Endobronchial treatments for emphysema emerged as a potential solution to the problem of high morbidity associated with lung volume reduction surgery. It was hypothesized that, if endobronchial occlusion and subsequent collapse of the hyperinflated lung segments can be safely maintained, it will have similar physiological and clinical benefits in patients with hyperinflation as lung volume reduction surgery, but without the associated morbidity.1
The first devices to acquire approval for safety and feasibility studies in humans were 2 types of endobronchial valves (Emphasys and Spiration). The addition of an expiratory valve to an inspiratory blocker was considered to offer a safety mechanism against the possibility of postobstructive pneumonia. These nitinol-composed devices, however, were designed to function as airflow blockers to achieve endoscopic LVR (ELVR) through absorption atelectasis and shift of ventilation to the more preserved lung segments. The initial case series were promising in terms of feasibility and safety.2 Some patients showed significant improvements even in the absence of radiologic atelectasis, although the most relevant improvements were seen in patients with evidence of atelectasis. Subsequently, industry sponsored large randomized trials.3,4 For a medical device development time line, however, these trials were probably premature. In cardiology, for instance, it took >15 years of clinical experience with percutaneous angioplasty in a registry before a randomized controlled trial (RCT) showed clear clinical benefits.5 It took, however, only 3 years to set up a randomized trial for the endobronchial valves. One could argue that percutaneous angioplasty was developed in a different age of evidence-based medicine; nevertheless, a clearer understanding of the mechanisms of action and correct patient selection are warranted for RCTs to demonstrate safety and efficacy. Premature RCTs, when unsuccessful, may not allow the evolvement of novel and potentially useful technologies beyond the early stages.
Two large RCTs evaluating endobronchial valves for emphysema have been funded and published, one in the current issue of the Journal.3,4 Both trials have failed the effectiveness criteria. The publication of all well-designed trials, irrespective of results, will avoid bias in future systematic reviews and meta-analyses. The first large RCT, the Endobronchial Valve for Emphysema Palliation Trial (VENT), was a multicenter, randomized, unblinded study that showed a modest improvement in spirometric measures and in the 6-minute walk test in the treatment group. Significant benefits, however, were observed in certain subgroups. The presence of intact interlobar fissures, degree of emphysema heterogeneity on HRCT, and correct valve placement play essential roles in achieving clinically meaningful effectiveness. The presence of intact fissures may indicate a low likelihood of significant collateral ventilation (CV). A US trial (EMPROVE) is testing ELVR through unilateral deployment of IBV valves in patients with fissure integrity on HRCT.6 UK investigators have proposed a similar algorithm.7
The trial reported in the current issue of the Journal had similar inclusion criteria to VENT, but tested a different distribution of endobronchial valves. Instead of unilateral complete lobar occlusion, Wood and colleagues tested an incomplete bilateral occlusion, which was suggested by early observations of benefit and less risk of pneumothorax. The study had a sham bronchoscopy procedure and used more precise endpoints compared with the VENT trial. It measured CT volumetric data to demonstrate volume changes and used quality-of-life endpoints. Although in some patients the results were compelling, this study failed to achieve clinically significant improvements in primary endpoints.
Both trials failed to reach the primary outcomes likely because of suboptimal patient and target airways selection for valve insertion and not because of device-related reasons. We learned that performing incomplete bilateral occlusions may not result in relevant physiological and clinical benefits. In fact, 1 study found unilateral complete occlusion aimed to achieve atelectasis to be superior to bilateral incomplete occlusion aimed to achieve redistribution of ventilation.8
ELVR proves to be a complex puzzle with missing pieces, one of which may be CV. While airflow has a predictable distribution in the normal lung, in emphysema the disturbance is heterogeneous and the pattern of distribution may be unique to every patient. Valves may have unanticipated effects on airflow distribution. In this regard, neither the VENT nor the IBV trial published herein addressed the role of CV in predicting patient outcome. CV in normal individuals is minimal. Inspired air leaves lung units through the same airways it entered. In emphysema, collateral pathways allow gas to backfill the occluded segments.9 Patients who lack significant CV in targeted lung segments may experience the greatest benefit from endobronchial valve therapy. Assessing CV may improve patient selection for future valve trials. Assessing interlobar fissures integrity alone is insufficient for this purpose. Systems have been developed to bronchoscopically isolate a target lung region and measure the pressure and flow, thus allowing for indirect measurement of CV by estimating collateral resistance.10 A US study (LIBERATE) is evaluating outcomes of ELVR in patients who have been found to have minimal CV on preprocedural assessment.11 An ongoing UK trial also measures CV in both control and treatment groups.7
Solutions to puzzles require pattern recognition. There are ongoing efforts to recognize anatomic patterns in emphysema that have a functional profile responsive to valve insertion. Patient and procedure techniques selection should be decided not by an individual but by a multidisciplinary committee.12 Pulmonary physiologists, radiologists, and bronchoscopists must all be involved in the decision-making process. To date, however, there are no trials to test the effectiveness of a multidisciplinary team on patient selection, device selection, and outcomes of endobronchial valve placement. The use of registries is encouraged. Observations from registries will define meaningful research hypotheses and provide a benchmark for practice. The development of functional and imaging markers or patterns for different phenotypes of emphysema may also assist in targeting ELVR. There is a need for a better understanding of regional airflow patterns in different radiologic phenotypes of emphysema and how to alter flow to achieve clinically meaningful outcomes.
1. Toma TP, Hopkinson NS, Hillier J, et al.. Bronchoscopic volume reduction with valve implants in patients with severe emphysema. Lancet. 2003;361:931–933.
2. Wan IY, Toma TP, Geddes DM, et al.. Bronchoscopic lung volume reduction for end-stage emphysema: report on the first 98 patients. Chest. 2006;129:518–526.
3. Sciurba FC, Ernst A, Herth FJ, et al.. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med. 2010;363:1233–1244.
4. Wood DE, Nader DA, Springmeyer SC, et al.. The IBV Valve Trial: a multicenter, randomized, double-blind trial of endobronchial therapy for severe emphysema. J Bronchology Interv Pulmonol. 2014;21:288–297.
5. O’Neill WW, O’Neill BP. The first generation of angioplasty. Circ Cardiovasc Interv. 2009;2:1–3.
7. Davey C, Zoumot Z, Jordan S, et al.. Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (The BeLieVeR-HIFi trial): study design and rationale. Thorax. 2014[Epub ahead of print]. doi: 10.1136/thoraxjnl-2014-205127.
8. Eberhardt R, Gompelmann D, Schuhmann M, et al.. Complete unilateral vs. partial bilateral endoscopic lung volume reduction in patients with bilateral lung emphysema. Chest. 2012;142:900–908.
9. Morrell NW, Wignall BK, Biggs T, et al.. Collateral ventilation and gas exchange in emphysema. Am J Respir Crit Care Med. 1994;150:635–641.
10. Herth FJ, Eberhardt R, Gompelmann D, et al.. Radiological and clinical outcomes of using Chartis to plan endobronchial valve treatment. Eur Respir J. 2013;41:302–308.
12. Zoumot Z, Jordan S, Hopkinson NS. Emphysema: time to say farewell to therapeutic nihilism. Thorax. 2014;pii:thoraxjnl-2014-205667.