Combination therapy in pulmonary arterial hypertension: do we have the right strategy?

References

• Humbert M, Sitbon O, Chaouat A et al. Pulmonary arterial hypertension in France: results form a national registry. Am. J. Respir. Crit. Care Med.173, 1023–1030 (2006).
   PubMed Web of Science ®Google Scholar
• Peacock AJ, Murphy NF, McMurray JV, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur. Respir. J.30, 104–109 (2007).
   PubMed Web of Science ®Google Scholar
• Chin KM, Rubin LJ. Pulmonary arterial hypertension. J. Am. Coll. Cardiol.51(16), 1527–1538 (2008).
   PubMed Web of Science ®Google Scholar
• Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N. Engl. J. Med.351(14), 1425–1436 (2004).
   PubMed Web of Science ®Google Scholar
• Rich S, Pogoriler J, Husain AL, Toth PT, Gomberg-Maitland M, Archer SL. Long-term effects of epoprostenol on the pulmonary vasculature in idiopathic pulmonary arterial hypertension. Chest138(5), 1234–1239 (2010).
   PubMed Web of Science ®Google Scholar
• Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M. Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur. Respir. J.35, 1079–1087 (2010).
   PubMed Web of Science ®Google Scholar
• 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. Circulation122, 156–163 (2010).
   PubMed Web of Science ®Google Scholar
• Benza RL, Miller DP, Gomberg-Maitland M et al. Predicting survival in pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL). Circulation122, 164–172 (2010).
   PubMed Web of Science ®Google Scholar
• Galiè N, Hoeper MM, Humbert M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. 2009 Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and Lung Transplantation (ISHLT). Eur. Respir. J.34(6), 1219–1263 (2009).
   PubMed Web of Science ®Google Scholar
• McLaughlin VV, Archer SL, Badesch DB et al. ACCF/AHA.ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation119(16), 2250–2294 (2009).
   PubMed Web of Science ®Google Scholar
• Gibbs JS. Treating pulmonary arterial hypertension: is it worth it? Heart96, 1607–1608 (2010).
   PubMed Web of Science ®Google Scholar
• Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest135, 794–804 (2009).
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, Barst RJ, Benza RL et al. Future perspectives for the treatment of pulmonary arterial hypertension. J. Am. Coll. Cardiol.54(Suppl. 1), S108–S117 (2009).
   PubMed Web of Science ®Google Scholar
• D’Alonzo GE, Barst RJ, Ayres SM et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann. Intern. Med.115, 343–349 (1991).
   PubMed Web of Science ®Google Scholar
• Voelkel NF, Quaife RA, Leinwand LA et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation114, 1883–1891 (2006).
   PubMed Web of Science ®Google Scholar
• Rich S, Brundage BH. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation76(1), 135–141 (1987).
   PubMed Web of Science ®Google Scholar
• Kerbaul F, Brimioulle S, Rondelet B, Dewachter C, Hubloue I, Naeije R. How prostacyclin improves cardiac output in right heart failure in conjunction with pulmonary hypertension. Am. J. Respir. Crit. Care Med.175, 846–850 (2007).
   PubMed Web of Science ®Google Scholar
• Handoko ML de Man FS, Allaart CP et al. Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart. Eur. Respir. Rev.19(115), 72–82 (2010).
   PubMedGoogle Scholar
• Kasimir MT. Reverse cardiac remodelling in patients with primary pulmonary hypertension after isolated lung transplantation. Eur. J. Cardiothorac. Surg.26(4), 776–781 (2004).
   PubMed Web of Science ®Google Scholar
• Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat. Med.6(6), 698–702 (2000).
   PubMed Web of Science ®Google Scholar
• Clapp LH, Finney P, Turcato S, Tran S, Rubin LJ, Tinker A. Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery. Am. J. Respir. Cell. Mol. Biol.26(2), 194–201 (2002).
