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Patients with pulmonary arterial hypertension with and without cardiovascular risk factors: Results from the AMBITION trial

Commented by Pilar Escribano-Subias

Pulmonary Hypertension
ESC Working Groups


Patients with pulmonary arterial hypertension with and without cardiovascular risk factors: Results from the AMBITION tria. McLaughlin VV, Vachiery JL, Oudiz RJ, et al. J Heart Lung Transplant. 2019;S1053-2498(19)31685-7. doi:10.1016/j.healun.2019.09.010

The paper of McLaughlin et cols shows the efficacy of initial combination therapy vs. pooled monotherapy for pulmonary arterial hypertension (PAH)  patients with multiple risk factors for left ventricular diastolic dysfunction in a complimentary analysis of the Ambition trial.

Nowadays, at least in Western countries, the proportion of patients being diagnosed at a more advanced age or with more risk factors for left ventricular diastolic dysfunction is increasing. Traditionally, older patients and patients with numerous comorbidities (obesity, essential hypertension, coronary artery disease, Diabetes mellitus)  have been excluded from clinical trials with PAH medications. Hence, the safety and efficacy of PAH treatments are not well established in such patients.

In this paper, the efficacy and safety of initial combination therapy vs pooled monotherapy  was compared between 500 typical PAH patients ( primary analysis set) and the 105 PAH patients at risk for left ventricular diastolic dysfunction ( ex-primary analysis set) enrolled in the AMBITION trial. The efficacy and safety assessments were made at screening; randomization; Weeks 4, 8, 16, and 24; every 12 weeks after that; and at the final assessment and end-of-study visits.

The primary endpoint was time from randomization to first adjudicated clinical failure event, defined as the first occurrence of a composite of the following: (1) death; (2) hospitalization for worsening PAH; (3) disease progression (>15% reduction from baseline in 6-minute walk distance [6MWD] plus WHO functional class III or IV symptoms at 2 consecutive visits separated by ≥14 days); or (4) unsatisfactory long-term clinical response (any reduction from baseline in 6MWD at 2 consecutive post-baseline visits separated by ≥14 days and WHO functional class III symptoms assessed at 2 clinic visits separated by ≥6 months). All reported clinical failure events were adjudicated by an independent clinical end point committee that was blinded to treatment assignment and investigator.

Results showed that the efficacy of treatment with initial combination therapy vs pooled monotherapy was similar (time from randomization to first adjudicated clinical failure event) for ex-primary analysis set patients as for primary analysis set patients. However, in ex-primary analysis set patients, the response was less than in the other group and did not achieve statistical significance in part due to the small sample size. Additionally, in the ex-primary analysis set clinical failure event rates, SAES and drug discontinuation increased.   

These findings highlight that the accuracy of PAH diagnosis is challenging in patients with comorbidities. The lesser effect of combination therapy and the high rate of secondary effects could be explained by the presence of misdiagnosed PAH enrolled in the ex-primary analysis set. In this condition, a multiparametric approach containing clinical phenotype, echocardiography and cardiopulmonary exercise testing (CPET) data and RHC with exercise testing or with fluid loading to make a proper PAH diagnosis is recommended. This information is not included in the AMBITION trial.

In summary, the clinical trial shows that initial combination therapy could be better in patients with comorbidities than the pooled monotherapy. Still, it is first necessary to refine the diagnostic process and avoid potential misdiagnosis.


Rose JA, Cleveland JM, Rao Y, Minai OA, Tonelli AR. Effect of age on phenotype and outcomes in pulmonary arterial hypertension trials. Chest 2016;149:1234-44.

Opitz CF, Hoeper MM, Gibbs JS, et al. Pre-capillary, combined, and post-capillary pulmonary hypertension: a pathophysiological continuum. J Am Coll Cardiol 2016;68:368-78.

Vachiery JL, Tedford RJ, Rosenkranz S, et al. Pulmonary hypertension due to left heart disease. European Respiratory Journal 2019 53: 1801897; DOI: 10.1183/13993003.01897-2018

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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