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

Q: What are the key findings of this study?

Four-pillar medication use in HFrEF, even at off-label low doses, significantly reduced all-cause mortality or HF hospitalization compared to no medications (21.6% vs 47.5%; P<0.001).

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Heart failure with reduced ejection fraction (HFrEF) (n=947). Intervention: Four-pillar medications (RAS inhibitors, beta-blockers, aldosterone antagonists, SGLT2 inhibitors) vs. No medications. Primary outcome: All-cause mortality HF hospitalization (p=< 0.001).

Q: What does this research mean for the field?

Off-label low-dose RAS inhibitors reduce heart failure hospitalization by 59.1% and mortality by 59.1% compared to non-users in HFrEF patients over 12 months. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

M Kim; S K Lee; J Y Choi; S W Han; M S Park; S E Kim; Y H Kim; S H Jo; S E Kim; S H Choi; S M Park; E J Kim

doi:10.1093/eurheartj/ehaf784.1261

November 1, 2025European Heart Journal

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

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Key result

Off-label low-dose four-pillar HFrEF therapy is linked to ~55% fewer major events vs no meds.

P<0.001
n=947

Why the study?

Four-pillar HFrEF medications are often initiated at off-label low doses rather than guideline-recommended doses, but the clinical impact of this practice is unclear.

Does off-label low-dose initiation of four-pillar medications reduce all-cause mortality or HF hospitalization in patients with HFrEF?

Study Design

Type

Cohort (n=947)

Multicenter

Yes

Structured PICO

Does off-label low-dose initiation of four-pillar medications reduce all-cause mortality or HF hospitalization in patients with HFrEF?

P

Population

947 consecutive patients with HFrEF (mean age 65.0 years, 31.5% women) followed for a mean of 12 months.

E

Exposure

Off-label low-dose initiation of four-pillar medications (RAS inhibitors, beta-blockers, aldosterone antagonists, SGLT2 inhibitors)

C

Comparator

Non-users or patients receiving fewer four-pillar medications

O

Outcome

Composite of all-cause mortality or HF hospitalization during 12 months follow-upcomposite

Main Result

Absolute Event Rate: 21.6% vs 47.5%

p-value: p=< 0.001

In patients with HFrEF, initiation of four-pillar medications even at off-label low doses is associated with significant reductions in mortality and heart failure hospitalization compared to non-use.

Implication

May support low-dose four-pillar initiation in HFrEF; extends observational data but leaves randomized confirmation open.

Discussion

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Cite This Study

Kim et al. (2025) conducted a cohort in Heart failure with reduced ejection fraction (HFrEF) (n=947). Four-pillar medications (RAS inhibitors, beta-blockers, aldosterone antagonists, SGLT2 inhibitors) vs. No medications was evaluated on All-cause mortality HF hospitalization (p=< 0.001). Four-pillar medication use in HFrEF, even at off-label low doses, significantly reduced all-cause mortality or HF hospitalization compared to no medications (21.6% vs 47.5%; P<0.001).

synapsesocial.com/papers/698585678f7c464f23008bb0 https://doi.org/10.1093/eurheartj/ehaf784.1261