Effect of early versus late statin and ezetimibe combination therapy on MACE after MI

In a SWEDEHEART registry analysis of >35,000 statin-treated patients with a recent MI, early addition of ezetimibe was associated with a lower MACE risk compared with late ezetimibe initiation or no combination therapy.

This summary is based on the publication of Leosdottir M, Schubert J, Brandts J, et al. - Early Ezetimibe Initiation After Myocardial Infarction Protects Against Later Cardiovascular Outcomes in the SWEDEHEART Registry. J Am Coll Cardiol. 2025 Apr 22;85(15):1550-1564. doi: 10.1016/j.jacc.2025.02.007.

Introduction and methods

Background

In patients with MI, combination lipid-lowering therapy (LLT) with statins and ezetimibe initiated before hospital discharge reduced LDL-c levels and improved CV outcomes compared with statin monotherapy [1]. Yet, clinical guidelines recommend a stepwise approach to lower LDL-c levels, starting with high-intensity statins early after MI and treatment escalation after subsequent LDL-c measurements, with addition of ezetimibe first and then PCSK9 inhibitors for patients failing to achieve LDL-c goals [2-4].

Aim of the study

The authors assessed the effects of early statin and ezetimibe combination therapy versus delayed addition of ezetimibe to statin therapy on CV outcomes in post-MI patients in real-world clinical practice.

Methods

In this observational study, prospectively collected data of 35,826 LLT-naïve patients (aged 18–79 years) hospitalized for MI in Sweden from January 1, 2015, to September 23, 2022, and with statin therapy at discharge were collected from the SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry. Exclusion criteria included baseline LDL-c <1.4 mmol/L (<55 mg/dL). Median follow-up time was 3.96 years (Q1–Q3: 2.15–5.81), during which 2570 participants experienced MACE.

The following 3 exposure groups were defined: (1) early combination LLT, with ezetimibe dispensed ≤12 weeks after discharge (i.e., reference group; n=6040; 16.9%); (2) late combination LLT, with ezetimibe dispensed 13 weeks–16 months after discharge (n=6495; 18.1%); and (3) no ezetimibe dispensed during the first 16 months after discharge (n=23,291; 65.0%). To minimize potential confounding and immortal time bias, the authors used the target trial emulation framework with a clone-censor-weight approach to mimic a hypothetical RCT based on observational data.

Outcomes

The primary endpoint was MACE, consisting of all-cause mortality, nonfatal MI, and nonfatal stroke. Secondary endpoints included the individual components of the primary endpoint and CV death.

Main results

• At 1 year, the unadjusted incidence rate of MACE (per 100 patient-years) was 1.79 in patients receiving early ezetimibe combination therapy, 2.58 in those receiving late combination LLT, and 4.03 in those with no ezetimibe.
• Compared with patients with early combination LLT, the weighted risk difference for MACE in patients with late combination LLT was 0.6% (95%CI: 0.1%–1.1%; P<0.01) at 1 year, 1.1% (95%CI: 0.3%–2.0%; P<0.01) at 2 years, and 0.7% (95%CI: –0.6% to 2.3%; P=0.18) at 3 years. Over 3-year follow-up, the adjusted HR was 1.14 (95%CI: 0.95–1.41).
• For patients not taking ezetimibe, the weighted risk difference for MACE compared with the reference group was 0.7% (95%CI: 0.2%–1.3%; P<0.01) at 1 year, 1.6% (95%CI: 0.8%–2.5%; P<0.01) at 2 years, and 1.9% (95%CI: 0.8%–3.1%; P<0.01) at 3 years. The adjusted 3-year HR was 1.29 (95%CI: 1.12–1.55).
• The cumulative incidence rates of the individual components of the primary endpoint showed a similar pattern, with patients not receiving ezetimibe having the highest risks compared with the reference group.
• Compared with patients with early combination LLT, the risk of CV death at 3 years was increased in both participants with late combination LLT (adjusted HR: 1.64; 95%CI: 1.15–2.63) and the group with no ezetimibe (adjusted HR: 1.83; 95%CI: 1.35–2.69).
• Hypothetically, if all patients received early combination LLT, this could prevent 477 MACE.

Conclusion

This observational study using SWEDEHEART registry data of >35,000 LLT-naïve patients with a recent MI indicated that early addition of ezetimibe (≤12 weeks after hospital discharge) to statin therapy was associated with a lower risk of MACE compared with late ezetimibe initiation (13 weeks–16 months after discharge) or no combination therapy. The authors note that the 2023 ESC Guidelines for the management of acute coronary syndromes do suggest considering combination therapy with a high-dose statin and ezetimibe during hospitalization of ACS patients (Class II, Level of Evidence B recommendation) [5].

Find this article online at J Am Coll Cardiol.

References

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3. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111–188.
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5. Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44:3720–3826.