A randomised controlled study of Bronchoscopic Lung Volume Reduction with endobronchial valves for patients with Heterogeneous emphysema and Intact interlobar Fissures: the BeLieVeR-HIFi study the BeLieVeR-HIFi study

Article history

The research reported in this issue of the journal was funded by the EME programme as project number 10/90/10. The contractual start date was in February 2012. The final report began editorial review in March 2014 and was accepted for publication in March 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The EME editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Pallav L Shah has received consultancy fees from PneumRx and Olympus and organises a bronchoscopy course, which is sponsored by ERBE, Cook Medical, Superdimension, Boston Scientific, Aquilant, Broncus, Pulmonx, Olympus and PneumRx. The valves used were provided by the manufacturer, Pulmonx, free of charge. Pulmonx had no input into trial design, data analysis or data presentation.

Copyright statement

© Queen’s Printer and Controller of HMSO 2015. This work was produced by Zoumot 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.

Lung volume reduction surgery

Novel techniques need to be considered in the context of LVRS. This involves resection of the worst-affected area of emphysematous lung. Lung volumes improve because bullous areas, which expand at the expense of more healthy lung, have been resected and because the remaining relatively healthier lung has greater elastic recoil, allowing it to empty more effectively. 19 The best evidence around the indications for this treatment comes from the National Emphysema Treatment Trial (NETT). 2 This multicentre trial randomised > 1200 patients to LVRS or usual care. An early finding was the identification of a high-risk group [FEV₁ < 20% predicted with either a homogeneous pattern of disease or the carbon monoxide transfer factor of the lung (TL_CO) < 20% predicted]. Subsequent enrolment from this patient group was stopped. Analysis was based on a priori categories of exercise capacity and pattern of emphysema. At 24 months a survival benefit was apparent in surgical patients with a low exercise capacity and upper lobe predominant emphysema. Excluding the high-risk group, procedural (90-day) mortality was 5.5% in the trial, with serious morbidity after LVRS observed in 59% of patients [persistent air leak (33%), respiratory failure (22%), pneumonia (18%), cardiac arrhythmias (24%)]. 2 A subsequent report from the trial demonstrated that the beneficial effects of LVRS were sustained, with increased survival in the LVRS group at a median 4.3 years of follow-up [0.11 deaths per person-year in the LVRS group vs. 0.13 deaths per person-year in the medical group; risk ratio 0.85, p < 0.02]. 20 Patients with upper lobe predominant emphysema and low baseline exercise capacity showed the largest benefit, with > 70% still alive at 5 years compared with < 50% of those treated medically (risk ratio 0.57, p < 0.01). This group also had improvements in exercise capacity (p < 0.001) and quality of life (p < 0.001). The cost of LVRS was US$140,000 per quality-adjusted life-year (QALY) gained at 5 years and was projected to be US$54,000 per quality-adjusted life-year gained at 10 years. 21 National and international guidelines now recommend that LVRS be considered in patients with upper lobe predominant disease and low exercise capacity. 22,23 The previous single-centre study performed at the Royal Brompton Hospital yielded similar results. 1,24 It should be noted that morbidity and mortality with modern LVRS practice [unilateral video-assisted thoracoscopic surgery (VATS)] are lower than in the NETT trial, in which bilateral procedures through a median sternotomy were performed. 2,4

Spiration valve

Spiration Incorporated (Redmond, WA, USA) developed an umbrella-shaped device that, when expanded, allows air and secretions to leave but not enter the occluded lobar segment. A central proximal rod can be grasped to collapse the umbrella and allow it to be removed. In a multicentre pilot trial of 91 patients with severe heterogeneous emphysema, a mean of 6.7 valves were inserted per patient, resulting in nine pneumothoraces and one fatality. 25 Although quality of life improved in this unblinded study, lung function did not improve. This may be because a non-lobar approach (e.g. targeting only two out of three right upper lobe segmental bronchi) was adopted. A double-blind, multicentre, randomised controlled trial using this device in 73 patients reported that, although non-lobar occlusion with the intrabronchial valve (Olympus, Tokyo, Japan) was safe, it was also generally ineffective. 26

