Oral Direct Thrombin Inhibitor Ximelagatran Research Articles

Two-Year Carcinogenicity Studies With the Oral Direct Thrombin Inhibitor Ximelagatran in the Rat and the Mouse

The results of 18 months mouse and 24 months rat carcinogenicity studies with the oral direct thrombin inhibitor ximelagatran are presented. In the mouse, gavage doses of ximelagatran up to 180 μmol/kg per d produced no neoplastic changes in any of the tissues examined. In the rat, gavage doses up to 240 μmol/kg per d produced multiple macroscopically detectable nodules in the pancreas, which are seen to be focal/multifocal acinar cell hyperplasia and focal/multifocal acinar cell adenoma upon histological evaluation. There were no other treatment-related effects on tumor incidence or distribution in the rat. The studies show a clear species difference in pancreatic effects between the rat and the mouse to long-term treatment with ximelagatran.

Clinical trials of direct thrombin and factor Xa inhibitors in atrial fibrillation

To review the large phase 3 clinical trials that compare direct thrombin or factor Xa inhibitors with dose-adjusted warfarin in patients with atrial fibrillation who have an increased risk of stroke. In large clinical trials, the oral direct thrombin inhibitor ximelagatran and the long-acting factor Xa inhibitor idraparinux were effective for reducing the risk of thromboembolic stroke, but were not marketed because of liver toxicity and excessive bleeding, respectively. In separate clinical trials, the oral direct thrombin inhibitor dabigatran etexilate and the short-acting oral factor Xa inhibitor rivaroxaban were noninferior or superior to dose-adjusted warfarin for prevention of thromboembolic stroke and systemic embolism, without increasing the risk of bleeding, and were well tolerated. Apixaban, another oral factor Xa inhibitor, is effective in reducing thromboembolic stroke compared with aspirin alone. Results of a trial comparing apixaban with dose-adjusted warfarin are awaited. Dabigatran and rivaroxaban are effective, safe alternatives to dose-adjusted warfarin for reducing thromboembolic risk in patients with atrial fibrillation at high risk of stroke.

