Karin Wåhlander

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.

Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers

The objectives were to investigate whether activation of the extrinsic coagulation cascade by recombinant factor VIIa (rFVIIa) reverses the inhibition of thrombin generation and platelet activation by melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. In a single-blind, randomized, parallel-group study, volunteers (20 per group) received a 5-hour intravenous (i.v.) infusion to achieve steady-state melagatran plasma concentrations of approximately 0.5 micromol/L, with a single i.v. bolus of rFVIIa (90 microg/kg) or placebo at 60 minutes. Prothrombin fragment 1+2, thrombin-anti-thrombin complex, fibrinopeptide A, beta-thromboglobulin, and thrombin-activatable fibrinolysis inhibitor were quantified for venous and shed blood. Activated partial thromboplastin time (APTT), prothrombin time (PT), endogenous thrombin potential, thrombus precursor protein (TpP), and plasmin-alpha(2)-antiplasmin complex concentrations were determined in venous blood. Shed blood volume was measured. Melagatran reduced markers of thrombin generation and platelet activation in shed blood and prolonged APTT. rFVIIa increased FVIIa activity, PT, and TpP in venous blood. All other parameters were unaffected. In conclusion, rFVIIa did not reverse the anticoagulant effects of high constant concentrations of melagatran. However, the potential value of higher, continuous or repeated doses of rFVIIa or its use with lower melagatran concentrations has not been excluded.

Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists

Aims Oral anticoagulation with vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF) is effective but has significant limitations. AZD0837, a new oral anticoagulant, is a prodrug converted to a selective and reversible direct thrombin inhibitor (AR-H067637). We report from a Phase II randomized, dose-guiding study (NCT00684307) to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of extended-release AZD0837 in patients with AF. Methods and results Atrial fibrillation patients (n = 955) with ≥1 additional risk factor for stroke were randomized to receive AZD0837 (150, 300, or 450 mg once daily or 200 mg twice daily) or VKA (international normalized ratio 2–3, target 2.5) for 3–9 months. Approximately 30% of patients were naïve to VKA treatment. Total bleeding events were similar or lower in all AZD0837 groups (5.3–14.7%, mean exposure 138–145 days) vs. VKA (14.5%, mean exposure 161 days), with fewer clinically relevant bleeding events on AZD0837 150 and 300 mg once daily. Adverse events were similar between treatment groups; with AZD0837, the most common were gastrointestinal disorders (e.g. diarrhoea, flatulence, or nausea). d-Dimer, used as a biomarker of thrombogenesis, decreased in all groups in VKA-naïve subjects with treatment, whereas in VKA pre-treated patients, d-dimer levels started low and remained low in all groups. As expected, only a few strokes or systemic embolic events occurred. In the AZD0837 groups, mean S-creatinine increased by ∼10% from baseline and returned to baseline following treatment cessation. The frequency of serum alanine aminotransferase ≥3× upper limit of normal was similar for AZD0837 and VKA. Conclusion AZD0837 was generally well tolerated at all doses tested. AZD0837 treatment at an exposure corresponding to the 300 mg od dose in this study provides similar suppression of thrombogenesis at a potentially lower bleeding risk compared with dose-adjusted VKA. This study is registered with ClinicalTrials.gov, number NCT00684307.

Trousseau’s syndrome – what is the evidence? A population-based autopsy study

Despite numerous studies documenting the association between cancer and venous thromboembolism (VTE), the reason for the excessive risk in certain cancers remains obscure. No large-scale studies have yet investigated the independent effects of cancer type, site and growth pattern. Between 1970 and 1982, 23,796 standardised autopsies were performed, representing 84% of all in-hospital deaths in an urban Swedish population. The relationship between cancer and PE was evaluated with logistic regression. The overall PE prevalence was 23%, and 10% of the population had a fatal PE. Forty-two per cent of pancreatic cancer patients had PE (OR 2.55; 95% CI 2.10-3.09) (p<0.001); gall bladder, gastric, colorectal and pulmonary adenocarcinomas were similarly independently associated with PE. In comparison with squamous cell lung cancer, patients with pulmonary adenocarcinoma had 1.65 times higher odds for PE (95% CI 1.20-2.29). Adenocarcinoma and metastatic cancer were independently associated with PE risk (OR 1.27; 95% CI 1.16-1.40; p<0.001, and OR 1.10;95% CI 1.01-1.20; p=0.024, respectively) but when controlling for cancer type and spread, pancreatic cancer was still associated with an OR of 2.10 (95% CI 1.71-2.58) of PE (p<0.001). We conclude that the risk of PE in cancer patients depends not only on the cancer site and spread but also on the histological type. The excess independent risk in pancreatic cancer is intriguing and should warrant further research.

Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis

INTRODUCTION Ximelagatran is a novel, oral direct thrombin inhibitor that is currently being investigated for the prophylaxis and treatment of thromboembolic events. This study evaluated the pharmacokinetics, pharmacodynamics, and clinical effects of melagatran, the active form of ximelagatran, in patients with both deep vein thrombosis (DVT) and pulmonary embolism (PE). MATERIALS AND METHODS In this open-label study, 12 patients received a fixed dose of 48 mg oral ximelagatran twice daily for 6-9 days. Plasma samples were collected for determination of melagatran concentrations and scintigraphic changes and adverse events were recorded. RESULTS Peak plasma concentrations of melagatran were attained approximately 2 h after administration of ximelagatran. Melagatran plasma concentration profiles were similar on Days 1, 2, and 6-9. Plasma activated partial thromboplastin time increased following administration of ximelagatran and reached a peak that was approximately twofold higher than the predose activated partial thromboplastin time and correlated with melagatran plasma concentrations (R(2) = 0.69). All but one patient (with malignancy) showed regressed or unchanged lung scintigraphic findings, and six of these demonstrated no, or only minor, perfusion defects at central evaluation after 6-9 days of ximelagatran treatment. Clinical symptoms, including chest pain, dyspnoea, cough, and oedema, and pain in the affected leg, were improved. Ximelagatran was well tolerated with no deaths or severe bleeding events reported during treatment. CONCLUSION Treatment with a fixed dose of oral ximelagatran, used without routine coagulation monitoring, showed reproducible pharmacokinetics and pharmacodynamics with a rapid onset of action and promising clinical results in patients with pulmonary embolism.

Safety and tolerability of an immediate-release formulation of theoral direct thrombin inhibitor AZD0837 in the prevention of stroke and systemic embolism in patients with atrial fibrillation

AZD0837 is an investigational oral anticoagulant which is converted to the active form, AR-H067637, a selective direct thrombin inhibitor. The present study, a multicentre, randomised, parallel-group, dose-guiding study, assessed the safety and tolerability of an immediate-release formulation of AZD0837 compared with dose-adjusted warfarin in the prevention of stroke and systemic embolic events in atrial fibrillation (AF) patients. Two hundred fifty AF patients with at least one additional risk factor for stroke were randomised to receive either immediate-release AZD0837 (150mg twice daily [bid] or 350mg bid, blinded treatment) or dose-adjusted warfarin (international normalised ratio 2.0-3.0, open treatment) for three months. The safety and tolerability of 150mg bid AZD0837 appeared to be as good as that of warfarin. Total bleeding events were six with 150mg bid AZD0837, 15 with 350mg bid AZD0837 and eight with warfarin. Alanine aminotransferase elevations (>3xupper limit of normal) were infrequent, without apparent differences between treatment groups. A numerically higher incidence of serious adverse events was observed with 350mg bid AZD0837 compared with 150mg bid, with six of 13 being cardiac related, all with different diagnoses. An increase in mean serum creatinine of approximately 10% was observed in both AZD0837 groups, which returned to baseline after completion of therapy. There were no strokes, transient ischaemic attacks or cerebral haemorrhages with any of the treatments. In conclusion, the safety and tolerability of 150mg bid immediate-release AZD0837 appeared to be as good as that of dose-adjusted warfarin. However, larger studies will be needed to define the safety profile of AZD0837.

No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor.

