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Study Summary

PRONOMOS was an international, multicenter, randomized, double-blinded non-inferiority study with a planned test for superiority if rivaroxaban was noninferior to enoxaparin for prophylaxis of venous thromboembolism in patients with nonmajor lower-limb orthopedic surgery (excluding total knee and hip replacements or hip fracture surgeries). In total, 1809 patients received rivaroxaban and 1795 received enoxaparin, with a mean duration of trial therapy of 28.6 ± 14.3 days and median total follow-up of 59 days in both groups. The primary outcome — a composite of symptomatic distal or proximal deep-vein thrombosis, pulmonary embolism, or venous-thromboembolism-related death during the treatment period or asymptomatic proximal deep-vein thrombosis at the end of treatment — occurred in 0.2% of the rivaroxaban group and 1.1% of the enoxaparin group (RR with multiple imputation 0.25, 95% CI 0.09-0.75, P <0.001 for noninferiority and P = 0.01 for superiority; see accompanying Hurst's Central Illustration). The frequency of bleeding outcomes was similar in both groups (1.1% in rivaroxaban and 1.0% in enoxaparin groups, RR 1.04, 95% CI 0.55-2.00).

Commentary

Study Strengths: Patients were randomized within 10 hours of surgery and received one trial drug and a placebo matching the other trial drug. All patients underwent lower extremity ultrasound at the end of immobilization and were contacted by telephone to screen for venous thromboembolism events, which were confirmed objectively. All suspected thrombotic or bleeding events were adjudicated by an independent committee blinded to treatment. Discontinuation of therapy and missed doses were low. A sensitivity analysis was performed, with similar results to the primary analysis. The primary efficacy results in the per-protocol analysis were similar to the intention-to-treat analysis.

Study Weaknesses: 8.4% of patients had incomplete or no assessment of the primary outcome, and not all events after the discontinuation of anticoagulation were confirmed by objective tests or submitted to the clinical-events committee; this necessitated the use of multiple imputation for missing data, e.g. imputation of pulmonary embolism in cases of unexplained death when pulmonary embolism could not be ruled out. Pre-randomization treatment with low molecular weight heparin for up to 48 hours was allowed and, although this accounted for only 14% of patients, it may have limited overall event rate. The small overall number of events limits the power of subgroup analysis, and a lack of a true placebo group limits information about event rates in a population without any prophylaxis. The population was relatively young and healthy (median age 41 years), which may limit generalizability to older patients. The same statistical techniques and populations were used to evaluate secondary outcomes without adjustment in confidence intervals for multiple comparisons, so inferences drawn from these intervals may not be reproducible. Slower-than-expected recruitment led to the expiration of treatment drugs and early termination of recruitment, so the sample size was smaller than planned (3604 instead 4400); however, due to higher-than-expected treatment effect size, the limitation of the sample size on precision of the efficacy estimation is likely reduced.

Next Steps/Clinical Perspective: There has been some debate in the literature over the benefit of venous thromboembolism prophylaxis in this patient population as prior studies of enoxaparin have shown benefit largely from reduction in distal deep-vein thrombosis, which is of questionable clinical significance; however, enoxaparin is used routinely in European hospitals for this population. This well-designed study of rivaroxaban showed superiority over enoxaparin driven primarily by symptomatic events. This finding may reflect a higher-risk population in this study compared to prior studies, and a need exists to better identify high-risk patients. That being said, this study shows benefit of rivaroxaban over enoxaparin for venous thromboembolism prophylaxis in this patient population with no significant difference in risk of bleeding.

Trial Reference

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Samama  CM, Laporte  S, Rosencher  N, et al. Rivaroxaban or enoxaparin in nonmajor orthopedic surgery. N. Engl. J. Med. doi:10.1056/NEJMoa1913808.

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