Negative-pressure wound therapy versus standard dressings for adults with an open lower limb fracture: the WOLLF RCT

Feasibility study

1. To conduct a qualitative assessment of (a) patients’ experience of sustaining fracture of the lower limb; (b) patients’ experience of being enrolled into a clinical trial, giving or declining consent for the trial; and (c) the acceptability of the trial procedures to patients and staff.

2. To determine the number of eligible, recruited and withdrawn patients in five trauma centres over the course of 6 months. In addition, to determine whether or not any trial participants lacked capacity to give consent 6 weeks post injury.

Main study

The primary objective for the main RCT was to:

1. estimate differences between the treatment groups in the Disability Rating Index (DRI) at 12 months after open fracture.

The secondary objectives were to:

1. estimate the rate of ‘deep infection’ (deep SSI) of the limb at 30 days after open fracture

2. estimate differences in health-related quality of life (HRQoL) [Short Form questionnaire-12 items (SF-12) and EuroQol-5 Dimensions, three-level version (EQ-5D-3L)] up to 12 months after open fracture

3. determine the number and nature of complications and further surgical interventions related to the injury during the first 12 months after open fracture

4. investigate, using appropriate statistical and economic analysis methods, health-care resource use and thereby the cost-effectiveness of NPWT versus standard dressing for wounds associated with open fractures of the lower limb.

Inclusion criteria

Patients were eligible for the trial if they:

• were aged ≥ 16 years

• presented (or were transferred) to a trial hospital within 72 hours of injury

• had sustained an open fracture of the lower limb assessed as G&A grade 2 or 3. The treating surgeon determined the G&A grade at the end of surgical debridement as per routine operative practice.

We anticipated that only a very small number of patients would present after 72 hours, but that, in such cases, it was likely that open-fracture wounds would already be infected.

Exclusion criteria

Patients were excluded from the trial if:

• there were any contraindications to anaesthesia such that the patient was unfit for surgery

• there was evidence that the patient was unable to adhere to trial procedures or complete questionnaires, such as permanent cognitive impairment. In a small proportion of patients, this exclusion criterion could be determined only after randomisation and emergency surgery had taken place. These patients were withdrawn from the study and no patient-identifiable data were retained.

Screening procedures

Patients with an open fracture of the lower limb are admitted to the hospital from the emergency department. All patients were screened in the emergency department or the trauma wards for eligibility by a trained research associate. Screening logs from each centre were used to determine the number of eligible patients and reasons for exclusions. Patients who declined to take part were offered the opportunity to discuss reasons for this with a member of the research team.

Recruitment challenges

The key challenge to recruitment was the procedure for obtaining the patients’ informed consent. The nature of these injuries meant that the majority of patients were operated on immediately or were allocated to the next available trauma operating list. Some patients were unconscious or had reduced levels of consciousness, and the great majority were given strong opiate-based analgesia. Therefore, many of the patients lacked capacity to provide informed consent before their surgery. The feasibility phase of the WOLLF study was designed to address this issue, as well as to estimate the rate of recruitment.

Consent

Conducting research in the emergency setting is regulated by the Mental Capacity Act (MCA) 2005. 15 As patients were likely to lack capacity, as described above, and because of the urgent nature of the treatment limiting access to, and appropriate discussion with, personal consultees, we acted in accordance with section 32, subsection 9b of the MCA for following a process approved by the Research Ethics Committee (REC).

Allocation of treatment

Trial participants were assigned to their treatment allocation intraoperatively at the end of initial surgery, but before a wound dressing was applied. All operating theatres included a computer with internet access. Therefore, a secure, 24-hour, web-based randomisation system was used to generate treatment allocation.

Blinding

As the wound dressings were clearly identifiable, it was not possible to blind trial participants or clinical teams to treatment allocation. However, outcome assessment was undertaken by trained research associates (nurses or research physiotherapists) independent of the clinical care team. For patient-reported outcomes [disability, pain, quality of life (QoL), resource use, other complications], trial participants completed follow-up questionnaires themselves and these were returned directly to the central trial office.

Usual-care group

Participants allocated to usual care had a standard dressing applied to the open wound. This comprised a non-adhesive layer applied directly to the wound covered by a sealed dressing or bandage. The standard dressing did not use ‘negative pressure’. The exact details of the materials used were left to the discretion of the treating surgeon as per routine care. Details of each dressing applied in the trial were recorded and classified according to British National Formulary (BNF) classification.

Negative-pressure wound therapy

The NPWT dressing used an ‘open-cell’ solid foam or gauze which was laid onto the wound followed by an adherent dressing. A sealed tube was connected from the dressing to a pump which created a partial vacuum over the wound. The basic features of the NPWT are universal, but the exact details of the dressing and pressure (mmHg) were left to the discretion of the treating health-care team as per routine care. Details of dressings used were recorded in trial documentation.

Post-randomisation withdrawals

Health-related quality of life

Health-related QoL was captured using the following measures.

• EuroQoL-5 Dimensions (EQ-5D): a validated measure of HRQoL, consisting of a five-dimension health status classification system and a separate visual analogue scale (VAS). 17 Responses to the health status classification system were converted into multiattribute utility (MAU) scores using a published utility algorithm, anchored at 1 (perfect health) and 0 (death). 18 These MAU scores were combined with survival data to generate quality-adjusted life-year (QALY) profiles for the economic evaluation. In addition, health status was also assessed using the EQ-5D VAS, which required participants to assess their own health from the worst imaginable (0) to the best imaginable (100). These assessments were made by study participants pre injury (retrospectively),19 immediately post injury and at 3, 6, 9 and 12 months post injury.

• SF-12: a validated and widely used health-related QoL measure. 17 The UK factor score coefficients20 were used to give physical component scores (PCSs) and mental component scores (MCSs). Each permutation of response to the SF-12 was converted into a Short Form questionnaire 6-Dimensions (SF-6D) health utility score using a published utility algorithm. 21 These data were also combined with survival data to generate QALY profiles for a sensitivity analysis within the economic evaluation. HRQoL using the SF-12 was assessed at pre-injury baseline (retrospectively recalled) and at 3, 6, 9 and 12 months post injury.

Surgical site infection and wound healing

The Centers for Disease Control and Prevention (CDC) definitions of SSIs were used (Box 1 and see Appendices 10 and 11). The CDC definition for superficial and deep SSIs is at 30 days following surgery (randomisation). Wounds were assessed and medical records reviewed at discharge, or at the first outpatient appointment after discharge from hospital if the patient was discharged before 30 days. Patients discharged before 30 days had their first follow-up appointment between 30 days and 6 weeks after surgery as part of normal clinical practice in the UK. Wounds were directly observed and infection characteristics were recorded by research staff. The CDC criteria23 for deep SSI also include any deep infection occurring within 1 year if an implant has been left in place. Therefore, we also recorded deep infection presenting within 12 months of the injury: any wound infection that required continuing medical or surgical intervention after 30 days, including infections leading to amputation, was considered a deep SSI.

Other postoperative complications

All complications and further surgical interventions related to the open-fracture wound or treatment of the wound were recorded using multiple approaches. Complications were documented at routine follow-up appointments, were self-reported by patients or were notified as adverse events (AEs) or serious adverse events (SAEs) (see Approval for main trial).

All participants were invited for clinical review and a radiograph at 12 months, as per routine practice after this type of injury. If a participant had not returned a 12-month postal questionnaire, this was completed in clinic.

