Safety of Ibuprofen After Major Orthopaedic Surgeries (PERISAFE)

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

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

Study Overview

• Status: Completed
• Conditions: Postoperative Complications; Postoperative Pain; Analgesia; Pain, Acute; Safety Issues; Knee Arthropathy; Hip Arthropathy; Analgesic Adverse Reaction
• Intervention / Treatment: Drug: Ibuprofen; Drug: Placebo

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:

• Serious adverse events relating to the renal system
• Serious adverse events relating to the cardiovascular system
• Serious adverse events relating to the gastrointestinal system, including major bleeding
• Persistent pain and opioid consumption at 90 days and one year postoperatively. Predictive co-factors include preoperative analgesic treatment, type of anesthesia, gender, age, ASA-classification, diabetes, and type of surgery
• Bayesian re-analysis of the primary and secondary outcomes up to 90 days postoperatively. Further details will appear in the statistical analysis plan
• Health-related quality of life via EQ-5D-5L questionnaire 90-days and one year postoperatively

• Study Type: Interventional
• Enrollment (Actual): 2904
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Brøndby, Denmark, 2605
    • Private Hospital Gildhøj
  • Copenhagen NV, Denmark, 2400
    • Bispebjerg Hospital
  • Farsø, Denmark, 9640
    • Aalborg University Hospital
  • Hellerup, Denmark, 2900
    • Gentofte Hospital
  • Hillerød, Denmark, 3400
    • Nordsjællands Hospital Hillerød
  • Køge, Denmark, 4600
    • Zealand University Hospital
  • Næstved, Denmark, 4700
    • Næstved Hospital
  • Odense, Denmark, 3900
    • Odense University Hospital
  • Silkeborg, Denmark, 8600
    • Silkeborg Regional Hospital
  • Svendborg, Denmark, 5700
    • Svendborg Hospital
  • Vejle, Denmark, 7100
    • Vejle Sygehus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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.
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.
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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Postoperative day 0 to 8.

Collaborators and Investigators

• Sponsor: Naestved Hospital
• Investigators: Study Chair: Ole Mathiesen, Professor, Zealand University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2023
• Primary Completion (Actual): August 19, 2025
• Study Completion (Actual): August 19, 2025

Study Registration Dates

• First Submitted: October 7, 2022
• First Submitted That Met QC Criteria: October 7, 2022
• First Posted (Actual): October 12, 2022

Study Record Updates

• Last Update Posted (Estimated): December 19, 2025
• Last Update Submitted That Met QC Criteria: December 12, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Safety; Analgesia; Knee Arthroplasty; Hip Arthroplasty; Postoperative pain; PERISAFE; Non-steroidal Anti-inflammatory drugs
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Nervous System Diseases; Pathologic Processes; Neurobehavioral Manifestations; Perceptual Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain, Postoperative; Acute Pain; Agnosia; Postoperative Complications; Organic Chemicals; Carboxylic Acids; Acids, Carbocyclic; Phenylpropionates; Ibuprofen
• Other Study ID Numbers: 001CCWL2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be published anonymised according to ICMJEs (International Committee of Medical Journal Editors) guidelines

IPD Sharing Time Frame

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.

• IPD Sharing Access Criteria: 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No