THE EFFECT OF PATIENT AGE, GENDER AND WEIGHT ON THE EFFICACY AND SAFETY OF RIVAROXABAN (BAY 59-7939) FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM AFTER MAJOR ORTHOPAEDIC SURGERY

Abstract

Rivaroxaban is an oral, direct Factor Xa inhibitor in clinical development for the prevention of VTE after major orthopaedic surgery. Data from three phase II trials of twice-daily (bid) rivaroxaban in patients undergoing elective, total hip or knee replacement were pooled to determine whether age, gender or weight affected the efficacy or safety of rivaroxaban, and thus whether dose adjustment would be necessary. Patients received 5–9 days of oral rivaroxaban (2.5–30 mg bid, post-operatively), or s.c. enoxaparin. A logistic regression model using total daily dose of rivaroxaban as a covariate, and adjusted for differences between dose groups with respect to study, age and gender, was used to estimate rates of the primary efficacy endpoint (DVT, PE or all-cause mortality; n=1380 intention-to-treat patients) and clinically relevant bleeding (major and non-major clinically relevant bleeding; safety population, n=1854). Rivaroxaban at total daily doses of 5–20 mg had similar efficacy and safety to enoxaparin. Overall, logistic regression showed a positive dose–response relationship with rivaroxaban for clinically relevant bleeding (p< 0.001), and a flat relationship for the primary efficacy endpoint (p=0.115). The risk of VTE increased with age – the efficacy endpoint was estimated to occur in 17.3–9.4%, 18.7–17.3% and 26.6–20.2% of patients aged < 60 yrs, 60–70 yrs and > 70 yrs receiving rivaroxaban (total daily dose 5–60 mg), respectively, in separate regression models. Age was also prognostic for clinically relevant bleeding with rates of 1.4–12.0% (< 60 yrs), 2.7–15.4% (60–70 yrs) and 5.7–15.4% (> 70 yrs). The rates are for a population distributed equally across the studies and genders. Incidences of the efficacy endpoint were higher in females (25.8–20.5%) than males (16.6–10.7%), while clinically relevant bleeding occurred more frequently in males (5.4–16.3%) than in females (1.7–11.6%), after adjustment for age. Weight was not prognostic for the efficacy endpoint or clinically relevant bleeding (p=0.87 and p=0.48, respectively, after adjustment for age, gender and study), nor did it modify the dose–response relationships with rivaroxaban. Incidences of the efficacy endpoint for a population of equal study and gender distribution and of mean patient age were 23.4–15.7% and 19.1–14.6% in patients weighing < 65 kg and ≥90 kg, respectively, with corresponding bleeding rates of 3.3–16.5% and 3.2–17.5%. This analysis indicates that age, gender or weight did not affect the dose–response relationships (or lack thereof) between rivaroxaban and the primary efficacy endpoint or clinically relevant bleeding. As expected, age was prognostic for VTE and bleeding. These findings suggest that rivaroxaban may not require dose adjustment for age, gender or weight in orthopaedic patients.