Early and rapid initiation of quadruple therapy for heart failure with reduced ejection fraction: A real-world experience

OBJECTIVES: To evaluate the feasibility, safety and efficacy of early and rapid initiation of quadruple therapy (four 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 four pillars of HFrEF therapy by heart failure specialist. MAIN OUTCOME: Proportion of patients initiated on four pillars of HFrEF therapy within 4 weeks. RESULTS: Of 100 patients approached, 19 patients were not suitable for the rapid initiation and up-titration pathway due to severe frailty and significant comorbidities. 81 patients were enrolled (61% male, median age = 73 years, median N-terminal pro-brain natriuretic peptide [NT-proBNP] = 3,764 ng/L). 39 patients (48%) achieved 4×4. Of the 42 patients who did not, 26 (62%), nine (21%) and seven (17%) patients were on three drugs, two drugs and one drug, respectively. 33 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 four pillars HFrEF therapy is clinically feasible and safe when implemented in selected patients and is associated with improved clinical outcomes.