Feasibility, efficacy and safety of early and rapid initiation of evidence-based treatment for patients with HFrEF- a real world experience of the "four drugs in four weeks" strategy

Abstract

Abstract Background Evidence-based treatment for heart failure with reduced ejection fraction (HFrEF) is associated with improved outcomes for patients. However, there is uncertainty as to how treatment with these foundational drugs should best be implemented. Objectives To evaluate whether early and rapid initiation of medications for patients with HFrEF using a 4 x 4 approach (4 pillars of HFrEF therapy in 4 weeks) is feasible, safe, and effective. Methods We recruited consecutive patients from April to July 2021 with a new diagnosis of HFrEF who were either assessed at our urgent HF clinic or had a recent HF hospitalisation. All patients had regular reviews (every 1-2 weeks, combination of telephone and face-to-face) at our hospital-based HF clinic by a HF consultant or senior HF specialist nurse for initiation and up-titration of guideline-recommended therapy including angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor neprilysin inhibitor (ARNI), beta blockers (BB), mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter inhibitor (SGLT2i). Results Of 100 patients approached, 19 patients were considered unsuitable for the 4x4 pathway (79% due to severe frailty or significant comorbidities). 81 patients were enrolled (61% male, median (IQR) age: 73 (67-82) years, median (IQR) NT-proBNP: 3764 (1597-7487) ng/L); 39 (48%) patients achieved "4 drugs at 4 weeks". Of the 42 patients who did not, 33 (79%) had contraindication to one or more of the drug classes at the outset, including renal impairment (28%), bradycardia (18%) and hyperkalaemia (15%). Patients who did not achieve "4 drugs at 4 weeks" were older, more symptomatic, and had higher NTproBNP and worse renal function. During a median follow up of 554 days, 6 (7%) patients died and 31 (38%) experienced the combined outcome of all-cause death / hospitalisation. Patients who did not achieve "4 drugs at 4 weeks", compared to those who did, had a 2.5 fold increased risk of the combined outcome (Figure 1). They were also less likely to be up-titrated to targeted doses of HF medications (Figure 2). There was noticeable improvement in NTproBNP with no significant change in renal function or systolic BP in both groups. Compared to those who did not achieve "4 drugs at 4 weeks", those who did showed larger improvement in LVEF (8% vs 2%) at 6 months. 5 patients (6%) experienced significant side effects during medication up-titration: 4 had symptomatic hypotension and 1 had hyperkalaemia. Conclusion The 4x4 strategy is clinically feasible and safe when implemented in selected patients with HFrEF and may be associated with improved outcomes. Our results support larger studies to further investigate the generalisability and effectiveness of the 4x4 strategy.