Safety of Ibuprofen After Major Orthopaedic Surgeries

Study Overview
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Brief Summary
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Safety of an eight-day treatment with ibuprofen after primary hip and knee arthroplasties.

Detailed Description
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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.

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

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

Intervention / Treatment
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* Drug: Ibuprofen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibuprofen<br>Participants received ibuprofen 400 mg tablet administered orally three times daily, with eight hour intervals, for eight days after surgery. | Drug: Ibuprofen<br>* 400 mg tablet three times daily<br>|
| Placebo Comparator: Placebo<br>Participants received identical placebo tablet administered orally three times daily, with eight hour intervals, for eight days after surgery. | Drug: Placebo<br>* tablet three times daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Postoperative day 0 to 90. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital free days within 90 days postoperatively. | Days outside the hospital within 90 days postoperatively. | Postoperative day 0 to 90. | 
| 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. | Postoperative day 0 to 8. | 
| 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. | Postoperative day 0 to 8. | 
| Health related quality of life questionnaire (EQ-5D-5L) after 90 days | 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. | Postoperative day 90. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PERISAFE, Hip Arthroplasty, Knee Arthroplasty, Postoperative pain, Analgesia, Safety, Non-steroidal Anti-inflammatory drugs