Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809–18.

 

Present therapies for PAH have been adopted on the basis of short-term trials with exercise capacity as the primary end-point. This long-term trial assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist using primary end-point of morbidity and mortality. Inclusion criteria included patients 12 years of age or older who had idiopathic or heritable PAH or PAH related to connective-tissue disease, repaired congenital systemic-to-pulmonary shunts, human immunodeficiency virus (HIV) infection, or drug use or toxin exposure. A total of 742 patients were randomly assigned to placebo, macitentan 3 mg or macitentan 10 mg in once a day dosages. Stable oral or inhaled therapy other than endothelin receptor antagonists was allowed at entry. The primary end-point was the time from the start of treatment to the first occurrence of a composite end-point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of PAH. A total of 287 patients had a primary end-point event over a median treatment period of 115 weeks. The primary end-point occurred in 46.4% in placebo, 38.0% in macitentan 3 mg group (hazard ratio 0.70, p=0.01) and 31.4% of the patients in macitentan 10 mg group (hazard ratio 0.55, p <0.001). The effect of macitentan was observed regardless of whether the patient was receiving therapy for PAH at baseline.

 

 

In this long-term event-driven study, macitentan was found to significantly reduce morbidity and mortality in patients with PAH.

 

Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330–40.

Riociguat, a soluble guanylate cyclase stimulator, has been previously shown to improve hemodynamic variables and exercise capacity in patients with PAH in phase 1 and 2 clinical studies. Riociguat has a dual mode of action, acting with endogenous nitric oxide and also directly stimulating soluble guanylate cyclase independently of nitric oxide availability. In this phase 3,double-blind study, 443 patients with symptomatic PAH were randomly assigned to receive placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg-maximum group), or riociguat in doses that were capped at 1.5 mg three times daily (1.5mg-maximum group). Patients with symptomatic PAH (idiopathic, familial, or associated with connective-tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, or anorexigen or amphetamine use) were included if they had a pulmonary vascular resistance greater than 300 dyn.sec.cm-5, a mean pulmonary-artery pressure of at least 25 mmHg and a 6-minute walk distance of 150–450 m. Both treatment naive and patients who were receiving endothelin-receptor antagonists or non-intravenous prostanoids were eligible. The primary end-point was the change from baseline to the end of week 12 in the 6-minute walking distance. Secondary end-points included the change in pulmonary vascular resistance, NT-proBNP levels, WHO functional class, time to clinical worsening, score on the Borg dyspnea scale, quality-of-life variables and safety. At 12 weeks, the 6-minute walk distance increased by a mean of 30 m in the 2.5 mg-maximum group and decreased by a mean of 6 m in the placebo group (p<0.001). There were also significant improvements in pulmonary vascular resistance (p<0.001), NT-proBNP levels (p<0.001), WHO functional class (p=0.003), time to clinical worsening (p=0.005) and Borg dyspnea score (p=0.002).

 

 

Riociguat, a soluble guanylate cyclise stimulator, significantly improved exercise capacity and secondary efficacy end-points in patients with PAH.

 

 

Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369:319–29.

 

Chronic thromboembolic pulmonary hypertension is characterized by obstruction of the pulmonary vasculature by residual organized thrombi, leading to increased pulmonary vascular resistance and progressive pulmonary hypertension. Pulmonary endarterectomy is the treatment of choice but all patients are not the candidates. In this phase 3, multicenter, randomized, double-blind, placebo-controlled study 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy were randomly assigned to receive placebo or riociguat. The primary end-point was the change from baseline to the end of week 16 in the 6-minute walking distance. At week 16, the 6-minute walk distance had increased by amean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (p<0.001).Pulmonary vascular resistance decreased by 226 dyn.sec.cm–5 in the riociguat group and increased by 23 dyn.sec.cm–5 in the placebo group (p<0.001). Riociguatwas also associated with significant improvements in the NT-proBNP level (p<0.001) and WHO functionalclass (p=0.003).

 

 

Riociguat significantly improved exercise capacityand pulmonary vascular resistance in patients withchronic thromboembolic pulmonary hypertensionwho were ineligible for surgery or who had persistentor recurrent pulmonary hypertension after pulmonaryendarterectomy.