Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients

The efficacy and safety of prolonging prophylaxis for venous thromboembolism in medically ill patients beyond hospital discharge remain uncertain. We hypothesized that extended prophylaxis with apixaban would be safe and more effective than short-term prophylaxis with enoxaparin. METHODS: In this double-blind, double-dummy, placebo-controlled trial, we randomly assigned acutely ill patients who had congestive heart failure or respiratory failure or other medical disorders and at least one additional risk factor for venous thromboembolism and who were hospitalized with an expected stay of at least 3 days to receive apixaban, administered orally at a dose of 2.5 mg twice daily for 30 days, or enoxaparin, administered subcutaneously at a dose of 40 mg once daily for 6 to 14 days. The primary efficacy outcome was the 30-day composite of death related to venous thromboembolism, pulmonary embolism, symptomatic deep-vein thrombosis, or asymptomatic proximal-leg deep-vein thrombosis, as detected with the use of systematic bilateral compression ultrasonography on day 30. The primary safety outcome was bleeding. All efficacy and safety outcomes were independently adjudicated. RESULTS: A total of 6528 subjects underwent randomization, 4495 of whom could be evaluated for the primary efficacy outcome - 2211 in the apixaban group and 2284 in the enoxaparin group. Among the patients who could be evaluated, 2.71% in the apixaban group (60 patients) and 3.06% in the enoxaparin group (70 patients) met the criteria for the primary efficacy outcome (relative risk with apixaban, 0.87; 95% confidence interval [CI], 0.62 to 1.23; P = 0.44). By day 30, major bleeding had occurred in 0.47% of the patients in the apixaban group (15 of 3184 patients) and in 0.19% of the patients in the enoxaparin group (6 of 3217 patients) (relative risk, 2.58; 95% CI, 1.02 to 7.24; P = 0.04). CONCLUSIONS: In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin. Apixaban was associated with significantly more major bleeding events than was enoxaparinSupported by Bristol-Myers Squibb and Pfize

Nonpeptide Factor Xa Inhibitors: I. Studies with SF303 and SK549, a New Class of Potent Antithrombotics

A series of benzamidine isoxazoline derivatives was evaluated for their inhibitory potency against purified human factor Xa (fXa) and in a rabbit model of arteriovenous shunt thrombosis for their antithrombotic activities, expressed as KIand IC50, respectively. A highly significant correlation was found between KI and IC50(r = 0.93, P 20,000 nM; plasmin, 2,500 nM] and SK549 [mol. wt. 546; KI: fXa, 0.52 nM; thrombin, 400 nM; trypsin, 45 nM; tissue plasminogen activator >33,000 nM; plasmin, 890 nM] were compared with recombinant tick anticoagulant peptide [KI(fXa) = 0.5 nM], DX-9065a [KI(fXa) = 30 nM], and heparin or low molecular weight heparin (dalteparin) in a rabbit model of arteriovenous shunt thrombosis. ID50 values for preventing arteriovenous shunt-induced thrombosis were 0.6 μmol/kg/h for SF303, 0.035 μmol/kg/h for SK549, 0.01 μmol/kg/h for recombinant tick anticoagulant peptide, 0.4 μmol/kg/h for DX-9065a, 21 U/kg/h for heparin, and 23 U/kg/h for low molecular weight heparin. SK549 produced a concentration-dependent antithrombotic effect with an IC50 of 0.062 μM. To evaluate its potential oral efficacy, SK549 was given intraduodenally at a dose of 5 mg/kg; it produced a peak antithrombotic effect of 59 ± 4% with a duration of action greater than 6.7 h. Therefore, our study suggests that SF303, SK549, and their analogs represent a new class of synthetic fXa inhibitors that may be clinically useful as antithrombotic agents

Enhancement of salvage of reperfused ischemic myocardium by diltiazem

Concomitant use of pharmacologie agents may be required for maximal salvage of ischemic myocardium by reperfusion. Accordingly, in dogs with induced thrombotic coronary occlusion, the effects of intravenous dil-tiazem given 30 minutes before administration of streptokinase on myocardial blood flow and myocardial salvage were evaluated. Two independent types of end points were employed. Positron emission tomography was utilized for noninvasive assessment of myocardial perfusion and infarct extent. Direct measurements included quantification of myocardial infarction by assay of creatine kinase activity in myocardial homogenates. Infarct extent averaged 27.9 ± 11.4% of left ventricular weight in 10 control dogs in which coronary occlusion was maintained for 24 hours. In eight dogs given streptokinase alone, the infarct extent averaged 16.7 ± 10.0% of left ventricular mass (p < 0.05 versus control). In nine other dogs given diltiazem (15 μg/kg per min continuously until death was induced) beginning 30 minutes before streptokinase, infarct extent averaged 9.4 ± 6.7% of left ventricular mass (p < 0.05 compared with reperfusion alone). At the dose administered, diltiazem did not alter blood flow, heart rate or mean arterial pressure after coronary occlusion or thrombolysis.The region at risk, determined in 16 dogs from perfusion images obtained with positron tomography and oxygen-15-labeled water after coronary occlusion, was similar in the three groups (30.6 ± 7.3% of the left ventricle in six control dogs, 31.8 ± 4.5% in five dogs with reperfusion alone and 30.5 ± 11.6% in five dogs with reperfusion plus diltiazem). Infarct size quantified in terms of the extent of myocardium exhibiting less than 50% of peak carbon-11-labeled palmitate uptake 24 hours after occlusion and expressed as the percent of the region at risk averaged 89.6 ± 11.4% in control dogs, was significantly reduced to 45.1 ± 29.8% in dogs with re-perfusion alone and was reduced further to 22.3 ± 16.4% in dogs given diltiazem and reperfusion. Thus, concomitant treatment with diltiazem markedly enhances salvage of reperfused myocardium after coronary thrombolysis