Safety of Ibuprofen After Major Orthopaedic Surgeries (PERISAFE)

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 an 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. 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 1/3 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. Sub-studies: 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.

Pain, Acute, Hip Arthropathy, Knee Arthropathy, Safety Issues, Analgesia, Analgesic Adverse Reaction, Postoperative Pain, Postoperative Complications

PERISAFE, Hip Arthroplasty, Knee Arthroplasty, Postoperative pain, Analgesia, Safety, Non-steroidal Anti-inflammatory drugs

The study medication will be masked by the pharmacy. The experimental medicine will be packed and labelled by Region Hovedstadens Pharmacy in accordance with the Good Manufacturing Practice regulations. The sponsor has a set of sealed, opaque envelopes with the participants' allocation, and these will only be revealed for the investigators when the data has been analysed and abstracts and conclusions covering the different possibilities for interpreting the trial results, have been agreed upon by the steering committee

Participants received ibuprofen 400 mg tablet administered orally three times daily, with eight hour intervals, for eight days after surgery.

Participants received identical placebo tablet administered orally three times daily, with eight hour intervals, for eight days after surgery.

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.

Proportion of patients with one or more severe adverse events defined in the 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.

A composite outcome of ibuprofen related adverse events based on an eight-day postoperative diary: dyspepsia, diarrhoea.

Proportion of patients with one or more adverse events of ibuprofen during intervention period, defined as dyspepsia or diarrhoea.

A composite outcome of opioid related adverse events based on an eight-day postoperative diary: nausea, vomiting, constipation, dizziness, confusion, sedation, headache.

Proportion of patients with one or more adverse events of opioid during intervention period, defined as nausea, vomiting, constipation, dizziness, confusion, sedation, or headache.

Evaluation of health related quality of life via EuroQol five-dimensions 5 point Likert-type scale (EQ-5D-5L) questionnaire, incl. the Euro Visual analogue scales (VAS) from 0-100. 100=the best health you can imagine, 0= the worst health you can imagine. The questionnaire of health related quality of life includes: mobility, self-care, usual activities, pain or discomfort, anxiety or depression from a scale of no problems, to slight, moderate, severe problems or unable condition.

Proportion of individual elements of the primary composite outcome: death, acute myocardial infarction, stroke, pulmonary embolism, deep venous thrombosis, renal failure, major bleeding, re-operation, gastrointestinal ulcer, or readmission.

Proportion of individual elements of secondary outcome of adverse events of ibuprofen and opioid: dyspepsia, diarrhoea, nausea, vomiting, constipation, dizziness, confusion, sedation, headache.

Postoperative pain levels, analgesic treatment, and opioid consumption based on an eight-day postoperative diary.

Pain levels will be measured by Numeric Rating Scale (NRS) from 0-10 (no pain = 0, worst pain = 10). Analgesic treatment including opioid consumption will be indicated in total daily doses in mg.

Inclusion Criteria: Patients scheduled for elective primary hip and knee arthroplasty. Age ≥ 18 years. Planned postoperative treatment with NSAID. Negative pregnancy test for women in the fertile age. Informed consent. Exclusion Criteria: Unable to understand or speak Danish. Allergy to or contraindications against ibuprofen.

Data will be published anonymised according to ICMJEs (International Committee of Medical Journal Editors) guidelines

Nine month after the trial has ended, and the primary results article has been published The study protocol and statistical analysis plan will be available after they have been published. Study protocol will be available at PERISAFE website.

We will make anonymized data available to other researchers' trough public database such as Zenodo open data repository (CERN), or another equivalent database. Furthermore, researchers wishing to access data from the PERISAFE trial should contact omat@regionsjaelland.dk in the first instance.