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 naive 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-naive subjects with treatment, whereas in VKA pre-treated patients, D-dinner levels started tow 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 similar to 10% from baseline and returned to baseline following treatment cessation. The frequency of serum alanine aminotransferase >= 3 x 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

Anticoagulation for non-valvular atrial aibrillation – towards a new beginning with ximelagatran

OBJECTIVES: Ximelagatran is a novel oral direct thrombin inhibitor. It has favorable pharmacodynamic properties, with a broad therapeutic range without the need for anticoagulation monitoring. We aimed to discover whether ximelagatran offers a genuine future replacement to warfarin for patients in persistent atrial fibrillation (AF). MATERIALS AND METHODS: We provide an evidence-based review of the relative merits and disadvantages of warfarin and aspirin. We subsequently present an overview of the evidence for the utility of ximelagatran in the treatment of AF. RESULTS: Adjusted dose warfarin is recommended over aspirin for patients in AF at high risk of future stroke. Some of this benefit is partially offset by the higher bleeding risks associated with warfarin therapy. The SPORTIF III and V studies have shown that ximelagatran is not inferior to warfarin in the prevention of all strokes in patients with AF (both persistent and paroxysmal). This benefit was partially offset by the finding of a significant elevation of liver transaminases (>3 × normal) in 6% of patients. CONCLUSIONS: Current data would suggest that ximelagatran might represent a future alternative to warfarin. The lack of need for anticoagulant monitoring has been partially offset by a need for regular monitoring of liver function. Further data from randomized clinical trials is clearly needed

Paediatric and adult congenital cardiology education and training in Europe

Background: Limited data exist on training of European paediatric and adult congenital cardiologists. Methods: A structured and approved questionnaire was circulated to national delegates of Association for European Paediatric and Congenital Cardiology in 33 European countries. Results: Delegates from 30 countries (91%) responded. Paediatric cardiology was not recognised as a distinct speciality by the respective ministry of Health in seven countries (23%). Twenty countries (67%) have formally accredited paediatric cardiology training programmes, seven (23%) have substantial informal (not accredited or certified) training, and three (10%) have very limited or no programme. Twenty-two countries have a curriculum. Twelve countries have a national training director. There was one paediatric cardiology centre per 2.66 million population (range 0.87-9.64 million), one cardiac surgical centre per 4.73 million population (range 1.63-10.72 million), and one training centre per 4.29 million population (range 1.63-10.72 million population). The median number of paediatric cardiology fellows per training programme was 4 (range 1-17), and duration of training was 3 years (range 2-5 years). An exit examination in paediatric cardiology was conducted in 16 countries (53%) and certification provided by 20 countries (67%). Paediatric cardiologist number is affected by gross domestic product (R-2 = 0.41). Conclusion: Training varies markedly across European countries. Although formal fellowship programmes exist in many countries, several countries have informal training or no training. Only a minority of countries provide both exit examination and certification. Harmonisation of training and standardisation of exit examination and certification could reduce variation in training thereby promoting high-quality care by European congenital cardiologists.Developmen

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