Diuretic use and outcomes in patients with HFrEF: Insights from the VICTORIA trial

Abstract

Abstract Background In the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial, vericiguat, compared with placebo, reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled shortly after a worsening heart failure (WHF) event. We examined the clinical outcomes and efficacy of vericiguat as it relates to the background use of loop diuretics in this population of patients with WHF. Methods We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as <40, 40, and >40 mg total daily dose (TDD). The primary composite outcome of CVD or HFH and its components were evaluated as clinical outcomes and expressed as adjusted hazard ratios (adjHR) and 95% confidence intervals (95% CI). Post-randomization rates of change in TDD and safety were also examined. Results Of 4434 patients with diuretic dose information available at randomization, 647 (14.6%) were on <40 mg, 1633 (36.8%) were on 40 mg, and 2154 (48.6%) were on >40 mg TDD. Patient characteristics revealed those patients taking >40 mg TDD were more often in NYHA Class III/IV, diabetic, and had higher NT-proBNP, lower eGFR, less triple guideline-based HF therapy, and a higher MAGGIC risk score. The composite event rate of CVD or HFH per 100 patient years (pt-yrs) progressively increased with higher doses of diuretics: 29.8 per 100 pt-yrs for 40 mg TDD: adjHR 1.23 (95%CI 1.02-1.49); 48.1 per 100 pt-yrs for >40 mg TDD adjHR 1.50 (95%CI 1.25-1.81), relative to <40 mg TDD (22.5 per 100 pt-yrs). Results were similarly observed for the components of the composite endpoint (Figure). There was no significant interaction for the efficacy of vericiguat vs placebo for any outcome examined according to TDD at randomization (p-interaction >0.72, 0.57 and 0.64 for the primary endpoint, CVD and HFH). Diuretic dose changes post-randomization were assessed in 3684 eligible patients (followed for a median duration of 14.2 months). By treatment group, there were similar rates of up-titration (26.7 and 29.4 per 100 pt-yrs), down-titration (13.8 and 15.4 per 100 pt-yrs), and stopping of diuretic use (23.4 and 24.2 per 100 pt-yrs) observed for vericiguat and placebo groups, respectively. Conclusions The amount of loop diuretic TDD at randomization was associated with a higher risk phenotype commensurate with worse outcomes. However, the efficacy of vericiguat was preserved across this range of different loop diuretic doses used by patients with recent WHF in VICTORIA.