Effect of PAH Specific Therapy on Pulmonary Hemodynamics and Six-Minute Walk Distance in Portopulmonary Hypertension: A Systematic Review and Meta-Analysis
Background. Little is known about the effect of pulmonary arterial hypertension (PAH) specific therapy on pulmonary hemodynamics and exercise capacity in patients with portopulmonary hypertension (PoPH) because such patients are usually excluded from randomized clinical trials (RCT) of such therapy. Methods. We searched PUBMED using the terms “(Therapy/Broad (filter)) AND (portopulmonary hypertension).” We included studies that met the following criteria: ≥5 patients, AND PoPH confirmed by right heart catheterization (RHC), AND follow-up RHC data, AND/OR baseline and follow-up 6MWD available. Results. 12 studies met our inclusion criteria. None was a RCT. The baseline mPAP was 48.6 ± 4.4？mmHg, cardiac output (CO) 5.6 ± 0.9？L/min, and pulmonary vascular resistance (PVR) 668.6 ± 219.1？dynes.sec/cm5. The baseline 6MWD was 348.2 ± 35.6 meters. The use of PAH specific therapy improved mPAP by 7.54？mmHg (95% CI 10.2 to 4.9), CO by 1.77？L/min (95% CI 1.1 to 2.4), and PVR by 253？dynes.sec/cm5 (95% CI 291.4 to 214.6) () and 6MWD by 61.8 meters (95% CI 47.5 to 76) (). Conclusions. The use of PAH specific therapy in PoPH results in significant improvement in both pulmonary hemodynamics and 6MWD. 1. Introduction Portopulmonary hypertension (PoPH) refers to pulmonary arterial hypertension (PAH) associated with portal hypertension with or without cirrhosis [1]. The reported incidence ranges from 2 to 9% [2]. PoPH falls under group I of the WHO classification of pulmonary hypertension as it is histopathologically indistinguishable from idiopathic PAH [3]. It is the third most common cause of PAH after idiopathic PAH and PAH associated with connective tissue disease. Pulmonary arterial hypertension specific therapy has been shown to result in significant improvement in pulmonary hemodynamics and exercise capacity in patients with idiopathic PAH and PAH associated with connective tissue disease [4]. However, little is known about the effectiveness of PAH specific therapy in patients with PoPH since such patients are usually excluded from randomized clinical trials (RCTs) of such therapy because of overall poor survival as well as concerns about adverse drug effects. The use of PAH specific therapy in patients with PoPH may, by causing systemic vasodilatation, potentially exacerbate the hyperdynamic circulatory state [5]. There is a concern that epoprostenol may worsen splenomegaly and cause hypersplenism [6, 7], and endothelin receptor antagonists (ERA) may worsen liver function [8]. The effect of PAH specific therapy on pulmonary hemodynamics is particularly important
References
[1]
R. Rodríguez-Roisin, M. J. Krowka, P. Hervé, and M. B. Fallon, “ERS Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee. Pulmonary-hepatic vascular disorders (PHD),” European Respiratory Journal, vol. 24, no. 5, pp. 861–880, 2004.
[2]
M. J. Krowka, “Portopulmonary hypertension,” Seminars in Respiratory and Critical Care Medicine, vol. 33, no. 1, pp. 17–25, 2012.
[3]
G. Simonneau, M. A. Gatzoulis, I. Adatia et al., “Updated clinical classification of pulmonary hypertension,” Journal of the American College of Cardiology, vol. 62, supplement 25, pp. D34–D41, 2013.
[4]
R. J. Barst, J. S. R. Gibbs, H. A. Ghofrani et al., “Updated evidence-based treatment algorithm in pulmonary arterial hypertension,” Journal of the American College of Cardiology, vol. 54, supplement 1, pp. S78–S84, 2009.
[5]
M. J. Krowka and K. L. Swanson, “How should we treat portopulmonary hypertension?” European Respiratory Journal, vol. 28, no. 3, pp. 466–467, 2006.
[6]
J. Y. Findlay, D. J. Plevak, M. J. Krowka, E. M. Sack, and M. K. Porayko, “Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension,” Liver Transplantation and Surgery, vol. 5, no. 5, pp. 362–365, 1999.
[7]
W. Touma, R. P. Nayak, Z. Hussain, B. R. Bacon, and G. C. Kudva, “Epoprostenol-induced hypersplenism in portopulmonary hypertension,” American Journal of the Medical Sciences, vol. 344, no. 5, pp. 345–349, 2012.
[8]
C. Eriksson, A. Gustavsson, T. Kronvall, and C. Tysk, “Hepatotoxicity by bosentan in a patient with portopulmonary hypertension: A case-report and review of the literature,” Journal of Gastrointestinal and Liver Diseases, vol. 20, no. 1, pp. 77–80, 2011.
