The Efficacy of Pharmacological Interventions in Pulmonary Arterial Hypertension (WHO Group 1): A Systematic Review of Randomized Controlled Trials
Keywords:
Pulmonary Arterial Hypertension, Randomized Controlled Trial, Combination Therapy, Endothelin Receptor Antagonist, Phosphodiesterase-5 Inhibitor, ProstacyclinAbstract
Introduction: Pulmonary arterial hypertension (PAH), WHO Group 1, is a progressive vasculopathy leading to right heart failure and premature death. Pharmacological therapies targeting the endothelin, nitric oxide, and prostacyclin pathways have improved outcomes, but the optimal treatment strategy remains a subject of ongoing investigation. This systematic review synthesizes evidence from randomized controlled trials (RCTs) to evaluate the efficacy of these interventions, with a focus on the comparative benefits of monotherapy versus combination therapy.
Methods: A systematic search of MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted for RCTs published from January 1990 to the present. Studies enrolling adult patients with WHO Group 1 PAH and evaluating approved pharmacological agents against placebo or another active therapy were included. Data on study design, patient characteristics, and a minimum of 15 predefined outcomes—including functional, hemodynamic, biomarker, and clinical event endpoints—were extracted. Methodological quality was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. A narrative synthesis was performed.
Results: Seventeen pivotal RCTs were included in the final analysis. Monotherapy with endothelin receptor antagonists (ERAs), nitric oxide pathway modulators (phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators), and prostacyclin pathway agents demonstrated significant improvements over placebo in exercise capacity (e.g., 6-minute walk distance), hemodynamic parameters (e.g., pulmonary vascular resistance, cardiac index), and functional class. Intravenous prostacyclins were unique in demonstrating a mortality benefit in a standalone RCT. Landmark event-driven trials established the superiority of combination therapy. The AMBITION trial showed that upfront dual combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure by 50% compared to pooled monotherapy, primarily by reducing PAH-related hospitalizations. Sequential add-on therapy yielded mixed results, with some combinations showing benefit (e.g., sildenafil added to epoprostenol in PACES) while others did not meet their primary endpoint (e.g., bosentan added to sildenafil in COMPASS-2).
Discussion: The evidence base for PAH treatment is robust, demonstrating a clear paradigm shift from sequential monotherapy to upfront combination therapy for most patients. The superiority of initial dual combination with an ERA and a PDE-5 inhibitor is well-established for delaying disease progression. The evolution of clinical trial endpoints from the 6-minute walk distance to composite morbidity/mortality outcomes reflects a more clinically meaningful assessment of therapeutic benefit.
Conclusion: Pharmacological interventions have significantly improved the prognosis for patients with PAH. The current evidence strongly supports initial, risk-stratified treatment with upfront dual combination therapy to delay clinical worsening. Intravenous prostacyclins remain a critical component of therapy for high-risk patients. Future research should focus on direct comparisons of combination strategies and the role of initial triple therapy.
References
Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913.
Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731.
Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37(1):67-119.
Galiè N, McLaughlin VV, Rubin LJ, Simonneau G. An overview of the 6th World Symposium on Pulmonary Hypertension. Eur Respir J. 2019;53(1):1802148.
Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50.
Galiè N, Manes A, Negro L, Palazzini M, Bacchi Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30(4):394-403.
Macchia A, Marchioli R, Tognoni G, et al. Systematic review of trials using vasodilators in pulmonary arterial hypertension: why a meta-analysis is not possible. Am Heart J. 2010;159(3):482-489.
Lau EMT, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol. 2017;14(10):603-614.
Farber HW, Miller DP, Poms AD, et al. Five-year outcomes of patients enrolled in the REVEAL Registry. Chest. 2015;148(4):1043-1054.
Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how the REVEAL Registry differs from historical cohorts. Chest. 2011;139(1):128-137.
Benza RL, Miller DP, Barst RJ, et al. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142(2):448-456.
Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122(2):156-163.
Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376-387.
McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1 Suppl):78S-92S.
Archer SL, Michelakis ED. The final frontier in pulmonary arterial hypertension: right ventricular failure. Circulation. 2009;120(13):1266-1270.
Vachiéry JL, Gaine S. Challenges in the diagnosis and treatment of pulmonary arterial hypertension. Eur Respir Rev. 2012;21(126):313-320.
Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328(24):1732-1739.
Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):13S-24S.
Rubin LJ, Roux S. The role of endothelin in the pathogenesis of pulmonary hypertension. Cardiovasc Res. 2002;55(1):22-29.
