Quadruple therapy in heart failure: Why, when, and in whom?

Current heart failure (HF) guidelines recommend quadruple therapy as first-line treatment for patients with HF with reduced ejection fraction, consisting of angiotensin receptor-neprilysin inhibitors, beta-blockers, sodium-glucose cotransporter-2 inhibitors, and mineralocorticoid receptor antagonists. This strategy has significantly improved outcomes by reducing mortality and hospitalization and is now the corner-stone of guideline-directed medical therapy. However, despite these advances, residual morbidity and mortality remain high, indicating that important pathophysiological and therapeutic questions are still unresolved. Although the major HF phenotypes share common mechanisms, including neurohumoral activation, inflammation, oxidative stress, fibrosis, and metabolic disturbance, HF remains a highly heterogeneous syndrome. Differences in etiology, comorbidities, frailty, renal function, and individual biological response may influence both disease progression and treatment efficacy. Consequently, a uniform therapeutic strategy may not provide equal benefit across the HF spectrum. In this comprehensive review, we discuss the rationale and pathophysiological basis of quadruple therapy, its limitations across different HF phenotypes, and the need to move from a predominantly phenotype-based strategy toward a more personalized and mechanism-based therapeutic approach.