SYDNEY, Australia—The use of ibuprofen as prophylaxis for ectopic bone formation following hip replacement surgery does not reduce pain or improve function but greatly increases  the risk of serious bleeding complications, according to results of a double-blind, randomized, placebo-controlled clinical trial conducted at 20 hospitals in Australia and New Zealand.¹ The research, led by Marlene Fransen, PhD, MPH, head of the Musculoskeletal Program at The George Institute for International Health at the University of Sydney, Australia, was published in the British Medical Journal.

"These data do not support the use of routine prophylaxis with NSAIDs [nonsteroidal anti-inflammatory agents] in patients undergoing total hip replacement surgery," Dr. Fransen and colleagues write.

Results Highlight Lack of Placebo-Controlled Studies
Dr. Fransen told CIAOMed that the somewhat surprising results of this study highlight the "absence of adequate placebo-controlled research" and "general uncertainty about what constitutes good practice" in orthopedic surgery. She voiced the hope that the new findings "will help clinicians make a more informed choice on the balance of risk and benefits associated with this preventive strategy."

Ectopic bone forms in the soft tissues around the operated hip in more than one third of all patients in the months following hip replacement surgery. Based on an assumed connection between the presence of ectopic bone and increased long-term pain and/or decreased function, many surgeons have routinely prescribed postoperative courses of ibuprofen or other NSAIDs to these patients.

Dr. Fransen's trial tested that assumption. The investigators randomized 902 patients of an average age of 66 years who were undergoing elective total hip replacement surgery to either 14 days of ibuprofen (two 200-mg tablets three times daily) or 14 days of matching placebo tablets, beginning within 24 hours of surgery. Six months and then 12 months later, the researchers took standard anteroposterior radiographs to check for ectopic bone formation and measured changes in self-reported hip pain and physical function using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC). Dr. Fransen reported data for 823 patients who completed the study, with a median follow-up of 7.6 months (range 5–18 mo) for the ibuprofen group and 7. 9 months (range 5–20 mo) for the placebo group.

The routine use of postoperative ibuprofen significantly reduced the risk of developing any grade of ectopic bone (risk ratio [RR] 0.69) or severe ectopic bone (Brooker grade 3 or 4, RR 0.44), but this did not result in better long-term clinical outcomes. There were no significant differences between the two groups in terms of improvements in hip pain or general health status 6 to 12 months after surgery.

However, patients receiving routine postoperative ibuprofen had a significantly increased risk of major bleeding complications (RR 2.09, P = .046).

Dr Fransen admitted that she was surprised by the main findings. The number of bleeding events in this group of "low-risk" patients, who had no prior history of serious adverse reaction to NSAIDs, major gastrointestinal bleed, or known bleeding disorder, was not expected.

Postoperative Care Guidelines Need Data, Not Surrogates
"It is now important to remember that even a moderate dose of NSAIDs in the immediate post-operative period after total hip replacement surgery is associated with an increased risk of clinically relevant adverse bleeding events," Dr. Fransen said. She called for further studies to clarify whether the long-term benefit of NSAIDs-based prophylaxis outweighs the risks in certain groups of patients. "We have shown that most grades of ectopic bone formation after total hip replacement surgery have little clinical relevance.  We need to determine whether certain patient or surgery characteristics can identify patients at high risk of developing clinically relevant ectopic bone," she told CIAOMed.

"Worldwide, there is evidence of considerable practice variation between, and within, countries as regards routine NSAIDs based prophylaxis for ectopic bone formation after total hip replacement surgery. General uncertainty of what would constitute best practice is a result of lack of placebo-controlled research, adequately powered to evaluate risks, with clinically relevant outcomes," Dr. Fransen said.

The investigators conclude, "Guidelines for routine clinical care in surgery, as in other specialties, must be based on clinically important outcomes rather than on surrogates such as radiographic ectopic bone formation. Without such evidence, the widespread use of routine prophylaxis with NSAIDs on the basis of radiographic changes may well have resulted in net harm rather than benefit."

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Reference

1. Fransen M, Anderson C, Douglas J, et al.  Safety and efficacy of routine postoperative ibuprofen for pain and disability related to ectopic bone formation after hip replacement surgery: randomised controlled trial. BMJ. 2006; 2 August 2006 [Epub ahead of print]