Título original: Riociguat for the Treatment of Pulmonary Arterial Hypertension. Referencia: Hossein-Ardeschir Ghofrani et al. N Engl J Med 2013;369:330-40.

Many drugs have been tested for pulmonary arterial hypertension (PAH) including PDE5 inhibitors, prostanoids and endothelin receptor antagonists, however there are still missed targets in the treatment of this disease.

Riociguat is a drug belonging to a new class, stimulating soluble guanylate cyclase with a dual mode of action which on the one hand acts in synergy with endogenous nitric oxide and on the other directly stimulates guanylate cyclase. Based on Phase 1 and 2 tests where Riociguat improved hemodynamic variables and exercise capacity in patients with PAH, this study was designed as Phase 3 (PATENT-1). 

All patients with symptomatic PAH, (idiopathic, familial, associated with collagen vascular disease, congenital heart disease, portal hypertension or anorectics), were included if they had pulmonary vascular resistance above 300 dyn / sec / cm, mean pulmonary artery pressure ≥ 25 mmHg after a test of 6 minutes walking from 150 to 450 meters. This double-blind, controlled, multicenter study randomized 443 patients to a placebo, oral Riociguat up to a 2.5 mg dose three times daily or one dose of 1.5 mg three times per day. Baseline characteristics were well balanced between the groups which can be found in most patients in functional class II-III with PAH being the most common diagnosis. 44% of the population also received an endothelin receptor antagonist (mainly bosentan), 6% prostanoids (mainly breathing iloprost) and the other 50% received specific treatment. At twelve weeks, the 6 minutes walk test (primary endpoint) showed an improvement from baseline of 30 meters in the Riociguat 2.5 mg group versus 6 meters below the baseline in the placebo group, (36 meters, CI 95%, 20 to 52; p <0.001). This result was consistent across all subgroups, however, patients in functional class III-IV showed the most benefit. Benefits were also seen in secondary end points such as decreased pulmonary vascular resistance, mean pulmonary pressure and NT-proBNP levels, increased cardiac output and improved Borg scale. A total of 396 patients joined the extended follow-up phase, (PATENT-2), where the exploratory analysis showed that results in the walk test continued to improve over time.

Conclusion:

Riociguat significantly improved the distance walked in six minutes as well as pulmonary resistance and other secondary efficacy end points in patients with symptomatic pulmonary hypertension.

Editorial Comment:

While the walk test end point looks soft, other studies have shown a modest reproducibility is the end point most frequently used in pulmonary hypertension work, since it correlates well with hemodynamic changes, functional status and survival. The same author also published in N Engl J Med the usefulness of this drug in chronic thromboembolic pulmonary hypertension (CTEPH).

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