Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time-to-event analysis.

AIMS: Increased exposure to fondaparinux, as observed in patients with renal impairment, may increase bleeding risk. This study aims to determine the time course of major bleeding after major orthopaedic surgery, identify predictors of bleeding and simulate the effect of a reduced dose of fondaparinux on bleeding for patients with moderate renal impairment (creatinine clearance = 20-50 ml min-1 ).
METHODS: Data including fondaparinux anti-Xa activities from two multicentre prospective cohorts were used. In the first cohort, patients (n = 957) received fondaparinux 2.5 mg once a day. In the second, patients with moderate renal impairment (n = 436) received 1.5 mg once per day. The time-to-major bleeding after the end of surgery was modelled using a parametric survival analysis in NONMEM.
RESULTS: The observed rate of major bleeding up to day 11 was 5.2%. The time-to-event analysis indicated that the hazard of bleeding was highest in the first days following surgery and then remained low thereafter. Independent significant predictors of an increased hazard of major bleeding were male sex, lower body weight and increased drug exposure. Simulated rates of major bleeding up to day 11 in patients with moderate renal impairment were 6.5% with fondaparinux 2.5 mg once daily and 3.8% with fondaparinux 1.5 mg once daily.
CONCLUSION: The hazard of major bleeding is highest in the first postoperative days and increases with fondaparinux exposure. To reduce the risk of bleeding in patients with moderate renal impairment, this study supports the use of a lower dose of fondaparinux 1.5 mg once daily.