Early intravenous diuretic administration and mortality in acute heart failure: A systematic review and dose-response meta-analysis

Abstract Background and Aims In acute coronary syndromes, “time is muscle.” In acute heart failure (AHF), time-sensitive decongestion may similarly influence outcomes. The door-to-diuretic (D2D) interval represents a potentially modifiable systems-level intervention analogous to door-to-balloon time. We evaluated the association between D2D time and short-term mortality using a dose-response meta-analytic approach. Methods We conducted a systematic review and dose-response meta-analysis of major AHF registries (REALITY-AHF, REPORT-HF, GREAT, K-CHF), comprising 28,124 patients. Adjusted odds ratios (aOR) for in-hospital mortality and adjusted hazard ratios (aHR) for 30-day mortality were analyzed separately. Random-effects models with Knapp-Hartung adjustment were applied. Dose-response relationships were modeled using generalized least squares for trend (GLST), anchored at a clinically defined ≤60-minute reference threshold. Results Early intravenous diuretic administration (≤60 minutes) was associated with lower 30-day mortality (pooled aHR 0.77, 95% CI 0.64–0.93; I²=58%). In-hospital mortality demonstrated substantial heterogeneity (I²=72%); while the REALITY-AHF registry showed a strong association (aOR 0.39, 95% CI 0.20–0.76), the pooled estimate showed a non-significant trend (pooled aOR 0.84, 95% CI 0.57–1.24). Dose-response modeling revealed a linear increase in mortality risk for every 30-minute delay beyond the first hour. Meta-regression suggested amplification of the survival gradient in registries with higher baseline mortality rates. Conclusion Earlier intravenous diuretic administration was associated with improved 30-day survival in AHF. Although residual confounding cannot be excluded, the observed dose-response relationship supports consideration of D2D time as a potential systems-level quality metric, warranting prospective validation.Figure 1.Dual-Panel Forest Plot of the Association Between Door-to-Diuretic Time and Short-Term Mortality in Acute Heart Failure. Panel A shows adjusted odds ratios (aOR) for in-hospital mortality comparing early (≤60 minutes) versus delayed (>60 minutes) intravenous diuretic administration. The pooled estimate using a random-effects model with Knapp–Hartung adjustment demonstrated a non-significant association (aOR 0.84, 95% CI 0.57–1.23; I² = 72%). Panel B displays adjusted hazard ratios (aHR) for 30-day mortality. Early diuretic administration was associated with significantly lower 30-day mortality (pooled aHR 0.77, 95% CI 0.64–0.93; I² = 58%). Squares represent study-specific effect estimates weighted by inverse variance, and diamonds indicate pooled random-effects estimates. Vertical lines denote 95% confidence intervals, and the reference line corresponds to an effect size of 1.0.