AbstractBackground: The oral direct thrombin inhibitor ximelagatran is a new class of anticoagulant currently in clinical development 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 influence of mild-to-moderate hepatic impairment on the pharmacokinetic and pharmacodynamic properties of ximelagatran. Study design: Nonblinded, nonrandomised study. Participants: Twelve volunteers with mild-to-moderate hepatic impairment (classified as Child-Pugh A or B) and 12 age-, weight-, and sex-matched control volunteers with normal hepatic function. Methods: Volunteers received a single oral dose of ximelagatran 24mg. Plasma and urine samples were collected for pharmacokinetic and pharmacodynamic analyses. Results: The absorption and bioconversion of ximelagatran to melagatran were rapid in both groups. The maximum plasma concentration of melagatran (Cmax) was achieved 2–3 hours after administration; the mean elimination half-life (t½z) was 3.6 hours for hepatically impaired volunteers and 3.1 hours for the control volunteers. The area under the plasma concentration-time curve (AUC) and Cmax of melagatran in volunteers with hepatic impairment were 11 and 25% lower than in control volunteers, respectively. However, after correcting for the higher renal function (i.e. higher calculated creatinine clearance) in the hepatically impaired volunteers, the ratio of melagatran AUC for hepatically impaired/control volunteers was 0.98 (90% CI 0.80, 1.22), suggesting that mild-to-moderate hepatic impairment had no influence on the pharmacokinetics of ximelagatran. Melagatran was the predominant compound in urine, accounting for 13–14% of the ximelagatran dose. Renal clearance of melagatran was 13% higher in hepatically impaired than in control volunteers. There were no significant differences between the two groups in the concentration-response relationship between plasma melagatran concentration and activated partial thromboplastin time (APTT). Baseline prothrombin time (PT) was slightly longer in the hepatically impaired patients than in the control volunteers, probably reflecting a slight decrease in the activity of coagulation factors. However, when concentrations of melagatran were at their peak, the increase in PT from baseline values was the same in both groups. Capillary bleeding time was measured in the hepatically impaired patients only, and was not increased by ximelagatran. Ximelagatran was well tolerated in both groups. Conclusion: There were no differences in the pharmacokinetic or pharmacodynamic properties of melagatran following oral administration of ximelagatran between the hepatically impaired and control volunteers. These findings suggest that dose adjustment for patients with mild-to-moderate impairment of hepatic function is not necessary.

Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis

Summary.  Background: Thrombin plays a major role in thrombus formation through activation of platelets and conversion of fibrinogen to fibrin. Objectives: To investigate the antithrombotic effects of the oral direct thrombin inhibitor (DTI) ximelagatran and the parenteral DTI r‐hirudin in humans. Subjects and methods: Healthy male volunteers randomized into four parallel groups each with 15 subjects received either ximelagatran (20, 40 or 80 mg orally) or r‐hirudin (0.4 mg kg−1 intravenous bolus + infusion of 0.15 mg kg−1 h−1 for 2 h and 0.075 mg kg−1 h−1 for 3 h). Antithrombotic effects were assessed as changes in total thrombus area (TTA) and total fibrin area (TFA) from baseline, using the Badimon perfusion chamber model at baseline and 2 h and 5 h after drug administration. Results: Two hours postdosing, ximelagatran showed antithrombotic effects at both high and low shear rates (TTA% of mean baseline value ± SEM was 76 ± 13% and 71 ± 17% [both P < 0.05] for the 20‐mg dose, 85 ± 11% [P > 0.05] and 62 ± 15% [P < 0.05] for the 40‐mg dose and 60 ± 11% and 26 ± 7% [both P < 0.05] for the 80‐mg dose, respectively). r‐Hirudin also showed a significant antithrombotic effect at high and low shear rates (76 ± 11% [P = 0.05] and 57 ± 17% [P < 0.05] of baseline values, 2 h postdosing, respectively). The inhibitory effects on TFA were similar to those on TTA. Conclusions: The oral DTI ximelagatran shows antithrombotic effects under both high and low shear conditions. The antithrombotic effect of 40–80 mg ximelagatran appeared comparable to that of parenterally administered r‐hirudin, which has been previously demonstrated to be clinically effective in acute coronary syndromes.

Pharmacokinetics of ximelagatran and relationship to clinical response in acute deep vein thrombosis.

Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis.

Developing New Treatments for Heart Failure: Focus on the Heart

Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability to identify homogeneous subsets of patients whose underlying disease is driven by a specific mechanism that can be targeted using a new therapeutic agent. Drug development strategies should increasingly consider therapies that facilitate reverse remodeling by directly targeting the heart itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. Advancements in cardiac imaging may allow for more focused and direct assessment of drug effects on the heart early in the drug development process. To better understand and address the array of challenges facing current HF drug development, so that future efforts may have a better chance for success, the Food and Drug Administration facilitated a meeting on February 17, 2015, which was attended by clinicians, researchers, regulators, and industry representatives. The following discussion summarizes the key takeaway dialogue from this meeting.