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Update on Combination Therapy for Pulmonary Arterial Hypertension

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Marco A. Caccamo, DO
Indiana University
Indianapolis, IN, USA

Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality, and is often diagnosed relatively late in the disease course. As a result, the consequences can be devastating in terms of impact on right ventricular function, functional capacity and ultimately survival.

A similarly high morbidity and mortality can be seen in many rheumatologic and oncologic disorders, but these disorders are often approached in a different manner than PAH traditionally has been. How are they treated differently, you might ask?

The general treatment paradigm in PAH has typically been to add drugs sequentially, with physicians adding more agents if patients fail therapy. In contrast, many rheumatologic and oncologic disorders are targeted using a multi-mechanistic approach from the start, in which physicians use several drug combinations to effectively treat the disease and gain disease remission, while being cognoscente of the possibility of causing more adverse events.

When a patient with newly diagnosed, treatment naïve World Health Organization (WHO) group I PAH presents to my office with significant functional limitations, I, like many PAH clinicians, often prescribe combination therapy, especially if there are high risk features present, with the thought that 2 or more agents with different mechanisms of action would have synergistic effects. But do I have evidence from any large clinical trials to support my practice?

The answer, until recently, was no, as no large trial had tested multi-drug combination therapy. However, this past fall, the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial was a landmark phase 4 study presented at the European Respiratory Society (ERS) International Congress in Munich, Germany. Five hundred patients were randomized (2:1:1) to receive ambrisentan and tadalafil (n=253) or monotherapy with ambrisentan (n=126) or tadalafil (n=121) (titrated from 5 mg to 10 mg once-daily and from 20 mg to 40 mg once-daily for ambrisentan and tadalafil, respectively).This was a multicenter, event driven study that included treatment-naïve patients with WHO functional class 2 and 3 PAH with a primary endpoint of time to first clinical failure event. The trial reached its primary end-point driven by a marked reduction in PAH related hospitalizations from 12% with monotherapy with either drug, to 4% with combination therapy at 24 weeks. There were no statistically significant differences in mortality between the two groups. The combination of the therapy did not result in new adverse events and discontinuation rates of drug were similar across all groups. Improvement in 6 minute walk was about 24 meters in the monotherapy arm and 49 meters in the combination arm of therapy. The finalized manuscript is yet to be published so full details of the results are to follow.

Just when it seemed that we had definitive evidence to support combination therapy in PAH, the Effects of Combination of Bosentan and Sildenafil vs Sildenafil Monotherapy on Morbidity and Mortality in Symptomatic Patients With Pulmonary Arterial Hypertension (COMPASS-2), was presented at the CHEST conference this past fall. COMPASS-2 was a prospective, double-blind, placebo-controlled, event-driven study evaluating the progression of PAH in two groups of patients already treated with sildenafil; one group receiving placebo and the second group receiving bosentan. COMPASS-2 did not meet the primary endpoint of time to first morbidity or mortality event; bosentan showed a risk reduction of 17% versus placebo (p=0.25), which was not statistically significant. Also of note, reductions in NT-proBNP were more pronounced in the combination therapy arm, but this was not a primary endpoint.

So how do we reconcile these 2 large studies of combination therapy with disparate results? Certainly, the COMPASS-2 trial had some methodologic limitations, including potential for selection bias, slow enrollment, and loss of follow-up, which may have impacted the primary efficacy endpoint. Another interpretation is that the current evidence suggests that up front combination therapy is superior to add-on sequential combination therapy. Yet another hypothesis might be that the combination of tadalafil and ambrisentan is superior to that of sildenafil and bosentan - that the benefits of combination therapy are specific to molecules studied rather than a class effect. The dialogue amongst PAH clinicians regarding these studies remains a lively one!

Have we learned enough from these studies to change our treatment paradigm? Certainly we are a step closer to the use of combination therapy in patients who have more than mild symptomatic limitations. The historical practice of sequential drug therapy was originally adopted partly due to the limited pharmacologic options physicians had to treat PAH and due to the expense associated with the individual therapeutic agents. Recall that just 20 years ago we did not have any PAH specific therapies and at the end of 2014, we have 12 PAH specific drugs which can be delivered by intravenous, subcutaneous, inhaled and oral routes, along with several different mechanisms of action.

It is certainly time for the PAH community to discuss these study results and to revisit our PAH treatment algorithms in light of these trials. We should also consider lessons learned from other disease states such as human immunodeficiency virus, which was once treated with a single agent with suboptimal results but can now be well controlled with multi-drug combination therapy with more efficacious agents. ■

Disclosure Statement: The author has no conflicts of interest to disclose.

1. Galiè N. The AMBITION study: design and results. Presented at: 2014 European Respiratory Society Annual Meeting. Eur Respir J 2014; 44: Suppl. 58, abstract 2916.

2. McLaughlin V; Channick R ; Ghofrani H, et al. Effect of Bosentan and Sildenafil Combination Therapy on Morbidity and Mortality in Pulmonary Arterial Hypertension (PAH): Results From the COMPASS-2 Study. Chest 2014;146(MeetingAbstracts):860A.

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