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

June 2014 Tucson Pulmonary Journal Club: Pirfenidone in Idiopathic Pulmonary Fibrosis

King TE, Bradford WZ, Castro-Bernardini S, et al. ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. New Engl J Med. 2014;370(22), 2083-92. [CrossRef] [PubMed]

Idiopathic pulmonary fibrosis is a chronic, progressive, and fatal lung disease that is characterized by irreversible loss of lung function. The 5-year survival rate that is similar to the rates for several cancers (1).

In the 2011, the official ATS/ERS/JRS/ALAT statement regarding idiopathic pulmonary fibrosis underlined that the preponderance of evidence to date suggests that pharmacologic therapy for IPF is without definitive, proven benefit (2). The committee made recommendations of varying strength against most therapies.

Pirfenidone is a pyridone compound with anti-inflammatory, antifibrotic, and antioxidant properties, with antagonism of Transforming Growth Factor (TGF)-  B1 effects. Pirfenidone inhibits fibroblast proliferation and collagen synthesis and reduce cellular and histological markers of fibrosis in animal models of lung fibrosis.

Three previous phase 3 randomized, double-blind, placebo-controlled, that examined pirfenidone for idiopathic pulmonary fibrosis had varying results (3,4). That led to the approval of pirfenidone for idiopathic pulmonary fibrosis by many governing bodies worldwide but not by the US Food and Drug Administration. This prompted US regulatory authorities to request an additional trial to support the approval of pirfenidone.

The Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) is the fourth in a series of randomized, double blind, placebo-controlled trials. Pirfenidone was compared with placebo in patients with idiopathic pulmonary fibrosis. The study was conducted at 127 sites in 9 countries. Eligible patients were between the ages of 40 and 80 years and had received a centrally confirmed diagnosis of idiopathic pulmonary fibrosis. Patients were recruited July 2011 through January 2013. A total of 555 patients were enrolled; 278 were assigned to receive pirfenidone, and 277 were assigned to receive placebo. Physical examination and clinical laboratory assessments were performed at baseline and at weeks 2, 4, 8, 13, 26, 39, and 52. Pulmonary function, exercise tolerance, and dyspnea were assessed at baseline and at weeks 13, 26, 39, and 52.

The major inclusion criteria were having clinical symptoms consistent with IPF of 12 months duration; diagnosis of IPF, defined as the first instance in which a patient was informed of having IPF, at least 6 months and no more than 48 months before randomization; age 40 through 80 years, inclusive, at randomization; diagnosis of UIP or IPF by High resolution CT or surgical lung biopsy.

Major exclusion criteria included end stage renal disease, obstructive lung disease, congestive heart failure, end stage liver disease, arrhythmias and recent IPF exacerbations.

The primary outcomes of the study were to confirm the treatment effect of pirfenidone 2403 mg/d compared with placebo on change in percent predicted forced vital capacity (%FVC) in patients with idiopathic pulmonary fibrosis (IPF) and confirm the safety of treatment with Pirfenidone 2403 mg/d compared with placebo in patients with IPF.

In this randomized, controlled trial, the use of pirfenidone in patients with idiopathic pulmonary fibrosis led to a slower rate of loss in forced vital capacity than the use of placebo. Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths.

The major strengths of the include the randomized double-blinded control study design, straightforward hypothesis, minimal drop out rates, similarity to previous studies, however with a larger sample size and more central confirmation of diagnosis.

The study offers “New Hope for Idiopathic Pulmonary Fibrosis” (5).  Major concerns would be extrapolating findings to treat patient populations that were not assessed in this study. That includes patients with more severe disease; other interstitial lung disease, and patients with comorbidities that were excluded in this study. The study also doesn't assess if the effects are durable beyond 1 year.

Mohammed Alzoubaidi MBBS and Kenneth S. Knox MD

University of Arizona

Tucson, Arizona

References

1. Nicholson AG, Colby TV, Dubois RM, Hansell DM, Wells AU. The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med. 2000;162(6):2213-7. [CrossRef] [PubMed]
2. Raghu G, Collard HR, Egan JJ, et al. ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. [CrossRef] [PubMed]
3. Noble PW, Albera C, Bradford WZ, et al. CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-9. [CrossRef] [PubMed]
4. Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone Clinical Study Group in Japan. (2010). Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2010;35(4):821-9. [CrossRef] [PubMed]
5. Hunninghake GM. A new hope for idiopathic pulmonary fibrosis. New Engl J Med. 2014:,370(22), 214-3. [CrossRef] [PubMed]

Reference as: Alzoubaidi M, Knox KS. June 2014 Tucson pulmonary journal club: pirfenidone in idiopathic pulmonary fibrosis. Southwest J Pulm Crit Care. 2014;9(4):244-6. doi: http://dx.doi.org/10.13175/swjpcc142-14 PDF