Radiographic images (radiographs)

Radiographic images were taken at 6 weeks and 12 months post surgery as part of routine follow-up for this group of patients. Standard anteroposterior and lateral radiographs were taken at each centre. Copies of original radiographs were stored on a secure compact disc and returned to the central trial office. The radiographs were reviewed by an independent surgeon who was blinded to the treatment allocation. As part of the assessment of complications, each set of radiographic images was assessed for failure of fixation (yes or no). For long-bone fractures, the sagittal and coronal angulation were measured for the index fixation; sagittal angulation > 10° and coronal angulation > 5° were considered to be clinically important. At 12 months, each set of radiographs was also assessed for bony union (bridging cortical bone across three cortices).

Health-care and social care resource use

Resource use was measured for the purposes of the health economic evaluation. Unit cost data were obtained from national databases such as the BNF24 and Personal Social Services Research Unit (PSSRU)’s Unit Costs of Health and Social Care 2012. 25 When these were not available, the unit cost was estimated in consultation with the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust finance department. The cost–consequences following hospital discharge, including NHS costs and patients’ out-of-pocket expenses, were estimated using questions included within a questionnaire sent to participants at 3, 6, 9 and 12 months post randomisation. Patient self-reported information on service use has previously been shown to be accurate in terms of the intensity of use of different services. 26

Risks and benefits

The risks associated with this trial were predominantly those related to the injury and surgery, for example postoperative infection and bleeding and damage to adjacent structures such as nerves, blood vessels and tendons. Participants in both groups underwent surgery and were potentially at risk from any/all of these complications. Allocation of the trial intervention took place at the end of the initial surgery so that there was no difference between the groups in terms of surgical or anaesthetic risk. Both standard dressings and NPWT have been used widely in the civilian and military settings, and there were no specific risks anticipated with the use of either type of wound management, which was the focus of this trial.

Sample size

The minimal clinically important difference (MCID) for the primary outcome measure (DRI) is 8 points. At an individual patient level, a difference of 8 points represented the ability to climb stairs or run with ‘some difficulty’ versus with ‘great difficulty’. At a population level, 8 points represented the difference between a ‘healthy patient’ and a ‘patient with a minor disability’.

In Table 2, the figure of 412 participants represents a conservative scenario, based on a standard deviation (SD) of 25 participants and 90% power to detect the selected MCID. Allowing a margin of 10% loss during follow-up, including the small number of patients who die in the first year following their injury, gave a total sample size of 460 patients. Therefore, 230 patients consented to each intervention arm would provide 90% power to detect a difference of 8 points in DRI at 12 months at the 5% significance level.

Analysis plan

Ethics committee approval

The WOLLF study was approved by the Coventry REC on 6 February 2012 (REC reference 10/57/20) and by the research and development department of each participating centre. The trial protocol31 was published in the BMJ Open.

Trial Management Group

The day-to-day trial management was the responsibility of the trial co-ordinator, based at WCTU, and supported by administrative staff. The Trial Management Group (TMG) met monthly to assess overall trial progress. It was also the responsibility of the trial co-ordinator to train the research associates at each of the trial centres.

Trial Steering Committee

A TSC was appointed by the NIHR HTA programme and was responsible for oversight, monitoring and supervising trial progress. The TSC consisted of four independent experts, a lay member and the chief investigator. Members of the TSC are listed in Acknowledgements.

Data Monitoring Committee

The DMC was also appointed by the NIHR HTA programme and was tasked with monitoring ethics, safety and data integrity. The trial statistician provided data and analyses requested by the DMC at each meeting. Members of the DMC are listed in Acknowledgements.

Patient and public involvement

Prior to the submission of the grant application for the WOLLF study, an informal survey was conducted at a large university hospital trust to establish the opinion of patients and their carers with regard to research in orthopaedic trauma. We established that patients place great importance on research comparing different types of interventions in the area of trauma surgery. Furthermore, they have demonstrated that they are willing to take part in such trials.

Throughout the trial, a patient with direct experience of sustaining an open lower limb fracture and the subsequent recovery path reviewed all patient documents prior to submission to the sponsor and the ethics committee. Furthermore, advice was sought from this lay collaborator during management meetings when issues were discussed directly related to patient engagement and commitment.

Independent lay representation was present on the TSC. Members of the Trauma Patient and Public Involvement Group also reviewed the progress of the WOLLF study at the annual NIHR Trauma Trials Meetings.

Theme 1: being emotionally fragile

Being emotionally fragile reflects the feelings required to make sense of the event, live with continued uncertainty and process their own strong emotions and those of others. It was expressed through being alive, being close to losing a leg, being a person with strong emotions and being aware of others.

Theme 2: being injured

Being injured was an emotional and physical shock for all participants and they struggled to manage their bodies through the categories of being a person with wounds, being constrained and being in pain.

Theme 3: living with injury

Living with injury evolved as they found mental space to rethink or reimagine how they might live their life at home and at work in the future and was conveyed through the categories of being at home and being at work. This thinking was done within the context of a high level of uncertainty.

Theme 4: being compromised

The decision to go into the trial was based on being compromised, defined as being dependent on others owing to the acute/emergency nature of the injury and a high degree of trust invested in the clinical team. Being grateful included feelings of altruism and the need to give something back, supported by prior research knowledge and the minimal burden of the research process. Being without prior experience of the two treatments led to a state of not knowing about the interventions; however, experience of the two treatments or information from others clearly identifed a technological preference for NPWT.

Overall summary

The core concept of embodied vulnerability conveyed the enormity of the impact of injury for this group; the experience of hospitalisation, while feeling grateful for being saved and lucky that it was not worse, was an emotional rollercoaster. They experienced strong emotions, often to a degree they had not felt before, severe pain, shock and fear in relation to their injured body. There was a physical and emotional fragility which, despite inner strength and determination, meant that they had few reserves to fall back on when they encountered a new threat to their body. Repeated surgery, severe pain, anxiety and fear lowered their ability to contain their emotions and led to what they described as meltdowns. Injury had changed their lives and they reframed their future in the context of uncertainty in relation to their return to normal function, their home lives, their hobbies and their work. Taking part in the trial was within the context of being compromised by the acute event, placing their trust in the clinical team and a feeling of being grateful for their care. A lack of experience of the two interventions limited their decision-making ability but, once they had experience of the interventions, a technological preference was identified.

Being emotionally fragile

Being emotionally fragile can be explained through notions of an ‘emotionally fragile body’: making sense of the event and injury, learning to live with uncertainty and processing strong emotions were part of recovery.

Being injured

Being injured highlighted the difficulty of being a person with wounds and of the visibly wounded body on the sense of self, living in a constrained way with the need for full intimate bodily help, and enduring and managing being in pain.

Living with injury

Living with injury incorporated a way of envisaging the future: both being at home and being at work.

Being compromised

The findings identify that making a decision to take part in a trauma trial takes place within the context of participants’ broader experience of recovery. Participants experienced being in the trial within the context of being compromised and being dependent on others to facilitate their recovery. The type of wound dressing was a small part of a much larger life-changing experience. This may be similar to the finding that women chose to take part in oncology drug trials because of their cancer treatment goals rather than because of information they received about the trial. 77 Therapeutic misconception37,38,40 was present on occasions, with some participants trusting the clinicians to provide the right treatment for them. However, the nature of their trust was also based on their belief that the team had saved them and that they were lucky to be alive; they focused on a longer-term hope that the clinical team would be able to lead them to recovery, not noted in other studies. There was some evidence that information about the study before surgery, despite being compromised, was useful for participants and could facilitate a feeling of being involved and having a say in their care. The principles of inclusionary consent in which individuals can actively take part despite their current limitations as identified in dementia care78 may, therefore, have utility in emergency orthopaedic trauma studies.