The Future of Anticoagulant Therapy

Major advances in the development of oral anticoagulants haveresulted in considerable progress towards the goal of safe and ef-fective oral anticoagulants that do not require frequent monitor-ing or dose adjustment, and have minimal food/drug interactionsas highlighted recently in several reports [1–7] and summarized inrecent reviews in Cardiovascular Therapeutics and other journals[1–4]. Indirect inhibitors of factor Xa and factor IIa such as low-molecular weight heparin (LMWH) and the pentasaccharide fon-daparinux represent improvements over traditional drugs, such asunfractionated heparin, for acute treatment of VTE, constituting amore targeted anticoagulant approach, with predictable pharma-cokinetic profiles, and no requirement for monitoring [6,7]. Vita-min K antagonist, with its inherent limitations in terms of multi-ple food and drug interactions and frequent need for monitoring,remains the only oral anticoagulant approved for long-term sec-ondary Thromboprophylaxis in VTE. The oral direct thrombin in-hibitor ximelagatran was withdrawn from the world market dueto safety concerns. Newer anticoagulant drugs such as oral directthrombin inhibitors (dabigatran), oral direct factor Xa inhibitors(rivaroxaban, apixaban, and several others) are being introducedinto the European and Canadian markets and have the potentialto greatly expand oral antithrombotics for both acute and long-term treatment of VTE, and for the prevention of stroke in atrialfibrillation patients [1–9]. See Figure 1 for historical progressionin anticoagulation and Figure 2 for the structure of the first oraldirect anti-Xa and the first direct anti-IIa.The current anti-thrombotic (anti-coagulant) strategies are ex-pected to change the landscape of thrombosis management dra-matically. A number of these new oral anticoagulant therapies areset to enter the market, raising a number of questions: How willit evolve? What are the future scenarios? Will it be cost effective?With so many drugs in development, will it turn into another ‘me-too’ market? Or, will one drug dominate? Can heparin, LMWHswarfarin be replaced?In a comprehensive RECORD clinical trial program involvingover 12,500 patients, rivaroxaban, a direct factor Xa inhibitor,taken as a once-daily tablet, demonstrated improved efficacy of upto 50% over the existing standard of care: the injectable, LMWHenoxaparin [8,9]. Rivaroxaban (Figure 2) is the only oral antico-agulant to have demonstrated superior efficacy over enoxaparin,the mainstay of current Thromboprophylaxis [8,9].Results of the RECORD 1 and 3 trials, which compared ri- The futureof all neworal factorXa or IIainhibitorswill dependon therelativeefficacy,safety, andcost.varoxaban with enoxaparin, demonstrated that prophylactic treat-ment with rivaroxaban was associated with a 70% relative riskreduction (RRR) in the development of venous blood clots inhip replacement patients (2.6% absolute risk reduction) and 49%RRR in knee replacement patients (9.2% absolute risk reduction),whilst demonstrating comparable bleeding and side effect profiles[2,3]. With its efficacy advantages and convenient oral administra-tion, which requires no coagulation monitoring, rivaroxaban hasthe potential to have a significant impact on clinical practice [3–7].In March 2009, the FDA Advisory panel recommended theapproval of rivaroxaban (Xarelto, Johnson & Johnson, NewBrunswick, NJ, USA), which would be the first new oral antico-agulant since the approval of warfarin in 1954 for the prophylaxisof deep vein thrombosis (DVT) and pulmonary embolism (PE) inpatients undergoing hip and knee replacement surgery. The rec-ommendation is based on data from the four phase 3 RECORD tri-als, which together compared the factor Xa inhibitor rivaroxabanat 10 mg per day, with the subcutaneously administered LMWHenoxaparin for prevention of venous thromboembolism after hipor knee surgery in more than 12,500 patients [6–9].In October 2010, the FDA approved the first new oral di-rect anti-IIa anticoagulant in 55 years, dabigatran (marketedby Boehringer Ingelheim Pharmaceuticals, Ingelheim, Germany,under the trade name Pradaxa) for stroke prevention in pa-tients with nonvalvular atrial fibrillation. As demonstrated inthe 18,113 patients RE-LY trial, Pradaxa 150 mg taken twicedaily significantly reduced stroke and systemic embolism by35% beyond the reduction achieved with warfarin, the cur-rent standard of care for patients with nonvalvular atrial fib-rillation. Pradaxa 150 mg twice daily significantly reducedboth ischemic and hemorrhagic strokes compared with war-farin. Treatment with Pradaxa does not require blood monitor-ing or related dose adjustments and has no recommended di-etary restrictions. The FDA also approved Pradaxa 75 mg twicedaily for the small sub-set of patients who have severe renalimpairment.

Management of major bleedings during anticoagulant treatment with the oral direct thrombin inhibitor ximelagatran or warfarin

Several new oral anticoagulants are currently investigated in phase III programmes, mainly with inhibition of factor Xa or thrombin as their pharmacological target. Advantages are expected with these new drugs compared with vitamin K antagonists, but one potential drawback is the lack of specific antidotes. During the clinical studies with ximelagatran, an oral direct thrombin inhibitor withdrawn due to hepatic side effects, investigators were instructed to manage bleedings with routine measures. We have retrospectively tried to assess whether this was sufficient or whether there was a need for reversal strategies. The study population consisted of patients with major bleedings in three long-term studies (104 ximelagatran, 155 warfarin). All individual patient narratives were reviewed with respect to management of the bleeding. Complementary data were retrieved from the data-based case report forms. Approximately, two of three of the patients in both groups were subject to some kind of treatment. One-third (1/3) in both groups had transfusions documented and/or received specific medication. Vitamin K was given more often to warfarin patients. Two ximelagatran patients received prothrombin complex (four-factor concentrate), but one was a patient with a severe hepatopathy suspected to be drug-induced. Overall, the case descriptions did not reveal any apparent differences in the course of events between groups. We found no indications that the lack of an antidote posed a clinical problem in patients treated with ximelagatran as compared with warfarin. The relatively short half-life of melagatran, the active metabolite of ximelagatran, may have contributed to these results.

