title: Riociguat (Adempas). Chronic thromboembolic pulmonary hypertension with markedly restricted physical activity.
abstract: 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.
mesh_terms: D000203:Activities of Daily Living; D000328:Adult; D000818:Animals; D002908:Chronic Disease; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D009043:Motor Activity / Q000502:physiology; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013923:Thromboembolism / Q000188:drug therapy* / Q000503:physiopathology; D014665:Vasodilator Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D014665:Vasodilator Agents; D006152:Cyclic GMP; C542595:riociguat