Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trialBMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i5351 (Published 25 October 2016) Cite this as: BMJ 2016;355:i5351
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Pounder and colleagues suggest that the effect of LIPUS on tibial fracture healing in the TRUST trial  has been obscured by low compliance. As we note in our study, patient compliance was moderate and is a possible explanation for differences in results between TRUST and previous studies. The level of compliance we observed is, however, high enough that, if effects on time to radiographic healing seen in previous studies were present in our patients, we would have seen a substantial (albeit possibly attenuated) impact of the device.
To further inform this issue, we have completed a systematic review of all randomized controlled trials that have explored LIPUS for fracture healing (submitted for publication) and pre-specified compliance as a factor to explain heterogeneity. We considered adherence to be high if patients applied 80% or more of the total LIPUS time prescribed. The majority of trials reported only the surrogate outcome of time to radiographic healing, and our sub-group analysis (Figure, below) shows no evidence for a difference in effect between trials reporting high or moderate treatment compliance (test of interaction p-value = 0.79). What does explain heterogeneity in treatment effect is risk of bias. We categorized trials at high risk of bias if they failed to report concealment of allocation, blinding of patients, caregivers, data collectors or outcome assessors, or reported >20% loss to follow-up. Studies at high risk of bias suggest accelerated radiographic fracture healing (32% reduction in radiographic healing, 95%CI, -39%, -24%) and studies at low risk of bias show no significant effect (2% reduction in radiographic healing, 95%CI, -11%, 9%) (test of interaction p-value <0.001).
Pounder and colleagues advise that “lack of compliance should result in withdrawal from the trial”. We disagree. Such post-randomization exclusions will bias estimates unless those who do not comply are prognostically identical with those who do – a very unlikely circumstance. This is the reason for the consensus among methodologists on the desirability of intention to treat analysis.
Pounder and colleagues further advise that future trials of LIPUS for fracture healing should “…incorporate clinically meaningful and objective endpoints such as incidence of non-union”. We disagree: no patient will present to their surgeon with a complaint of incomplete radiographic union. The issues of importance to patients are whether use of LIPUS for fracture healing can reduce pain and accelerate functional recovery. Our systematic review found no evidence that LIPUS significantly influences either outcome: (1) -6.5 days of tenderness (95%CI, -24.1, 15.1); (2) -2.7 days to full weight-bearing (95%CI, -8.3, 3.1).
Jason W. Busse
Thomas A. Einhorn
James D. Heckman
Paul Tornetta III
Gordon H. Guyatt
On behalf of the TRUST Investigators
1. TRUST Investigators writing group, Busse JW, Bhandari M, Einhorn TA, Schemitsch E, Heckman JD, Tornetta III P, Leung K-S, Heels-Ansdell D, Makosso-Kallyth S, Rocca GJD, Jones CB, Guyatt GH. Low Intensity Pulsed Ultrasound Following Operative Fracture Fixation. BMJ. 2016; 355: i5351
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: TAE, ES, and MB have received consulting fees from Smith & Nephew, the manufacturer of the study device. PT receives royalties from Smith & Nephew. GJDR is a paid consultant for Bioventus LLC, which is 51% owned by Essex Woodlands and 49% by Smith & Nephew. MB is supported, in part, by a Canada research chair, McMaster University.
Re: Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial
I note that in their article on Low intensity ultrasound for fractures of the tibia, Bussell et al conclude that “post-operative use of low intensity pulsed ultrasound after tibial fracture fixation does not accelerate radiographic healing and fails to improve function” ( BMJ 2016;355:i5351).
In my MD Thesis of 1987, I investigated the Effect of Ultrasound on Fracture Repair (University of London).
The effect of ultrasound on fracture repair was investigated by studying the rate of healing of a standard lower tibial osteotomy in three groups of similar New Zealand White rabbits – an untreated group and groups treated with ultrasound and mock ultrasound. Parameters of treatment were an intensity of 0.5 W/cm², and a frequency of 1.5 KHz ( S.A.T.P.) using a pulsed regime (2msec on, 8 msec off) administered for 10 minutes per day, five days a week for four weeks postoperatively. A fracture gap was maintained throughout repair by a specially designed external fixator. Three animals from each group were studied two weekly up to twelve weeks by intra-arterial perfusion with Micropaque. Investigation was by radiography, histology, angiography and densitometry.
To compare the rate of fracture repair between the different groups, a numerical method combining histological and radiological systems, was devised. Statistical analysis of the results showed that treatment of the standard osteotomy with ultrasound did not accelerate the rate of repair across the osteotomy gap.
There was no significant difference in the rate of repair among the three groups and treatment with ultrasound had not changed the rate or repair of the standard osteotomy.
It is of interest that both the above laboratory study in 1987 and the clinical study by Bussell et al in 2016 show that ultrasound has no effect on fracture repair.
This brings into question the advisability and effectiveness of treating fractures with ultrasound.
Richard Brueton MA MD FRCS
Honorary Consultant Orthopaedic Surgeon
Royal Free Hospital
Competing interests: No competing interests
" Patient compliance......". An outrageous phrase. An expression that invites hostility, instead of COOPERATION.
May I request Pounder et al to seek cooperation?
Competing interests: No competing interests
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), 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  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 ). 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  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). 
The TRUST authors speculate that the compliance observed in the study may reflect patient utilization in routine clinical settings.  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.  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. 
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.
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.
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