STUDY SUMMARY: CTD-PAH Subgroup Analysis From the AMBITION Trial

STUDY SUMMARY: CTD-PAH subgroup analysis from the AMBITION trial

Coghlan JG, Galiè N, Barberà JA, et al; AMBITION investigators. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial. Ann Rheum Dis. 2017;76(7):1219-1227. doi: 10.1136/annrheumdis-2016-210236.

Systemic sclerosis—associated pulmonary arterial hypertension (SSc-PAH) is a leading etiology in patients with connective tissue disease–associated PAH (CTD-PAH). Previous trials have reported patients with CTD-PAH, including SSc-PAH, have attenuated response to PAH-targeted therapies compared with cohorts with idiopathic PAH (iPAH) in markers of therapeutic response including survival, 6-minute walking distance (6MWD), and clinical worsening. Other studies have indicated a similar reduction in PAH event risk in patients with CTD-PAH, but not specifically in the SSc-PAH population.¹

The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial evaluated the response to administration of initial combination therapy with tadalafil and ambrisentan, agents of 2 different classes, to demonstrate improved long-term clinical outcomes in treatment-naïve patients with PAH. In a separate post hoc analysis, investigators of the AMBITION trial aimed to identify differences in treatment response in the subpopulation of patients with CTD-PAH enrolled in the AMBITION trial compared with the patient population with iPAH/hereditary PAH (hPAH).¹

Patients included in the primary analysis were stratified into cohorts based on diagnosis of PAH: iPAH/hPAH (n = 279) and CTD-PAH (n = 187). Of 187 patients with CTD-PAH enrolled in this subanalysis, the minority of patients had non—SSc-CTD (n = 69), and 63% (n = 118) had a diagnosis of SSc-PAH. Patients were randomized (2:1:1) to receive combination therapy with 10 mg ambrisentan and 40 mg tadalafil, monotherapy with placebo and 10 mg ambrisentan, or monotherapy with placebo and 40 mg tadalafil.¹

As the primary end point, the safety and efficacy of combination therapy in each patient population was evaluated by the time to the patient’s first adjudicated event of clinical failure, which was defined as any of the following: death, worsening of PAH leading to hospitalization, disease progression, or unsatisfactory long-term clinical response. Combination therapy was associated with fewer first events of clinical failure than monotherapy treatment across all patient populations (Table). The overall incidence of clinical failure events with combination therapy was 19% in the iPAH/hPAH group, 19% in the CTD-PAH group, and 21% in the SSc-PAH subgroup. The incidence of primary outcome of clinical failure with pooled monotherapy was 32% in the iPAH/hPAH group, 36% in the CTD-PAH group, and 40% of patients in the SSc-PAH subgroup. In this analysis, patients with CTD-PAH who received initial combination therapy with ambrisentan and tadalafil had a 57% lower risk of defined events of clinical failure than did patients in the pooled monotherapy group analysis (HR, 0.43; 95% CI, 0.24-0.77); this was similar to a 56% reduction in risk of clinical failure in the SSc-PAH population. Patients with iPAH/hPAH treated with combination therapy had a 49% reduction of risk compared with those in the pooled monotherapy treatment group (HR, 0.51; 95% CI, 0.31-0.83).¹

The largest benefit of combination therapy compared with monotherapy treatment was observed in the primary end point of hospitalization for worsening PAH: lung or heart-and-lung transplantation; atrial septostomy; or initiation of parenteral prostanoid therapy. The overall reduction of risk of hospitalization for worsening of PAH with combination treatment in the SSc-PAH population was 64% (HR, 0.36; 95% CI, 0.13-1.04); hospitalization events occurred in 8% of patients treated with combination therapy compared with 19% of patients treated with monotherapy. Similar event rates of hospitalization were observed in the overall CTD-PAH population; 8% of patients treated with combination therapy experienced hospitalization events, compared with 21% of patients treated with monotherapy. The overall reduction of risk of hospitalization for worsening of PAH with combination treatment in the CTD-PAH population was 71% (HR, 0.29; 95% CI, 0.12-0.67).¹

