Oral apixaban for the treatment of acute venous thromboembolism.

BACKGROUND: Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism. METHODS: In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding. RESULTS: The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], -0.4 percentage points; 95% CI, -1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups. CONCLUSIONS: A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding (Funded by Pfizer and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00643201).

Adenoviral-mediated gene transfer of vascular endothelial growth factor in critical limb ischemia: safety results from a phase I trial.

Critical limb ischemia (CLI) is typified by rest pain and/or tissue necrosis secondary to advanced peripheral arterial disease (PAD) and is characterized by diminution in limb perfusion at rest. We tested the safety of an angiogenic strategy with CI-1023 (Ad(GV)VEGF121.10), a replication-deficient adenovirus encoding human vascular endothelial growth factor isoform 121 in patients with CLI as part of a phase I trial. Fifteen subjects >35 years of age with CLI and angiographic disease involving the infra-inguinal vessels underwent intramuscular injection of CI-1023 (4 x 10(8) to 4 x 10(10) particle units, n = 13) or placebo (n = 2). All of the patients tolerated the injection well and there were no serious complications related to the procedure. Transient edema was noted in one patient. A total of 79 adverse events were reported over the course of one year. One death (day 136) and one malignancy (day 332) occurred in the CI-1023 group. CI-1023 appears to be well tolerated and safe for single-dose administration in patients with critical limb ischemia due to PAD. Further studies are needed to determine the efficacy of this form of therapeutic angiogenesis.

Phase I study of direct administration of a replication deficient adenovirus vector containing the vascular endothelial growth factor cDNA (CI-1023) to patients with claudication.

The long-term safety and efficacy of adenoviral delivery of growth factors in patients with peripheral arterial disease (PAD) is unknown. CI-1023 (Ad(GV)VEGF(121.10)) is a replication-deficient adenovirus encoding human vascular endothelial growth factor isoform 121. In this phase I trial, we investigated the safety and efficacy of CI-1023 in subjects with advanced claudication symptoms secondary to infra-inguinal disease. Eighteen subjects >35 years of age with a median ankle brachial index (ABI) at rest of 0.525 (interquartile range 0.4) and angiographic disease involving the infra-inguinal vessels underwent intramuscular injection of CI-1023 (4 x10(8) to 4 x10(10) particle units, n = 15) or placebo (n = 3). Eleven of 15 patients (73%) who received CI-1023 and 1 of 3 subjects (33%) who received placebo, completed 1 year of follow-up. Edema and rash were the most common early adverse event. One infra-inguinal bypass procedure occurred in each of the placebo and CI-1023 groups at days 29 and 104, respectively. One death (day 160) and 1 malignancy (day 274) occurred in the CI-1023 group. Conclusions on efficacy could not be made due to the small number of patients. However, there were encouraging trends in ABI at rest and peak walking time at follow-up.