Off-label low-dose therapy in heart failure reduced ejection fraction: can we achieve the benefits of the four pillars?

초록

Background: Guidelines recommend the use of these agents and titration to their target doses. However, in real-world clinical practice, the implementation of four-pillar (4P) therapy is often limited, and achieving target doses remains challenging. Consequently, these medications are sometimes initiated and continued at off-label low doses rather than the guideline-recommended starting doses. This study investigates the clinical impact of off-label low-dose initiation of four-pillar medications in HFrEF patients. Methods: We analyzed the data from a prospective, observational multicenter cohort for HF: Steady Movement with Innovating LEadership for Heart Failure (SMILE-HF) registry. Overall, 947 consecutive patients with HFrEF were included. The primary outcome was all-cause mortality HF hospitalization during 12 months follow-up. Results: At baseline, the mean age was 65.0±15.9 years, 31.5% were women, the mean left ventricular ejection fraction was 27.8±8.1%. The 70.3% of patients were taking RAS inhibitors, 74.6% beta-blockers, 57.6% aldosterone antagonists, and 40.3% sodium-glucose cotransporter-2 (SGLT2) inhibitors. The distribution of 4P medication usage in this study population revealed significant variations in treatment implementation. A notable 8.4% of patients received none of the four recommended medications, 10.1% were on one, 28.8% on two, 35.5% on three, and only 17.1% received full four-pillar therapy. No patients achieved the target dose for all four-pillar medications. During the mean 12-month follow-up, 103 patients (10.9%) were readmitted due HF aggravation and 35 paitents (3.7%) were expired. The primary outcome showed a significant inverse relationship with the number of prescribed four-pillar medications (P < 0.001, left figure), with event rates decreasing as the number of prescribed medications increased (47.5% with no medications vs. 21.6% with four). Subgroup analysis revealed a significant association between individual medication classes and outcomes (right figures). Patients on low-dose RAS inhibitors had a significantly lower event rate (12.4%) compared to non-users (30.3%, P < 0.001), with further reductions seen at routine and target doses. A similar pattern was observed for beta-blockers (P < 0.001) and aldosterone antagonists (P = 0.006). However, SGLT2 inhibitors showed a trend to improve outcome in target dose. However, follow-up echocardiography (n=415) showed that an improvement in LVEF of ≥10% was more frequently observed in patients who had achieved the target dose of each medication. (Target dose RASi= 79.4%, BB= 72.5%, MRA=61.8%, and SGLT2i=64.8% Conclusion: In this study, the use of four-pillar medications was strongly associated with clinical outcomes. Although the use of off-label low-dose therapy was limited, it demonstrated a meaningful improvement in clinical outcomes, reinforcing the importance of early and individualized treatment strategies