Participants’ rationale for taking part or continuing with the study was gratitude for the care they received, which included some element of altruism also found in other studies. 38,39,43,79 Some subgroups of patients felt that they were helping their peer-group as well as society more generally, for example the motorcycle community, whose fractures are often open. The limited burden of follow-up activities on participants was also important. 38,39 In relation to understanding the trial, not having experience of the two dressings added to participants’ belief that they were not really in a position to judge the utility of the dressings and, hence, they trusted that staff would not support a trial that would cause them harm. Experiential knowledge was also important to participants in the ankle injury management study. 37 However, once the NPWT had been experienced, there was a strong technological preference for the dressing as it was considered cleaner and had a visible, dynamic component of suction, which removed exudate away from the wound. Participants reported that they wanted this intervention if they ever had a wound again, suggesting that experience was important to how they make sense of an intervention.

Overall recruitment and recruitment by centre

A total of 625 patients were recruited and randomised into the study. Of these, 460 were consented. Recruitment started in July 2012 and was completed in December 2015. Recruitment took place at 24 centres:

1. Royal London Hospital

2. Poole Hospital

3. Aintree University Hospital

4. Leeds General Infirmary

5. Addenbrookes Hospital, Cambridge

6. University Hospital Southampton

7. Northern General Hospital Sheffield

8. Queen Alexandra Hospital

9. Royal Berkshire Hospital

10. Kings College Hospital

11. University Hospital of North Staffordshire

12. Plymouth Hospitals

13. University Hospital Coventry and Warwickshire

14. Norfolk and Norwich University Hospital

15. Queen Elizabeth Hospital, Birmingham

16. Royal Victoria Infirmary

17. Royal Derby Hospital

18. John Radcliffe Hospital

19. Frenchay Hospital

20. Hull Royal Infirmary

21. University Hospital Leicester

22. Nottingham University Hospital

23. Royal Sussex County Hospital, Brighton

24. Morriston Hospital Swansea.

For those patients who lacked capacity to consent prospectively, consent for continuation in the trial was made at the first appropriate time point in the postoperative period. Therefore, a proportion of randomised patients did not consent to be in the study. Table 4 shows that a total of 625 patients were recruited and randomised, with 460 consenting to take part in the study and 165 not consenting.

The planned overall required recruitment rate for the WOLLF study was approximately 0.75 patients per centre per month, based on 460 patients recruited and consented over 36 months at 24 centres.

Overall recruitment across centres was 0.7 patients per month. This was lower than the planned rate, based on the original recruitment period, therefore the trial recruitment period was extended by 3 months to the end of 2015 to reach the target of 460. Full details of recruitment by centre are shown in Appendix 1 (see Table 34).

Population characteristics

The breakdown of the recruited population (n = 625) by age group (< 40 and ≥ 40 years), gender and treatment group is shown in Table 5.

The majority (444/625; 71.0%) of patients recruited to the trial were male. There was also a clear difference in age structure between genders. Figure 3 shows age distributions by gender.

FIGURE 3.

Age distribution by 10-year age bands for (a) males and (b) females. Solid lines show smoothed distributions.

The figures show the relative size of male and female population recruited to the study and also the differing age structure between genders. Males were predominantly younger [median age 39 years; interquartile range (IQR) 26–52 years] and females were older (median age 61 years; IQR 44–79 years). This is probably due to differences in the mechanism of injury between genders (see Table 10).

Consented and non-consented participants

Figure 4 shows the study CONSORT (Consolidated Standards of Reporting Trials) plot. Of the 625 participants recruited into the study, 460 consented to take part. The pattern and number of pre-consent withdrawals were well balanced between intervention groups (NPWT group, n = 85; standard dressing group, n = 80). Only a small proportion of those randomised decided subsequently not to consent to take part in the study [NPWT group, n = 14 (4.5%); standard dressing group, n = 15 (4.8%)]. The main reason for post-randomisation (pre-consent) withdrawal was primary closure of the index wound during surgery (NPWT group, n = 20; standard dressing group, n = 18). This made the patients ineligible for entry into the study.

FIGURE 4.

The WOLLF study CONSORT plot. FU, follow-up.

Table 6 presents the characteristics of those consented and those not consented.

A chi-squared test indicated that the proportion of females was significantly (p = 0.037) higher in the non-consented population than in the consented population: 34.5% (57/165) versus 25.7% (118/460). The difference in median age between the consented and non-consented population was 5 years (43 years for consented; 48 years for non-consented). Analysis indicated that this difference did not quite reach statistical significance (Mann–Whitney U-test; p = 0.056). Therefore, we conclude that patients who declined to consent, who were not able to consent or who were ineligible for inclusion in the study after initial recruitment were generally older and more likely to be female than those who consented to take part (see Figure 3, distribution of patient age by gender).

Interventions

Table 7 shows the details of operative procedures by study intervention arm. There were no important differences in the length of the operation, surgeon experience, intraoperative problems or additional injuries between the intervention groups.

Treatment allocation

There were 23 deviations (crossovers) from the allocated treatment (NPWT group, n = 15; standard dressing group, n = 8). Unavailability of equipment accounted for two crossovers in the NPWT group and one in the standard dressing group. In nine cases in the NPWT group, the surgeon chose to use a different dressing, and, in three cases in the standard dressing group, the surgeon chose to use NPWT. There were four cases in each group in which the allocated dressing was not communicated to the operating team.

The details of the types of dressing used for the standard and NPWT interventions are shown in Table 8. There were 241 standard dressing procedures in total (226 in the standard dressing arm of the study and 15 in the NPWT arm). The median number of dressing changes was 1 for the standard dressing arm (IQR 0–2). There were 219 NPWT procedures in total (211 in the NPWT arm of the study and eight in the standard dressing arm). The median number of dressing changes for the NPWT arm was 1 (IQR 0–2).

Baseline participant characteristics

Table 9 shows the baseline patient characteristics for the 460 participants recruited and consented into the WOLLF study.

Table 10 shows details of the mechanism of injury and the participants’ previous medical history.

Operative procedures

Table 11 reports the methods used for fixation (temporary and definitive) and wound closure in planned operations.

There was no evidence to suggest that methods of closure or fixation differed between treatment groups (see p-values in Table 11).

Analysis of primary outcome

The primary outcome for the WOLLF study is DRI at 12 months post injury. DRI scores recover in the postoperative period in both groups, but function is still worse than before the injury.

Table 12 shows the means and SDs by treatment group. A mixed-effects linear regression model is used to estimate treatment differences (and 95% CIs). The full (planned) model incorporated terms that allowed for possible heterogeneity in responses for patients owing to the recruiting centre (random effect), in addition to the fixed effects of the wound grade (G&A grade), gender (male or female), patient age (< 40 years and ≥ 40 years), pre-injury DRI and the intervention groups (NPWT and standard dressing) on an ITT basis.

Table 13 shows the raw and adjusted estimates of treatment effects for DRI at 12 months and earlier occasions; a negative value is in favour of the standard treatment, as lower DRI scores indicate less disability. The covariates used to adjust the treatment effect estimates generally showed strong statistical significance, indicating that the inclusion of these terms improved the overall model fit. For the 12-month DRI model, a higher pre-injury DRI was associated with a higher 12-month DRI (p < 0.001); 12-month DRI was higher (i.e. they were more disabled) for participants aged ≥ 40 years than those aged < 40 years (p < 0.001); and 12-month DRI was higher for those participants with G&A grade of 3, or 3 with vascular involvement, than for those participants with G&A grade of 2 (p = 0.047).

