Global Initiative for Chronic Obstructive Lung Disease (GOLD) defined chronic obstructive pulmonary disease (COPD) as persistent airflow limitation that is progressive in nature and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious elements, which is common and preventable.1 Emphysema is associated with COPD when there are structural changes, which includes abnormal and irreversible enlargement of the airspaces distal to the terminal bronchioles along with destruction of airspace walls without evidence of obvious fibrosis.2 It is estimated that COPD affects >5% of the population and it is ranked the third leading cause of death in the United States, with mortality of >120,000 individuals each year.3
Airway obstruction in COPD can be managed effectively via pharmacotherapy such as bronchodilators, but their mechanism of action may be limited in the emphysema phenotype, where the airflow limitation is due to loss of elastic recoil associated with air trapping causing hyperinflation.4,5 Multiple studies of existing pharmacotherapy or a combination pharmacotherapy along with pulmonary rehabilitation have not been proven to alleviate symptoms or significantly improve long-term lung function and patients remain very disabled.6 This led to therapies such as lung volume reduction surgery (LVRS) for patients with severe emphysema. The National Emphysema Treatment Trial (NETT) compared LVRS with medical therapy and showed significant improvement in survival, exercise capacity and quality of life, especially in patients with upper lobe predominant disease and low baseline exercise capacity.7,8 The eligibility for LVRS is limited by strict patient selection criteria, the choice of surgical techniques to perform LVRS, cost and safety profile. Because of all these factors, LVRS was not widely accepted in the pulmonary community when it was introduced.9 There was no more than an estimated of 300 LVRS performed annually in the United States10 and a review of Society of Thoracic Surgeons was only able to identify 538 LVRS in 8 years.11
Similar concept arose from LVRS to use bronchoscopic method to treat severe emphysema with 1-way bronchial valves without the associated risks in LVRS.12,13 The 1-way valves allow air to leave but not enter the target lobe, causing the affected lung to collapse, which leads to reduction in air trapping and hyperinflation. The relationship of reduction in air trapping and hyperinflation is predicted to show an improvement in the pulmonary function, exercise tolerance, and quality of life in patients with advanced emphysema. This concept has led to multiple randomized controlled trials (RCTs) to compare the efficacy of endobronchial valves (EBV) and standard medical therapy (SMT) or sham procedure. There has yet to be a meta-analysis of randomized trials, with adequate studies to provide a more confident assessment of hard outcomes [forced expiratory volume in 1 second (FEV1)]. Existing meta-analyses included data from both randomized and nonrandomized studies,14,15 and also have limited data on hard outcomes.16 Our aim is to summarize data from RCTs to assess the safety and efficacy of EBV.
A systematic literature review was performed using methods specified in the Cochrane and reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic review and meta-analysis.17 Both controlled vocabulary terms (eg, MeSH) and key words used to search for articles addressing the use of EBV in advanced emphysema. The following databases were searched: PubMed/MEDLINE, Embase, Cochrane Library, Web of Science, EBSCO/CINAHL (Plus with Full Text) and ClinicalTrials.gov. Literature searches were completed on November 2016. Citations to and reference lists within the selected articles were also searched for studies that would meet inclusion criteria. All retrieved references were reviewed to identify prospective randomized trials that compared the clinical outcome of EBV and SMT or sham procedure in advanced emphysema patients. No language or study type restriction was used for initial extraction of the data. No restrictions on the subheadings were applied. All references of relevant trials were also reviewed. We did not limit the language of the manuscript to be included in our meta-analysis.
Our prespecified selection criteria were as follows: (1) RCTs, (2) studies comparing use of EBV versus SMT or sham procedure, (3) study participants who were diagnosed with advanced emphysema, and (4) primary endpoint of outcome is percentage change in FEV1. Exclusion criteria were: (1) studies with inadequate reporting of outcome data to meet our primary endpoint, (2) studies on EBV placement for other reasons besides advanced emphysema. Our primary endpoint was the change in the percentage of FEV1. Other outcomes of interest included other improvement in quality of life and the incidence of adverse events.
