Hemodynamics and risk assessment 2 years after the initiation of upfront ambrisentan‒tadalafil in pulmonary arterial hypertension

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BACKGROUND

Upfront combination therapy with ambrisentan and tadalafil has been reported to improve the condition of patients with pulmonary arterial hypertension (PAH) more than with either drug alone. However, little is known about the long-term associated changes in hemodynamics and risk assessment scores.

METHODS

This was a multicenter, retrospective analysis of clinical data in 106 patients with newly diagnosed PAH. Clinical evaluations, including demographics, medical history, World Health Organization (WHO) functional class (FC) and 6-minute walk distance (6MWD), right heart catheterization, and Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score 2.0, were assessed over 48 months of ambrisentan‒tadalafil therapy.

RESULTS

At baseline, 9 patients (9%) showed a low (<7), 48 patients (45%) showed an intermediate (7–8), and 49 patients (46%) showed a high (>8) REVEAL risk score. At a median follow-up of 2 years, 45 patients (43%) showed a low, 47 patients (44%) showed an intermediate, and 14 patients (13%) showed a high REVEAL score, along with improvements in WHO FC, 6MWD and a decrease in mean pulmonary artery pressure and N-terminal pro brain natriuretic peptide (all p < 0.001). Pulmonary vascular resistance (PVR) decreased by 37% from 11.5 ± 6.5 to 7.2 ± 4.1 Wood units (p < 0.001). A total of 61 patients (57%) remained in intermediate-risk or high-risk categories. Low-risk patients had either a decrease in PVR of >50% or a stroke volume within the limits of normal.

CONCLUSIONS

Initial combination therapy with ambrisentan and tadalafil in PAH improves the REVEAL risk score in proportion to decreased PVR and preserved stroke volume but still insufficiently so in approximately 50% of the patients.

Section snippets

Methods

This was a multicenter, retrospective cohort study conducted between 2013 and 2018. The participating centers all belonged to the Italian Pulmonary Hypertension Network, which shares a common database for the prospective follow-up of the patients.18 All newly diagnosed, treatment-naive patients with idiopathic PAH (IPAH) or PAH related to connective tissue disease (CTD) or congenital heart disease with closed shunt were considered. The patients underwent a step-by-step diagnostic workup in

Results

Overall, 106 patients with PAH were enrolled from 11 European centers (10 Italian and 1 English). Demographics and clinical characteristics of the 106 patients treated with upfront double combination therapy with ambrisentan and tadalafil are reported in Table 1.

The majority of the patients had IPAH (78%), and most were in WHO FC III (73%).

The 6MWD, NT-proBNP, WHO FC, REVEAL risk score, and hemodynamics at baseline and 24-month follow-up are presented in Table 2.

During the 24-month (median 24

Discussion

This study's results show that the improvements of FC, 6MWD, and NT-proBNP reported in the AMBITION trial persist during a median of 2 years of follow-up after the initiation of upfront ambrisentan and tadalafil therapies and are accompanied by better risk assessment scores. However, 7% of the patients were treated with parenteral prostanoids because of initial severity or deterioration, and there was an 8% mortality. Moreover, 44% of the patients still had an intermediate-risk REVEAL 2.0

Author contributions

M.D.A. and R.B. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects.

Concept and design: M.D.A., R.B., R.N.

Acquisition, analysis, or interpretation of data: M.D.A., R.B., R.N., M.D.A., R.B., R.N., F.L.G., P.A., G.C., Ma.C., Mi.C., S.G., A.G., M.L., V.M., G.P., S.P., R.P., E.R., M.G.R., A.T., P.V., C.D.V., P.G.

Drafting of the manuscript: M.D.A., R.B., R.N.

Disclosure statement

M.D.A., R.B., C.D.V., S.G. received fees for participating in advisory boards and received benefits (travel and accommodation for scientific meetings) from Actelion, Bayer, Dompè, Ferrer, GlaxoSmithKline, and Merck Sharp & Dohme. P.A. received fees for participating in advisory boards and received benefits (travel and accommodation for scientific meetings) from Actelion, Dompè, GlaxoSmithKline, and Merck Sharp & Dohme. G.C. received fees for participating in advisory boards and received

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