Safety of Ibuprofen After Major Orthopaedic Surgeries.
The PERISAFE Randomized Clinical Multicentre Trial

Hip and knee arthroplasty surgeries are some of the most frequently performed planned procedures in the western world. Multimodal analgesic treatment is the leading analgesic treatment principle, with NSAIDs as an essential part. Ibuprofen, the most frequently prescribed NSAID, is effective in reducing acute postoperative pain. However, ibuprofen may be associated with various serious adverse events, including death, cardiovascular morbidity, gastrointestinal ulcer, and renal impairment. The balance between beneficial and harmful effects of a short-term postoperative treatment with ibuprofen after elective hip and knee arthroplasty is unknown.

Objectives: to assess the adverse events of a eight-day treatment of postoperative pain with ibuprofen in patients undergoing elective primary hip or knee arthroplasty.

Intervention: the participants will be randomized in two groups:

a) oral ibuprofen 400 mg 3 times daily for eight days.

b) identical oral placebo 3 times daily for eight days.

The intervention will begin in the afternoon or evening after surgery, and continue the following seven days. 

Design and trial size: PERISAFE is a randomized, placebo-controlled multicentre trial with centralized computer-generated allocation sequence and allocation concealment with unknown block size. Patients, investigators, assessors, caregivers, data-managers, writers of the manuscript, and statisticians will be blinded. A total of 2904 eligible patients are needed to detect or discard an effect corresponding to a relative risk reduction of 33 % with an acceptable risk of type I error of 5 % and of type II error of 20 %, and a proportion of the composite outcome of serious adverse events of 8 % in the experimental group.

Primary outcome: 

  • A composite outcome of either death, acute myocardial infarction, stroke, pulmonary embolism, deep venous thrombosis, renal failure, major bleeding, re-operation, gastrointestinal ulcer, or readmission within 90 days postoperatively. 

Seconday outcomes: 

  • Hospital free days within 90 days postoperatively. 
  • A composite outcome of ibuprofen related adverse events, based on an eight-day postoperative diary: pain or discomfort from the epigastrium, reflux, diarrhoea. 
  • A composite outcome of opioid related adverse events based on eight-day postoperative diary: nausea, vomiting, constipation, sedation, headache, mood changes, mouth dryness.
  • Health related quality of life questionnaire (EQ-5D-5L) after 90 days and one year postoperatively.

Exploratory outcomes: 

  • Proportion of individual serious adverse events in the composite primary outcome.
  • Proportion of individual adverse events of ibuprofen and opioid in the composite secondary outcomes.
  • Postoperative pain levels, analgesic treatment, and opioid consumption based on eight-day postoperative diary and questionnaire 14 days after surgery.


  • One-year follow-up on the composite primary outcome.
  • Subgroup analysis on predictors of chronic pain and opioid consumption at 90-days, and one-year after surgery.
  • Coherence of preoperative use of diuretics, ACE-inhibitors or Angiotensin-II-antagonists and postoperative risk of renal failure.

Eligibility: patients meeting all of the following inclusion criteria and non of the exclusion criteria, is eligible for inclusion in the trial. 

Inclusion criteria:

  • Patients scheduled for elective primary hip and knee arthroplasty.
  • Age ≥ 18 years.
  • Planned postoperative treatment with NSAID.
  • Negative HCG-pregnancy test and use of anti-conception for women in the fertile age.
  • Informed consent.

Exclusion criteria 

  • Unable to understand or speak Danish.
  • Allergy to or contraindications against ibuprofen.

Trial duration: estimated recruitment period is 2 years, beginning from april 2023. The trial will continue to a maximum of 90-days post-randomization and follow-ups will be done at 90-days, and at 1-year.