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CADTH Health Technology Review
Authors; Nazia Darvesh, Qiukui Hao, and Jennie Horton.
Emphysema is one of a group of lung conditions collectively called chronic obstructive pulmonary disease (COPD)1, which is a disease that worsens over time and causes breathing difficulties, a reduction in quality of life, and potentially serious complications if untreated.1,2 In emphysema specifically, airspaces enlarge, destroying the lungs’ alveoli, affecting air exchange, reducing lung function and resulting in shortness of breath.1,3,4
Globally, COPD is the third leading cause of death and the seventh leading cause of poor health.5 In Canada, 10% of adults and close to 20% of older adults experience the effects of COPD.6 In Canada, trends over time show that both the prevalence of COPD and hospital admissions for COPD have been rising each year.6 Across Canadian provinces, COPD increased from 7.2% to 7.6% between 2019 and 2020 for adults aged 65 years and above.7 COPD hospitalizations in large Canadian cities for people under 75 years increased over time from 83 per 100,000 between 2006 to 2010 to 86 per 100,000 people between 2011 to 2015.8 In Ontario specifically, COPD prevalence increased from 2006 to 2016 in younger and middle-aged adults.9 In Canada, the population level direct annual costs of COPD range from CA$182 to CA$254 million for managing moderate exacerbation and CA$469 to CA$642 million for managing severe exacerbations.10
The social determinants of health affect how COPD manifests6 and may disproportionately affect equity-deserving groups who face barriers to health care access. According to the Canadian Institute for Health Information, between 2011 and 2015, people with COPD in the lowest income quintile had 5.7 times higher hospital admissions compared to those in the highest income quintile;6 this value was 4.5 between 2006 and 2010.8 A study in Toronto, Ontario showed that people with COPD and limited English proficiency were more likely to be readmitted to the hospital.6
Although there is no cure for COPD, medication, procedures, vaccinations, physical activity, and reducing smoke exposure can help people manage it.5 People with more serious emphysema who have tried these methods without success may need lung volume reduction surgery (LVRS), bronchoscopic lung volume reduction (using valves, coils, sealants or vapour ablation), or lung transplant.11
Endobronchial valve treatment is a technique where one-way valves are placed in the lung to reduce trapped air and hyperinflation, to improve a patient’s exercise capacity and quality of life.3 Endobronchial valves may be preferred because they are less invasive than LVRS or transplants, involve no stitches or incisions, which reduces the chance of infections, have shorter recovery times, may be less painful, and are removable;12 however there can also be complications such as pneumothorax, hypoxemia, central airway distortion, pneumonia, or COPD exarcerbation.3
In the US, 2 endobronchial valves are US FDA-approved; in Canada, 1 of these has a Health Canada medical device licence.13
Respirologists in Canada are increasingly interested in the applicability of endobronchial valves as an alternative therapy for people with severe emphysema who have tried medication. In 2019, CADTH published a Rapid Review summarizing the clinical effectiveness of endobronchial valves from literature published between 2014 and 2019.14 The current report aims to update this information to include any new information on clinical effectiveness published since then. In addition, the current report includes a second research question to determine the cost-effectiveness of endobronchial valves. This will provide decision-makers with updated information on clinical effectiveness to review together with the previous CADTH report 14 and refer to more recent summarized information on cost-effectiveness.
To support decision-makers on the clinical effectiveness and the cost-effectiveness of endobronchial valves for people living with severe emphysema.
The literature search strategy used in this report is built upon one developed for a previous CADTH report.14 For the current report, an information specialist conducted a literature search on key resources, including MEDLINE, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were emphysema and endobronchial valves. The search was completed on November 25, 2023 and limited to English-language documents published since January 1, 2018.
One reviewer screened citations and selected studies. In the first screening level, we reviewed titles and abstracts and then retrieved and assessed potentially relevant full-text articles for inclusion. Since this report updates evidence from a previous CADTH report,14 we only included articles if they were made available since the previous search date and were not included in the 2019 CADTH report.14 We selected the final set of full-text articles based on the inclusion criteria in Table 1.
Selection Criteria.
