BACKGROUND: Few controlled clinical trials exist to support oral combination therapy in pulmonary arterial hypertension (PAH). METHODS: Patients with PAH (idiopathic [IPAH] or associated with connective tissue disease [APAH-CTD]) taking bosentan (62.5 or 125 mg twice daily at a stable dose for ≥3 months) were randomized (1:1) to sildenafil (20 mg, 3 times daily; n = 50) or placebo (n = 53). The primary endpoint was change from baseline in 6-min walk distance (6MWD) at week 12, assessed using analysis of covariance. Patients could continue in a 52-week extension study. An analysis of covariance main-effects model was used, which included categorical terms for treatment, baseline 6MWD (<325 m; ≥325 m), and baseline aetiology; sensitivity analyses were subsequently performed. RESULTS: In sildenafil versus placebo arms, week-12 6MWD increases were similar (least squares mean difference [sildenafil-placebo], -2.4 m [90% CI: -21.8 to 17.1 m]; P = 0.6); mean ± SD changes from baseline were 26.4 ± 45.7 versus 11.8 ± 57.4 m, respectively, in IPAH (65% of population) and -18.3 ± 82.0 versus 17.5 ± 59.1 m in APAH-CTD (35% of population). One-year survival was 96%; patients maintained modest 6MWD improvements. Changes in WHO functional class and Borg dyspnoea score and incidence of clinical worsening did not differ. Headache, diarrhoea, and flushing were more common with sildenafil. CONCLUSIONS: Sildenafil, in addition to stable (≥3 months) bosentan therapy, had no benefit over placebo for 12-week change from baseline in 6MWD. The influence of PAH aetiology warrants future study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00323297 (registration date: May 5, 2006).

Charles University Ovocný trh 3 5 116 36 Praha 1 Prague Czech Republic

Pfizer Inc 4 E Carol Ave Burlingame New York CA 94010 USA

Pfizer Inc Eastern Point Rd Groton CT 06340 USA

Pfizer Limited Tadworth Berlin UK

Unita' di Ipertensione Polmonare Dipartimento di Scienze Respiratorie e Cardiovascolari Universita' degli Studi di Roma La Sapienza Viale del Policlinico 155 Rome Italy

See more in PubMed

Task Force for D. Treatment of Pulmonary Hypertension of European Society of C. European Respiratory S. International Society of H. Lung T, Galie N, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34:1219–1263. doi: 10.1183/09031936.00139009. PubMed DOI

Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425–1436. doi: 10.1056/NEJMra040291. PubMed DOI

Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330–340. doi: 10.1056/NEJMoa1209655. PubMed DOI

Galie N, Corris PA, Frost A, Girgis RE, Granton J, Jing ZC, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62:D60–D72. doi: 10.1016/j.jacc.2013.10.031. PubMed DOI

McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. 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. J Am Coll Cardiol. 2009;53:1573–1619. doi: 10.1016/j.jacc.2009.01.004. PubMed DOI

Levinson AT, Klinger JR. Combination therapy for the treatment of pulmonary arterial hypertension. Ther Adv Respir Dis. 2011;5:419–430. doi: 10.1177/1753465811411602. PubMed DOI

Fox BD, Shimony A, Langleben D. Meta-analysis of monotherapy versus combination therapy for pulmonary arterial hypertension. Am J Cardiol. 2011;108:1177–1182. doi: 10.1016/j.amjcard.2011.06.021. PubMed DOI

Bai Y, Sun L, Hu S, Wei Y. Combination therapy in pulmonary arterial hypertension: a meta-analysis. Cardiology. 2011;120:157–165. doi: 10.1159/000334431. PubMed DOI

Gruenig E, Michelakis E, Vachiery JL, Vizza CD, Meyer FJ, Doelberg M, 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. 2009;49:1343–1352. doi: 10.1177/0091270009341182. PubMed DOI

Benza R, Gupta H, Soto F, Park M, Torres F, Frey N, et al. Safety and efficacy of bosentan in combination with sildenafil in PAH patients who experience inadequate clinical response to monotherapy: the COMPASS-3 study [abstract] Chest. 2010;138:840A. doi: 10.1378/chest.10295. PubMed DOI

Torres F, Gupta H, Soto F, Park M, Frey N, Murali S, et al. Safety and efficacy of bosentan in combination with sildenafil in pulmonary arterial hypertension: The COMPASS-3 study [abstract] Amsterdam, Netherlands: European Respiratory Society International Congress: September 25; 2011.

Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–2157. doi: 10.1056/NEJMoa050010. PubMed DOI

US Food and Drug Administration. In: Pfizer Inc. 2005.

Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:40S–47S. doi: 10.1016/j.jacc.2004.02.032. PubMed DOI

Borg G. Psychophysical scaling with applications in physical work and the perception of exertion. Scand J Work Environ Health. 1990;16(Suppl 1):55–58. doi: 10.5271/sjweh.1815. PubMed DOI

Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14:377–381. PubMed

Barst RJ, Oudiz RJ, Beardsworth A, Brundage BH, Simonneau G, Ghofrani HA, et al. Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension. J Heart Lung Transpl. 2011;30:632–43. doi: 10.1016/j.healun.2010.11.009. PubMed DOI

Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903. doi: 10.1056/NEJMoa012212. PubMed DOI

Treiber A, Schneiter R, Hausler S, Stieger B. Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin a, rifampicin, and sildenafil. Drug Metab Dispos Biol Fate Chem. 2007;35:1400–1407. doi: 10.1124/dmd.106.013615. PubMed DOI

Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008;64:43–50. doi: 10.1007/s00228-007-0408-z. PubMed DOI

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. 2005;60:107–112. doi: 10.1111/j.1365-2125.2005.02383.x. PubMed DOI PMC

Zhuang Y, Jiang B, Gao H, Zhao W. Randomized study of adding tadalafil to existing ambrisentan in pulmonary arterial hypertension. Hypertens Res Official J Japanese Soc Hypertens. 2014;37:507–512. doi: 10.1038/hr.2014.28. PubMed DOI

Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, et al. Initial use of Ambrisentan plus Tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373:834–844. doi: 10.1056/NEJMoa1413687. PubMed DOI

McLaughlin V, Channick RN, Ghofrani HA, Lemarie JC, Naeije R, Packer M, et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015;46:405–413. doi: 10.1183/13993003.02044-2014. PubMed DOI

Farber HW. Validation of the 6-minute walk in patients with pulmonary arterial hypertension: trying to fit a square peg into a round hole? Circulation. 2012;126:258–260. doi: 10.1161/CIRCULATIONAHA.112.118547. PubMed DOI

Savarese G, Paolillo S, Costanzo P, D'Amore C, Cecere M, Losco T, et al. Do changes of 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;60:1192–1201. doi: 10.1016/j.jacc.2012.01.083. PubMed DOI

Rubin LJ. The 6-minute walk test in pulmonary arterial hypertension: how far is enough? Am J Respir Crit Care Med. 2012;186:396–397. doi: 10.1164/rccm.201206-1137ED. PubMed DOI

Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT) Eur Heart J. 2009;30:2493–2537. doi: 10.1093/eurheartj/ehp297. PubMed DOI

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. 2004;24:1007–1010. doi: 10.1183/09031936.04.00051104. PubMed DOI

Lunze K, Gilbert N, Mebus S, Miera O, Fehske W, Uhlemann F, et al. First experience with an oral combination therapy using bosentan and sildenafil for pulmonary arterial hypertension. Eur J Clin Investig. 2006;36:32–38. doi: 10.1111/j.1365-2362.2006.01692.x. PubMed DOI

van Wolferen SA, Boonstra A, Marcus JT, Marques KM, Bronzwaer JG, Postmus PE, et al. Right ventricular reverse remodelling after sildenafil in pulmonary arterial hypertension. Heart. 2006;92:1860–1861. doi: 10.1136/hrt.2005.085118. PubMed DOI PMC

Mathai SC, Girgis RE, Fisher MR, Champion HC, Housten-Harris T, Zaiman A, et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J. 2007;29:469–475. doi: 10.1183/09031936.00081706. PubMed DOI

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. 2008;15:427–430. doi: 10.1155/2008/897102. PubMed DOI PMC

D'Alto M, Romeo E, Argiento P, Sarubbi B, Santoro G, Grimaldi N, et al. Bosentan-sildenafil association in patients with congenital heart disease-related pulmonary arterial hypertension and Eisenmenger physiology. Int J Cardiol. 2012;155:378–382. doi: 10.1016/j.ijcard.2010.10.051. PubMed DOI

Iversen K, Jensen AS, Jensen TV, Vejlstrup NG, Sondergaard L. Combination therapy with bosentan and sildenafil in Eisenmenger syndrome: a randomized, placebo-controlled, double-blinded trial. Eur Heart J. 2010;31:1124–1131. doi: 10.1093/eurheartj/ehq011. PubMed DOI

Galie N, Rubin L, Hoeper M, Jansa P, Al-Hiti H, Meyer G, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093–2100. doi: 10.1016/S0140-6736(08)60919-8. PubMed DOI

See more in PubMed

ClinicalTrials.gov
NCT00323297