Study Design and Population
The study design, methods, and primary results of the AMPLIFY trial have been published previously . Briefly, patients were eligible for inclusion in the study if they were aged 18 years or older with an objectively confirmed, symptomatic proximal deep vein thrombosis (DVT) involving the popliteal, femoral, or iliac veins, or acute symptomatic pulmonary embolism (PE) with or without DVT. Exclusion criteria were active bleeding, a high risk of bleeding, or other contraindications to treatment with enoxaparin and warfarin. Patients with cancer whose VTE was to be treated for 6 months or more with low molecular weight heparin were excluded. Patients were also excluded if their DVT or PE was provoked in the absence of a persistent risk factor for recurrence; if less than 6 months of anticoagulant treatment was planned; or if they had another indication for long-term anticoagulation therapy, dual antiplatelet therapy, treatment with aspirin at a dosage of more than 165 mg daily, or treatment with potent inhibitors of cytochrome P450 3A4.
The protocol was approved by the institutional review board of each participating study center (full list of institutional review boards that approved the study is included as supplementary material). All patients provided written informed consent. This study was conducted in accordance with the Declaration of Helsinki. An independent committee unaware of study group assignments adjudicated all suspected outcomes. No patients were involved in the design of the study or the dissemination of the results.
Randomization was stratified by the qualifying index event (DVT alone or PE with or without DVT). Eligible patients were randomized 1:1 to apixaban (10 mg twice daily) for the first 7 days followed by 5 mg twice daily for 6 months, or to subcutaneous enoxaparin (1 mg/kg of body weight every 12 h) for at least 5 days and warfarin initiated concomitantly and continued for 6 months. The warfarin dosage was adjusted to an international normalized ratio (INR) of 2.0–3.0. Enoxaparin was discontinued when a blinded INR of 2.0 or more was achieved. To measure apixaban plasma concentrations, blood samples were collected at steady state at − 2 h (ca. 2 h prior to dosing), 0 h (pre-dose), and 2 and 4 h post-dose .
In this post hoc analysis, patients were analyzed according to body weight (≤ 60, > 60 to < 100, ≥ 100 to < 120, and ≥ 120 kg) and BMI categories (≤ 25, > 25 to 30, > 30 to 35, > 35 to 40, and > 40 kg/m2).
The primary efficacy outcome was the incidence of the adjudicated composite of recurrent symptomatic VTE or VTE-related death. Recurrent VTE included fatal or nonfatal PE and DVT. Causes of death were classified as related to VTE, cardiovascular disease, bleeding, or other causes. PE was considered the cause of death if there was objective documentation, or if death could not be attributed to another documented cause and PE could not be ruled out.
The primary safety outcome was adjudicated major bleeding and the secondary safety outcome was the composite of major bleeding and clinically relevant non-major (CRNM) bleeding. Major bleeding was defined as overt bleeding associated with a decrease in the hemoglobin level of ≥ 2 g/dL, requiring the transfusion of ≥ 2 units of blood, occurring into a critical site (intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal), or contributing to death. CRNM bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, contact with a physician, interruption of the study drug, or discomfort or impairment in carrying out activities of daily life. The criteria for the diagnosis and adjudication of all outcomes have been previously reported .
Finally, a population PK analysis was conducted to characterize apixaban exposure in patients treated for VTE as published previously .
All efficacy analyses included data for patients in the intention-to-treat population for whom the outcome status at 6 months was documented. Patients with missing endpoint events were excluded from the efficacy analysis. All safety analyses included data obtained from treated patients during the study treatment period, defined as the time from the administration of the first dose until 48 h after the last dose was administered.
For each subgroup, the relative risk (RR) and 95% confidence intervals (CIs) were calculated using the Cochran–Mantel–Haenszel test, stratified by index event strata. The 95% CIs for single event rates were calculated on the basis of the Wald asymptotic confidence limits. P values for interaction were based on a logistic model using Wald’s chi-square test.
Using the published population PK analysis of apixaban in patients undergoing VTE treatment, steady-state daily (0–24 h) exposure was predicted for each patient using the empirical Bayes’ prediction of their oral clearance value from the final population PK model and total daily dosage of apixaban, and was summarized by body weight category .