Dataset Information

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.

ABSTRACT: Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH.To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial.This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response).In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups.This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy.NCT01178073, post results.

SUBMITTER: Coghlan JG

PROVIDER: S-EPMC5530350 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.

Coghlan John Gerry JG Galiè Nazzareno N Barberà Joan Albert JA Frost Adaani E AE Ghofrani Hossein-Ardeschir HA Hoeper Marius M MM Kuwana Masataka M McLaughlin Vallerie V VV Peacock Andrew J AJ Simonneau Gérald G Vachiéry Jean-Luc JL Blair Christiana C Gillies Hunter H Miller Karen L KL Harris Julia H N JHN Langley Jonathan J Rubin Lewis J LJ

Annals of the rheumatic diseases 20161230 7

<h4>Background</h4>Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH.<h4>Objective</h4>To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with C ...[more]

PMID: 28039187

Similar Datasets

Project description:BackgroundScleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH.MethodsIn this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints.ResultsAt 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05).ConclusionsUp-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).

Project description:BackgroundThe efficacy and safety of ambrisentan has been previously evaluated in Chinese patients with pulmonary arterial hypertension (PAH). This post-hoc analysis assessed the efficacy and safety of ambrisentan in a subgroup of connective tissue disease (CTD) patients with PAH.MethodsIn this open-label, single-arm study, patients received ambrisentan 5 mg once daily for 12 weeks, followed by 12-week dose titration period (dose up to 10 mg). Efficacy endpoints included change from baseline in exercise capacity (measured by 6-min walk test [6MWT]), N-terminal pro B type natriuretic peptide (NT-proBNP) plasma levels, WHO Functional Class (FC) and Borg Dyspnoea Index (BDI) scores from baseline to weeks 12 and 24. Safety endpoints included time to clinical worsening and incidence of adverse events (AEs).ResultsIn total, 71 Chinese patients with CTD-PAH were included in this analysis. Ambrisentan treatment significantly improved exercise capacity (6MWT) from baseline (mean: 366.4 m) to week 12 (63.8 m, p < 0.001) and week 24 (73.2 m, p < 0.001). A significant reduction in NT-proBNP levels was observed from baseline (mean: 1837.5 ng/L) to week 12 (- 1156.8 ng/L, p < 0.001) and week 24 (- 1095.5 ng/L, p < 0.001). BDI scores decreased significantly at week 12 (- 0.6, p < 0.001) and week 24 (- 0.4, p = 0.002) from baseline (mean: 2.7). The WHO FC improved in 29 (40.8%) and 34 (47.9%) patients at weeks 12 and 24, respectively. Adverse events were reported in 52 (73.2%) patients. One patient (1.4%) experienced clinical worsening at week 24.ConclusionAmbrisentan showed significant improvement in exercise capacity and no clinical worsening in the majority of Chinese patients with CTD-PAH in the 24-week treatment period. The AEs observed in the CTD-PAH subgroup were consistent with the known safety profile of ambrisentan in the overall Chinese PAH population.Trial registrationClinicalTrial.gov Identifier, https://clinicaltrials.gov/, NCT01808313 Registration date (first time): February 28, 2013.

Project description:Women with pulmonary arterial hypertension (PAH) experience multiple symptoms, including dyspnea, fatigue, and sleep disturbance, that impair their health-related quality of life (HRQOL). However, we know little about phenotypic subgroups of patients with PAH with similar, concurrent, multiple symptoms. The objectives of this study were to define the "symptome" by symptom cluster phenotypes and compare characteristics such as biomarkers, cardiac structure and function (echocardiography), functional capacity (6-min walk distance), and HRQOL between the groups. This cross-sectional study included 60 women with PAH. Subjects completed an assessment battery: Pulmonary Arterial Hypertension Symptom Scale, Pittsburgh Sleep Quality Index, Multidimensional Dyspnea Profile, Patient-Reported Outcomes Measurement Information System (PROMIS®) Physical Function, PROMIS® Sleep-Related Impairment, and the emPHasis-10. Subjects also underwent transthoracic echocardiography, phlebotomy, 6-min walk distance, and actigraphy. The three symptoms of dyspnea, fatigue, and sleep disturbance were used to define the symptom clusters. Other PAH symptoms, plasma and serum biomarkers, cardiac structure and function (echocardiography), exercise capacity (6-min walk distance), sleep (actigraphy), and HRQOL were compared across phenotypes. The mean age was 50 ± 18 years, 51% were non-Hispanic white, 32% were non-Hispanic Black and 40% had idiopathic PAH. Cluster analysis identified Mild (n = 28, 47%), Moderate (n = 20, 33%), and Severe Symptom Cluster Phenotypes (n = 12, 20%). There were no differences for age, race, or PAH etiology between the phenotypes. WHO functional class (p < 0.001), norepinephrine levels (p = 0.029), right atrial pressure (p = 0.001), physical function (p < 0.001), sleep onset latency (p = 0.040), and HRQOL (p < 0.001) all differed significantly across phenotypes. We identified three distinctive symptom cluster phenotypes (Mild, Moderate, and Severe) for women with PAH that also differed by PAH-related symptoms, physical function, right atrial pressure, norepinephrine levels, and HRQOL. These phenotypes could suggest targeted interventions to improve symptoms and HRQOL in those most severely affected.

Dataset Information

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.

Publications

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets