Preemptive cardiorenal phenotyping to forecast diuretic resistance in acute heart failure: derivation and internal validation of the RAPID-HF sequential hybrid model

Background Standard reactive strategies for acute heart failure (AHF) decongestion inherently delay the identification of loop diuretic resistance. This delayed recognition sustains critical elevations in ventricular wall stress and exacerbates structural organ injury. Existing predictive frameworks frequently suffer from statistical dichotomization penalties and consistently neglect the mechanical role of backward venous congestion in pharmacological failure. Purpose We aimed to derive and internally validate the RAPID-HF (Right-heart, Admission-biochemical, Phenotypic Identification of Diuretic resistance in Heart Failure) algorithm. This sequential hybrid model was designed to synthesize static baseline risk profiling with a dynamic two-hour physiological gate to preemptively isolate patients requiring upfront sequential nephron blockade. Methods A prospective observational cohort comprising 182 consecutive adult AHF admissions was analyzed. The primary endpoint was early diuretic resistance, objectively defined by suboptimal cumulative volumetric output following initial intravenous loop diuretic administration. The predictive framework integrated fundamental cardiorenal parameters: right ventricular strain, venous capacitance exhaustion, intrinsic renal impairment, and osmotic derangement. The algorithm stratified the cohort into Rule-In, Rule-Out, and indeterminate (Gray Zone) tiers. For Gray Zone phenotypes, a targeted early two-hour urine output (UOP₂ₕᵣ) threshold was utilized as a definitive mechanical tie-breaker to resolve diagnostic ambiguity. Bio-statistical validation included multivariable logistic regression and Receiver Operating Characteristic (ROC) analysis. Results Early diuretic resistance manifested in 47.2% of the study population. Multivariable regression highlighted right heart echocardiographic signs of profound venous congestion (Odds Ratio: 15.53; 95% CI: 1.62–148.47; P=0.017) and chronic loop diuretic exposure (Odds Ratio: 15.32; 95% CI: 2.81–83.33; P=0.002) as the most potent independent drivers of pharmacological failure. The static diagnostic phase demonstrated exceptional discrimination, achieving an Area Under the Curve of 0.981 (95% CI: 0.960–0.996). The integration of the dynamic physiological gate for indeterminate cases elevated overall predictive accuracy to 98.4%. Notably, the sequential pathway yielded a Positive Predictive Value of 100% for the Rule-In tier, completely eliminating false-positive overtreatment. Conclusion The RAPID-HF sequential hybrid protocol resolves the mathematical uncertainty inherent in standard clinical scoring. By definitively predicting monotherapy failure either prior to or immediately following the initial dose, this architecture provides rigorous clinical justification for the immediate initiation of adjunctive diuretic therapies in precisely targeted high-risk cohorts, bypassing the traditional 24-hour observational delay.