Use of Emerging Oral Anticoagulants in Clinical Practice

A review of clinical data from oral anticoagulant studies in orthopedic/general surgery and extrapolation to actual clinical practice. In all surgical patients, there is a risk of postoperative venous thromboembolism (VTE). Parenteral unfractionated heparin, low-molecular-weight heparin, and fondaparinux are available for VTE prophylaxis. Vitamin K antagonists, the only available oral anticoagulants, are widely used in the United States for thromboprophylaxis in joint replacement surgery in spite of being associated with several disadvantages, limiting their effectiveness in the postoperative setting. The oral direct thrombin inhibitor ximelagatran, briefly approved outside the United States for thromboprophylaxis in orthopedic patients, was discontinued due to severe hepatotoxicity concerns. Recently, the oral factor Xa inhibitors rivaroxaban and apixaban have entered late phase development for VTE thromboprophylaxis and treatment and the oral direct thrombin inhibitor dabigatran has received marketing approval from the European Medicines Agency. Review of clinical studies of the oral anticoagulants in VTE prevention in orthopedic surgery and comparison with large observational registries. : Results from Phase II/III studies suggest that new oral anticoagulants may provide an efficacious alternative in VTE prevention in orthopedic surgery. Furthermore, these new oral agents have, so far, shown a good overall safety profile, with no evidence of increased hepatotoxicity. However, comparison with large observational registries reveals differences between real-life patient populations, which make extrapolation of clinical trial data to actual clinical practice difficult. Differences in endpoint definitions also prevent indirect comparison of agents. Specific compliance and postmarketing safety issues (especially liver enzyme monitoring requirements) need to be clarified before these agents are widely accepted into routine clinical practice. Although new oral anticoagulants appear promising, clinical trial results should be viewed with caution until they can be replicated in routine care settings across a broad spectrum of surgical patients.

Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran

Causality assessment in drug-induced liver injury is often based on circumstantial evidence rather than a formal, systematic review. The Roussel Uclaf Causality Assessment Method (RUCAM) provides a more objective means of assessing causality of a suspected hepatotoxin but, to our knowledge, has never been used in the assessment of a single drug with unknown hepatotoxic potential in a clinical trial setting. We studied the utility of RUCAM in assessing the hepatic events during the long-term clinical trials of the oral direct thrombin inhibitor ximelagatran, which has been associated with an increased incidence of alanine aminotransferase (ALT) elevations. A total of 233 subjects with elevated ALT values signalling possibly severe hepatic injury were eligible for RUCAM analysis (198 ximelagatran and 35 comparator anticoagulants). RUCAM scores, calculated independently by the assessors, using the existing numerical criteria provided in its methodology, suggested a possible or probable causal relationship between ALT and ximelagatran in 37 and 27% of cases, respectively. Causality was excluded or unlikely in the remaining 36% of cases. However, in the course of utilizing RUCAM, several limitations to the methodology came to light, including awarding additional points for age > 55 years, an unspecified use of alcohol, and a latency period of < 90 days, which may have had the unintentional effect of raising the overall score. Moreover, rechallenge is highly rewarded by RUCAM but is seldom done in clinical practice or in clinical trials. We also found ambiguities in the extent to which other causes of liver injury were excluded, what constitutes a significant hepatotoxic concomitant medication, and whether a clinical trial drug should be considered as having an unknown hepatotoxic potential for purposes of RUCAM scoring. Increasing familiarity with the RUCAM over the course of the study allowed for only a slight improvement in concordance between and among the assessors regarding the scoring. While the results indicate that RUCAM can provide for an objective assessment of causality of the hepatotoxicity of a drug under development in the clinical trial setting, this study highlights a number of problems with the current scoring system that should be addressed by future enhancements of the methodology.

