Pulmonary arterial hypertension (PAH) is characterized by the progressive remodeling of the pulmonary vasculature; if left untreated, PAH can lead to fatal right-sided heart failure. Single-class agents are often ineffective treatments for patients with PAH because they target just one of the intracellular pathways implicated in its pathogenesis (prostacyclin, nitric oxide-cyclic guanosine monophosphate, or endothelin). The standard treatment approach for PAH used to start with monotherapy and be followed by the sequential addition of single-class agent therapies for patients with an inadequate response. However, initial combination therapy provides clinical benefits by targeting multiple pathogenic mechanisms to increase the overall therapeutic effect.
Pulmonary arterial hypertension (PAH) is characterized by the progressive remodeling of the pulmonary vasculature; if left untreated, PAH can lead to fatal right-sided heart failure. Single-class agents are often ineffective treatments for patients with PAH because they target just one of the intracellular pathways implicated in its pathogenesis (prostacyclin, nitric oxide-cyclic guanosine monophosphate, or endothelin). The standard treatment approach for PAH used to start with monotherapy and be followed by the sequential addition of single-class agent therapies for patients with an inadequate response. However, initial combination therapy provides clinical benefits by targeting multiple pathogenic mechanisms to increase the overall therapeutic effect.1
Evidence from the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial demonstrated that initiation of ambrisentan, an endothelin receptor antagonist, and tadalafil, a phosphodiesterase-5 inhibitor in treatment-naïve patients with PAH, reduced the risk of clinical failure events (composite endpoint of death, hospital admission for worsening of PAH, or disease progression), with significant reduction in the rate of hospital admissions for worsening PAH compared with monotherapy (P = .0002). The impact of initial combination therapy on mortality is unknown; initial treatment with ambrisentan and tadalafil was associated with a low first mortality event rate (4%) in the AMBITION trial, but the mortality rate throughout the trial period was higher (12%).1
In a secondary analysis of the AMBITION trial, investigators studied the potential of the combination therapy of ambrisentan and tadalafil over monotherapy, with the aim to increase the probability of survival. The majority of the population enrolled had a diagnosis of idiopathic PAH (55%) and PAH associated with connective tissue disease (36%); patients with PAH associated with drugs/toxins, connective tissue disease, HIV, or congenital heart defects were also eligible. Patients enrolled also presented with either WHO functional class II or III symptoms; the majority of patients had class III symptoms (68%).1
A total of 605 patients with PAH were randomized (2:1:1) to receive initial combination therapy with ambrisentan and tadalafil (n = 302), placebo with ambrisentan monotherapy (n = 152), or tadalafil monotherapy (n = 151). Patients initiated treatment with 5 mg of ambrisentan orally each day for the first 8 weeks, with dose escalation to 10 mg daily. Tadalafil was initiated at a daily dose of 20 mg and then escalated to 40 mg after 4 weeks.1
Mortality analyses were conducted for any patient who received study medication, including patients who withdrew from treatment and those who consented to follow-up (Table1). Patients treated with combination therapy remained on treatment for a median of 96 weeks, and the pooled monotherapy group remained on treatment for 91 weeks. Although the analysis included all patients who received AMBITION study treatment, 176 patients (29%) discontinued medication before study completion due to adverse events, investigator discretion, consent withdrawal, protocol deviation, or loss to follow-up. Of the 605 patients enrolled, 34 had unknown survival status at the end of the study, including 15 in the combination therapy group and 19 patients in the pooled monotherapy group.1
Investigators explored the effect of combination therapy on all-cause mortality from randomization to the end of the study, where the median follow up time was 101 weeks in the combination group and 96 weeks in the pooled monotherapy group. Combination therapy was not associated with significant advantages in mortality between the combination therapy and pooled monotherapy groups (10% vs 14%, respectively).1 Additionally, choice of monotherapy agent did not impact survival; mortality rates for patients treated with ambrisentan or tadalafil monotherapy were similar (13% vs 15%, respectively).1
In an exploratory analysis of the AMBITION trial, patients were assessed for mortality events 7 days following the final dose of their assigned treatment. This analysis included mortality events that occurred while the patient was receiving assigned treatments. Combination therapy was associated with a significant reduction in risk of all-cause mortality events compared with monotherapy (HR, 0.21, 95% CI, 0.06-0.73, P = .0065). A greater proportion of patients treated with tadalafil monotherapy died within the 7-day follow-up period compared with ambrisentan monotherapy (7% vs 2%, respectively). Overall, 1% (n = 3) of patients treated with combination therapy died compared with 4% (n = 13) treated with either monotherapy. Investigators proposed that the demonstrated advantage of ambrisentan on survival 7 days following end-of-study treatment was likely by chance, as mortality rates were comparable between the tadalafil and ambrisentan monotherapy groups for the entire study.1
As the primary limitation of the AMBITION trial, investigators noted the study was not powered or designed to determine the survival benefit of combination therapy compared with pooled monotherapy and with individual monotherapies. Additionally, although there was a great number of discontinuations from study treatment, they did not appear to be biased toward one treatment over another, as the comparative number of patients who discontinued treatment and their reasons for discontinuation were similar between treatment groups. Investigators noted that treatment modifications over the study course may have affected long-term survival rates, as patients with clinical failure events were permitted to switch or add treatments. Interestingly, patients assigned to receive monotherapy more commonly switched treatment to combination therapy and prostacyclin analogues compared with patients who initiated treatment with combination therapy.1
Although this secondary analysis of the AMBITION trial generated evidence and promising potential for combination therapy with ambrisentan and tadalafil in treatment-naïve patients with PAH, no conclusion can be derived regarding the potential survival advantage of initiating this combination therapy. Larger, longitudinal studies that focus on survival are needed and necessary.1
1. Hoeper MM, McLaughlin VV, Barberá JA, et al. Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study. Lancet Respir Med. 2016;4(11):894-901. doi: 10.1016/S2213-2600(16)30307-1.