Do endobronchial valves improve outcomes in patients with emphysema?

Abstract

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether endobronchial valves improve outcomes in patients with severe emphysema. Eighty-seven papers were found using the reported search, of which seven represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Endobronchial Valve for Emphysema Palliation Trial demonstrated that endobronchial valve increased forced expiratory volume in one second by 4.3% (95% confidence interval 1.4–7.2) and decreased by 2.5% in the control group (95% confidence interval −5.4 to 0.4) at a 6-month interval. This benefit is more marked in patients who do not have collateral ventilation into the area of lung being isolated as mapped by bronchoscopic physiological mapping (Chartis) or by computed tomography imaging documenting intact fissures. This evidence is reflected in the Endobronchial Valve for Emphysema Palliation Trial. Patients treated with endobronchial valve with high heterogeneity and complete fissures had greater improvement in forced expiratory volume in one second at 6- and 12-month intervals. We conclude that endobronchial valve placement improves lung function, exercise capacity and quality of life in selected patients with emphysematous diseases.

INTRODUCTION

A best evidence topic was constructed according to a structured protocol. This is fully described in ICVTS [1].

THREE-PART QUESTION

In [patients with severe emphysema treated with endobronchial valve (EBV)] is [quality of life, spirometry, exercise tolerance] equivalent to [medical management]?

CLINICAL SCENARIO

A patient with heterogeneous bilateral upper lobe predominant emphysema asks about less-invasive alternatives to surgery. Due to the presence of heterogeneity of the disease and complete lobar involvement, we decided to look up the evidence in the literature including these criteria.

SEARCH STRATEGY

Medline 1990 to January 2012, with results limited to English language articles: ((‘endobronchial valve’) OR (‘intrabronchial valve’) AND (‘lung volume reduction’) OR (‘emphysema’) [All fields]). Finally, a hand search was used to follow-up references from the retrieved studies.

SEARCH terms—EBV, intrabronchial valve (IBV), lung volume reduction, emphysema.

SEARCH OUTCOME

Eighty-seven papers were found using the reported search. Studies were included if they had clear inclusion criteria and reported on clinically important outcomes such as changes in quality of life, spirometry and exercise capacity. From these, only seven papers were identified that provided best evidence to answer the question. These are presented in Table 1.

Table 1:

