An update on the efficacy of endobronchial valve therapy in the management of hyperinflation in patients with chronic obstructive pulmonary disease

Abstract

Lung volume reduction surgery has been shown to be effective in patients with heterogeneous emphysema, but is also associated with a relatively high perioperative morbidity and mortality. Accordingly, several novel and potentially less invasive methods for bronchoscopic lung volume reduction have been developed. Endobronchial valve (EBV) therapy is one such therapeutic approach in patients with advanced emphysema. It has been the most widely studied technique over the past years and represents an effective treatment option for patients with severe heterogeneous upper- or lower-lobe-predominant emphysema. The choice of EBV therapy largely depends on the distribution of emphysema and the presence or absence of interlobar collateral ventilation. Adequate patient selection and technical success of valve implantation with the intention of lobar exclusion are predictive factors for positive outcomes. This review attempts to highlight the milestones in the development of bronchoscopic lung volume reduction with one-way valve implantation over the past few years.

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive disease which presents a major health problem around the world. Medical treatment is well established and widely used but is of limited efficacy in advanced disease. Nonpharmaceutical treatment options including smoking cessation, long-term oxygen treatment, noninvasive ventilation for severe exacerbations, and lung surgery demonstrated a positive impact on mortality in patients with COPD. Surgical options for emphysema include bullectomy, lung volume reduction surgery (LVRS), or lung transplantation. LVRS for emphysematous type of COPD has been found to alleviate symptoms and improve survival rate in patients with heterogeneous (upper lobe predominant) emphysema [Fishman et al. 2003; Naunheim et al. 2006b]. However, despite an estimated 3 million patients with emphysema in the USA, less than 15 LVRS procedures are performed monthly [Berger et al. 2010]. Among the reasons for these numbers could be the unfavorable cost of the treatment, the substantial proportion of patients with comorbidities, and the reports of significant morbidity and mortality associated with the surgical procedure itself [Naunheim et al. 2006a]. Thus, few therapeutic options remain for patients with emphysema and this unmet clinical need has spawned several less invasive techniques to reduce the lung volume via endoscopic procedures. One such method is the insertion of unidirectional endobronchial valves (EBVs) that aim to reduce the volume of hyperinflated lung regions by selectively occluding the airways supplying the most affected regions of the emphysematous lung, while allowing trapped gas to escape from the targeted lobe. EBV therapy is intended to mimic the health benefit effects of LVRS with overall lower morbidity and mortality. Earlier proof of concept case series demonstrated improved lung function, particularly in patients with valve induced atelectasis [Toma et al. 2003; Wan et al. 2006]. Successful volume reduction was associated with improvements in chest-wall asynchrony [Zoumot et al. 2015], increased exercise capacity and a reduction in the work of breathing [Hopkinson et al. 2005]. These benefits are most likely due to airflow redistribution into less affected areas of the lung with better mechanical properties, thereby reducing not only static, but also dynamic hyperinflation during exercise [Hopkinson et al. 2005]. The results of the earlier uncontrolled trials were encouraging and resulted in the conduct of prospective, randomized, clinical, multicenter trials.

EBV therapy in randomized clinical trials: the importance of collateral ventilation and lobar exclusion