Polymeric lung volume reduction

Polymeric lung volume reduction (Aeris Therapeutics Incorporated, Woburn, MA, USA) involves deployment of a biodegradable gel into subsegmental bronchi bronchoscopically. The solution, which contains aminated polyvinyl alcohol and glutaraldehyde, creates a hydrogel foam when delivered to the distal airways. As gas within the foam (which fills damaged alveoli) is absorbed, the foam, which is now adherent to the alveolar tissue, collapses and as it does so it reduces lung volume and hyperinflation. An open-label multicentre exploratory Phase II clinical study with polymeric lung volume reduction hydrogel administered to eight subsegmental sites in 25 patients with upper lobe emphysema showed improvements in lung function and functional parameters, which persisted at 6 months. 27 The safety profile was acceptable in this study; however, the Medicines and Healthcare products Regulatory Agency has objected to the use of the AeriSeal^® system in the UK on the grounds of patient safety, because of the presence of potentially toxic glutaraldehyde in the gel and two deaths in preliminary studies.

Bronchoscopic thermal vapour ablation (‘steam’)

The bronchoscopic thermal vapour ablation system (Uptake Medical, Seattle, WA, USA) delivers heated water vapour bronchoscopically, via a dedicated catheter, into the targeted emphysematous lung segments. The delivered heat causes acute tissue injury, which is followed by scarring and fibrosis, leading to lung volume reduction. In a pilot safety and feasibility study, Eberhardt et al. 28 unilaterally treated 20 patients with heterogeneous emphysema. Two patients developed pneumonia with a prolonged hospital stay, but all patients showed physiological benefits at 30 days. Longer-term follow-up data are not yet available.

Bronchoscopic instillation of autologous blood for volume reduction

The use of autologous blood and fibrinogen to trigger a scarring response and achieve volume reduction could avoid the need for expensive devices, and expensive and potentially toxic agents. Pilot work in Japan has shown promise29 and further trials are under way.

RePneu Coil^© lung volume reduction

The RePneu^© Coil (PneumRx Inc., Mountain View, CA, USA) is an implantable coil-like device comprising Nitinol, a super-elastic shape memory alloy. The implant is delivered bronchoscopically under fluoroscopic guidance into the targeted airways and when its sheath is removed it recoils to its original shape, preventing expansion of lung tissue. It may also act as a tensioning stent preventing larger airway collapse. A multicentre randomised controlled trial in heterogeneous emphysema has shown encouraging results, with significant improvements in lung function. 30 Safety data after more than 1350 coils have been implanted in 164 patients have shown no deaths, no device migration or expectoration, six pneumothoraces (resolved quickly with intercostal chest drain insertion) and nine cases of pneumonia in eight patients (which did not require a prolonged hospital stay). 30–34 Preliminary data suggest that the improvements seen are sustained for at least 1 year. 35

Airway bypass stents

Exhale^® Airway Bypass drug-eluting stents (Broncus Inc., Mountain View, CA, USA) are placed bronchoscopically through cartilaginous airways into emphysematous lung parenchyma. CT mapping is used to target the areas with the most severe emphysema and a Doppler probe is used to avoid airway wall blood vessels. Initial pilot data in patients with homogeneous emphysema showed encouraging persistent benefits with regard to physiological and functional parameters at 6 months. 36 However, a double-blind multicentre pivotal trial has been disappointing. 37 Significant reductions in lung volumes were seen immediately post procedure but these did not persist. This appears to be because of a loss of stent patency. Although the concept of transbronchial airway bypass has been proven, the problem of stent occlusion will need to be addressed before it can be of value for patients.

