Atherosclerotic cardiovascular disease patients starting treatment with statin monotherapy had rates of myocardial infarction (MI) and stroke that were over similar at three years to those who started with a combination therapy using a statin plus ezetimibe, when medications were adjusted to reach an assigned goal for low-density lipoprotein (LDL) cholesterol, according to the findings of a prespecified secondary analysis of the randomised Ez-PAVE trial.
This and other findings from the analysis were presented at the American Heart Association (AHA) 2026 scientific session (6–9 November, Chicago, USA) and published simultaneously in Circulation.
“Lowering high LDL is among the most effective ways to reduce the risk of heart attack and stroke,” said study author Byeong-Keuk Kim (Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea). “Doctors can lower LDL cholesterol with a statin alone or in combination with ezetimibe, which lowers cholesterol more. However, it remains unclear if starting both together reduces heart attacks, strokes and other heart issues compared to starting with a statin alone and adding additional medications like ezetimibe later. This is a crucial question for doctors.”
Researchers in the Ez-PAVE study enrolled more than 3,000 adults with heart or blood vessel disease across 17 study sites in South Korea. At enrolment, participants were randomly assigned to one of two LDL cholesterol goals: a lower LDL goal (less than 55mg/dL) or a conventional LDL goal (less than 70 mg/dL). Participants were also randomly assigned to start treatment with either a statin plus ezetimibe or a statin alone, with about half of participants in each group.
In both groups, medication doses were adjusted during follow-up to help reach the target LDL goals. During follow-up visits, lipid-lowering therapy could be modified in either group according to a predefined protocol, based on each participant’s LDL cholesterol level relative to the assigned target. Medication changes were permitted in both directions, from monotherapy to combination therapy, and from combination therapy to monotherapy, as long as they were consistent with the protocol. Then, all participants’ results were analysed according to the group to which they were originally assigned.
At three years, after annual follow-up, the analysis reviewed rates of heart-related death, heart attack, stroke, procedures to reopen blocked arteries and hospitalisation for worsening chest pain for all participants.
Patients receiving combination treatment with a statin plus ezetimibe achieved lower LDL cholesterol levels than those treated with statins alone. For the lower cholesterol goal group (<55mg/dL), average LDL was 53mg/dL with combination therapy vs. 62mg/dL for those in the statin-only group.
For the conventional LDL goal group (<70mg/dL), average LDL was 63mg/dL with combination therapy vs. 70mg/dL for the statin-only group.
Many participants who started treatment with only a statin eventually had ezetimibe added during follow-up, as directed by the study protocol, to reach their LDL goal: about one in three people (more than 34%) in the lower-goal LDL group, and about one in four people (nearly 25%) in the conventional LDL-goal group.
During the three-year study, the rate of heart disease-related death, heart attack, stroke, revascularisation or hospitalisation for worsening chest pain was 8.5% among people who started on combination therapy vs. 7.9% among those in the statin-only group. This small difference is not statistically meaningful.
Side effects and safety concerns were similar whether adults started on combination therapy or statin-only treatment.
“We expected that starting with combination therapy would lead to fewer heart attacks, strokes and other heart problems, but this was not the case,” Kim said. “A previous large study published in the New England Journal of Medicine showed that adding ezetimibe to a statin reduced the rate of cardiovascular deaths, non-fatal heart attacks, unstable angina requiring rehospitalization, coronary revascularisation or non-fatal stroke. However, that study was not primarily designed to adjust treatment to reach a target LDL cholesterol goal, and medication dose changes were limited. We believe the difference was that in our study, medication doses in both treatment groups were adjusted to reach the target LDL cholesterol goal.”
“Starting with a statin and adding ezetimibe as needed appears to be a reasonable strategy for people with long-term, stable heart or blood vessel disease whose cholesterol levels are checked regularly and medication doses are adjusted to reach their goals,” said Kim. “Starting with combination therapy can lower cholesterol more quickly and may be a practical option, particularly for people whose LDL cholesterol numbers are much higher than their goal LDL level.”