The Endobronchial Valve for Emphysema Palliation Trial (VENT) was a multicenter, prospective, randomized, controlled study conducted in the USA and in Europe to evaluate safety and effectiveness of EBV therapy compared with optimal medical management [Sciurba et al. 2010]. Eligibility criteria included an age of 40–75 years, a diagnosis of heterogeneous emphysema, a forced expiratory volume in 1 s (FEV1) of 15–45% predicted, and evidence of hyperinflation with a total lung capacity of more than 100% and a residual volume of more than 150% predicted [Strange et al. 2007]. Before randomization, patients underwent 6–8 weeks of pulmonary rehabilitation and optimized medical management. High-resolution computed tomography (CT) performed at baseline and at 6 months was used to determine eligibility, on the basis of quantitative and visual indexes of lobar emphysema severity, as well as treatment outcomes. All images were analyzed at a core laboratory. The target lobe for volume reduction was the one with the most emphysematous destruction and the most severe hyperinflation. A flexible bronchoscope with or without rigid bronchoscopy was used for valve implantation. Antibiotics (second- or third-generation cephalosporin or fluoroquinolone) were given intravenously before the procedure, for 24 h after the procedure, and then orally for 7 days. Valves were placed unilaterally in lobar, segmental, or subsegmental bronchi on the basis of individual anatomy to completely isolate the targeted lobe. Both the US and European cohorts of the VENT trial demonstrated statistically significant but clinically modest improvements in lung function, exercise tolerance, and symptoms, with a moderately higher risk of complications compared with medical therapy [Sciurba et al. 2010; Herth et al. 2012]. However, subgroup analyses demonstrated that patients with more than 50% target lobar volume reduction on CT scan at 6 months post-valve treatment had a mean residual volume reduction of 900 ml, which corresponded to a mean 26% FEV1 improvement [Valipour et al. 2014]. The degree of lung volume reduction and the associated clinical improvements were far more pronounced in the patients showing complete interlobar fissures on CT and when EBV placement had resulted in complete lobar occlusion.

Lobar fissures consist of a double layer of visceral pleura that separates the anatomical lung lobes. As such, they serve as important anatomical landmarks in recognizing the pulmonary lobar structure and the regional assessment of the distribution of lung disease. Complete interlobar fissures suggest absence of relevant collateral ventilation and are characteristic for a good outcome after valve treatment. Incomplete fissures suggest parenchymal fusion between the lobes and consequently collateral ventilation via channels that bypass the usual airways across the lobes (Figure 1). This phenomenon is present both in normal human lungs [Terry et al. 1978; Morrell et al.1993] and in patients with emphysema [Higuchi et al. 2006; Valipour et al. 2014]. Thoracic high-resolution CT scan, which has been used to quantify the heterogeneity of emphysema to select the patients potentially eligible for valve treatment, can further be used to evaluate the integrity of interlobar fissures [Koenigkam-Santos et al. 2012; Reymond et al. 2013]. Analyzing data from 622 CT scans from previously healthy subjects and patients with mild lung disease, Aziz and colleagues detected an incomplete left and incomplete right major fissure in 43% and 48% of the population, respectively [Aziz et al. 2004]. The right minor fissure was incomplete in 63%. Importantly, interlobar collateral ventilation appears to occur to a much greater extent in patients with radiologically homogeneous emphysema than in those with heterogeneous emphysema [Higuchi et al. 2006].

Figure 1.

Computed tomography showing an incomplete major fissure on the right and a complete interlobar fissure on the left.

Visual evaluation of fissure completeness, however, is time consuming and requires assessment of fissure integrity on multiple planes of chest CT scan reconstructions. Alternatively, automatic methods of detecting and assessing the completeness of fissural surfaces have been described and tested [van Rikxoort et al. 2012] (Figure 2). Advantages of computer-based schemes are that quantification is more robust, precise, and reproducible. These systems, however, require specific and expensive software and are not readily available in most treatment centers.

Figure 2.

Automatic quantification of fissure integrity using the VIDA software indicating almost complete interlobar fissures bilaterally.

Recently, an endoscopic catheter-based technique was developed, which enables real-time assessment of collateral ventilation [Aljuri and Freitag, 2009]. The Chartis Pulmonary Assessment System consists of a single-patient-use catheter with a compliant balloon component at the distal tip, which upon inflation blocks the airway. Air can then flow out from the target compartment into the environment through the Chartis catheter’s central lumen. By connecting to a console, airway flow and pressure can be displayed. Airway resistance can be calculated and collateral ventilation in isolated lung compartments can be measured. The assessment can be performed during spontaneous breathing or mechanical ventilation (including jet ventilation) under general anesthesia (Figure 3). In a prospective multicenter trial of 96 patients who underwent the Chartis measurement, patients with no evidence of collateral ventilation demonstrated a median target lobar volume reduction of 55% and a mean 16% FEV1 improvement [Herth et al. 2013]. In contrast, patients with collateral ventilation had no significant radiological or functional benefits. Overall, the Chartis assessment was able to predict the response to valve therapy with 75% accuracy. In a direct comparison of both techniques, high-resolution CT fissure analysis and the Chartis System were found to be equally effective for predicting the response to EBV therapy [Gompelmann et al. 2014a], thus confirming a strong relationship between fissure morphology and functional measurements of collateral ventilation.

