When
pulmonary hypertension results in marked limitation in
activities of daily living (functional class III), the first-choice
vasodilator is
bosentan, despite its limitations. There is no proven advantage of adding another
vasodilator. The adverse effects of
vasodilators outweigh their uncertain efficacy in patients with only a slight limitation of physical activity (class II). When surgery is not feasible or when chronic thromboembolic
pulmonary hypertension persists despite surgery, there are no
vasodilators with a favourable harm-benefit balance.
Riociguat (
Adempas, Bayer) is a
vasodilator that acts by enhancing the synthesis of cyclic
guanosine monophosphate (cGMP), a mediator of vasodilation. This mechanism of action is similar to that of
sildenafil, which inhibits cGMP catabolism.
Riociguat has been authorised in the European Union in adult patients with class II or III
pulmonary arterial hypertension or chronic thromboembolic
pulmonary hypertension.
Riociguat monotherapy has not been compared with another
vasodilator in patients with
pulmonary arterial hypertension. In a 12-week randomised, double-blind, placebo-controlled trial in 380 patients,
riociguat had modest symptomatic efficacy, improving the functional class in 21% of patients (versus 14% in the placebo arm). There was no statistically significant difference in mortality. The symptomatic benefit appeared to be similar in patients who continued to take
bosentan and in those who were not taking a
vasodilator other than
riociguat. In a 16-week, double-blind trial in 261 patients with chronic thromboembolic
pulmonary hypertension in whom surgery was not feasible or had failed,
riociguat was more effective than placebo on symptoms; there was improvement in functional class in respectively 33% and 15% of patients. There was no statistically significant change in mortality. In these two clinical situations, subgroup analyses showed no benefit of
riociguat in patients who had only slight limitation of physical activity (class II). The main adverse effects of
riociguat are related to its vasodilatory properties, and include
headache, arterial
hypotension,
dizziness and peripheral oedema.
Riociguat can also cause
bleeding, including potentially severe pulmonary haemorrhage. More data are needed on its cardiac, renal and osseous adverse effects.
Riociguat is subject to pharmacodynamic interactions with many other drugs. In particular,
riociguat coadministration with a
phosphodiesterase type 5 inhibitor such as
sildenafil can lead to additive, life-threatening vasodilation. Additive adverse effects when co-administered with
nitrates and antithrombotic drugs are likely.
Riociguat is also subject to multiple pharmacokinetic interactions.
Riociguat was teratogenic in experimental animals. In practice, in the absence of a better alternative,
riociguat is an option for some patients with chronic thromboembolic
pulmonary hypertension that markedly restricts their
activities of daily living. It has no demonstrated advantage for other patients.