We excluded articles if they did not meet the selection criteria outlined in Table 1, were duplicate publications, or were about interventions applied after endobronchial valve failure. We excluded systematic reviews or randomized controlled trials (RCTs) if the evidence was already captured in the previous CADTH report.14
One reviewer critically appraised RCTs using the Downs and Black checklist15 and economic evaluations using the Drummond checklist.16 We did not calculate summary scores for the included studies; rather, we narratively describe the strengths and limitations of each included publication in this report.
CADTH recognizes the need for and importance of equity considerations in health technology reviews. In this Rapid Review, we used PROGRESS-Plus17 to guide data extraction and report writing. We did not explicitly search for information related to inequity or equity-deserving groups and their access to endobronchial valves.
This report includes evidence from 3 RCTs18-20 for clinical effectiveness and 2 economic evaluations21,22 for cost-effectiveness. We did not identify any systematic reviews or health technology assessments that met the inclusion criteria and whose evidence was not already summarized in the 2019 CADTH report.14
Appendix 1 presents the PRISMA23 flow chart of the study selection and Appendix 5 includes additional references of potential interest.
Appendix 2 contains detailed characteristics of included publications.
Of the 3 included RCTs,18-20 118 is from the single-blind CELEB trial, which compared endobronchial valves to LVRS and was not reported in the previous CADTH report.14 Two RCTs19,20 reported longer term follow-up from the open-label trials EMPROVE and IMPACT reported in the previous CADTH report14 and each used different valve types compared to standard care. The 3 RCTs18-20 were all conducted in North American or European centres and the mean population age was between 64.0 and 66.7 years.
The RCTs included 3 different clinical populations: heterogeneous emphysema and no collateral ventilation,18 severe heterogeneous emphysema with little-to-no collateral ventilation,19 and severe homogeneous emphysema with little-to-no collateral ventilation.20 Although 1 study18 did not explicitly describe emphysema as severe, the study population had “significant hyperinflation” and was therefore included in this report.
Two articles reported gender,18,19, which were 41.2% to 53.7% females and 46.3% to 58.8% males across study groups. These 2 articles18,19 did not report how sex and gender were defined or measured and did not report on other genders. The third included article20 did not report sex or gender at all. One study18 included self-reported ethnicity of 100% white, 0% Middle Eastern in the intervention group and 97.6% white, 2.4% Middle Eastern in the comparator group; the other studies did not report on race or ethnicity. No studies reported on other PROGRESS-Plus criteria,1,7 such as place of residence, occupation, religion, education, socioeconomic status, social capital, or disability status.
Outcomes across studies included:
Both cost-effectiveness studies21,22 evaluated the same endobronchial valve type in people with severe emphysema. One study22 compared the cost-effectiveness of endobronchial valves to standard care while the other study21 compared endobronchial valves to LVRS.
The study21 comparing valves to LVRS used a within-study time horizon (mean 81 days) and was from the payer’s perspective (using health insurance and a service-providing hospital in in Switzerland). Data on effectiveness were from 1 retrospective study performed in a single centre in Switzerland, with the costs calculated based on the SwissDRG system during hospital stay and the number of valves implanted.21 The study enrolled 67 patients with pulmonary emphysema and hyperinflation; the intervention group had a mean age of 70 years and were 51% female, while the surgical group had a mean age of 66 years and were 37% male.21 Cost-effectiveness was evaluated based on 3 clinical outcomes: either FEV1, residual volume, or 6MWD.21 The authors reported the incremental cost-effectiveness ratios (ICERs) for endobronchial valves compared to LVRS for each clinical outcome, however, the main assumptions of the cost-effectiveness models were not clearly reported.21
The study22 comparing valves to standard care used 2 time horizons (6 months and 10 years) and was from the Dutch hospital and health insurance perspective. The study enrolled 68 people with severe emphysema from the STELVIO trial. The STELVIO trial results were included in a systematic review captured in the previous CADTH report.14 The mean age was 59 years and 68% were female.22 The effectiveness of the intervention was measured using data from the STELVIO trial, which used the EuroQol5-Dimensions (EQ5D) and the SGRQ to measure health-related quality of life, and the 6MWD to measure exercise capacity.22 Dutch tariffs were used to determine the utility values corresponding to EQ5D scores.22 Additionally, an established algorithm was used to predict EQ5D utility scores using the SGRQ score.22 The economic evaluation only included direct medical costs and was calculated from the perspective of Dutch health insurance at the 2016 price level.22 ICERs per quality-adjusted life-year (QALY) gained were calculated at 6 months and 10 years after the intervention.22 The cost-effectiveness analysis assumed that there would be no transitions on disease progression after 6 months from the intervention until death.22 The Markov model for the long-term time horizon (10-years) was initialized with 100 patients in each group, and the average age of patients at the start of the simulation was 50 years.22
Appendix 3 contains detailed about strengths and limitations of included publications.