Figure 3.

Chartis assessment under jet ventilation using a rigid bronchoscope. There is a reduction in target lobe ventilation within 2:30 min, indicating no collateral ventilation. Patient showed substantial improvements to valve treatment.

More recently, results from a single-center, double-blind sham-controlled trial in patients with both heterogeneous emphysema and a target lobe with intact interlobar fissures have been published (the BeLieVeR-HIFi study) [Davey et al. 2015]. The authors have been able to demonstrate favorable outcomes with respect to lung function, exercise capacity, and symptom scores after valve insertion at 3 months, with a magnitude of improvement that is consistent with subgroup analysis from previous trials; that is, mean FEV1 improvement of 24.8% in the treatment group versus 3.9% patients who underwent a sham-intervention (median FEV1 improvement 8.7% bronchoscopic lung volume reduction (BLVR) versus 2.8% sham). When excluding those patients, who demonstrated collateral ventilation during Chartis measurements despite evidence of intact interlobar fissures, the responder rates increased further, with 58% of the population demonstrating at least 350 ml reduction in residual volume and 63% showing a 26 m or higher increase in the 6 min walking test distance.

Outcome of valve treatment is further largely influenced by the presence or absence of lobar exclusion (i.e. all airways of the targeted lobe of one lung are blocked by EBVs). In fact, pooled analysis from the US and European cohort of the VENT trial identified lobar exclusion at 6 months as the strongest independent predictor of health outcomes, such as the Body Mass Index, Obstruction, Dyspnea, Exercise Capacity index (BODE index) [Valipour et al. 2014]. These observations are further supported by findings from another multicenter, randomized controlled clinical trial of bilateral, upper lobe valve treatment [Ninane et al. 2012]. In this study incomplete lobar occlusion was required per protocol, with the intention to achieve volume reduction on the one hand, but avoid pneumothorax associated with atelectasis from the adjacent untreated lobe on the other hand. Nonlobar exclusion in that study similarly showed no improvements in lung function or exercise capacity and only modest reductions in target lobar volume, indicating a high degree of intersegmental collateral ventilation. While incomplete lobar treatment was required in the latter trial, technical problems associated with valve placement during the endoscopic procedure in the first place, or migration and dislocation during follow up were responsible for incomplete lobar exclusion in VENT. Particularly placement of valves in the apical segments of the upper lobe or the apical lower lobe (sub)segments might be difficult due to anatomical reasons in some patients. Developments in valve sizing and catheter delivery in the recent past, however, resulted in better access and a higher likelihood of ensuring proper placement and lobar exclusion during the bronchoscopic procedure. Thus, from a practical point of view, the interventionist should always start with valve placement in the airway which is technically most difficult to access, and if not successful, abstain from continuation of valve treatment for volume reduction, as the current data do not support any clinically relevant benefits for incomplete lobar exclusion.

Patient selection and disease distribution

Major selection criteria used in the valve trials were almost identical to those used in the surgical volume reduction trials, such as the National Emphysema Treatment Trial (NETT) study [Fishman et al. 2003]. Patients were generally required to have moderate–severe airflow obstruction on spirometry, hyperinflation on body plethysmography, and evidence of (heterogeneous) emphysema on thoracic CT. In the VENT trial, 656 out of 977 (67%) patients with COPD screened for valve treatment were excluded on the basis of these lung function or CT criteria [Sciurba et al. 2010]. The true proportion of patients potentially eligible for valve treatment in emphysema, however, remains unknown.

