Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis

Abstract

Objectives: To evaluate initial combination therapy with ambrisentan plus tadalafil (COMB) compared with monotherapy of either agent (MONO), and the utility of baseline characteristics and risk stratification in predicting outcomes, in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and the systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) subpopulation.

Methods: This post hoc analysis of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study included patients with CTD-PAH from the modified intention-to-treat population. Time to clinical failure (TtCF) was assessed by baseline characteristics, treatment assignment and risk group (low, intermediate and high) at baseline and week 16. TtCF was compared between groups using Kaplan-Meier curves and Cox proportional hazards regression modelling.

Results: The analysis included 216 patients (COMB, n=117; MONO, n=99). The risk of clinical failure was lower with COMB versus MONO (risk reduction: CTD-PAH 51.7%, SSc-PAH 53.7%), particularly in patients with haemodynamic parameters characteristic of typical PAH without features of left heart disease and/or restrictive lung disease at baseline. The risk of clinical failure was lower with COMB versus MONO in the baseline low-risk group (HR not calculated due to no events in COMB), baseline intermediate-risk group (HR 0.519, 95% CI 0.297 to 0.905) and in the week 16 low-risk group (HR 0.069, 95% CI 0.009 to 0.548).

Conclusions: The benefit of COMB over MONO was demonstrated in patients with CTD-PAH, particularly in those with typical PAH haemodynamic characteristics at baseline. COMB is appropriate for patients categorised as low risk and intermediate risk at baseline and low risk at follow-up.

Trial registration number: NCT01178073.

Keywords: arterial hypertension; outcomes research; systemic sclerosis; treatment.

Conflict of interest statement

Competing interests: MK has received personal fees from GSK, Bayer and Nippon Shinyaku, and research grants and personal fees from Actelion and Pfizer. CB is an employee and shareholder at Gilead Sciences. JL is a former employee and shareholder of GSK. TT is an employee at GSK. JGC has received research grants and personal fees from Actelion and GSK, and personal fees from Bayer, Endotronix, Pfizer and United Therapeutics.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Participant disposition and aetiology: (A) population distribution among treatment arms and (B) CTD-PAH population aetiologies (post hoc summary). *Five patients did not receive the study drug. CTD, connective tissue disease; ITT, intention to treat; MCTD, mixed connective tissue disease; mITT, modified intention to treat; PAH, pulmonary arterial hypertension; SSc, systemic sclerosis; SLE, systemic lupus erythematosus.

Figure 2

Kaplan-Meier plots of time to first adjudicated clinical failure in the modified intention-to-treat population: (A) connective tissue disease-associated pulmonary arterial hypertension and (B) systemic sclerosis pulmonary arterial hypertension. 95% CIs (using log–log transform method) are presented for each treatment group at weeks 4, 8, 16 and 24, and then every 12 weeks up to week 96.

Figure 3

Forest plot of time to first adjudicated clinical failure: combination therapy versus monotherapy (pooled) per baseline subgroup. *Significant treatment by subgroup interaction; †evidence of non-proportionality (see online supplementary table S2); ‡hypertension, diabetes and coronary artery disease; §low-risk valid HR could not be calculated; ¶indication for immunosuppressant use unknown. FEV1, forced expiratory volume in one second; mPAP, mean pulmonary arterial pressure; NA, not applicable; PAS, primary analysis set; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; SSc, systemic sclerosis; TLC, total lung capacity; TPG, transpulmonary pressure gradient.

Figure 4

Kaplan-Meier curves for time to clinical failure in the CTD-PAH population by risk category according to the abbreviated COMPERA method at baseline and week 16: (A) baseline CTD-PAH: overall, (B) baseline CTD-PAH: combination versus monotherapy (pooled), (C) week 16 CTD-PAH: overall and (D) week 16 CTD-PAH: combination versus monotherapy (pooled (low risk and intermediate risk only)). *NO HR calculation due to NO event in the combination therapy group (log-rank test: p=0.048). Week 16 Kaplan-Meier plots were described based on the period from week 16 to the last assessment visit. Patient numbers were too low in the week 16 high-risk group to provide a meaningful comparison. CTD-PAH, connective tissue disease-associated pulmonary arterial hypertension.