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).

Apixaban for extended treatment of venous thromboembolism.

BACKGROUND: Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism. METHODS: In this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months. RESULTS: A total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group. CONCLUSIONS: Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding. (Funded by Bristol-Myers Squibb and Pfizer; AMPLIFY-EXT ClinicalTrials.gov number, NCT00633893.).

Extended anticoagulation with apixaban reduces hospitalisations in patients with venous thromboembolism. An analysis of the AMPLIFY-EXT trial.

Treatment with apixaban versus placebo for 12 months significantly reduced symptomatic recurrent venous thromboembolism (VTE) or all-cause death without increasing the rate of major bleeding in the AMPLIFY-EXT trial. This analysis examined the effects of apixaban versus placebo on the rate of all-cause hospitalisations, time to first hospitalisation, and predictors of first hospitalisation in patients with VTE enrolled in AMPLIFY-EXT. Treatment with apixaban 2.5 mg and 5 mg twice daily significantly reduced the rate of all-cause hospitalisations versus placebo (hazard ratio [95% confidence interval], 0.64 [0.43, 0.95]; p=0.026 and 0.54 [0.36, 0.82]; p=0.004, respectively). Apixaban prolonged mean time to first hospitalisation versus placebo by 43 and 49 days for the 2.5-mg and 5-mg twice-daily groups, respectively. Median length of hospital stay during the first hospitalisation was longer for placebo than for apixaban 2.5 mg or 5 mg twice daily (7.0, 5.0, and 4.5 days, respectively). Treatment with apixaban was a significant predictor of lower rates of hospitalisations versus placebo, and severe/moderate renal impairment was a significant predictor of an increased rate. This study supports extended use of apixaban for reducing all-cause hospitalisations and extending time to first hospitalisation in patients with VTE enrolled in AMPLIFY-EXT (www.clinicaltrials.gov registration: #NCT00633893).

Apixaban Reduces Hospitalizations in Patients With Venous Thromboembolism: An Analysis of the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) Trial.

BACKGROUND: In the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial, apixaban was noninferior to enoxaparin/warfarin in preventing recurrent symptomatic venous thromboembolism (VTE) or venous thromboembolism-related death, with significantly less bleeding. This analysis evaluated the effects of apixaban versus enoxaparin/warfarin on all-cause hospitalizations during AMPLIFY. METHODS AND RESULTS: Of the 5365 patients included, 2676 received apixaban and 2689 received enoxaparin/warfarin. All-cause hospitalizations during the treatment period after the index event were captured using dedicated case report forms. Outcomes included all-cause hospitalizations and time from randomization to first hospitalization. Patients were censored at death, loss to follow-up, or end of study, whichever came first. Treatment effects were assessed using Cox proportional hazards regression models. During the treatment period after the index event, 343 patients were hospitalized at least once: 153 (5.72%) in the apixaban group and 190 (7.07%) in the enoxaparin/warfarin group. Compared with enoxaparin/warfarin, apixaban significantly reduced all-cause hospitalizations (hazard ratio 0.804, 95% CI=0.650-0.995, P=0.045). All-cause hospitalization rates within the first 30 days after the index event were 2.28% and 3.35% in the apixaban and enoxaparin/warfarin groups, respectively (hazard ratio 0.676, 95% CI=0.488-0.935, P=0.018). For all patients, the average per-patient estimated mean length of hospital stay was also shorter with apixaban than enoxaparin/warfarin (0.57 days versus 1.01 days, P<0.0001). CONCLUSIONS: Apixaban significantly reduced all-cause hospitalizations versus enoxaparin/warfarin, and shortened the length of hospital stay in patients with acute venous thromboembolism. CLINICAL TRIAL REGISTRATION: URL: https://Clinicaltrials.Gov/. Unique identifier: NCT00643201.

Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial: 5-year gynecological outcomes.

OBJECTIVE: The aim of this study was to establish the gynecological effects of 5 years of treatment with lasofoxifene versus placebo in postmenopausal osteoporotic women. METHODS: A total of 8,556 women aged 59 to 80 years with femoral neck or spine bone mineral density T scores of -2.5 or lower were randomized to receive lasofoxifene 0.25 mg/day, or lasofoxifene 0.5 mg/day, or placebo, for 5 years. RESULTS: Endometrial cancer was confirmed for two women in each lasofoxifene group and for three women in the placebo group. Endometrial hyperplasia occurred in three, two, and zero women in the lasofoxifene 0.25 mg/day, lasofoxifene 0.5 mg/day, and placebo groups, respectively. Vaginal bleeding occurred in 2.2% (P = 0.012 vs placebo), 2.6% (P = 0.001 vs placebo), and 1.3% of women treated with 0.25 mg/day lasofoxifene, 0.5 mg/day lasofoxifene, and placebo, respectively. Lasofoxifene treatment resulted in a small increase in endometrial thickness versus placebo (least-squares mean change from baseline 1.19 mm [P = 0.001], 1.43 mm [P < 0.001], and -0.72 mm for 0.25 mg/day lasofoxifene, 0.5 mg/day lasofoxifene, and placebo). Similar numbers of women required surgery for pelvic organ prolapse or urinary incontinence in the placebo and 0.5 mg/day lasofoxifene groups (1.2% vs 1.6%, P = 0.224; 0.25 mg/day group: 1.9%, P = 0.036). The absolute incidence rates of endometrial polyps were 8.8%, 5.5%, and 3.3% for lasofoxifene 0.25 mg/day (P = 0.003 vs placebo), lasofoxifene 0.5 mg/day (P = 0.163 vs placebo), and placebo groups, respectively. CONCLUSION: These findings indicate that 5 years of lasofoxifene treatment result in benign endometrial changes that do not increase the risk for endometrial cancer or hyperplasia in postmenopausal women.