Early treatment with ambrisentan of mildly elevated mean pulmonary arterial pressure associated with systemic sclerosis: a randomized, controlled, double-blind, parallel group study (EDITA study)

Zixuan Pan, Alberto M Marra, Nicola Benjamin, Christina A Eichstaedt, Norbert Blank, Eduardo Bossone, Antonio Cittadini, Gerry Coghlan, Christopher P Denton, Oliver Distler, Benjamin Egenlauf, Christine Fischer, Satenik Harutyunova, Panagiota Xanthouli, Hanns-Martin Lorenz, Ekkehard Grünig, Zixuan Pan, Alberto M Marra, Nicola Benjamin, Christina A Eichstaedt, Norbert Blank, Eduardo Bossone, Antonio Cittadini, Gerry Coghlan, Christopher P Denton, Oliver Distler, Benjamin Egenlauf, Christine Fischer, Satenik Harutyunova, Panagiota Xanthouli, Hanns-Martin Lorenz, Ekkehard Grünig

Abstract

Objective: The objective of this randomized, placebo-controlled, double-blind, parallel group, trial was to assess the effect of ambrisentan on mean pulmonary arterial pressure (mPAP) in patients with systemic sclerosis (SSc) and mildly elevated pulmonary hypertension (PH).

Methods: Thirty-eight SSc patients with mildly elevated mPAP at rest between 21 and 24 mmHg and/or > 30 mmHg during low-dose exercise were randomly assigned to treatment with either ambrisentan 5-10 mg/day or placebo. Right heart catheterization and further clinical parameters were assessed at baseline and after 6 months. The primary endpoint was the difference of mPAP change at rest between groups.

Results: After 6 months, the two groups did not differ in the primary endpoint (ambrisentan mPAP - 1 ± 6.4 mmHg vs. placebo - 0.73 ± 3.59 mmHg at rest, p = 0.884). However, three patients from the placebo group but none of the ambrisentan group progressed to SSc-associated pulmonary arterial hypertension. Furthermore, ambrisentan treatment showed significant improvements in the secondary endpoints cardiac index (CI) and pulmonary vascular resistance (PVR) at rest (CI 0.36 ± 0.66 l/min/m2 vs. - 0.31 ± 0.71 l/min/m2, p = 0.010; PVR - 0.70 ± 0.78 WU vs. 0.01 ± 0.71 WU, p = 0.012) and during exercise (CI 0.7 ± 0.81 l/min/m2 vs. - 0.45 ± 1.36 l/min/m2, p = 0.015; PVR - 0.84 ± 0.48 WU vs. - 0.0032 ± 0.34 WU, p < 0.0001).

Conclusion: This is the first randomized, double-blind, placebo-controlled study testing the effect of ambrisentan in patients with mildly elevated mPAP and/or exercise PH. The primary endpoint change in mPAP did only tendentially improve in the ambrisentan group, but the significant improvement of other hemodynamic parameters points to a possible benefit of ambrisentan and will be helpful to design future trials.

Trial registration: www.ClinicalTrials.gov, unique identifier NCT: NCT02290613 , registered 14th of November 2014.

Keywords: Ambrisentan; Borderline pulmonary hypertension; Exercise PH; Mildly elevated mPAP; Placebo-controlled; Treatment.

Conflict of interest statement

ZP, AMM, CAE, EB, AC, CF, and PX declare that they have no competing interests. NBe has received speaker honoraria from Actelion pharmaceuticals, not related to this study. NoB has received speaker honoraria from Actelion pharmaceuticals, not related to this study. GC reports research support, consultancy fees, and speaker honoraria from Actelion pharmaceuticals. CPD reports speaker honoraria from Actelion pharmaceuticals. OD reports research support and consultancy fees from Actelion pharmaceuticals. BE reports speaker honoraria from Actelion pharmaceuticals. SH reports speaker honoraria from Actelion pharmaceuticals. HML reports speaker and consultancy fees from Actelion pharmaceuticals. EG has received speaker honoraria and advisory board fees from Actelion pharmaceuticals.

Figures

Fig. 1
Fig. 1
Study flowchart. A total of 38 patients were enrolled into our study and randomly assigned to be treated with ambrisentan 5 or 10 mg/day or to receive placebo. After 6 months, 32 patients completed the study, 17 in the ambrisentan group, and 15 in the placebo group. Among the 6 dropout patients, 1 in the ambrisentan group and 2 in the placebo group withdrew their written informed consents. One in each group quit because of adverse events, one in the ambrisentan group for gingival bleeding, and one in the placebo group for angina pectoris. One patient in the placebo group was lost to follow-up
Fig. 2
Fig. 2
Changes of mPAP over 6 months. No patients at baseline had a resting mPAP of ≥ 25 mmHg. After 6 months, 2 patients in the ambrisentan group developed a resting mPAP of > 25 mmHg. The dotted line indicates a resting mPAP of 25 mmHg. *: Two patients in the ambrisentan group had a resting PAWP of > 15 mmHg after 6 months; they were reclassified as PH due to left heart disease. #: Three patients in the placebo group developed a resting mPAP of ≥ 25 mmHg at month 6 with a resting PAWP of ≤ 15 mmHg; thus, they were diagnosed as having SSc-APAH after 6 months. The mean change of resting mPAP over 6 months in the ambrisentan group was − 1 ± 6.4 mmHg, and that in the placebo group was − 0.73 ± 3.59 mmHg. The changes between the two groups were not significantly different (p = 0.884). Ambrisentan did not significantly decrease the mPAP at rest over 6 months compared to placebo
Fig. 3
Fig. 3
Changes of peak CI over 6 months. The mean change of CI at maximal exercise over 6 months in the ambrisentan group was 0.70 ± 0.81 L/min/m2 and that in the placebo group was − 0.45 ± 1.36 L/min/m2. Ambrisentan significantly increased the CI at maximal exercise over 6 months compared to placebo (p = 0.015)
Fig. 4
Fig. 4
Changes of PVR at rest over 6 months. Ambrisentan patients had on average a lower PVR at 6 months compared to placebo. The mean change of PVR at rest over 6 months in the ambrisentan group was − 0.70 ± 0.78 WU and that in the placebo group was 0.01 ± 0.71 WU. Ambrisentan significantly decreased the PVR at rest over 6 months compared to placebo (p = 0.012)

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