Best evidence papers

Author, date, country, journal Study type (level of evidence)	Patient group	Outcomes	Key results	Comments
Sciurba et al., 2010, USA, N Eng J Med Multicentre prospective randomized controlled trial (level 1b)	Inclusion and exclusion criteria were similar to LVRS VENT 321 patients with heterogeneous emphysema were enrolled. 2:1 allocation (valve: standard medical care) at 31 centres in USA Zephyr valves	% change in FEV1 at 6 months	EBV 4.3% (CI 1.4–7.2) Control 2.5% (CI −5.4–0.4) P = 0.005	Change in FEV1 only significant due to concomitant drop in medical group Complete lobar exclusion, high heterogeneity or a complete inter-lobar fissure associated with marked improvement in all domains Reported adverse events included haemoptysis, pneumothorax and COPD exacerbation Limitations: High loss to follow-up at 12 months. EBV group 11.8% vs medical group 20.8%, (P = 0.04) Missing data for primary efficacy end point in EBV group 19.1 vs 27.7% in medical group
		% improvement 6MWD	EBV 2.5% (CI −1.1 to 6.1) Control −3.2% (CI −8.9 to 2.4) P = 0.04
		Mean change in SGRQ	EBV −2.8 (CI −4.7 to −1.0) Control 0.6 (CI −1.8 to 3.0) P = 0.04
		High heterogeneity % change in FEV1 at 12 months % improvement 6MWD at 12 months	EBV 13.3% (CI 5.7–20.9) P <0.001 EBV 7.1% (CI −0.8 to 14.9) P = 0.08
		Complete fissure % change in FEV1 at 6 months % improvement 6MWD at 12 months	EBV 17.9% (CI 9.8–25.9) P < 0.001 EBV 3.9% (CI −4.0 to 11.8) P = 0.20
Herth et al., 2012, Europe, Eur Respir J Multicentre prospective randomized controlled trial (level 1b)	Inclusion and exclusion criteria were similar to LVRS (European arm of VENT study) 161 patients with advanced emphysema were enrolled. 2:1 allocation (valve: standard medical care) Zephyr valves	Mean change in FEV1 at 6 months	EBV group 7 ± 20% Control group 0.5 ± 19% P = 0.067	Similar magnitude of changes at 12 months. Complication rates not significantly different Complete inter-lobar fissures and complete lobar exclusion associated with better outcomes. Heterogeneity not critical for determining outcome
		Mean change in cycle ergometry at 6 months (W)	EBV group 2 ± 14 W Control group −3 ± 10 W P = 0.04
		Mean change in SGRQa at 6 months	EBV group −5 ± 14 points Control group 0.3 ± 13 points P = 0.047
Venuta et al., 2011, Italy, Eur Respir J Single centre prospective cohort study (level 2b)	40 patients with severe heterogeneous emphysema enrolled and received unilateral EBV Zephyr valves Median follow-up 32 months. 33 patients had >12 months follow-up	% improvement 6MWD	Baseline 0.88 ± 0.3 5 years 1.2 ± 0.5 P = 0.004	Statistically significant improvements in lung volumes and supplemental oxygen also noted Patients with visible inter-lobar fissures on HRCT had a significant survival and functional advantage Limitations: During the study period mortality is high (40% overall), while 3 patients transplanted and 1 underwent LVRS. Only 9 patients reached 5 years follow-up
		Mean change in SGRQ	Baseline 268 ± 97 5 years 402 ± 113 P = 0.003
		Change in Medical Research Council Dyspnoea Score	Baseline 3.9 ± 0.8 5 years 2.6 ± 0.7 P < 0.0001
Sterman et al., 2010, USA, Respiration Multicentre prospective cohort study (level 2b)	Patient selection criteria similar to NETT† criteria namely heterogeneous, upper lobe predominant emphysema 91 patients enrolled at 11 centres in USA using an IBV (spiration valve)	Mean FEV1 at 12 months (litres)	Baseline 0.87 ± 0.25 12 months 0.85 ± 0.33 P = not significant	Primary end-point safety Health-related quality of life improvements associated with a decreased volume in the treated lobe (P = 0.007) Low incidence of valve migration, erosion and infection (<2.5%) Limitations: Only 59 patients followed up because 26 patients withdrew consent and 6 died. Valve was removed in 16 patients for pneumonia, bronchospasm, recurrent COPD exacerbation and pneumothorax
		Mean 6MWD (feet)	Baseline 1108 ± 313 12 months 1173 ± 303 P = 0.19
		Change in SGRQ total score at 12 months	−9.5 ± 14.4 P < 0.001
		Change in SF-36b scores at 12 months	8.0 ± 22.5 P = 0.013
Chung et al., 2010, Australia, Respirology Single centre prospective cohort study (level 2b)	8 patients with severe heterogeneous emphysema were enrolled, but only 6 patients completed the study. All patients had their left upper lobe targeted Inclusion and exclusion criteria were similar to those in the VENT study Zephyr valves	Change in mean FEV1 (% predicted) at 3 months (SD)	Baseline 36% (12) 3 months 45% (16) P = 0.09	Primary end-point was changed in regional ventilation and perfusion Limitation: Small sample size Only 90 days follow-up after EBV implantation
		Change in mean 6MWD at 3 months	Baseline 268 m (128) 3 months 305 m (135) P = 0.54
		Change in mean score on SGRQa	Baseline 56 (27) 3 months 47 (25) P = 0.60
Wan et al., 2005, Hong Kong, Chest Multicentre retrospective cohort study (level 2b)	98 patients were enrolled at nine centres in seven countries Inclusion and exclusion criteria were similar to those in NETT Zephyr valves	Mean change in FEV1 at 3 months	10.7 ± 26.2% P = 0.007	Improvement in pulmonary function and exercise tolerance can be achieved by using EBV in emphysematous patients Patients with lobar exclusion had a greater magnitude of benefit than segmental occlusion. Patients with worse baseline FEV1 and RV showed more significant improvement than those with better baseline values Limitation: Only 90 days follow-up after EBV implantation
Herth et al., 2012, Europe, Eur Respir J Multicentre prospective non-randomized controlled trial (level 1b)	Inclusion and exclusion criteria were similar to LVRS (European arm of VENT study) 105 patients enrolled, of these, 51 were classified as CV– and 29 as CV+ using Chartis	Reached MCIDc n (%) in FEV1 at 30 days	CV− responders 21 (58%) CV− non-responders 1 (7%) CV+ non-responders 2 (8%) CV+ responders 4 (80%)	Primary end-point is targeted lung volume reduction >350 ml defined responders CV− 36/51 (71%) and CV+ 5/29 (17%) Limitation: Small sample size Only 30 days follow-up after EBV implantation
		Reached MCIDc n (%) improvement 6MWD at 30 days	CV− responders 18 (53%) CV− non-responders 4 (27%) CV+ non-responders 9 (41%) CV+ responders 3 (60%)
		Reached MCIDc n (%) in SGRQ at 30 days	CV− responders 19 (73%) CV− non-responders 6 (54%) CV+ non-responders 9 (50%) CV+ responders 2 (67%)

COPD: chronic obstructive pulmonary disease; EBV: endobronchial valve; HRCT: high resolution computed tomography; IBV: intrabronchial valve; LVRS: lung volume reduction surgery; MWD: minute walk distance; NETT: national emphysema treatment trial; RV: residual volume; SGRQ: St George's respiratory questionnaire.

^aSGRQ range from 0 to 100, with higher scores indicating a worse quality of life. The minimal clinically important difference is four points.

^bShort-Form Health Survey (SF-36) scores.

^cMinimal clinically important difference (MCID) defined as an improvement of ≥15% in FEV₁, an improvement of ≥26 m in the 6MWD and an improvement (i.e. decrease) of ≥4 points on the SGRQ.

Papers were excluded for a variety of reasons, namely review paper (n = 3), papers reporting increasing experience from the same group (n = 5) and animal studies (n = 3). Other papers did not adequately assess clinical outcomes and were excluded.

RESULTS

Sciurba et al. [2] conducted the first multicentre randomized controlled trial of the EBV (Zephyr) for Endobronchial Valve for Emphysema Palliation Trial (VENT) compared with best medical therapy. Herth et al. [3] published the European arm of this trial. Their inclusion criteria [2] are slightly more relaxed when compared with the criteria for lung volume reduction surgery (LVRS) proposed by the National Emphysema Treatment Trial (NETT) [4]; age 40–75 years, heterogeneous emphysema, forced expiratory volume in one second (FEV₁) 15–45% of predicted value, total lung capacity >100% of predicted value, residual volume (RV) >150% of predicted value, body mass index ≤31.1 kg/m² in males, ≤32.3 kg/m² in females, PaCO₂ <50 mm of Hg, PO₂ >45 mm of Hg, 6 minute walk distance (6MWD) <140 m. Exclusion criteria were total lung carbon monoxide transfer (TL_CO) <20% of the predicted value, presence of large bullae or α₁antitrypsin deficiency, previous thoracotomy, severe pulmonary hypertension, active infection and unstable cardiac condition. Both investigators reported significant improvements in exercise tolerance and quality of life. Moreover, an improvement in FEV₁, which was only significant in Scurbia's study due to a concomitant drop in FEV₁ seen in the medical group. Both studies showed that patients in the complete lobar exclusion and/or complete fissure subgroups had greater improvement in both FEV₁ and 6MWD than their counterparts. Herth reported that the heterogeneity of emphysema was not critical, while Sciurba reported significant improvements in the high-heterogeneity group.

Venuta et al. [5] conducted a cohort study of 40 patients using EBVs (Zephyr) and reported the long-term outcome after unilateral EBV implantation in patients with severe heterogeneous emphysema. They demonstrated significant improvements in spirometry, lung volumes, exercise capacity, breathlessness and supplemental oxygen use at 5 years postinsertion.

Sterman et al. [6] conducted a multicentre cohort study using an IBV (spiration). The selection criteria were similar to those used by NETT, after exclusion of high-risk patients. They demonstrated that bilateral upper lobe EBV implantation significantly improved the health-related quality of life. This was associated with decreased volume in the targeted lobes. Although FEV₁, exercise tolerance, and total lung volumes were unchanged, ventilation-perfusion mismatch was improved. Unfortunately, follow-up was only 65% complete due to withdrawals and death.

Chung et al. [7] conducted a prospective cohort study following unilateral EBV (Zephyr) replacement in patients with severe heterogeneous emphysematous. At 30 days, FEV₁ increased and RV decreased.

Wan et al. [8] conducted an international multicentre cohort study in which 98 patients suitable for LVRS underwent EBV insertion (Zephyr). They reported improvements in FEV₁ and 6MWD. TL_CO also improved, but not significantly. Eight patients (8.2%) developed serious complications including one death (1%) in the first 90 days. The greatest magnitude of benefit was found in unilaterally treated patients with lobar exclusion and patients with baseline FEV₁ <30 vs >30%.

Herth et al. [9] conducted a study to determine whether EBV placement guided by collateral ventilation (CV) determination with use of Chartis pulmonary assessment system resulted in better outcomes. In the absence of CV, FEV₁, 6MWD and St George's Respiratory Questionnaire (SGRQ) score improved more than for those patients with CV. Thus, Chartis can predict the success of LVR with EBV in the targeted lobe with an accuracy of 75%.

CLINICAL BOTTOM LINE

EBVs potentially offer a low-risk procedure. Initial studies used criteria common to surgical LVRS to select patients. Overall improvements in physiological and patient-related outcomes in these studies were, at best, modest. However, in a sub-group of patients with complete lobar exclusion and complete inter-lobar fissures, remarkable improvements were noted, suggesting a role for CV in patient selection. Using bronchoscopic Chartis Pulmonary Assessment System to determine the presence of CV has a 75% accuracy rate of predicting which patients will have a significant LVR after valve placement.

One cannot assume that long-term outcomes including survival and health economic benefits after surgical LVR cannot be extrapolated to EBV: these will need to be tested. Nor has any direct comparison of EBV and surgical LVR been undertaken, though neither procedure precludes the other. It is likely that the indications for each procedure will differ. Surgical LVRS is likely to be performed in patients with predominantly upper lobe heterogenous emphysema and good exercise capacity. While the selection of patients for EBV-LVR may not be limited to these criteria, but be determined by the presence or absence of CV.

The majority of reported studies are small cohort studies. Only one randomized study comparing EBV's and medical therapy has been published to date. However, the current evidence does suggest a role for EBVs in the management of selected emphysema patients suitable for LVR.

Conflict of interest: none declared.