PAH: Comparing Upfront Therapies

Andrew Shorr, MD, MPH


December 09, 2015

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Andrew Shorr, MD, MPH: This is Andy Shorr from Washington, DC, with the pulmonary critical care literature update. I'd like to point out the recently published results from the AMBITION trial in the New England Journal of Medicine.[1]

The AMBITION trial focused on our approach to pulmonary arterial hypertension (PAH). We have a plethora of agents for PAH, some of which have been recently approved only in the past 2 years by both US and European regulatory authorities. The currently available drugs—phosphodiesterase type 5 (PDE5) inhibitors, endothelial receptor antagonists (ERAs), and prostacyclin analogs—target various pathways. But we have little data that tell us how to use these agents in combination or whether we should be using them sequentially when patients are not meeting endpoints.

The AMBITION trial tried to get at this very important question. In AMBITION, researchers took patients with World Health Organization functional class II or III PAH and randomly assigned them to one of three arms. The first arm was tadalafil alone as monotherapy; the second arm was ambrisentan (alone); and the intervention arm combined both agents concurrently. The study offered a new way to look at using dual therapy—a PDE5 inhibitor and an ERA together—up front as opposed to waiting until treatment fails before adding a second drug.

The study was also novel in that it was an event-driven trial. It kept going until the number of events needed was achieved. It wasn't set to finish after reaching a single statistical endpoint or sample size. Rather, the event-driven strategy allowed [the trial] to achieve the power needed to actually answer the important question.

In the trial, patients were randomly assigned in 2:1:1 fashion, with twice as many receiving combination therapy as those receiving each monotherapy. A pooled endpoint comprised four components: death, hospitalization, clinical worsening, and unsatisfactory clinical response. That's important because it avoided the use of a surrogate marker that's not necessarily clinically meaningful in the long term—say, 6-minute walk distance. The study examined a host of other secondary points that we'll talk about in a second.

One reason the study was unique was that it went for nearly 1.5 years, if not 2 years, on some subjects—so, a long follow-up. Of note, the study did not only include patients with idiopathic PAH, but it also included a large cohort of patients with connective tissue disease-related PAH. We often lack data on those patients because many trials seem favor enrollment of idiopathic PAH patients.

Compared with either or both of the monotherapy arms, the combination therapy led to a 50% reduction in risk for clinical failure (pooled endpoint).

When you look at the four components of the primary endpoint individually, each of them directionally favor combination therapy. Secondary endpoints, such as changes in biomarkers and in 6-minute walk distance, all favored the combination therapy.

The study is certainly limited because it doesn't tell us anything about the use of other kinds of combinations. And even though the drugs were well tolerated in that they had equal rates of discontinuations and predictable side effects, the research still may have been underpowered to tell us about the safety of aggressive combination therapy up front. But, the data are, in that sense, reassuring because there wasn't any evidence signaling a concern.

What concerns me most about this trial is that it suggests the combination therapy up front is better than monotherapy. But, when you look at the Kaplan-Meier survival curves, they separate at 24 weeks (for about 6 months) because that's when one of the endpoints was adjudicated, but they do begin to separate earlier.

And so, it raises a question: Is combination therapy up front really better than monotherapy? Or, is it that we're just too late to offer combination therapy to our patients, and we're re-evaluating them too late in the process? Then, maybe monotherapy up front might be fine for some patients, but we should wait only 3 months to assess their response and be aggressive about adding a second agent—as opposed to, say, waiting 6 months, 9 months, or a year. That wasn't answered in the study.

Nonetheless, this landmark study looks at a novel way to treat PAH by targeting two different pathways, leading to changes that are clinically meaningful and patient-centered. So, I urge you to look at this trial. It's received a lot of attention—the AMBITION trial in the New England Journal of Medicine.

This is Andy Shorr from Washington, DC.


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