Safety of Ibuprofen After Major Orthopaedic Surgeries

Phase 4

Recruiting

• Conditions: Knee Arthropathy; Analgesia; Analgesic Adverse Reaction; Postoperative Pain; Pain, Acute; Hip Arthropathy; Postoperative Complications; Safety Issues
• Interventions: Drug: Placebo; Drug: Ibuprofen

• Registration Number: NCT05575700
• Lead Sponsor: Naestved Hospital

Brief Summary

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

Detailed Description

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.

Study Timeline

• Study First Submitted: 2022-10-07
• Study First Submitted QC: 2022-10-07
• Study First Posted: 2022-10-12
• Status Verified: 2023-04
• Study Start: 2023-04-17
• Last Update Submitted: 2023-04-26
• Last Update Posted: 2023-04-28
• Primary Completion: 2025-07-01
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 2904

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants received identical placebo tablet administered orally three times daily, with eight hour intervals, for eight days after surgery.
Ibuprofen	Ibuprofen	Participants received ibuprofen 400 mg tablet administered orally three times daily, with eight hour intervals, for eight days after surgery.

Primary Outcome Measures

Name	Time	Method
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.	Postoperative day 0 to 90.	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.

Secondary Outcome Measures

Name	Time	Method
Hospital free days within 90 days postoperatively.	Postoperative day 0 to 90.	Days outside the hospital within 90 days postoperatively.
A composite outcome of ibuprofen related adverse events based on an eight-day postoperative diary: dyspepsia, diarrhoea.	Postoperative day 0 to 8.	Proportion of patients with one or more adverse events of ibuprofen during intervention period, defined as dyspepsia or diarrhoea.
Health related quality of life questionnaire (EQ-5D-5L) after 90 days	Postoperative day 90.	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.
A composite outcome of opioid related adverse events based on an eight-day postoperative diary: nausea, vomiting, constipation, dizziness, confusion, sedation, headache.	Postoperative day 0 to 8.	Proportion of patients with one or more adverse events of opioid during intervention period, defined as nausea, vomiting, constipation, dizziness, confusion, sedation, or headache.

Trial Locations

Locations (11)

Bispebjerg Hospital; 🇩🇰 Copenhagen NV, Denmark

Private Hospital Gildhøj; 🇩🇰 Brøndby, Denmark

Gentofte Hospital; 🇩🇰 Hellerup, Denmark

Nordsjællands Hospital Hillerød; 🇩🇰 Hillerød, Denmark

Zealand University Hospital; 🇩🇰 Køge, Denmark

Aalborg University Hospital; 🇩🇰 Farsø, Denmark

Næstved Hospital; 🇩🇰 Næstved, Denmark

Silkeborg Regional Hospital; 🇩🇰 Silkeborg, Denmark

Svendborg Hospital; 🇩🇰 Svendborg, Denmark

Odense University Hospital; 🇩🇰 Odense, Denmark

Vejle Sygehus; 🇩🇰 Vejle, Denmark