Nitrates in combination with hydralazine in cardiorenal syndrome: a randomized controlled proof‐of‐concept study

AIMS: Cardiorenal syndrome (CRS) is a common problem of great morbidity and mortality. Hydralazine–isosorbide dinitrate (H‐ISDN) may be used in renal failure and may improve exercise capacity in heart failure (HF). Our proof‐of‐concept study aimed to evaluate early evidence of efficacy, safety, and feasibility of H‐ISDN compared with standard of care in CRS. METHODS AND RESULTS: This multi‐centre, single‐blind, randomized trial in Singapore enrolled CRS patients, defined as chronic HF with concomitant renal failure [estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2)]. The primary outcome was 6 min walk test (6MWT) distance measured at 6 months. Secondary outcomes included study feasibility; efficacy outcomes which included renal, cardiac, and endothelial functions, health‐related quality of life using Short Form‐36, clinical outcomes; and adverse events. Forty‐four patients [71 ± 10 years; 75% male; median (inter‐quartile range) N‐terminal prohormone brain natriuretic peptide 1346 (481–2272) pg/mL] with CRS (left ventricular ejection fraction 42 ± 12% and eGFR 46 ± 15 ml/min/1.73 m(2)) were randomized into two equal groups. Of these, 39 (89%) had hypertension, 27 (61%) had diabetes mellitus, and 17 (39%) had atrial fibrillation. Six (27%) discontinued H‐ISDN owing to intolerance and poor compliance. There was a trend towards improved 6MWT distance with H‐ISDN compared with standard of care at 6 months (mean difference 27 m; 95% CI, −12 to 66), with little differences in secondary efficacy outcomes. Giddiness and hypotension occurred more frequently with H‐ISDN, but HF hospitalizations and mortality were less. CONCLUSIONS: Our pilot study does not support the addition of H‐ISDN on top of standard medical therapy to improve exercise capacity in patients with CRS.