Charles Burger, MD: Infusion prostanoids are basically replacing what we know to be a suboptimal level of endogenously produced prostacyclin or prostaglandin I2, which has several beneficial effects in the pulmonary circulation. Some of that effect is acting on prostaglandin receptors. A variety of prostaglandin receptors cause the vascular smooth muscle, which is in the wall of the blood vessels, to relax. And when that muscle relaxes, the lumen of the blood vessel opens up. You get what’s called vasodilation, and there’s more blood flow through that circulation. The majority of those receptors that open up blood vessels are systemic. One specific receptor that is quite important in the pulmonary circulation is IP. And the exogenously delivered prostanoid, such as epoprostenol or treprostinil, acts to an extent on that IP receptor, which is opening up blood vessels in the pulmonary circulation. What’s not really known is how exactly these agents reverse a lot of the pathologic changes that have occurred in these blood vessels they do circulate to an extent, whether it’s through these receptors specifically or some other mechanism of signaling.

Modern oral prostanoids really involve a couple of choices. One is Orenitram, which is an oral representation of treprostinil. That agent probably acts through more traditional signaling mechanisms as do the inhaled and infusion treprostinil. An exception to that is a more recently approved medication, selexipag, which is a receptor agonist. So, the pharmacologic agent is not in and of itself a prostanoid. But, it acts on the IP receptor which is affected, to a great degree, by the exogenously delivered prostanoids, epoprostenol and treprostinil. Selexipag is acting on the IP receptor as an agonist, but it isn’t, in and of itself, a prostanoid. It’s been proven in a randomized prospective study to have a very clear beneficial effect on pulmonary arterial hypertension. Whether it has some of the additional positive benefits of the actual prostanoid medications being delivered is unknown. We’re certainly hopeful that that’s true, but that’s not known conclusively.

In 2013, the World Health Organization sponsored what was referred to as the 5th World Symposium on Pulmonary Hypertension. At that time, several of the currently approved medications for pulmonary arterial hypertension were not yet proven in a prospective randomized study that was published. Although, there was quite a bit of preliminary information suggesting a quite robust positive impact on the disease. Much of the conversation at the 5th World Symposium on Pulmonary Hypertension in Nice, France in 2013 centered around what was to come. There were several recommendations on the newer agents, but most commonly in isolation. So, for example, it was felt that one of the newer endothelin receptor antagonists called macitentan was going to have a very positive effect in the efficacy study. It was given a preliminary scientific rating as being an option for use as a single drug in patients with functional class II or III pulmonary arterial hypertension. There was very little evidence at that time that using medications together immediately after the patient was diagnosed was beneficial over starting with one drug. And then reevaluating the patient and making a decision about whether sequential, what was referred to as add-on therapy, was the preferred way to manage the patient.

The guidelines in 2013 basically had all of the individual drugs in the various recommended categories of when they could be used. But, as single drug interventions, with consideration that if the patient didn’t do as well as anticipated or to the patient’s expectations or the clinician’s expectations, that additional therapy could be added on to that first choice. So, sequential therapy was allowed. Upfront therapy was not recommended.

Since that time, a trial referred to as AMBITION with upfront therapy of tadalafil and ambrisentan showed a significant positive impact on a composite endpoint that evaluated PAH progression, hospitalization, need for transplant, and death rate. And it is included in more recent guidelines out of the European Society of Cardiology and the European Respiratory Society that were published in August 2015 online in the European Heart Journal as a high-level recommendation, based on the science for consideration in patients with group 1 pulmonary arterial hypertension, partial class II or III using those specific agents. There was some discussion in the guidelines that since you’re combining two separate classes, that the other medications in those classes used in combination could be considered as an option. But, they are without scientific proof that they are as necessarily as beneficial as the combination of tadalafil and ambrisentan. So, the guideline was very narrow with respect to upfront combination therapy with those two agents as being a high-level recommendation, but with conversation embedded in the text that it could be that some of these other agents used in combination would have a similar effect, but without proof. And secondly, there’s not a head-to-head comparison in a prospective trial that would tell you that one way or the other.

There are several more modern studies that have evaluated newly approved medications for pulmonary arterial hypertension. Two of the three more recent studies are with agents that were added to patients already on treatment, what’s called background therapy. So, for example, in the SERAPHIN study, macitentan was added in a significant group of the patients that were studied who were already on background therapy. Some patients were not, but a significant number were. With the GRIPHON study with selexipag, the majority of the patients were on background therapy. It’s certainly seen that adding both macitentan in the SERAPHIN study and selexipag in the GRIPHON study to existing therapy provided a significant benefit when no subgroups were analyzed at the end of the study, which is indirect evidence that combination therapy is beneficial. But, of course, in those studies, it was sequentially added.

AMBITION has the advantage going at it from the very beginning immediately after diagnosis with two drugs in different classes. Comparing the two drugs together, the combination upfront therapy with the single therapies in the other arms of the trial, also showed that the combination of the drugs given upfront had a more significant improvement and benefit to the patients than did single drug therapy alone. So, the modern therapies are really, in my mind, demonstrating that more drugs given sooner are better for the patients. Which drug should be combined, which combinations would have the most powerful and long-lasting benefit, needs further study.