   PubMed Web of Science ®Google Scholar
• Yang Z, Krasnici N, Lüscher TF. Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade. Circulation100(1), 5–8 (1999).
   PubMed Web of Science ®Google Scholar
• Wharton J, Strange JW, Møller GM et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am. J. Respir. Crit. Care Med.172(1), 105–113 (2005).
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, Morrell NW, Hoeper MM et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am. J. Respir. Crit. Care Med.182(9), 1171–1177 (2010).
   PubMed Web of Science ®Google Scholar
• Klein M, Schermuly RT, Ellinghaus P et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodelling. Circulation118(20), 2081–2090 (2008).
   PubMed Web of Science ®Google Scholar
• Chintalgattu V, Ai D, Langley RR et al. Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress. J. Clin. Invest.120(2), 472–484 (2010).
   PubMed Web of Science ®Google Scholar
• Nagendran J, Archer SL, Soliman D et al. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation116(3), 238–248 (2007).
   PubMed Web of Science ®Google Scholar
• Wilkins MR, Paul GA, Strange JW et al. Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am. J. Respir. Crit. Care Med.171(11), 1292–1297 (2005).
   PubMed Web of Science ®Google Scholar
• van Wolferen SA, Boonstra A, Marcus JT et al. Right ventricular reverse remodelling after sildenafil in pulmonary arterial hypertension. Heart92(12), 1860–1861 (2006).
   PubMed Web of Science ®Google Scholar
• Bogaard HJ, Natarajan R, Mizuno S et al. Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats. Am. J. Respir. Crit. Care Med.182, 652–660 (2010).
   PubMed Web of Science ®Google Scholar
• Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts. Circulation121, 2045–2066 (2010).
   PubMed Web of Science ®Google Scholar
• Handoko ML, Lamberts RR, Redout EM et al. Right ventricular pacing improves right heart function in experimental pulmonary arterial hypertension: a study in the isolated heart. Am. J. Physiol. Heart Circ. Physiol.297, H1752–H1759 (2009).
   Web of Science ®Google Scholar
• Galie N, Manes A, Negro L, Palazzini M, Bacchia-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur. Heart J.30, 394–403 (2009).
   PubMed Web of Science ®Google Scholar
• Ryerson CJ, Nayar S, Swiston JR, Sin DD. Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis. Respir. Res.11, 12 (2010).
   PubMed Web of Science ®Google Scholar
• Macchia A, Marchioli R, Marfisi R et al. A meta-analysis of trials of pulmonary hypertension: a clinical condition looking for drugs and research methodology. Am. Heart J.153, 1037–1047 (2007).
   PubMed Web of Science ®Google Scholar
• Macchia A, Marchioli R, Tognoni G et al. Systematic review of trials using vasodilators in pulmonary arterial hypertension: why a new approach is needed. Am. Heart J.159(2), 245–257 (2010).
   PubMed Web of Science ®Google Scholar
• Barst RJ, Rubin LJ, Long WA et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N. Engl. J. Med.334, 296–302 (1996).
   PubMed Web of Science ®Google Scholar
• 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.327, 70–75 (1992).
   PubMed Web of Science ®Google Scholar
• Tuder RM, Cool CD, Gearci MW et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am. J. Respir. Crit. Care Med.159, 1925–1932 (1999).
   PubMed Web of Science ®Google Scholar
• Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann. Intern. Med.121(6), 409–415 (1994).
   PubMed Web of Science ®Google Scholar
• Simonneau G, Barst RJ, Galie N et al.; Treprostinil Study Group. 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.165(6), 800–804 (2002).
   PubMed Web of Science ®Google Scholar
• Olschewski H, Simonneau G, Galiè N et al. Aerosolized iloprost randomized study group. Inhaled iloprost for severe pulmonary hypertension. N. Engl. J. Med.347(5), 322–329 (2002).