The 3 RCTs’18-20 strengths included clear reporting and descriptions of objectives, participant eligibility criteria, trial registration, interventions, comparators, outcomes, loss to follow-up information, and adverse events. The trials18-20 were also randomized and authors reported that study groups were comparable. The primary outcome in 2 trials19,20 was FEV1, a measure of lung function using a spirometer machine24 and in 1 trial was BODE.18
In 1 RCT,18, the primary outcome assessor was blinded to study assignment; however, a limitation was that the participants and trial coordinator were not blinded. The other 2 RCTs19,20 had no blinding. It may have been difficult to blind participants or researchers since the intervention involved a specific procedure; however, knowledge of study assignment may have introduced performance bias (e.g., participants being treated differently if researchers knew what treatment they received, participants self-reporting outcomes differently if they knew what study group they were in) or detection bias in the 2 RCTs19,20 where outcomes assessors were not blinded.
Although the 3 RCTs18-20 took place across multiple centres, which may have the potential to include more variable populations, results from each specific study may not be generalizable to people who do not match the specific population in each trial based on age, emphysema type, comorbidity exclusion criteria, or collateral ventilation in lung alveoli, which is a limitation. For example, the 3 RCTs18-20 were conducted in middle-aged and older adults, so the results are not generalizable to children or younger adults.
Other limitations were inadequate power for safety outcomes in the IMPACT trial results,20 a nonvalidated primary outcome in the CELEB trial (as indicated by study authors),18 missing outcome data due to delays in study visits because of the COVID-19 pandemic in the CELEB trial,18 variability in post-intervention care for participants in the CELEB trial,18 and patient-reported outcomes such as CAT score and dyspnea in all included trials,18-20 which may have biased outcomes since participants were not blinded. The CELEB trial18 addressed missing data by imputation and sensitivity analyses, showing similar results for BODE and a smaller difference between groups for CAT score.
There may have been potential conflicts of interest because multiple study authors from 2 RCTs18,20 received funding or resources from PulmonX, a manufacturer of endobronchial valves, and in the third RCT,19 the funder, Olympus Corporation, was involved in study aspects such as trial design, review, and clarification of study methods. It is unclear whether this affects results for the trials19,20 that showed favourable effects for valves.
The economic evaluation studies21,22 outlined their research questions, the form of economic evaluation, and the analysis perspectives. The study design, data collection, and outcome measures were also well-defined.21,22 The authors of the 2 studies21,22 presented their conclusions with appropriate caveats. The directions of the intervention effectiveness measures were consistent with the previous CADTH report14 and the current report. However, the magnitudes of the effectiveness were based on single studies with small sample sizes (n = 67 for the retrospective study and n = 68 for the RCT) rather than systematic reviews or meta-analyses of estimates from multiple sources.21,22 Additionally, the 2 studies21,22 lacked details on currency price adjustments for inflation or conversion. Economic evaluation studies were based on the payer’s perspectives in Switzerland21 or the Netherlands22 and may not apply to the health care system in Canada.
The study21 comparing vales to LVRS lacks details on the cost-effectiveness models and model assumptions. The statistical analysis for effectiveness did not account for possible confounding variables, and the follow-up for effectiveness data differed between the intervention and control groups (mean 63 versus 103 days, P = 0.0001).21 Additionally, the quantities of resources were not reported separately from costs, and sensitivity analyses were not performed.21 The disaggregated form of the reported ICERs for FEV1, residual volume, and 6MWD were not provided.21 The time horizon or observation period for cost-effectiveness may be considered relatively short (mean 81 days) when considering pulmonary emphysema as a chronic condition.21
In the other study,22 cost-effectiveness models only considered direct medical costs and assumed no transitions between disease progression 6 months after treatment.22 The methods for estimating quantities and unit costs were not provided.22 The effectiveness estimates were taken from the STELVIO trial, which was an RCT, however the baseline measures for EQ5D score were not well-balanced between the intervention and comparator groups; the comparator group had a higher score than the intervention group meaning the ICERs (which were based on the EQ5D scores) were not reliable, particularly at 6 months.22
Appendix 4 presents the main study findings.
