An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 10/82/01. The contractual start date was in January 2012. The draft report began editorial review in February 2016 and was accepted for publication in May 2016. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Andrew Fisher is deputy director of the National Institute for Health Research (NIHR) Blood and Transplant Research Unit in Organ Donation and Transplantation, has received grants from the NIHR Health Technology Assessment (HTA) programme and Cystic Fibrosis Trust, and received non-financial support in the form of a loan of perfusion machines to study centres from Vivoline Medical. Catherine Exley is a member of the NIHR Programme Grants for Applied Research (PGfAR) panel and acknowledges the contribution of the NIHR HTA programme. Elaine McColl is a member of the NIHR PGfAR panel and was previously an editor for the NIHR PGfAR journals series. Luke Vale is a member of the NIHR PGfAR panel and the NIHR HTA panel. He is also the Director of the NIHR Research Design Service in the North East. Andreas Andreasson, Thomas Chadwick, Steven Tsui, Nizar Yonan, Andre Simon, Nandor Marczin, Jorge Mascaro and John Dark acknowledge the contribution of the NIHR HTA programme, the Cystic Fibrosis Trust and Vivoline Medical. Mark Pearce acknowledges the contribution of the NIHR HTA programme and also leads the radiation epidemiology theme of the NIHR-funded Health Protection Research Unit on radiation and chemicals in Newcastle.

Disclaimer

This report contains transcripts of interviews conducted in the course of research and contains language that may offend some readers.

Copyright statement

© Queen’s Printer and Controller of HMSO 2016. This work was produced by Fisher et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Introduction

Respiratory diseases account for one in five deaths in the UK. 1 Lung transplantation is the only realistic therapeutic option for selected patients with end-stage chronic lung disease and provides dramatic improvements in both survival and quality of life. In younger patients with life-threatening cystic fibrosis (CF) lung disease, median survival after lung transplant now exceeds 10 years. However, 20–30% of patients waiting for lung transplantation will die before a donor organ becomes available. Although a shortage of multiorgan donors contributes, the main problem is that in multiorgan donors lungs are very susceptible to dysfunction, and about 80% of potential donor lungs in the UK are deemed unusable for clinical lung transplantation. It has previously been suggested that, in addition to promoting more organ donation, better use of existing organ donors is an important way to increase the numbers of lung transplants performed,2 and many centres worldwide have increased donor lung use by accepting more ‘marginal’ or ‘extended criteria’ donors. This, however, is not without risks to early post-transplantation outcomes. 3 The major early cause of death after lung transplantation is primary graft dysfunction (PGD), a severe lung injury akin to acute respiratory distress syndrome. Evidence that PGD has a major impact on survival comes from experience in several centres worldwide,4 and from the International Society for Heart and Lung Transplantation (ISHLT); the reported incidences of PGD are up to 25%, and PGD is associated with 30-day mortality of 50%, compared with < 10% among those without PGD. 5 There is, therefore, an urgent clinical need to safely increase the utilisation of donor lungs from the existing donor pool without negatively impacting on early survival after lung transplant.

Background

Ex vivo lung perfusion (EVLP) is a novel technique in which donor lungs that are unusable because of poor or uncertain function can be assessed objectively and potentially reconditioned for safe use in clinical lung transplantation, thereby increasing the donor pool. Evaluation of human donor lungs in isolated perfusion circuits, as seen in Figure 1, offers unique advantages, as isolation of the lung may alleviate injurious factors associated with the donor or recipient haemodynamics, hormonal derangements and their pro-inflammatory milieu. This allows time for optimisation of the donor lung without the immediate risk associated with fully supporting the recipient. EVLP can also objectively identify lungs that are not suitable for transplantation either because poor function is a result of irreversible damage, or because pre-existing lung disease is identified in the donor lung. In this respect, EVLP may provide reassurance to potential recipients that ‘marginal’ or ‘extended criteria’ donor lungs that might previously have been considered unusable are now acceptable for lung transplantation.

FIGURE 1.

Schematic diagram of an EVLP circuit. HCU, heater cooler unit; LA, left atrium; PA, pulmonary artery. (a) A line diagram of an EVLP circuit; and (b) a donor lung undergoing EVLP on the Vivoline LS1 system (Vivoline Medical AB, Lund, Sweden). Reproduced from Wallinder et al. , Early results in transplantation of initially rejected donor lungs after ex vivo lung perfusion: a case-control study. Eur J Cardiothorac Surg 2014;45:40–4, by permission of the European Association for Cardio-Thoracic Surgery. 6

As of June 2011, approximately 25% of the world’s early experience with EVLP, 17 out of 65 cases, had been gained in the UK. Although initial experience has been very promising, a large-scale trial of the procedure was required to demonstrate its effectiveness in increasing lung transplant activity in a safe and cost-effective way.

The Donor Ex Vivo Lung Perfusion in UK lung transplantation (DEVELOP-UK) study was therefore designed to address this urgent clinical need by assessing how effective EVLP assessment and reconditioning of donor lungs is at safely increasing UK lung transplant activity. The overall objective of this study was to evaluate the clinical effectiveness and cost-effectiveness of the novel technique of donor EVLP in increasing UK lung transplant activity by allowing previously unusable donor lungs to be safely used in clinical lung transplantation. Furthermore, the DEVELOP-UK study would allow the applicability of EVLP to lung transplant services in the NHS to be determined.

Impact of donor lung injury

The lung is very susceptible to injury in the critical care environment, and the vast majority of donor lungs become unusable because of the dysfunction that develops in the hours or days leading up to the donor’s death. Korovesi et al. 7 observed that pulmonary and systemic inflammation occurred in patients who required mechanical ventilation for severe head injury. Characteristic changes in lung mechanics, suggesting subclinical pulmonary inflammation, also developed before the patients became eligible to be organ donors. 7 Fisher et al. 8 have shown that acute inflammation in the donor lung with elevated levels of interleukin 8 in donor bronchoalveolar lavage (BAL) is important in determining early outcomes after human lung transplantation. 9 These observations have subsequently been reproduced elsewhere in the world. 10 In addition, an imbalance between inflammatory interleukin 6 and anti-inflammatory interleukin 10 (IL-10) gene expression in the donor lung predicts adverse early outcomes after human lung transplantation. 11 These clinical observations have been modelled by Avlonitis et al. 12 using a rat model of brain death-induced donor lung injury and subsequent rat lung transplantation. Brain death, together with trauma, infection, aspiration or transfusions, is now considered an important cause of donor lung inflammation and significant progress in understanding its pathophysiology has been made. 13 Other animal models of lung transplantation have demonstrated that adenoviral gene therapy to upregulate expression of the anti-inflammatory cytokine IL-10 in the donor lung downregulates inflammation and improves function in the recipient animal after transplant. 14–17 These observations suggest that attenuating the donor lungs’ inflammatory response before implantation may improve early outcome after lung transplantation, and help to safely maximise lung use from the existing donor pool.

Assessment of donor lung usability

Assessing whether or not potential donor lungs are usable for transplantation is a process that takes into consideration available donor history, subjective evaluation of chest radiograph appearance, bronchoscopy and more exact physiological data such as arterial blood gases (ABGs) following high-concentration oxygen challenge. Despite improvements in donor management practices, currently < 20% of lungs from multiorgan donors in the UK are accepted for transplantation. The internationally accepted selection criteria of the ‘optimal donor’ are primarily opinion based rather than evidence based, and their accuracy in determining the physiological status of the donor lung and predicting post-operative lung function is not optimal. 18 Fisher et al. 19 have shown that current clinical donor lung assessment criteria are poor predictors of existing inflammation or infection in the donor lung, suggesting that many donor lungs deemed unusable may be unnecessarily excluded. Ware et al. 20 evaluated 29 pairs of unusable lungs by physiological, microbiological and histological methods, and concluded that as many as 40% of these lungs would have been potentially suitable for transplantation. Thus, there is urgent need to improve the donor lung selection process through more objective physiological assessment; EVLP can provide a platform to achieve this. In practice, not all of the unused donor cohort will be suitable donors, as some will have absolute contraindications to lung donation, while for others there will not be a suitable matching recipient on the waiting list. It is nonetheless suggested that EVLP could have the potential to increase availability of donor lungs for transplant by 50–100%. However, the current clinical transplantation infrastructures would not cope with a near doubling in activity, therefore, in this study, we were aiming for a 30% overall increase in lung transplant activity.

Early pathway development

Ex vivo lung perfusion was first reported in a canine model in 1970 as a technique to assess the quality of the donor organ in animal models of lung transplantation. 21 Subsequently, porcine studies showed that maintenance of intact vascular function was achievable for up to 24 hours using EVLP, and that functioning lungs could be obtained from donors after circulatory arrest in a porcine model. The clinical EVLP technique was initially developed by Steen et al. 22 in Sweden to assess lungs from donation after circulatory death (DCD) before transplantation. Their initial work in animal models was subsequently translated into the world’s first successful clinical report in 2001 of a lung transplant performed using lungs from a human DCD donor assessed by EVLP prior to successful transplantation. 22 Further experimental work in human donor lungs demonstrated that assessment and reconditioning of unusable organs using EVLP could result in significant improvements in arterial oxygenation and pulmonary vascular resistance. 23 This led to the first clinical report in 2007 of actual reconditioning of an unusable donor lung prior to successful lung transplantation. 24

Clinical ex vivo lung perfusion experience worldwide

Publication of the first successful lung transplantation using a reconditioned donor lung led to a rapid growth in interest in the EVLP technique. 22 The Steen group described successful reconditioning and transplantation of six out of nine donor lungs previously deemed unusable for transplant. 24 All six survived the first 3 months and four of the six were alive and well 12 months after transplant. 25 Subsequently, Cypel et al. 26 in Toronto modified the EVLP protocol significantly to include an acellular perfusate, a closed perfusion circuit and low perfusion pressures of no more than 40% of calculated cardiac output, and demonstrated that lungs can be maintained on EVLP for more prolonged periods with this approach. 26 This group have published their experience of the Human Ex-vivo Lung Perfusion study27 performing EVLP on 23 donor lungs unacceptable for transplant that translated into 20 clinical lung transplants. Outcomes in this group were comparable to that achieved with standard transplants performed over the same time period, with a 15% incidence of PGD in the EVLP group and of 30% in the standard transplant group (p = 0.11).

The UK was the third country worldwide to perform a lung transplantation using EVLP-assessed and -reconditioned donor lungs. The first case was performed by the Manchester group, followed rapidly by the programmes in Harefield,28 Newcastle and Cambridge. By June 2011, UK activity had totalled 17 transplants performed with lungs that would not have been used without EVLP assessment and reconditioning. The 90-day survival in these 17 cases was 100%, with one subsequent death from pneumonia at 9 months, and one further death at 18 months due to rejection. When the Swedish and UK experience was added to the Toronto experience, the findings suggested that early survival is very good, with only two deaths within 90 days among over 65 EVLP transplants. The UK experience revealed that the successful conversion rate during EVLP from unusable to usable donor organs was approximately 50%, which was lower than that reported in the Toronto experience. This may represent the high proportion of DCD donors in Toronto, where EVLP was being used primarily for assessment rather than for reconditioning.

International experience has since grown, with case series now reported by multiple groups internationally, including in Paris, Madrid, Vienna, Milan and Gothenburg, with patients successfully transplanted with EVLP lungs recovered from uncontrolled and controlled DCD donors. 29,30

In 2010–11, the UK was in a unique position, with four of its five adult lung transplant centres having already developed clinical experience in EVLP. At that time, there had been no systematic studies powered to evaluate the clinical effectiveness, safety and cost-effectiveness of EVLP performed anywhere in the world, and this was the impetus for the UK lung transplant community to come together in a collaborative effort in the DEVELOP-UK study.

Keshavjee et al. , in Toronto, have, with their extensive contributions, changed the landscape of EVLP into a technique to significantly expand the limited donor pool currently used in transplant centres all around the world. 27,30–32 The focus of Keshavjee and Cypel’s studies in Toronto has not been just to evaluate whether a graft is usable or not, but also to prolong the perfusion times to be able to potentially treat and better recondition injured lungs before transplantation. They have most notably revised the Lund protocol to potentially increase the option of longer-term perfusion with an acellular perfusate to avoid potential detrimental haemolysis. This is combined with a low-flow strategy with only 40% of estimated cardiac output to reduce pulmonary vascular shear stress and oedema formation, and closed circuit with both the pulmonary artery and left atrium cannulated, creating a positive left atrium pressure. The prospective, non-randomised, multicentre study NOVEL (NOrmothermic ex Vivo lung perfusion as an assessment of Extended/marginal donor Lungs) has recently been completed in the USA with the Toronto EVLP protocol and the XPS^TM system (XVIVO Perfusion AB, Gothenburg, Sweden) to approve its clinical use.

Warnecke et al. ,33 in 2012, investigated the effect of normothermic preservation and transportation of standard criteria human donor lungs on a portable EVLP system. Twelve pairs of standard donor lungs were, instead of being brought to their centres by means of cold preservation on ice, preserved by normothermic perfusion and ventilation on the transportable Organ Care System^TM (OCS) lung (TransMedics Inc., Andover, MA, USA). This was the first report of a portable EVLP system used in clinical transplantation, with short-term outcomes shown to be non-inferior to controls. 33

The OCS protocol used in this pilot study was a hybrid of the Lund and Toronto EVLP protocols. A cellular perfusate based on Steen Solution™ (XVIVO Perfusion AB, Gothenburg, Sweden) supplemented with erythrocytes and an open left atrium was combined with a perfusate flow limited to 2.5 l/minute, resembling the protective approach developed by the Toronto group. The OCS protocol is currently being evaluated on a larger scale in a prospective, randomised multicentre pivotal trial, OCS International Randomized Study of the TransMedics Organ Care System for Lung Preservation and Transplantation (INSPIRE), comparing transplant outcomes of standard criteria lungs preserved and transported by either normothermic EVLP or standard cold preservation. 34 Moreover, the international EXPAND (Evaluate the Safety and Effectiveness of The Portable OCS Lung For Recruiting, Preserving and Assessing Expanded Criteria Donor Lungs for Transplantation) trial was recently launched as a clinical pilot to evaluate the more traditional use of assessing and, possibly, reconditioning lungs deemed unusable for standard transplantation on the OCS lung portable system. 35

The development of semiautomated systems with disposable kits has made conducting EVLP more standardised, and has allowed protocols to be developed, as seen in the Vivoline LS1 (Vivoline Medical AB, Lund, Sweden) in Figure 2. The LS1 is a semiautomated EVLP system that was used at all sites in the DEVELOP-UK study.

FIGURE 2.

Photograph of (a) the Vivoline LS1 EVLP machine and (b) the disposable lung kit.

Ex vivo lung perfusion biological mechanisms of action

There are a number of mechanisms by which the reconditoning effects of EVLP are believed to occur. These are outlined in the following sections.

Study design

The DEVELOP-UK study was designed as a multicentre, unblinded, non-randomised, non-inferiority observational study with an adaptive design, to evaluate the clinical and economic effectiveness of EVLP in assessing and reconditioning donor lungs for transplantation compared with standard lung transplantation. The study also includes an embedded qualitative substudy.

Primary outcome measure

Survival during the first 12 months following lung transplantation was chosen as the primary outcome measure in the study. It is a robust, well-recognised, clinically relevant outcome that is used in the Royal College of Surgeons national audit of UK cardiothoracic transplant activity and in the ISHLT lung transplant registry. A dichotomous outcome such as survival ‘yes/no’ at 30 or 90 days would be less informative, and would omit valuable information about potentially differing survival patterns between the two study groups.

Secondary outcome measures

The secondary outcome measures in this study were all deemed to be important, clinically relevant, patient-centred outcomes that are influenced by the effectiveness of lung transplantation, contribute to the health-care costs and impact on health-related quality of life (HRQoL).

Primary graft dysfunction is a clinical entity that reflects the development of early acute lung injury after lung transplantation. PGD was first defined by a working group (which included a number of the study investigators) of the ISHLT in 2005. 39 Its severity is graded between 0 and 3 and it is measured at 0–6, 24, 48 and 72 hours after lung transplantation. The grade is determined by the degree of gas exchange impairment, and by the presence of infiltrate on the post-operative chest radiograph. The PGD grade has been validated in both retrospective and prospective studies, and presence of PGD grade 3 at 72 hours is associated with a reduced early survival. A full PGD score was requested to be determined for all patients in the study.

The durations of invasive ventilation and ITU stay after lung transplantation were collected for all study participants, and provide a valuable source of a range of complications in early post-operative course. In addition, the duration of hospital stay before first discharge home gives a good indication of how effectively the patient is rehabilitating after their lung transplant. These measurements also provided useful information on health resource utilisation for economic evaluation.

The presence of specific post-operative complications was also collected as a secondary outcome measure. These complications included anastomotic complications scored using the recognised and validated Couraud Classification (see Appendix 1),40 which scores airway complications including dehiscence or stricture requiring dilatation or stent placement. Episodes of infection requiring treatment with or without associated hospital admission during the first year, and episodes of acute rejection of ISHLT grade A2 or higher, B1 or higher, or clinically diagnosed acute rejection requiring treatment during the first year, were also collected.

Details of lung function measurements by forced expiratory volume in 1 second (FEV₁) and vital capacity at 1, 3, 6 and 12 months post transplant were collected to demonstrate changes in lung allograft function in the first year. Data on chest radiograph appearance at the same time points as lung function were collected to look for any persistent abnormalities such as effusions, cavitation or chronic scarring from the time of transplantation.

Patient survival rate at 90 days post transplantation was collected as an internationally recognised outcome measure in lung transplantation that can be benchmarked against outcomes reported in both the UK and international (ISHLT) registries.

An assessment of HRQoL using the Short Form questionnaire-36 items (SF-36) was collected at three time points in the study (while participants were waiting for transplant and again at 90 days and 1 year post lung transplantation) allowing comparison of HRQoL measured while on the waiting list with that measured post transplant. The HRQoL scores have allowed health state utility scores to be determined using the Short Form questionnaire-6 Dimensions (SF-6D) as part of the economic evaluation.

Health economic assessment

In addition, the full economic impact of using EVLP-reconditioned lungs was assessed, allowing policy-makers to consider these costs in comparison with benefits of increased donor utilisation and reduced waiting list mortality. We aimed to determine whether or not EVLP is a cost-effective intervention for the NHS to support as standard care within UK lung transplant centres in the future.

Patients’ attitudes and experiences

To gain an understanding of the potential impact of EVLP provision to service users, we explored attitudes towards EVLP in patients awaiting lung transplantation, and the experiences of patients receiving EVLP-reconditioned lungs, in a qualitative interview substudy.

Predicting ex vivo lung perfusion success or failure

The DEVELOP-UK study provided a unique opportunity to better understand the donor- and procedure-related clinical determinants of successful or failed EVLP donor lung reconditioning. Objective clinical and physiological indices in the donor lungs before and during EVLP can therefore be correlated with the decision of whether or not to accept the donor lungs for transplant and with clinical outcomes in recipients of EVLP donor lungs.

Sample collection and storage

To add significant value to the DEVELOP-UK study, standardised protocols for BAL, perfusate and lung tissue sampling during EVLP and subsequent storage have been developed. The collection and storage of samples during EVLP was part of the DEVELOP-UK study, and allowed complementary mechanistic studies of EVLP to be performed from the data set. Details of the laboratory-based mechanistic work are, however, not included in this report, as this element of the study was funded from sources other than the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme.

Justification for non-randomised design

This is a non-randomised study, as randomisation between EVLP and standard lung transplantation was not considered a viable option. The matching of potential donor lungs to potential recipients is dictated by a number of independent factors, including donor and recipient size, blood group and, if applicable, human leucocyte antigen (HLA) tissue matching to avoid any pre-formed HLA antibodies in the recipient. It was, therefore, not logistically possible to randomise recipients to receive either standard or EVLP donor lungs as part of the study. Furthermore, any attempt to randomly pre-allocate patients on the waiting list to an EVLP or standard group could give rise to a situation where a recipient may not be able to access a well-matched donor organ because it did not fall into his or her pre-allocated group, which would not be ethically acceptable. Randomisation would be possible only if all donor organs were being randomly allocated to EVLP or control, but this is a different research question and was not an objective of this study.

