Another Push for Upfront Ezetimibe-Statin Combo Soon After MI

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Swedish study suggests more MACE with delayed addition of ezetimibe to statins after heart attack

by
Nicole Lou, Senior Staff Writer, MedPage Today
April 14, 2025

Adding ezetimibe (Zetia) therapy to statins early after a heart attack improved outcomes, Swedish national records suggested.

With statins almost universally used in this setting, people who also got upfront ezetimibe in the first 12 weeks after the index myocardial infarction (MI) had fewer major adverse cardiovascular events (MACE) in the first and second years after initiation compared with those who waited 13 weeks to 16 months to start the combination (absolute difference 0.6% and 1.1%, both P<0.01).

Although that difference in death, MI, and stroke lost significance at 3 years compared with late combination (0.7 percentage points, P=0.18), early add-on ezetimibe did remain superior to no ezetimibe at all (1.9 percentage points, HR 1.29, 95% CI 1.12-1.55), reported Margret Leosdottir, MD, PhD, of Skåne University Hospital in Malmö, Sweden, and colleagues in the Journal of the American College of Cardiology.

Additionally, early ezetimibe was linked to fewer cardiovascular deaths at 3 years relative to late combination (HR 1.64, 95% CI 1.15-2.63) and no ezetimibe at all (HR 1.83, 95% CI 1.35-2.69).

Given that approximately 75-80% of MI patients failed to achieve LDL cholesterol goals with statins alone and that the combo lowers LDL cholesterol beyond what statins can achieve alone, the analysis of the large SWEDEHEART registry thus lends additional support to the concept that ezetimibe upfront combination therapy is better for high-risk patients and should be the initial approach after MI, Leosdottir’s team argued, not the guideline-recommended stepwise therapy starting with statins alone.

“[I]t’s often the case that this escalation takes too long, it’s ineffective and patients are lost to follow-up,” Leosdottir said in a press release.

“When all evidence is considered, we think 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, which only delays the inevitable” need for combination therapy for most patients, Leosdottir and colleagues urged.

A “reasonable and pragmatic” approach might be to start even before hospital discharge, suggested an accompanying editorial by Clara Chow, MBBS, PhD, of the University of Sydney, and colleagues.

While the researchers characterized ezetimibe as an inexpensive but underutilized therapy, they did report a rising proportion of MI survivors receiving combination therapy within 16 months, from approximately 14% in 2015 to almost 60% in 2021.

The group also cited the relatively few safety concerns of bringing LDL cholesterol very low with combination therapies.

“Future studies could look more closely at side effect profiles of differing approaches and impact on adherence and clinical inertia,” suggested Chow’s group. “It is also relevant to note that moderate-intensity statin in combination with ezetimibe is at least noninferior to high-intensity statin.”

Leosdottir’s observational study used a target trial emulation design using data from the SWEDEHEART registry on 35,826 adults up to age 80 years who had been hospitalized for MI in 2015-2022 without any preexisting lipid-lowering therapy (e.g., statins, ezetimibe, or PCSK9 inhibitors).

They were divided into patients who had ezetimibe added to statins ≤12 weeks after discharge (early combination therapy; 16.9%), ezetimibe added from 13 weeks to 16 months (late combination therapy; 18.1%), or no ezetimibe within the first 16 months (65.0%).

High-intensity statins were prescribed at discharge to more than 98% across groups. At 1 year, 85% had filled a prescription for any statin, and fewer than 1.0% had filled a prescription for a PCSK9 inhibitor.

Study participants had a median age of 65.1 years, and 26.0% of them were women. Compared with patients receiving ezetimibe combination therapy at some point, the no-ezetimibe group was older, had more comorbidities, and had lower baseline LDL cholesterol (3.1 vs >3.5 mmol/L for the other two groups).

The investigators acknowledged the limited duration of follow-up in the study and the possibility of residual confounding due to the study’s observational design.

Chow’s group agreed that “it is very difficult to rule out selection bias completely. For example, it could be that doctors were more likely to prescribe intense combination treatments to patients more willing to take intense therapies, who may in turn be more likely to adhere, afford, and use intense therapies, all of which are predictors of good outcomes.”

Even so, Leosdottir and colleagues said, it would be ethically challenging to conduct a more rigorous randomized controlled trial in which a known effective therapy is withheld for some time in some patients.