Effect of Ximelagatran and Warfarin on Stroke Subtypes in Atrial Fibrillation

The most common stroke subtype among atrial fibrillation (AF) patients not receiving anticoagulants is cardioembolic. In the SPORTIF III and V trials, the oral direct thrombin inhibitor ximelagatran was as effective as warfarin in reducing the risk of stroke in patients with nonvalvular AF. We assessed any differential effect of warfarin versus ximelagatran on the risk and outcome of cardioembolic and noncardioembolic stroke. 7329 patients with AF and > or = 1 risk factors for stroke were randomized to treatment with warfarin (target international normalized ratio 2.0--3.0) or fixed-dose ximelagatran. Strokes were classified into specific subtypes. Therapeutic effect of warfarin and ximelagatran, adverse events, and stroke outcomes were assessed according to stroke subtype. The annual stroke rate was low for both cardioembolic (ximelagatran, 0.39%; warfarin, 0.47%) and noncardioembolic stroke (ximelagatran, 0.57%; warfarin, 0.37%). In ischemic strokes, 33.9% (ximelagatran) and 34.3% (warfarin) had strokes of presumed cardioembolic origin. When fatal stroke, disabling stroke, myocardial infarction, and death from any cause were combined as poor outcome, patients with cardioembolic strokes had the highest rate of poor outcome (40%) but this was non- significant. In SPORTIF III and V the efficacy of warfarin and ximelagatran were similar for prevention of cardioembolic and noncardioembolic strokes. Overall outcome tended to be worse following cardioembolic stroke. Ximelagatran has been withdrawn from the market due to hepatic side effects, but similar compounds are presently being studied.

Effect of ximelagatran on ischemic events and death in patients with atrial fibrillation after acute myocardial infarction in the efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial damage (ESTEEM) trial

New-onset trial fibrillation (AF) occurs commonly after acute myocardial infarction (MI) and is associated with a poor prognosis due to stroke or death. The optimal antithrombotic therapy is unknown. The aim of this study was to investigate whether an oral direct thrombin inhibitor, ximelagatran, added to aspirin, reduced the risk of death, myocardial infarction (MI), and stroke in patients who developed AF after their qualifying MI in the efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial damage (ESTEEM) trial. The ESTEEM trial evaluated 6 months treatment with ximelagatran together with aspirin, compared to aspirin alone, for prevention of ischemic events in 1883 patients randomized within 14 days after an MI. After their qualifying MI, 174 (9%) patients developed AF in hospital. Multivariate hazard ratios for ximelagatran compared with placebo were calculated by presence AF. Of 101 patients with AF treated with ximelagatran 7 (6.9%) had either death, MI, or stroke, compared with 15 (20.6%) in 73 patients allocated to placebo. Ximelagatran reduced the risk of death, MI, or stroke by 70% (hazard ratio 0.30, 95% CI 0.12-0.74). For the separate outcome events, we found similar, nonsignificant trends. One major bleeding event occurred in each treatment group. For patients with MI complicated by AF, the combination of aspirin and an oral direct thrombin inhibitor seems beneficial. The high risk for death, MI, and stroke in this population and the increasing use of percutaneous interventions in MI patients may suggest a combination of long-term antiplatelet and anticoagulant therapy. Randomized clinical trials are warranted.

Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis

One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case-control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1(*)07 and DQA1(*)02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.

Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data

Objective:In heart failure, digitalis increases exercise capacity and reduces morbidity, but has no effect on survival. This raises the suspicion that the inotropic benefits of digitalis may be counteracted by...

Pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran co-administered with different classes of antibiotics in healthy volunteers

To study the effects of amoxicillin, doxycycline, ciprofloxacin, azithromycin, and cefuroxime on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, which is a substrate for the P-glycoprotein pump (P-gp) transporter but is not metabolized by the cytochrome P450 (CYP450) enzyme system. Five parallel groups of 16 healthy volunteers received two sequential treatments. The first treatment was a single 36-mg dose of ximelagatran. During the second treatment period, one of the above antibiotics was given on days 1-5 after a washout of at least 2 days. A single 36-mg oral dose of ximelagatran was given on the mornings of days 1 and 5 of the second treatment period. No pharmacokinetic interactions were detected between ximelagatran and amoxicillin, doxycycline, or ciprofloxacin as the least-squares geometric mean treatment ratio of ximelagatran with-to-without antibiotic fell within the intervals of 0.80-1.25 for the area under the curve (AUC) and 0.7-1.43 for C(max). After co-administration with azithromycin, the least square mean ratio with-to-without antibiotic for AUC of melagatran was 1.60 (90% CI, 1.40-1.82) on day 1 and 1.41 (90% CI, 1.24-1.61) on day 5. For melagatran C(max), the corresponding ratios were 1.63 (90% CI, 1.38-1.92) and 1.40 (90% CI, 1.18-1.66). After co-administration with cefuroxime, the ratios were 1.23 (90% CI, 1.07-1.42) and 1.16 (90% CI, 0.972-1.38) for AUC and 1.33 (90% CI, 1.07-1.66) and 1.19 (90%CI, 0.888-1.58) for C(max) of melagatran. Co-administration with the antibiotics did not change mean time to C(max), half-life, or renal clearance of melagatran. The melagatran plasma concentration-response relationship for activated partial thromboplastin time (APTT) prolongation was not altered by any of the studied antibiotics, but the increased plasma concentrations of melagatran after co-administration of ximelagatran with azithromycin resulted in a minor increase in the mean maximum APTT of about 15%. The pharmacokinetics of ximelagatran were not affected by amoxicillin, doxycycline, or ciprofloxacin. Melagatran exposure was increased when ximelagatran was co-administered with azithromycin and, to a lesser extent, with cefuroxime. APTT was not significantly altered by any of the antibiotics.

Investigational treatments of venous thromboembolism

The antithrombotic management of venous thromboembolism (VTE) has gone through major developments. Indirect inhibitors such as low molecular weight heparin and the pentasaccharide fondaparinux represent improvements over traditional drugs such as unfractionated heparin for acute treatment of VTE with more targeted approaches, predictable pharmacokinetic profiles and lack of need for monitoring. Vitamin K antagonists, with inherent limitations of multiple food and drug interactions and frequent need for monitoring, remain the only oral anticoagulants approved for long-term secondary thromboprophylaxis in VTE with the removal of the oral direct thrombin inhibitor ximelagatran from the world market due to safety concerns. Newer anticoagulant drugs such as parenteral pentasaccharides (idraparinux and SSR-126517-E), oral direct thrombin inhibitors (dabigatran), oral direct Factor Xa inhibitors (rivaroxaban, apixaban, YM-150 and DU-176b) and tissue factor–Factor VIIa complex inhibitors (NAPc2) are tailor-made to target specific procoagulant complexes and have the potential to greatly expand our antithrombotic armamentarium for both acute and long-term treatment of VTE, especially as non-monitored parenteral and oral anticoagulants with a wide therapeutic window and a predictable anticoagulant response.

Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischaemic events: observations from the ESTEEM trial