Percutaneous transpleural airway bypass (‘spiracles’)

An alternative to the transbronchial approach to airway bypass is to create a transpleural pneumonostomy. This is similar to an intrabullous drainage procedure (the Brompton/Monaldi technique38) but with a permanent track being fashioned to allow a pathway for air to escape. The Portaero Pneumostoma System (Portaero Inc., Cupertino, CA, USA) creates a pneumonostomy channel through a minimally invasive transthoracic surgical approach in a procedure that takes approximately 1 hour to complete. The patient is required to change the Portaero tube daily to maintain patency. This has now been trialled in six patients with encouraging results. 39 In the four patients who retained the bypass tube for ≥ 3 months there was a 23% increase in FEV₁.

Airway bypass techniques depend on collateral ventilation to be effective and are therefore likely to be most effective in patients with homogeneous disease and are less relevant to the population targeted in the present study.

Rationale for the Bronchoscopic Lung Volume Reduction with endobronchial valves for patients with Heterogeneous emphysema and Intact interlobar Fissures study

The Bronchoscopic Lung Volume Reduction with endobronchial valves for patients with Heterogeneous emphysema and Intact interlobar Fissures (BeLieVeR-HIFi) study involved the prospective, independent validation of the use of a medical device, the Zephyr endobronchial valve, through a double-blind randomised controlled trial. The population was patients with severe or very severe COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III and IV] with a heterogeneous pattern of emphysema and intact interlobar fissures. The intervention was the placement of endobronchial valves to achieve lobar occlusion. The comparator was a control group who had a bronchoscopy and ‘sham’ valve placement. Outcomes were change in lung function, exercise capacity and health status 3 months post procedure.

The project fitted the National Institute for Health Research Efficacy and Mechanisms Evaluation programme remit because there was some initial evidence that endobronchial valves were effective but it had not been shown that a population of responders could be identified prospectively to give evidence for effect size. Inconsistency of response, probably because of collateral ventilation between lobes where the interlobar fissures are incomplete, has been a major problem in refining the use of this therapy. We aimed to demonstrate efficacy under ideal conditions, conducting the trial at a highly experienced centre and recruiting patients carefully but in a transparent and reproducible way. Confirming the effect on lung function and exercise capacity would be an essential step to allow commissioners to consider whether or not they wished to support this form of treatment.

Although a positive outcome of the trial could lead to more widespread use of bronchoscopically deployed valves, which would be of interest to device manufacturers, a potential strength of our non-commercial study was that we would define a narrow subset of patients who experience a substantial benefit, whereas commercial trials will tend to try to identify as wide a population as possible. Use of valves in patients with emphysema outside the criteria defined in this trial would need to be justified by subsequent studies.

Study hypotheses

Studies have to date demonstrated some dramatic responses to the placement of endobronchial valves in COPD but modest overall group benefits. We hypothesised that it would be possible to identify a group of COPD patients prospectively with heterogeneous emphysema and intact interlobar fissures in whom lobar occlusion, and hence lung volume reduction, could be achieved, both to a significant degree and consistently. The study therefore addressed the following questions, with outcomes assessed at 3 months post procedure:

1. Does endobronchial valve placement in this subgroup of COPD patients lead to a significant improvement in airflow obstruction (FEV₁) compared with control patients?

2. Does endobronchial valve placement in this group lead to significant improvement in lung volumes [residual volume (RV), total lung capacity (TLC) and functional residual capacity (FRC)] measured by body plethysmography compared with control patients?

3. Does endobronchial valve placement in this group lead to a significant improvement in exercise capacity (endurance time at 70% of maximum workload) and dynamic hyperinflation measured during endurance cycle ergometry as isotime end-expiratory lung volume (EELV)?

4. Does endobronchial valve placement lead to an improvement in walking distance assessed using the 6-minute walk test?

5. Does endobronchial valve placement in this group lead to a significant improvement in health-related quality of life?

6. Will the benefit seen in this group be of a magnitude likely to be sufficient to justify the cost of the procedure and complications that occur?

