Key points

Introduction

Emphysema continues to be a significant cause of morbidity and mortality in the United States and worldwide. Despite optimal medical management, survivors with end-stage emphysema are significantly limited in their functional status, with associated poor patient-reported outcomes and quality of life. It is in this subset of patients where surgical and endoscopic interventions hope to improve survival, quality of life, and functional capacity.

Irreversible destruction of alveolar tissue results in increased size of air spaces distal to the terminal bronchioles. This destruction and coalescence of alveoli lead to loss of elastic recoil within the lung tissue that causes small airways to collapse, leading to a functional obstruction of gas outflow with subsequent air trapping and dynamic hyperinflation of the lungs. Over time, this process results in lung and chest wall hyperexpansion, limiting inspiratory capacity and increasing work of breathing.

Surgical or interventional treatments attempt to resect or functionally limit flow to disproportionately hyperexpanded portions of the lung in an effort to redistribute ventilation to healthier lung tissue with better perfusion. Surgical removal of hyperexpanded portions of lung, or lung volume reduction surgery (LVRS), has a long history but was reinvigorated in the current era with the work of Dr Joel Cooper. As outlined in previous articles, the National Emphysema Treatment Trial (NETT) demonstrated a significant improvement in survival with bilateral LVRS in addition to improvements in FEV ₁ , 6-minute walk distance (6MWD), quality of life, and dyspnea scores in well-selected patients with severe emphysema. ^, Using appropriate selection criteria in patients with heterogeneous disease, 90-day mortality was 5.2% (vs 1.5% in medically treated control group). ^, Despite the demonstration of the clinical efficacy of LVRS in the NETT trial, utilization of LVRS for the treatment of severe symptomatic emphysema has been disappointingly limited. This is multifactorial but partially related to a reticence to refer patients for LVRS because of the surgery-related morbidity and mortality. This concern was the impetus to identify less invasive techniques that mimic the physiologic impact of LVRS.

Endobronchial valves (EBVs) were developed to block inspiration of air into severely diseased pulmonary segments while allowing egress of air to produce atelectasis of the target segment or lobe ( Fig. 1 ). Multiple valves are available commercially and generally comprise a metal matrix covered in silicone. The valves come in different diameters and lengths to accommodate various sizes of segmental bronchi. The valves easily are deployed via standard flexible bronchoscopy either under general anesthesia or monitored sedation.

( A ) Pulmonx EBV. ( B ) Spiration Valve System (SVS).

( Courtesy of Pulmonx Corp, Redwood City, California, with permission; and Olympus, Center Valley, PA, with permission.)

Indications

Indications for utilization of EBVs have evolved since their inception, but there still is significant overlap with indications for traditional surgical LVRS. General indications, with some variability based on the trial, include FEV ₁ less than 45% to 50% predicted and greater than 15% to 20% predicted, hyperinflation with total lung capacity greater than 100%, residual volume (RV) greater than 150% predicted, limited exercise capacity (ie, 6MWD <450 m), and dyspnea (ie, Medical Research Council [MRC] dyspnea score >3), in patients undergoing optimal medical therapy. Patients also are required to quit smoking and to participate in pulmonary rehabilitation. Most trials have been limited to patients with smoking-related disease, although additional series have suggested a benefit in patients with α ₁ -antitrypsin deficiency. ^,

Initial studies of EBV therapy, as with LVRS, generally focused on patients with heterogeneous predominantly upper lobe disease. Subsequent series have suggested that EBV therapy may be beneficial in select patients with homogeneous disease. Relative exclusion criteria include severe coexisting comorbidity restricting exercise capacity or having an impact on overall survival, significant daily sputum production, giant bullae, pulmonary hypertension, or patients considered too frail to undergo complex bronchoscopic procedures.

