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Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial

BMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i5351 (Published 25 October 2016) Cite this as: BMJ 2016;355:i5351

A Matter of TRUST: An Issue of Compliance

Patient compliance with the administration of a prescribed treatment is a critical requirement in assessing its clinical effectiveness. In the Trial to Re-evaluate Ultrasound in the Treatment of Tibial Fractures (TRUST),[1] healing outcomes for surgically treated patients were evaluated for the adjunctive effects of EXOGEN low intensity pulsed ultrasound (LIPUS) versus the application of a sham device. Information for duration and date of patient usage (electronic data files) were retrieved from units returned to the sponsor, and compliance rates were calculated as described [2] for the percentage of subjects who used the device greater than or equal to 18 minutes per day over 80% of the days in their treatment period (i.e. met the minimum criteria for therapeutic compliance [3]). Results of this analysis demonstrate that overall patient compliance for TRUST was on average only about 43% (44.6% in the active arm, and 42.3% in the sham arm).

The conclusions reported for the clinical outcomes of TRUST [1] are therefore likely to be confounded by low patient compliance. The original participant sample size chosen to adequately power the study, assuming appropriate patient adherence to the treatment protocol, can thus be seen as being substantially underestimated. Exclusion of data from non-compliant patients would lead to the study being underpowered, which would directly decrease the ability to detect a true statistically significant difference between treatment arms (type II or beta error). [4]

The TRUST authors speculate that the compliance observed in the study may reflect patient utilization in routine clinical settings. [1] However, a separate evaluation of 10,763 patient usage files from EXOGEN units used in routine clinical practice (and obtained from the same device model used in TRUST) demonstrates an average compliance rate of 74.2% over 6 months of use. [5] Similar evaluation of 2,221 files obtained from the currently marketed EXOGEN device, which now incorporates a visual on-screen calendar to display patient compliance, demonstrates a further, significant improvement for the rate of compliance of 83.8% over 6 months. [5]

Lessons learned from TRUST can help guide future clinical research. Diligent measuring and monitoring of patient compliance is essential, and lack of compliance should result in withdrawal from the trial. New studies to evaluate the effects of LIPUS on fresh fractures should focus on inclusion of large numbers of patients at higher risk for failure to heal, [6,7] and should incorporate clinically meaningful and objective endpoints such as incidence of nonunion.

References
1. Busse JW, Bhandari M, Einhorn TA, et al. Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial. BMJ. 2016;355:i5351.
2. Trial to evaluate ultrasound in the treatment of tibial fractures (TRUST). https://clinicaltrials.gov/show/NCT00667849. Accessed 24 October 2016.
3. Jin J, Sklar GE, Min Sen Oh V, Chuen Li S. Factors affecting therapeutic compliance: A review from the patient's perspective. Ther Clin Risk Manag. 2008;4(1):269-86.
4. Mundi R, Chaudhry H, Mundi S, Godin K, Bandhari M. Design and execution of clinical trials in orthopaedic surgery. Bone Joint Res. 2014;3(5):161-8.
5. Pounder NM, Jones JT, Tanis K. Design evolution enhances patient compliance for low intensity pulsed ultrasound (LIPUS) device usage. Med Devices (Auckl). In press.
6. Zura R, Mehta S, Della Rocca GJ, Steen RG. Biological risk factors for nonunion of bone fracture. JBJS Rev. 2016;4(1):e2.
7. Zura R, Xiong Z, Einhorn T, et al. Epidemiology of fracture nonunion in 18 human bones. JAMA Surg. 2016; Sep 7:e162775.

Signed
Peter Heeckt, Bioventus LLC, Durham, NC, USA
Mark Phillips, London Bridge Hospital Diagnostic & Treatment Centre, London, UK
Johannes Rueger, University Hospital Hamburg Eppendorf, UKE, Hamburg, Germany
Neill Pounder, Bioventus LLC, Durham, NC, USA

Competing interests: Mr. Phillips has no competing interests Professor Rueger is a paid consultant to Smith & Nephew, Stryker, Bioventus, and Merete Dr. Pounder and Dr. Heeckt are employees of Bioventus LLC

26 October 2016
Neill M Pounder
Director - Project Management
Mark Phillips MA (Cantab) MBBChir FRCS, Prof. Dr. med.Johannes Rueger, Dr. Peter Heeckt
Bioventus LLC
4721 Emperor Blvd, Suite 100, Durham, NC 27703