Charles Burger, MD: Patients with pulmonary arterial hypertension often need close follow-up to evaluate their treatment. If the disease state is relatively mild or on the moderate end at diagnosis, often they’re started on oral therapies. More severe disease with functional class IV heart failure is an example, or hospitalization for the pulmonary arterial hypertension at the time of diagnosis. Often the therapy will start with prostanoid infusion, such as treprostinil or epoprostenol. If we’re dealing with the former group of patients, more mild disease that start on oral therapies as an example, when they’re seen in follow-up as an outpatient, obviously their symptom burden is evaluated. Their physical examination, surrogate markers such as a blood test for brain natriuretic peptide or 6-minute walk distance, are often performed to evaluate whether or not they’re headed in the correct direction. They’re all things moving toward an improvement. Generally, the therapy is unchanged and continued. If, however, the patient is not making progress or is deteriorated, then the therapy is accelerated.
The current state of the art is using sequential medications as you would evaluate the patient with one exception. There is a more modern study that shows that at least two of the medications that are now approved for pulmonary arterial hypertension might best be used very early in the course of the treatment, a trial that’s called AMBITION, where tadalafil is used together with the ambrisentan. But short of that one trial, often patients are started on one therapy, evaluated in a very short term. If not doing as well as anticipated, then another oral therapy or a higher-level therapy, such as an inhaled prostanoid, or an infusion prostanoid, or now some oral prostanoids which have been more recently approved, may be added. That’s referred to as sequential therapy. So, it appears that more medications are early in the course after the diagnosis, where the practice is headed in terms of current evidence that’s been forthcoming over the last year or so. But, more needs to be done for confirmation of that.
I would estimate that the majority of pulmonary arterial hypertension experts are inclined to use as aggressive a therapy as indicated as early as possible to get the right heart size and function to a more normal state. Because, clearly, that has the best chance of keeping people out of the hospital, keeping them off of transplant lists, and improving survival. So, sequential therapy is where we’ve been, and that’s how it’s generally evaluated. Although, using more drugs earlier in the course may be where the practice and state-of-the-art for treatment intervention moves really over the next year or two, quite frankly, as we look at changes that have already occurred in current guidelines.
As more therapies have become available, the decision making on upfront therapy or sequential therapy becomes a bit more complex. We now have oral medications with three different targets for intervening on the pulmonary arterial narrowing. We have a pathway that involves prostacyclin, so oral prostanoids. We have a pathway involving endothelin, so blocking endothelin with endothelin receptor antagonists. And a pathway involving nitric oxide, which has two different types of oral medications. It would make sense, from a scientific perspective, to hit each of those targets aggressively as quickly as possible to improve the patient’s symptom state, and to lessen these harder endpoints. How quickly all of these medications need to be added really needs some additional investigation to enhance the guideline recommendations, so that practicing clinicians who are prescribing these therapies have a bit more in the way of at least consensus-based recommendation, if not scientifically proven recommendation, on how to use the various drugs that are now FDA approved for this disease.