 Given the serious limitations of the randomized trials, our clinical guidelines committee decided that its judgments regarding whether targeted PAH therapy is indicated in SCD patients with an elevated PVR and normal PCWP should be informed by indirect evidence from Group 1 PAH populations and our own clinical experience. In Group 1 PAH patients, it has been well-established by meta-analyses of randomized trials that targeted PAH therapy consistently improves exercise capacity, functional status, symptoms, cardiopulmonary hemodynamics and outcome 12-14. This indirect evidence is supported by four case series in which SCD patients with RHC-confirmed pre-capillary PH received targeted PAH therapy with bosentan, sildenafil, andor epoprostenol. Targeted PAH therapy was associated with improvement in exercise capacity, with the six minute walk distance increasing 41 to 144 m beyond baseline 15-18. There were also improvements in the mean PAP, PVR, and cardiac index, although these parameters were measured in only a few patients 18. The magnitude of the benefits was greatest among symptomatic patients. The most common adverse effects were headache 15 and peripheral edema 21; transaminase elevation was reported in 14 of patients during endothelin receptor antagonist therapy 15-18. Based upon these results and the increased morbidity associated with sildenafil use, we are weakly recommending a trial of either a prostanoid or an endothelin receptor antagonist for select patients with SCD who have a RHC-confirmed marked elevation of their PVR, normal PCWP, and related symptoms 8. 