The adjusted estimate of the treatment effect for the 12-month DRI is –3.9 (95% CI –8.9 to 1.2) in favour of the standard dressing group; a lower DRI score indicates less disability. The p-value of 0.132 (see Table 13) indicates that there is no evidence for a statistically significant difference in DRI scores between the treatment groups at 12 months post injury. The MCID for the DRI is 8 points. Therefore, we must conclude, based on our estimated CIs that show evidence in favour of the standard dressing group, that it is extremely unlikely that there is a clinically important difference in DRI scores in favour of the NPWT dressing.

Disability Rating Index at 12 months was positively correlated with earlier DRI scores; the Pearson correlation coefficient with pre-injury DRI is 0.23, 3-month DRI is 0.53, 6-month DRI is 0.71 and 9-month DRI is 0.70. The strong associations between 12-month DRI and earlier (3, 6 and 9 months) DRI can be seen in the similar adjusted treatment effect estimates for these outcomes in Table 13 to those for 12-month DRI. There was no evidence of statistically significant differences in early DRI outcomes between the NPWT and standard dressing treatment groups.

Secondary analyses of the Disability Rating Index data

There were 23 deviations (crossovers) from the allocated treatment (NPWT group, n = 15; standard, n = 8). The PP treatment means for the groups, as defined by the actual treatment participants received rather than the treatment to which they were allocated, were as follows: for NPWT, mean DRI at 12 months was 45.4 points (SD 27.7 points) and for the standard dressing mean DRI at 12 months was 42.5 points (SD 24.5 points), giving a raw mean difference of –2.9. A mixed-effects regression analysis, adjusting exactly as for the ITT model (see Table 13), gave an adjusted treatment effect estimate of –4.0 (95% CI –9.1 to 1.0) in favour of standard dressings with a p-value of 0.119.

Missing data analysis

There were 86 study participants with missing DRI data at the 12-month study end point; 33 participants withdrew from the study after consenting but prior to the 12-month study end point and so, based on the available participants, the study end point is 88% (374/427) towards being complete. Three participants returned 12-month DRI assessments that were classed as missing because more than six of the items were missing. A summary of missing values, by age group and sex, for DRI at 12 months is shown in Appendix 2 (see Table 36).

Health-related quality of life

Health-related QoL was assessed using the EQ-5D-3L and the SF-12. Table 14 shows the observed means and SDs and Figures 6–9 show the full data distributions and trends in the mean scores.

FIGURE 6.

(a) Box plots of EQ-5D-3L utility scores and (b) trends in means (with 95% CIs) pre injury, at post-injury baseline and at 3, 6, 9 and 12 months post injury.

FIGURE 7.

(a) Box plots of EQ-5D VAS scores and (b) trends in means (with 95% CIs) pre injury, at post-injury baseline and at 3, 6, 9 and 12 months post injury.

FIGURE 8.

(a) Box plots of SF-12 PCSs and (b) trends in means (with 95% CIs) pre injury, at post-injury baseline and at 3, 6, 9 and 12 months post injury.

FIGURE 9.

(a) Box plots of SF-12 MCSs and (b) trends in means (with 95% CIs) pre injury, at post-injury baseline and at 3, 6, 9 and 12 months post injury.

Analysis of health-related quality of life

Health-related QoL was measured using the EQ-5D-3L utility score, EQ-5D VAS score, physical health score (PCS from SF-12) and mental health score (MCS from SF-12) at 12 months post randomisation. There appears to be, from a visual inspection of Figures 6–9, very little evidence of a treatment group difference in these outcomes. Scores for all outcome measures other than MCS improve significantly in the postoperative period in both groups, indicating improved physical health, but participants never recover to pre-injury levels. Mental health score, as measured by MCS, does not vary much in the 12 months following injury, but is always marginally lower than pre-injury levels.

Table 15 shows raw and adjusted estimates of treatment effects for QoL measures across all time points. There is no evidence to support statistically significant differences between treatment groups for any of these measures, at any time point in the first year after injury.

There is no evidence that missingness patterns differed between treatment groups. Of the 86 study participants who did not provide DRI score data at 12 months, 47 were in the NPWT group and 39 were in the standard dressing group. Only nine study participants who provided consent had no post-baseline DRI data: six in the NPWT group and three in the standard dressing group.

Logistic regression, with missing data coded as 1 and complete data as 0, indicated that none of age group, gender, wound grade or treatment allocation was predictive of DRI missingness at 12 months; p-values from chi-squared tests for age group, gender, wound grade and treatment group in the logistic regression model were 0.723, 0.306, 0.787 and 0.318, respectively Given that these variables are the most likely to affect missingness patterns and they show no statistically significant association with missingness, it seems reasonable to assume that data are missing at random (MAR).

Imputing the missing data and rerunning the analysis on fully complete data provides a useful sensitivity analysis. Missing data were imputed using the MICE (multiple imputation by chained equations) package in R and pooled estimates of model parameters based on 50 data imputations, and were obtained for the mixed-effects regression models (see Table 13). The pooled estimate of the treatment group effect for DRI at 12 months was –4.5 (95% CI –4.2 to 1.9), with the percentage of the variability attributable to the uncertainty caused by the missing data estimated at 12.8%. Equivalent analyses for the early outcomes at 3, 6 and 9 months were 0.2 (95% CI –4.0 to 4.5), –4.0 (95% CI –8.6 to 0.7) and –5.3 (95% CI –10.5 to –0.1), respectively, with percentages for the variability attributable to the uncertainty caused by the missing data estimated at 19.8%, 18.9% and 24.7%, respectively.

In summary, the inferences based on the complete data, after imputation, are not markedly different from those reported from the complete-case analysis in Appendix 2 (see Table 37).

Local complications related to the open fracture or its treatment

Systemic complications potentially related to the open fracture or its treatment

There were 10 participant deaths reported during the study: six in the NPWT group and four in the standard dressing group. Table 21 shows details of the events.

Kaplan–Meier curves based on cause-specific survival (censoring the unrelated house fire death) are shown in Figure 10. The number of deaths was small, so a cause-specific analysis was not attempted.

FIGURE 10.

Kaplan–Meier survivor curves: plus symbols show censored events in which participants withdrew from the study before the end of 12 months’ follow-up.

A log-rank test provided no evidence to support a difference in survival between treatment groups; the chi-squared statistic is 0.1 on 1 degree of freedom and p-value is 0.699.

Unrelated serious adverse events

There was no evidence to suggest that numbers of SAEs differed between treatment groups (see p-values in Table 22).

In addition, there was no evidence to suggest that numbers of unrelated reoperations differed between treatment groups (see p-value in Table 23).

Costings of negative-pressure wound therapy and standard dressings

The components of both types of dressing and their standard NHS costs were obtained from the finance department within the UHCW NHS Trust. The costs of dressing changes were determined from a sample of trial participants for whom additional details were recorded on dressing changes during the initial hospital admission. This data were used to calculate the average number and cost of dressing changes within each trial arm for 38 WOLLF study participants (randomised to NPWT, n = 20; randomised to standard, n = 18). The NPWT dressing comprised the dressing pack (an average cost for the available sizes was used), the canister and the pump (a daily rental cost was applied to the period of initial hospitalisation relevant to the open-fracture wound). The standard dressing comprised Mepitel^® (Mölnlycke Health Care, Gothenburg, Sweden) (a non-adhesive dressing), dressing gauze and a wool and crepe bandage.

