LDL cholesterol and clinical outcomes in heart failure with reduced ejection fraction a competing risk analysis

While low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD), its prognostic role in heart failure with reduced ejection fraction (HFrEF) remains controversial. This study aimed to investigate the association between baseline LDL-C levels and ischemic cardiovascular events or all-cause mortality in HFrEF patients, with further stratification by ischemic or non-ischemic etiology.

Using data from the HF-ACTION trial, we analyzed 1,274 patients with chronic stable HFrEF, categorized into low LDL-C (< 100 mg/dL) and high LDL-C (≥ 100 mg/dL) groups. The primary endpoints were a composite of ischemic cardiovascular events (myocardial infarction, unstable angina, ischemic stroke, or transient ischemic attack) and all-cause mortality. Cox proportional hazards and Fine-Gray competing risk models were employed to assess the association between LDL-C and outcomes, with subgroup analysis by HF etiology.

Over a median follow-up of 2.9 years, 184 (14.4%) patients experienced ischemic events, and 213 (16.7%) died. Traditional survival analysis showed that the low LDL-C group had a significantly higher risk of all-cause mortality (unadjusted HR = 1.82, 95% CI 1.35-2.45, P < 0.001; adjusted HR = 1.57, 95% CI 1.15-2.16, P = 0.005). However, LDL-C levels were not associated with ischemic events (unadjusted HR = 1.06, 95% CI 0.79-1.43, P = 0.696; adjusted HR = 0.92, 95% CI 0.67-1.26, P = 0.589). Competing risk analysis confirmed these findings, and subgroup analysis revealed no significant interaction between LDL-C and HF etiology (P_interaction>0.05).

In chronic stable HFrEF, lower baseline LDL-C (< 100 mg/dL) is associated with higher all-cause mortality but not with ischemic events. The net benefit of lipid-lowering therapy in ischemic HFrEF remains uncertain and merits validation in phenotype-specific randomized trials.