According to the World Health Organization (WHO) classification of pulmonary hypertension, chronic thromboembolic pulmonary hypertension (CTEPH) represents a discrete group (group 4) distinct from pulmonary arterial hypertension (group 1), pulmonary hypertension as a consequence of left heart disease (group 2), pulmonary hypertension as a consequence of hypoxemia and lung disease (group 3), and multifactorial pulmonary hypertension (group 5). Treatment strategies differ across groups. Whereas a number of medical therapies are available for pulmonary arterial hypertension, to date no pharmacologic therapy has been approved for CTEPH. Instead, the standard of care for CTEPH is pulmonary endarterectomy. Unfortunately, endarterectomy is efficacious only for proximal clot burden, with only about two-thirds of patients deemed eligible for the procedure. Preliminary studies suggested that riociguat, a soluble, direct guanylyl cyclase stimulator that acts on guanylyl cyclase in a nitric oxide (NO)-independent fashion and increases sensitivity of soluble guanylyl cyclase to NO, may offer therapeutic benefit in this population.
The Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator (CHEST-1) trial was a double-blind, randomized, controlled, phase 3 study examining the efficacy and safety of riociguat in CTEPH patients deemed ineligible for endarterectomy, or with recurrent pulmonary hypertension after endarterectomy (Ghofrani et al., 2013). Inclusion criteria included a 6-min walk distance of 150–450 m, mean pulmonary artery pressure of ≥25 mmHg, and pulmonary vascular resistance >300 dyn·sec/cm5. Patients who had received pharmacologic treatment for pulmonary hypertension within the past 3 months were excluded from the study. Patients were randomly assigned (1:2 ratio) to placebo or riociguat, with protocol-specified dose adjustment of riociguat. Patients were followed for 16 weeks at 2- to 4-week intervals; an open-label extension study (CHEST-2) was available for enrollment after completing the 16-week CHEST-1 study.
A total of 261 patients were successfully randomized, with 173 receiving riociguat. The majority of patients were WHO functional class III (68% of placebo, 62% of riociguat) at enrollment. After 16 weeks of therapy, 6-min walk time increased by an average of 39 m in riociguat patients compared with 6 m in placebo patients (p<.001). Pulmonary vascular resistance decreased by 226 dyn·sec/cm5 in riociguat patients compared with 23 dyn·sec/cm5 in placebo patients (p<.001). Pulmonary artery pressure, mean arterial pressure, and cardiac output were all significantly improved with riociguat relative to placebo. Riociguat was also associated with an improvement in Borg dyspnea score, quality of life, and WHO functional class, although 5% of patients randomized to riociguat experienced worsening of functional class during the study (as did 7% of patients randomized to placebo). Adverse events occurred at equal rates in the two groups; serious adverse events were rare. Preliminary data from the CHEST-2 open-label extension study suggest continued improvements may be observed in 6-min walk distance with continued therapy.
Riociguat is the first drug to demonstrate improved hemodynamics and function in patients with CTEPH. In this unfortunate patient population, to whom clinicians have previously had very little to offer, the drug appears to offer clinically significant benefit. Further work will be required to determine the role, if any, of riociguat in patients who are eligible for endarterectomy.
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