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The Coming of Age of Endoscopic Lung Volume Reduction

Toma, Tudor P. FRCP, PhD

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Journal of Bronchology & Interventional Pulmonology: April 2019 - Volume 26 - Issue 2 - p 75-77
doi: 10.1097/LBR.0000000000000568
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On June 29, 2018, the Food and Drug Administration (FDA) from United States approved the Zephyr valve for the treatment of breathing difficulty associated with severe emphysema ( It happened almost 15 years after the first publication of a case series suggesting that lung volume reduction can be achieved with bronchoscopically placed valve implants in patients with severe emphysema, with acceptable short-term safety and worthwhile functional benefits.1 This is an important milestone after a long period of waiting for patients with severe shortness of breath for a new treatment that can help their symptoms, but, in the era of evidence-based medicine and strict regulations, we need to be absolutely sure that the treatment works and is not harmful. Was it worth the wait?

Zephyr valves are the most studied devices for endoscopic lung volume reduction (ELVR), but are not the only devices for treating symptoms in chronic obstructive pulmonary disease (COPD) patients. The initial observations of safety with Zephyr valves, the need for new emphysema treatments, and the creativity of startup device companies open up the possibility of diversifying the ELVR options to different valves, coils, spigots, steam, and glue—all commercial ventures funded by the US capital market. Very recently, on December 5, 2018, the FDA announced the approval of Spiration valve system for the treatment of severe emphysema, which is similar to Zephyr technology, but with a differently designed valve. However, treatments for severe emphysema remain very limited (

FDA approves devices based on clear, mathematical evidence on patient selection, safety, and benefit, and this can only come from a large volume of information and large randomized trials. But for these trials to be successful and relevant, we need to first have a clear understanding of the procedure. The failure of the VENT trial to convince FDA to approve Zephyr valves for endoscopic treatment in 2010 is a reminder, both for medics and for venture capitalist investors, of the risks of perhaps going too early into an expensive randomized trial.2 One needs to know first how the procedure should be correctly performed, who would benefit most, and what are the most relevant outcome measures. This information usually comes from case series, retrospective analyses, and meta-analyses.

Meta-analyses are studies that sum multiple studies and pool the data with the major benefit that they can offer a more powerful evidence by a higher statistical power than is not possible from individual studies. Studies of various designs continued with the Zephyr valve after VENT, and a meta-analysis published in print in this issue of the journal by Low et al3 combined these studies. The authors searched all the respectable databases for randomized controlled trials comparing valve implantation versus standard medical treatment or sham bronchoscopy and concluded that the use of valves in advanced emphysema patients is safe and would increase the percentage change of forced expiratory volume in one second (FEV1) and improve St George’s Respiratory Questionnaire scores when compared with standard medical treatment or sham procedure.

In performing a meta-analysis, the investigators must make choices that can affect the results. The paper of Low and colleagues looked only at the studies having FEV1 as an outcome, and therefore ended up excluding all the studies conducted with any other valve than Zephyr. Nothing unscrupulous in doing so, but their study is therefore limited to one type of valve design and to studies sponsored by the company producing the Zephyr valve.

And why FEV1? Measures of lung volumes correlate better with impairment of patient functional capabilities than do measures of airflow.4 However, FEV1 is required for the diagnosis and staging of COPD, although FEV1 is only a surrogate for the airway obstruction.5 Moreover, the proposed valve treatment is called “endoscopic lung volume reduction treatment” and not “endoscopic airway dilatation treatment.” Despite this, the standard for measuring valve benefits remains FEV1 improvements. Whether this has historical reasons and originates in the models of inhaler trials for COPD, it is not clearly documented in the literature, although some tiotropium and tiotropium/olodaterol trials showed clearly the importance of volume reduction in achieving a symptomatic benefit.6 Choosing FEV1 as a primary outcome makes, therefore, the meta-analysis of Low and colleagues relevant and useful only for the approval of the Zephyr valves, but this seems to be in line with what regulators want to see.

Another remarkable observation from the study of Low and colleagues is on the large number of the studies that have been excluded from the final analysis. From 392 potentially relevant citations identified, 36 full-text articles were reviewed, and only 5 studies were included, because the primary outcome measured was percentage change in baseline of FEV1. Perhaps this is reiterating the suggestion that FEV1 may not be relevant for ELVR, and maybe one should look at other primary outcomes to show ELVR efficacy.

Despite some indications that mortality is reduced, ELVR procedures remain palliative interventions.7 But patients with severe disease are generally excluded for safety reasons. There are still insufficient data regarding the safety of ELVR in patients with chronic respiratory insufficiency and end-stage disease. National Emphysema Treatment Trial (NETT) study limited the volume reduction procedures to patients with a partial pressure of carbon dioxide <60 mm Hg.8 A study by Gülsen9 published also in this print issue of the journal is exploring the effects of ELVR coil treatment on arterial blood gases. The author is showing that ELVR coil treatment is reliable and effective in emphysema patients who have hypoxic or mild hypercapnic respiratory failure, and that the treatment can increase the partial pressure of oxygen and decrease the partial pressure of carbon dioxide in the medium term. This study adds to the evidence that ELVR with coils is safe and has multiple benefits for patients with severe emphysema.

The study of Gülsen also illustrates that trials need to be designed to remain relevant primarily to our patients and not to our regulators. The approval of Zephyr and Spiration valves by FDA, and no doubt, shortly after this, the approval of coils and other endobronchial devices for COPD, will open up the possibility of more rapid developments in the ELVR field from postmarketing experience and real-life observations. Further effort is still needed to understand better how these devices work, what is the best design for valves and coils, and what exactly are the differences between different ELVR approaches. With the FDA approvals, the endoscopic lung volume treatment is now, finally, coming of age. This is an exciting time, and we are seeing probably only the beginning of new interventional pulmonology procedures for severely symptomatic patients with no other options of treatment.


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. 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.
3. Low SW, Lee JZ, Desai H, et al. Endobronchial valves therapy for advanced emphysema: a meta-analysis of randomized trials. J Bronchology Interv Pulmonol. 2018. Doi: 10.1097/LBR.0000000000000527. [Epub ahead of print].
4. Ferguson GT. Why does the lung hyperinflate? Proc Am Thorac Soc. 2006;3:176–179.
5. Vogelmeier CF, Criner GJ, Martinez F, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am J Respir Crit Care Med. 2017;195:557–582.
6. Ichinose M, Minakata Y, Motegi T, et al. Efficacy of tiotropium/olodaterol on lung volume, exercise capacity, and physical activity. Int J Chron Obstruct Pulmon Dis. 2018;13:1407–1419.
7. Garner J, Kemp SV, Toma TP, et al. Survival after endobronchial valve placement for emphysema: a 10-year follow-up study. Am J Respir Crit Care Med. 2016;194:519–521.
8. Criner GJ, Cordova F, Sternberg AL, et al. The National Emphysema Treatment Trial (NETT) Part II: lessons learned about lung volume reduction surgery. Am J Respir Crit Care Med. 2011;184:881–893.
9. Gülsen A. Effects of bronchoscopic lung volume reduction coil treatment on arterial blood gases. J Bronchology Interv Pulmonol. [Epub ahead of print].
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