Lung donations from donors with brain death and DCD donors were considered in both arms of this study. The number of DCD donors is increasing year on year in the UK. 41 Evidence has emerged that, when lungs from these donors are transplanted, outcomes in recipients are comparable to those achieved with lungs from donation after brain death (DBD) donors. 42 However, only a fraction of the UK DCD donors, currently about 5%, have their lungs used for standard transplantation. 41 Frequently, there are insufficient data available to be able to objectively assess the function of the lungs from DCD donors, or there is a prolonged warm ischaemic phase after withdrawal of life support that renders the lungs unusable for standard transplantation. EVLP does, however, provide the potential to assess and potentially recondition lungs from DCD donors that cannot be used for standard transplantation.

It was anticipated that a direct result of the DEVELOP-UK study would be an increase in the proportion of DCD donor lungs being used, as DCD donor lungs are often deemed unusable because functional information about the organs is unavailable, which is an indication for use of EVLP assessment. It was considered likely that as the number of DCD donors increases, more lungs from this cohort of donors would be transplanted in the EVLP arm of the study than in the standard arm. This reflects the potential for EVLP to significantly increase the use of lungs from DCD donors. To ensure that the possible higher proportion of DCD donor lungs in the EVLP arm of the study did not bias the results, we planned to use the donor type (DCD or DBD) as a covariate in the multiple regression analysis of the primary and secondary outcome measures to determine their influence.

Justification for adaptive study design

The study statistics and trial methodology teams, in consultation with the clinical investigators, made the decision to use an adaptive design for the DEVELOP-UK study, to allow for the possibility of stopping the trial early should non-inferiority in our primary outcome be determined at an interim analysis, and to allow for re-evaluation of the sample size requirements on the basis of a potentially improved standard of care. It was felt that a total of three analyses, two interim and one final, would achieve a suitable balance between allowing for early stopping and ensuring that sufficient data were collected on secondary outcome variables to make these meaningful. The plan was for the interim analyses to be carried out once a prespecified number of patients had been recruited to each arm (see Power calculation and definition of non-inferiority). The O’Brien–Fleming critical values for the analyses during our study were chosen so that the overall study would have sufficient power to detect our target differences at a significance level of 0.05 once allowance had been made for the interim analyses.

Power calculation and definition of non-inferiority

In the standard arm, the initial best available estimate for survival to 30 days was 94.2%, for survival to 90 days was 91.2% and for survival to 1 year was 78.7%. These data were determined from the Royal College of Surgeons’ UK national audit of lung transplant outcomes. Our aim was to demonstrate that using reconditioned EVLP lungs does not increase the hazard rate of death during the first year by a factor of > 2. A doubling of the hazard rate would imply that survival rates on EVLP would be 88.7% for 30 days, 83.2% for 90 days and 61.9% for 1 year. It was considered that such a difference is not clinically significant and still represents an advantage over waiting longer for a transplant.

It was anticipated that over the predicted 3 years of the study, about 100 EVLP lungs would be transplanted and ≥ 300 normal lung transplants would take place. If both treatment arms matched the standard 78.7% rate of survival over 12 months, then approximately 85 deaths would occur within 1 year of transplantation. Using a fixed sample design, this would be sufficient to ensure 80% power of claiming a significant finding of non-inferiority (at a one-sided 5% level) if both treatment groups actually have the same survival pattern. 31 The study was therefore powered to detect a difference of 2, meaning that non-inferiority is assumed to have been achieved if the hazard rate of 12-month survival is not doubled by the use of EVLP.

To obtain sample sizes for an adaptive design, we took the standard sample size and multiplied it by the appropriate inflation factor (which depends on the choices of critical values, number of analyses, significance level and power). For our choices, the inflation factor was 1.0128, resulting in a sample size of 304 in the standard arm and 102 in the EVLP arm. We increased the sample size to 306 in the standard arm while keeping it at 102 in the EVLP arm so that the sample size in both arms would be divisible by 3, to allow for equally spaced interim analyses. This resulted in a required minimum total sample size of 408 with interim analyses after 12-month survival data were available from 102 and 204 patients in the standard arm (34 and 68 in the EVLP arm).

Risks and anticipated benefits for study participants, NHS and society

There is a huge discrepancy between the supply of usable donor lungs and the number of patients with end-stage lung disease who could potentially benefit from lung transplantation surgery in terms of extended longevity and improved quality of life. As a result, many patients die on the waiting list before suitable donor lungs become available. EVLP allows otherwise unusable donor lungs to be meticulously assessed and potentially reconditioned for successful transplantation. The study would also help to understand better how to optimise the use of lungs procured from DCD donors. This technology, therefore, has the potential to expand the donor pool and increase UK lung transplant activity, thereby shortening time spent on the waiting list and reducing waiting list deaths.

The primary risk for the individual participant awaiting lung transplantation is that if they are enrolled in the EVLP arm they may receive a lung or lungs that do not function well, but that risk also exists for standard donor lungs accepted by the current assessment methods. Compared with standard criteria organs, it was not anticipated that EVLP should expose recipients to any different risk profile in terms of microbiological exposure, intensity of induction and maintenance immunosuppression or early post-transplant complications. This was based on reported worldwide experience with EVLP at the time (2010–11) the study was designed and launched. Patients awaiting lung transplantation have severe, often complex, morbidity and place a heavy resource burden on both health and social services. Data from the ISHLT registry clearly demonstrate that nearly 80% of successful lung transplant recipients have no or little functional limitation and around 40% return to either full- or part-time employment, the rest being close to or over retirement age. 43 Fewer than 20% of transplant recipients require inpatient treatment related to their lung disease post hospital discharge following the transplant procedure. Thus, by increasing the numbers of successful transplants, EVLP may help to reduce the UK health- and social-care costs of patients awaiting lung transplantation. Furthermore, by assessing the economic impact of using EVLP-reconditioned lungs, the study results should allow policy-makers to balance these costs against the benefits of increased donor utilisation and reduced waiting time mortality. The study aimed to help determine if EVLP is a cost-effective use of tax-payers’ money and an intervention applicable to NHS lung transplant services.

Study population

The DEVELOP-UK study was a UK national multicentre study involving all five officially designated NHS lung transplant centres: Freeman Hospital, Newcastle upon Tyne; Harefield Hospital, London; Papworth Hospital, Cambridge; Wythenshawe Hospital, Manchester; and Queen Elizabeth Hospital, Birmingham. These five centres provide all adult lung transplant activity to potential recipients with end-stage chronic lung disease in England, Scotland, Wales and Northern Ireland.

The target population for the study was adult patients aged ≥ 18 years with advanced lung disease, who had already been accepted (at study inception) onto an active lung transplant waiting list in one of the five UK centres, plus any new adult patients who were added to the active waiting list during the study recruitment period of April 2012 to June 2014. The full network coverage means all patients awaiting lung transplantation in the UK, at any one time approximately 250, had the opportunity to take part in the study, and our previous pilot experience suggested that > 90% would consent to take part. The study was designed to have no effect on how potential lung transplant recipients were assessed or selected, or the timing of when they were added to the active transplant waiting list. The flow chart in Figure 3 shows the planned recruitment targets and summary of data collection for the DEVELOP-UK study.

FIGURE 3.

Diagram to explain planned recruitment targets, study end points and planned analysis. QoL, quality of life.

Study inclusion criteria

Male or female adult patients (aged ≥ 18 years) who were either already on or added to the active waiting list for their first lung transplant while the DEVELOP-UK study was in its recruitment phase were eligible to participate; patients provided informed consent for participation in the DEVELOP-UK study at the time of study commencement or time of listing for transplant and reconfirmed informed consent for the DEVELOP-UK study on the day of lung transplant.

Study exclusion criteria

Patients aged < 18 years and adult patients listed for lung retransplantation, heart–lung transplantation, multiorgan transplantation including lung or live donor lobar transplantation were excluded. Patients not in possession of the patient information sheets for the DEVELOP-UK study prior to the day of lung transplantation or those not reconfirming consent for the DEVELOP-UK study on the day of lung transplant were excluded. Patients in the ITU requiring invasive ventilation, extracorporeal membrane oxygenation (ECMO) or interventional lung assist (iLA) support when a donor lung became available were excluded. Patients enrolled in other trials within the preceding 12 months of signing an expression of interest (EOI) or giving full consent had to be discussed with the principal investigator (PI) and chief investigators before being excluded on this basis.

Inclusion and exclusion criteria for interview substudy

All patients who were eligible for the DEVELOP-UK study at The Newcastle Hospitals NHS Foundation Trust and the Royal Brompton and Harefield NHS Foundation Trust were eligible for the interview study. All patients who consented to the DEVELOP-UK study, as a whole, at the above centres were eligible to take part in the interview substudy regardless of whether or not they received a transplant. All patients who consented to the DEVELOP-UK study from Manchester, Papworth and Birmingham sites were excluded from the qualitative study.

Concomitant medications

All standard prescribed medications taken by patients on the waiting list for lung transplantation were permitted in the study. Some medications are stopped at the time of transplant or in the perioperative period. These changes are in line with standard clinical processes and were felt to be equally likely to occur in lung transplant recipients in both arms of the study.

Peri- and post-transplant immunosuppression, including any induction therapy and maintenance immunosuppression, may vary slightly between centres, but continued as per usual practice during the study. In any of the centres, patients in both the EVLP and standard arms of the study got the same standard routine immunosuppressive approach normally used in that centre. The immunosuppressive regimes could, however, be changed, intensified or reduced in line with standard transplant clinical management of the individual patient and his or her circumstances. It was possible that patients awaiting lung transplantation might already be enrolled in a clinical trial of investigational medicinal product (CTIMP) for their underlying disease. Such medications were stopped at the time of transplant and participation in the CTIMP was censored as an event and, therefore, the participation of these patients in the DEVELOP-UK study was not affected.

Patients enrolled in the DEVELOP-UK study who underwent lung transplant in either the standard or EVLP arm should not have been enrolled in any other interventional study in their first 12 months post transplant that might have an effect on 12-month survival. If there was any question of this, then the local PI discussed this with the DEVELOP-UK study chief investigator, who then liaised with the chief investigator of the other study and reported back to the trial steering committee. Observational non-interventional studies were allowable but, again, the local PI had to check with the chief investigator to make sure that there was no interference between the studies. Participants were free to be entered in interventional studies started after their first 12 months post lung transplantation.

Limiting the potential for bias

As a non-randomised, non-blinded study, it was important that the potential for bias in the selection of recipients to receive donor lungs from the EVLP or standard arms was considered and carefully monitored. There was, however, no a priori reason to expect a systematic difference to exist in characteristics between the recipients in the two arms of the study. This is because the donor–recipient match was established before the clinical decision on the usability of the donor lungs was made, meaning that recipient selection should not be influenced by whether EVLP-conditioned or standard lung donation occurs. In particular, there was no evidence to suggest that sicker recipients, whose transplant might be seen as more urgent, would be more likely to receive EVLP-reconditioned lungs than standard donor lungs.

Only when donor lungs were available that had more than one potentially matching recipient was urgency taken into account by the transplant centre. This scenario would be likely to happen as frequently in the standard transplant arm as in the EVLP arm. The two arms of the study were monitored carefully to ensure that no systematic differences occurred in the recipient characteristics. Additionally, it was planned that recognised covariates that are known from the international registry to influence outcomes after lung transplantation would be adjusted for in the statistical analysis. Our pilot experience of transplants performed using EVLP-reconditioned lungs across the UK centres indicated that patients with a range of disease indications, ages, disease severity and both single and bilateral transplants have been included, reflecting the variability that exists on the lung transplant waiting list.

Interventions common to experimental (ex vivo lung perfusion) and control (standard) groups

Donor and next of kin consent

Consent for potential donor lungs to be used for lung transplantation was obtained from the donor’s next of kin at the donor hospital by the SNODs, who were employed by NHSBT. This process is standardised nationally and was performed completely independently of the DEVELOP-UK study.

If standard consent for lung donation was granted, the SNODs also asked the next of kin for generic research consent, which is a standard part of the donor consent process. This allowed the study team to collect and store samples from the donor lung before and after EVLP, as described in Appendix 2, for parallel mechanistic studies even if the donor lungs were not deemed transplantable after EVLP. If the donor’s next of kin did not provide generic research consent, then only clinical data measured during the EVLP process were collected and used in the study, and no lung tissue samples were taken for mechanistic work. This did not compromise the delivery of the primary and secondary end points of the study.

Lung recipient pathway pre and post transplantation

Patients referred to any of the five participating sites for consideration of lung transplantation over the course of the study recruitment phase underwent a standard clinical assessment. Those deemed eligible for, and who consented to, lung transplantation were added to the active lung transplant waiting list. Those on the transplant list at the time of study inception would already have been through the same assessment process.

At the time of listing for transplant, patients were offered the opportunity to take part in the DEVELOP-UK study. In addition, at the time of study inception, any patient who was already on the active lung transplant list was also offered the opportunity to take part in the DEVELOP-UK study. The consent process was performed in accordance with National Research Ethics Service guidance, as described in Lung recipient consent. As the period of waiting for lung transplantation can vary widely and commonly exceeds 12 months, it was necessary to reconfirm consent for the study at the time when a potential donor lung(s) became available and the study participant was called in for possible transplantation. However, if the original consent form had been signed on the day of transplant, reconfirmation of consent was not required.

Patients were told on the day of transplant whether they were to receive a donor lung that had undergone EVLP assessment and reconditioning or a standard donor lung. Patients received either standard donor lungs direct from a donor (standard transplant, control arm) or donor lungs after EVLP assessment and reconditioning (intervention arm) in accordance with donor organ–recipient matching. Transplanted lungs, whether ‘standard’ or EVLP reconditioned, always remain vulnerable to the possibility of rejection and one of the main risk factors is low immunosuppression levels. For this reason, patients were thoroughly counselled prior to being accepted onto the transplant list about the need for absolute concordance with their treatment and to attend all arranged post-transplant follow-up visits. As a result, during the multidisciplinary pre-transplant assessment, a considerable amount of time was spent explaining this aspect of care to the patients. If, despite these attempts, there remained evidence of likely non-compliance with treatment, these individuals were not usually offered the option of transplantation.

Lung recipient consent

Informed and voluntary consent was obtained via an iterative process, first at the initial discussion of the clinical and research aspects of the study, and then again, provided this occurred not less than 24 hours later, on the day of possible transplant. If, however, the consent form was signed on the day of transplant, reconsent was not required. Consent for the DEVELOP-UK study participation was sought separately from the standard consent for lung transplant surgery. No additional screening procedures, over and above those necessary to determine eligibility and suitability for lung transplant, were required to determine eligibility for the trial element of the DEVELOP-UK study. Therefore, all adult patients being considered for lung transplant who satisfied the inclusion criteria were approached to take part in the DEVELOP-UK study. Patients waiting for transplantation are desperately sick, very vulnerable and grasping at any lifeline. Securing genuinely informed consent was therefore an important consideration. The initial consent process took place well ahead of the time of transplant and the stressful environment that this generates. Consent was taken either at inception of the study for those already on the transplant waiting list or at the time of listing for transplant for those added to the active transplant list during the course of the study. A copy of the consent documentation is included in Appendices 3 and 4.

Consent was taken by the site PI or a member of the study team with appropriate designated responsibility on behalf of the local PI. In the consent process, care was taken not to unjustifiably inflate hope of a shorter waiting time for transplantation as a result of EVLP being available. A clear definition of what constitutes an unusable donor lung in the study was explained; definitions of acceptability of lungs for standard transplantation and for transplantation after EVLP were agreed and standardised across all centres. Patients were offered firm reassurance that if donor lungs did not improve sufficiently after EVLP reconditioning to satisfy acceptability criteria, they would not be used. Any potential recipient who decided not to participate in the DEVELOP-UK study continued to have equal access to donor lungs for standard transplant. Those choosing not to give consent were not obliged to give a reason, but if they provided a reason this was recorded in an anonymised way to inform the Trial Steering Committee.

Additional informed consent, using a separate participant information sheet and consent form, was sought from the subset of patients approached to take part in the qualitative interviews. Lack of consent to take part in this element of the study did not preclude participation in the trial.

For both the trial and the qualitative substudy, if a potential participant had the capacity to consent for him/herself, but was unable to provide written consent because of visual or motor impairments, or literacy problems, oral informed consent was taken in the presence of an independent witness, who initialled, signed and dated the consent form on the participant’s behalf.

We did not anticipate that any potential study participants would lack capacity to consent on initial recruitment to the study or at the point of reconfirming consent at the time a donor lung became available. It was, however, possible, although unlikely, that they could lose capacity over the follow-up period. For example, if as a result of transplant surgery, any participant were to lose capacity temporarily or permanently, such as by requiring prolonged ventilation in the ITU or by suffering a stroke, we planned to continue to collect outcome measures in relation to such patients, working with personal or nominated consultees and in line with the requirements of the Mental Capacity Act. 44

We did not seek separate written consent from nominated consultees in the event of loss of capacity, as this scenario was included in the initial participant consent form and patients were specifically asked to give consent for continued collection of observational data as part of the study if they lost capacity after transplantation. As many of the data in the follow-up period were observational, their collection did not impact on the standard care that any participant who has lost capacity would expect to receive.

The original signed consent form and reconsent form were retained in the investigator site file, with a copy in the clinical notes and a copy provided to the participant. Participants were asked to consent explicitly to their general practitioner (GP) being informed of their participation in the trial element of the DEVELOP-UK study.

The right to refuse to participate without giving reasons was respected. Owing to the small subject population, the information sheet and consent form for the study were available only in English. Interpreters were available for all visits of patients who required them either for verbal translation to another language or for deaf subjects wishing to take part in the study, via local NHS arrangements.

Protocol compliance

The protocols determining the selection of donor lungs to undergo EVLP and indices that determine whether or not the lungs were suitable for transplant after EVLP were clearly described in the study protocol and are presented in an appendix to this report (see Appendix 2). To ensure compliance with the protocol, data were collected about the donor assessment and EVLP procedure. This allowed confirmation that the donor lung was appropriately allocated to undergo EVLP and that the decision on its suitability was correctly determined. If any instances were identified when the protocol was not followed, this was recorded as a protocol deviation and the site PI was asked to document why the protocol deviation occurred.

Ethics and regulatory issues

The conduct of this study was in accordance with the recommendations for physicians involved in research on human subjects adopted by the 18th World Medical Assembly, Helsinki, 1964, and later revisions. 45 All members of the research team, the investigators and supporting staff at each of the participating sites received training in those aspects of good clinical practice appropriate to their role in the trial, in particular the processes for obtaining informed consent, including the requirements of the Mental Capacity Act,44 and were expected to operate to principles of good clinical practice.

A favourable ethical opinion from the National Research Ethics Service (reference number 11/NE/0342) and NHS research and development (R&D) approval was secured prior to commencement of the study. Local NHS approvals were secured before recruitment commenced at each site. The Newcastle Clinical Trials Unit, in its capacity as study co-ordination centre, obtained a written copy of local approval documentation before initiating each centre and accepting participants into the study.

Information sheets were provided to all eligible subjects, and written informed consent was obtained prior to any study procedures. Patients on the transplant waiting list who lived a significant distance from the transplant centre were given the opportunity to sign an EOI form that allowed them to subsequently consent when next attending the transplant centre (which might be on the day of transplant). Signing of the EOI form permitted completion of the first SF-36 questionnaire and collection of waiting list survival data. Copies of the patient information sheet and consent forms are included in Appendix 4.

We obtained informed and voluntary consent via an iterative process, providing adequate time (i.e. a period of not < 24 hours) for consideration and discussion of the clinical and research aspects of the study. For incident cases, initial consent was taken at the time a patient was listed for lung transplant. For those patients already on the transplant list at the time of study initiation, consent was sought when the study opened at their transplant centre. Reconsent on the day of transplant was sought only from patients initially consenting to the study prior to the day of lung transplant.

