Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension.

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Abstract

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

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Most cited references 17

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An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry.

Raymond Benza, Dave Miller, Robyn Barst … (2012)

The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) was established to characterize the clinical course, treatment, and predictors of outcomes in patients with pulmonary arterial hypertension (PAH) in the United States. To date, estimated survival based on time of patient enrollment has been established and reported. To determine whether the survival of patients with PAH has improved over recent decades, we assessed survival from time of diagnosis for the REVEAL Registry cohort and compared these results to the estimated survival using the National Institutes of Health (NIH) prognostic equation. Newly or previously diagnosed patients (aged ≥ 3 months at diagnosis) with PAH enrolled from March 2006 to December 2009 at 55 US centers were included in the current analysis. A total of 2,635 patients qualified for this analysis. One-, 3-, 5-, and 7-year survival rates from time of diagnostic right-sided heart catheterization were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91% ± 2%, 74% ± 2%, 65% ± 3%, and 59% ± 3% compared with estimated survival rates of 68%, 47%, 36%, and 32%, respectively, using the NIH equation. Comprehensive analysis of survival from time of diagnosis in a large cohort of patients with PAH suggests considerable improvements in survival in the past 2 decades since the establishment of the NIH registry, the effects of which most likely reflect a combination of changes in treatments, improved patient support strategies, and possibly a PAH population at variance with other cohorts

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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.

Nazzareno Galiè, Horst Olschewski, Ronald Oudiz … (2008)

Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension. Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P 3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m. Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

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Tadalafil therapy for pulmonary arterial hypertension.

Nazzareno Galiè, Bruce H Brundage, Hossein Ghofrani … (2009)

Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway. In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance (P<0.01). Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95% confidence interval, -2 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to clinical worsening (P=0.041), incidence of clinical worsening (68% relative risk reduction; P=0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing. In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.

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Author and article information

Journal

Journal ID (iso-abbrev): N. Engl. J. Med.

Title: The New England journal of medicine

ISSN (Electronic): 1533-4406

ISSN (Print): 0028-4793

Publication date (Electronic): Aug 27 2015

Volume: 373

Issue: 9

Affiliations

[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.).