Association between up-titration of guideline-directed medical therapy and clinical outcomes in patients with chronic heart failure with reduced ejection fraction

Background The optimisation of guideline-directed medical therapy (GDMT) is associated with favourable clinical outcomes in heart failure (HF), particularly in HFrEF. The GDMT score has been proposed to quantify GDMT optimisation. However, it remains unclear whether an increase in the GDMT score is associated with clinical outcomes in a contemporary cohort of patients with chronic HFrEF. Purpose To investigate the association between optimisation of GDMT and subsequent clinical outcomes in patients with chronic HFrEF. Methods In this multicentre observational study, 674 patients with chronic HFrEF were enrolled from 29 centres between January 2020 and February 2025 (median age 69 years; median LVEF 31%). The GDMT score was calculated based on the use and dose of the quadruple therapy, ivabradine, vericiguat, and hydralazine/nitrates (Figure 1).1 Patients were classified into an up-titration group or a no up-titration group according to the change in GDMT score from baseline to 9 months after enrolment. Inverse probability of treatment weighting (IPTW) was applied to adjust for baseline differences. The primary outcome was a composite of all-cause death or hospitalisation for worsening HF. We also evaluated the association between up-titration and left ventricular reverse remodelling (LVRR) defined as an absolute increase in LVEF ≥10% with an LVEF ≥40% at 18 months after enrolment. Results At baseline, 485 patients (72%) were receiving three or more of the quadruple therapy. At 9 months, 277 (41%) patients were classified as up-titration group, whereas 397 (59%) were as no up-titration group. Patients in the up-titration group were younger and had higher LVEF, heart rate, and estimated glomerular filtration rateand lower potassium levels than those in the no up-titration group, whereas sex, systolic blood pressure, NT-proBNP, and NYHA class were similar between the groups. The median GDMT score at baseline was 6 (IQR 5–8) in no up-titration and 5 (IQR 3–6) in up-titration groups (P < 0.001). During a median follow-up of 755 days (IQR 357–1127), up-titration was significantly associated with a lower risk of the primary outcome after IPTW (weighted HR 0.62, 95%CI 0.42–0.92; Figure 2). In a multivariable Cox regression, up-titration was independently associated with a lower risk of the primary outcome (HR 0.63, 95%CI 0.42–0.95) adjusting for NT-proBNP and MAGGIC risk score. In a multivariable logistic regression, up-titration was independently associated with the incidence of LVRR (OR 1.67, 95%CI 1.09–2.55) even after adjustment for age, sex, body mass index, non-ischaemic aetiology, NYHA class, systolic blood pressure, prior hospitalisation for worsening HF, baseline GDMT score, LVEF, and NT-proBNP. Conclusions In patients with HFrEF, up-titration of GDMT was independently associated with favourable clinical outcomes and LVRR. The GDMT score could facilitate optimisation of GDMT even in patients with chronic HFrEF.