CTD-PAH: Overview of Treatment Strategies

Optimal treatment strategies in the setting of connective tissue disease—associated pulmonary arterial hypertension are reviewed


Charles D. Burger, MD: In making decisions about treatment for pulmonary artery hypertension [PAH] in association with CTD [connective tissue disease], I have a general bias—based on published literature and my experience—to be relatively aggressive because of the coexisting connective tissue disease and the ongoing risk that it may affect the pulmonary vasculature. In addition, those patients can be at risk for developing lung scarring, or interstitial lung disease. I recommend getting out in front of the treatment of the pulmonary hypertension as aggressively as possible, based on risk assessment.

There are a lot of ways to do that now. In the 2015 published guidelines on pulmonary hypertension, the European Respiratory Society and the European Society of Cardiology created 3 groups of risk for patients—low, intermediate, and high—based on symptoms; the blood tests that we use, such as BNP [B-type natriuretic peptide]; 6-minute walk distance; and results of additional diagnostic testing, such as the echocardiogram or the right heart catheterization. Those patients who are in the low-risk category should start on at least 2 oral medications as soon as possible after diagnosis, based on results out of the AMBITION trial.

For any patient with connective tissue disease—associated pulmonary artery hypertension who has a higher risk than that, I want to move aggressively to triplet therapy, which might involve an oral prostacyclin medication. Oral treprostinil is a prostacyclin analogue. Selexipag is a prostacyclin receptor agonist. Those are options, or perhaps I would even use infusion therapy for the more severely affected.

Another way to perform risk stratification is a REVEAL Registry risk score, and an updated REVEAL risk score was published in Chest in 2019. We participated in that update in my practice in terms of looking at the data and refining the analysis in a way that allows you to actually establish a numeric score. Patients with a high score are at higher risk of poor outcome. For those patients, you would treat more aggressively than for those with a low REVEAL risk score, who have a better prognosis. You could start with the 2 oral medications that I mentioned. The agents in the AMBITION trial that were shown to work together were ambrisentan and tadalafil. Ambrisentan is in the endothelin receptor antagonist class, and tadalafil is in the PDE5 [phosphodiesterase type 5] inhibitor class, which blocks the breakdown of nitric oxide.

Over the past several years, more trials have become available showing the benefit of using more than 1 PAH medication for most types of pulmonary hypertension. Certainly, in practice, we have used more than 1 medication for many patients, often in a sequential fashion. We will start with 1 medication, reevaluate, and then determine whether or not an additional medication will be useful. Trials have allowed for FDA approval of additional medication, such as SERAPHIN, which showed that macitentan provides benefit for patients and demonstrated that’s true even if they were already on background PAH medication. Many patients, about two-thirds, were already on medication. Adding the macitentan showed additional benefit by reducing serious events, such as hospitalization.

A second trial similar in that regard is called GRIPHON, with about 1156 patients. It showed that adding selexipag, which is a prostaglandin receptor agonist, has benefit for patients, even though 80% of the patients on that trial were on background therapy. If you looked at the breakdown of those patients, many were on more than 1 drug. It really confirmed that multidrug therapy has additional benefit.

On the heels of those 2 large trials, which allowed for approval of macitentan and then selexipag, was the AMBITION trial. In a nutshell, it took 2 drugs, ambrisentan and tadalafil, and patients were randomized to receive both drugs as soon as possible after diagnosis. It compared those patients with patients who only had ambrisentan as monotherapy and a third group of patients who only had tadalafil as monotherapy.

At the end of the day, scientists compared the patients who had both drugs started as soon as possible to the patients, pooled together, who had single-drug therapy with either ambrisentan or tadalafil. There was benefit with starting 2 medications as early as possible, or up-front dual oral combination therapy. Now, in full transparency, it took about 2 months to get the patients up to full dose of both ambrisentan and tadalafil in the up-front dual oral combination therapy group. Sometimes it takes a little while to get drug approval, to make sure patients tolerate these medications, and to get them on combination therapy. But the message is to do that as quickly as possible because it’s been shown to be beneficial for these patients.

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