LODESTAR

Treat-to-target LDL-C vs fixed high-intensity statin therapy in coronary artery disease
Targeting LDL-C 50–70 mg/dL was noninferior to routine high-intensity statin therapy for major cardiovascular outcomes in patients with CAD

Study design

  • Investigator-initiated, randomized, open-label, noninferiority trial
  • 12 centers in South Korea
  • 4,400 patients randomized
  • 98.7% completed 3-year follow-up
  • Noninferiority margin 3.0 percentage points
  • Primary outcome: all-cause death, MI, stroke, or any coronary revascularization at 3 years

Population

Included
  • Clinically diagnosed coronary artery disease
  • Stable ischemic heart disease or acute coronary syndrome
  • Mean age 65 years
  • 72% male
  • 33% diabetes
Clinical setting
  • Secondary ASCVD prevention
  • Patients eligible for long-term statin therapy
  • Both rosuvastatin and atorvastatin permitted

Interventions

Treat-to-target
  • LDL-C goal 50–70 mg/dL
  • Statin intensity adjusted according to LDL-C
  • 43% received moderate-intensity statin
  • 54% received high-intensity statin
n = 2,200
High-intensity statin
  • Rosuvastatin 20 mg daily
  • Or atorvastatin 40 mg daily
  • 92% remained on high-intensity therapy
n = 2,200

LDL-C achieved

Treat-to-target

Mean LDL-C 69.1 mg/dL over 3 years

High-intensity statin

Mean LDL-C 68.4 mg/dL over 3 years

Primary outcome

Death, MI, stroke, or coronary revascularization
8.1% with treat-to-target vs 8.7% with high-intensity statin
Absolute difference −0.6%
Upper boundary of 1-sided 97.5% CI 1.1%
P < 0.001 for noninferiority

3-year primary outcome

All-cause death, MI, stroke, or any coronary revascularization

10% 8% 6% 4% 2% 0%
8.1%
Treat-to-target
n = 2,200
8.7%
High-intensity
n = 2,200
8.1% vs 8.7%  |  Difference −0.6%  |  P < 0.001 for noninferiority

Treat-to-target LDL-C therapy met criteria for noninferiority

Secondary outcomes

All-cause death

2.5% vs 2.5%
P = 0.99

Myocardial infarction

1.6% vs 1.2%
P = 0.23

Stroke

0.8% vs 1.3%
P = 0.13

Prespecified secondary outcomes

No significant between-group differences

Safety

Post hoc composite safety outcome
6.1% with treat-to-target vs 8.2% with high-intensity statin
New diabetes, aminotransferase or CK elevation, or end-stage kidney disease
Absolute difference −2.1%, 95% CI −3.6 to −0.5, P = 0.009

Clinical interpretation

  • An LDL-C target of 50–70 mg/dL produced similar 3-year outcomes to routine high-intensity statin therapy
  • Similar LDL-C levels were achieved with substantially less high-intensity statin exposure
  • Supports tailoring statin intensity to achieved LDL-C rather than requiring high-intensity therapy in every patient
  • The trial does not show that moderate-intensity statins are equivalent when LDL-C remains above target
  • Getting LDL-C adequately low appears more important than the specific statin-intensity strategy used to get there

Limitations

  • Open-label treatment assignment
  • Conducted entirely in South Korea
  • Only about 60% of treat-to-target patients had LDL-C <70 mg/dL at most follow-up visits
  • Ezetimibe and other combination lipid-lowering therapy were infrequently used
  • 3-year follow-up may not capture longer-term differences between strategies
  • The favorable safety composite was post hoc and should be considered exploratory
Hong SJ, Lee YJ, Lee SJ, et al. Treat-to-target or high-intensity statin in patients with coronary artery disease: a randomized clinical trial. JAMA. 2023;329(13):1078–1087. doi:10.1001/jama.2023.2487. JAMA