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.