Assessments and data collection

All study-specific follow-up data were collected during the time of the clinical admission to hospital for the lung transplantation procedure and, subsequently, at study visits that were co-ordinated to coincide with routine post-lung transplantation clinic visits. The study research nurse ensured that routine clinic visits were mapped to the study visit requirements by liaison with study participants and the transplant outpatient facilities in each centre.

The scheduled outpatient study visits were at 1, 3, 6 and 12 months post transplant. A window of ± 10 days around each timetabled study visit was allowed. If a participant was unable to attend a study visit within the allowable window, for example because he or she was an inpatient at an external hospital that was not the study centre, then every effort was made to acquire the same study-specific information from the non-study hospital. The HRQoL questionnaire (SF-36) was self-completed by each study participant (or in conjunction with their nominated proxy).

Patients’ views and perceptions of EVLP were explored through qualitative interviews conducted by a trained researcher. When possible, these interviews were performed face to face at study visits after transplantation. Those interviewed prior to transplant were interviewed either in their own home or, more usually because of the large geographic spread of individuals, by telephone.

All clinical tests required to determine the success of EVLP assessment and reconditioning of donor lungs, including ABG analysis, glucose and lactate concentration measurement, and microbiological cultures, were performed in each study centre using local laboratories and equipment.

Standard blood profiles during follow-up were performed as part of the recipients’ routine clinic care in each participating centre’s certified NHS laboratories, and results were obtained from hospital data systems.

Data were collected by direct clinical observation, by clinical interpretation and from source patient records or NHS documentation by the study clinical research fellow and the study research nurse, and the required data fields were completed on the case report form (CRF) by the research nurse or a designated data manager in each centre under the supervision of the local PI. A paper CRF was initially used in the study, but in early 2014 an electronic CRF (MACRO; InferMed, Elsevier, London, UK) began to be used, in line with regulations at the sponsoring trust. The donor data required for the study (such as age, comorbidities and oxygenation, among others) were collected routinely by the SNODs, and were then captured electronically by linking to the core data data set collected by NHSBT centrally.

Serious adverse event reporting

Guidance on adverse event (AE) and serious adverse event (SAE) reporting, as well as determining the degree of relatedness and assessment of causality for SAEs that may be related to study participation, was provided in the study protocol.

As lung transplant recipients experience a significant number of AEs as part of their normal recovery from transplant surgery, the study protocol provided clear guidance on what constituted a SAE that required expedited reporting. This was to avoid a huge burden of reporting that had no relevance to this observational study (no CTIMP involved to monitor). Hospitalisations for elective treatment of a pre-existing condition, and hospitalisations as part of routine post-transplant surveillance did not need reporting as SAEs. Unrelated hospitalisations were elicited at the scheduled follow-up appointments and at all emergency appointments.

Serious adverse events requiring expedited reporting included death within 90 days of lung transplantation, severe PGD requiring ECMO/iLA support, bronchial anastomotic dehiscence or any unexpected SAE felt to be probably or definitely causally related to EVLP.

Some SAEs were excluded from expedited reporting to reduce the burden of reporting of events that are common in the transplant journey. These were death on the waiting list prior to transplant or later than 90 days after lung transplantation; PGD grades 1–3 not requiring ECMO/iLA support or severe sepsis associated with consolidation, necrosis or cavitation of lung tissue within 30 days of transplant; renal failure necessitating renal replacement therapy, gastrointestinal complications, central nervous system complications; and infections requiring an addition or change in antimicrobial therapy.

Medium- and longer-term outcomes that did not require reporting as urgent SAEs were bronchial strictures (whether or not they required bronchial stenting), acute rejection requiring augmented immunosuppression, development of post-transplant lymphoproliferative disease or obliterative bronchiolitis. Finally, deterioration of any pre-existing medical conditions both before and after transplantation did not require urgent reporting.

Public and patient involvement and engagement

The DEVELOP-UK investigators were committed to ensuring appropriate public and patient engagement throughout the study.

The CF Trust was approached to provide patient and service user expertise in the design of the study. Oli Lewington, who has previously undergone lung transplantation, agreed to join the study team in order to help prepare the application for funding, and to contribute to the study design and to the writing of the Plain English summary. The chief investigator presented the study proposal to the board of directors of the trust, and the concept of the study to the annual public meeting of the CF Trust. Following award of the funding, Mr Lewington assisted in producing the participant documentation and the final study report.

Lay members were appointed to the Trial Steering Committee to regularly review study progress and to provide valuable public input into key decision-making during the study.

Study objectives

The DEVELOP-UK study is the first prospective multicentre study to be performed involving all of the adult cardiopulmonary transplant units across the UK. The objective was to assess the clinical effectiveness and cost-effectiveness of EVLP, a technology allowing objective assessment and reconditioning of unusable donor lungs, in increasing UK lung transplantation activity. Its strategic importance was recognised by the British Transplantation Society, the NHSBT, NHS specialist commissioners and by patient groups during the study design and funding application process.

The DEVELOP-UK study was designed as a non-randomised, non-inferiority observational study with an adaptive design, with two interim analyses planned for when one-third and two-thirds of total enrolment was reached. The planned interim analyses provided the opportunity to determine if the primary end point had been achieved, but also to calculate if any change in sample size was required. The original primary objective was to determine if the 12-month survival of recipients of ex vivo assessed and reconditioned donor lungs (EVLP intervention group) is non-inferior to 12-month survival in recipients of standard donor lungs (control group). The secondary objective was to measure key early clinical outcomes in recipients and changes in their HRQoL in the treatment and control groups in their first post-transplant year. These data were planned to be used in a within-study cost–utility analysis and a Markov model-based evaluation. The former comparison was to be a direct head-to-head comparison of outcomes over 12 months, and the latter was to model the change in availability of lungs as well as extrapolating over the expected lifetime of those needing a lung transplant. In addition, patients’ perceptions and understandings of EVLP-reconditioned donor lungs were evaluated in a qualitative substudy.

Timelines and targets

The official start date for the study was 1 January 2012 based on release of NIHR funds to the study team. To allow for local R&D approvals, research staff recruitment and subcontractor contracts with sites to be secured, a 3-month run-in period was proposed, anticipating that recruitment would have started in all sites by 1 April 2012. The actual start date of the study was therefore 1 April 2012. Study recruitment and enrolment was scheduled to run for 36 months, with data collection ending by 42 months, and the final study report was scheduled at 45 months in October 2015. The recruitment targets for the study were set based on official waiting list numbers across the UK in the five adult lung transplant centres. The aim was for a total of 600 patients from the lung transplant waiting list to consent to participate. As this was a non-randomised study, enrolment into the two arms of the study, as defined by undergoing lung transplantation (standard and EVLP transplant), occurred independently, and the study was powered on a predicted 3 : 1 (standard arm to EVLP arm) enrolment ratio. The target for enrolment as lung transplant recipients was 408 patients (306 in standard arm and 102 in EVLP arm).

Trial hypothesis

Had the study run to its planned duration in terms of recruitment, the tested hypothesis was to have been that survival during the first 12 months after transplantation in recipients of EVLP-assessed and -reconditioned donor lungs is non-inferior to that in recipients of standard donor lungs. The primary outcome measure was survival during the first 12 months after lung transplantation.

Consequences for the study analyses of the early closure of the study

The study was powered on survival during the first year post transplant and the target recruitment as 306 patients in the standard transplant arm and 102 in the EVLP transplant arm. This chapter reflects the analysis possible following the early closure of the study, with recruitment of patients stopping in early July 2014 on the advice of the Trial Steering Committee because of a combination of poor recruitment rates into the EVLP arm of the study, and also a safety signal from a higher than expected SAE rate resulting from the need for ECMO support in the EVLP arm. The analyses described below are appropriate to the achieved sample size and differ from that intended and described in the original protocol. The analysis to compare standard with EVLP transplant groups, as well as the analysis of overall survival of patients awaiting transplantation, are descriptive in nature and, as such, do not reflect the initial intention of testing for non-inferiority of EVLP to standard transplants. The originally planned interim analyses, intended to test for the possibility of stoping the study early if non-inferiority was achieved and to re-examine the sample size, did not take place, as the recruitment threshold to trigger the first of these (34 EVLP transplants) was never reached.

Planned timelines for study analysis

In light of the change of circumstances of the analysis, the intent has changed from one of conducting interim analyses to inform the continuation of the study while it was in progress, to one of a single main report of outcome data to the funder. The plan was that data should be available for this analysis from the end of May 2015. In practice, the collection and validation of data were delayed because of the large number of missing data and data queries to sites, meaning that the analysis started in October 2015 and continued into early 2016.

Longer-term analysis plans

It is important to recognise that, despite the early closure of the study, there remains a rich data set, particularly in respect of information on standard transplants and on the total cohort of donor lungs exposed to EVLP. Consideration of this alone was not part of the original comparative analysis plans and, as a result, this is outside the scope of the main study analysis.

Following completion of the main study analyses, and outside the scope of the report to the funder, it will be possible to consider further analysis of the data from the standard transplant arm. This did not form part of the trial statistical analysis plan, as it was not in scope of the originally planned study, but the information from this large contemporary cohort of 200 transplants, including extensive follow-up data, is likely to be useful to future study. Possible approaches include modelling of outcome variables using baseline clinical covariates to identify possible predictors of successful outcome at baseline.

In addition, a comprehensive sampling protocol was in place to collect perfusate, lung tissue and BAL from the donor lungs undergoing EVLP. This will provide a valuable assessment of events at a cellular and molecular level that can be correlated with clinical information within the main study data set. The work on the mechanistic understanding of EVLP falls outside this report (as it is not the subject of the NIHR HTA programme funding), but the tissue sample data will contribute to this subsequent analysis.

Recruitment

The study officially commenced on 1 January 2012, opened to recruitment on 1 April 2012, and closed to recruitment on 9 July 2014. There was a temporary halt in recruitment into the EVLP arm from 6 April 2013 until mid-July 2013, when the study activity in the EVLP arm recommenced with a modified protocol.

The timings for study recruitment in each individual site are shown in Table 1. The data analysed and presented in this report were downloaded from the MACRO database in October 2015. Additional data were assembled in Microsoft Excel^® 2010 (Microsoft Corporation, Redmond, WA, USA) files for some of the outcome measures (e.g. SF-36 and some lung function measurements) not recorded on CRFs, and for the donor characteristics, which were imported from the NHSBT database.

A total of 593 patients were screened (from records) for eligibility, of whom 98 did not meet eligibility criteria and a further eight declined to participate. Reasons for not meeting the eligibility criteria included age, need for pre-transplant cardiorespiratory support, and listed for heart–lung transplantation or transplantion of lungs and another organ. The screening failure rate was, therefore, only 16.1%, and the refusal rate for participation was just 1.3%.

A total of 487 patients consented to participate or completed an EOI form while on the transplant waiting list, of whom 19 were subsequently removed from the waiting list because of a change in their transplant eligibility, leaving 468 participants eligible to be included in the study. The breakdown of patients consented per participating site is shown in Table 2, and the rate at which patient consents were accrued is shown in Figure 4.

FIGURE 4.

Cumulative recruitment numbers across all five centres defined as signing EOI or consent forms.

By the end of the study, 158 participants remained on the waiting list for transplant; 74 had died while waiting, before transplant had occurred, and 34 were excluded after transplant as they did not reconfirm their consent, died before giving consent or were erroneously included after the recruitment cut-off date.

A total of 202 participants were included in the two transplant arms of the study, 184 in the standard transplant arm [60.1% of the target recruitment of 306, 95% confidence interval (CI) 55.4% to 65.7%] and 18 in the EVLP transplant arm (17.6% of target recruitment of 102, 95% CI 10.8% to 26.4%). A total of 53 EVLP assessments were performed, leading to the 18 transplants, giving a conversion rate of 34.0% (95% CI 26.6% to 42.0%). The transplant activity in the participating sites is shown in Table 3. It is the small number in the EVLP transplant arm that drives the need to restrict the comparative analysis to the use of descriptive statistics. A Consolidated Standards of Reporting Trials (CONSORT) diagram showing study activity is shown in Figure 5.

FIGURE 5.

The CONSORT diagram: withdrawals.

The main delay to commencing recruitment to the study resulted from obtaining NHS R&D approvals across the study sites, which equated to 31 centre-months lost.

Two groups of patients were approached: patients already on a transplant waiting list and patients added to the waiting list during the study. As a result, some patients signed an EOI form only, some signed both (an EOI form followed by a consent form during a subsequent routine visit to the transplant centre or on the day of transplant), and some signed only a consent form on the day of transplant, having received study information previously.

No patients requested to be withdrawn from the study after transplantation, and none was withdrawn by study staff on safety grounds. All withdrawals were due to changes in patients’ eligibility for lung transplantation or to issues with completion of all necessary consent documents.

Analysis groups

Patients were analysed in groups defined by the type of transplant received [i.e. standard (control) or EVLP (intervention)]. Allocation was not random, and it was not possible to switch between groups. All donors who provided lungs assessed by EVLP (n = 53) were included in the descriptive analyses described in Identifying clinical predictors of successful ex vivo lung perfusion reconditioning. Table 4 summarises the times at which the various data were collected for each patient.

Study population

Compliance

Seventeen protocol violations were reported in 15 separate patients (7.4% of the total of 202 patients consented and transplanted). Five were major and were due to patients being transplanted with donor lungs that did not fully meet protocol criteria for transplant after EVLP assessment and reconditioning. In all these cases the decision to proceed to transplant was made by the supervising transplant surgeon on the basis of the balance of risks to the patient.

Twelve violations were minor, including approaching patients to give consent for retrospective data collection post standard transplant even though they had not returned an EOI form; failure to obtain full informed consent as the wrong consent form was signed; failure to obtain reconsent to continue on the night of transplant; and, on nine occasions, a > 24-hour delay in the submission of a SAE to the clinical trials unit. Seven of the protocol violations (all minor) were in standard transplant patients, whereas 10 (five major and five minor) were in EVLP transplant patients.

Serious adverse events

There were 42 SAEs affecting 38 patients (16 patients in Newcastle, four patients in London, four patients in Manchester, 11 patients in Cambridge and three patients in Birmingham). Fifteen (35.7%) of these SAEs (affecting 12 patients) occurred in EVLP transplant patients. Details of the SAEs reported are shown in Table 7.

Of the 42 SAEs, 18 (42.9%) were a result of death within 90 days of transplant; 14 (77.8% of all fatal SAEs) of these were in standard transplant patients and four (22.2%) were in EVLP patients. Of the total of 42 SAEs, four of these events (9.5%) arising in four patients were judged to be possibly causally related to study procedures; all of these serious adverse reactions were initially considered by the site PI to be possibly unexpected AEs. However, after review by the chief investigator, it was decided that all were in fact events that could be expected to occur after lung transplantation, such as PGD or infection.

Activity in the EVLP arm was halted temporarily on 9 April 2013 for just over 3 months to allow an independent review of the early study outcomes as part of a due diligence process. Before this point, four out of eight transplant recipients in the EVLP arm required ECMO support post-operatively; following resumption of EVLP transplants with a revised protocol, 3 out of 10 transplant recipients required ECMO, but in all cases ECMO duration was limited, all patients were successfully weaned from ECMO, and all except one were successfully discharged from the ITU.

Outcomes analyses

The original intention was that the statistical analysis be conducted in a number of parts: first, a comparison of outcomes between recipients of standard and EVLP transplants to establish non-inferiority; and, second, modelling of the effect of EVLP transplants on the overall survival of patients accepted for lung transplantation in the UK, in order to assess the impact on the service. Furthermore, additional analyses were also to be undertaken to identify clinical predictors with respect to donor characteristics of successful EVLP reconditioning.

The early closure of the study and low numbers in the EVLP arm mean that the analysis methods originally described in the protocol are no longer appropriate. Consequently, the comparative analysis of standard and EVLP transplant groups, as well as the analysis of overall survival of patients awaiting transplantation, reported in Primary outcome analysis, are descriptive in nature and, as such, do not reflect the initial intention of testing for non-inferiority of EVLP to standard transplants.

Missing data

From clinical experience of this patient group, it had not been anticipated that there would be significant numbers of dropouts or loss to follow-up of patients with respect to the primary outcome measure. Loss to follow-up or missing data on the secondary outcome measures was assessed but, because of the low numbers in the EVLP group, no imputation was performed for any outcome data. However, a significant number of data were missing because they were not collected at the study sites. Most sites worked very hard to keep data collection as complete as possible, but in one site the proportion of missing data was > 20%. The missing data included, but were not limited to, SF-36 questionnaires, detail from outpatient follow-up visits and some information collected during the EVLP procedure.

Primary outcome analysis

Survival in the 12 months following transplantation

The primary outcome of survival in the first 12 months post transplantation was compared in the EVLP and standard transplant groups. Figure 6 shows the Kaplan–Meier plot of the survival (in days) during the first 12 months post transplantation, split by study group. This analysis takes account of censoring; specifically, one patient (in the standard arm) emigrated during the follow-up, and has been included in the analysis up to the time of the last visit (at 30 days post transplantation).

FIGURE 6.

Kaplan–Meier survival estimates post transplantation, by study group.

The numbers of patients who died, survived or were censored during the 12-month follow-up are shown in Table 8. The median follow-up was 365 days for both the EVLP and standard transplant groups.

TABLE 8 - Numbers of patients who died, survived or were censored during the first 12 months following transplantation

Study group	Died	Survived	Censored	Total
EVLP	6	12	0	18
Hybrid protocol	4	4	0	8
Lund protocol	2	8	0	10
Standard	36	147	1	184
Total of standard and EVLP groups	42	159	1	202

The Kaplan–Meier estimate of survival at 12 months was 0.67 (95% CI 0.40 to 0.83) for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. Based on Cox regression, the hazard ratio for all-cause mortality in the EVLP arm relative to the standard arm over the 12-month follow-up was 1.96 (95% CI 0.83 to 4.67). This equates to roughly a doubling of the risk of death in the EVLP arm relative to the standard arm, although with a wide CI that encompasses the possibility that mortality might be lower in the EVLP arm than in the standard arm. The width of this CI is influenced greatly by the small number of patients who received an EVLP transplant.

Of the 18 patients who received an EVLP transplant, eight received a transplant based on the hybrid protocol, and 10 received a transplant based on the Lund protocol (see Table 8). Survival was then assessed by considering the EVLP protocol groups separately, and Figure 7 shows the Kaplan–Meier plot of survival separately for patients in the standard, EVLP-Lund and EVLP-hybrid groups.

FIGURE 7.

Kaplan–Meier survival estimates post transplantation for the standard, EVLP-hybrid and EVLP-Lund study groups.

The Kaplan–Meier estimate of survival at 12 months was 0.80 (95% CI 0.41 to 0.95) for the Lund protocol patients and 0.50 (85% CI 0.15 to 0.77) for the hybrid protocol patients. Based on Cox regression, the hazard ratio for all-cause mortality in the EVLP-hybrid group relative to the EVLP-Lund group over the 12-month follow-up was 2.92 (95% CI 0.53 to 15.95). This wide CI reflects the small numbers of patients in these two EVLP protocol groups.

Secondary outcome measures

Primary graft dysfunction

Primary graft dysfunction is the clinical syndrome of chest radiographic changes and poor oxygenation that represents early acute injury to the transplanted lung. The PGD scores used in the study were as defined in the ISHLT consensus definition. 39 The distribution of the PGD score by study group, measured at baseline and 24, 48 and 72 hours after the transplant, is shown in Table 11. A score of 0 represents no evidence of PGD and a score of 3 represents the most severe form of PGD.

TABLE 11 - Primary graft dysfunction score by trial arm and time since transplant

Note

Excluding patients with missing data.