Patients with a recent myocardial infarction have an increased risk of recurrent ischaemic events. In the ESTEEM trial, the oral direct thrombin inhibitor ximelagatran reduced the risk of new ischaemic events when compared with placebo in aspirin treated post myocardial infarction patients. Ximelagatran persistently reduced markers of coagulation activity, i.e. prothrombin fragment 1 + 2 (F1 + 2) and D-dimer levels. The aim of this substudy was to evaluate the levels of these markers and activated thromboplastin time (APTT) in relation to new ischaemic events or bleeding.In the substudy, 518 out of 1883 patients were included and within 14 days after a myocardial infarction randomized to ximelagatran or placebo for 6 months. The clinical endpoints death, myocardial infarction, severe recurrent ischaemia, ischaemic stroke, and bleeding were evaluated. The levels of F1 + 2, D-dimer, and APTT were analysed at randomization and in serial samples during the study. Ximelagatran treatment appeared to have a larger treatment effect in patients with F1 + 2 and D-dimer levels above the median at randomization with a reduction of ischaemic events from 18 to 9% (P = 0.03) for F1 + 2 and from 20 to 9% for D-dimer (P = 0.009). A reduction of D-dimer levels was found in 60% of the patients 1 week after randomization and these patients had less ischaemic events when compared with patients with unchanged or increased levels (P = 0.03) regardless of treatment. F1 + 2 and D-dimer levels were unrelated to bleeding risk. In the ximelagatran group, increased APTT was not related to ischaemic events but associated with a raised risk of bleeding.A reduction of initially high coagulation activity, as measured by the D-dimer level, in patients with recent myocardial infarction identifies patients with a decreased risk of new ischaemic events, regardless whether the reduction occurs spontaneously or is induced by pharmacological means. Patients with higher initial coagulation activity seemed to benefit most from long-term treatment with ximelagatran.

Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischaemic events: observations from the ESTEEM trial

Patients with a recent myocardial infarction have an increased risk of recurrent ischaemic events. In the ESTEEM trial, the oral direct thrombin inhibitor ximelagatran reduced the risk of new ischaemic events when compared with placebo in aspirin treated post myocardial infarction patients. Ximelagatran persistently reduced markers of coagulation activity, i.e. prothrombin fragment 1 + 2 (F1 + 2) and D-dimer levels. The aim of this substudy was to evaluate the levels of these markers and activated thromboplastin time (APTT) in relation to new ischaemic events or bleeding. In the substudy, 518 out of 1883 patients were included and within 14 days after a myocardial infarction randomized to ximelagatran or placebo for 6 months. The clinical endpoints death, myocardial infarction, severe recurrent ischaemia, ischaemic stroke, and bleeding were evaluated. The levels of F1 + 2, D-dimer, and APTT were analysed at randomization and in serial samples during the study. Ximelagatran treatment appeared to have a larger treatment effect in patients with F1 + 2 and D-dimer levels above the median at randomization with a reduction of ischaemic events from 18 to 9% (P = 0.03) for F1 + 2 and from 20 to 9% for D-dimer (P = 0.009). A reduction of D-dimer levels was found in 60% of the patients 1 week after randomization and these patients had less ischaemic events when compared with patients with unchanged or increased levels (P = 0.03) regardless of treatment. F1 + 2 and D-dimer levels were unrelated to bleeding risk. In the ximelagatran group, increased APTT was not related to ischaemic events but associated with a raised risk of bleeding. A reduction of initially high coagulation activity, as measured by the D-dimer level, in patients with recent myocardial infarction identifies patients with a decreased risk of new ischaemic events, regardless whether the reduction occurs spontaneously or is induced by pharmacological means. Patients with higher initial coagulation activity seemed to benefit most from long-term treatment with ximelagatran.

Ximelagatran/melagatran against conventional anticoagulation: A meta-analysis based on 22,639 patients

Background The oral direct thrombin inhibitor ximelagatran, and its active form, melagatran, have been tested in various clinical conditions as a promising alternative to conventional anticoagulant therapy (CAT), despite some concerns over potentially serious liver injury. Objectives To assess its risk/benefit profile, a systematic review and meta-analysis of all randomised controlled trials (RCTs) comparing xi-/melagatran to CAT was performed. Methods Leading medical databases were searched. The rates of major adverse events (MAE: all cause death, nonfatal myocardial infarction, nonfatal thromboembolic stroke, nonfatal pulmonary embolism), major bleeds (MB), and hepatotoxicity were compared. Out of 140 potentially relevant citations, 13 RCTs enrolling 22,639 patients were included. Indications for treatment were: 1) perioperative prophylaxis of deep vein thrombosis (DVT); 2) management of DVT; and 3) stroke prevention in atrial fibrillation. Results Overall, the risk of MAE (OR 0.98 [0.83–1.17]) and MB (OR 1.01 [0.69–1.47]) did not differ significantly between xi-/melagatran and CAT. There was a clear trend towards an increased risk of hepatotoxicity (OR 1.74 [0.50–6.01]), with an incidence of 5.8% with xi-/melagatran versus 2.3% with CAT ( p < 0.001); more specifically, the rate of hepatotoxicity was markedly augmented in the management of DVT (OR 5.16 [3.38–7.89]), for treatment durations ≥ 3 months (OR 6.73 [5.01–9.05]), and in the prevention of atrial fibrillation-related stroke (OR 8.31 [5.65–12.23]). Two fatal cases of liver injury occurred with xi-/melagatran. Conclusions Although comparable to CAT in terms of MAE and MB, xi-/melagatran carries a prohibitive risk of hepatotoxicity that cannot be ignored. Newer long-term alternatives are urgently needed.

