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N Engl J Med. 2015 Aug 27;373(9):834-44. doi: 10.1056/NEJMoa1413687.

Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension.

Collaborators (172)

Corte T, Celermajer D, Youssef PP, Keogh A, Kermeen FD, Kilpatrick D, Lavender MA, Williams TJ, Kaehler C, Lang IM, Delcroix M, Vachiery JL, Bshouty Z, Granton J, Hirani N, Provencher S, Swiston JR, Bourdin A, Chabot JF, Cottin V, De Groote P, Dromer C, Frachon I, Paganin F, Pison C, Reynaud-Gaubert M, Simonneau G, Tetu L, Ewert R, Ghofrani HA, Grünig E, Held M, Hoeffken G, Hoeper MM, Klose HF, Lange TJ, Pfeifer MW, Neurohr C, Opitz C, Rosenkranz S, Skowasch D, Sorichter S, Staehler G, Wilkens H, Wirtz HR, Anthi A, Athanasopoulos G, Blamis K, Bouros D, Georgopoulos D, Konstantinides S, Stanopoulos I, Styliadis I, Galiè N, Marini C, Mulè M, Ussia GP, Porcu M, Vizza CD, Abe K, Kishi T, Hatano M, Yao A, Tsujino I, Watanabe H, Boomars KA, Van Den Toorn L, Vonk-Noordegraaf A, Barberá JA, Lamarca M, Palma MJ, Sánchez MA, Salvador M, Reyes R, Manzur DN, Verdugo J, Veloso P, Broto A, Luna F, Cubero J, Bendito A, Combas J, Goñi F, Hubbert L, Jansson K, Rådegran G, Ekmehag BL, Rundqvist B, Selimovic N, Söderberg S, Wikström GG, Coghlan JG, Kiely D, Peacock AJ, Pepke-Zaba J, Wort SJ, Allen R, Allen SA, Aris RM, Badesch DB, Bajwa AA, Benza RL, Bourge RC, Chakinala MM, Costanzo MR, Criner GJ, Cummings RJ, DeBoisblanc BP, Eggert MS, Elliott CG, Elwing JM, Engel PJ, Fagan KA, Farber HW, Farmer MJ, Feldman JP, Fisher MR, Gerke AK, Hansdottir S, Grinnan DC, Harvey WL, Hassan AM, Hill NS, Horn EM, Kim HS, Klinger JR, Mathier MA, Michaelson JE, Migliore C, Studer SM, Minkin R, Mobin SI, Oudiz RJ, Parambil J, Minai OA, Park MH, Rahaghi FF, Rischard F, Robbins IM, Rosenthal SM, Rosenzweig EB, Rubenfire M, Safdar Z, Satterwhite LG, Williamson T, Saydain G, Shapiro S, Smart FW, Smith KA, Forfia PR, Sood N, Spradley C, Sulica R, Talwar A, Torres F, Trichon BH, Urdaneta-Jaimes JA, Waxman AB, Weder MM, White RJ, Wichman TO, Schuller D, Wirth JA, Zwicke DL, Beghetti M, Brundage B, Gaine S, McGoon M, Ford I, Gibbs JS, De Marco T, Olschewski H.

Author information

1
From the Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy (N.G.); Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer and University of Barcelona, Barcelona, and Biomedical Research Networking Center on Respiratory Diseases, Madrid (J.A.B.); Baylor College of Medicine, Houston (A.E.F.); Universities of Giessen and Marburg Lung Center, Giessen (H.-A.G.), Hanover Medical School and German Center of Lung Research, Hanover (M.M.H.), and Thoraxklinik at University Hospital Heidelberg, Heidelberg (E.G.) - all in Germany; University of Michigan Health System, Ann Arbor (V.V.M.); Regional Heart and Lung Centre, Glasgow (A.J.P.), and GlaxoSmithKline, Uxbridge (J.H.N.H., J.L.) - both in the United Kingdom; Université Paris-Sud, Faculté de Médecine, and Assistance Publique-Hôpitaux de Paris, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie, Hôpital de Bicêtre, Le Kremlin Bicêtre, INSERM Unité Mixté de Recherche S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson - all in France (G.S.); Universitaires de Bruxelles-Hôpital Erasme, Brussels (J.-L.V.); Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (R.J.O.), Gilead Sciences, Foster City (C.B., H.G., K.L.M.), and University of California at San Diego, La Jolla (L.J.R.) - all in California; VU University Medical Center, Amsterdam (A.V.-N.); and the University of Rochester, Rochester, NY (R.J.W.).

Abstract

BACKGROUND:

Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce.

METHODS:

In this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.

RESULTS:

The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooled-monotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, -67.2% vs. -50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P=0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia.

CONCLUSIONS:

Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.).

PMID:
26308684
DOI:
10.1056/NEJMoa1413687
[Indexed for MEDLINE]
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