Why the study?
Despite strong guideline recommendations for early implementation and up-titration of quadruple therapy in HFrEF, target doses achieved in daily clinical practice remain significantly lower than recommended, warranting analysis of long-term quadruple therapy use, achieved doses, and their prognostic effect after heart failure hospitalisation.
Does achieving higher target doses (≥50%) of quadruple guideline-directed medical therapy at 1 year reduce the composite of all-cause mortality and heart failure hospitalisation in patients with HFrEF following a heart failure hospitalisation?
Cohort (n=551)
Does achieving higher target doses (≥50%) of quadruple guideline-directed medical therapy at 1 year reduce the composite of all-cause mortality and heart failure hospitalisation in patients with HFrEF following a heart failure hospitalisation?
Maintaining ≥50% of target doses for quadruple therapy at 1 year after heart failure hospitalisation is associated with a 55% reduction in the composite risk of all-cause mortality and heart failure rehospitalisation in HFrEF patients.
Achieving ≥50% target doses was associated with lower events; supports up-titration efforts but leaves causal benefit open pending RCTs.
Introduction The 2021 ESC Heart Failure (HF) Guidelines (GLs) and their 2023 Focused Update clearly recommend the early implementation and up-titration of quadruple therapy (QT: RASi + βB + MRA + SGLT2i) to target doses (TDs) in patients with HF with reduced ejection fraction (HFrEF), emphasising the prognostic role of “time-to-GDMT”. Despite the strong recommendations in the recent international HF Guidelines, the TDs achieved in daily clinical practice are significantly lower than those recommended in the GLs. Aims To analyse the long-term use and the achieved doses of QT after a hospitalisation for HF (HFH) in a consecutive cohort of HFrEF patients; and to evaluate the effect of the achieved doses on prognosis (all-cause mortality [ACM], HFH, composite of ACM/HFH). Patients and methods: We retrospectively evaluated the data of a consecutive HFrEF patient cohort hospitalised for HF between 2021 and 2025 (n=551, male: 75%, age: 63 [52-71] years, de novo HF: 42%, LVEF: 25 [20-30]%, coronary artery disease: 45%, hypertension: 68%, diabetes: 40%, eGFR < 60 mL/min/1.73m2: 52%, NT-proBNP at hospital admission: 5866 [2728-10616] pg/mL, GDMT at discharge: RASi/TD RASi: 94%/18%, βB/TD βB: 85%/7%, MRA/TD MRA: 95%/64%, SGLT2i: 68%, triple therapy [TT: RASi + βB + MRA]/TD TT: 82%/2%, QT /TD QT: 61%/2%). QT and its achieved TDs (not on QT vs 1-49% of TD QT vs 50-100% of TD QT) at 1-year follow-up were investigated. ACM, HFH and the composite of ACM/HFH were analysed, and the independent predictors of the composite of ACM/HFH were examined by Cox-regression analysis. Results At 1 year, the use of GDMT was as follows: RASi/TD RASi: 89%/34%, βB/TD βB: 85%/22%, MRA/TD MRA: 89%/55%, SGLT2i: 69%, TT/TD TT: 76%/9%, QT/TD QT: 60%/7%. At 1 year, 40% of the total cohort (TC) were not on QT, 31% of TC had 1-49% TD QT, while 29% of the TC were on 50-100% TD QT. During the median 670 [335-1085] days of follow-up, ACM affected 25% of the TC, while 25% of TC were re-hospitalised for HF, and the composite endpoint of ACM/HFH was observed in 39% of TC. Higher doses of QT were associated with a more favourable prognosis (ACM: 3% vs 7% vs 21%, p<0.001; ACM/HFH: 18% vs 24% vs 38%, p=0.005; not on QT vs 1-49% TD QT vs 50-100% TD QT, respectively). According to the multivariate Cox-regression analysis, the application of CRT (HR: 2.089, 95% CI: 1.041-4.191, p=0.038) and NT-proBNP (/100 pg/mL, HR: 1.006, 95% CI: 1.001-1.012, p=0.032) at discharge proved to be positive-, while ≥50% of TD QT use at 1 year (HR: 0.452, 95% CI: 0.212-0.964, p=0.040) was a negative predictor of ACM/AHF. Conclusions Dose-dependent, long-term QT use remarkably influenced the risk of ACM and the composite endpoint of ACM/HFH in a consecutive HFrEF patient population after an HFH. ≥50% of TD QT use at 1 year reduced the risk of ACM/HFH by 55%, highlighting the need for continuous efforts to optimise doses of GDMT and to maintain long-term the prognosis-modifying pharmacotherapy.File 1
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Forrai et al. (2026) conducted a cohort in Heart failure with reduced ejection fraction (HFrEF) hospitalized for heart failure (n=551). Quadruple therapy (RASi + beta-blocker + MRA + SGLT2i) at ≥50% of target dose at 1 year vs. Not on quadruple therapy or <50% of target dose was evaluated on Composite of all-cause mortality (ACM) and heart failure hospitalization (HFH) (HR 0.452, 95% CI 0.212-0.964, p=0.040).
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