Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study.
We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n = 42) or pulmonary arterial hypertension (PAH; n = 33) in World Health Organization (WHO) functional class II/III. In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral riociguat 1.0-2.5 mg t.i.d. titrated according to systemic systolic blood pressure (SBP). Primary end-points were safety and tolerability; pharmacodynamic changes were secondary end-points. Riociguat was generally well tolerated. Asymptomatic hypotension (SBP <90 mmHg) occurred in 11 patients, but blood pressure normalised without dose alteration in nine and after dose reduction in two. Median 6-min walking distance increased in patients with CTEPH (55.0 m from baseline (390 m); p<0.0001) and PAH (57.0 m from baseline (337 m); p<0.0001); patients in functional class II or III and bosentan pre-treated patients showed similar improvements. Pulmonary vascular resistance was significantly reduced by 215 dyn·s·cm(-5) from baseline (709 dyn·s·cm(-5); p<0.0001). 42 (56%) patients were considered to have experienced drug-related adverse events (AEs; 96% mild or moderate). Dyspepsia, headache and hypotension were the most frequent AEs. Study discontinuation because of AEs was 4%. These preliminary data show that riociguat has a favourable safety profile and improves exercise capacity, symptoms and pulmonary haemodynamics in CTEPH and PAH. Randomised controlled trials are underway.
Ghofrani
H A
HA
Dept of Internal Medicine, Medical Clinic II/V, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, 35392 Giessen, Germany. ardeschir.ghofrani@innere.med.uni-giessen.de
Hoeper
M M
MM
Halank
M
M
Meyer
F J
FJ
Staehler
G
G
Behr
J
J
Ewert
R
R
Weimann
G
G
Grimminger
F
F
D000284:Administration, Oral; D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015444:Exercise; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013923:Thromboembolism / Q000188:drug therapy*; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D011720:Pyrazoles; D011743:Pyrimidines; D006162:Guanylate Cyclase; C542595:riociguat