Score	Time point
	Baseline		24 hours		48 hours		72 hours
	EVLP, n (%)	Standard, n (%)	EVLP, n (%)	Standard, n (%)	EVLP, n (%)	Standard, n (%)	EVLP, n (%)	Standard, n (%)
Grade 0	1 (5.6)	42 (26.4)	1 (5.6)	43 (27.4)	1 (5.6)	34 (22.5)	1 (5.6)	34 (23.9)
Grade 1	0 (0)	27 (17.0)	3 (16.7)	43 (27.4)	7 (38.9)	51 (33.8)	7 (38.9)	52 (36.6)
Grade 2	1 (5.6)	42 (26.4)	6 (33.3)	43 (27.4)	3 (16.7)	33 (21.9)	5 (27.8)	24 (16.9)
Grade 3	16 (88.9)	48 (30.2)	8 (44.4)	28 (17.8)	7 (38.9)	33 (21.9)	5 (27.8)	32 (22.5)
Total	18	159	18	157	18	151	18	142

The same information, but with the results for grades 0 and 1 combined, is shown in graph format in Figure 8. The percentage of patients with PGD grade 3 at baseline was much higher in the EVLP group than in the standard group (88.9% vs. 30.2%). However, this difference narrowed as time passed, with 27.8% of patients in the EVLP group and 22.5% of those receiving a standard transplant having PGD grade 3 at 72 hours after transplant. Nevertheless, the percentages of patients with grade 0 remained fairly static over time and were higher in the standard group than in the EVLP group (22.5–27.4% and 5.6%, respectively).

FIGURE 8.

Primary graft dysfunction score by trial arm and time since transplant.

Post-operative infection

The number of patients with at least one post-operative infection, both at baseline and during subsequent follow-up periods, is shown in Table 13. The associated percentages are displayed graphically in Figure 9. At baseline, just under half of patients in both the EVLP group and the standard group had at least one post-operative infection. In both groups, the percentage of patients with at least one post-operative infection dropped subsequently, as shown in Figure 6. This percentage tended to be lower in the EVLP group than in the standard group. However, inferences are limited by the small numbers of patients with infections in the EVLP group.

TABLE 13 - Numbers of patients with at least one post-operative infection, at baseline and during subsequent periods

Notes

Percentages are given relative to the total.

The number at risk is based on those at risk at the start of the relevant period.

Category	Time period
	Baseline, n (%)		Baseline–1 month, n (%)		1–3 months, n (%)		3–6 months, n (%)		6–12 months, n (%)
	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard
Number of patients with at least one episode	7 (46.7)	81 (45.5)	2 (15.4)	37 (23.9)	2 (15.4)	38 (21.5)	3 (23.1)	38 (24.5)	2 (18.2)	39 (29.1)
Number at risk	18	184	18	184	17	178	14	172	13	165

FIGURE 9.

Percentage of patients with at least one post-operative infection, at baseline and during subsequent periods, by study group. Note that the number at risk is based on those at risk at the start of the relevant period.

The number of episodes and number of organisms involved in specific post-operative infections are detailed in Table 14. The most common organisms involved were Pseudomonas, Staphylococcus, Escherichia coli and Candida species. Owing to small numbers, it is difficult to compare any differences in the spectra of infections in the EVLP and standard groups.

TABLE 14 - Numbers of episodes and organisms involved in specific post-operative infections, at baseline and during subsequent follow-up periods

Notes

Percentages are given relative to the total number of organisms. Each episode may have involved more than one organism. Patients may have had more than one episode. Anastomotic complications.

Organism	Time period
	Baseline, n (%)		Baseline–1 month, n (%)		1–3 months, n (%)		3–6 months, n (%)		6–12 months, n (%)
	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard
Pseudomonas	5 (29.4)	19 (12.8)	1 (33.3)	6 (15.0)	1 (50.0)	4 (7.7)	0 (0)	5 (12.2)	0 (0)	5 (11.1)
Staphylococcus	4 (23.5)	27 (18.1)	0 (0)	6 (15.0)	0 (0)	3 (5.8)	0 (0)	2 (4.9)	0 (0)	2 (4.4)
Coliforms	0 (0)	7 (4.7)	0 (0)	1 (2.5)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Escherichia coli	1 (5.9)	11 (7.4)	1 (33.3)	0 (0)	0 (0)	1 (1.9)	0 (0)	1 (2.4)	0 (0)	1 (2.2)
Clostridium difficile	0 (0)	4 (2.7)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Klebsiella	0 (0)	5 (3.4)	0 (0)	1 (2.5)	0 (0)	1 (1.9)	2 (50.0)	2 (4.9)	0 (0)	1 (2.2)
Haemophilus	1 (5.9)	5 (3.4)	0 (0)	1 (2.5)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Aspergillus	0 (0)	5 (3.4)	0 (0)	2 (5.0)	0 (0)	3 (5.8)	0 (0)	2 (4.9)	1 (25.0)	5 (11.1)
Candida	1 (5.9)	14 (9.4)	0 (0)	2 (5.0)	0 (0)	3 (5.8)	0 (0)	0 (0)	0 (0)	1 (2.2)
Influenza virus	1 (5.9)	1 (0.7)	0 (0)	1 (2.5)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	2 (4.4)
Adenovirus	0 (0)	1 (0.7)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Rhinovirus	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	3 (5.8)	0 (0)	0 (0)	1 (25.0)	0 (0)
Herpesvirus	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (2.4)	0 (0)	3 (6.7)
Streptococcus	0 (0)	2 (1.3)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Mycobacterium	0 (0)	1 (0.7)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Scedosporium	0 (0)	1 (0.7)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Stenotrophomonas	1 (5.9)	1 (0.7)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	2 (4.4)
Other specified	3 (17.6)	34 (22.8)	1 (33.3)	12 (30.0)	0 (0)	21 (40.4)	1 (25.0)	14 (34.1)	1 (25.0)	10 (22.2)
Organism not specified	0 (0)	11 (7.4)	0 (0)	8 (20.0)	1 (50.0)	13 (25.0)	1 (25.0)	14 (34.1)	1 (25.0)	13 (28.9)
Total number of organisms	17	149	3	40	2	52	4	41	4	45
Total number of episodes	16	144	3	38	2	52	4	41	4	44

It is recognised that ischaemic injury to the donor lung could adversely affect the bronchus and lead to bronchial complications. It was therefore important to consider if there was any difference in rates of anastomotic complications between the study groups. In Table 15, the numbers of patients with anastomotic complications are presented by study group and time since transplant. None of the patients in the EVLP group had such complications at any of the follow-up times. In the standard group, the percentage of patients with these complications varied between 4.4% and 9.6% over the follow-up period.

TABLE 15 - Numbers of patients with anastomotic complications, by study group and time since transplant

Note

Percentages are given relative to the total.

Category	Time period
	Baseline–1 month, n (%)		1–3 months, n (%)		3–6 months, n (%)		6–12 months, n (%)
	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard
Number of patients with anastomotic complications	0 (0)	12 (6.7)	0 (0)	7 (4.4)	0 (0)	12 (8.0)	0 (0)	14 (9.6)
Total	18	179	14	160	13	150	12	146
Number at risk	18	184	17	178	14	172	13	165

The Couraud Classification of anastomotic healing provides a means to quantify the degree of healing that may be an indicator of low-level ischaemic injury. 40 These scores are presented numerically by study group and time since transplant in Table 16, and as percentages in graphical format in Figure 10. Among both EVLP and standard transplant patients, the percentage with grade 1 healing tended to increase over the period of the follow-up, from around 40% between baseline and 1 month to just over 80% between 6 and 12 months. Over the same period, the percentage of patients with grade 2 healing decreased, from around 50% between baseline and 1 month to roughly 16% between 6 and 12 months.

TABLE 16 - Anastomotic healing among patients (based on the Couraud Classification), by study group and time since transplant

Note

Percentages are given relative to the total.

Score	Time period
	Baseline–1 month, n (%)		1–3 months, n (%)		3–6 months, n (%)		6–12 months, n (%)
	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard
Grade 1	4 (36.4)	38 (41.3)	2 (25.0)	51 (47.2)	6 (85.7)	68 (68.7)	5 (83.3)	67 (82.7)
Grade 2A	5 (45.5)	30 (32.6)	6 (75.0)	39 (36.1)	1 (14.3)	24 (24.2)	1 (16.7)	12 (14.8)
Grade 2B	1 (9.1)	17 (18.5)	0 (0)	13 (12.0)	0 (0)	2 (2.0)	0 (0)	1 (1.2)
Grade 3A	1 (9.1)	4 (4.3)	0 (0)	4 (3.7)	0 (0)	5 (5.1)	0 (0)	1 (1.2)
Grade 3B	0 (0)	3 (3.3)	0 (0)	1 (0.9)	0 (0)	0 (0)	0 (0)	0 (0)
Total	11	92	8	108	7	99	6	81
Number at risk	18	184	17	178	14	172	13	165

FIGURE 10.

Anastomotic healing among patients (based on the Couraud Classification), by study group and time since transplant.

Lung function measurements

Measurement of FEV₁ in both absolute volume in litres and as a percentage of the patient’s predicted values based on age, sex, height and measurement of forced vital capacity (FVC) in litres is routinely performed as part of post-lung transplant follow-up. This information is presented in Table 17 and also displayed in box plots in Figures 11–13. Each of these measures tended to increase with increasing length of follow-up. In addition, median values for the EVLP and standard transplant groups were generally similar.

TABLE 17 - Lung function measurements by study group and time since transplant

Number from which data are available.

Range: minimum–maximum.

Lung function parameter	Time point
	1 month		3 months		6 months		12 months
	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard
Number at risk	17	178	14	172	13	165	12	147
FEV1
na	10	124	13	150	13	149	11	129
Median (l)	2.26	2.07	2.26	2.29	2.53	2.38	2.82	2.44
IQR (l)	1.87–3.15	1.68–2.60	1.89–2.68	1.79–2.70	2.23–3.65	1.85–2.83	2.12–3.37	1.95–2.93
Rangeb (l)	1.54–3.89	0.77–3.85	1.17–4.46	0.80–4.53	1.53–4.83	0.74–4.75	1.88–4.30	0.78–4.90
FEV1
na	9	111	12	138	13	129	9	116
Median (% predicted)	58	69	71	71	85	78	93	77.5
IQR (% predicted)	45–74	55–81	51–84	57–87	65–106	63–91	62–97	65.5–91.5
Rangeb (% predicted)	44–97	25–100	34–131	29–135	44–142	23–143	51–99	30–143
FVC
na	10	123	13	150	12	149	11	128
Median (l)	2.70	2.49	2.80	2.70	3.23	3.03	3.35	3.53
IQR (l)	2.60–3.15	1.91–3.08	2.48–3.71	2.25–3.27	2.67–4.28	2.41–3.60	2.66–3.89	2.75–4.34
Rangeb (l)	1.90–4.10	1.16–4.80	1.82–4.53	0.92–5.35	1.82–5.88	0.85–5.84	1.98–5.56	1.14–5.96

FIGURE 11.

Box plot of FEV₁ by time since transplant.

FIGURE 12.

Box plot of FEV₁% by time since transplant.

FIGURE 13.

Box plot of FVC by time since transplant.

Abnormalities on chest radiographs

The number of patients with abnormalities on chest radiographs, both at baseline and at subsequent follow-up visits over the 12 months after transplant, is shown in Table 18. The associated percentages are also displayed graphically in Figure 14. These percentages were lower at 6 and 12 months than at earlier times. There is also some suggestion that abnormalities were slightly less common in the EVLP group than in the standard group, although inferences are limited because of the small numbers of EVLP patients with abnormalities.

TABLE 18 - Numbers of patients with abnormalities on chest radiographs, by study group and time since transplant

Note

Percentages are given relative to the total.

Category	Time point
	Baseline, n (%)		1 month, n (%)		3 months, n (%)		6 months, n (%)		12 months, n (%)
	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard
Number of patients with abnormality on chest radiographs	7 (46.7)	105 (61.8)	7 (53.8)	96 (60.0)	7 (58.3)	66 (42.9)	2 (18.2)	48 (33.3)	2 (22.2)	28 (24.6)
Total	15	170	13	160	12	154	11	144	9	114
Number at risk	18	184	17	178	14	172	13	165	12	147

FIGURE 14.

Percentage of patients with abnormalities on chest radiographs, by study group and time since transplant.

The nature of the specific abnormalities on chest radiographs is shown in Table 19. Overall, effusion was the most common abnormality, followed by pneumothorax, consolidation, atelectasis and shadowing. Owing to the small numbers in EVLP group, it is not possible to compare the spectra of abnormalities between the EVLP and standard groups.

TABLE 19 - Numbers of specific abnormalities on chest radiographs, by study group and time since transplant

Notes

Percentages are expressed relative to the total number of abnormalities.

Acute rejection and associated alloimmune injury.

Type of abnormality	Time point
	Baseline, n (%)		1 month, n (%)		3 months, n (%)		6 months, n (%)		12 months, n (%)
	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard
Pneumothorax	0 (0)	21 (15.9)	1 (8.3)	12 (9.3)	0 (0)	6 (9.0)	0 (0)	3 (6.7)	0 (0)	2 (6.9)
Effusion	3 (37.5)	55 (41.7)	4 (33.3)	57 (44.2)	4 (50.0)	29 (43.3)	1 (100.0)	15 (33.3)	1 (50.0)	7 (24.1)
Consolidation	3 (37.5)	20 (15.2)	3 (25.0)	22 (17.1)	0 (0)	3 (4.5)	0 (0)	4 (8.9)	0 (0)	3 (10.3)
Atelectasis	1 (12.5)	16 (12.1)	2 (16.7)	17 (13.2)	3 (37.5)	9 (13.4)	0 (0)	8 (17.8)	1 (50.0)	7 (24.1)
Collection	0 (0)	5 (3.8)	1 (8.3)	4 (3.1)	0 (0)	2 (3.0)	0 (0)	0 (0)	0 (0)	0 (0)
Shadowing	0 (0)	13 (9.8)	1 (8.3)	16 (12.4)	1 (12.5)	12 (17.9)	0 (0)	11 (24.4)	0 (0)	5 (17.2)
Elevated hemidiaphragm	1 (12.5)	0 (0)	0 (0)	0 (0)	0 (0)	4 (6.0)	0 (0)	3 (6.7)	0 (0)	1 (3.4)
No valid description	0 (0)	2 (1.5)	0 (0)	1 (0.8)	0 (0)	2 (3.0)	0 (0)	1 (2.2)	0 (0)	4 (13.8)
Total number of abnormalities	8	132	12	129	8	67	1	45	2	29

The number of episodes of allograft alloimmune injury was collected in both study groups. Data on acute vascular rejection by ISHLT score, presence of antibody-mediated rejection and lymphocytic bronchiolitis are presented in Table 20 as numbers of rejection episodes by rejection type, study group and time period. Overall, these episodes were less frequent > 3 months after transplant than at earlier times. This decrease was particularly notable for A2+ episodes. The percentage of patients with at least one rejection episode was generally similar for the EVLP and standard groups.

TABLE 20 - Number of rejection episodes by rejection type, study group and time period

The percentage of patients with at least one rejection episode is given relative to the number of patients at risk.

Based on those at risk at the start of the period.

Note

Precentages are expressed relative to the total number of episodes.

Category	Time period
	Baseline–1 month, n (%)		1–3 months, n (%)		3–6 months, n (%)		6–12 months, n (%)
	EVLP	Standard	EVLP	Standard	EVLP	Standard	EVLP	Standard
A1	0 (0)	11 (22.9)	1 (16.7)	13 (26.5)	0 (0)	5 (19.2)	0 (0)	12 (57.1)
A2+	4 (100.0)	30 (62.5)	4 (66.7)	25 (51.0)	1 (50.0)	11 (42.3)	1 (50.0)	8 (38.1)
Antibody-mediated rejection	0 (0)	0 (0)	0 (0)	1 (2.0)	0 (0)	0 (0)	0 (0)	0 (0)
Clinical rejection without biopsy	0 (0)	1 (2.1)	0 (0)	2 (4.1)	0 (0)	0 (0)	0 (0)	0 (0)
Lymphocytic bronchiolitis	0 (0)	1 (2.1)	0 (0)	2 (4.1)	0 (0)	1 (3.8)	0 (0)	0 (0)
Not classified	0 (0)	5 (10.4)	1 (16.7)	6 (12.2)	1 (50.0)	9 (34.6)	1 (50.0)	1 (4.8)
Total number of episodes	4	48	6	49	2	26	2	21
Number of patients with at least one rejection episodea	4 (22.2)	48 (26.1)	6 (35.3)	46 (27.0)	2 (14.3)	26 (15.1)	2 (15.4)	20 (12.1)
Number of patients at riskb	18	184	17	178	14	172	13	165

Short Form questionnaire-36 items data analysis

The SF-36 questionnaires were completed while the recipients were still on the waiting list, as well as at 3 and 12 months post transplant, and their mean scores were converted into health-state utilities using the SF-6D algorithm48 described in Chapter 4. In the SF-36 data analysis, the mean (SD) and median (IQR) score for each of the eight domain scores were estimated for each one of the two study groups and for each time point. The SF-36 data were also used to estimate the mean, SD, median and IQR for MCS and PCS scores by study group. No hypothesis testing or modelling was undertaken and no imputation was performed other than that which forms part of the standard scoring system for the SF-36.

The SF-36 data, available at each time point of the study, as well as the number of participants with missing data for both the standard and EVLP trial arms, are summarised in Table 21. A significant number of participants did not complete the SF-36 at each of the three time points identified in the study protocol. The absolute number of patients for whom SF-36 data were collected at different stages of the study is shown in Table 22.

TABLE 21 - Number of SF-36 measurements at each time point of the study and by study group

To aid interpretation, six participants in the EVLP arm did not complete the SF-36 at any data collection time points and eight completed the questionnaire while on the waiting list.

Time point	Study group		Total, n (%)
	EVLP, n (%)a	Standard, n (%)
Waiting list	8 (38.1)	67 (40.1)	75 (39.9)
3 months post transplant	7 (33.3)	52 (31.1)	59 (31.4)
12 months post transplant	6 (28.6)	48 (28.7)	54 (28.7)
Total number of measurements	21	167	188
Number of patients with no SF-36 data	6	83	89

TABLE 22 - Numbers of patients with SF-36 data available for each stage of the study

Percentages are given relative to the number of patients at risk at the latest of the times considered.

Category	Time point
	Baseline	3 months	12 months	Baseline and 3 months	Baseline and 12 months	3 and 12 months	Baseline, 3 and 12 months
EVLP
Number of patients (%)a	8 (44.4)	7 (50.0)	6 (50.0)	4 (28.6)	2 (16.7)	4 (33.3)	1 (8.3)
Number at risk	18	14	12	14	12	12	12
Standard
Number of patients (%)	67 (36.4)	52 (30.2)	48 (32.7)	31 (18.0)	27 (18.4)	26 (17.7)	18 (12.2)
Number at risk	184	172	147	172	147	147	147
Total
Number of patients (%)	75 (37.1)	59 (31.7)	54 (34.0)	35 (18.8)	29 (18.2)	30 (18.9)	19 (11.9)
Number at risk	202	186	159	186	159	159	159

The detailed scores of the SF-36 questionnaires are presented in Tables 23 and 24. The mean, SD, median, IQR and range of the eight domain scores and the two summary scores, respectively, at each data collection point for each of the two transplant procedures are presented. These two tables also report the number of responses at each time point, together with the number of patients at risk (i.e. the number that would have been eligible to complete the SF-36).