Costing of initial hospitalisation and readmissions

Inpatient resource use for many participants within the WOLLF study was complex and featured multiple procedures and complications as well as multiple readmissions. Given the importance of capturing the costs associated with complications and further surgeries, all of the trial data related to the initial admission were collated from the background information, operation notes, 6-week follow-up and SAE forms. This information was then assessed for each participant individually to determine the procedures carried out. Procedures were then grouped manually for all participants to determine Healthcare Resource Groups (HRGs) for each initial admission, using the HRG4+ 2015/16 Reference Costs82 code to group guidance, which could then be related to costs using the NHS Reference Costs 2014 to 2015 schedule. 83 When insufficient information was available to reliably assess the procedure(s) carried out during the initial inpatient admission, operation notes and/or discharge letters were requested from trial sites for further clarification.

In order to assign costs to readmissions, it was necessary first to determine which admissions were related to the WOLLF study wound, the process of which was based on clinical judgement, using data from the 3-, 6-, 9- and 12-month follow-up forms as well as the SAE forms. This process was analogous to the process that determined whether AEs were related or unrelated to the open fracture or its treatment. Operation notes were then requested from sites for all relevant admissions, allowing the procedures carried out during each readmission to be determined. HRG codes could then be determined for each readmission and related to NHS Reference Costs. For cases in which there was evidence of a related readmission but the specific procedure carried out was unknown, a weighted average of the base costs, average length of stay and excess bed-day cost of the five most common procedures carried out during readmissions were assumed.

Measurement of broader resource use

As well as inpatient resource use related to the initial admission and readmissions, data were also collected about broader NHS and PSS resource use as well as broader societal resource use for the period between randomisation and 12 months post randomisation. Trial participants self-completed resource use questionnaires at 3, 6, 9 and 12 months post randomisation, covering their use of outpatient and day-case hospital services and community health care, as well as their use of medications, PSSs, and aids and adaptations (e.g. crutches, walking sticks, grab rails, etc.). The 3-month questionnaire covered the period following initial hospitalisation to 6 months post randomisation, with subsequent questionnaires covering the 3 months since the previous questionnaire. Further questionnaires captured wider societal resource use, with data collected on time off work, over-the-counter medications, aids and adaptations purchased privately, as well as any additional costs (e.g. travel costs, lost earnings, child care costs and help with housework) borne by themselves, their partners or their friends and relatives. A copy of the follow-up questionnaire can be found in Appendix 8.

Study population

A total of 460 participants were consented into the WOLLF study, of whom 226 were randomised to the NPWT dressing and 234 were randomised to the standard dressing. These participants formed the baseline study population for the trial-based health economic evaluation. A complete profile of resource use, from a NHS and PSS perspective, was collected for 285 participants (62%) at 3 months post randomisation, 277 participants (60%) at 6 months post randomisation, 262 participants (57%) at 9 months post randomisation and 322 participants (70%) at 12 months post randomisation. A complete profile of EQ-5D data was collected for 218 participants (47%) and a complete profile of both EQ-5D and resource use values (from a NHS and PSS perspective), across all time points, was collected for 144 participants (31%). Results of the primary clinical and health economic outcomes collected are detailed in Table 24. The completeness of the relevant health economic data items, by follow-up point and by resource category, is detailed in Table 25.

Initial hospitalisation

The costs associated with each participant’s initial hospitalisation were based on the primary procedure, which was the most resource-intensive procedure during their hospitalisation. The number of primary procedures, and their associate lengths of hospital stay, are broken down by trial arm and detailed in Table 26. The most common primary procedure was microvascular free tissue transfer of flap of muscle of shoulder (latissimus dorsi), with 130 participants having this as their primary procedure. There was a statistically significant difference between the two trial arms in the number of participants receiving primary open reduction of fracture of long bone and extramedullary fixation using plate of hip as their primary procedure (p = 0.005), with none of the participants receiving NPWT having this as their primary procedure, compared with eight participants in the standard dressing arm. There were no other differences in the type of fixation. There were no statistically significant differences in length of stay for each primary procedure between the two trial arms.

Costs of negative-pressure wound therapy and standard dressings

The resource components associated with NPWT and standard dressings and their associated costs are summarised in Table 27. A further component of dressing costs is those costs associated with dressing changes. In order to estimate these costs, data on dressing changes were collected for 38 participants (randomised to NPWT, n = 20; randomised to standard dressing, n = 18) and the mean costs associated with dressing changes as well as the mean number of dressing changes in each group is also summarised in Table 27.

Broader resource use

Table 28 presents resource use for trial participants with complete data (for each resource category and follow-up point) by trial allocation and study period. The resource use values are presented for each resource category (inpatient care, outpatient care, community care, medication, PSSs, and aids and adaptations) and by individual items within each category. Resource use values were combined with unit costs for each resource item (Table 29) to estimate economic costs for each resource category.

In terms of inpatient resource use, readmissions related to the WOLLF study wound were broadly similar in both trial arms, varying between 0.11 readmissions per participant during the 9- to 12-month follow-up period (in both trial arms) and 0.26 readmissions per participant during the 3- to 6-month follow-up period, for participants receiving standard dressings. Within outpatient resource use, the department with the highest average visits per participant was NHS physiotherapy, which peaked at 3.99 visits per participant during the 3- to 6-month follow-up period for participants receiving standard dressings. In the 6- to 9-month follow-up period, participants receiving standard dressings made statistically significantly (p = 0.040) more NHS physiotherapy visits (3.21 compared with 1.64), an effect mirrored for private physiotherapy visits (0.78 compared with 0.41 visits), although the latter difference was not statistically significant. This was followed by orthopaedics, with 2.55 visits per patient in the 0- to 3-month follow-up period for participants receiving standard dressings. This fell to 0.98 visits per participant during the 9- to 12-month follow-up period. Within community care, the district nurse category received the greatest average number of visits per participant, with 4.74 visits per participant during the 0- to 3-month follow-up period, for participants randomised to NPWT. Within the aids and adaptations category, statistically significantly (p = 0.008) more grab rails were utilised on average by the participants in the standard dressing arm during the 3- to 6-month follow-up period (0.12 grab rails on average, compared with 0.01 for those receiving NPWT).

Prescription medication usage was highest during the first 3 months of the post-randomisation period, with 53% of all participants using some form of prescription medication. In the 3- to 6-month follow-up period, this fell to 42% of participants, with statistically significantly (p = 0.044) higher usage for those participants randomised to standard dressings (48% compared with 36%).

Base-case analysis

The base-case analysis used multiply imputed data and produced an ICER of £267,910 per QALY gained, reflecting higher costs on average and marginally higher QALYs on average in the NPWT arm. The probability that NPWT was cost-effective was also computed at the cost-effectiveness thresholds referred to previously but never exceeded 27% (24.4% at the widely used £20,000 per QALY cost-effectiveness threshold). The base-case analysis indicates that NPWT is highly unlikely to be cost-effective in this patient population. The cost-effectiveness plane and CEAC for the base-case analysis are displayed in Figure 11.

FIGURE 11.

Base-case analysis. (a) Cost-effectiveness plane; and (b) CEAC.

Sensitivity analyses

Societal perspective

When taking a broader costing perspective that additionally included costs that fell outside the NHS and PSS sectors, the ICER increased to £282,858 per QALY gained, largely driven by an increased incremental cost attributable to NPWT; the probability that NPWT is cost-effective did not exceed 11% (8.1% at a £20,000 cost-effectiveness threshold). The cost-effectiveness plane and CEAC for the analysis carried out taking a societal perspective is shown in Figure 12.

FIGURE 12.

Sensitivity analysis adopting a societal perspective. (a) Cost-effectiveness plane; and (b) CEAC.