Effects of melagatran on activated partial thromboplastin time and on ecarin clotting time in cord versus adult plasma

Melagatran is the active form of the oral direct thrombin inhibitor ximelagatran. Melagatran does not require antithrombin as a cofactor. Its administration is therefore of special interest in neonatal patients, whose plasma is relatively deficient in antithrombin. We investigated the effects of increasing amounts of melagatran (0.05-1 micromol/l) on the activated partial thromboplastin time (APTT) and ecarin clotting time (ECT) in cord versus adult plasma. Both the APTT and ECT were dose-dependently prolonged in the presence of increasing amounts of melagatran. Furthermore, the ECT revealed a higher susceptibility of cord plasma to addition of melagatran than adult plasma. Whereas similar amounts of melagatran were required in cord and adult plasma samples to double the APTT (IC(50), 0.47 vs 0.46 micromol/l), significantly less melagatran was required in cord versus adult plasma to double the ECT (IC(50), 0.26 vs 0.56 micromol/l). Based on APTT measurements, similar plasma levels of melagatran might be required in neonates and in adults to treat thromboembolic complications. The APTT, however, is relatively insensitive to plasma melagatran concentrations. When the sensitive indicator ECT is used, results suggest that lower amounts of melagatran might be required in neonates than in adults. This has to be scrutinized in future clinical studies.

Oral Direct Thrombin Inhibitor Ximelagatran Compared with Warfarin for the Prevention of Venous Thromboembolism After Total Knee Arthroplasty

Colwell, Clifford W. Jr. MD; Berkowitz, Scott D. MD; Lieberman, Jay R. MD; Comp, Philip C. MD; Ginsberg, Jeffrey S. MD; Paiement, Guy MD; McElhattan, Jennifer MS; Roth, Anne W. MS; Francis, Charles W. MD Author Information

Observations of Alanine Aminotransferase and Aspartate Aminotransferase in THRIVE Studies Treated Orally with Ximelagatran

Treatment of acute venous thromboembolism (VTE) and prophylaxis of recurrent events has been investigated in the THRIVE (THRombin Inhibitor in Venous Thrombe Embolism) Treatment and the THRIVE III trial using the oral direct thrombin inhibitor ximelagatran. Alanine aminotransferase (ALAT) increased in 9.6% and 6.4% of patients in the THRIVE Treatment and THRIVE III trials, respectively. The authors analysed the time course of the ALAT and in additionally of aspartate aminotransferase (ASAT) in blood from 52 and 23 patients participating in the THRIVE Treatment and the THRIVE III trials in Germany. Analysis of variance for repeated measures and t test were performed. In the THRIVE Treatment trial, ALAT was significantly higher at week 2 for enoxaparin/warfarin (p => .0039, t test) and at months 3 and 6 for ximelagatran (p = .0453, p = .0014, respectively). ASAT and ASAT/ALAT ratio values did not increase and not differ for both groups. In the THRIVE III trial, ALAT and ASAT did not increase and did not differ compared to the comparator placebo. 2 x 36 mg Ximelagatran, induced higher ALAT values at months 3 and 6 compared to 2 x 24 mg ximelagatran (p = .0105, p = .0063, respectively). ASAT did not differ between the two doses of ximelagatran. The ASAT/ALAT ratios were lower at week 2 for enoxaparin/warfarin (t-test, p = .0032) and at month 3 and 6 for 2 x 36 mg versus warfarin or 2 x 24 mg Ximelagatran (p between .0187 and .0002). The authors conclude that ALAT increases dose dependently during therapy with ximelagatran. The less frequent and lower increase of ASAT values compared to ALAT values indicates a nontoxic effect of ximelagatran on liver cells.

Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Non-Valvular Atrial Fibrillation

Background: To show results of a prespecified pooled analysis of the studies SPORTIF III (open-label) and SPORTIF V (double-blind), to assess the homogeneity of the results and to explore subgroup analyses and adverse events. Methods and Results: 7,329 patients with atrial fibrillation (AF) and ≧1 additional stroke risk factor were randomized to warfarin (international normalized ratio 2.0–3.0) or ximelagatran (36 mg twice daily). Over 11,346 patient-years (mean 18.5 months/patient), 184 patients developed primary events of stroke and systemic embolism (ximelagatran 1.62 vs. warfarin 1.65%/year; p = 0.94). Heterogeneity between trials with respect to the primary event rate (study-by-treatment interaction p = 0.026) was found. This could not be explained statistically by baseline patient characteristics or by treatment (except perhaps by the better anticoagulation with warfarin in SPORTIF V) and was not evident for secondary end-points. There was no conclusive difference in major bleeding rates (ximelagatran 1.88 vs. warfarin 2.46%/year; p = 0.054), but combined minor plus major bleeding was lower with ximelagatran (31.7 vs. 38.7%/year; p < 0.0001). Elevation of liver enzymes occurred more frequently in patients taking ximelagatran (6.1% vs. warfarin 0.8%; p < 0.0001) and was reversible except in rare cases. Conclusions: Fixed-dose oral ximelagatran without coagulation monitoring prevented stroke and systemic embolism as effectively as warfarin in patients with AF. Differences in the results of the two trials might relate to consistency of warfarin anticoagulation, different degree of blinding in the two trials, other concomitant therapies or chance. Further investigation is required to explore the long-term safety profile of ximelagatran.

Incidence of recurrent venous thromboembolism of patients after termination of treatment with ximelagatran

Recurrent thromboembolic events may occur after termination of anticoagulant therapy for acute venous thromboembolism (VTE) using oral direct thrombin inhibitor ximelagatran. Patients with VTE recruited at the German study centres were followed-up for an additional 18 months, treated initially with 2x36 mg ximelagatran daily or with enoxaparin/warfarin over 6 months (THRIVE Treatment study) and 2x24 mg ximelagatran daily or placebo over 18 months (THRIVE III study). Recurrent VTE and the combined outcome events consisting of recurrent VTE, other thrombotic complication, major bleeding and mortality were analysed. In the THRIVE Treatment study, no patient suffered from a recurrent VTE, but 1 patient randomised to enoxaparin/warfarin experienced major bleeding. During follow-up, 4/32 and 3/32 patients initially randomised to ximelagatran and enoxaparin/warfarin developed recurrent VTE (p=0.7024). No major bleed occurred. One patient in each group died. The incidences of the combined outcome events were not different (p=0.9326). In the THRIVE III study, 0/9 versus 5/14 patients randomised to ximelagatran and placebo developed recurrent VTE including 1 fatal pulmonary embolism (p=0.0501). During follow-up, 3/9 and no patients initially randomised to ximelagatran and placebo developed recurrent VTE. One and 3 other outcome events occurred in patients initially randomised to ximelagatran or placebo. During follow-up, recurrent VTE (p=0.6893) and combined outcome events (p=0.3642) were not different between the groups. The results of the follow-up studies suggest that thromboembolic events may re-occur in patients with acute VTE after termination of treatment with both vitamin K-antagonists and ximelagatran.