No abstract

Background: Atrial fibrillation is common in heart failure, but data regarding beta-blockade in these patients and its ability to prevent new occurrence of atrial fibrillation are scarce. Methods: Baseline ECGs in MERIT-HF were coded regarding baseline rhythm, and outcome was analyzed in relation to rhythm. Occurrence of atrial fibrillation during follow-up was also analyzed. Results: At baseline atrial fibrillation was diagnosed in 556patients (13.9%). Mean metoprolol CR/XL dose in patients in atrial fibrillation (154 mg) and sinus rhythm (158 mg) was similar, as well as decrease in heart rate (14.8 and 13.7 bpm, respectively). Only 61 (total of 362) deaths occurred in those in atrial fibrillation at baseline, 31 on placebo and 30 on metoprolol (RR 1.0; 95% CI 0.61 -1.65). During follow-up, new atrial fibrillation was observed in 85 patients on placebo and 47 patients on metoprolol (RR 0.53; 95% CI 0.37 -0.76; p = 0.0005). Conclusion: First, given the wide confidence interval, it was impossible to detect an interaction between metoprolol and mortality in patients with atrial fibrillation and heart failure. Second, in patients with sinus rhythm at baseline, metoprolol reduced the incidence of atrial fibrillation during follow-up. However, we must be extremely cautious in over-interpreting effects in these subgroups.

PDS and EPS overlap in the majority of patients with functional dyspepsia. The value of dividing functional dyspepsia into the subgroups of PDS and EPS is thus questionable. A new approach to classifying functional dyspepsia is needed.

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 À1 intravenous bolus þinfusion of 0.15 mg kg À1 h À1 for 2 h and 0.075 mg kg À1 h À1 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 AESEM was 76 AE 13% and 71 AE 17% [both P < 0.05] for the 20-mg dose, 85 AE 11% [P > 0.05] and 62 AE 15% [P < 0.05] for the 40-mg dose and 60 AE 11% and 26 AE 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 AE 11% [P ¼ 0.05] and 57 AE 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 rhirudin, which has been previously demonstrated to be clinically effective in acute coronary syndromes.

The pharmacokinetic dose linearity and reproducibility, the effects on ex-vivo coagulation time assays and bleeding time, and tolerability of the direct thrombin inhibitor melagatran following subcutaneous (s.c.) dosing were investigated in two open-label studies in healthy males: (i). a dose-escalation study in which subjects received single s.c. doses of melagatran (0.1-5 mg); and (ii). a repeated-dosing study in which 3 mg s.c. melagatran was administered at 12-h intervals for 4 days. In both studies, melagatran was rapidly absorbed with maximum plasma concentrations (C(max)) observed about 0.5 h post dosing. The half-life of melagatran was about 2 h. The area under the melagatran plasma concentration versus time curve increased linearly with dose. No time dependency in the area under the curve or Cmax was observed over 4 days of twice-daily dosing. The variability in pharmacokinetic parameters was low and the bioavailability of melagatran appeared to be complete. There was a steep and linear prolongation of thrombin time, a non-linear prolongation of both activated partial thromboplastin time and activated coagulation time, and a decrease in prothrombin complex activity with increasing melagatran plasma concentration. Only moderate increases in capillary bleeding time were observed with s.c. doses up to 5 mg melagatran. Melagatran was well tolerated after s.c. injection, with good local tolerability at the injection site.