Many studies have documented that LVRS outcomes are better in patients with heterogeneous emphysema, especially of the upper lobes, than in those with diffuse emphysema [Ingenito et al. 2001; Fishman et al. 2003]. There are several potential explanations for this finding. First, resection limited to areas extensively replaced by cysts and bullae would largely remove pure residual volume. Second, bullous destruction can, via an interaction of elastic recoil forces between the adjacent normal and destructed lung, distort airways, cause microscopic areas of atelectasis, or impair the surface-active properties of the lung. Allowing these compressed areas to inflate more fully could reverse these changes. This would attenuate the decrease in lung compliance after LVRS (maximizing improvement in vital capacity (VC)), and could improve airway resistance. In contrast to LVRS, however, patients undergoing valve treatment may benefit from upper lobe or lower lobe treatment [Herth et al. 2013]. Furthermore, heterogeneity may be less important when treated by endoscopic lung volume reduction techniques [Herth et al. 2012; Klooster et al. 2014; Valipour et al. 2012, 2014]. A prospective, randomized controlled study is currently trying to address the effects of valve therapy on health outcomes compared with no valve therapy in patients with homogeneous emphysema and absence of collateral ventilation.

On the other spectrum of disease distribution are patients with α-1-antitrypsin deficiency and giant bulla. These patients usually have been excluded from the above mentioned randomized controlled trials (RCTs). Recently published case series, however, demonstrated successful treatment outcomes in this group of patients [Hillerdal and Mindus, 2014; Santini et al. 2011; Tuohy et al. 2013]. Prospective RCTs in this field are pending.

Caution should be taken in patients with repeated infections (more than three hospitalizations due to acute exacerbated COPD), asthma-like hyperreactivity, and increased sputum production due to bronchiectasis. Physicians should further be made aware not to select a target lobe which has a parenchymal lesion, which requires further CT scan follow up, unless proven benign. Patients with pulmonary hypertension, hypercapnia, or FEV1 below 20% have similarly not been considered suitable candidates in the pivotal valve treatment trials [Sciurba et al. 2010; Ninane et al. 2012]. In clinical practice the decision to treat these patients, however, needs to be based on individual assessment and judgment. In fact, more recently, Eberhardt and coworkers reported both safe and effective valve treatment in a small case series of patients with emphysema and established pulmonary arterial hypertension [Eberhardt et al. 2015]. Increased lung function was accompanied by reductions in mean pulmonary arterial pressure and enhanced cardiac index. These findings indicate improvements in cardiac preload and afterload associated with successful volume reduction, an observation which is consistent with data from patients who underwent LVRS. Come and colleagues previously demonstrated a relationship between the magnitude of improvements in oxygen pulse during exercise testing and the degree of ‘deflation’ in patients with COPD [Come et al. 2012]. Similar findings have recently been reported for patients who underwent endoscopic valve treatment. In a case series of 16 patients who underwent comprehensive exercise testing prior to and after EBV therapy, VO2 kinetics were accelerated in those effectively treated with valves, but remained unchanged in controls [Faisal et al. 2015]. Oxygen consumption (VO2) kinetics in the valve treatment group was significantly correlated with reductions in residual volume, confirming the concept of mechanical ‘cardiopulmonary unloading’.

Complications

Like all interventional procedures, valve therapy for emphysema may be associated with a number of adverse events, including minor hemoptysis immediately after the intervention, a postprocedural pneumothorax, and a slightly elevated risk of acute COPD exacerbations within the first 3 months after the intervention [Sciurba et al. 2010]. Hemoptysis usually requires observation only and is not likely to last beyond 1 week. Patients with anticoagulation therapy for cardiovascular disease may further experience hemoptysis at follow up, either due to some granulation tissue formation or infections. Bronchoscopic exploration is rarely indicated, but may be required in patients with repeated hemoptysis despite conservative therapy. The increased risk of exacerbations is most likely due to foreign body reaction, although the true mechanism is not known. Most patients receive antibiotic prophylaxis and a steroid burst per intervention. Thereafter patients should be informed and advised to seek medical help as soon as they are experiencing signs and symptoms of an exacerbation at follow up.