M. J. Krowka, R. P. Frantz, M. D. Mcgoon, C. Severson, D. J. Plevak, and R. H. Wiesner, “Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): a study of 15 patients with moderate to severe portopulmonary hypertension,” Hepatology, vol. 30, no. 3, pp. 641–648, 1999.
[11]
M. M. Hoeper, M. Halank, C. Marx et al., “Bosentan therapy for portopulmonary hypertension,” European Respiratory Journal, vol. 25, no. 3, pp. 502–508, 2005.
[12]
F. Reichenberger, R. Voswinckel, E. Steveling et al., “Sildenafil treatment for portopulmonary hypertension,” European Respiratory Journal, vol. 28, no. 3, pp. 563–567, 2006.
[13]
N. Sussman, V. Kaza, N. Barshes et al., “Successful liver transplantation following medical management of portopulmonary hypertension: a single-center series,” American Journal of Transplantation, vol. 6, no. 9, pp. 2177–2182, 2006.
[14]
O. K. Fix, N. M. Bass, T. De Morco, and R. B. Merriman, “Long-term follow-up of portopulmonary hypertension: Effect of treatment with epoprostenol,” Liver Transplantation, vol. 13, no. 6, pp. 875–885, 2007.
[15]
M. M. Hoeper, H. J. Seyfarth, G. Hoeffken et al., “Experience with inhaled iloprost and bosentan in portopulmonary hypertension,” European Respiratory Journal, vol. 30, no. 6, pp. 1096–1102, 2007.
[16]
M. S. Gough and R. J. White, “Sildenafil therapy is associated with improved hemodynamics in liver transplantation candidates with pulmonary arterial hypertension,” Liver Transplantation, vol. 15, no. 1, pp. 30–36, 2009.
[17]
A. R. Hemnes and I. M. Robbins, “Sildenafil monotherapy in portopulmonary hypertension can facilitate liver transplantation,” Liver Transplantation, vol. 15, no. 1, pp. 15–19, 2009.
[18]
M. T. Melgosa, G. L. Ricci, J. C. García-Pagan et al., “Acute and long-term effects of inhaled iloprost in portopulmonary hypertension,” Liver Transplantation, vol. 16, no. 3, pp. 348–356, 2010.
[19]
M. Halank, L. Knudsen, H.-J. Seyfarth et al., “Ambrisentan improves exercise capacity and symptoms in patients with portopulmonary hypertension,” Zeitschrift für Gastroenterologie, vol. 49, no. 9, pp. 1258–1262, 2011.
[20]
T. J. Hollatz, A. Musat, S. Westphal et al., “Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension,” Liver Transplantation, vol. 18, no. 6, pp. 686–695, 2012.
[21]
L. Savale, R. Magnier, J. Le Pavec et al., “Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension,” European Respiratory Journal, vol. 41, no. 1, pp. 96–103, 2013.
[22]
M. J. Krowka, M. B. Fallon, D. C. Mulligan, and R. G. Gish, “Model for End-Stage Liver disease (MELD) exception for portopulmonary hypertension,” Liver Transplantation, vol. 12, no. 12, pp. S114–S116, 2006.
[23]
C. Gilbert, M. C. J. Brown, J. C. Cappelleri, M. Carlsson, and S. P. McKenna, “Estimating a minimally important difference in pulmonary arterial hypertension following treatment with sildenafil,” Chest, vol. 135, no. 1, pp. 137–142, 2009.
[24]
S. Provencher, P. Herve, X. Jais, et al., “Deleterious effects of β-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension,” Gastroenterology, vol. 130, no. 1, pp. 120–126, 2006.
[25]
R. Channick, D. B. Badesch, V. F. Tapson, et al., “Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: a placebo-controlled study,” The Journal of Heart and Lung Transplantation, vol. 20, pp. 262–263, 2001.
[26]
L. J. Rubin, D. B. Badesch, R. J. Barst et al., “Bosentan therapy for pulmonary arterial hypertension,” The New England Journal of Medicine, vol. 346, no. 12, pp. 896–903, 2002.
[27]
N. Galiè, L. Rubin, M. Hoeper et al., “Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial,” The Lancet, vol. 371, no. 9630, pp. 2093–2100, 2008.
[28]
M. Ashfaq, S. Chinnakotla, L. Rogers et al., “The impact of treatment of portopulmonary hypertension on survival following liver transplantation,” American Journal of Transplantation, vol. 7, no. 5, pp. 1258–1264, 2007.
[29]
R. Cartin-Ceba, K. Swanson, V. Iyer, R. H. Wiesner, and M. J. Krowka, “Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension,” Chest, vol. 139, no. 1, pp. 109–114, 2011.
