OBJECTIVES: To evaluate the feasibility, safety and efficacy of early and rapid initiation of quadruple therapy (4 drugs in 4 weeks - "4×4 approach") for heart failure with reduced ejection fraction (HFrEF) patients in a real-world clinical setting. DESIGN: Prospective service evaluation study SETTING: Secondary care PARTICIPANTS: Consecutive patients with de-novo HFrEF between March and August 2021 INTERVENTION: "4×4 approach" - individualised initiation and up-titration of 4 pillars HFrEF therapy by heart failure specialist MAIN OUTCOME: Proportion of patients initiated on 4 pillars of HFrEF therapy within 4 weeks RESULTS: Of 100 patients approached, 19 patients were not suitable for rapid up-titration pathway due to severe frailty and significant comorbidities. Eighty-one patients were enrolled [61% male, median age=73 years, median N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) = 3764 ng/L]. 39 patients (48%) achieved 4×4. Of the 42 patients who did not, 26 (62%), 9 (21%), and 7 (17%) patients were on 3 drugs, 2 drugs, and 1 drug, respectively. Thirty-three patients had one or more contraindication at the outset
most commonly renal impairment (28%), bradycardia (18%) and hyperkalaemia (15%). Five patients experienced significant side effects during medication up-titration, most commonly symptomatic hypotension. During median follow up of 554 days, 32 (40%) patients experienced the combined outcome (all-cause hospitalisation/ death). Patients who did not achieve 4×4 had an increased risk of the combined outcome [HR 2.25 (1.09-4.68), p=0.029] compared to those who achieved 4×4. CONCLUSION: Early and rapid initiation of 4 pillars HFrEF therapy is clinically feasible and safe when implemented in selected patients and is associated with improved clinical outcomes.