The Adverse Effects Associated With Ibuprofen Use After Major Orthopaedic Surgeries—A Detailed Statistical Analysis Plan for the PERISAFE Randomized Clinical Trial

The PERISAFE trial aims to assess the adverse effects associated with an 8-day postoperative treatment with ibuprofen after hip and knee arthroplasties. This paper outlines the detailed statistical analysis plan for the primary data. The PERISAFE trial is a randomized, placebo-controlled, blinded multicentre trial allocating 2904 hip- or knee-arthroplasty patients 1:1 to ibuprofen 400 mg ×3/day or identical placebo ×3/day for 8 days postoperatively. The primary outcome is a composite of death, acute myocardial infarction, stroke, pulmonary embolism, deep venous thrombosis, renal failure, major bleeding, re-operation, gastrointestinal ulcer, or readmission within 90 days postoperatively. Secondary outcomes are hospital-free days within 90 days postoperatively, a composite of ibuprofen and opioid-related adverse reactions based on an 8-day postoperative diary, and health-related quality of life after 90 days postoperatively. All randomized patients who undergo surgery will be included in all analyzes. Binary data will be analyzed using a mixed-effects generalized linear model, count data will be analyzed using the van Elteren test, and continuous data will be analyzed using a mixed-effects linear regression. Additionally, the win ratio will be calculated for the primary outcome. The statistical analyzes will be conducted in accordance with this pre-planned statistical analysis plan with one interim analysis after the inclusion of 1400 patients. All analyzes will be adjusted for site. We expect that the PERISAFE trial will provide high-quality data based on predefined detailed methodology regarding the safety of postoperative treatment with ibuprofen after elective hip and knee arthroplasties.