Two independent reviewers performed the study selection (S.-W.L., J.Z.L.). In case of disagreements, a third reviewer (H.D.) casts the deciding vote. Titles and abstracts of retrieved references were screened for inclusion and full texts of potential articles were further analyzed to see if they met inclusion criteria. Editorials, letters, case reports, meta-analysis, and systemic reviews were excluded. Both individuals who collected the data used the following study specific characteristics: study name, protocol, follow-up duration, sample size of treatment group and control group, inclusion and exclusion criteria of each study, primary and secondary outcomes event rates, rate of adverse events, and baseline patient characteristics within each study including number of pack years smoking, body mass index, use of oxygen therapy, and baseline arterial blood gas.
Statistical analysis was performed using Review Manager 5.3 software. A study or trial level pooled analysis of the included RCT was performed to evaluate the effect of use of EBV versus SMT or sham procedure in advanced emphysema patients. The analysis was performed according to the intention-to-treat strategy when applicable. Mantel-Haenszel risk ratio with 95% confidence interval (CI) was calculated. A random effects model accounting for both within and between-study variations was used to perform meta-analysis by Review Manager 5.3 software. The weighted mean difference (WMD) in the outcomes along with 95% CIs was estimated. Forest plots were constructed to analyze and report the results. The I2 index was used to summarize the proportion of the total variability in the estimates due to between-study variation. We regarded I2 of <25%, 25% to 50%, and >50% as low, moderate, and high amounts of heterogeneity, respectively. Majority of the RCTs included in our analysis18,19 prespecified their protocol as having the minimum clinically important differences as at least 15% increase or improvement of at least 100 mL and 12%20,21 except Klooster and colleagues who used >10% increase,21 4 points decrease in St. George’s Respiratory Questionnaire (SGRQ)22,23 and increase in 26 m in 6-minute walking test.24 The baseline study characteristics were analyzed to assess the difference in proportions using t test. We separately analyzed the pooled changes in primary and secondary outcomes. All the tests were 2-tailed and a P-value <0.05 was regarded as significant in this meta-analysis.
We found 392 articles through database searching, and of the 264 articles, which remained after duplicates were removed, 228 were excluded because of irrelevance to the topic, abstract, reviews, and animal experiments (Fig. 1). Strict inclusion and exclusion criteria were applied to the full texts where the primary outcome measured was percentage change in baseline of FEV1 when compared with SMT or sham procedure. Hence, we yielded 5 RCTs with 703 patients,18,19,25–27 with 433 patients randomized to receive bronchoscopic lung volume reduction (BLVR) and 270 patients to be in the control group (245 patients received SMT and 25 patients underwent sham procedure). SMT includes smoking cessation, bronchodilators, pulmonary rehabilitation programs, and long-term oxygen therapy.
Patient Characteristics and Interventions
Table 1 summarizes the study characteristics of the 5 included RCTs. All 5 RCTs were prospective, randomized, controlled trials. Among the RCTs, 3 trials18,26,27 had 6 months follow-up and 2 trials19,25 had 3 months follow-up.
Baseline clinical characteristics of selected studies were reported in Table 2. The mean age was 62 years and males accounted for 58% of subjects. Comparison between both patient groups revealed no difference in body mass index (24.1 in EBV group vs. 24.0 in the control group, with P-value of 0.86), number of pack years (55 y in EBV group vs. 48 y in control group, with P-value of 0.41), arterial blood gas values, lung function test, 6-minute walk distance (339.4-m in the EBV group vs. 350.0-m in the control group, with P-value of 0.46), SGRQ scores (62.3 in the EBV group vs. 61.3 in the control group, with P-value of 0.81).
