed, in randomised sequence, by a 20mg immediate-release tablet of ximelagatran with breakfast, a 20mg immediate-release tablet of ximelagatran while fasting, and a 7.5mg subcutaneous injection of ximelagatran. The primary variables were the plasma concentration of melagatran, the active form of ximelagatran, and the activated partial thromboplastin time (APTT), an ex vivo coagulation time measurement used to demonstrate inhibition of thrombin. Results: After oral and subcutaneous administration, ximelagatran was rapidly absorbed and biotransformed to melagatran, its active form and the dominant compound in plasma. The metabolite pattern in plasma and urine was similar in young and older subjects after both oral and subcutaneous administration of ximelagatran. Clearance of melagatran was correlated with renal function, resulting in about 40% (after intravenous melagatran) to 60% (after oral and subcutaneous ximelagatran) higher melagatran exposure in the older than in the young subjects. Renal clearance of melagatran, determined after intravenous administration of melagatran, was 7.7 L/h and 4.9 L/h in the young and older subjects, respectively. The interindividual variability in the area under the melagatran plasma concentration-time curve was low following all regimens (coefficient of variation 12–25%). The mean bioavailability of melagatran in young and older subjects was approximately 18 and 21%, respectively, following oral administration of ximelagatran, and 38 and 45%, respectively, following subcutaneous administration of ximelagatran. The bioavailability of melagatran following oral administration of ximelagatran was unaffected by whether subjects were fed or fasting, although the plasma concentration of melagatran peaked about 1 hour later under fed than fasting conditions, due to delayed gastric emptying of the immediate-release tablet formulation used. The APTT was prolonged with increasing melagatran plasma concentrations and the concentration-effect relationship was independent of age. Conclusion: There were no age-dependent differences in the absorption and biotransformation of ximelagatran, and the observed differences in exposure to melagatran can be explained by differences in renal function between the young and older subjects.

Ximelagatran, an Oral Direct Thrombin Inhibitor, Has a Low Potential for Cytochrome P450-Mediated Drug-Drug Interactions

AbstractBackground: Ximelagatran is an oral direct thrombin inhibitor currently in clinical development for the prevention and treatment of thromboembolic disorders. After oral administration, ximelagatran is rapidly absorbed and extensively bioconverted, via two intermediates (ethyl-melagatran and hydroxy-melagatran), to its active form, melagatran. In vitro studies have shown no evidence for involvement of cytochrome P450 (CYP) enzymes in either the bioactivation or the elimination of melagatran. Objective: To investigate the potential of ximelagatran, the intermediates ethyl-melagatran and hydroxy-melagatran, and melagatran to inhibit the CYP system in vitro and in vivo, and the influence of three CYP substrates on the pharmacokinetics of melagatran in vivo. Methods: The CYP inhibitory properties of ximelagatran, the intermediates and melagatran were tested in vitro by two different methods, using heterologously expressed enzymes or human liver microsomes. Diclofenac (CYP2C9), diazepam (CYP2C19) and nifedipine (CYP3A4) were chosen for coadministration with ximelagatran in healthy volunteers. Subjects received oral ximelagatran 24mg and/or diclofenac 50mg, a 10-minute intravenous infusion of diazepam 0.1 mg/kg, or nifedipine 60mg. The plasma pharmacokinetics of melagatran, diclofenac, diazepam, N-desmethyl-diazepam and nifedipine were determined when administered alone and in combination with ximelagatran. Results: No inhibition, or only minor inhibition, of CYP enzymes by ximelagatran, the intermediates or melagatran was shown in the in vitro studies, suggesting that ximelagatran would not cause CYP-mediated drug-drug interactions in vivo. This result was confirmed in the clinical studies. There were no statistically significant differences in the pharmacokinetics of diclofenac, diazepam and nifedipine on coadministration with ximelagatran. Moreover, there were no statistically significant differences in the pharmacokinetics of melagatran when ximelagatran was administered alone or in combination with diclofenac, diazepam or nifedipine. Conclusion: As ximelagatran did not exert a significant effect on the hepatic CYP isoenzymes responsible for the metabolism of diclofenac, diazepam and nifedipine, it is reasonable to expect that it would have no effect on the metabolism of other drugs metabolised by these isoenzymes. Furthermore, the pharmacokinetics of melagatran after oral administration of ximelagatran are not expected to be altered by inhibition or induction of CYP2C9, CYP2C19 or CYP3A4. Together, the in vitro and in vivo studies indicate that metabolic drug-drug interactions involving the major human CYP enzymes should not be expected with ximelagatran.

Active-control clinical trials to establish equivalence or noninferiority: methodological and statistical concepts linked to quality

The randomized, double-blind, placebo-controlled trial is the optimum method for clinical evaluation of new treatments, as assessed by clinicians and statisticians. However, if a known standard of therapy exists, it may be difficult to prove that a new therapy is superior. Equivalence and noninferiority clinical trial designs are now frequently utilized in clinical medical research. This article reviews the statistical differences between superiority, equivalence, and noninferiority design schemes, which pose specific ethical questions and have important implications for interpretation and clinical application of trial results. A guideline is proposed as a standard approach for reporting to facilitate qualitative assessment of the methodology of these trials.

Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran.

AbstractBackground: Ximelagatran is an oral direct thrombin inhibitor currently in clinical development as an anticoagulant for the prevention and treatment of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran. Objective: To investigate the effect of severe renal impairment on the pharmacokinetics and pharmacodynamics of melagatran following administration of subcutaneous melagatran and oral ximelagatran. Study design: This was a nonblinded randomised crossover study with 2 study days, separated by a washout period of 1–3 weeks. Twelve volunteers with severe renal impairment and 12 controls with normal renal function were included, with median (range) glomerular filtration rates (GFR) of 13 (5–24) and 86 (70–105) mL/min, respectively. All volunteers received, in a randomised sequence, a 3mg subcutaneous injection of melagatran and a 24mg immediate-release tablet of ximelagatran. Blood samples were collected up to 12 and 14 hours after administration of the subcutaneous and oral doses, respectively, for determination of melagatran plasma concentrations and the activated partial thromboplastin time (APTT), an ex vivo measurement of coagulation time. Urine was collected for 24 hours after each dose for determination of melagatran concentration. Results: For the volunteers with severe renal impairment, the area under the plasma concentration-time curve (AUC) and the half-life of melagatran were significantly higher than in the control group with normal renal function. Least-squares mean estimates of the ratios of the mean AUC for volunteers with severe renal impairment and controls (95% confidence intervals) were 4.03 (3.29–4.93) after subcutaneous melagatran and 5.33 (3.76–7.56) after oral ximelagatran. This result was related to the decreased renal clearance (CLr) of melagatran, which was linearly correlated with GFR. In the severe renal impairment and control groups, respectively, the mean CLr of melagatran was 12.5 and 81.3 mL/ min after subcutaneous administration of melagatran and 14.3 and 107 mL/min after oral administration of ximelagatran. There was a nonlinear relationship between the APTT ratio (postdose/predose APTT value) and melagatran plasma concentration. A statistically significant higher slope of the concentration-effect relationship, described by linear regression of the APTT ratio versus the square root of melagatran plasma concentrations, was estimated for the group with severe renal impairment compared to the control group; however, the increase in slope was minor and the estimated differences in APTT ratio between the groups in the studied concentration range was less than 10% and not considered clincially relevant. Ximelagatran and melagatran were well tolerated in both groups. Conclusions: After administration of subcutaneous melagatran and oral ximelagatran, subjects with severe renal impairment had significantly higher melagatran exposure and longer half-life because of lower CLr of melagatran compared with the control group with normal renal function, suggesting that a decrease in dose and/or an increase in the administration interval in patients with severe renal impairment would be appropriate.

Disparate Stroke Rates on Warfarin Among Contemporaneous Cohorts With Atrial Fibrillation Potential Insights Into Risk From a Comparative Analysis of SPORTIF III Versus SPORTIF V

Background and Purpose— The rate of stroke among warfarin-treated patients in SPORTIF V was approximately half that of patients enrolled in SPORTIF III (1.16%/year versus 2.30%/year). SPORTIF III was an open-label trial comparing ximelagatran with warfarin for stroke prevention in atrial fibrillation. SPORTIF V was a double-blind trial performed in North America. The trial design was otherwise identical. We sought to determine if differences in baseline characteristics, use of potentially risk-modifying medications, or anticoagulation control help to explain the lower risk of stroke among warfarin-treated patients in SPORTIF V. Methods— Cox regression with stepwise model selection was used to define the covariates independently associated with stroke. Secondary analyses identified covariates with the strongest influence on the study factor (V/III). These covariates were then added to the primary model. Cox regression was used to determine the degree of confounding exerted by these covariates that might help to explain the differences between the trials. Results— Independent risk factors for stroke on warfarin included prior stroke/transient ischemic attack, coronary artery disease, international normalized ratio, weight, and study. Patients in SPORTIF V were at half the risk as those in SPORTIF III. We found that lower international normalized ratio variability, a higher proportion of prevalent warfarin use, lower systolic blood pressure, high-density lipoprotein, and a greater proportion of statin use among patients in SPORTIF V collectively conferred a lower risk of stroke. Conclusion— Differences in blood pressure control, international normalized ratio variability, proportion of prevalent warfarin users, statin exposure, and high-density lipoprotein collectively conferred a lower risk of stroke to patients in SPORTIF V. These findings suggest that the different event rates were not due to chance and provide potential insights into stroke risk among warfarin-treated patients with atrial fibrillation.

Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis.

AbstractObjective: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated Creatinine clearance was examined. Design and methods: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8–11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model. Results: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated Creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on Creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT. Conclusions: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.