Highlights
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Employing multivariate regression approaches, post hoc exposure–response analyses were performed using data from the EINSTEIN–DVT/EINSTEIN–PE studies to assess the impact of model-predicted rivaroxaban exposure and patient characteristics on clinical outcomes.
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Model-predicted rivaroxaban exposure–response relationships with both efficacy and safety were shallow sloped or absent within the investigated exposure range.
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Monitoring rivaroxaban levels is unlikely to be beneficial when managing venous thromboembolism treatment.
Introduction
Methods
Study design
Study | EINSTEIN–DVT [7] | EINSTEIN–PE [8] |
---|---|---|
Population | Patients with acute, symptomatic DVT without symptomatic PE | Patients with acute, symptomatic PE with or without DVT |
Total number of patients randomized | 8282 | |
Pertinent exclusion criteria | Concomitant use of strong CYP3A4 inhibitors (e.g., HIV protease inhibitors or systemic ketoconazole) or strong CYP3A4 inducers like rifampicin | |
Rivaroxaban dose and regimen | 15 mg BID for 21 days followed by 20 mg OD for 3, 6 or 12 months at the investigator’s discretion | |
Comparator dose and regimen | Standard therapy with enoxaparin 1.0 mg/kg BID and warfarin or acenocoumarol (INR 2.0–3.0) | |
Maximum follow-up | 12 months | |
Mean treatment duration | Rivaroxaban: 208 days Standard therapy: 204 days | |
Total number of patients for ER analysis | 4130 (15 mg BID phase) 3953 (20 mg OD phase) | |
Efficacy outcomes for ER analysis | 1. Composite of recurrent DVT or fatal/non-fatal PE 2. Composite of recurrent DVT, fatal/non-fatal PE and death from any cause | |
Safety outcomes for ER analysis | 1. ISTH major bleedinga 2. Major or NMCRb bleeding |
Patient characteristics
Model-predicted rivaroxaban exposure
Regression analyses
Results
Patient characteristics
Rivaroxaban exposure predictions and event rates
Regression analyses
Variables | Efficacy | Safety | ||
---|---|---|---|---|
DVT/PE | DVT/PE/all-cause death | Major bleeding | Major/NMCR bleeding | |
BID period | ||||
Active malignancy at randomizationa | n.s | n.s | n.s | n.s |
Agea | n.s | n.s | n.s | n.s |
CrCla | X | X | n.s | n.s |
Best exposure | Ctrough | Ctrough | n.s | n.s |
Other significant covariate | None | None | Baseline hemoglobin | Baseline hemoglobin, bleeding history, NSAID use |
OD period | ||||
Active malignancy at randomizationa | n.s | X | n.s | n.s |
Agea | n.s | n.s | n.s | n.s |
CrCla | n.s | X | n.s | n.s |
Best exposure | Ctrough | n.s | n.s | n.s |
Other significant covariate | None | None | Baseline hemoglobin, bleeding history | Baseline hemoglobin, bleeding history, clinically relevant bleeding in the BID period |