Overall, patients who received EBV showed a significant increase in mean change in baseline of FEV1 when compared with SMT or sham procedure (WMD=11.43%; 95% CI, 6.05-16.80; I2, 57%; P<0.0001) (Fig. 2). The RCTs compared EBV with control (SMT or sham procedure) produced a statistically significant improvement in patient’s SGRQ scores in the EBV arm (WMD=−5.69; 95% CI, −8.67 to −2.70; I2, 42%; P=0.0002) (Fig. 3). Pooled data showed no statistically significant improvement in the 6-minute walk test among patients who received EBV compared with SMT (WMD=14.12; 95% CI, −4.71 to 32.95; I2, 82%; P=0.14) (Fig. 4). All 5 studies revealed no significant difference between mortality rates (1.6% in EBV arm vs. 0.8% in control arm, 95% CI, 0.46-6.99; P=0.40).18,19,25–27 Among studies that only included patients with intact interlobar fissures, or without interlobar collateral ventilation, there was a significant increase in mean change in baseline of FEV1 when compared with SMT or sham procedure (WMD=16.5%; 95% CI, 11.3-21.7; I2, 0%; P<0.0001) (Fig. 5).
Comparing EBV with SMT or sham EBV, there were no significant differences in the rate of massive hemoptysis (0.6% vs. 0%; 95% CI, 0.15-13.50; P=0.76).18,26 EBV also did not increase the risk of COPD exacerbation18,19,25–27 (23.7% vs. 25.4%; 95% CI, 0.74-1.68; P=0.61), pneumonia18,19,25–27 (3.5% vs. 1.6%; 95% CI, 0.64-5.10; P=0.27), respiratory failure18,19,25,26 (2.0% vs. 1.4%; 95% CI, 0.36-3.76; P=0.81), and no empyema was found in all cases. However, there was a significant increase in incidence of pneumothorax in EBV group compared with SMT or sham EBV18,19,25–27 (7.0% vs. 0%; 95% CI, 2.21-30.11; P=0.002), some hemoptysis18,19,26,27 (4.5% vs. 0%; 95% CI, 1.12-22.49; P=0.04), and valve migration (6.6% vs. 0%; 95% CI, 2.01-37.13; P=0.004) (Table 3).
This meta-analysis based on 5 RCTs demonstrates that the use of EBV in advanced emphysema patients would (1) increase percentage change of FEV1 and (2) improve SGRQ scores when compared with SMT or sham procedure.
The current report from GOLD 2017 to manage severe emphysema is directed at the use of pharmacological and nonpharmacological treatments.28 These include beta-2-agonists, anti-cholinergic, inhaled corticosteroids, phosphodiesterase-4 inhibitor, smoking cessation, vaccinations, oxygen therapy in selected patients, and pulmonary rehabilitation.29 However, due to the progressive and debilitating nature of emphysema, many studies have been trying to investigate for other effective treatment regimen to improve patients’ lung function and functional capacity. BLVR has been proposed by the recent GOLD report to be a possible option in the interventional treatment of emphysema. BLVR is suggested to have a favorable effect in improving overall lung function, tolerance to exercise and quality of life by reducing hyperinflation when EBV is placed appropriately.
