Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension

Hassoun, Paul M.; Zamanian, Roham T.; Damico, Rachel; Lechtzin, Noah; Khair, Rubina; Kolb, Todd M.; Tedford, Ryan J.; Hulme, Olivia L.; Housten, Traci; Pisanello, Chiara; Sato, Takahiro; Pullins, Erica H.; Corona‐Villalobos, Celia P.; Zimmerman, Stefan L.; Gashouta, Mohamed A.; Minai, Omar A.; Torres, Fernando; Girgis, Reda E.; Chin, Kelly; Mathai, Stephen C.

doi:10.1164/rccm.201507-1398oc

Cited by 145 publications

(111 citation statements)

References 43 publications

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“…21 In this open-label study of 24 ‡In each case, the investigator reported the events using additional text not captured in the preferred term, describing this as worsening of pulmonary hypertension. However, an AE report of worsening pulmonary hypertension does not necessarily become a primary endpoint event, which has specific criteria.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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BackgroundPatients 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.ObjectiveTo 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.MethodsThis 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).ResultsIn 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.ConclusionsThis post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy.Trial registration number NCT01178073, post results.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Twenty-four consecutive, treatment-naive patients with SSc-PAH without significant interstitial or obstructive lung disease, as previously described, were enrolled. 13 Fourteen of these patients were evaluated again 4 months after initiation of targeted PAH therapy. A randomly selected cohort of 103 control subjects with SSc without evidence of pulmonary involvement was studied for compari-son.…”

Section: Subjectsmentioning

confidence: 99%

Exhaled Nitric Oxide in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis

et al. 2016

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Abstract:The fractional exhaled concentration of nitric oxide (FE NO ) has been shown to be reduced in idiopathic pulmonary arterial hypertension (PAH) but has not been adequately studied in PAH associated with systemic sclerosis (SSc). We measured FE NO at an expiratory flow rate of 50 mL/s in 21 treatment-naive patients with SSc-associated PAH (SSc-PAH), 94 subjects with SSc without pulmonary involvement, and 84 healthy volunteers. Measurements of FE NO at additional flow rates of 100, 150, and 250 mL/s were obtained to derive the flow-independent nitric oxide exchange parameters of maximal airway flux (J′aw NO ) and steady-state alveolar concentration (CA NO ). FE NO at 50 mL/s was similar (P = 0.22) in the SSc-PAH group (19 ± 12 parts per billion [ppb]) compared with the SSc group (17 ± 12 ppb) and healthy control group (21 ± 11 ppb). No change was observed after 4 months of targeted PAH therapy in 14 SSc-PAH group patients (P = 0.9). J′aw NO was modestly reduced in SSc group subjects without lung disease (1.2 ± 0.5 nl/s) compared with healthy controls (1.64 ± 0.9; P < 0.05) but was similar to that in the SSc-PAH group. CA NO was elevated in individuals with SSc-PAH (4.8 ± 2.6 ppb) compared with controls with SSc (3.3 ± 1.4 ppb) and healthy subjects (2.6 ± 1.5 ppb; P < 0.001 for both). However, after adjustment for the diffusing capacity of CO, there was no significant difference in CA NO between individuals with SSc-PAH and controls with SSc. We conclude that FE NO is not useful for the diagnosis of PAH in SSc. Increased alveolar nitric oxide in SSc-PAH likely represents impaired diffusion into pulmonary capillary blood.

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“…The results of the Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension (AMBITION) study demonstrate that initial combination therapy with ambrisentan and tadalafil in newly diagnosed, treatment-naïve PAH patients with WHO Group I PAH results in a significant reduction in the risk of clinical failure events compared to initial monotherapy 21 . Specific to the CTD-PAH population, the Ambrisentan and Tadalafil Upfront Combination Thearapy in SclerodermaAssociated PAH (ATPAHSS) study demonstrated that upfront combination therapy with ambrisentan and tadalafil in treatment-naïve SSc-PAH patients significantly improved hemodynamics, RV structure and function, as well as functional status 22 . While our analyses reveal a majority of patients continuing in the study received monotherapy at each yearly interval, there were a substantial number of dropouts and patients receiving add-on therapy over the evaluation period.…”

Section: Discussionmentioning

confidence: 99%

Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) – A subgroup analysis of the ARIES-E clinical trial

Fischer

Denton

Matucci‐Cerinic

et al. 2016

Respiratory Medicine

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ABSTRACT:Objective: Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and early mortality and is an important complication in patients with connective tissue disease (CTD). Previously, the endothelin A selective receptor antagonist, ambrisentan, has demonstrated efficacy and safety in treating patients with PAH due to a WHO Group I etiology. In this report, we describe the 3-year efficacy and safety of ambrisentan in patients with CTD associated PAH (CTD-PAH). Methods:Patients with CTD-PAH participating in the ARIES-1 and -2 clinical trials and their long-term extension were evaluated. Efficacy evaluations including 6-minute walk distance (6MWD), clinical worsening, and survival were collected at routine study visits. Categorical (30m) breakpoints for 6MWD were evaluated and additional analyses were conducted to determine any relationship between 6MWD and survival.Results: 124 patients with CTD-PAH were evaluated. Survival information at 3 years was available for 112 (90%) subjects; clinical worsening data was available for 68% of subjects at 3 years, and 6MWD results were available for 73%, 60%, and 44% of subjects at 1-, 2-, and 3-years, respectively. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3-years respectively. At 3 years, 64% of patients were free from clinical worsening and 76% of patients were still alive (Kaplan-Meier estimates). Factors with prognostic relevance included: improving 6MWD ≥ 30m over the first 12 weeks of treatment, the most recent 6MWD, and a 6MWD absolute threshold of 222m. Conclusion:These analyses of the 3-year treatment of CTD-PAH patients with ambrisentan revealed improved clinical worsening and survival compared to historical controls. Furthermore, several key exercise parameters were identified which appear important in guiding individual patient treatment.

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Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension

Abstract: Background: Scleroderma-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.

Cited by 145 publications

References 43 publications

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

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

Exhaled Nitric Oxide in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis

Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) – A subgroup analysis of the ARIES-E clinical trial

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