Assessment of collateral ventilation

Essential criteria include selection of patients with limited collateral ventilation to the target lobe. Objective assessment of collateral ventilation can be performed utilizing high-resolution computed tomography (HRCT) evaluation of fissure completeness (ideally >90%). HRCT also is utilized to identify the ideal target lobe with the greatest degree of emphysema destruction based on Hounsfield units and to assess the degree of heterogeneity (>10%–15% difference vs ipsilateral lobe). Software has been developed to help standardize the initial HRCT assessment of fissure completeness and the severity of emphysematous destruction and is essential for the planning and work-up of these patients.

More contemporary trials have supplemented the HRCT assessment with utilization of the Chartis system (Pulmonx, Redwood City, California) to establish formal objective assessment of collateral ventilation. Using bronchoscopic-guided balloon catheter occlusion with a central channel, the Chartis system can measure air flow from the occluded segment/lobe. With the Chartis output graph, demonstration of continuous expiratory flow indicates collateral ventilation whereas a flow curve declining to zero indicates no collateral ventilation.

Other studies have solely utilized HRCT, rather than supplementing with Chartis, to visually estimate the completeness of fissures. These reports suggest that HRCT and Chartis alone may be similar in accuracy (75%–84%) for classification of collateral ventilation and that HRCT may decrease procedure time and procedure-related costs for target lobe assessment during valve deployment. The combined use of HRCT plus Chartis has a reported accuracy of 90% and allows evaluation of a broader range of patients with fissure scores as low as 80%. Pulmonary scintigraphy also is performed routinely to objectively quantify the degree of perfusion and aid in the selection of the target lobe.

Predefined outcome measures

Most clinical trials have utilized outcome variables previously used in the evaluation of LVRS, including changes in pulmonary function tests (ie, FEV ₁ ), exercise capacity, and quality of life assessment. Efforts also have been made to standardize what would be considered the minimal clinically important difference (MCID) for assessment of change in chronic obstructive pulmonary disease (COPD) treatment strategies. Suggested criteria for MCID include at least a 10% increase in FEV ₁ from baseline, at least a 26-m increase in 6MWD, and at least a 0.4-point improvement in the St. George’s Respiratory Questionnaire (SGRQ).

Early clinical results

Table 1 provides a summary of outcomes associated with clinical trials of EBV therapy in patients with severe end-stage emphysema. Early trials of EBV therapy attempted to focus on bilateral partial occlusion of upper lobe predominant disease similar to the physiologic approach with LVRS. The IBV Valve trial (Spiration Valve System [SVS]) was a multicenter randomized sham-controlled, double-blind trial enrolling 277 subjects. Patients treated with partial bilateral upper lobe valve occlusion had a significant decrease in lobar volume compared with controls (224 mL vs 17 mL, respectively). The a priori primary outcome of disease-related quality of life, however, as measured by the SGRQ at 6 months, resulted in similar proportion of responders in the treatment and control groups. In addition, 14.1% of patients in the EBV treatment group experienced serious adverse events (SAEs) versus 3.7% in the control group.

Table 1

Clinical outcomes in randomized trials of endobronchial valve therapy for severe refractory emphysema