Dupuis J, Cernacek P, Tardif JC, et al. Reduced pulmonary clearance of endothelin-1 in patients with primary pulmonary hypertension. Am Heart J. 1998;135(4):614-620.
Channick RN, Sitbon O, Barst RJ, Manes A, Galiè N. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):62S-67S.
Ghofrani HA, Grimminger F, Schermuly RT, et al. A novel pathway for the treatment of pulmonary hypertension: the role of soluble guanylate cyclase. Eur Respir J. 2006;28(3):655-662.
Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011;123(20):2263-2273.
Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353(20):2148-2157.
Barnett CF, Machado RF. Sildenafil in the treatment of pulmonary hypertension. Vasc Health Risk Manag. 2006;2(4):411-422.
Grimminger F, Weimann G, Frey R, et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009;33(4):785-792.
Clapp LH, Finney P, Turcato S, et al. Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human pulmonary arteries. Am J Respir Cell Mol Biol. 2002;26(2):194-201.
Jones DA, Benjamin CW, Lin A. Activation of the p38 mitogen-activated protein kinase pathway by prostacyclin in human aortic smooth muscle cells. J Biol Chem. 1999;274(2):1196-1203.
Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159(6):1925-1932.
Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992;327(2):70-75.
Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D60-72.
McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol. 2015;65(18):1976-1997.
Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373(26):2522-2533.
Galiè N, Palazzini M, Manes A. Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur Heart J. 2010;31(17):2080-2086.
Galiè N, Rubin LJ, Tuder R, et al. Treatment of patients with pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):68S-77S.
Mathai SC, Pugsley MK, Ataga KI, et al. The 6-minute walk test in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol. 2022;79(12):1196-1208.
Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012;126(3):349-356.
Savarese G, Paolillo S, Costanzo P, et al. Do changes in 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol. 2012;60(13):1192-1201.
Food and Drug Administration. Clinical Trial Endpoints for the Approval of Drugs and Biologics for Human Use. Guidance for Industry. 2022.
Yuan K, Zhang Y, Zhou Q, et al. Combination therapy for pulmonary arterial hypertension: a network meta-analysis. J Am Coll Cardiol. 2024.
Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M. A USA-based registry for pulmonary arterial hypertension: 1982-2006. Eur Respir J. 2007;30(6):1103-1110.
Liu C, Chen J, Gao Y, et al. Oral targeted therapies for pulmonary arterial hypertension: a systematic review and meta-analysis. Ther Adv Respir Dis. 2018;12:1753466618791336.
Zelt JGE, Sugarman J, Weatherald J, et al. Comparative efficacy and safety of drug therapies for pulmonary arterial hypertension: a systematic review and network meta-analysis. Eur Respir Rev. 2022;31(165):220036.
UCSF Health. Pulmonary Hypertension Clinical Trials. 2024.
American Lung Association. Treating and Managing PAH. 2024.
Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.
Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
Higgins JPT, Thomas J, Chandler J, et al. (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane, 2023.
Risk of Bias Info. RoB 2 tool (revised tool for Risk of Bias in randomized trials). 2024.
Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296-302.
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896-903.
Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353(20):2148-2157.
Galiè N, Rubin LJ, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371(9630):2093-2100.
Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-818.
Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(26):2522-2533.
Galiè N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834-844.
Simonneau G, Barst RJ, Galiè N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165(6):800-804.
Olschewski H, Simonneau G, Galiè N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347(5):322-329.
Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117(23):3010-3019.
Simonneau G, Rubin LJ, Galiè N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149(8):521-530.
Galiè N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119(22):2894-2903.
Jing ZC, Yu ZX, Shen JY, et al. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2011;183(12):1723-1729.
Tapson VF, Torres F, Kermeen F, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest. 2012;142(6):1383-1390.
Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension. Circulation. 2013;127(5):624-633.
Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-340.
McLaughlin V, Channick RN, Ghofrani HA, et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015;46(2):405-413.
Vachiéry JL, Galiè N, Barberà JA, et al. Initial combination therapy with ambrisentan/tadalafil on pulmonary arterial hypertension-related hospitalization in the AMBITION trial. J Heart Lung Transplant. 2018;37(10):1233-1238.
Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR. Bosentan decreases the plasma concentration of sildenafil when co-prescribed in pulmonary hypertension. Br J Clin Pharmacol. 2005;60(1):107-112.
Vizza CD, Jansa P, Teal S, Dombi T, Zhou D. Sildenafil dosed concomitantly with bosentan for adult pulmonary arterial hypertension in a randomized controlled trial. BMC Cardiovasc Disord. 2017;17(1):213.
Simonneau G, Galiè N, Jansa P, et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. Int J Cardiol. 2014;172(2):332-339.
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