   PubMed Web of Science ®Google Scholar
• Vizza CD, Sciomer S, Morelli S et al. Long term treatment of pulmonary arterial hypertension with beraprost, an oral prostacyclin analogue. Heart86(6), 661–665 (2001).
   PubMed Web of Science ®Google Scholar
• Gomberg-Maitland M, Olschewski H. Prostacyclin therapies for the treatment of pulmonary arterial hypertension. Eur. Respir. J.31(4), 891–901 (2008).
   PubMed Web of Science ®Google Scholar
• Lüscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation102, 2434–2440 (2000).
   PubMed Web of Science ®Google Scholar
• Channick RN, Simonneau G, Sitbon O et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet358(9288), 1119–1123 (2001).
   PubMed Web of Science ®Google Scholar
• Galiè N, Olschewski H, Oudiz RJ et al. Ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy studies (ARIES) group. 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. Circulation117(23), 3010–3019 (2008).
   PubMed Web of Science ®Google Scholar
• Opitz CF, Ewert R, Kirch W, Pittrow D. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur. Heart J.29(16), 1936–1948 (2008).
   PubMed Web of Science ®Google Scholar
• Barst RJ, Langleben D, Frost A et al. STRIDE-1 Study Group. Sitaxsentan therapy for pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.169(4), 441–447 (2004).
   PubMed Web of Science ®Google Scholar
• Dinh-Xuan AT. Endothelial modulation of pulmonary vascular tone. Eur. Respir. J.5, 757–762 (1992).
   PubMed Web of Science ®Google Scholar
• Galiè N, Ghofrani HA, Torbicki A et al. Sildenafil use in pulmonary arterial hypertension (SUPER) study group. sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med.353(20), 2148–2157 (2005).
   PubMed Web of Science ®Google Scholar
• Galiè N, Brundage BH, Ghofrani HA et al. Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) study group. Tadalafil therapy for pulmonary arterial hypertension. Circulation119(22), 2894–2903 (2009).
   PubMed Web of Science ®Google Scholar
• Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N. Engl. J. Med.361(19), 1864–1871 (2009).
   PubMed Web of Science ®Google Scholar
• Gokhman R, Smithburger PL, Kane-Gill SL, Seybert AL. Pharmacologic and pharmacokinetic rationale for combination therapy in pulmonary arterial hypertension. J. Cardiovasc. Pharmacol.56(6), 686–695 (2010).
   PubMed Web of Science ®Google Scholar
• Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br. J. Clin. Pharmacol.60(1), 107–112 (2005).
   PubMed Web of Science ®Google Scholar
• Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur. J. Clin. Pharmacol.64(1), 43–50 (2008).
   PubMed Web of Science ®Google Scholar
• Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ. Res.93, 280–291 (2003).
   PubMed Web of Science ®Google Scholar
• Wedgwood S, Black SM. Endothelin-1 decreases endothelial NOS expression and activity through ETA receptor-mediated generation of hydrogen peroxide. Am. J. Physiol. Lung Cell. Mol. Physiol.288, L480–L487 (2005).
   PubMed Web of Science ®Google Scholar
• Girgis RE, Champion HC, Diette GB et al. Decreased exhaled nitric oxide in pulmonary arterial hypertension: response to bosentan therapy. Am. J. Respir. Crit. Care Med.172, 352–357 (2005).
   PubMed Web of Science ®Google Scholar
• Gruenig E, Michelakis E, Vachiéry JL et al. Acute hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients with pulmonary arterial hypertension: results of the COMPASS-1 study. J. Clin. Pharmacol.49(11), 1343–1352 (2009).
   PubMed Web of Science ®Google Scholar
• Provencher S, Sitbon O, Humbert M et al. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur. Heart J.27, 89–95 (2006).
   PubMedGoogle Scholar
• 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. Lancet371(9630), 2093–2100 (2008).
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, Wilkins MR, Rich S. Uncertainties in the diagnosis and treatment of pulmonary arterial hypertension. Circulation118, 1195–1201 (2008).