	N	Key Inclusion Criteria	Defined Follow-up Duration	Primary Endpoint	Treatment Arm	Forced Expiratory Volume in 1 Second (L)	Forced Expiratory Volume in 1 Second (>15% Responders	St. George’s Respiratory Questionnaire	St. George’s Respiratory Questionnaire (0.4), Responders (%)	Six-Minute Walk Distance (m)	Six-Minute Walk Distance (>25 m), Responders (%)	Residual Volume (L)
VENT Zephyr EBV vs SC	220	FEV 1 15%–45% predicted; RV >150% predicted; TLC >100% predicted; 6MWD of ≥140 m; DLCO ≥20%	6 mo	% change in FEV 1 %; Change in 6MWD	EBV	+0.034	23.5%	−2.8		+9.3	25.3
					SC	−0.025	10.7%	+0.6		−10.7	17.8
					Change	+0.060		−3.4		+19.1	NS	NS
IBV SVS vs SC	72	FEV 1 ≤45% predicted; TLC ≥100% predicted; RV ≥150% predicted; 6MWD of ≥140 m; DLCO ≥20%	3 mo	Reduction in SGRQ total score ≥4; Change in CT measured lobar lung volume	EBV	−0.09				+7		+0.21
					SC	−0.01				+7		−0.21
					Change	−0.08 (NS)				NS
IBV SVS vs SC	277	FEV 1 ≤45% predicted; TLC ≥100% predicted; RV ≥150% predicted; 6MWD of ≥140 m	6 mo	Reduction in SGRQ total score ≥4; Change in CT measured lobar lung volume	EBV	−0.07		+2.15	32.2	−24.02		+0.31
					SC	0.00		−1.41	39.8	−3.4		−0.07
					Change			NS
BeLieVeR-HIFi Zephyr EBV vs SC	50	FEV 1 <50% predicted; TLC >100% predicted; RV >150% predicted; 6MWD <450 m; MRC dyspnea Score ≥3	3 mo	% change in FEV 1 %	EBV	+0.06	39%	−4.4	48	+25	52	−0.26
					SC	+0.03	4%	−3.57	46	+3	17	−0.08
					Change	+0.03		NS	NS	+22		+0.18 NS
STELVIO Zephyr EBV vs SC	68	FEV 1 <60% predicted; TLC >100% predicted; RV >150% predicted; mMRC scale >1; Absence of collateral ventilation	6 mo	% difference from baseline for FEV 1 , FVC and 6MWD from baseline	EBV	+0.161	59%	−21.8	79	+60	59
					SC	+0.021	24%	−7.6	33	−14	6
					Change	+0.14		−14.7		+74
IMPACT Zephyr EBV vs SC	93	FEV 1 15%–45% predicted; RV ≥200% predicted; absence of collateral ventilation; Homogeneous emphysema	3 mo	% difference from baseline for FEV 1	EBV	+0.10	34.9%	−8.63	56.8	+22.6	50	−0.42
					SC	−0.02	4.0%	+1.01	25	−17.3	14	+0.05
					Change	+0.12		−9.64		+40		−0.48
TRANSFORM Zephyr EBV vs SC	97	FEV 1 15%–45% predicted; RV ≥180% predicted; TLC >100% predicted; 6MWD 150–450 m; absence of collateral ventilation; Heterogeneous emphysema	3 mo	FEV 1 ≥12% (% difference from baseline for FEV 1 )	EBV	+0.14	56.3% a	−7.2	61.7	+36.2	52.4	−0.66
					SC	−0.09	3.2%	−0.7	34.4	−42.5	12.9	+0.01
					Change	+0.23		−6.5		+78.7		−0.67
LIBERATE Zephyr EBV vs SC	190	FEV 1 15%–45% predicted; RV ≥175% predicted; TLC >100% predicted; 6MWD 100–500 m; absence of collateral ventilation; heterogeneous emphysema	12 mo	FEV 1 ≥15% (% difference from baseline for FEV 1 )	EBV	+0.104	47.7%	−7.55	56.2	+12.98	41.8	−0.49
					SC	−0.003	16.8%	−0.5	18	−26.33	19.6	+0.03
					Change	+0.106		−7.05		+39.31		−0.52
REACH SVS vs SC	107	FEV 1 ≤45% predicted; TLC ≥100% predicted; RV ≥150% predicted; MRC dyspnea Score ≥2	3 mo	% change in FEV 1 % predicted;	EBV	+0.104	48%					−0.42
					SC	+0.003	13%					−0.08
					Change	+0.101						NS
EMPROVE SVS vs SC	172	FEV 1 <45% predicted; RV ≥150% predicted; TLC ≥100% predicted; 6MWD ≥140 m; absence of collateral ventilation; Heterogeneous emphysema	6 mo	FEV 1 ≥15% (% difference from baseline for FEV 1 )	EBV	+0.099	36.8%	−8.1	54	−4.4	32.4	−0.402
					SC	−0.002	10%	+4.8	18	−11.3	22.9	−0.042
					Change	+0.101		−13		+6.9	NS	−0.361

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