A multinational expert panel from the most experienced centers in Europe has made recommendations on selection criteria for consideration of patients with advanced emphysema for BLVR30 to optimize patient outcomes, which includes hyperinflation with residual volume >175% of predicted, FEV1 <50% of predicted, a 6-minute walking distance >100 m and minimal to no collateral ventilation in the targeted lobe. It is essential to select patients with evidence of hyperinflation as measured by increased residual volume >175% of predicted or total lung capacity >100% of predicted because BLVR mainly works to reduce lung hyperinflation, which improves symptoms. Although these selection criteria are recommended as “expert best practices” by the team with extensive experience, it exists to guide us in patient selection, as it is fundamental to ensure successful outcome of a medical procedure, such as EBV implantation. LVRS was shown to improve lung function and quality of life for selected patient groups who have heterogenous form of emphysema and have lower surgical risk7 and a recent retrospective study by Ginsburg et al31 showed no surgery-related mortality at 6 months follow-up. However, LVRS has increased length of hospital stay when compared with less invasive procedure like BLVR, which can alleviate symptoms when used in selected patients as mentioned compared with those who only receive medical treatment.32,33 Ginsburg and colleagues showed a median length of hospital stay post-LVRS was 8 days with a range of 6 to 10 days, but 82% of the patients were discharged home after the stay. The most common complication from LVRS was prolonged air leak at 57% followed by pneumonia at 4% and respiratory failure at 4%.31 Venuta et al34 has reported a 5-year survival rate exceeding 80% in patients who received BLVR. In GOLD 2017 report based on the NETT research group study, it was reported that in patients with FEV ≤20% predicted and either homogenous emphysema proven high-resolution computed tomography (CT) or a DLCO of ≤20% predicted who received LVRS had higher mortality than medical management.35
Our meta-analysis showed that BLVR for the advanced emphysema is associated with an improvement in FEV1. This suggests that reduction of the most severely diseased lung units permits expansion of more viable and less emphysematous nontreated lung, leading to improvement in lung mechanics. There was also improvement in SGRQ scores, especially in patients without collateral ventilation. The improvement in SGRQ score has been shown to correlate with changes in regional lung volume, suggesting that the mechanism for improvement is redirection of inspired air to less diseased lung tissue as opposed to total lung volume reduction.36 Our meta-analysis showed that BLVR using EBV, similar to LVRS, has the potential to improve both hard outcome of objective improvement in lung function, and soft outcome of improvement of quality of life. There are currently 2 commercially available types of EBVs: the Zephyr EBV (Pulmonx Inc., Redwood City, CA) and the IBV (Spiration, Redmond, WA). All 5 of our included trials used the Zephyr EBV. Trials on BLVR using the IBV did not have data on change in FEV1.37,38
Interlobar collateral ventilation is an important predictor of treatment response. A surrogate for interlobar collaterals is fissure completeness as seen on CT-scan. A prior meta-analysis showed that intact fissure group had superior improvement in mean change in FEV1, 6-minute walk distance, and SGRQ compared with without intact fissure.14 Most of the included studies only included patients without collateral ventilation, assessed using the Chartis system (Pulmonx Inc.). Two of our included studies that did not exclude patients with collateral ventilation found that fissure completeness was associated with improvement in FEV1.18,26 In Herth et al,26 there was no improvement in FEV1 in patients with incomplete fissure who received EBV. Therefore, it is important to assess presence of collateral ventilation in potential candidates for EBV.
Our meta-analysis reveals that BLVR has an encouraging safety profile with minimal adverse outcomes in the short limited available follow-up period. There was no statistically significant increase in mortality, COPD exacerbation, pneumonia or respiratory failure. However, there was a 7% rate of pneumothorax in patients who received EBV. Pneumothorax is a common complication, which is also mentioned in prior meta-analysis,16 which is thought to be due to a prompt alteration in lung volumes due to ruptured existing subpleural blebs or bullae in the contiguous diseased lobe.18,26,39 All the pneumothorax occurrences reported were managed medically with conventional placement of chest tube when indicated. Rarely, repeat bronchoscopy may be needed to remove the valve if there is present of recurrent pneumothorax or to promote pneumothorax healing39,40 after chest tube placement. Thus far, all reported pneumothorax occurred within 48 hours postprocedure, and hence, it is unquestionably essential to monitor the patients diligently for at least the first 48 hours postprocedure. In Skowasch et al,41 it is postulated that 80% of pneumothorax usually occurs in the first 48 hours, 10% within the third to fifth day and 10% after day 6. Because of limited trials to potentially demonstrate the safest timing to monitor versus to discharge a patient, more trials and close follow-up for concerning complications will be beneficial. Slebos et al30 mentioned that the current practice is to monitor patient for 3 to 5 days. In patients who are discharged, they should definitely be educated on signs and symptoms of pneumothorax to allow symptom recognition and clear steps to take if pneumothorax were to occur.