   PubMed Web of Science ®Google Scholar
• McLaughlin VV, Oudiz RJ, Frost A et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med.174(11), 1257–1263 (2006).
   PubMed Web of Science ®Google Scholar
• Simonneau G, Rubin LJ, Galiè N et al.; for the PACES study group. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann. Intern. Med.149, 521–530 (2008).
   PubMed Web of Science ®Google Scholar
• McLaughlin VV, Benza RL, Rubin LJ et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J. Am. Coll. Cardiol.55(18), 1915–1922 (2010).
   PubMed Web of Science ®Google Scholar
• Hoeper MM, Leuchte H, Halank M et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur. Respir. J.28(4), 691–694 (2006).
   PubMed Web of Science ®Google Scholar
• Channick RN, Olschewski H, Seeger W, Staub T, Voswinckel R, Rubin LJ. Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension. J. Am. Coll. Cardiol.48(7), 1433–1437 (2006).
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, Wiedemann R, Rose F et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann. Intern. Med.136(7), 515–522 (2002).
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, Rose F, Schermuly RT et al. Amplification of the pulmonary vasodilatory response to inhaled iloprost by subthreshold phosphodiesterase types 3 and 4 inhibition in severe pulmonary hypertension. Crit. Care Med.30(11), 2489–2492 (2002).
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, Rose F, Schermuly RT et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J. Am. Coll. Cardiol.42(1), 158–164 (2003).
   PubMed Web of Science ®Google Scholar
• Humbert M, Barst RJ, Robbins IM et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur. Respir. J.24(3), 353–359 (2004).
   PubMed Web of Science ®Google Scholar
• Coghlan JG, Pope J, Denton CP. Assessment of endpoints in pulmonary arterial hypertension associated with connective tissue disease. Curr. Opin. Pulm. Med.16(Suppl. 1), S27–S34 (2010).
   Google Scholar
• Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur. Respir. J.26(5), 858–863 (2005).
   PubMed Web of Science ®Google Scholar
• Sitbon O, Humbert M, Nunes H et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J. Am. Coll. Cardiol.40(4), 780–788 (2002).
   PubMed Web of Science ®Google Scholar
• Wensel R, Opitz CF, Anker SD et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation106(3), 319–324 (2002).
   PubMed Web of Science ®Google Scholar
• Benza RL, Gupta H, Soto F et al. Clinical Worsening Of Pulmonary Arterial Hypertension: The COMPASS-3 Study. ClinicalTrials.gov Identifier: NCT00433329. Am. J. Respir. Crit. Care Med.181, A2512 (2010).
   Google Scholar
• McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation114(13), 1417–1431 (2006).
   PubMed Web of Science ®Google Scholar
• Hoeper MM. Observational trials in pulmonary arterial hypertension: low scientific evidence but high clinical value. Eur. Respir. J.29, 432–434 (2007).
   PubMed Web of Science ®Google Scholar
• Mereles D, Ehlken N, Kreuscher S et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation114(14), 1482–1489 (2006).
   PubMed Web of Science ®Google Scholar
• Redelmeier DA, Bayoumi AM, Goldstein RS, Guyatt GH. Interpreting small differences in functional status: the six minute walk test in chronic lung disease patients. Am. J. Respir. Crit. Care Med.155(4), 1278–1282 (1997).
   PubMed Web of Science ®Google Scholar
• Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med.346(12), 896–903 (2002).
   PubMed Web of Science ®Google Scholar
• Kuwano K, Hashino A, Asaki T et al. 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]-N-(methylsulfonyl)acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J. Pharmacol. Exp. Ther.322(3), 1181–1188 (2007).
   PubMed Web of Science ®Google Scholar
• Grimminger F, Weimann G, Frey R et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur. Respir. J.33(4), 785–792 (2009).
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, Hoeper MM, Halank M et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a Phase II study. Eur. Respir. J.36(4), 792–799 (2010).