TABLE 23 - Short Form questionnaire-36 items domain scores at each data collection point of the study, by study group

Domain	Study group
	Standard			EVLP
	Baseline (n = 67)	3 months (n = 52)	12 months (n = 48)	Baseline (n = 8)	3 months (n = 7)	12 months (n = 6)
Number at risk	184	172	147	18	14	12
Bodily pain
Median (IQR)	46.68 (38.21–55.55)	49.10 (40.63–55.55)	55.55 (46.68–62.00)	53.53 (46.68–62.00)	51.51 (51.51–62.00)	62.00 (55.55–62.00)
95% CI	42.61 to 48.36	45.35 to 51.00	48.55 to 54.85	43.02 to 61.22	42.29 to 61.89	56.36 to 63.35
General health
Median (IQR)	23.71 (21.33–30.84)	48.43 (38.92–55.56)	48.43 (42.02–55.56)	28.46 (22.52–29.65)	57.94 (50.81–62.70)	55.56 (54.61–55.56)
95% CI	24.41 to 28.25	43.87 to 49.67	45.19 to 51.28	22.95 to 32.19	52.62 to 62.60	50.53 to 62.02
General mental health
Median (IQR)	45.64 (37.79–53.48)	53.48 (44.33–58.72)	53.48 (45.64–58.72)	44.33 (41.71–49.56)	58.72 (53.48–61.33)	60.03 (53.48–63.95)
95% CI	42.06 to 47.33	48.38 to 54.07	50.81 to 55.40	39.18 to 50.13	54.35 to 61.59	48.95 to 65.87
Physical functioning
Median (IQR)	23.09 (19.26–26.92)	46.06 (37.45–51.80)	46.06 (34.58–53.71)	24.05 (22.14–31.71)	53.71 (46.06–57.54)	48.93 (46.06–55.63)
95% CI	23.57 to 27.18	40.55 to 46.71	40.65 to 47.25	20.91 to 31.97	46.72 to 57.42	31.41 to 60.71
Role limitations owing to emotional health
Median (IQR)	38.76 (28.31–56.17)	56.17 (35.28–56.17)	56.17 (43.98–56.17)	40.50 (35.28–54.43)	56.17 (49.20–56.17)	54.43 (49.20–56.17)
95% CI	36.46 to 43.66	42.30 to 49.82	45.66 to 52.02	30.87 to 52.75	49.64 to 57.72	36.34 to 62.07
Role limitations owing to physical health
Median (IQR)	25.72 (21.23–32.46)	43.68 (33.58–52.66)	47.05 (35.83–54.91)	30.21 (25.72–39.20)	57.16 (41.44–57.16)	49.30 (41.44–57.16)
95% CI	25.87 to 29.79	39.06 to 45.37	41.79 to 48.01	24.62 to 40.29	42.65 to 58.19	31.79 to 60.07
Social functioning
Median (IQR)	27.26 (22.25–37.29)	52.33 (37.29–57.34)	47.31 (39.80–57.34)	37.29 (24.76–39.80)	57.34 (52.33–57.34)	52.33 (47.31–57.34)
95% CI	27.83 to 33.73	43.24 to 50.04	44.77 to 50.48	25.00 to 40.80	50.83 to 58.12	33.87 to 62.43
Vitality
Median (IQR)	31.80 (28.83–40.72)	55.57 (40.72–61.51)	52.60 (46.66–58.54)	36.26 (34.77–42.20)	55.57 (46.66–61.51)	60.03 (55.57–70.42)
95% CI	32.29 to 36.37	48.25 to 55.23	49.67 to 55.28	31.29 to 44.94	48.16 to 63.83	41.45 to 73.65

TABLE 24 - Short Form questionnaire-36 items measurements by study group at each time point

Time and category	Number at risk	Number of patients measured in group	Minimum	Maximum	Median	IQR	95% CI
Baseline
EVLP	18
SF-36 MCS		8	31.49	57.42	43.46	41.49–47.31	37.96 to 50.40
SF-36 PCS		8	22.70	45.68	29.50	24.98–37.19	24.55 to 38.38
Standard	184
SF-36 MCS		67	18.93	69.36	40.96	33.73–54.05	40.52 to 46.40
SF-36 PCS		67	13.19	51.12	27.61	22.30–30.94	25.39 to 29.02
3 months
EVLP	14
SF-36 MCS		7	50.05	59.45	58.18	57.30–59.43	54.21 to 60.25
SF-36 PCS		7	41.16	59.50	48.68	47.17–59.19	44.92 to 57.60
Standard	172
SF-36 MCS		52	23.58	65.62	55.70	42.4–60.08	47.73 to 54.35
SF-36 PCS		52	25.82	59.45	45.47	38.36–50.07	41.22 to 46.26
12 months
EVLP	12
SF-36 MCS		6	33.32	62.80	58.96	53.06–62.19	43.19 to 66.57
SF-36 PCS		6	34.56	59.91	52.41	46.39–56.37	40.94 to 59.74
Standard	147
SF-36 MCS		48	33.79	68.47	54.92	45.79–59.51	50.24 to 55.42
SF-36 PCS		48	24.22	60.40	47.69	36.18–54.08	42.47 to 48.27

The results show a general increase in the mean scores of the eight SF-36 domains from baseline to 12 months post transplant (see Table 23). The two domains that show the biggest increase in their scores are general health and vitality. Furthermore, although the physical functioning, role limitations owing to physical health and social functioning domains appear to show the same increase after 3 and 12 months from the day of the surgery in the standard arm of the study, they appear to increase at 3 months and then decrease at 12 months for the EVLP arm. The data are, however, too few for the relevance of this change to be sensibly interpreted. Similarly, the same pattern is seen for the general mental health and role limitations owing to emotional health dimensions. For the bodily pain domain there was a slight drop, on average, at 3 months and then an increase at 12 months for the EVLP arm. Nevertheless, the fact that few data are available for these three domains means that further interpretation must be done with caution.

The values of both the SF-36 summary measures, namely MCS and PCS, increase after transplant no matter which transplant procedure was performed. These data are presented in Table 24, and graphically in the box plots in Figures 15 and 16. In other words, the HRQoL of the patients improves throughout the follow-up of the lung recipients. In the standard procedure, the mean MCS score of the lung recipients increases from 43.5 at baseline to 51.0 at 3 months post transplant and 52.8 at 12 months post transplant, whereas the mean PCS score increases from 27.2 at baseline to 43.7 and 45.4 at 3 and 12 months, respectively. As far as the EVLP group is concerned, the mean MCS score changes from 44.2 at baseline to 57.2 at 3 months post transplant and 54.9 at 12 months post transplant, whereas the mean PCS score increases from 31.5 to 51.3 at 3 months after the transplant and drops slightly to 50.3 at 12 months’ follow-up. This slight decrease in the mean 12-month MCS and PCS scores in the EVLP arm of the study is consistent with the decrease in the scores for most of the eight domains at this time point. As mentioned above, any results regarding the effectiveness of the EVLP based on these scores given would not be reliable because of the very limited number of data available.

FIGURE 15.

Box plot of SF-36 MCS scores, by study group and time point.

FIGURE 16.

Box plot of SF-36 PCS scores, by study group and time point.

Examining the effect of ex vivo lung perfusion on the overall survival of patients awaiting transplantation

To capture the effects that an increased availability of donor organs due to EVLP might have on the survival of patients awaiting lung transplantation, waiting time in each of the two treatment groups was compared, and then waiting time in each group was compared with survival of those remaining on the waiting list. Waiting time is defined as the time from the date the participant is placed on the waiting list until the date transplant is performed. The waiting times until transplantation in the two study groups is shown in Table 25.

The median waiting time for standard transplant was 197 days (IQR 95–373 days), whereas the median waiting time for a transplant using an EVLP donor was 142 days (IQR 60–199 days), as shown in Table 25. There was a median difference of 55 days between transplant groups, showing a reduction in waiting time if having a transplant using an EVLP-assessed donor organ. This is also illustrated by Figure 17, which shows a maximum waiting time of 551 days for transplant using a EVLP donor compared with a maximum waiting time of 2143 days for a standard transplant. A log-rank test for difference in waiting times between transplant type using the Kaplan–Meier estimates gave a p-value of 0.042, which shows a significant difference in waiting times between the two groups. However, these findings should be interpreted with caution, in view of the small numbers of patients in the EVLP group.

FIGURE 17.

Kaplan–Meier graph of waiting time until transplant by transplant type (each event in this graph indicates a transplant performed).

Survival from listing

To assess overall survival between transplant groups and those remaining on the waiting list, the time from being placed on the waiting list until 12 months post transplant or 1 May 2015, with censoring for death or loss to follow-up, is presented in Table 26. Waiting list dates were collated for all participants during recruitment to the study; however, for those remaining on the waiting list, some of this information was not collated. For these participants, waiting list dates were obtained from the NHSBT registry.

TABLE 26 - Summary of survival time from listing

Group	Survival time (days)
	Mean	SD	Media	IQR	Minimum	Maximum
Standard (n = 184)	631	362	536	429–703	46	2508
EVLP (n = 18)	453	197	479	412–543	73	916
No transplant (n = 212)	621	438	543	324–830	18	2867
Total (N = 414)	618	399	535	394–741	18	2867

For the purpose of this analysis, 1 May 2015 was chosen as the end date for those who did not have a transplant, since this is approximately 12 months after the last transplant was performed. Of the 232 participants remaining on the waiting list, 20 have been excluded from the analysis. Thirteen were excluded because they were recruited to another study in which they had a transplant, four were excluded because they no longer wanted to be part of the study and three were excluded because there is no record of the date they were removed from the waiting list. Thirty-nine participants who were included in the analysis have been censored: 11 of these were censored by the date they were removed from the waiting list or were lost to follow-up and 28 were censored by the date on which they had a transplant outside of this trial. There were 41 participants for whom we had been unable to confirm their status as of 1 May 2015. Since we have not received information regarding their death (which we would have expected), we have assumed these participants remained on the waiting list on 1 May 2015.

The Kaplan–Meier estimates of survival from being placed on the transplant list to transplant or death/censoring are shown in Figure 18 for the three study groups. The median survival time from listing was 536 days (IQR 429–703 days), 479 days (IQR 412–543 days) and 543 days (IQR 324–830 days) for standard transplant, EVLP transplant and waiting list groups, respectively (see Table 26). The log-rank test of difference in survival times was significant (p = 0.007), implying that those having a standard lung transplant had better survival than those who remained on the waiting list and those having an EVLP transplant. However, these findings should be interpreted with caution in view of possible selection bias and the small number of patients in the EVLP group.

FIGURE 18.

Kaplan–Meier graph of survival time from being placed on the transplant waiting list.

Identifying clinical predictors of successful ex vivo lung perfusion reconditioning

Between 1 April 2012 and 9 July 2014, lungs from 53 UK multiorgan donors were identified as unsuitable for immediate standard transplantation despite extensive donor management. These donors all satisfied the strict entry criteria for inclusion in the EVLP arm of the study (Boxes 1 and 2).

Of these 53 donors, 35 died from spontaneous intracranial haemorrhage (66%), eight from hypoxic brain injury (15%), five from traumatic brain injury (9%), three from thrombotic stroke (6%), one from an expansive brain tumour (2%) and one from meningitis (2%). The donor lungs were procured in a routine fashion and transported on ice to the accepting institution. A total of 27 (51%) were assessed in Newcastle, nine in Harefield (17%), seven in Manchester (13%), six in Birmingham (11%) and four in Papworth (8%). Fourteen donor lungs were from donors without a circulation (DCD) (Maastricht category III, 26%) and 39 were from brain-dead donors (DBD) (Maastricht category IV, 74%). The EVLP assessments were evenly distributed between donor sexes [26 female (49%) and 27 male (51%)] and the median donor age was 50 years (range 16–65 years). If one lung did not meet entry criteria and was deemed unusable because of severe consolidation or extensive contusion on inspection, or if the intended recipient was for a specific side (i.e. single-lung transplant), only one lung was procured. Fifty lungs (94%) were perfused as double lungs and three (6%) as singles (two right lungs and one left lung). They were assessed for a median time of 175 minutes (range 73–383 minutes) while being normothermically perfused on the Vivoline LS1 EVLP circuit.

The study protocol allowed for lungs that satisfied certain criteria, as outlined in Box 1, to be assessed using EVLP. The primary indications for EVLP assessment were grouped into three general categories: 35 donor lungs (66%) were found unsuitable for standard transplantation because of poor lung function with an optimised donor ratio of arterial partial pressure of oxygen (PaO₂) – shown throughout the report as kPa (mmHg) – to FiO₂ < 40 (300) and/or a selective pulmonary vein gas < 30 (225) with a FiO₂ of 1.0 (100%) at procurement; 13 lungs (25%) were turned down as a result of abnormalities during inspection (pulmonary oedema, abnormal bronchoscopy, extensive atelectasis, etc.); and three lungs (6%) were turned down for standard transplantation for logistical reasons. Some lungs were excluded from EVLP as they had absolute contraindications to transplant (see Box 2).

Of the donor lungs turned down for logistic purposes, two had a suspicious mass in need of urgent histological evaluation before a decision on transplant was made. One was revealed to be cancerous and the lungs were discarded after an otherwise successful EVLP perfusion, and the other was confirmed benign and the lungs were transplanted. In one case, no theatre team was available as they had just started another transplantation. In this case, the lungs also remained stable or improved measurable physiological parameters during preservation on the EVLP circuit, but were in the end turned down for transplantation because of deteriorating oedema formation on inspection.

Of the 53 donors, 24 (45%) were current smokers, 18 (34%) had abnormal chest radiographs at the time of procurement and 22 (42%) had airway secretions deemed prohibitive of standard transplantation, predominantly purulent secretions. The median ventilation time for the EVLP donors before procurement was 2 days (range < 1–10.3 days) and 27 donors (51%) had positive microbiology cultures from sputum, BAL fluid or cerebrospinal fluid. The median optimised PaO₂ : FiO₂ ratio for the 53 EVLP donors at the time of procurement was 39.9 [299 (range 95–535 mmHg)] and after EVLP was 50.9 [381.5 (range 74–638 mmHg)]. The EVLP assessments followed one of two standardised perfusion protocols depending on when the lungs were entered into the study. Initially, between 1 April 2012 and 31 March 2013, a hybrid protocol combining elements of the Toronto and Lund protocols was used with an open left atrium, an acellular perfusate and a reduced perfusate flow to 40–60% of the donor’s calculated cardiac output. After a pause midway through the study because of concerns over the rate of ECMO use in transplants performed after assessment using the hybrid EVLP protocol, the perfusion strategy was altered and the study was restarted in August 2013 and the hybrid protocol replaced by the Lund protocol.

The Lund protocol uses a cellular perfusate (haematocrit 10–15%) and a full-flow perfusion strategy (100% of cardiac output), but is otherwise identical to the hybrid protocol. The assessment and ventilation strategies, airway and vascular pressure limits, and perfusate composition was otherwise unaltered (Table 27).

Lung performance during ex vivo lung perfusion assessment

Transplant suitability was assessed as soon as the lungs had stabilised, at 37 °C and perfusing at full flow, and thereafter hourly until the end of perfusion. Lungs meeting transplant suitability at any time point were cooled and transplanted (Boxes 3 and 4). Lungs deemed to have futile prospects for improvement were taken off the circuit and discarded.

BOX 3 - Criteria for transplant after successful EVLP assessment and reconditioning

All of the following

• Any DBD or DCD donor lungs meeting previously stated criteria for standard transplant.

• Pulmonary artery pressure < 20 mmHg, while achieving target perfusate flow.

• Oxygen capacity shown by ΔPaO₂ of > 300 mmHg (perfusate left atrium PaO₂– perfusate pulmonary artery PaO₂)/FiO₂.

• Selective pulmonary vein gas > 225 mmHg on 100% FiO₂ and 5 cmH₂O PEEP.

• Stable or improving lung compliance and stable or falling lung resistance.

• No pulmonary oedema build-up in the endotracheal tube.

• Satisfactory assessment on inspection and palpation.

• Confirmed reconsent of potential matched recipient to receive an EVLP-reconditioned lung.

BOX 4 - Criteria for failed EVLP assessment and reconditioning: transplant will not proceed

Any of the following

• Any DBD or DCD donor lungs not meeting stated criteria for standard transplant.

• Not satisfying criteria for transplant after successful EVLP assessment and reconditioning.

The performance of the 53 donor lungs undergoing EVLP assessment in the study is reported in two different ways to give as robust a description as possible of this cohort.

First, clinical EVLP success was defined as any EVLP-assessed donor lung deemed clinically suitable for transplantation at the end of perfusion by the surgical team performing the assessment (n = 22). This included all EVLP lungs that were transplanted within the study (n = 18) and all lungs that were accepted for transplantation on the basis of EVLP performance, but had to be turned down due to unforeseen logistical reasons (n = 4) (Figure 19).

FIGURE 19.

Flow chart for clinical EVLP success (n = 22).

Of these four cases, one pair of lungs accepted for double lung transplant had to be discarded as the recipient presented with an active airway infection and was found to be at too high risk for the operation on arrival at the hospital. The lungs were offered on urgently, but turned down by all UK centres owing to logistics. One lung had an unreported irreparable left pulmonary artery laceration with haematoma formation from the retrieval surgery. The right lung was selectively perfused and deemed suitable for transplantation. There was, at this point, no available matching single lung recipient and the lung had to be discarded after having been offered on to all other UK centres. One left single lung accepted for transplantation for a matched recipient had to be aborted due to an emergency in theatres and lack of additional surgical capacity at the site. One lung was put on EVLP for logistical reasons while awaiting histology of suspicious masses found during the organ procurement. Evaluation of a liver nodule showed chronic lymphatic lymphoma. Although the lung biopsy was found benign, the transplant was aborted because of the elevated risk of tumour transmission to the recipient. The lungs were meanwhile successfully reconditioned on the circuit and deemed to be in a suitable condition for transplant had it not been for the histological liver findings.

Second, per-protocol success was defined as all perfused donor lungs meeting the complete set of predefined study criteria for EVLP success, regardless of clinical transplant result (n = 17). This included all EVLP lungs that were transplanted in the study while meeting all predefined transplant criteria (n = 13) and all non-transplanted EVLP lungs that met all transplant criteria but were discarded purely on logistical grounds (n = 4) (Figure 20).

FIGURE 20.

The flow chart for per-protocol EVLP success (n = 17).

Of the 18 EVLP lungs that were transplanted in the study, five had to be defined as per-protocol non-successful perfusions as, although deemed clinically suitable for transplantation, they failed to meet all predefined transplant criteria and were transplanted as a result of a protocol violation.

Two of these five lungs were transplanted even though their mixed pulmonary vein PaO₂ : FiO₂ ratio was 40.0 (< 300) during the assessment. One of these almost doubled its optimised retrieval PaO₂ : FiO₂ ratio during the perfusion, increasing from 22.0 (166) to 38.6 (290), and the other had a recorded mixed pulmonary vein PaO₂ : FiO₂ ratio of 35 (262), while all selective pulmonary vein gases were well above the study cut-off point [range 46.0–72.0 (345–540)]. Three EVLP lungs were transplanted while having one or two selective lower lobe pulmonary vein gases < 30 (225); however, their mixed pulmonary vein PaO₂ : FiO₂ met the study transplant criterion of > 40 (300). All five of these lungs were subsequently transplanted into recipients with satisfying post-transplant outcomes and a 100% 1-year survival. Of the 13 recipients receiving lungs that met all study criteria for transplantation, only seven (54%) remained alive 12 months post transplant.

Archiving

The trial data were stored on the Newcastle Clinical Trials Unit’s MACRO database system, provided by Infermed’s MACRO software as a service system. The hardware was located at their hosting partner Rackspace’s secure premises in London, UK, and is managed and supported by the Rackspace team. All data were stored and transmitted securely. Data were hosted and backed up only in the UK and were never transferred overseas. Only authorised staff can grant and have control of access. Any snapshots of the database taken will be kept on the Newcastle University server, which is backed up daily.

Once all trial-related analysis and activities are completed, the database will remain on MACRO, with permissions removed. The data will be archived onto disk for each site file and also centrally in accordance with the Newcastle Clinical Trials Unit’s standard operating procedures (SOPs).

Overall aims of the economic evaluation

The original aim of the economic analysis of the DEVELOP-UK study was to estimate the cost-effectiveness of EVLP compared with standard donor lung transplantation. Cost-effectiveness was to be estimated in terms of the incremental cost per quality-adjusted life-year (QALY) gained and compared with the current National Institute for Health and Care Excellence (NICE) cost-effectiveness threshold (£20,000 per QALY). This analysis was to take the form of a within-study economic evaluation and a model to extrapolate findings over patients’ lifetime. As previously described, the DEVELOP-UK study was terminated before the target participant recruitment was reached. Therefore, the originally planned economic evaluation of the study was conducted with a few changes within its initial design.

Given the smaller than planned recruitment numbers in the EVLP arm of the study, the aims of the economic section were recast to:

1. provide a descriptive ‘within-study’ analysis of the available data in terms of costs and QALYs for both EVLP and standard donor lung transplantation, without directly comparing the two procedures

2. estimate a regression model to explore predictors of NHS costs for transplants that may aid future modelling studies involving a lung transplant as one of the events of interest

3. report an exploratory economic model populated for both types of lung transplantation (standard and EVLP) with data obtained from the relevant literature and from the DEVELOP-UK study.