Quality-adjusted life-years calculated using the Short Form questionnaire-6 Dimensions

With QALYs calculated using the SF-6D utility measure rather than the EQ-5D-3L, NPWT was strictly dominated by standard dressings, meaning that NPWT resulted in both higher costs and worse outcomes, on average. The probability that NPWT is cost-effective did not exceed 13% (12.0% at a £20,000 per QALY cost-effectiveness threshold). The cost-effectiveness plane and CEAC for the analysis with QALYs calculated using the SF-6D is shown in Figure 13.

FIGURE 13.

Sensitivity analysis calculating QALYs using SF-6D rather than EQ-5D. (a) Cost-effectiveness plane; and (b) CEAC.

Complete-case analysis

The complete-case analysis restricted the analysis to individuals with complete data and resulted in a qualitative change in the direction of the results, with NPWT becoming dominant in health economic terms; that is, it generated both lower costs and higher QALYs, on average. The probability that NPWT is cost-effective was estimated as 71%, 72% and 74% at cost-effectiveness thresholds of £15,000, £20,000 and £30,000 per QALY, respectively. The cost-effectiveness plane and CEAC for the complete-case analysis are shown in Figure 14. Although there was a clear difference in the results of the base-case analysis using multiply imputed data and the results of the complete-case analysis, this difference is plausible given the large number of missing data. For the base-case analysis, complete cases were available for only 31% of the total cases and logistic regressions on missingness of total QALYs and total costs support the MAR assumption.

FIGURE 14.

Sensitivity analysis restricted to complete case. (a) Cost-effectiveness plane; and (b) CEAC.

Subgroup analyses

A post hoc subgroup analysis was also carried out to explore the cost-effectiveness of NPWT in those participants with a deep infection. NPWT was dominated in this group of participants, generating increased costs and lower QALYs, on average. The probability of cost-effectiveness did not exceed 15% and, as such, the results suggest that NPWT is highly unlikely to be cost-effective in this subgroup. The cost-effectiveness plane and CEAC for the deep infection subgroup is shown in Figure 15.

FIGURE 15.

Deep infection subgroup. (a) Cost-effectiveness plane; and (b) CEAC.

Declined to participate

In total, 625 patients were randomised into the WOLLF study. Of these, 460 were eligible and consented to participate in the trial. A total of 165 patients did not consent to enter the trial: 85 in the NPWT group and 80 in the standard dressing group.

The patients who declined to consent, were not able to consent or were ineligible for inclusion in the study after initial recruitment (see Table 6) were generally older and more likely to be female. One of the exclusion criteria was that patients were unable to adhere to trial procedures, including filling out questionnaires, and this was most commonly because of permanent cognitive impairment. This may explain why the patients who did not consent were older than those who did consent. However, the number of patients in this category was small, so it seems more likely that older female patients were either less likely to survive their injuries, or simply less likely to agree to participate.

There were two main reasons for patients being unable to take part in the trial post randomisation.

First, owing to the emergency nature of the surgery, many patients went straight to the operating theatre before their eligibility for the trial could be definitively confirmed. For example, some patients were unconscious or had been anaesthetised before transfer to the hospital, so that, at the time of surgery, it was not clear whether or not they would be able to ‘adhere to trial procedures’. Therefore, it was anticipated that a number of patients randomised would subsequently be deemed ineligible to participate in the trial.

Second, and in keeping with the findings of the integrated qualitative study, we anticipated that a small number of patients who were not able to consent to enter the trial prospectively, owing to lack of capacity, would subsequently choose not to take part in the trial.

Regarding the first group, 140 out of the 165 patients who did not consent for the trial were found to be ineligible in the postoperative period and were therefore not consented to take part. Of these, 75 were in the NPWT group and 65 in the standard dressing group (see Figure 6). Some of the reasons for ineligibility were anticipated. These included 28 patients in each group who were deemed ‘unable to adhere to trial procedures’ or ‘unable to consent before 6 weeks’, most of whom had significant head injuries in association with their open fracture of the lower limb or were found to have permanent cognitive impairment which could not be identified preoperatively. In keeping with the major trauma sustained by patients in this trial, 14 patients died in the postoperative period and were never able to consent. However, of the ‘other’ reasons (see Figure 6), the great majority were actually related to failure of the surgical team to follow the trial procedures. Several sites, particularly at the beginning of the trial, chose to randomise the patients during surgery, rather than waiting until the end of the operation. This was understandable, as it allowed the operating theatre team to prepare the dressings in advance of the wound closure. However, the result was that several patients were randomised before a final decision about the open-fracture wound was taken. A total of 20 patients in the NPWT group and 18 patients in the standard dressing group went on to have a primary wound closure and were therefore no longer eligible for the trial. One patient in each group went on to have an amputation as the extent of the injury became clear during surgery. As this issue was recognised, the sites received further training and the number of patients randomised before the end of surgery reduced as the trial continued. When possible, all patients who were randomised into the trial but who were subsequently found to be ineligible were told about the trial but no other data were collected on these patients.

There is no reason to suspect that these patients, who were randomised but later found to be ineligible, created a selection bias within the trial.

Of more potential concern were the second group of patients who were eligible and were randomised, but who later declined to participate. If this group of patients was large, it could draw into question the external validity of the trial, that is, the ability to generalise the results of the trial to the broader population of patients with an open fracture of the lower limb. However, in keeping with the findings of the integrated qualitative study, the great majority of patients were happy to take part. In fact, only 25 potentially eligible patients declined to participate in the WOLLF study: 10 in the NPWT group and 15 in the standard dressing group. The most common reason for declining was that the patient ‘did not want to be part of a research project’ or ‘did not want to complete questionnaires’. Overall, 460 out of the 485 (95%) patients who were randomised and eligible for the trial agreed to participate in the WOLLF study. Therefore, we can be very confident that the patients who took part were representative of the population with open fractures of the lower limb.

Treatment according to allocation

There were 23 deviations (crossovers) from the allocated treatment: 15 in the NPWT group and eight in the standard dressing group. Eight of these (four in each group) were because of miscommunication between the surgical team and the operating theatre staff and three were caused by lack of equipment. However, nine cases in the NPWT group and three in the standard dressing group were because of interoperative surgeon preference, which may reflect a lack of equipoise. However, as this number was a very small proportion of the total number of patients we did not expect it to affect the results of the trial (i.e. we did not anticipate a difference between the ITT and secondary per-treatment analysis).

Recruitment by centre

There was considerable variation in the rate of recruitment by centre. The fastest rate of recruitment was in Bristol MTC, at just under two patients per month. Other units struggled to recruit to the trial. In some cases, this was caused by the increasing effects of the Major Trauma Network service reconfiguration. For example, the only centre to withdraw from the trial was Reading after a Network decision that all patients with a suspected open fracture of the lower limb were to bypass the Royal Berkshire Hospital and go directly to the regional MTC in Oxford. In general, recruitment in the ‘Trauma Units’ reduced over time as more patients with an open fracture of the lower limb were diverted to the regional MTCs as they matured. In some centres, the slow rate of recruitment was largely caused by staffing issues in the local research team.

However, more pertinently, the breakdown of recruited participants by centre and G&A grade showed good balance between treatments both across and within centres (see Table 6).

Patients

The largest group of patients in the WOLLF study were young men, with the most common age group being in their 20s. This fits with the idea that younger men are more likely to suffer the sort of high-energy trauma associated with open fractures of the lower limb, the sort of trauma that can cause severe injuries even in the presence of normal bone quality. Over half of all the open fractures were caused by road traffic accidents, many of which involved motorcycles.

Only 30% of the open fractures occurred in women. However, in this group, the most common age group was in their 70s. This suggests that the mechanism of injury is different in women, being more likely to be low-energy trauma in association with osteoporosis (brittle bones).