   PubMed Web of Science ®Google Scholar
• Klein M et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation118, 2081–2090 (2008).
   PubMed Web of Science ®Google Scholar
• Gomberg-Maitland M, Maitland ML, Barst RJ et al. A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension. Clin. Pharmacol. Ther.87(3), 303–310 (2010).
   PubMed Web of Science ®Google Scholar
• Hoeper MM, Taha N, Bekjarova A et al. Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids. Eur. Respir. J.22(2), 330–334 (2003).
   PubMed Web of Science ®Google Scholar
• Seyfarth HJ, Pankau H, Hammerschmidt S et al. Bosentan improves exercise tolerance and Tei index in patients with pulmonary hypertension and prostanoid therapy. Chest128(2), 709–713 (2005).
   PubMed Web of Science ®Google Scholar
• Benza RL, Rayburn BK, Tallaj JA, Pamboukian SV, Bourge RC. Treprostinil-based therapy in the treatment of moderate-to-severe pulmonary arterial hypertension: long-term efficacy and combination with bosentan. Chest134(1), 139–145 (2008).
   PubMed Web of Science ®Google Scholar
• Akagi S, Matsubara H, Miyaji K et al. Additional effects of bosentan in patients with idiopathic pulmonary arterial hypertension already treated with high-dose epoprostenol. Circ. J.72(7), 1142–1146 (2008).
   PubMed Web of Science ®Google Scholar
• Jacobs W, Boonstra A, Marcus JT, Postmus PE, Vonk-Noordegraaf A. Addition of prostanoids in pulmonary hypertension deteriorating on oral therapy. J. Heart Lung Transplant.28(3), 280–284 (2009).
   PubMed Web of Science ®Google Scholar
• Gomberg-Maitland M, McLaughlin V, Gulati M, Rich S. Efficacy and safety of sildenafil added to treprostinil in pulmonary hypertension. Am. J. Cardiol.96(9), 1334–1336 (2005).
   PubMed Web of Science ®Google Scholar
• Ruiz MJ, Escribano P, Delgado JF et al. Efficacy of sildenafil as a rescue therapy for patients with severe pulmonary arterial hypertension and given long-term treatment with prostanoids: 2-year experience. J. Heart Lung Transplant.25(11), 1353–1357 (2006).
   PubMed Web of Science ®Google Scholar
• Reichenberger F, Voswinckel R, Steveling E et al. Sildenafil treatment for portopulmonary hypertension. Eur. Respir. J.28(3), 563–567 (2006).
   PubMed Web of Science ®Google Scholar
• Voswinckel R, Reichenberger F, Enke B et al. Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension. Pulm. Pharmacol. Ther.21(5), 824–832 (2008).
   PubMed Web of Science ®Google Scholar
• Kim SY, Shim JK, Shim YH, Hong SW, Choi KH, Kwak YL. Sildenafil and beraprost combination therapy in patients with pulmonary hypertension undergoing valvular heart surgery. J. Heart Valve Dis.19(3), 333–340 (2010).
   PubMed Web of Science ®Google Scholar
• Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur. Respir. J.24(6), 1007–1010 (2004).
   PubMed Web of Science ®Google Scholar
• Lunze K, Gilbert N, Mebus S et al. First experience with an oral combination therapy using bosentan and sildenafil for pulmonary arterial hypertension. Eur J. Clin. Invest.36(Suppl. 3), 32–38 (2006).
   PubMed Web of Science ®Google Scholar
• Mathai SC, Girgis RE, Fisher MR et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur. Respir. J.29(3), 469–475 (2007).
   PubMed Web of Science ®Google Scholar
• Porhownik NR, Al-Sharif H, Bshouty Z. Addition of sildenafil in patients with pulmonary arterial hypertension with inadequate response to bosentan monotherapy. Can. Respir. J.15(8), 427–430 (2008).
   PubMed Web of Science ®Google Scholar