Within-study descriptive analysis of costs and quality-adjusted life-years

There are five parts of analysis that were proposed to be presented in this element of the study. First, the unit costs and the sources of these costs for standard donor and EVLP lung transplantation were to be described. Second, an analysis of the resource use was to be conducted to estimate the mean (SD) and the median (IQR) use of each type of resource. In the third part of the analysis, resource use and unit cost data were to be combined in order to estimate the average cost for each area of resource use and in total for each one of the two types of transplantation. The fourth part of the analysis that gives information on HRQoL was to be used to estimate QALYs for each type of transplantation based on the responses of the participants to the SF-36. Fifth, and finally, the net benefits of standard and EVLP lung transplantation were to be calculated based on the costs and QALYs of the two different approaches to achieving a lung transplant.

As the study was terminated early because of a lack of patient recruitment in one of its two arms, it was agreed that no direct within-study comparison would be drawn in terms of cost-effectiveness, and that the presentation of results would be limited to descriptive data. These descriptive data were, however, used to populate an exploratory economic model.

Results

Cost analysis

The total average cost per recipient, by each area of resource use for each one of the eight stages of the study, is listed in Economic evaluation methods (see Tables 30–37).

Table 30 shows that there were no large variations in the costs of the screening and testing of the donor before the lung retrieval in either of the two types of transplantation. This is because the hospital staff always perform the same type and number of tests in order to examine the person’s health condition before requesting a retrieval team to arrive at the hospital. Any small variations observed in the donor’s initial assessment costs (standard transplant, SD £6; EVLP transplant, SD £18) might be caused by the fact that some of the tests might not be needed in some cases or had been provided recently to the donor. In this stage, medication costs constitute a small component of the total costs, as only methylprednisolone was given as a single dose, whereas the main component of costs for both standard and EVLP lung transplants are the diagnostic tests. In addition, the large differences in mean costs between the two transplant procedures (Cost_STD = £403; Cost_EVLP = £1182) are because in the EVLP arm only 18 lungs were transplanted out of 53 that were retrieved, while in the standard arm all retrieved lungs were transplanted.

TABLE 30 - Total average cost per recipient by each area of resource use: donor’s hospital total average cost per recipient

SE, standard error.

Resource use	Patient details	Study group				Mean (SE) difference in cost per recipient	95% CI based on bootstrapping
		Standard (n = 184)		EVLP (n = 18)
		Mean (SD)	Median (IQR)	Mean (SD)	Median (IQR)
Total initial assessment costs	Donor	£392 (£6)	£393 (£391–395)	£1156 (£18)	£1163 (£1151–1163)	–£765 (£2)
Total drug costs	Donor	£11 (£10)	£17 (£0–17)	£26 (£26)	£26 (£0–51)	–£14 (£3)
Total donor’s hospital costs	Donor	£403 (£12)	£408 (£395–412)	£1182 (£35)	£1182 (£1163–1214)	–£779 (£4)	–£786 to –£771

The retrieval of the lung involves very similar resources regardless of the subsequent procedure. As can be seen from Table 31, there is some variability in the costs of the equipment used for a DCD and a DBD donor. This is because, during a DBD, the heart is still working and, therefore, an ABG test can also be performed. This also explains the small differences observed in the cost of the tests provided by the retrieval team (standard, SD £9; EVLP, SD £36). Moreover, some variation is observed in the cost of the lung perfusion. This might mean that some of the medications that are normally used during the perfusion of the organ were not needed in practice or that there were several missing patient data items that caused these differences in costs. In this stage, the main components of costs are the staff time and the team’s travelling costs, which would be expected given the potential distances that the scout and retrieval teams have to travel and the time needed to complete the organ retrieval. As mentioned before, the large increase in the costs of the EVLP compared with the standard transplant was mainly caused by the different retrieval-to-transplant ratio of the two transplant procedures.

TABLE 31 - Total average cost per recipient by each area of resource use: lung retrieval total average cost per recipient

SE, standard error.

Resource use	Patient details	Study group				Mean (SE) difference in cost per recipient	95% CI based on bootstrapping
		Standard (n = 184)		EVLP (n = 18)
		Mean (SD)	Median (IQR)	Mean (SD)	Median (IQR)
Total DCD donor equipment costs	Donor	£25 (£4)	£21 (£21–29)	£63 (£0)	£63 (£63–63)	–£38 (£2)
		n = 30		n = 4
Total DBD donor equipment costs	Donor	£273 (£3)	£274 (£274–274)	£799 (£11)	£806 (£782–806)	–£527 (£1)
		n = 154		n = 14
Total staff time costs	Donor	£1005 (£0)	£1005 (£1005–1005)	£2958 (£0)	£2958 (£2958–2958)	–£1954 (£0)
Total test costs	Donor	£21 (£9)	£25 (£25–25)	£49 (£36)	£74 (£0–74)	–£28 (£3)
Total perfusion costs	Donor	£623 (£142)	£655 (£655–655)	£1822 (£455)	£1929 (£1929–1929)	–£1199 (£47)
Total travelling costs	Donor	£6770 (£0)	£6770 (£6770–6770)	£19,934 (£0)	£19,934 (£19,934–19,934)	–£13,164 (£0)
Total lung retrieval costs	Donor	£8651 (£170)	£8729 (£8695–8729)	£25,398 (£524)	£25,688 (£24,957–25,700)	–£16,747 (£55)	–£16,856 to –£16,639

Table 32 describes the costs of the preparation of the patient before lung transplant. As with the previous two stages of the analysis, there is some variation in the use of the screening tests performed, which might mean either that the test was performed but these data were missing, or that or no test was required during the preparation of the patient. The table also indicates that the most costly resource used during this stage of the transplant process was the time spent in the hospital ward before surgery (£265 per hour). Obviously, the retrieval-to-transplant EVLP ratio (53/18) results in the higher costs for the EVLP arm of the study. Furthermore, as mentioned above in the description of the lung transplant procedure, in this study it was difficult to obtain detailed information about the resources used for the patient transportation to the transplant site. As a result, these costs are missing from Table 31. Given the difference in retrieval-to-transplant ratios between the two arms of the study and the nature of these costs, it might be expected that the costs of travelling would increase the cost of the patient preparation and, subsequently, the cost of the total transplant procedure.

TABLE 32 - Total average cost per recipient by each area of resource use: transplant preparation total average cost per recipient

SE, standard error.

Resource use	Patient details	Study group				Mean (SE) difference in cost per recipient	95% CI based on bootstrapping
		Standard (n = 184)		EVLP (n = 18)
		Mean (SD)	Median (IQR)	Mean (SD)	Median (IQR)
Total potential recipient contacting costs	Recipient	£30 (£0)	£30 (£30–30)	£90 (£0)	£90 (£90–90)	–£59 (£0)
Total potential recipient meeting costs	Recipient	£61 (£0)	£61 (£61–61)	£179 (£0)	£179 (£179–179)	–£118 (£0)
Total tissue typing costs	Recipient	£60 (£0)	£60 (£60–60)	£176 (£0)	£176 (£176–176)	–£116 (0)
Total test costs	Recipient	£50 (£8)	£51 (£51–55)	£140 (£28)	£149 (£149–149)	–£90 (£3)
Total ward time costs	Recipient	£265 (£0)	£265 (£265–265)	£780 (£0)	£780 (£780–780)	–£515 (£0)
Total drug costs	Recipient	£0 (£0)	£0 (£0)	£0 (£0)	£0 (£0)	£0 (£0)
Total transfer to ward costs	Recipient	Missing	Missing	Missing	Missing	Missing
Total transplant preparation costs	Recipient	£466 (£8)	£467 (£467–471)	£1365 (£28)	£1375 (£1375–1375)	–£899 (£3)	–£905 to –£894

Table 33 describes the costs for the EVLP procedure. Obviously, because the EVLP procedure is performed only during EVLP lung transplant, no costs are presented for the standard arm of the study. This process includes the assessment and reconditioning of the lung in order to make it suitable for transplant, and it is a stage that occurs between the transplant preparation and the transplant surgery. As expected, the most costly resources used in this stage are the consumables needed for the procedure. These include the lung set in which the lung is reconditioned (Vivoline disposable lung set, £6963). The medications used for the reconditioning of the organ add to the costs of the procedure, as do the cost of staff time and theatre time, because the EVLP procedure lasts for approximately 6 hours. As described in the stages above, the retrieval-to-transplant ratio causes an additional increase in the costs of the EVLP procedure by 53/18.

TABLE 33 - Total average cost per recipient by each area of resource use: EVLP procedure total average cost per recipient

SE, standard error.

Resource use	Patient details	Study group				Mean (SE) difference in cost per recipient	95% CI based on bootstrapping
		Standard (n = 184)		EVLP (n = 18)
		Mean (SD)	Median (IQR)	Mean (SD)	Median (IQR)
Total staff time costs	EVLP recipient	–	–	£1533 (£0)	£1533 (£1533–1533)
Total equipment costs	EVLP recipient	–	–	£59 (£0)	£59 (£59–59)
Total consumable costs	EVLP recipient	–	–	£22,958 (£606)	£23,017 (£22,487–23,193)
Total miscellaneous equipment costs	EVLP recipient	–	–	£220 (£0)	£220 (£220–220)
Total theatre usage costs	EVLP recipient	–	–	£10,382 (£0)	£10,382 (£10,382–10,382)
Total drug costs	EVLP recipient	–	–	£7482 (£1965)	£7991 (£6362–8057)
Total EVLP procedure costs	EVLP recipient	–	–	£42,633 (£2172)	£42,675 (£41,167–43,414)	–	–

The cost of the single lung transplant procedure or a double lung transplant procedure does not vary according to whether it is a standard or EVLP lung transplantation. In this study, only 26 transplants were reported as single, of which two were in the EVLP arm. The rest of the transplants were either reported as double or assumed to be double in this analysis given that more double transplants were performed. A double lung transplant increases the time needed for the surgery by approximately 3 hours, which leads to a significant increase in the mean transplant costs (single transplant cost £4177; double transplant cost £6934), because of increased theatre usage and staff time costs. The variability within the total costs of the transplant (standard, SD £931; EVLP, SD £892) is mainly caused by the difference in the proportion of single or double lung transplants performed in the standard and EVLP arms of the study. As indicated in Table 34, the total cost of the equipment/consumables used during the operation is missing. This is because every surgeon and clinic may differ in how the surgery is performed and, hence, may use different equipment. In this study it was difficult to collect more details about the resources used in order to retrieve their respective costs.

TABLE 34 - Total average cost per recipient by each area of resource use: lung transplant total average cost per recipient

SE, standard error.

Resource use	Patient details	Study group				Mean (SE) difference in cost per recipient	95% CI based on bootstrapping
		Standard (n = 184)		EVLP (n = 18)
		Mean (SD)	Median (IQR)	Mean (SD)	Median (IQR)
Total anaesthetic preparation costs	Recipient	£501 (£0)	£501 (£501–501)	£501 (£0)	£501 (£501–501)	£0 (£0)
Total single lung surgery staff time costs	Recipient	£1325 (£0)	£1325 (£1325–1325)	£1325 (£0)	£1325 (£1325–1325)	£0 (£0)
		n = 24		n = 2
Total double lung surgery staff time costs	Recipient	£2320 (£0)	£2320 (£2320–2320)	£2320 (£0)	£2320 (£2320–2320)	£0 (£0)
		n = 160		n = 16
Total single lung surgery theatre usage costs	Recipient	£2351 (£0)	£2351 (£2351–2351)	£2351 (£0)	£2351 (£2351–2351)	£0 (£0)
		n = 24		n = 2
Total double lung surgery theatre usage costs	Recipient	£4114 (£0)	£4114 (£4114–4114)	£4114 (£0)	£4114 (£4114–4114)	£0 (£0)
		n = 160		n = 16
Total equipment/consumable costs	Recipient	Missing	Missing	Missing	Missing	Missing
Total single transplant costs	Recipient	£4177 (£0)	£4177 (£4177–4177)	£4177 (£0)	£4177 (£4177–4177)	£0 (£0)
		n = 24		n = 2
Total double transplant costs	Recipient	£6934 (£0)	£6934 (£6934–6934)	£6934 (£0)	£6934 (£6934–6934)	£0 (£0)
		n = 160		n = 16
Total lung transplant costs	Recipient	£6574 (£931)	£6934 (£6934–6934)	£6627 (£892)	£6934 (£6934–6934)	–£53 (£229)	–£505 to £399

The post-operative and outpatient care of the patients shows the largest variability in total costs (see Tables 35 and 36) because it is dictated by the nature and severity of any complications and AEs that might occur, which vary markedly between patients. Given the nature of events that might occur and the cost of their management, it would be expected that these costs would be highly skewed, and the mean cost, especially for the EVLP arm, would be greatly affected by the very high costs incurred by a small number of patients. As indicated in Table 35, the highest costs in this stage are the ward use (standard arm, £20,064; EVLP arm, £21,276) and staff time costs (standard arm, £4828; EVLP arm, £5265). This is because the length of hospital stay (especially in the ITU/HDU) varies between different patients and, consequently, different amounts of staff time are required. Table 35 also shows a large variation in the costs of the equipment used. In this case, the variation is mainly caused by the use of the ECMO machine (ECMO cost, £34,000). In addition, variation is also observed in the costs caused by complications and infection episodes. This is to be expected given the fact that each recipient responds differently to their transplanted organ, and thus some patients become more prone to infections than others. (It should be mentioned that the infection episodes and airway complication costs presented in Table 35 include the costs from infections that occur either straight after the transplant or during the subsequent outpatient care of the patient.)

TABLE 35 - Total average cost per recipient by each area of resource use: post-operative care total average cost per recipient

SE, standard error.

Resource use	Patient details	Study group				Mean (SE) difference in cost per recipient	95% CI based on bootstrapping
		Standard (n = 184)		EVLP (n = 18)
		Mean (SD)	Median (IQR)	Mean (SD)	Median (IQR)
Total staff time costs	Recipient	£4828 (£5331)	£2895 (£1721–6059)	£5265 (£5065)	£2741 (£1996–7795)	–£436 (£1311)
Total test costs	Recipient	£135 (£77)	£183 (£14–183)	£115 (£87)	£183 (£14–183)	£19 (£19)
Total ward usage costs	Recipient	£20,064 (£20,582)	£12,143 (£7459–25,453)	£21,276 (£23,651)	£11,605 (£5944–28,700)	–£1212 (£5152)
Total procedure costs	Recipient	£158 (£167)	£135 (£0–340)	£336 (£150)	£340 (£340–475)	–£178 (£41)
Total equipment costs	Recipient	£3696 (£13,726)	£0 (£0–0)	£22,667 (£30,855)	£0 (£0–68,000)	–£18,971 (£3931)
Total consumable costs	Recipient	£826 (£1711)	£453 (£164–791)	£1469 (£3009)	£708 (£360–1320)	–£644 (£459)
Total inotrope costs	Recipient	£16 (£15)	£10 (£4–27)	£22 (£17)	£23 (£4–34)	–£6 (£4)
Total post-implantation haemodynamic support costs	Recipient	£43 (£160)	£2 (0–14)	£278 (£437)	£120 (£8–224)	–£235 (£49)
Total complication costs	Recipient	£699 (£1799)	£0 (0–70)	£2246 (£2973)	£0 (£0–4580)	–£1547 (£476)
Total airway complication costs	Recipient	£622 (£2020)	£0 (£0–0)	£0 (£0–0)	£0 (£0–0)	£622 (£477)
Total ITU rejection episode costs	Recipient	£59 (£224)	£0 (£0–0)	95 (275)	£0 (£0–0)	–£36 (£57)
Total ward rejection episode costs	Recipient	£242 (£452)	£0 (£0–851)	198 (381)	£0 (£0–0)	£45 (£110)
Total infection episode costs	Recipient	£3925 (£14,046)	£286 (£0–1755)	£3518 (£7830)	£39 (£0–1738)	£407 (£3366)
Total post-operative care costs	Recipient	£34,109 (£39,561)	£20,112 (£11,639–42,340)	£56,136 (£57,345)	£21,931 (£12,713–86,464)	–£22,027 (£10,217)	–£42,174 to –£1879

The data in Table 36 demonstrate that the outpatient care of a lung recipient varies markedly between participants. Some patients might require more outpatient or GP visits, whereas others might need several unplanned hospital admissions and longer duration of treatment with immunosuppressive medications. The last two resources constitute almost the 70% of the outpatient care costs. As expected, the unplanned hospital admissions of the recipients show a large variation, as their occurrence varies between different patients.

TABLE 36 - Total average cost per recipient by each area of resource use: outpatient care total average cost per recipient

SE, standard error.

Resource use	Patient details	Study group				Mean (SE) difference in cost per recipient	95% CI based on bootstrapping
		Standard (n = 184)		EVLP (n = 18)
		Mean (SD)	Median (IQR)	Mean (SD)	Median (IQR)
Total outpatient review costs	Recipient	£1420 (£699)	£1515 (£895–2170)	£994 (£842)	£766 (£209–1855)	£426 (£176)
Total staff time costs	Recipient	£130 (£50)	£159 (£120–159)	£100 (£70)	£139 (£40–159)	£31 (£13)
Total rejection episode costs	Recipient	£750 (£3443)	£0 (0–653)	£290 (£463)	£0 (£0–379)	£460 (£814)
Total GP visit costs	Recipient	£9 (£22)	£0 (£0–0)	£18 (£29)	£0 (£0–34)	–£9 (£6)
Total unplanned hospital admission costs	Recipient	£2748 (£10,864)	£0 (£0–559)	£689 (£2395)	£0 (£0–392)	£2059 (£2572)
Total immunosuppressive medication costs	Recipient	£2923 (£1049)	£3187 (£2680–3522)	£2475 (£1522)	£3222 (£1003–3475)	£447 (£271)
Total outpatient care costs	Recipient	£7981 (£12,263)	£5746 (£4552–7025)	£4567 (£3931)	£4969 (£1423–5805)	£3414 (£2911)	–£2326 to £9153

Concomitant medications can be considered as an additional part of the analysis of this study. A recipient might need an additional treatment or a change in the current treatment as a result of complications. The duration of treatment is also variable and depends on the condition of the patient. Therefore, the medications given vary between patients, and this explains why such a large variation in the total cost of concomitant medications exists (standard, SD £4505; EVLP, SD £3614) in Table 37.

TABLE 37 - Total average cost per recipient by each area of resource use: concomitant medication total average cost per recipient

SE, standard error.

Resource use	Patient details	Study group				Mean (SE) difference in cost per recipient	95% CI based on bootstrapping
		Standard (n = 184)		EVLP (n = 18)
		Mean (SD)	Median (IQR)	Mean (SD)	Median (IQR)
Total concomitant medication costs	Recipient	£1424 (£4505)	£0 (£0–328)	£1172 (£3614)	£0 (£0–0)	£252 (£1096)	–£1908 to £2412

Table 38 presents the total average cost per recipient for the standard donor and the EVLP lung transplantation. These costs were calculated by adding the total costs of each stage of the transplant procedure for each patient and calculating the average cost for each lung recipient. As can be seen from Table 38, the mean and median cost of EVLP per recipient is substantially greater than for standard lung transplant. This is partially because of the different retrieval-to-transplant ratio between the two lung transplants, which leads to higher costs in the early stages of the analysis and, partially, as a result of the actual cost of the EVLP procedure (£14,479 per lung assessed). Also presented in Table 38 is the mean difference and bootstrapped 95% CI. The CI suggests that EVLP recipients are, on average, at least £57,910 more costly and may be as much as £101,036. These data are only suggestive given the very small number of participants in the EVLP arm (n = 18).

TABLE 38 - Total average cost per recipient per procedure

SE, standard error.

