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).
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
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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