No abstract

SummaryA multicenter, randomized double-blind study compared in two parallel groups the efficacy and safety of a low molecular weight heparin (LMWH) enoxaparin 20 mg once daily, with unfractionated heparin (UFH) 5000 IU twice daily, administered subcutaneously for 10 days, in the prevention of venous thrombosis disease in 442 hospitalized elderly patients bedridden for an acute medical illness. The main efficacy endpoint was defined as the occurrence of venous thrombosis, diagnosed by a daily fibrinogen uptake test, and/or documented clinical pulmonary embolism.Intention-to-treat analysis of efficacy showed that the incidence of venous thromboembolic events was low: 4.8% (10/207) in the LMWH group (9 episodes of isotopic venous thrombosis and one of scintigraphic pulmonary embolism), and 4.6% (10/216) in the UFH group (10 episodes of isotopic venous thrombosis). The two treatments were equivalent, where equivalence was defined as a maximum difference of 7% between the two groups (p = 0.0005).There were no significant differences in terms of safety between the 216 patients in the LMWH group and the 223 patients in the UFH group who received at least one injection of the randomized treatment. During the study period, 15 patients (3.4%) died (7 in the LMWH group and 8 in the UFH group): 2 sudden deaths, one in each group, including one case in which pulmonary embolism could not be excluded since no autopsy was performed, and 13 others deaths unrelated to the study treatments. Six patients (1.4%) presented a bleeding complication: 2 (0.9%) in the enoxaparin group (one major and one minor hemorrhage), and 4 (1.8%) in the UFH group (2 major and 2 minor hemorrhages).These results indicate that subcutaneous enoxaparin 20 mg once daily for 10 days is as effective and well tolerated as subcutaneous UFH 5000 IU twice daily in the prevention of venous thromboembolic disease in bedridden elderly in-patients presenting an acute medical illness.

Background: In previous studies (the RITZ project), tezosentan, an intravenous (i.v.)-balanced dual endothelin (ET-A/B) antagonist, in doses of 50 and 100 mg/h, improved the hemodynamics but not the clinical outcome of patients with acute heart failure (AHF). Objective: To evaluate the effect of lower doses of tezosentan in patients with AHF. Subjects and methods: Included were 130 patients hospitalized due to AHF with dyspnea at rest, despite initial treatment, and were in need of hemodynamic monitoring with cardiac index (CI) < 2.5 l/min/m 2 and wedge pressure z 20 mm Hg. Patients were randomized in a double-blind fashion to receive placebo or tezosentan: 0.2, 1, 5, or 25 mg/h for 24 h. Results: The primary endpoint of the study, CI increase at 6 h of treatment, was significant in the 5 and 25 mg/h groups. Tezosentan induced a dose-dependent increase in CI and a decrease in wedge pressure, peaking after 3 h in the 5 and 25 mg/h groups. In the 1-mg/ h group, this effect was smaller during the first 6 h and increased gradually, becoming significant at 24 h and beyond treatment discontinuation. There was no hemodynamic effect in the 0.2 mg/h arm. Type-B natriuretic peptide (BNP) decreased in the 1, 5, and 25 mg/ h groups but not on placebo. Endothelin levels were significantly increased by the 5 and 25 mg/h groups but not in the lower ( V 1 mg/h) tezosentan doses. Urine output decreased on the 25-mg/h dose. There was a trend towards improvement in patients' subjective dyspnea score and worsening heart failure events, mainly in the 1 mg/h group. Conclusions: In patients admitted with AHF, tezosentan doses of 1 -25 mg/ h are efficacious in improving the hemodynamics and reducing BNP. Tezosentan doses beyond 1 mg/h increased plasma endothelin levels and reduced urine output, probably limiting their clinical efficacy, as compared to tezosentan 1 mg/h.

Abstract-The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria Ͼ0.5 and Ͻ3.0 g, systolic blood pressure Ͼ135 and Ͻ170 mm Hg, and/or diastolic blood pressure Ͼ85 and Ͻ110 Key Words: diabetic nephropathy Ⅲ urotensin antagonist Ⅲ RAAS blockade Ⅲ hypertension Ⅲ albuminuria Ⅲ palosuran U rotensin II, initially described as the most potent vasoconstrictor known in mammals, 1,2 is upregulated in hypertension and diabetic nephropathy and, therefore, has been hypothesized to be involved in the development of albuminuria. 3-5 Palosuran (ACT-058362) is an oral, selective, competitive, nonpeptidic antagonist of the human urotensin receptor and has been extensively studied in experimental models of renal failure. In these models, palosuran displayed renoprotective potential by beneficial effects on renal blood flow, proteinuria, and development of glomerular and tubulointerstitial damage. 6,7 Thus far, no controlled data in humans are available. This multicenter, randomized, doubleblind, placebo-controlled, 2-period crossover, proof-ofconcept study was designed to assess whether palosuran would reduce urinary albumin excretion (UAE) and/or systemic blood pressure in hypertensive patients with type 2 diabetic nephropathy on stable treatment with either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II-receptor type 1 antagonist. MethodsPatients of both sexes, age Ͼ30 to Ͻ75 years, with type 2 diabetes mellitus (with or without insulin treatment) and hemoglobin A1c Ͻ10%, hypertension (systolic/diastolic blood pressure Ն135 to Ͻ170 mm Hg and/or Ն85 to Ͻ110 mm Hg), macroalbuminuria (UAE Ն0.5 and Ͻ3.0 g/24 hours), and a measured creatinine clearance Ն30 mL/min per 1.73 m 2 were recruited. Diabetic nephropathy was defined as the presence of macroalbuminuria. Renal biopsy for confirmation was not required. All of the patients gave their written informed consent. The study was conducted in full adherence to the principles of the Declaration of Helsinki. Patients had to be on stable single renin-angiotensin-aldosterone system (RAAS) blockade for Ն3 months. Any treatment with other antihypertensives, statins, and nonsteroidal antiinflammatory drugs had to be stable. Patients had stable renal function in the last 6 months. Exclusion criteria included combined angiotensin II-receptor type 1 antagonist and angiotensin-