We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n542) or pulmonary arterial hypertension (PAH; n533) 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.
BackgroundPersistent congestion with deteriorating renal function is an important cause of adverse outcomes in heart failure. We aimed to characterize new approaches to evaluate renal congestion using Doppler ultrasonography.Methods and ResultsWe enrolled 205 patients with suspected or prediagnosed pulmonary hypertension (PH) undergoing right heart catheterization. Patients underwent renal Doppler ultrasonography and assessment of invasive cardiopulmonary hemodynamics, echocardiography, renal function, intra‐abdominal pressure, and neurohormones and hydration status. Four spectral Doppler intrarenal venous flow patterns and a novel renal venous stasis index (RVSI) were defined. We evaluated PH‐related morbidity using the Cox proportional hazards model for the composite end point of PH progression (hospitalization for worsening PH, lung transplantation, or PH‐specific therapy escalation) and all‐cause mortality for 1‐year after discharge. The prognostic utility of RVSI and intrarenal venous flow patterns was compared using receiver operating characteristic curves. RVSI increased in a graded fashion across increasing severity of intrarenal venous flow patterns (P<0.0001) and was significantly associated with right heart and renal function, intra‐abdominal pressure, and neurohormonal and hydration status. During follow‐up, the morbidity/mortality end point occurred in 91 patients and was independently predicted by RVSI (RVSI in the third tertile versus referent: hazard ratio: 4.72 [95% CI, 2.10–10.59; P<0.0001]). Receiver operating characteristic curves suggested superiority of RVSI to individual intrarenal venous flow patterns in predicting outcome (areas under the curve: 0.789 and 0.761, respectively; P=0.038).ConclusionsWe propose RVSI as a conceptually new and integrative Doppler index of renal congestion. RVSI provides additional prognostic information to stratify PH for the propensity to develop right heart failure.Clinical Trial Registration
URL: https://www.clinicaltrials.gov/. Unique identifier: NCT03039959.
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