October 2015 Phoenix Pulmonary Journal Club: Lung Volume Reduction

The October 2015 pulmonary journal club focused on the review of older studies evaluating lung volume reduction surgery and how this has transitioned toward the development of non-surgical modes of lung volume reduction. The physiology behind dyspnea in chronic obstructive pulmonary disease (COPD) is a complex process. One of the proposed mechanisms has been hyperinflation associated with air trapping. In the mid 1990s studies by Cooper and Peterson (1) offered a promising approach in which lung volume reduction (LVR) could improve ventilatory mechanics and improve dyspnea. As the procedure gained more popularity, additional larger scale trials were performed to support its validity.

We reviewed 2 studies looking at lung volume reduction. The first was "The Effect of Lung Volume Reduction Surgery In Patients With Severe Emphysema” (2) . This was a smaller, randomized controlled trial (RCT) that looked at 2 groups of 24 patients. Once group received LVR while the other received medical therapy. The primary outcome was mortality at 6 months and change in FEV1. The study did not show any mortality benefit but showed there was an increase in FEV1 of 150 ml by 6 months in the surgical group whereas the medical group showed no improvement. We reviewed a larger subsequent study, “A Randomized Trial Comparing Lung Volume Reduction Surgery with Medical Therapy for Severe Emphysema”, a RCT that included 1218 patients divided into 2 groups of 608 pts (surgical) and 610 pts (medical) (3). The primary outcome was mortality at 2 years and exercise capacity. The results showed that there was no overall mortality benefit, but there was an overall increase in exercise capacity. A subgroup analysis showed that patients that had poor baseline exercise tolerance and upper lobe predominant emphysema did the best with lower mortality rate and increased exercise capacity. This study was useful in defining a subset of patients most likely to benefit from LVR surgery.

The cost, expertise and risk of complications associated with lung volume reduction surgery led to expanding the physiology of reducing lung volumes via nonsurgical approaches. The use of one way endobronchial valves in allowing air to leave bronchial segments to promote lung volume reduction via atelectasis has been explored for over a decade. Our group was involved in the earlier trials which evaluated efficacy and safety of endobronchial valves (4) . The results from our experience did not show that the endobronchial valves reduced lung volumes. 

A subsequent study, "A Randomized Study of Endobronchial Valves for Advanced Emphysema" was reviewed (5). This was a large RCT that divided a total of 321 pts in a 2:1 format to 2 groups of 220 patients that received endobronchial valves pts and 101 patients that received medical treatment. The primary outcome was change in FEV1 and distance in 6 minute walk test. The placement of endobronchial valves was via bronchoscopy was guided based on emphysema seen on CT of the chest. The large majority of valves were placed in either right upper lobe (52%) or left upper lobe (14%). The study did show a mild increase in FEV1 of 4.3% in the patients treated with endobronchial valves and also resulted in an increase in 6 min walk distance of 9.3 m. However, patients receiving the endobronchial valves also noted higher rates of hemoptysis and COPD exacerbations. The reason for less than optimal results has been explained by the persistence of hyperinflation through collateral ventilation.

The physiologic basis why lung volume reduction may work in COPD remains the same. The surgical resection of apical emphysematous regions may be of some benefit in patients with apical emphysema and decreased exercise tolerance. The role of volume reduction via use of endobronchial valves may become useful if subsequent studies show that collateral ventilation does not lead to persistent hyperinflation and the reduction n volumes shows a sustained increase in FEV1 and 6 min walk test.

Manoj Mathew, MD FCCP

References

1. Cooper JD, Patterson GA. Lung volume reduction surgery for severe emphysema. Semin Thorac Cardiovasc Surg. 1996;8(1):52-60. [PubMed]
2. Geddes D, Davies M, Koyama H, Hansell D, Pastorino U, Pepper J, Agent P, Cullinan P, MacNeill SJ, Goldstraw P. Effect of lung-volume-reduction surgery in patients with severe emphysema. N Engl J Med. 2000;343(4):239-45. [CrossRef] [PubMed]
3. Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Weinmann G, Wood DE; National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;348(21):2059-73. [CrossRef] [PubMed]
4. Shah PL, Slebos DJ, Cardoso PF, Cetti E, Voelker K, Levine B, Russell ME, Goldin J, Brown M, Cooper JD, Sybrecht GW; EASE trial study group. Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial. Lancet. 2011;378(9795):997-1005. [CrossRef] [PubMed]
5. Sciurba FC, Ernst A, Herth FJ, Strange C, Criner GJ, Marquette CH, Kovitz KL, Chiacchierini RP, Goldin J, McLennan G; VENT Study Research Group. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med. 2010 Sep 23;363(13):1233-44. [CrossRef] [PubMed] 

Cite as: Mathew M. October 2015 Phoenix pulmonary journal club: lung volume reduction. Southwest J Pulm Crit Care. 2015;11(5):215-6. doi: http://dx.doi.org/10.13175/swjpcc138-15 PDF

July 2011 Pulmonary Journal Club

Reference as: Mathew MJ. July, 2011 pulmonary journal club. Southwest J Pulm Crit Care 2011;3:25-6. (Click here for PDF version)

Donohue JF, Fogarty C, Lötvall J, Mahler DA, Worth H, Yorgancioglu A, Iqbal A, Swales J, Owen R, Higgins M, Kramer B; INHANCE Study Investigators. Once-Daily Bronchodilators for Chronic Obstructive Pulmonary Disease: Indacaterol Versus Tiotropium. Am J Resp Crit Care 2010;182:155-162. (Click here for full manuscript)

The once-daily, long-acting, beta-2 agonist, indacaterol was initially released in Europe in 2009. On July 1st 2011 it was approved by the FDA for the United States under the trade name Arcapta Neoinhaler. There have been studies demonstrating Indacaterol as an efficacious alternative to twice daily bronchodilators such as formoterol (1). We reviewed the study published by Donahue et al. and examined how Indacaterol compared to the only other once daily long acting bronchodilator tiotropium.

This was a large, two stage, randomized, controlled study performed between April, 2007 – August, 2008. The inclusion criteria were an age > 40, smoking history of > 20 pack/yrs and GOLD criteria COPD of moderate – severe COPD. The study was performed in 2 stages. A total of 2059 patients were included in the 1st stage which was performed to test dose efficacy. In this stage patients were randomized to receive either once daily indacaterol at doses of 75 ug, 150 ug, 300 ug or 600 ug, formoterol, tiotropium or placebo. At the end of this stage, two doses of indacaterol were selected for the second stage based on efficacy and safety. In the second stage, 1683 patients were randomized to once daily indacaterol 150 ug, 300 ug, tiotropium or placebo.

Primary endpoints were FEV1 response against placebo at 24 hours, and again at 12 weeks. The secondary endpoint was to compare FEV1 at 12 weeks against

tiotropium. A total of 1291 patients completed the study. The results showed there was a statistically significant increase in FEV1 at 24hrs and 12 weeks when compared to placebo. The study also demonstrated non-inferiority to tiotropium at 12 weeks with regards to improvement in FEV1 (see table below).

The study was not designed to measure clinical outcomes but noted were a decrease in the use of daily albuterol, a decrease in daytime symptoms and nocturnal awakenings in the indacaterol arm vs. placebo. The medication was well tolerated with main side effects being reported as cough, tachycardia and dry mouth.

The study was well done and it accomplished its primary endpoint. The main limitations were the lack of blinding in the tiotropium arm and the relative short study period of 26 weeks. It would have also been useful to extend the study period to 1 year to obtain clinical outcome data.

The availability of a once-daily, long-acting beta-2 agonist is now a promising alternative in the treatment of COPD. Although more studies are needed to demonstrate an improvement in clinical outcomes (such as a reduction in COPD

exacerbations) the once a day dosing offers at the very least, a compliance advantage. The cost of the medication (which is currently unknown) and formulary restrictions will limit initial availability.

Manoj Mathew, MD MCCM, FCCP

References

1. Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax 2010;65:473–9.