Helping Pulmonary Artery Hypertension Patients Take a Breath

Volume 7, Issue 5

Pulmonary artery hypertension (PAH) is a progressive disease characterized worsening symptoms of right-heart failure and death. This disease—which can be drug induced but is often idiopathic—is particularly dreadful given its high prevalence in young women. Because the disease is uniformly fatal, drug therapy is required to preserve right-ventricular (RV) function and decrease mortality risk while alleviating patient symptoms and improving exercise capacity and quality of life.

In this week’s installment of Talking Therapeutics, we explore the PAH drug therapy landscape and highlight the findings from a seminal paper published this past week.

Point 1: Two-drug Combination Therapy Is Superior

Currently available pharmacotherapies for PAH aim to slow or interrupt disease progression by targeting 3 signaling pathways germane to pulmonary vascular homeostasis: nitric oxide–cyclic guanosine monophosphate, prostacyclin–cyclic adenosine monophosphate, and endothelin. While patients with more advanced disease require parenteral therapy with a prostacyclin analog, those with milder forms (ie WHO class II) can be managed with oral medications.

Several years ago, results from the AMBITION trial of upfront combination therapy with ambrisentan and tadalafil alleviated symptoms and improved exercise tolerance and clinical outcome as compared to either drug as monotherapy.

The results of this trial changed the PAH guidelines to recommend this as a first-line strategy for patients with WHO functional class II.

Point 2: Three-drug Combination Therapy May Be Superior

A prespecified analysis from the GRIPHON trial found that the 179 patients randomized to selexipag who were already on two-drug combination therapy had a lower hazard of clinical worsening or death compared with 197 similar patients randomized to placebo.

Based on this promising signal, the TRITON study evaluated initial triple (macitentan, tadalafil, and selexipag) versus initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH. Upfront triple therapy did not improve the change in pulmonary vascular resistance at 26 weeks compared with standard combination therapy. Patients in both groups showed similar gains in functional status; however, exploratory analyses suggested that triple therapy may decrease the risk for disease progression and first clinical events—namely, hospitalizations for worsening PAH and death. Rates of adverse drug events were comparable between groups.

While there was no benefit in the primary endpoint (change in PVR), the signal of reduced risk for disease progression and the absence of alarming safety issues for simultaneous triple combination therapy supports further investigation.

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