July 25th, 2013
The Changing Landscape of Pulmonary Hypertension
In the New England Journal of Medicine this week, Ghofrani et al. present two multicenter clinical trials on the role of a new oral pulmonary vasodilator in pulmonary hypertension. Riociguat is a soluble guanylate cyclase stimulator that promotes vasodilation in the pulmonary circulation. Riociguat represents a new class of medicines available for pulmonary hypertension and therefore will change the landscape of therapeutic options available in this disease process. However, there are a couple of aspects worth noting about these studies.
In the PATENT-1 trial, the researchers study the effects of riociguat in Group 1 PH, pulmonary arterial hypertension (PAH). Current treatment options available for this group are prostacyclins, endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5i), and calcium-channel blockers (the latter used only in those deemed reversible on right heart catheterization). Epoprostenol (prostacyclin) has been shown to improve survival in PAH but is administered via continuous intravenous infusion, and is thus limited in terms of ease of use as well as its cost. ERA and PDE5i have been shown to improve 6-minute walk distance, which is the same primary outcome used in PATENT-1. Most of these agents typically improve 6-minute walk distance by about 30 to 50 meters. In the PATENT-1 study, only 21% of treated patients had a functional improvement at 12 weeks. Therefore, it appears that riociguat is going to be another PAH drug of modest efficacy. Because of the near-equivalent outcomes, decision making regarding which agents to use as first-line or in combination therapy is subject to remarkable physician variability, depending on cost, familiarity, experience, access, and pharmaceutical company influence. To address this variability in care, primary outcomes that include endpoints such as mortality and hospitalization are becoming more standard in PAH trials, with decreasing emphasis being placed on 6-minute walk distance. Also, the trials in PAH remain small because it is still a rare disease with a prevalence of 6.6 cases/million adults. In addition, this study does not reflect the largest population of pulmonary hypertension in clinical practice, namely Group 2 PH (PH secondary to left heart disease), for which are still no dedicated therapies.
The CHEST-1 trial of riociguat in chronic thromboembolic pulmonary hypertension (CTEPH, Group 4 PH) is a unique study as it marks the first large, multicenter RCT of medical therapy to demonstrate marked clinical benefit in CTEPH. The primary outcome again is 6-minute walk distance, which improved by 46 meters in the treatment group compared with placebo. However, this surrogate clinical outcome is markedly inferior to the outcomes observed from pulmonary endarterectomy for treatment of this rare disease (accounting for about 2% of all cases of pulmonary hypertension). Therefore, it is important that patients identified as having CTEPH should still be presented with pulmonary endarterectomy as the first-line therapeutic option. In fact, to enter into CHEST-1, patients had to be deemed inoperable or had residual PH after undergoing pulmonary endarterectomy. The rare incidence of CTEPH coupled with the infrequent determination of inoperability should ultimately make riociguat a rarely prescribed agent for this group with PH.