Resource use	Patient details	Study group				Mean (SE) difference in cost per recipient	95% CI based on bootstrapping
		Standard (n = 184)		EVLP (n = 18)
		Mean (SD)	Median (IQR)	Mean (SD)	Median (IQR)
Total donor’s hospital costs	Donor	£403 (£12)	£408 (£395–412)	£1182 (£35)	£1182 (£1163–1214)	–£779 (£4)	–£786 to –£771
Total lung retrieval costs	Donor	£8651 (£170)	£8729 (£8695–8729)	£25,398 (£524)	£25,688 (£24,957–25,700)	–£16,747 (£55)	–£16,856 to –£16,639
Total transplant preparation costs	Recipient	£466 (£8)	£467 (£467–471)	£1365 (£28)	£1375 (£1375–1375)	–£899 (£3)	–£905 to –£894
Total EVLP procedure costs	EVLP recipient	–	–	£42,633 (£2172)	£42,675 (£41,167–43,414)	–	–
Total lung transplant costs	Recipient	£6574 (£931)	£6934 (£6934–6934)	£6627 (£892)	£6934 (£6934–6934)	–£53 (£229)	–£505 to £399
Total post-operative care costs	Recipient	£34,109 (£39,561)	£20,112 (£11,639–42,340)	£56,136 (£57,345)	£21,931 (£12,713–86,464)	–£22,027 (£10,217)	–£42,174 to –£1879
Total outpatient care costs	Recipient	£7981 (£12,263)	£5746 (£4552–7025)	£4567 (£3931)	£4969 (£1423–5805)	£3414 (£2911)	–£2326 to £9153
Total concomitant medication costs	Recipient	£1424 (£4505)	£0 (£0–328)	£1172 (£3614)	£0 (£0–0)	£252 (£1096)	–£1908 to £2412
Total cost per procedure	–	£59,608 (£42,664)	£43,630 (£33,833–68,748)	£139,081 (£58,916)	£108,255 (£93,492–171,768)	–£79,473 (£10,935)	–£101,036 to –£57,910

In Figure 21, the costs of each stage of both standard and EVLP lung transplant procedures are presented as a bar chart. This reveals the significant difference in costs for certain parts of the procedure pathways between standard and EVLP transplants.

FIGURE 21.

Total average cost per recipient per procedure.

Analysis of the quality of life

As indicated in Table 39, there were only a small number of lung recipients who contributed SF-6D data (22/202) at all expected time points. These patients were those who completed the SF-36 questionnaire at all three time points, or were known to have died by a given time point, in which case SF-6D scores for that and any subsequent time points were given as zero. As a result, Table 40 presents the mean and median SF-6D utility scores for each stage that a questionnaire was completed or a patient was reported as being dead (i.e. at baseline, 3 and 12 months post transplant). It also presents the number of observations (n) based on which the means and the medians were calculated at each time point. At the bottom of the table, the total mean QALYs of each transplant type are shown, which were estimated by measuring the area under the curve created from the mean utility scores of each one of the three time points.

TABLE 39 - Percentage of SF-6D data available for each arm and stage of the study

Study group	Time point
	Baseline only, % (n)	3 months only, % (n)	12 months only	Baseline and 3 months, % (n)	Baseline and 12 months, % (n)	3 and 12 months, % (n)	Baseline, 3 and 12 months, % (n)
Standard (N = 184)	36.41 (67)	33.15 (61)	41.30 (76)	17.94 (33)	18.48 (34)	23.37 (43)	11.41 (21)
EVLP (N = 18)	44.44 (8)	55.56 (10)	55.56 (10)	22.22 (4)	16.67 (3)	38.89 (7)	5.56 (1)
Total (N = 202)	37.13 (75)	35.15 (71)	42.57 (86)	18.32 (37)	18.32 (37)	24.75 (50)	10.89 (22)

TABLE 40 - Health-related quality of life (QALYs): SF-6D scores

The QALYs presented in this table were calculated from the area under the curve created by the mean SF-6D scores of each time point by using the trapezoid rule.

Questionnaires	Study group
	Standard (n = 184)		EVLP (n = 18)
	Mean (SD)	Median (IQR)	Mean (SD)	Median (IQR)
At baseline	0.5510 (0.0846)	0.5450 (0.5010–0.5970)	0.5880 (0.0382)	0.6000 (0.5590–0.6125)
Number of observations	67		8
3 months post-transplant	0.5884 (0.2766)	0.6660 (0.5540–0.7570)	0.5551 (0.3942)	0.7345 (0.0000–0.7990)
Number of observations	61		10
12 months post-transplant	0.4527 (0.3709)	0.6125 (0.0000–0.7550)	0.4689 (0.4267)	0.6010 (0.0000–0.8410)
Number of observations	76		10
QALYs (from SF-6D mean scores)a	0.5328		0.5269

Figure 22 presents the differences between the mean SF-6D scores between the two lung transplant procedures. As was expected from the numbers provided in Table 40, the differences are negligible. However, because these are the mean SF-6D scores reported, a comparison between the numbers of QALYs gained from each one of the two procedures would be meaningless.

FIGURE 22.

Health-related quality of life (QALY).

Predicting NHS expenditure costs for UK patients receiving a lung transplant: a regression-based analysis

Results

Base-case analysis

Figure 23 shows the distribution of costs based on the DEVELOP-UK study data. As expected, the costs were highly skewed (i.e. several patients needed additional or more expensive health-care resources), which meant that a simple linear model would not give robust results. As a consequence, the total cost variable was log-transformed. This transformation had the effect of diminishing the impact of the outlier observations on the total lung transplant costs per recipient.

FIGURE 23.

Distribution of total transplant costs based on the DEVELOP-UK study data.

Table 42 presents the variables that were finally selected for the model as well as their marginal effect on arithmetic costs. As shown in Table 42, the regression model was a log-linear model. In other words, there was a linear (additive) relationship between each one of the explanatory variables and the log-form of the total lung transplant costs, which is reasonable when considering that the explanatory variables were mainly qualitative (e.g. age, sex) or categorical (e.g. type of transplant procedure, number of lungs transplanted). Obviously, Table 42 presents the exponential results of this regression model (i.e. the results of the analysis in a normal arithmetic scale).

TABLE 42 - Explanatory variables used in the regression and their impact on total lung transplant costs

SE, standard error.

dy/dx is the marginal effect of the independent variable.

When p > z, the probability is higher than the z-score (p-value).

Note

Values in bold represent p < 0.05 and are, therefore, statistically significant.

Explanatory variables	dy/dx (£)a	SE	z-score	p > zb	95% CI
Recipient age (years)	246	274	0.900	0.368	–290 to 782
Recipient sex (male as reference sex)
Female	4214	5945	0.710	0.478	–7437 to 15,866
Time on the waiting list (days)	–1	9	–0.100	0.924	–19 to 17
Transplant indication (CF as reference indication)
Non-CF bronchiectasis	36,051	24,816	1.450	0.146	–12,587 to 84,690
Interstitial lung disease	11,415	9447	1.210	0.227	–7101 to 29,931
Chronic obstructive pulmonary disease	559	7459	0.070	0.940	–14,061 to 15,179
Emphysema	–9506	7777	–1.220	0.222	–24,748 to 5736
Obliterative bronchiolitis	–11,629	9578	–1.210	0.225	–30,402 to 7144
Pulmonary hypertension	19,404	6380	3.040	0.002	6899 to 31,910
Other and missing indication	24,850	15,737	1.580	0.114	–5995 to 55,695
SF-36 score (MCS) while on the waiting list (score units, i.e. 0–100)	656	277	2.370	0.018	112 to 1199
SF-36 score (PCS) while on the waiting list (score units, i.e. 0–100)	784	372	2.110	0.035	56 to 1513
Donor type (DBD as reference type)
DCD	5078	7639	0.660	0.506	–9894 to 20,050
Transplant procedure (standard transplant as reference procedure)
EVLP	58,097	13,041	4.450	0.000	32,537 to 83,658
Number of lungs transplanted	30,401	10,205	2.980	0.003	10,400 to 50,403

As indicated in Table 42, there were nine variables that were included in the model instead of the 11 that were initially considered. The reasons for this reduction are listed below. First, the condition of the patient due to comorbidities or medications taken was found to be captured by the SF-6D score of the patient while on the waiting list. Second, the data for the donor–patient compatibility test were difficult to identify, and were possibly not recorded by the transplant sites. Third, the distance between the donor’s hospital and the transplant site was difficult to calculate based on the available data, and the total costs calculated in the descriptive analysis of the study were based on estimates given by the NHS staff. Finally, it was decided that rather than using the SF-6D, the SF-36 should be used with the scores reported as the two main SF-36 summary components (i.e. MCS and PCS), where MCS and PCS are reported on a 0–100 scale, with higher scores indicating better health, in order to have a more accurate understanding of the factors that affect the patient.

In Table 42, four variables are shown to be significant (p < 0.05) when predicting the total cost of a lung transplant for the NHS. These are the two subcomponents of the SF-36 scores (p = 0.018 and p = 0.035 for the MCS and the PCS scores, respectively), the type of the transplant procedure (p < 0.001) and the number of lungs transplanted (p = 0.003). The final two parameters were expected to be statistically significant because an EVLP transplant leads to higher costs because of the addition of the EVLP procedure before the operation (β_PROC = 58,097, which means that moving from a standard to an EVLP transplant will cost at least £58,097 more to the NHS), whereas if a double lung surgery is conducted, then more time is needed for the operation, resulting in higher staff and theatre costs. As far as the two subcomponents of the SF-36 scores are concerned, both were significant and both had a coefficient of similar magnitude (β_MCS = 656 and β_PCS = 784). This suggests that, in addition to the physical health driving lung transplant cost, the mental health of the recipient also increases the cost. Nevertheless, these effects were relatively small when compared with the total cost of transplant.

One interesting issue when looking at the impact of the SF-36 scores on the total transplant costs is the positive symbol of their coefficients. That is, the healthier a person is, the higher the costs are. There are a number of potential explanations for this. First, it could reflect the limited numbers of the SF-36 questionnaire completed at baseline (73/202 participants). This may mean that estimates derived were not very robust and were biased due to missing data, especially if those who did not complete the SF-36 were less well at baseline. Second, and related to the first reason, recipients that had lower scores were more likely to die or had a shorter time to death between the 12-month follow-up of the study than patients with higher scores, which therefore means they had less time to accrue costs. It is also interesting to mention that when the two scores were excluded from the regression model, the impact of EVLP on the total costs was higher (see Sensitivity Analysis).

Regarding the reason for the transplant, Table 42 indicates that pulmonary hypertension is a predictor of cost (p = 0.002), whereas the rest of the indications are not. In order to examine further the significance of the indication variable and compare the different indications, an F-test was performed. The F-test is normally used when comparing two different populations of different sizes in order to examine if the variance between the two groups is bigger than the variance within each group. If the groups are significantly different, the variation in group will be bigger than the variation because of differences among individuals in each group. This test proved that the reason of transplant is a significant predictor for the model as a total (p = 0.006), so it would be wrong to remove it from the model, as this would lead to inaccurate coefficients for the rest of the variables of the model. Based on this test, it was also understood that there is a big difference in costs when the reason for transplant is pulmonary hypertension instead of CF, which was the reference indication during the analysis.

The demographic characteristics of the potential recipient (i.e. age and sex) seem to have a limited effect, that is, almost entirely captured by the two SF-36 subcomponent scores. This was expected since the condition of the patient, as well as the tissue compatibility between the donor and the recipient, would be the main reasons for any complications or AEs. However, age and sex should always be in this type of regression model to represent the characteristics of the patient. The same argument can be also used when examining the low impact of the donor type on the total costs. Perhaps the donor’s cause of death does not influence the cost of the transplant directly, and it is the tissue compatibility that plays the most important role here. Additionally, the time on the waiting list has the smallest impact (β_TIME = –1) of all variables. In other words, for every additional day on the waiting list, transplant costs reduce by £1. Again, the longer the time on the waiting list the worse the condition of the patient gets and potentially the less likely they will survive to accrue costs. However, it is worth noting that the impact is very small and, although statistically significant, may not be of any practical significance.

Finally, based on the analysis of the DEVELOP-UK study data, it was calculated that the constant (β₀) of the regression model is equal to 3898. In this regression, this number is the minimum or average cost for a lung transplant for a reference participant who is male, was referred for transplant as a result of CF, received a standard single lung transplant, where the organ retrieved was from DBD. The intercept was also calculated by controlling for age, time on the waiting list and SF-36 subcomponent summary scores.

Exploratory model-based economic evaluation

Model structure

A decision-analytic model (Figure 24) was built in Microsoft Excel following the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines on conceptualising models. 55 The model represents the UK adult lung transplant service care pathway; beginning on the waiting list (state A) and progressing to being removed from the waiting list (state G); dying (state F); or receiving a standard (state B), or EVLP lung transplant (state D). From the lung transplant state, recipients progress either to death or, if they survive 1 year post lung transplant, to a post-lung transplant state; either states C or E depending on the type of lung transplant received.

FIGURE 24.

Model structure.

The post-lung transplant states were split into first year post lung transplant (including the cost of the lung transplant), and from year 2 onwards. This method was chosen as existing evidence suggested that the first year post lung transplant is key and should be modelled separately. 56,57

An area-under-the-curve Markov-type model was developed for post-lung transplant progression, where the length of time a lung transplant recipient survived from year 2 post lung transplant onwards was determined from a survival curve and allocated (as a fixed number of years) to each recipient in states C and E. To calculate the area under the curve, UK Cardiothoracic Transplant Audit survival data for 1, 3, 5 and 10 years post lung transplant were used and information on maximum life expectancy was sought. 58 More precisely, the ISHLT data for adults receiving a lung transplant between January 1990 and June 2012 report that survival of 19 years post lung transplant is 12%.

Half-cycle corrections were used for life-years gained in line with ISPOR guidelines,59 which are useful when the timing of the transition within the cycle is not known. On the other hand, no adjustment was made for QALY and cost calculations and, therefore, the QALY incremental cost-effectiveness ratio (ICER) would not be affected by the adjustment. A cohort of 1000 patients start in the waiting list state in the same year, and their progression was modelled over a lifetime horizon. The cycle length was 1 year, reflecting waiting list transitions and survival data.

Target population/location

The target population was adults on the UK lung transplant waiting list.

Study perspective

The perspective was the UK NHS using direct health-care costs only.

Comparators

The comparators are a UK adult lung transplant service that includes the use of both EVLP and standard lung transplants as the intervention (EVLP service) and a UK adult lung transplant service that includes only standard lung transplant as the control (standard service).

Time horizon

The time horizon used was lifetime, enabling consideration of costs and effects over the cohort’s lifetime.

Discount rate

The base-case analysis used a 3.5% discount rate for both costs and effects following NICE guidelines. 52,60

Outcomes

The principal outcome measure used was the QALY. Life-years gained was also measured, for the cost-effectiveness analysis, along with the number of lung transplants carried out.

Measurement of effectiveness/transitions

Lung transplant activity witnessed at the Newcastle centre during the study was used to inform the transition from waiting list to lung transplant in order to replicate within trial transitions. The Newcastle centre was chosen as it was the largest study centre. During the trial, standard lung transplants increased by 25% at the Newcastle centre, and this increase was applied to the pre-study transition from waiting list to lung transplant to calculate a within-study transition. A 10% increase in lung transplant activity because of EVLP lung transplant, also witnessed during the study overall by all centres, was used to calculate the transition to EVLP lung transplant. The pre-trial transition was taken from NHSBT data. 61 For transitions from waiting list to removal from waiting list and to death, NHSBT transitions were used from a cohort added to the waiting list in 2010/11 and followed for 3 years (to 2013/14), 2 of which were during the DEVELOP-UK study, reflecting in-trial waiting list transitions. 62

Post-transplant survival during the DEVELOP-UK study was not used to inform the model because of the small number of EVLP transplants carried out during the trial. In the absence of conclusive data from the literature, survival following EVLP and standard lung transplant were taken to be the same. Survival data were taken from the UK Cardiothoracic Transplant Audit, 1-year survival includes surgical mortality. 58 Area-under-the-curve methods were used to calculate a survival estimate that was applied to all recipients of a lung transplant who survived 1 year post transplant. The transitions used in the model are presented in Table 43.

TABLE 43 - Model transitions and survival: base case and scenario analyses

Parameters	Base case	Source	NHSBT 2013/14 transitions	Source	Pre-trial transitions	Source
Waiting list transitions
Removal from waiting list
Year 1	0.04	NHSBT 2013/1462	0.04	NHSBT’s Annual Report on Cardiothoracic Transplantation 2013–1462	0.08	NHSBT’s Organ Donation and Transplantation Activity Report 2011–201261
Year 2	0.04	NHSBT 2013/1462	0.04	NHSBT’s Annual Report on Cardiothoracic Transplantation 2013–1462	0.03	NHSBT’s Organ Donation and Transplantation Activity Report 2011–201261
Year 3 onwards	0.25	NHSBT 2013/1462	0.25	NHSBT’s Annual Report on Cardiothoracic Transplantation 2013–1462	0.11	NHSBT’s Organ Donation and Transplantation Activity Report 2011–201261
Transition to death
Year 1	0.17	NHSBT 2013/1462	0.17	NHSBT’s Annual Report on Cardiothoracic Transplantation 2013–1462	0.17	NHSBT’s Organ Donation and Transplantation Activity Report 2011–201261
Year 2	0.08	NHSBT 2013/1462	0.08	NHSBT’s Annual Report on Cardiothoracic Transplantation 2013–1462	0.09	NHSBT’s Organ Donation and Transplantation Activity Report 2011–201261
Year 3 onwards	0.02	NHSBT 2013/1462	0.02	NHSBT’s Annual Report on Cardiothoracic Transplantation 2013–1462	0.17	NHSBT’s Organ Donation and Transplantation Activity Report 2011–201261
Transition to standard lung transplant
Year 1	0.5	Freeman Hospital	0.5	NHSBT’s Annual Report on Cardiothoracic Transplantation 2013–1462	0.4	NHSBT’s Organ Donation and Transplantation Activity Report 2011–201261
Year 2	0.56	Freeman Hospital	0.4	NHSBT’s Annual Report on Cardiothoracic Transplantation 2013–1462	0.38	NHSBT’s Organ Donation and Transplantation Activity Report 2011–201261
Year 3 onwards	0.58	Freeman Hospital	0.069	NHSBT’s Annual Report on Cardiothoracic Transplantation 2013–1462	0.28	NHSBT’s Organ Donation and Transplantation Activity Report 2011–201261
Transition to EVLP lung transplant
Year 1	0.050	Freeman Hospital	0.1
Year 2	0.056	Freeman Hospital	0.08
Year 3 onwards	0.058	Freeman Hospital	0.0138
Increase in transplants	0.1	Freeman Hospital	0.2	Boffini et al.;63 Cypel et al.;30 and Henriksen et al.64
Post lung transplant survival
1 year survival (standard and EVLP)	0.766	UK cardiothoracic audit62
Area under the curve
1 year survival	0.766	UK cardiothoracic audit62

Model results

Probabilistic sensitivity analysis results

The results of this analysis are presented for the cost–utility analysis only. The ICER was £72,000, similar to the base case. Figure 25 shows the predicted cost and QALY plots for each intervention, whereas Figure 26 shows the predicted plots for the difference in costs and QALYs between the two interventions, with a threshold of £30,000 per QALY. Figure 25 indicates that the EVLP service is marginally more effective and costly than the standard lung transplant service. Figure 26 indicates that the majority of the simulations fall in the north-east quadrant, where the EVLP service is more costly and more effective than the standard service, but several simulations fall into the north-west quadrant of the figure, where the EVLP service is less effective and more costly than standard service. The incremental effectiveness in QALYs varies between –0.05 and 0.3, with a mean of 0.061 (95% CI –0.006 to 0.152), and the incremental costs vary between £680 and £16,180 with a mean of £4349 (95% CI £1167 to £9742).

FIGURE 25.

Cost-effectiveness plane.

FIGURE 26.

Incremental cost-effectiveness plane.

The data from the Monte Carlo simulation were used to plot a cost-effectiveness acceptability curve (Figure 27). The results indicate that at the typical ceiling ratio adopted by NICE of £20,000, the standard service has a 99.9% chance of being considered cost-effective compared with the EVLP service.

FIGURE 27.

Post-trial cost-effectiveness acceptability curve.