In a secondary end point analysis, satisfactory clinical response was measured at week 24 in patients with an improvement of 10% from baseline in the 6MWD, reduction or maintenance of World Health Organization functional class I or II symptoms with improved exercise capacity, and an absence of clinical events. Rates of satisfactory clinical response at week 24 were similar between patient cohorts and treatment groups: 35% of CTD-PAH patients treated with combination therapy and 29% of CTD-PAH patients treated with monotherapy achieved a satisfactory response, compared with 31% and 29% of SSc-PAH patients treated with combination therapy and monotherapy, respectively. At week 24, patients treated with combination therapy achieved a greater increase in exercise capacity measured by the median 6MWD from baseline, compared with patients treated with pooled monotherapy in the overall CTD-PAH group who saw an increase of 19.7 meters. The SSc-PAH group saw an increase of 30.3 meters. Investigators suggested that the 6MWD may be an appropriate marker of response to therapy despite suggestions that it may not be an appropriate endpoint for patients with SSc-PAH; the investigators propose that attenuated response could be attributed to veno-occlusive disease, occult left heart, associated lung disease, and musculoskeletal impairment.¹

In a post hoc analysis, the proportion of patients with a ≥15% decrease in 6MWD at any time post baseline was greater with pooled monotherapy than with combination therapy across all subgroups (CTD-PAH, SSc-PAH, and non—SSc-PAH). A decrease of more than 15% from baseline 6MWD acts as a marker of disease progression. In the iPAH/hPAH patient group, 24% of patients treated with combination therapy and 32% of patients receiving monotherapy in the SSc-PAH group had a ≥15% worsening of 6MWD; similarly, in the SSc-PAH group, 31% of patients treated with combination therapy and 44% treated with monotherapy had reductions in the 6MWD. Investigators suggested that these results support that patients with CTD-PAH, specifically SSc-PAH, may require more aggressive treatment regimens to match the responses in patients with iPAH/hPAH.¹

The most common adverse events (AEs) occurring in at least 25% of patients with CTD-PAH and SSc-PAH were peripheral edema, headache, and diarrhea. Peripheral edema occurred at a greater incidence in patients from CTD-PAH (47%) and SSc-PAH (45%) cohorts treated with combination therapy compared with either ambrisentan (34% and 26%) or tadalafil (33% and 33%) monotherapy treatment. In the CTD-PAH cohort, headache and diarrhea were more commonly reported than in the SSc-PAH cohort across treatment groups. In patients with CTD-PAH, serious AE rates were 44% with combination therapy, 34% with ambrisentan monotherapy, and 50% with tadalafil monotherapy; similar rates were observed in patients with SSc-PAH (44%, 39%, and 58%, respectively).¹

In patients with iPAH/hPAH, AEs occurring with an incidence of at least 25% in the combination therapy patients were peripheral edema (48% combination vs 31% ambrisentan and 27% tadalafil) and headache (45% combination vs 32% ambrisentan and 31% tadalafil). In patients with iPAH/hPAH, rates of serious AEs were 33% with combination therapy, 37% with ambrisentan monotherapy, and 39% with tadalafil monotherapy. Serious AEs led to permanent discontinuation of study drug in 11% of patients treated with combination therapy, 8% of patients treated with ambrisentan, and 11% of patients treated with tadalafil.¹

This separate post hoc analysis of initial combination therapy with ambrisentan and tadalafil from the AMBITION trial found a reduced clinical failure risk and improved exercise capacity in the subpopulation of patients with CTD-PAH, with a similar effect in the patient population with iPAH/hPAH. As a result, investigators noted that patients with CTD-PAH may require an aggressive combination therapy regimen as opposed to monotherapy.

Reference

1. Coghlan JG, Galiè N, Barberà JA, et al; AMBITION investigators. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial. Ann Rheum Dis. 2017;76(7):1219-1227. doi: 10.1136/annrheumdis-2016-210236.