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Open label study of ambrisentan in patients with exercise pulmonary hypertension.

ABSTRACT: A growing body of evidence suggests that exercise pulmonary hypertension (ePH) is an early form of pulmonary arterial hypertension (PAH). Identifying the disease at an early, potentially more responsive phase, and initiating treatment may improve functional status and prevent progression to severe forms of PAH. This was a single-center, open-label six-month treatment trial to evaluate the effect of ambrisentan on pulmonary hemodynamics and exercise capacity in ePH utilizing invasive cardiopulmonary exercise testing (iCPET). After six months of treatment with ambrisentan, patients repeated iCPET; exercise capacity, symptoms, and pulmonary hemodynamics were reassessed. Twenty-two of 30 patients completed the treatment phase and repeat iCPET. After six months of treatment there was a significant decline in peak exercise mPAP (-5.2 ± 5.6 mmHg, P = 0.001), TPG (-7.1 ± 8.0 mmHg, P = 0.001), PVR (-0.9 ± 0.7 Woods units, P = 0.0002), and Ca-vO₂ (-1.8 ± 2.3 mL/dL, P = 0.0002), with significant increases in peak PCWP (+2.9 ± 5.6 mmHg, P = 0.02), PVC (+0.8 ± 1.4 mL/mmHg, P = 0.03), and CO (+2.3 ± 1.4 L/min, P = 0.0001). A trend toward increased VO₂max (+4.4 ± 2.6% predicted, P = 0.07) was observed. In addition, there were improvements in 6MWD and WHO FC after 24 weeks. Our findings suggest that treatment of ePH with ambrisentan results in improved pulmonary hemodynamics and functional status over a six-month period. Treatment of ePH may prevent the progression of vascular remodeling and development of established PAH.

SUBMITTER: Segrera SA

PROVIDER: S-EPMC5467947 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlthough several new drugs have been approved in recent years, pulmonary arterial hypertension (PAH) remains a rapidly progressive disease with a poor prognosis. Ambrisentan, a selective endothelin type A antagonist, has been approved for treatment of PAH. This open label study assessed the efficacy and safety of ambrisentan in Chinese subjects with PAH.MethodsEligible patients with PAH (World Health Organisation [WHO] functional class [FC] II orIII) were enrolled and received Ambrisentan (5 mg) once daily for a 12-week preliminary evaluation period, and a 12-week dose-adjustment period (dose titration to 10 mgallowed). Endpoints included: change from baseline in 6-Minute Walk Distance (6-MWD), N-Terminal Pro B-Type Natriuretic Peptide (NT-pro-BNP), WHO FC, Borg Dyspnoea Index (BDI), clinical worsening of PAH and incidences of adverse events (AE).ResultsOne hundred thirty-three subjects (85 % women, mean age: 36 years) with PAH (WHOFC II or III) were enrolled and received ambrisentan (5 mg) once daily for a 12-week preliminary evaluation period, and a 12-week dose-adjustment period. Mean (SD) duration of drug exposure was 161.7 (27.13) days. Ambrisentan (average daily dose of 6.27 mg) significantly improved exercise capacity (6MWD) from baseline (mean: 377.1 m [m]) at week 12 (+53.6 m, p < 0.001) (primary endpoint). Improvement in exercise capacity was noted as early as week 4, and was sustained up to week 24 (+ 64.4 m, p < 0.001). NT-pro-BNP plasma levels decreased significantly (p < 0.001) at week 12 (-861.4 ng/L) and week 24 (-806 ng/L) from baseline (mean: 1600.7 ng/L). The WHO FC showed improvements for 44 subjects at week 12 and 51 subjects at week 24. BDI scores decreased significantly at week 12 (-0.3, p < 0.001) and week 24 (-0.2, p = 0.003) from baseline (mean: 2.5). Four patients died during the study (sudden cardiac death [n = 2], cerebral haemorrhage [n = 1], cardiac failure [n = 1]). Drug related adverse events occurred in 34.3 % of subjects; peripheral oedema (11.2 %) and flushing (8.2 %) occurred most frequently.ConclusionAmbrisentan (5 and 10 mg, orally) significantly improved the exercise capacity in Chinese PAH subjects with a safety profile similar to that observed in global studies.Trial registrationNCT No. (ClinicalTrials.gov): NCT01808313 ; Registration date (first time): February 28, 2013.

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).

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Open label study of ambrisentan in patients with exercise pulmonary hypertension.

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