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

November 2013 Tucson Pulmonary Journal Club: Macitentan

Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-18. [CrossRef] [PubMed]

Treatment of pulmonary arterial hypertension (PAH) with endothelin receptor antagonists (ERA) has been shown to improve exercise capacity and functional status, but not mortality. A recent systematic review found uncertainty regarding ERAs’ effects on mortality (1). Macitentan, a new molecule structurally similar to bosentan, targets endothelin-A and endothelin-B receptors, offers greater tissue penetration, and has more sustained receptor binding.

SERAPHIN was an industry-sponsored, double-blinded, randomized controlled trial which examined the effect of long-term macitentan use on PAH morbidity and mortality. Between May 2008 and December 2009, 742 patients in 39 countries were randomized to placebo, macitentan 3 mg daily, or macitentan 10 mg daily. Participants had to be ≥12 years of age with Group 1 PAH confirmed by right heart catheterization and have WHO functional class II, III, or IV heart failure. Participants taking intravenous or subcutaneous prostanoids were excluded, but other concomitant treatments were allowed. The composite endpoint of worsening of PAH (initiation of intravenous or subcutaneous prostanoids, lung transplantation, or atrial septostomy) or death from any cause was the primary endpoint. Secondary outcomes included the composite outcome of hospitalization or death due to PAH, change in 6-minute walk (6MW), improvement in WHO functional class, and adverse events.

As compared to placebo, both the 3 mg and 10 mg daily dose of macitentan were found to reduce the composite endpoint of worsening PAH or death with hazard ratios of 0.70 (CI 95% 0.52-0.96) and 0.55 (CI 95% 0.32-0.76), respectively. Both also improved the composite endpoint of hospitalization or death due to PAH, 6MW and WHO functional class. The proportions of participants with elevated liver enzymes were comparable across the 3 groups (1-5%); however, participants in the 3 mg and 10 mg macitentan groups were more likely to experience anemia, 8.8% and 13.2%, respectively, than the 3.2% of participants in the placebo group.

Treatment with macitentan significantly decreased the composite endpoint of worsening PAH or death. The major driver of this reduction was fewer instances of worsening of PAH rather than fewer deaths. Similar to previous trials, SERAPHIN fails to clearly demonstrate that ERA use reduces all cause or PAH-specific mortality. While macitentan use did appear to result in meaningful reductions in symptom burden and hospitalization, the effect on 6MW is smaller than that previously reported for other ERAs (1). Macitentan use does appear to be safe with a slightly higher risk of anemia being observed. The incremental benefit of macitentan over existing treatments is unknown.

Candy Wong, MD; Cristine Berry, MD; Joe Gerald, PhD

University of Arizona

Tucson, AZ

Reference

1. Liu C, Chen J, Gao Y, Deng B, Liu K. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD004434. DOI: 10.1002/14651858.CD004434.pub5. [CrossRef] [PubMed]

Reference as: Wong C, Berry C, Gerald J. November 2013 Tucson pulmonary journal club: macitentan. Southwest J Pulm Crit Care. 2013;7(6):349-50. doi: http://dx.doi.org/10.13175/swjpcc174-13 PDF

October 2013 Pulmonary Journal Club: Pulmonary Artery Hypertension

Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-18. [CrossRef] [PubMed]

The October pulmonary journal club was focused on pulmonary hypertension. We reviewed a total of 5 articles on pulmonary hypertension. The 2 articles on riociguat that appeared in the New England Journal of Medicine have been reviewed and summarized in the September Pulmonary Journal Club (1-3).

Current therapies in the treatment of pulmonary hypertension have been based on their efficacy in improving exercise tolerance and 6 minute walk time. Macitentan is a new endothelin receptor antagonist that has now been approved by the FDA for the treatment of Class I pulmonary hypertension. The trial was a multicenter double-blind, placebo-controlled study. A total of 742 patients were included and divided into 3 arms (placebo, 3mg, and 10mg). Inclusion criteria were Class I pulmonary hypertension, World Health Organization (WHO) class 2-4, and confirmation of pulmonary hypertension by right heart catheterization.  Patients were excluded if they were receiving subcutaneous or IV prostacyclin therapy. Composite primary endpoints were monitored for morbidity (decrease in 6 minute walk, increase in symptoms, need for additional therapy, septoplasty, lung transplantation) and mortality. The results showed that there was a reduction in composite endpoint for morbidity but this was largely due to an improvement in 6 minute walk time. There was no significant reduction in mortality. The studying initially looks exciting in that it was a large study and the first to look at morbidity and mortality. The problem however lies in using composite endpoints in defining morbidity. By using multiple variables as 1 composite endpoint it’s easier to report a significant effect when there really is not much of one. The study is promising and the medication does show an improved exercise tolerance.  A longer term study would be more fruitful in further evaluating mortality.  Our review yielded that we would consider using this medication, but were unsure as to what tier it would fall in. Cost will likely be a prohibitive factor especially since other less expensive endothelin receptor antagonists have similar efficacy.

Minai OA, Yared JP, Kaw R, Subramaniam K, Hill NS.Perioperative risk and management in patients with pulmonary hypertension. Chest. 2013;144(1):329-40. [CrossRef] [PubMed]

Kosarek L, Fox C, Baluch AR, Kaye AD. Pulmonary hypertension and current anesthetic implications. Middle East J Anesthesiol. 2009;20(3):337-46

The perioperative care of patients with pulmonary hypertension remains a challenge with no formal guidelines on management. The above 2 articles were a review on the physiology of pulmonary hypertension, and the rationale for use of certain medications. Our review of the articles led to the consensus that our current model of practice follows that of expert opinion. We often start a PDE5 inhibitor as first line therapy preoperatively and will delay surgery in high risk patients until pulmonary hypertension management has been optimized. The main differences we encountered were in the use of pulmonary artery catheters over continuous TEE probes and whether to initiate IV prostacyclin therapy based on echo findings alone. Our practice style has been to place pulmonary artery catheters preoperatively and leave them in during the post operative period for the first 24-48hrs while medications such as inhaled nitric oxide or IV prostacyclin infusions are in use.  Echocardiograms are often misleading in identifying the severity of pulmonary hypertension, but once you identified that that a severe pulmonary hypertension scenario is present, we advocate having an experienced cardiac anesthetist and/or pulmonologist experienced with inhaled nitric oxide, IV prostacyclin therapy on standby while undergoing moderate sedation or anesthesia, and this even includes the initial right heart catheterization. Much of the perioperative management is recognizing the potential needs of the patient and having the appropriate meds and personnel available. I think it goes without saying that these patients should be managed in specialized centers.

Manoj Mathew, MD FCCP

Associate Editor

Pulmonary Journal Club

References

1. Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319-29. [CrossRef] [PubMed]
2. Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-40. [CrossRef] [PubMed] 
3. Robbins RA. September 2013 pulmonary journal club: riociguat; pay the doctor. Southwest J Pulm Crit Care. 2013;7(3):190-2. [CrossRef]

Reference as: Mathew M. October 2013 pulmonary journal club: pulmonary artery hypertension. Southwest J Pulm Crit Care. 2013;7(4):267-8. doi: http://dx.doi.org/10.13175/swjpcc146-13 PDF