Early initiation of ezetimibe within 12 weeks of myocardial infarction was associated with reduced risks of major adverse cardiovascular events and cardiovascular death compared with delayed or no ezetimibe use, according to a nationwide analysis of 35,826 patients from the Swedish SWEDEHEART registry.
Among lipid-lowering therapy–naïve patients discharged on high-intensity statins between 2015 and 2022, 16.9% received ezetimibe early (within 12 weeks), 18.1% received it between 13 weeks and 16 months, and 65.0% did not receive ezetimibe during this period. High-intensity statin use was more than 98% in all groups. Over a median follow-up of 3.96 years, 2,570 patients experienced a major adverse cardiovascular event (MACE), defined as all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke.
At 1 year, MACE incidence per 100 patient-years was 1.79 with early combination therapy, 2.58 with late therapy, and 4.03 with no ezetimibe. In adjusted analyses, 3-year hazard ratios (HRs) for MACE were 1.14 (95% CI, 0.95–1.41) for late initiation and 1.29 (95% CI, 1.12–1.55) for no ezetimibe, using early initiation as the reference.
Cardiovascular mortality at 3 years was also higher in the delayed and no ezetimibe groups. HRs were 1.64 (95% CI, 1.15–2.63) for late use and 1.83 (95% CI, 1.35–2.69) for no use, relative to early initiation.
The study, published in the Journal of the American College of Cardiology as an open access article in 2025, used a clone-censor-weight approach to emulate a target trial and reduce immortal time bias. Statin adherence remained high throughout follow-up. At 1 year, 55% of patients in the early ezetimibe group achieved the LDL-C target of <1.4 mmol/L (<55 mg/dL) and a ≥50% reduction from baseline, despite having a higher median baseline LDL-C (3.8 mmol/L vs 3.1 mmol/L in the no-ezetimibe group).
Weighted risk differences in MACE for late vs early initiation were 0.6% at 1 year (95% CI, 0.1%–1.1%), 1.1% at 2 years (95% CI, 0.3%–2.0%), and 0.7% at 3 years (95% CI, −0.2% to 1.3%). For patients not receiving ezetimibe, the 3-year MACE difference was 1.9% (95% CI, 0.8%–3.1%). Cardiovascular death differences at 3 years were 0.8% for late vs early use and 1.6% for no use vs early use.
The number needed to treat (NNT) over 3 years to prevent one MACE was 53 (95% CI, 32–125) when comparing early use vs, no ezetimibe, and 143 (95% CI, 44–167) for early vs late use. Modeling projected that if all patients had received early ezetimibe, 477 additional MACE events might have been prevented in this cohort.
Patients not prescribed ezetimibe were generally older, had more comorbidities, and lower baseline LDL-C. A sensitivity analysis using skeletal fractures as a negative control outcome found no significant between-group differences, supporting the validity of the findings.
Between 2015 and 2021, the use of combination lipid-lowering therapy in Sweden increased from 14% to nearly 60%, although two-thirds of patients remained on statin monotherapy 16 months after MI.
The authors concluded that "MI care pathways should implement early combination therapy with statins and ezetimibe as standard care, because delaying use of combination LLT or using high-intensity statin monotherapy is associated with avoidable harm." They further noted that "implementation of cholesterol management after an MI, reducing variability in care, and improving prognosis are best served by moving away from a stepwise strategy."
The SWEDEHEART registry includes more than 90% of MI cases in Swedish patients under age 80. Patients with prior lipid-lowering therapy, familial hypercholesterolemia, or baseline LDL-C <1.4 mmol/L (<55 mg/dL) were excluded.
Limitations of the study include its observational design, the low rate of in-hospital ezetimibe initiation, and potential residual confounding despite rigorous modeling.
Full author disclosures are available in the study.