No outcomes showed effectiveness for valves compared to LVRS.
The following outcome showed effectiveness for LVRS compared to valves:
The following outcomes showed little-to-no difference between valves and LVRS:
The following outcomes showed effectiveness for valves compared to standard care:
The following outcomes showed little-to-no difference between valves and standard care:
The following outcomes showed mixed results for valves and standard care:
Where statistical significance was reported in studies, safety outcomes showed little-to-no difference between endobronchial vales and standard care or LVRS for adverse events,18 COPD exacerbations,20 death,19 pneumothorax,19,20 or serious adverse events.19,20 None of these safety outcomes were reported with uncertainty in the estimates or in individual groups, so the precision of these findings is unknown, and no treatment effects comparing intervention and comparator groups were provided, only the P values.
One study21 reported the ICERs for endobronchial valves compared to LVRS, but these numbers are difficult to interpret. We noted that the cost per unit of FEV1 improvement was higher in the endobronchial valves group compared to LVRS, while the cost per residual volume (mL) and 6MWD (metres) was lower in the endobronchial valves group compared to LVRS.21 The results indicate that the endobronchial intervention may not be cost-effective according to FEV1.It could be a cost-effective alternative to LVRS based on residual volume and 6MWD; however, the willingness-to-pay threshold was not reported.21
Endobronchial valves have a favourable cost-effectiveness profile compared to standard care, particularly for the long-time horizon of 10 years.22 The assumption of a discount increased the ICER-Cost, which indicates the endobronchial valves were less cost-effective after the discount because the discount assumption had a greater effect on life-years than on costs.22 The details of the cost-effectiveness profile after considering the discount (annual discount rate of 4%) are:
The clinical and cost-effectiveness studies were conducted in adults and older adults, so the applicability to younger adults and children, given that more younger adults have been developing COPD over time, is unclear.9 One clinical study was conducted in Canada,19 while the rest were conducted in the US and European countries; similarly, the cost-effectiveness studies were based on payers’ perspectives in Switzerland21 and the Netherlands.22 As a whole, the generalizability of these findings to settings in Canada is unknown because of where the research was conducted and because Canada does not currently offer multiple valve types for treatment.
The clinical studies all had sample sizes of less than 115 total, and no intervention or comparator groups had more than 80 participants; the magnitude of the treatment effects reported may not be as precise as they would be if the studies had larger sample sizes. Another limitation of the clinical studies was the variety of ways that effectiveness or safety were measured in the included studies. The evidence included 13 measurements or scales for effectiveness and 7 measures for safety. Given the variability in measurement tools and their results, it is unclear how some evidence can be compared across studies using different outcome measurements. Clinical studies also had poor reporting of safety outcomes; study authors provided P values for the difference between groups but no treatment effects comparing groups were reported.
The quality of the economic evaluation studies was low; 1 study21 had unclear models and assumptions in their cost-effectiveness analysis, while the other study22 assumed that the COPD severity would remain the same 6 months after the intervention. We are unsure how these limitations affect the certainty or direction of the evidence.
No clinical or economic studies described how gender or sex were defined and did not include gender identities outside of male and female. We retained the original term that the study authors used when describing sex or gender. One clinical study reported on ethnicity for a population that was more than 97% white in both intervention and comparator groups, and no clinical or economic studies reported on other PROGRESS-Plus criteria,17 or discussed these criteria in the context of the results. Because of this limited information, the generalizability of the evidence is unclear and potential health inequities are unknown. It is unclear whether the study populations included people from equity-deserving groups or whether these groups have access to the intervention. This Rapid Review did neither include a formal evaluation of the equity considerations for people with severe emphysema who may be eligible for receiving endobronchial valve treatment, nor did it search explicitly for information related to inequity or groups with this condition that may be underserved. PROGRESS-plus17 was used to guide our data extraction and discussion of whether dimensions of equity were reported and where there may be gaps in the included evidence.
