'Raising the bar' for the treatment of pulmonary arterial hypertension.

Historically, idiopathic pulmonary arterial hypertension (IPAH, formerly referred to as primary pulmonary hypertension) has been considered a fatal disease. The natural history of IPAH was well described by the American National Institutes of Health (NIH) Registry of the 1980s. A median survival of 2.8 years with estimated single-year survival rates at 1, 3, and 5 years of 68, 48, and 35%, respectively were documented. Predictors of a poor prognosis included advanced functional class and haemodynamics (right atrial pressure, cardiac index, and pulmonary artery pressure). Fortunately, much has changed since the 1980s. We now several novel therapeutic options including prostacyclins, endothelin receptor antagonists, and phosphodiesterase type-5 inhibitors, all of which have improved exercise endurance in clinical trials. Surely, we have improved survival in IPAH, haven’t we? Classically, controlled clinical trials in pulmonary arterial hypertension (PAH) have studied the primary endpoint of 6-min walk distance over a short duration (12–16 weeks). Regulatory authorities have accepted the 6-min walk distance as a reliable and reproducible indicator of drug efficacy. Withholding therapy for more than 12–16 weeks was felt to be unethical, particularly early on, when the most ill patients were being entered into clinical trials. The only randomized controlled trial to ever demonstrate a survival benefit in IPAH was the open label trial with intravenous (IV) epoprostenol reported by Barst et al. In that 81-patient trial, 8 patients, all of whom were randomized to conventional therapy alone, died over the 12-week study, resulting in a mortality of 20%. Notably, a quarter of the patients in that trial were functional class IV at baseline. Subsequent open label observational experiences have also demonstrated a survival benefit with IV epoprostenol, either compared with historical controls, or the expected survival based on the NIH equation. Despite this apparent survival benefit, the 3-year survival with IV epoprostenol monotherapy in both these series of functional class III and IV IPAH patients was 63%. In both series, functional class was predictive of survival, both at the initiation of therapy, and when assessed after 3 or more months of therapy. Consequently, and appropriately, the most ill patients are no longer entered into clinical trials, but are treated with active medications. With less ill patients in clinical trials, over short periods of time, other therapies such as bosentan, sildenafil, treprostinil, and iloprost have established improvements in 6-min walk, leading to regulatory approval. The important question of longer term outcomes has not been answered by these brief trials. Provencher et al. describe the long-term outcomes of 103 consecutive functional class III and IV IPAH patients treated with the oral endothelin receptor antagonist, bosentan, as first-line therapy. Using a stringent treatment algorithm, additional therapy with prostanoids (primarily IV epoprostenol) was recommended for patients with functional class IV symptoms on treatment, or persistent functional class III symptoms after at least 4 months of treatment, together with (1) a 6-min walk distance of ,250 m; (2) a .10% decrease in 6-min walk distance from the previous value in two tests performed at least 2 weeks apart; or (3) a cardiac index of ,2.2 L min m. At 4 months, improvements in 6-min walk distance (42 m) and haemodynamics were similar to the findings of the randomized controlled trials. Functional class improved in 48% of patients, remained stable in 42%, and deteriorated in 9%. Overall survival estimates at 1 and 2 years were 90 and 87%, respectively. However, event-free survival estimates were 61 and 44% at 1 and 2 years, respectively. During the mean follow-up period of 24+ 15 months, 13 patients died (8 after the initiation of a prostanoid) and 36 were treated with a prostanoid. Prostanoid therapy was proposed to an additional nine patients who either declined (n 1⁄4 5) or were unable to manipulate the complex delivery system (n 1⁄4 4). Important predictors of outcome included the 6-min walk distance and right atrial pressure at baseline, and the 6-min walk distance, increase in 6-min walk distance, and decrease in total pulmonary resistance at 4 months of therapy. These overall survival data are similar to those previously reported among the 169 IPAH patients who were followed in an open label fashion after