The overall rate of postprocedural pneumothorax was recently reported to be 6% [Gompelmann et al. 2014b], although the risk appears to increase up to 30% with higher target lobar volume reduction [Valipour et al. 2014]. The median onset of a pneumothorax was 2 days after the procedure, with a median duration of 11.5 days [Gompelmann et al. 2014b]. The occurrence of a pneumothorax following EBV therapy involves the untreated ipsilateral lobe or a collapsed target lobe that is unable to reexpand due to the presence of the one-way valves [Valipour et al. 2014]. Postprocedurally the untreated ipsilateral lobe expands to occupy the newly created space in the thoracic cavity. The subsequent shifting of volumes on one side of the lung, which could be rapid in some cases, may be associated with tensioning and in some cases tearing of the already compromised lung tissue. The magnitude of the lobar volume shift, that is, the proportional size of the target lobe reduction that is shifted to the nontreated ipsilateral lobe, might result in rupture of blebs or bullae causing a pneumothorax. Another mechanism could be parenchymal rupture as the lobes shift volumes due to preexisting pleural adhesion. All of the above conditions describe a pneumothorax that may result in a bronchopleural fistula that could cause pneumothorax expansion over time if not treated by chest tube insertion. Another less common but potential manifestation is pneumothorax ex vacuo (Figure 4). In this condition, acute lobar collapse results in a sudden increase in the negative intrapleural pressure surrounding the collapsed lobe. As a result, gas originating from the ambient tissues and blood are drawn into the pleural space surrounding the collapsed lobe while the seal between the visceral and parietal pleura of the adjacent lobe or lobes remains intact [Woodring et al. 1996]. In this latter condition, a bronchopleural fistula is not present and the pleural air would resolve spontaneously over time without the need for tube thoracostomy.

Figure 4.

Pneumothorax ex vacuo without an air leak after valve treatment of the left lower lobe.

Patients who are candidates for endoscopic valve therapy are less likely to tolerate a pneumothorax than patients with a primary spontaneous pneumothorax. Therefore, skilled and aggressive pneumothorax management is warranted in this patient population and every pneumothorax, in particular a tension pneumothorax, can be life threatening. Fortunately, however, the majority of cases resolve with the insertion of a chest tube, without any further surgical interventions necessary [Gompelmann et al. 2014b]. A recently published expert-based management recommendation provides guidance to physicians dealing with these cases in clinical practice [Valipour et al. 2014]. By following these recommendations, traumatic scenarios, prolonged drainage, extended hospital stays, or surgery might be avoidable in many cases. Importantly, patients with pneumothorax are those with large target lobar volume reduction and thus are highly likely to show lung function improvements at mid- to long-term follow up after resolution of the event [Gompelmann et al. 2014b].

Future aspects and conclusions

Despite rather disappointing results from initial RCTs, the clinical experience with valve treatment for emphysema is ahead of the scientific evidence and the patient population likely to benefit from the treatment is well defined. Nevertheless, results from randomized, controlled prospective trials using an algorithm of patient selection based upon complete fissures or collateral ventilation and ensuring lobar exclusion are pending.

EBV treatment when used in the recommended patient population may further be a cost-effective strategy compared with other, well accepted medical treatments [Pietzsch et al. 2014]. The projected EBV-associated 5-year gain of 0.24 quality-adjusted life years (QALYs) obtained in a recent report is higher than the QALY gains estimated in recent analyses of pharmaceutical interventions. Specifically, the multinational economic analysis of the TORCH (Towards a Revolution in COPD Health) study showed a 3-year gain of 0.081 QALYs for combination treatment with salmeterol/fluticasone propionate compared with placebo [Briggs et al. 2010]. Over a 4-year time horizon, tiotropium, when compared with usual care, was found to add 0.052 QALYs [Hettle et al. 2012]. Thus, EBV placement seems to offer substantive value over time, despite the upfront costs of valves and valve placement. The ultimate question that needs to be addressed is whether or not valve treatment may improve overall survival in these patients. Long-term follow-up data from earlier cohorts indeed suggest that patients who underwent valve treatment for emphysema demonstrate long-term survival benefits in the presence of significant lung volume reduction compared with patients with emphysema who did not develop volume reduction [Hopkinson et al. 2011; Venuta et al. 2012].