We conducted a Rapid Review to update evidence from a 2019 CADTH report13 and provide new information on the clinical effectiveness of endobronchial valves for people with severe emphysema; we also included economic evaluations to determine the cost-effectiveness of endobronchial valves, which was not reported on in the previous review. We found 5 studies with evidence published since 2018; 3 RCTs18-20 on clinical effectiveness and 2 economic evaluations21,22 on cost-effectiveness.
This Rapid Review shows that different valve types are effective compared to standard care based on lung function, breathing ability, and physical activity measured through a walking test. One valve type19 showed little-to-no difference in well-being, lung function responders, and survey-measured physical activity. The previous CADTH review13 showed similar results; lung function, breathing ability, and physical activity were favourable for valves compared to standard care. The current review suggests that quality of life measured through CAT scores has mixed results, with 1 valve type19 being favoured over standard care and another valve20 showing little-to-no difference between groups; the previous CADTH review13 showed favourable results for quality of life outcomes for different valves compared to standard care. The previous CADTH review13 showed increased adverse events in valve groups compared to standard care; however, in the current review, safety was difficult to assess due to poor reporting.
The current review suggests that there is no evidence for the effectiveness of 1 valve type18 compared to LVRS; quality of life was more favourable in the LVRS group compared to the valve group, however all other outcomes (lung function, body composition, breathing difficulty, physical activity) showed little-to-no difference.18
Of the 2 economic evaluations identified for the same valve type, 1 study22 showed favourable cost-effectiveness compared to standard care, particularly at a longer time horizon, and another study21 showed valves were not cost-effective compared to LVRS based on 1 lung function outcome, but a cost-effective alternative to LVRS based on a different lung function outcome and a physical activity outcome based on a walking test.
Across the 5 included studies, only 1 RCT had participants in Canada;19 generalizability of the evidence to the Canadian context is unclear. All studies included research conducted in middle-aged and older adults; it is unclear whether the findings apply to younger age groups. Similarly, since there was limited information on equity-deserving groups, it is unclear whether they have access to the intervention and how it might affect them. All studies had small sizes so it is unknown whether the treatment effects could have been more precise with larger sample sizes. While 1 RCT had a blinded outcome assessor,18 participants across all studies were not blind to study assignment, and it is unclear how this may have affected outcome measurement.
Further high-quality clinical research (including larger sample sizes, better safety outcome reporting, and blinding where feasible) may be needed in the following areas: different valve types compared to LVRS, inclusion of younger populations, implementation of more research in Canada, and clear inclusion of equity-deserving groups. The following factors may need to be considered in future economic evaluations: cost accounting for currency price changes for inflation or conversion, efficacy based on a high-quality systematic review(s), acceptable and unambiguous model assumptions, and inclusion of broader perspectives such as the social perspective.
Decision-makers can use CADTH evidence from the current and 201913 reports to assess the clinical- and cost-effectiveness of endobronchial valves compared to standard care or LVRS, keeping in mind the safety risks reported in the previous CADTH report13 and unclear safety outcomes in the current report. Health care providers may also wish to consider the training involved with the valve procedure, how patients are selected for treatment, the resources required to conduct the procedure (e.g., number of valves, time required, hospital stay), patient preferences, and safety risks.13 Given Health Canada’s existing licence for 1 valve type,13 there may be an interest in considering this treatment for people with severe emphysema who have not experienced favourable outcomes from non-invasive therapies such as medication, physical activity, or smoking reduction.
6-minute walking distance
COPD assessment test
chronic obstructive pulmonary disease
EuroQol5-Dimensions
forced expiratory volume in 1 second
incremental cost-effectiveness ratio
lung volume reduction surgery
quality-adjusted life-year
randomized controlled trial
St. George's Respiratory Questionnaire
Contributors: Chris Kamel, Shannon Hill
Selection of Included Studies.
Note that this appendix has not been copy-edited.
Characteristics of Multicentre Randomized Controlled Trials.
Characteristics of Economic Evaluations.
Note that this appendix has not been copy-edited.
Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist.
Strengths and Limitations of Economic Evaluations Using the Drummond Checklist.
Note that this appendix has not been copy-edited.
Summary of Findings by Outcome — Effectiveness.
Summary of Findings by Outcome — Safety.
Summary of Findings of Included Economic Evaluations.
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