Fractures

Over 80% of all of the open fractures in the trial occurred in the tibia. The tibia is subcutaneous for its entire length from the knee down to the ankle (i.e. there is very little soft tissue covering the tibia so the bone is more likely to penetrate the overlying skin when it is broken). The next most commonly broken bone was the femur, closely followed by the bones in the foot.

Just over one-third of the patients in the trial required concomitant surgery for other injuries sustained at the time of the open fracture. This highlights the fact that the majority of patients sustained high-energy trauma, during which other areas of the body were also likely to be injured. The most common other areas requiring surgery were the contralateral lower limb (≈17%) and another part of the ipsilateral limb (≈12%), followed by upper limb injuries in around 10% of patients. Head (≈3%), spine (≈2%), chest (≈1%), abdominal (≈2%) and pelvic (≈4%) surgery were much less common.

Surgeons and surgery

Two-thirds of operations were performed by consultant surgeons, with the majority of the other procedures performed by trainees under the supervision of consultant surgeons. Associate specialist surgeons performed < 5% of operations in each treatment group. In keeping with the principle of joint orthoplastic surgical operating, there was a median of two surgeons involved in each case. On average, the primary wound debridement and associated surgery took 2 hours. However, as expected given the wide range of injuries and variable requirement for fixation of the broken bones, there was considerable variation around this 2-hour average operating time.

Current clinical guidelines8 suggest that definitive fixation of the bone involved in an open fracture should be performed at the same time as definitive closure of the wound. Therefore, it is no surprise that the most common form of initial fixation was external fixation, this being the common ‘temporary’ method to hold the position of the broken bone pending definitive internal fixation at a second sitting when the wound was closed.

A total of 47% of patients in both groups had ‘half-pin’ external fixation at their initial surgery. Half-pins were generally used for temporary fixation rather than ‘fine-wire’ external fixators (see Table 7), with the latter being more commonly used for definitive fixation. Table 11 shows that in the great majority of patients treated with a half-pin external fixator at the initial surgery this was later converted to definitive internal fixation at the second procedure when the wound was closed. In some cases, external fixation may be the definitive form of fixation. This most commonly involved ‘fine-wire’ fixation. However, in only 1.3% of the NPWT group and 4.7% of the standard dressing group was fine-wire fixation the first operation. These figrures rose to 8.1% and 14.7%, respectively, at the second operation. This probably reflects the fact that application of circular frames using fine-wires is technically demanding (not all surgeons perform this procedure) and can be time-consuming, so surgeons are less likely to perform fine-wire external fixation in the emergency setting of the first wound debridement. Interestingly, despite the current NICE guidelines,8 half of the patients in both groups had definitive internal fixation at their first operation. This may reflect the fact that the WOLLF study started before the guidelines were developed, so surgeons may have been unaware of the evidence behind this particular NICE guideline. In keeping with the fact that the most commonly injured bone was the tibia, the most common type of internal fixation was intramedullary nail (around 22% in both groups), followed by plate and screw fixation (around 15%). It is important to note that the choice of initial fixation took place before the patient was randomised, so it did not influence the choice of dressing at the end of the procedure.

As anticipated, there was also considerable variation in the type of procedure used to close the wound definitively (see Table 11). The most commonly used option was a free flap – this option was used in 40% of patients in the NPWT group and 35% of the standard dressing group. Free flaps are a technique whereby tissue is transported from a site away from the zone of injury into the open-fracture wound together with its own blood vessels. These blood vessels are then ‘anastamosed’ (sewn into) the local blood vessels to restore blood supply. The formation of free flaps is a technically demanding procedure and may take several hours to perform but, providing that the local blood vessels are intact, a free flap can be used to cover essentially any type of wound. Local flaps were used in 15% of NPWT patients and 14% of the patients in the standard dressing group. Local flaps, as the name would suggest, involve moving tissue locally using that tissue’s existing blood supply. Although generally less time-consuming, the surgeon’s ability to use a local flap depends on how much damage there has been to the tissues around the open-fracture wound. The amount of damage may not always be obvious, so local flaps are considered less reliable than free flaps in many cases. Approximately 20% of both groups had a simple split skin graft. A split skin graft involves taking a partial thickness area of skin from a part of the body outside the zone of injury and transporting it into the area of the open fracture. A split skin graft does not need its own blood vessels so it is a relatively simple and quick procedure. However, it can be used only if there is healthy muscle covering the broken bone, as split skin grafts do not heal when applied directly to the surface of bone. Therefore, split skin grafts are generally used only in less severe open fractures. The majority of the remaining patients underwent delayed primary closure of their wound (i.e. the surgeons were able to sew together the edges of the open-fracture wound without the need for a graft). In the context of the WOLLF study, there was no statistically significant difference in the proportion of patients having skin grafting or primary closure of the wound.

In some areas of the world, NPWT is used for prolonged periods of time following an open fracture of the lower limb, the theory being that NPWT may reduce the size of the wound over time and, therefore, reduce the need for complex free-tissue transfer surgery. This is particularly the case in the developing world, where access to the resources and skills needed for flap reconstruction is limited. Since the start of the WOLLF study, there have been two other reports of the use of NPWT in association with open fractures. The first trial compared two types of fixation for one particular fracture (heel fracture) rather than comparing NPWT with another type of dressing and, therefore, is not relevant to this research question. 102 The second trial103 did, however, compare NPWT with standard dressings. This single-centre trial randomised 90 patients into two groups and followed them for 1 month only. The ‘rate’ of wound healing (defined by the ‘wound surface area’) was noted to be quicker in the group treated with NPWT, but there was no difference in the incidence of infection. This trial describes the use of NPWT over a prolonged period of time, as described in the following text:

Wounds were examined weekly and following, measurements were recorded presence of granulation tissue, wound bed becomes redder, decrease in wound drainage, and decrease in dimensions of wound.

Arti et al. 103

This trial also describes when the use of NPWT was stopped:

V.A.C Therapy [a trade name for NPWT] was terminated when adequate granulation base was achieved allowing for change to conventional dressing, split-thickness skin graft, or flap closure.

Arti et al. 103

This is a very different use of NPWT from that advocated by the BOAST7 and NICE8 guidelines for the management of open fractures, in which early definitive wound closure (within 72 hours) is recommended. It is unlikely that NPWT applied for < 72 hours would have led to a reduction in the size of the open-fracture wound and hence an increase in the use of simple split skin grafting or primary closure. This is borne out in the trial results; if anything, fewer patients in the NPWT group (16%) had primary closure of their open-fracture wound than in the standard dressing group (20%). The length of follow-up in the Arti et al. 103 trial was short and no patient-reported outcomes were described. Therefore, although that trial ostensibly addresses the same question as the WOLLF study, it is not clear whether or not the results are pertinent to the UK NHS or indeed other health-care systems.

Primary outcome

The primary outcome measure for the WOLLF study was the DRI. The DRI allowed the study participants to make their own assessment of their disability between 0 and 100 points, where 0 represents no disability and 100 represents complete disability. The primary end point for the trial was 12 months. Baseline (retrospective, pre-injury) DRI was also assessed, as was earlier outcome at 3, 6 and 9 months.

Table 12 shows observed means and SDs for the DRI and Figure 6 shows the full data distributions and trends in the mean scores. At baseline, pre injury, the majority of patients reported that they had no disability or only minor disability. However, a few patients had quite significant pre-existing disability and so the mean DRI before the open fracture was 12 points. This correlates with the fact that, although the open fractures occurred most commonly in young fit patients, older patients and those with significant pre-injury disability were also affected. The DRI scores improved in the 12 months following the open fracture. However, in keeping with the existing literature,1–4 patients still had considerable disability at 1 year after this very significant injury. At 3 months, the mean DRI score was 65 points, improving to 52 points at 6 months, 47 points at 9 months and finally 44 points at 12 months.

