Patients with pulmonary arterial hypertension in clinical trials: who are they?

Results from clinical trials serve as the basis for approval of therapies by regulatory agencies as well as for treatment decisions by clinicians. But these findings are relevant only to patients who are similar to the ones enrolled into the trials. This is germane to clinical trials on pulmonary arterial hypertension (PAH) because the disease is uncommon but highly heterogeneous and results can easily be misapplied. The characteristics of patients entering the trials are largely determined by inclusion/exclusion criteria, with the result that most participants have idiopathic, connective tissue disease- and congenital heart disease-related PAH. Earlier trials enrolled patients mainly with New York Heart Association functional class III and IV disease and with severe pulmonary hemodynamic abnormalities. Because it has been the major outcome variable in most of the trials, eligibility is also dependent on six-minute-walk distance, ensuring that patients are moderately but not too severely functionally impaired, thereby maximizing the likelihood of detecting a favorable response to therapy. More recent trials have enrolled less ill patients, with more patients with New York Heart Association functional class II disease, less severe hemodynamic abnormalities, and more stability over time. This reflects, in part, ethical concerns about enrolling sicker patients into placebo-controlled trials. Trials have mainly enrolled white females in their 40s and 50s and have consistently excluded non-WHO group 1 forms of pulmonary hypertension. These characteristics must be carefully considered when applying the findings of pulmonary hypertension trials in clinical practice.