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