We also found a statistically significant increase in rate of hemoptysis of 4.5% in patients undergoing BLVR. This finding is also expected, as bronchoscopy is a minimally invasive procedure into the airway, which may injure bronchial wall and blood vessels, or it may also be related to the pressure fit induced by the valve. However, postprocedural hemoptysis is often self-limiting. There was no difference in rates of massive hemoptysis (defined as blood loss >300 mLs in 24 h) in our study. The risk of valve migration was found to be 6.6% with statistical significance compared with SMT. Valve migration can be recognized or suspected when a patient experiences increasing cough or sudden awareness loss of efficacy of the valve. Valve migration is usually due to initial incorrect seating or undersized valve. In the event if valve migration is confirmed on CT chest or bronchoscopy after ruling out pneumothorax, the displaced valve should immediately be removed or replaced.30
The patient population for which EBV may be most beneficial are patients with advanced emphysema, FEV1 of <50%, significant hyperinflation, who have substantial breathlessness despite optimization of medical therapy, and have good targets for EBV placement (ability to achieve lobar occlusion in the target lobe, without evidence of collateral ventilation). A patient-physician discussion about the risk and benefit of the procedure would be important.
A number of limitations of this meta-analysis should be considered. The follow-up period in the studies included is limited to 6 months (3 studies had 6 mo follow-up,18,26,27 and 2 other studies had only 3 mo follow-up19,25); hence, the long-term effectiveness and safety of EBV placement is not well defined. Among the 5 RCTs, there is only 1 study (Davey et al),25 which had a control arm of sham procedure. Davey and colleagues had a total of 50 patients, with 25 patients randomized to sham procedure. Because of the small number of participants in the study, we are limited to conclude if there is a benefit for meaningful comparison as to whether sham procedure has an advantage versus none. The advantage of having a sham procedure, as the controlled arm compared with SMT is that clinical assessment in terms of patient’s symptoms and exercise tolerance can be assessed more assuredly as it enables a double-blind sham controlled trial. The rest of the studies are randomized trials, but not double-blinded. Because of the short follow-up period and no established studies currently to investigate the long-term benefits and the survival rate following BLVR, we are unable to predict the long-term outcome. We did not include Ninane et al37 and Wood et al38 as our primary endpoint was hard outcome of change in FEV1, as opposed to soft outcome of improvement in SGRQ score. Therefore, the result of our meta-analysis is not generalizable to IBV (Spiration). There was no statistical significant difference in 6-minute walking test. It may have been due to inconsistent availability of pulmonary rehabilitation before enrollment. Supplemental appendix for each trials were reviewed, however, we found that only 2 RCTs18,26 had patients undergo 6 to 8 weeks of full pulmonary rehabilitation before selection. In Herth and collegues, patients in the trials were selected postpulmonary rehabilitation. In Sciurba and colleagues, selected patients underwent 6 to 8 weeks of pulmonary rehabilitation before randomization. In the other 3 RTCs25,27,39 included, there is no mention if their patients underwent pulmonary rehab before randomization or selection. There were too few studies to permit analysis of the efficacy of EBV in different types of emphysema.
The result of this meta-analysis suggests that BLVR using EBV may be effective in improving the lung function and quality of life in patients with advanced emphysema patients in the short-term. However, there was an increased risk of minor hemoptysis, pneumothorax, and valve migration. In patients with advanced emphysema who have substantial breathlessness despite optimization of medical therapy, and have good targets for EBV placement, discussion about the benefit and risk of BLVR using EBV is important. Further studies with long-term follow-up are required to determine its long-term efficacy and safety.
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