Sponsorship, ethics and registration

The study sponsor was Imperial College London. The study was approved by the London – Bentham Research Ethics Committee (reference 11/LO/1608). All patients gave written informed consent to participate. The trial was registered as ISRCTN04761234. The study design and trial protocol have been published previously. 15

Public and patient involvement

The initial study design was discussed with the Kensington and Chelsea Breathe Easy group. Once the scientific results are published we will work with the British Lung Foundation and the Imperial College and Royal Brompton media departments to ensure that they are disseminated appropriately.

Study design

The study was a double-blind, randomised, sham-controlled trial to investigate the effect of BLVR with endobronchial valves in patients with severe (GOLD stage III and IV) heterogeneous emphysema and intact interlobar fissures.

Patient recruitment

Patients were recruited from the advanced COPD clinic at Royal Brompton Hospital between March 2012 and September 2013. When clinically appropriate, patients had investigations including thoracic CT scans and pulmonary function tests to assess their eligibility for LVRS. All patients were discussed in a multidisciplinary meeting including a respiratory physician, a radiologist and a thoracic surgeon with additional physiotherapy and nursing input.

Inclusion criteria were as follows:

1. Adult patients with stable severe COPD (GOLD stage III or IV with FEV₁ < 50% predicted).

2. Medical Research Council (MRC) dyspnoea score between 3 and 5.

3. TLC > 100% predicted and RV > 150% predicted, assessed using body plethysmography.

4. 6-minute walk distance of < 450 m.

5. Patient on optimum medical therapy including inhaled corticosteroids and long-acting beta2-agonist and anticholinergic agents unless intolerant or declined to use them.

6. Thoracic CT scan demonstrating heterogeneous emphysema with a defined target lobe with lung destruction and intact adjacent interlobar fissures. Scans were reviewed by two radiologists independently and a third adjudicated on any disagreements. Radiologists agreed that the worst-affected lobe of the lung has an emphysema score of > 2 (according to the NETT scoring system), that it is at least 1 point higher than the ipsilateral lobes and that it has intact fissures visible on at least one projection.

Exclusion criteria were as follows:

1. significant comorbidity that limits exercise capacity or prognosis

2. significant daily sputum production

3. hypoxia [i.e. arterial oxygen tension (PaO₂) < 6.5 kPa while breathing air]

4. smoker.

Outcome measures are described in detail later in this chapter. At baseline patients underwent full pulmonary function testing, a thoracic CT scan and a 6-minute walk test. Health status was also assessed. A symptom-limited incremental exercise test on a cycle ergometer was performed and then an endurance cycle test at 70% of peak workload with measurements of IC to track dynamic lung volumes. These measures were repeated at 90 days.

Flow through the study is described in Figure 3.

FIGURE 3.

Study flow chart. 6MWT, 6-minute walk test; CAT, COPD Assessment Test; CXR, chest radiography; FFM, fat-free mass; MDT, multidisciplinary team; PFT, pulmonary function test.

Randomisation and blinding

Two separate teams were used to maintain blinding. A treatment team (PLS, ZZ, WHM) undertook the randomised procedures and a separate assessment team (CD, MIP, NSH) was blind to study assignment and responsible for the assessments. This approach has been successfully employed in previous trials of bronchoscopic therapies for emphysema. 37

A random sequence with block randomisation was generated by trial statistician Winston Banya. Treatment allocation was obtained by the treatment team by telephoning the Imperial Clinical Trials Unit (ICTU) hotline from the bronchoscopy suite once the patient had been sedated.

Sample size

We considered an absolute difference in response between the two arms of 15% to be clinically significant. For 80% power and a significance level of 0.05, 21 subjects would be needed in each arm assuming that the mean change in FEV₁ from baseline in the control group was 0 [standard deviation (SD) 2.5%] and the mean change in the group receiving BLVR was 15% (SD 25%). To allow for dropout we have increased the sample size target by 20%; hence, we aimed to recruit 50 patients in total.

