Apixaban in doses of 2.5 mg b.i.d. or 5 mg q.d. has a promising benefit-risk profile compared with the current standards of care following TKR.

Summary. Background: Cancer patients receiving chemotherapy are at increased risk for thrombosis. Apixaban, a factor Xa inhibitor, is oral and does not require laboratory monitoring. Objectives: A pilot study was conducted to evaluate whether apixaban would be well tolerated and acceptable in cancer patients receiving chemotherapy. Patients/ Methods: Subjects receiving either first-line or second-line chemotherapy for advanced or metastatic lung, breast, gastrointestinal, bladder, ovarian or prostate cancers, cancer of unknown origin, myeloma or selected lymphomas were randomized to 5 mg, 10 mg or 20 mg once daily of apixaban or placebo in a double-blind manner for 12 weeks. Use of the study drug began within 4 weeks of the start of chemotherapy. The primary outcome was either major bleeding or clinically relevant non-major (CRNM) bleeding. Secondary outcomes included venous thromboembolism (VTE) and grade III or higher adverse events related to the study drug. Thirty-two patients received 5 mg, 30 patients 10 mg, 33 patients 20 mg, and 30 patients placebo. In these groups, there were 0, 0, 2 and 1 major bleeds, respectively. The corresponding data for CRNM bleeds were 1, 1, 2, and 0. The rate of major bleeding in the 93 apixaban patients was 2.2% (95% confidence interval 0.26-7.5%). There were no fatal bleeds. Three placebo patients had symptomatic VTE. Conclusions: Apixaban was well tolerated in our study population. These results support further study of apixaban in phase III trials to prevent VTE in cancer patients receiving chemotherapy.

To cite this article: On behalf of the Botticelli investigators, the writing committee, Buller H, Deitchman D, Prins M, Segers A. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008; 6: 1313-8.Summary. Background: Apixaban, an oral potent reversible direct inhibitor of activated factor X, has shown promise in the prevention of venous thromboembolism following major orthopedic surgery. We conducted a dose-ranging study in patients with deep vein thrombosis. Methods: Consecutive patients with symptomatic deep vein thrombosis were included and randomized to receive 84-91 days of apixaban 5 mg twicedaily, 10 mg twice-daily, or 20 mg once-daily, or low molecular weight heparin (LMWH) followed by a vitamin K antagonist (VKA). The primary efficacy outcome was the composite of symptomatic recurrent venous thromboembolism and asymptomatic deterioration of bilateral compression ultrasound or perfusion lung scan. The principal safety outcome was the composite of major and clinically relevant, non-major bleeding. Results: The mean age of the 520 included patients was 59 years, and 62% were male. The primary outcome occurred in 17 of the 358 apixaban-treated patients [4.7%, 95% confidence interval (CI) 2.8-7.5%] and in five of the 118 LMWH/VKA-treated patients (4.2%, 95% CI 1.4-9.6%) who were evaluable. The incidence in all three apixaban groups was low and comparable without evidence of a dose response. The principal safety outcome occurred in 28 (7.3%) of the 385 apixaban-treated patients and in 10 (7.9%) of the 126 LMWH/ VKA-treated patients. No dose response for apixaban was observed. Conclusion: These observations warrant further evaluation of apixaban in phase III studies. The attractive fixed-dose regimen of this compound may meet the demand to simplify anticoagulant treatment in patients with established venous thromboembolism.

BACKGROUND Animal studies have demonstrated a burst of oxygen free radical generation after reperfusion of ischemic myocardium that could be blocked by administration of the free radical scavenger recombinant human superoxide dismutase (h-SOD). A multicenter, randomized, placebo-controlled clinical trial was designed to test the hypothesis that free radical-mediated reperfusion injury could be reduced by intravenous administration of h-SOD begun before percutaneous transluminal coronary angioplasty (PTCA) in patients with acute transmural myocardial infarction. METHODS AND RESULTS One hundred twenty patients were randomized to receive placebo (n = 59) or h-SOD (n = 61) given as a 10-mg/kg intravenous bolus followed by a 60-minute infusion of 0.2 mg.kg-1.min-1. Left ventricular function was analyzed via paired contrast left ventriculograms performed before PTCA and after 6 to 10 days and paired radionuclide ventriculograms performed within 24 hours of PTCA and after 4 to 6 weeks. Both h-SOD- and placebo-treated patients showed improvement in global and regional left ventricular function after successful reperfusion. Compared with the placebo group, no additional improvement was observed in the patients treated with h-SOD. CONCLUSIONS The results of this clinical trial failed to demonstrate a beneficial effect of h-SOD on global or regional left ventricular function in patients who underwent successful PTCA for treatment of acute myocardial infarction.

The hemodynamic effects of 3-adrenergic blockade with bucindolol, a nonselective ,8-antagonist with mild vasodilatory properties, were studied in patients with congestive heart failure. Fifteen patients (New York Heart Association class I-IV) underwent cardiac catheterization before and after 3 months of oral therapy with bucindolol. The left ventricular ejection fraction increased from 0.23+±0.12 to 0.29±0.14 (p=0.007), and end-systolic elastance, a relatively load-independent determinant of contractility, increased from 0.60±0.40 to 1.11±0.45 mm Hg/ml (p =0.0049). Both left ventricular stroke work index (34± 13 to 47±+19 g-m/m2, p=0.0059) and minute work (5.5+2.2 to 7.0+2.6 kg-m/min, p=0.0096) increased despite reductions in left ventricular end-diastolic pressure (19± 8 to 15±5 mm Hg, p =0.021).There was an upward shift in the peak +dP/dt..,,-end-diastolic volume relation (p=0.0005).These data demonstrate improvements in myocardial contractility after f3-adrenergic blockade with bucindolol. At a matched paced heart rate of 98+15 min'1, the time constant of left ventricular isovolumic relaxation was significantly reduced by bucindolol therapy (92±+17 versus 73±11 msec, p=0.0013), and the relation of the time constant to end-systolic pressure was shifted downward (p=0.014) with therapy. The slope of the logarithm left ventricular end-diastolic pressure-end-diastolic volume relation was unchanged (p=O.S1) after bucindolol. These data suggest that chronic f-adrenergic blockade with bucindolol improves diastolic relaxation but does not alter myocardial chamber stiffness. Myocardial oxygen extraction, consumption, and efficiency were unchanged despite improvement in contractile function and mechanical work. Thus, in patients with congestive heart failure, chronic (S-adrenergic blockade with bucindolol significantly improves myocardial contractility and minute work, yet it does not do so at the expense of myocardial oxygen consumption. Additionally, bucindolol improves myocardial relaxation but does not affect chamber stiffness.