The covariates used to adjust the treatment effect estimates generally showed strong statistical significance, indicating that the inclusion of these terms improved the overall model fit. For example, a higher pre-injury DRI was associated with a higher 12-month DRI (p < 0.001). Participants aged ≥ 40 years had a higher 12-month DRI than those aged < 40 years (p < 0.001). As per the existing literature, the 12-month DRI was higher for those participants with a G&A grade of 3, or 3 with vascular involvement, than for those participants with a G&A grade of 2 (p = 0.047). 2

The main results of the WOLLF study is that there was no evidence of a difference in the DRI at 12 months between those patients treated with NPWT and those treated with standard wound dressings. The mean DRI in the NPWT group was 45.5 points (SD 28.0 points), compared with 42.4 points (SD 24.2 points) in the standard dressing group, giving a difference of –3.9 points (95% CI –8.9 to 1.2 points) in favour of standard dressings (p = 0.132). As the MCID for the DRI is 8 points, we conclude that it is extremely unlikely that NPWT dressings confer a clinically important difference in DRI scores for patients with an open fracture of the lower limb. Similarly, there was no evidence of a difference in DRI scores at 3, 6 or 9 months.

A systematic review of the literature before this trial showed only one RCT comparing standard wound dressing with NPWT for patients with open fractures of the lower limb. Stannard et al. 14 did not report a Disability Rating so there is no existing evidence with which to compare this result.

Pre-planned subgroup and secondary analyses of the Disability Rating Index

The secondary PP (per treatment) analysis did not differ from the primary ITT analysis, and the difference between groups was –4.0 points (95% CI –9.1 to 1.0 points) in favour of the standard dressings with p-value of 0.119. This was as expected because the number of patients who crossed over (i.e. did not receive the treatment allocated) within the trial was small.

As noted above, the number of participants who did not complete the trial was small. However, we performed a secondary analysis using imputation to account for missing data (see Table 37, Appendix 2). As expected, the results were very similar to those from the complete-case analysis, indicating that missing data do not affect the result of the trial.

Secondary outcome measures

Complications

When interpreting the primary outcome of any trial, it is important to take account of the complication profile of the two interventions. This is particularly important in the WOLLF study as the interventions under investigation are specifically designed to improve wound healing and thereby reduce the risk of deep infection at the site of the open fracture. We have broken these AEs down into ‘complications local to the open fracture’, most notably infection, ‘systemic complications of the open fracture or its treatment’ and ‘unrelated adverse events’, during the 12 months after the injury.

Complications local to the open fracture

Systematic complications

As noted previously, open fractures frequently occur in the context of patients suffering multiple injuries. It may be difficult to separate the systemic effects of an open fracture of the lower limb from the effects of trauma to other areas of the body. For the purposes of the trial, we took a conservative view and presumed that systemic complications, including death, were related to the open fracture and its treatment, unless demonstrably otherwise. Seven participants died of systemic complications during the 12 months after the injury.

Unrelated adverse events

Medical complications included the treatment of chest and urinary infections, etc. These were the most common systemic complications occurring in 40 patients: 19 in the NPWT group and 21 in the standard dressing group. There were relatively few psychiatric referrals, which is somewhat surprising given the patient experiences documented in Chapter 3. This may reflect the lack of psychiatric/psychological support services available to trauma patients, rather than a lack of need.

Surgical complications included any return to the operating theatre for treatment other than to the open fracture. These were common, occurring in 143 participants: 68 in the NPWT group and 75 in the standard dressing group. Some of these were for the treatment of injuries sustained at the same time as the open fracture, but most were entirely unrelated, for example elective removal of gallstones. There was no evidence to suggest that the number of unrelated reoperations differed between treatment groups.

In total, 10 participant deaths were reported during the study: six in the NPWT group and four in the standard dressing group. As noted previously, two deaths were related to complications following amputation of the limb with the open fracture and so were deemed related and local and seven were possibly related but systemic (chest infection, pulmonary embolus, etc.). Only one death was considered completely unrelated. That patient died in a house fire.

Cost-effectiveness

Given that there was very little difference in HRQoL outcomes measured during the 12 months after the injury and little difference in cost, the cost-effectiveness analysis is very clear. The base-case analysis used multiply imputed data and produced an ICER of £267,910 per QALY gained, reflecting higher costs on average and marginally higher QALYs, on average, in the NPWT arm. The probability that NPWT was cost-effective was low.

The conclusion from the base-case analysis is not altered by the various sensitivity analyses. When broader social costs are included (e.g. time off work), the ICER increases to £282,858 per QALY gained. With QALYs calculated using the SF-6D rather than the EQ-5D-3L, NPWT was strictly dominated by standard dressings, meaning that NPWT resulted in both higher costs and worse outcomes. The only doubt is raised by the complete-case analysis, for which NPWT generated slightly lower costs and slightly higher QALYs, on average. The probability that NPWT is cost-effective was estimated as 72% at cost-effectiveness thresholds of £20,000 per QALY in the complete-case analysis. However, under the MAR assumption, it is multiple imputation that produces unbiased estimates of treatment effect. 106 Given that complete health economic data were available in only 31% of cases, it is thus reasonable and unsurprising that the complete-case analysis produced different results, as this analysis is based only on a subset of the data and a subset for which missingness could be predicted from the other covariates, rather than being missing completely at random. Therefore, it is the base-case analysis using multiple imputation that makes use of all the relevant health economic data and that, under the MAR assumption, provides an unbiased estimate of the cost-effectiveness of NPWT dressings.

Trial management team

Professor Matthew Costa, chief investigator; Dr Nick R Parsons, trial statistician; Dr Juul Achten, research manager; Dr Julie Bruce, principal research fellow; Mrs Sonia Davis, trial co-ordinator; Professor Stavros Petrou, Professor of Health Economics; Ben Parker, health economist; Professor Sarah Lamb, Professor of Rehabilitation; Mrs Susie Hennings, senior project manager; James Masters, specialist registrar; Rishpal Rai, trial administrator; and Liz Weaver, data clerk.

Trial applicants

Professor Matthew Costa, chief investigator; Dr Juul Achten, coapplicant; Professor Sarah Lamb, coapplicant; Professor Keith Willett, coapplicant; Professor Stavros Petrou, coapplicant; Lt.Col. Steven Jeffery, coapplicant; Professor Damian Griffin, coapplicant; Dr Elizabeth Tutton, coapplicant; and Dr Julie Bruce, coapplicant.

Trial Steering Committee

Professor Matthew Costa, chief investigator; Professor James Mason, Professor of Health Economics; Professor Amar Rangan, Professor of Orthopaedic Surgery (independent member); Professor Mike Reed, consultant orthopaedic surgeon (independent member); Mrs Carole Beamish, lay member, quality assurance (independent member); Mrs Ceri Jones, manager, research and development, and UHCW (sponsor representative).

Data Management Committee

Professor Lee Shepstone, Professor of Medical Statistics (chairperson); Professor Simon Donell, consultant orthopaedic surgeon (independent member); and Mr Phillip Johnston, consultant orthopaedic surgeon (independent member).

Statistician

Dr Nick Parsons.

Health economists

Professor Stavros Petrou and Mr Ben Parker.

Radiological evaluation

Mr James Masters.

Programming team

Henry Adjei (Programmer, University of Warwick), Chockalingam Muthiah (Programmer, University of Warwick) and Adrian Willis (Senior Programmer, University of Warwick).

Research team