Outcome measures

Procedures

Study participants underwent bronchoscopy performed using moderate sedation [midazolam (average dose 1.9 mg) and alfentanil (Rapifen^®, Janssen) (average dose 208 µg)]. The average procedure time was 25 minutes. Depending on their allocation patients had either unilateral lobar endobronchial valve placement aiming to achieve lobar atelectasis or bronchoscopy and ‘sham’ valve placement. A single operator (PLS) with expertise in interventional bronchoscopy who had performed > 50 endobronchial valve procedures before study commencement carried out all procedures.

Although target lobe selection was based on CT appearances alone, measurements of collateral ventilation using the Chartis balloon catheter system were carried out in all participants so that the accuracy of the two approaches could be compared. 48 This also served to reinforce blinding of the sham-treated patients as they underwent a ‘procedure’. Endobronchial valves were placed to occlude segmental bronchi leading to the target lobe (irrespective of Chartis results).

Patients underwent post-procedure chest radiography to check for the presence of a pneumothorax, which was reviewed by the treatment team. All were counselled and provided with an information sheet, irrespective of treatment allocation, giving advice on seeking medical attention in the presence of chest pain or sudden breathlessness. Advice was also provided for medical staff for patients presenting as an emergency.

A 1-month follow-up telephone call to ask about any adverse events was also made.

Statistical analysis and presentation

Data were entered into an electronic database developed by the ICTU using InForm version 4.6 (Oracle; Reading, UK) and analysis was performed by the trial statistician (WB) using Stata version 12 (StataCorp LP, College Station, TX, USA) and SAS version 9.3 (SAS Institute Inc., Cary, NC, USA).

Data were monitored by the ICTU with frequency distribution checks carried out on the data for possible outliers. Reference ranges were set before the start of the study and queries were generated on the data for any values that sat outside the predefined ranges.

Analysis was on an intention-to-treat basis as prespecified in a formal statistical analysis plan. Categorical data are presented as percentages and comparisons are carried out using the Pearson chi-square test. Normally distributed numerical data are presented as means with SDs or 95% confidence intervals (CIs). Non-normally distributed numerical data are presented as medians [interquartile ranges (IQRs)]. The two-sample independent t-test was used to compare means between the two treatment groups or the Mann–Whitney test was used for non-parametric data. A post-hoc univariate analysis of factors associated with change in cycle endurance time, using regression with the cluster option, that is, taking into account the paired nature of the data and relaxing the conditions for independence, was performed. A p-value of < 0.05 was taken to indicate statistical significance. Missing data were imputed using the Markov chain Monte Carlo method, which creates multiple imputations by using simulations from a Bayesian prediction distribution.

Collateral ventilation was measured during all bronchoscopies so that outcomes could also be compared across the two groups (excluding collateral ventilation-positive patients in intervention and control groups as predefined groups). A mixed linear model procedure was used to evaluate the effects of predefined covariables on dependent outcome variables.

In addition to this, a responder analysis was performed based on the achievement of minimum clinically important differences (MCIDs) for various parameters, prespecified as a 15% increase for FEV₁, a 350-ml reduction for RV,49 a 4-point decrease for the SGRQc,47,50 a 2-point decrease for the CAT,45,51 a 105-second increase for T_lim52 and a 26-m increase for the 6-minute walk test. 53

Safety data analysis

Safety data were collected during the course of the study. Severe adverse events were defined as those resulting in death, a life-threatening illness or injury, or permanent impairment of a body structure or a body function, requiring hospital admission, prolonging existing hospitalisation or resulting in medical or surgical intervention to prevent a life-threatening illness or injury, or permanent impairment to a body structure or a body function. Pneumothorax was documented on a separate severe adverse event form with addition details.

