Two-Year Implementation, Adherence, and Outcomes of Quadruple Guideline-Directed Medical Therapy in Newly Diagnosed HFrEF: Insights from the Prospective CaRD Registry

Background: Contemporary guidelines recommend rapid initiation of four classes of guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF); however, real-world persistence, adherence, and dose optimization remain suboptimal. Methods: We analysed a predefined subregistry within the prospective Cardiology Research Dubrava (CaRD) registry, a real-world HF registry at a tertiary centre that includes patients across the ejection-fraction spectrum in whom contemporary HF therapy, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), is introduced or optimised in routine practice. For this analysis, we included patients with newly diagnosed HFrEF (left ventricular ejection fraction (LVEF) ≤ 40%) who were discharged on all four GDMT classes; 167 of 179 patients with newly diagnosed HFrEF during the study period had an available 6-month medication assessment and comprised the final analytic cohort. The four GDMT pillars (beta-blocker; angiotensin-converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI); mineralocorticoid receptor antagonist (MRA); and SGLT2i) were initiated within 4 days when clinically feasible. Medication adherence and target-dose attainment were assessed at 6, 12, and 24 months using a structured self-report questionnaire. Major adverse events (MAE) and all-cause mortality were recorded over 24 months. Patients were classified as adherent if they reported regular intake (≥80% of prescribed doses) of all four drug classes at 6 months; otherwise, they were classified as nonadherent. Results: Among the 167 analysed patients (median age 64 years, 74% men, median LVEF 30%), regular adherence at 6, 12, and 24 months was 65%, 55%, and 59% for beta-blockers; 66%, 50%, and 49% for ACEi/ARB/ARNI; 62%, 52%, and 49% for MRAs; and 84%, 57%, and 68% for SGLT2i. Target doses were achieved in 25–33% for beta-blockers, 42–50% for ACEi/ARB/ARNI, and 73–78% for MRAs. At 24 months, 56 survivors (37%) were adherent to all four drug classes. Over 24 months, all-cause mortality was 9.0% and MAE 18.6%, occurring less frequently in adherent vs. nonadherent patients (mortality 0% vs. 13.5%; MAE 8.9% vs. 23.4%). Conclusions: In this real-world, non-randomized HFrEF subregistry, in-hospital initiation of quadruple GDMT was feasible, yet maintaining long-term adherence and achieving target doses remained challenging. These data underscore the gap between guideline recommendations and routine practice and support structured follow-up and protocol-driven titration to optimize implementation.