Combination therapy associated with improved outcomes in pulmonary arterial hypertension

1. Combination therapy with ambrisentan and tadalafil in patients with pulmonary arterial hypertension was associated with a 50% decrease in the primary outcome of first event of clinical failure over the follow-up period.

2. Combination therapy was not associated with a significant benefit in terms of change in WHO functional class at week 24.

Evidence Rating Level: 1 (Excellent)      

Study Rundown: Current therapies for pulmonary arterial hypertension (PAH) target one of three pathways: the prostacyclin, nitric oxide, or endothelin pathways. Previous studies have examined the sequential addition of therapies addressing each pathway in subjects with PAH. In this randomized controlled study involving 500 participants (in primary analysis), the investigators compared the use of combined ambrisentan (selective endothelin-A receptor antagonist) and tadalafil (a phosphodiesterase type 5 inhibitor) to monotherapy with each agent alone.

The primary end point for the time-to-event analysis was the first event of clinical failure, defined as the first occurrence of a composite of death, hospitalization for worsening PAH, disease progression, or an unsatisfactory long-term clinical response. The hazard ratio comparing the combined therapy group to the pooled monotherapy groups was 0.50, in favor of combination therapy; this benefit of combo therapy was seen for other outcomes including greater reduction in pro-brain natriuretic peptide levels and percentage of patients with a satisfactory clinical response. There was no statistically significant change in WHO functional class at week 24 across the comparison groups.

This study derives its strength from its relatively large size and its randomized design. It also substantiates the hypothesis that PAH could be treated by targeting multiple pathophysiologic mechanisms at once. The findings are hampered by a few quirks in the design. Notably, the authors instituted a post hoc amendment to exclude subjects with left ventricular diastolic dysfunction causing PAH, which limits the generalizability of the findings.

Click to read the study, published today in NEJM

Relevant Reading: Diagnosis and assessment of pulmonary arterial hypertension

In-Depth [randomized controlled trial]: This randomized controlled study initially began with 610 subjects randomized to either receive combination therapy with ambrisentan and tadalafil, or monotherapy with one of these agents. Subjects were18 to 75 years of age (mean age 54.4 years, 78% female) and had WHO functional class II or III symptoms of PAH (idiopathic, hereditary, or PAH associated with connective tissue disease, drugs, toxins, HIV, or repaired congenital heart defects). The mean pulmonary artery pressure was 48.7 mmHg. The analysis was carried out on 500 subjects who met amended entry requirements excluding those whose PAH may have been due to left ventricular dysfunction.

In terms of the primary outcome, the hazard ratio comparing the combination-therapy group to pooled monotherapy groups was 0.50 (95% [CI], 0.35 to 0.72; p<0.001); the hazard ratio for this comparison in terms of NT-proBNP levels, satisfactory clinical response at week 24, and 6-minute walk distance were all statistically significant as well. The comparison for change in WHO functional class at week 24 did not reach significance (p=0.24). Interestingly, the Kaplan-Meyer event curves for the combination versus pooled monotherapy groups in terms of primary outcome separate around 24 weeks but appear to converge somewhat after 144 weeks. The most common side effects in the combination therapy group included peripheral edema, headache, nasal congestion, and anemia.

Image: PD

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