Adverse events were recorded (severity, outcome, relationship to intervention and action taken). Expected adverse events were defined as (1) related to bronchoscopy – cough, acute exacerbation and haemoptysis – and (2) related to valve placement – pneumothorax, valve expectoration and acute exacerbation.

Adverse events

Adverse events are outlined in Table 9. There were two deaths in the treatment arm before 90 days. One patient developed a troublesome cough and a decision was taken to remove his valves 49 days after they had been placed. At the time of removal a tension pneumothorax developed with an ongoing significant air leak. He progressed to respiratory failure, dying 17 days later despite intensive care treatment including endotracheal tube intubation and use of a Novalung device (Novalung^® GmbH, Heilbronn, Germany). The second patient died suddenly 3 days after valve placement. At post mortem there was no evidence of pneumonia or pneumothorax and a diagnosis of death from COPD with cor pulmonale was made.

One patient in the control group was too unwell to attend for follow-up because of a spontaneous pneumothorax with prolonged air leak, with onset 66 days after his sham bronchoscopy. In addition, two patients in the treatment arm had pneumothoraces, which both responded to intercostal tube drainage, one at 3 and one at 12 days post procedure.

Four patients expectorated a valve before 3 months. These were replaced in three out of four individuals before their follow-up visit. The patients were instructed not to inform the assessment team of these additional procedures.

In one patient the valve was removed because the patient felt more breathless and had an externally audible wheeze. This was because of a high degree of collateral ventilation and continuing expiratory airflow through the valve. Removal was uneventful.

Significance of the findings

The data suggest that, in appropriately selected patients, endobronchial valve placement results in improvements in lung function that are of a similar order of magnitude to those that have been seen with LVRS. 1,2,4 This prospective study confirms the retrospective analysis of the VENT trial. 17 When collateral ventilation is absent, lobar atelectasis is more likely to occur, which is a key determinant of effectiveness associated with improved lung function response6,17 and survival. 14

There is a significant overlap between the indications for BLVR and those for LVRS and it may be that a stepwise approach with bronchoscopic techniques considered at an earlier stage to defer, prevent or act as a bridge to LVRS is required. Alternatively, it may be that LVRS is the definitive treatment that should be offered earlier. Prospective trials comparing LVRS and valve placement will be needed to clarify this.

The scale of potential valve treatment remains to be established. It has been estimated that about 16,000 COPD patients in the UK may be eligible for LVRS and, given the powerful evidence base, the lack of a systematic approach to this is a failure of the UK and other health systems. 4,55,56 There are so far no reliable data on the proportion of patients who have intact interlobar fissures and who would therefore be suitable for BLVR, but it is likely that several thousand UK patients could benefit.

Safety

In part, bronchoscopic treatment for emphysema has been developed for people considered to be too disabled to withstand LVRS, but caution is needed given the pneumothorax risk. Pneumothorax can occur when valve placement leads to a change in the conformation of the lung, producing tears in the lung parenchyma. Pneumothorax is therefore, to an extent, a marker of effective lobar occlusion. As such, better patient selection will mean an increase in the pneumothorax rate to levels much higher than in trials to date, in which patient selection has been poor. In the present study it occurred in two treated patients (8%) and there was also one spontaneous pneumothorax in a control patient (4%). The management of pneumothorax in this context is conventional, usually with intercostal tube drainage. It is therefore important that patients are selected who are considered likely to be able to withstand the associated acute lung function impairment a pneumothorax will cause. It is likely that the pneumothorax rate in properly selected patients will be between 10% and 20%. Our clinical practice is now to allow an inpatient stay of 3 nights after valve placement, although later pneumothorax can also occur. 6

One death occurred as a result of valve removal, indicated because of a troublesome cough. An important learning point is to limit the force used to try to extract valves and to have a low threshold for abandoning a flexible bronchoscopy approach and converting to a rigid bronchoscopy. This is in general carried out by a thoracic surgeon and highlights the need for collaboration within an integrated team. The other death was not obviously mechanistically linked to valve placement and may have been coincidental (as was the pneumothorax in the control patient), although it occurred only a few days after valve placement. It remains to be established what the ‘true’ mortality rate is and it is important to resist extrapolating from a relatively small series. By analogy, we described a zero surgical mortality rate in our experience with unilateral VATS LVRS between 2000 and 2012. 4 It would, however, be absurd to suggest that the ‘true’ mortality rate for LVRS is zero.