The conclusions of the economic evaluation are discussed in Chapter 6.

Introduction

There is currently no published literature examining patients’ views of EVLP, and research related to people’s experiences of receiving donor organs is also limited. 67–72 It is imperative that if new heath-care technologies, such as EVLP, are to be implemented successfully and achieve real benefits for patients, the views of those receiving them are taken into account. This substudy critically examined patients’ attitudes towards, and understanding of, EVLP; their reasons for participation in the DEVELOP-UK study; and their experiences of waiting for and receiving a transplant.

Research objectives

The aim of this 24-month qualitative substudy was to identify, describe and understand patients’ pre- and post-operative perceptions of EVLP, and to explore how these are mediated by individual, social, physical and clinical factors.

Methods

This qualitative study used focused interviews to explore patients’ views and experiences of consenting to be part of DEVELOP-UK study and their views of EVLP both before and after transplantation. Focused interviews are particularly useful when researching a new area about which relatively little is known. 73 This substudy was conducted with patients from two study sites: the Freeman Hospital, Newcastle, and Harefield Hospital, London. These two sites were chosen as they both provide care to diverse populations across large geographical areas, and they were expected to recruit the largest number of patients to the DEVELOP-UK study.

Prior to commencing data collection, an outline interview topic guide was developed that covered the following key areas:

• pre transplantation

  • patients’ understandings of EVLP and the perceived acceptability of this procedure in comparison with other donor lungs

  • patients’ hopes and expectations for EVLP

  • patients’ accounts of their own health and experience of living with their condition

  • patients’ experiences of waiting for lung transplantation

• post transplantation

  • patients’ retrospective accounts of their pre-operative health and experiences

  • patients’ accounts of waiting for a transplant

  • patients’ views and experiences of receiving and living with an EVLP or standard transplant.

Results

In total, interviews were conducted with 44 participants (24 men and 20 women) aged 21–69 years. Of these, only 19 were interviewed before transplantation, seven both before and after transplantation and 11 after transplantation.

Patients were located across a wide geographic area across the UK, Ireland and the Channel Islands. The patients interviewed had been diagnosed with a range of conditions: pulmonary fibrosis (n = 7), emphysema (n = 9), CF (n = 8), α₁-antitrypsin deficiency (n = 5), idiopathic fibrosis (n = 2) and others (n = 6). Twenty-six interviews (14 Newcastle; 12 Harefield) were conducted before transplantation with 12 women (aged 23–61 years) and 14 were with men (aged 25–69 years). Eighteen interviews were conducted post transplantation (13 Newcastle; 5 Harefield) with eight women (aged 21–62 years) and 10 men (aged 25–69 years). Two patients interviewed had received an EVLP transplantation, the rest a standard transplantation. Seven people (two women and five men) were interviewed both before and after transplantation, and, as outlined above, a further 11 (six women and five men) were interviewed only after transplantation.

Post-transplant experiences and hopes

Of the 18 patients interviewed post transplantation, seven had been interviewed before their transplantation as well, and 11 were interviewed only after receiving their transplant. Two people had received an EVLP transplantation. All the data from post-transplantation interviews are presented together for two reasons: first, to protect the anonymity of the small number of EVLP patients; and, second, from these two interviews it is not possible to ascertain any obvious differences in the reported experiences.

When participants described the events leading up to their transplant, they were often very specific about events, timings and how they felt. Some details they could recall themselves, and other aspects they had been told by relatives after the operation:

It was 1.30 in the morning, no sorry it was 9.30 on the Thursday night the phone rang again, it was Karen [transplant co-ordinator] and she said guess what I’ve been made an offer she said but someone else has also been offered the organs so start making your way to the hospital. I started getting prepped yet again and about quarter to five in the morning Karen got a call from the retrieval team to say, the organs are good it’s a go ahead. So I was then wheeled down to theatre at about 5.30 that was the last time I saw my wife then. Surgery commenced around 5.30 in the morning, 5.30/6.00 in the morning and I believe it took about 10/10.5 hours.

Mark, post transplant, centre 1

A key factor in the transplant process is the need for a donor. Those patients who mentioned the donor referred to the emotion and grief that they felt for the donor’s family and the effect it had on them, which varied between individuals:

Yeah it was definitely emotional time, there’s no doubt about that, thinking about the donor, donor family all the time. Quite a lot of tears, emotional having to you know, them to pass away for me to live like you know. And it’s not an easy thing to digest you know . . . I suppose the whole emotional thing was that I was alive and that someone had lost a brother, a dad, a husband you know a friend it was very raw for a long time and I just couldn’t, I’d be walking down the corridor and just fall out crying you know any little small thing at all emotionally would set me off so actually recently we sent a letter to the donor’s family which helped a lot like and hope to God helps them as well, like you know I wanted to show that I was up and about and achieving stuff before I sent the letter rather than send it at the saying thanks kind of gave them hope what I was beforehand and what my life is today yeah, so it was mentally tough and anything at all, even a song or something on the telly would set you off like you know you ended up watching cookery programmes.

Barry, post transplant, centre 2

Several participants spoke of wanting to make contact with the donor family to thank them and show how well they were doing, but were uncertain as to how this would be received:

What can you do that has any impact on anyone to say thank you? I mean you can write a letter and say thank you and if they get it, even better, but it’s . . . might be a crumb comfort I suppose. If you say who you are in terms of middle-aged or you know, whatever – do they say ‘Christ, what a waste, why didn’t it go to a younger patient?’ – All those conflicts, you know.

Tim, post transplant, centre 1

In addition to talking about their donors, participants spoke of their physical recovery post transplantation and their plans for the future. For all patients the first thing they recalled was the sensation of being able to breathe without struggling. For some this new way of breathing took a while to get used to:

I found the breathing quite hard because I didn’t understand what was going on and I had to kind of make myself do it [right] I didn’t trust it to do it on its own. It was a very strange experience [right] especially at night I was frightened to go to sleep in case it stopped because it felt so different. It’s very eh and the fact that the even now the breath is such a long breath in I think I’m going to stop breathing because it’s such a long time. Yeah I think it is you think oh god it can’t really be that slow a breath surely but then you think well it’s 3 litres instead of 0.5.

Beth, post transplant, centre 2

Some participants also experienced new health problems that they believed were in some way related to the transplant or post-transplant medication. However, the majority felt that living with their new health problem was not a significant issue compared with their condition pre transplant.

After receiving a transplant many patients expected to return to ‘normal’ life, restart work, go on holiday, start running. However, this was not always straightforward or at the rate hoped for, leaving some feeling disappointed:

It’s been ok since I’ll still be out, I’ll still be out of breath, I’m not, I’m not 100% there’s a lot of things I still can’t do I can’t like, I can walk into town but there, I got, I got to rest and I get out of breath very quickly there’re certain jobs I do I get dizzy quickly but other than that, no, I’m fine it’s good.

Keith, post transplant, centre 2

Strengths and weaknesses of the main DEVELOP-UK study

The DEVELOP-UK study has a number of strengths. It was the first study that brought together all five lung transplant centres in the UK to investigate a new technology for the benefit of patients waiting for lung transplantation. By involving all centres, the opportunity to demonstrate impact was maximised, and UK-wide policies could take account of the study. All centres were following the same protocols and using the same EVLP system to perform their assessments; this ensured the highest possible level of standardisation of the use of the technology across the study. The level of engagement of the population of patients waiting for lung transplant surgery was an additional strength, as this enabled the opportunities to perform EVLP assessments to be maximised.

Nonetheless, there are a number of weaknesses in the study that affect our ability to draw robust conclusions. The major limitation is the fact that – due to early study termination – the small sample size in the EVLP arm limited the analyses to descriptive statistics and exploratory modelling. The other significant limitation is that the EVLP protocol used changed mid-way through the study from a hybrid protocol to the Lund protocol. This change came about following an analysis of the early safety data by the Data Monitoring Committee and based on advice received after independent safety reviews.

Challenges to study enrolment activity

As each donor lungs offer was made to a transplant centre, the lungs were assessed for suitability for standard transplantation. If they failed to satisfy criteria for standard transplantation, they were considered for EVLP assessment and reconditioning. This was possible only if there was an appropriate potential recipient for that donor organ (based on blood group, tissue typing and size matching) who had signed at least an EOI form for the study. The criteria by which the decisions to perform EVLP were made were clearly defined in the study protocol. If there was no matching recipient or no consented recipient available, then the opportunity to perform an EVLP assessment was lost to the study.

The predicted activity for EVLP assessments of 240 over the 3.5 years of the study was based on the need to enrol 102 EVLP transplants and the expected conversion rate of EVLP assessment to transplantation of approximately 40–50%. The predicted EVLP assessment rate across the study was 6.6 per month. The actual number of EVLP assessments performed in the study was, however, lower across the study sites at < 3 per month, even when allowing for R&D delays to sites opening.

There were five potential reasons for the lower level of EVLP assessment activity seen in the study. There was a learning curve for the teams in each site both with the EVLP technique and with confidence in decision-making in the first few months of performing EVLP assessments. The delays in securing R&D approvals impacted on this during the first 11 months of the study, meaning that many centres did not hit the ground running. Difficulty in recruiting appropriately skilled clinical fellows to support the study in sites meant that no dedicated clinical fellow time was available to support study activities initially. Overcautious interpretation of EVLP inclusion/exclusion criteria by on-call transplant surgeons in sites led to missed opportunities to perform EVLP on donor lungs offered but not accepted for transplant. At one centre, technical issues with the EVLP system led to a delay in recruitment because of a change of equipment and a lack of confidence by the local team, which needed to be overcome. Finally, on numerous occasions, the organ retrieval team were sent out to evaluate donor lungs for EVLP that were not initially suitable for standard transplant to discover that with some simple management the donor lungs improved to satisfy criteria for standard transplant. These were then used in the standard arm of the study. Although a limitation of the study, this does suggest that consideration could be given in future to optimising methods of retrieval of lungs for standard transplantation.

All sites performed audits of donor offer suitability for EVLP over a 1- to 2-month period in November and December 2012 and this revealed at least three missed opportunities for EVLP assessment at each site. This suggested that donor lungs suitable for EVLP were regularly available, but that the opportunities to perform EVLP were not always taken.

Low conversion rate from ex vivo lung perfusion assessment to transplant

Once EVLP assessment and reconditioning of a donor lung was performed, the decision of whether or not the lungs were used in transplantation was determined by the criteria outlined in the study protocol and listed in Appendix 2. The conversion rate in moving from EVLP assessment and reconditioning to EVLP transplant was below our predicted rate of 40–50%, with 18 EVLP transplants performed from 53 EVLP assessments (34%). The number of EVLP transplants in the treatment arm of the study therefore fell behind predicted targets. The lower conversion rate was compounded by the lower than expected numbers of EVLP assessment activity. Previous single-centre publications have suggested that much higher conversion rates can be achieved, with levels of 82% reported in one large series. 32

However, these single-centre reports can be very selective as to which donor lungs are placed on EVLP and were not driven by a study protocol that defined the lungs that should be exposed to EVLP. It is interesting that in the multicentre NOVEL study, in which selection of lungs to undergo EVLP is protocol driven, a conversion rate of 55% was reported. Furthermore, in the NOVEL study the rate of PGD grade 3 was 21% in the 42 EVLP transplants. 83

Actions performed to increase study enrolment activity

Health economic analysis

The study included both a within-study assessment of costs and HRQoL, and an exploratory economic model. For the within-study data, it is obvious from the large SDs of Tables 30–37 that there is significant variation in the cost associated with the transplant of each individual, no matter which one of the two procedures was followed. This means that there is a large variability between the lung recipients regarding the resources required in each stage of the study.

Based on the calculations made, the average total cost per recipient for the standard donor lung transplantation is equal to £59,608 (SD £42,664). Almost half of this cost (£34,109) consists of the cost of the post-operative care, which also shows the biggest variability between the patients (SD £39,561). This large difference mainly lies on the need for ECMO and the length of stay in the ITU. In the standard arm, the mean total QALYs gained per recipient were estimated to be 0.533.

As far as the EVLP lung transplant is concerned, the total cost of the transplant was estimated to be around £139,081 (SD £58,916). This high cost is partially a result of the cost of the EVLP procedure (mean cost £42,633) and partly because of the cost of the post-operative care (mean cost £56,136). The variability in the total EVLP cost is similarly high, showing that the cost of the EVLP transplant might vary up to £58,916 from the average cost per recipient. This variability is, again, because of the use of ECMO and the length of hospital stay that the recipient might require after the transplant. Finally, the total QALYs gained per EVLP recipient were estimated to be 0.527.

A regression model on cost identified three statistically significant predictors of increased total cost: higher quality of life when the person joined the waiting list; use of EVLP procedure; and transplanting two lungs rather than one lung. A sensitivity analysis excluding quality of life on joining the waiting list (because relatively few respondents completed the SF-36 at this point) gave broadly similar results, but was a much poorer fit for the model data. One value of the regression model results is that information is now available to assist researchers involved in modelling events that include lung transplantation. They now have an additional data source that can be used and tailored to the characteristics of the patients modelled.

The exploratory model-based analysis estimated an incremental cost per QALY was £73,000, well over the typical ceiling ratio adopted by NICE.

The average discounted lifetime cost for a standard lung transplant was £64,861 and £69,358 for when EVLP available. The number of discounted life-years was 5.38 for standard transplant and 5.41 in the EVLP service, the increased life-years in the EVLP service reflect the increased number of lung transplants in the EVLP service: 726 transplants in the standard service and 742 in the EVLP service. The discounted QALYs are 3.48 and 3.54 in the standard and EVLP services, respectively. The higher level of QALYs in the EVLP service reflected both the increased life-years in this service and the higher utilities in the EVLP recipients. The conclusion was broadly consistent across the range of scenarios considered. Given the novel nature of the therapy, it is not possible to put these findings into the context of other research. A comprehensive literature review identified no other cost-effectiveness studies comparing EVLP lung transplantation with standard lung transplantation.

As far as the exploratory model-based analysis is concerned, the analysis suggests that non-technical solutions to increasing the availability of lungs for transplant may be worthwhile investigating. At present, the Newcastle and Birmingham lung transplant teams are carrying out EVLP lung transplant again as part of a service evaluation. This will provide a valuable opportunity to assess whether or not the increase in standard lung transplant witnessed during the DEVELOP-UK study is replicated when EVLP is again available as a back-up for substandard lungs.

The qualitative interview substudy

The DEVELOP-UK study implications for practice

The DEVELOP-UK study is the first to report poorer outcomes in a group of EVLP transplants than a contemporaneous standard lung transplant group. It is, however, the first non-commercial multicentre EVLP study performed and relied on a small number of centres (five) in a single country to aim to deliver a substantial number of EVLP assessments and subsequent transplants. To date, two commercially funded multicentre EVLP studies have been performed, but have not yet published their results other than in abstract format. 97,98

The slow enrolment into the EVLP arm of the study was because of a combination of the low number of EVLP assessments performed, and the low conversion rate from EVLP assessment to transplant. This demonstrates the challenge of running an EVLP assessment service alongside an active clinical transplant programme, when logistics and staff availability because of competing transplant activity can significantly affect units’ ability to perform EVLP assessments, even if resourced.

The higher rate of early PGD grade 3 and need for ECMO support in the EVLP arm has raised issues about the selection of the best lungs on which to perform EVLP. Although there was a much higher ECMO rate in the EVLP arm, it was not associated with a higher mortality risk in the recipients undergoing ECMO, which in most cases was limited to a few days’ support. The almost uniform use of cardiopulmonary bypass in recipients of EVLP donor lungs (89%) may have also contributed to the high early PGD 3 rates and the frequent use of ECMO as a second hit to donor lungs, which already have a disrupted vascular integrity.

Finally, it appears that use of our hybrid EVLP protocol was not as effective in terms of conversion rate and possibly 1-year survival after transplant as the Lund protocol, suggesting that mixing elements of established protocols is not advisable and that matching the appropriate protocol to the appropriate EVLP circuit is an important consideration.

Overall, our main conclusion is that EVLP using a Lund protocol has the potential to offer an increased chance of achieving effective lung transplant in patients at high risk of death on the waiting list.

The DEVELOP-UK study implications for future research

After completing a study of the complexity of DEVELOP-UK, it is important that time is taken to reflect on what lessons can be learnt and how these should guide future research in this area. Although the overall findings of the DEVELOP-UK study were not what was hoped for, and did not allow the original research question to be definitively answered, there are still a significant number of factors to consider that will help to direct further research in the area of EVLP.

Contributions of authors

Andrew Fisher (Professor of Respiratory Transplant Medicine) was the study chief investigator, designed the study, was principal applicant for funding, wrote the study protocol, supervised the overall conduct of the study, interpreted study data, and co-wrote and edited the final report.

Anders Andreasson (Clinical Research Associate in Cardiothoracic Surgery) conducted the Newcastle EVLP assessments, collected and interpreted study-wide data, and co-wrote and edited the final report.

Alexandros Chrysos (Research Associate in Health Economics) collected and interpreted study data, and co-wrote and edited the final report.

Joanne Lally (Research Associate in Qualitative Research) designed the interview study protocol, conducted participant interviews, collected and interpreted study data and co-wrote part of the final report.

Chrysovalanto Mamasoula (Research Associate in Medical Statistics) conducted the main study analysis and co-wrote part of the final report

Catherine Exley (Professor of Qualitative Health Research) was a co-applicant, secured funding, co-wrote the study protocol, interpreted study data, and co-wrote and edited the final report.

Jennifer Wilkinson (Senior Clinical Trial Manager) led the clinical trials unit teams involvement the study, co-wrote the study protocol, interpreted study data and co-wrote the final report.

Jessica Qian (Trial Manager) was responsible for day-to-day running of the study, co-ordinated communications across sites and managed study governance, and provided editorial input into the final report.

Gillian Watson (Trial Manager) was responsible for day-to-day running of the study, co-ordinated communications across sites and managed study governance, and provided editorial input into the final report.

Oli Lewington (Patient and Service User Representative) represented the views of patients in the design of the study, reviewed and edited all participant documentation, and reviewed the final report and our dissemination strategy.

Thomas Chadwick (Clinical Trials Statistician) designed the statistical plan in the study protocol, was a co-applicant for funding and led the final study statistical analysis.

Elaine McColl (Director of Newcastle Clinical Trials Unit) designed the protocol, was a co-applicant for funding, reviewed study results and edited the final report.

Mark Pearce (Professor of Applied Epidemiology) designed the protocol, was a co-applicant for funding, led the survival modelling analysis, reviewed study data and contributed to the final report.

Kay Mann (Research Associate in Clinical Epidemiology) conducted the survival modelling analysis, reviewed study results and contributed to the final report.

Nicola McMeekin (Research Assistant in Health Economics) performed part of the health economic assessment study, interpreted results and contributed to the final report.

Luke Vale (Professor of Health Economics) supervised the health economic assessment part of the study, assessed and interpreted data, and co-wrote and edited the final report.

Steven Tsui (Consultant Cardiothoracic Transplant Surgeon) designed the protocol, was a co-applicant for funding, led study activity at his site, reviewed study results and contributed to the final report.

Nizar Yonan (Professor of Cardiothoracic Surgery) designed the protocol, was a co-applicant for funding, led study activity at his site, reviewed study results and contributed to the final report.

Andre Simon (Consultant Cardiothoracic and Transplant Surgeon) designed the protocol, was a co-applicant for funding, led study activity at his site, reviewed study results and contributed to the final report.

Nandor Marczin (Senior Lecturer in Intensive Care Medicine) designed the protocol, was a co-applicant for funding, assisted study activity at his site, reviewed study results and contributed to the final report.

Jorge Mascaro (Consultant Cardiothoracic and Transplant Surgeon) designed the protocol, was a co-applicant for funding, led study activity at his site, reviewed study results and contributed to the final report.

John Dark (Professor of Cardiothoracic Surgery) designed the protocol, was a co-applicant for funding, led study activity at his site, reviewed study results and contributed to the final report.

Data sharing statement

We shall make the study data available to the scientific community with as few restrictions as feasible, while retaining exclusive use until the publication of our major outputs. The data will be made available by contacting the corresponding author.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health.