Exacerbations have been described previously as a complication of valve placement and early after placement a degree of irritation causing an ‘exacerbation-like’ pattern of symptoms can occur. 6,10,17,26 In the present study, exacerbations occurred in the majority of patients, reflecting the severity of the population, but there was no significant difference in the occurrence of exacerbations between the two study arms.

Although the success rate of valve placement was higher than in previous studies because of the inclusion of only patients with intact interlobar fissures, the presence of collateral ventilation assessed using the Chartis system was associated with no benefit from treatment. The ideal strategy for selecting patients in whom lobar exclusion can be achieved remains to be defined and will remain unclear as refinements in technology and CT scoring of fissure integrity evolve. Direct measurement with the Chartis system is not always possible for technical reasons (approximately 10%) and in other studies it has been assessed as 75% accurate. 57 It adds cost and time to procedures and this will need to be weighed against the likely increase in the responder rate. The positive and negative predictive power of collateral ventilation measured with the Chartis system will vary depending on the CT criteria used in the initial selection strategy. In addition, in some patients ideal positioning of the valves is not possible because of patient anatomy, for example insufficient length of bronchus to place the valve adequately, leading to early expectoration, or difficult access to a particular segment, which may impact on the effectiveness of valves as a treatment strategy.

Methodological issues

A strength of the study was the blinding of patients and assessors. The presence of a sham bronchoscopy procedure meant that a more confident estimate could be made of changes in health status, which have often been large in unblinded studies, even in the absence of significant changes in lung function. 26 The assessment of collateral ventilation in all participants using the Chartis system meant that control subjects also underwent a ‘procedure’, which helped to maintain the blinding. Although subjects in whom a pneumothorax occurred or who expectorated a valve were unblinded, valves are difficult to visualise on chest radiographs and this maintained blinding of physicians and patients alike if they underwent investigations for a clinical deterioration in the absence of a pneumothorax.

Follow-up was for a short period as the purpose of the study was to test the hypothesis that a responder phenotype could be prospectively identified. Previous data have shown that a response to treatment is associated with improved survival in the longer term14 but there has been a need to produce a response rate with treatment that justifies the upfront cost of the procedure. The cohort will be followed up longer term although following the end of the trial patients will be offered the opportunity to have open-label valves or LVRS.

Contribution of authors

Zaid Zoumot, William H McNulty and Pallav L Shah performed the procedures.

Claire Davey performed the assessments.

Simon Jordan, David M Hansell, Michael I Polkey, Pallav L Shah and Nicholas S Hopkinson developed the study.

Denis H Carr, Simon Jordan, Matthew D Hind, Michael B Rubens, Michael I Polkey and Nicholas S Hopkinson were involved in patient selection.

Winston Banya with Nicholas S Hopkinson and Claire Davey developed the statistical analysis plan and performed the analyses.

Zaid Zoumot, Claire Davey and Nicholas S Hopkinson, prepared the first draft of this paper, which all authors subsequently contributed to and approved.

Nicholas S Hopkinson is the guarantor.

Publication

Davey C, Zoumot Z, Jordan S, McNulty WH, Carr DH, Hind MD, et al. Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi study): a randomised controlled trial. Lancet 2015;386:1066–73.

Disclaimers

This report presents independent research. 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, MRC, NETSCC, the EME 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 EME programme or the Department of Health.