Targeting LDL Cholesterol Below 55 mg/dL Beat the 70 mg/dL Target in Patients With Clogged Arteries

Table of Contents

• Key Points
• Why This Research Matters
• How the Study Was Conducted
• Who Took Part in the Study
• What Treatments Patients Received
• Key Finding 1: How Low Did Cholesterol Actually Go?
• Key Finding 2: Fewer Heart Attacks, Strokes, and Procedures
• Safety Results
• What This Means for Patients
• Limitations: What the Study Could Not Prove
• Practical Recommendations
• Frequently Asked Questions
• Source Information

Key Points

• In a trial of 3,048 patients with established cardiovascular disease, targeting LDL cholesterol below 55 mg/dL reduced cardiovascular events by 33% compared with targeting below 70 mg/dL over a median of 3 years.
• The benefit was driven mainly by nonfatal heart attacks and revascularization procedures, with safety outcomes similar between groups except fewer kidney-marker rises in the intensive group.
• Most of the extra benefit came from higher statin doses and adding ezetimibe; PCSK9 inhibitors were used by fewer than 2.5% of patients in either group.
• Not everyone reached the lower target: at 3 years, 60.8% of the intensive group hit below 55 mg/dL, but 85.2% were below 70 mg/dL, showing progress counts.
• The trial was open-label, lasted a median of 3 years, and enrolled mostly men in South Korea, so long-term effects and results in other populations remain uncertain.

Why This Research Matters

People who already have atherosclerotic cardiovascular disease (ASCVD — arteries narrowed by fatty plaque) face a high or very high risk of future heart attacks, strokes, and other cardiovascular events. For these patients, lowering low-density lipoprotein (LDL) cholesterol — often called "bad" cholesterol — is the central treatment goal.

Clinical guidelines have shifted over the past several years. They once advised patients with ASCVD to aim for an LDL cholesterol level below 70 mg per deciliter (1.8 mmol per liter). Now they advise a stricter target: below 55 mg per deciliter (1.4 mmol per liter).

The problem is the evidence. Previous randomized trials showed that high-intensity statins, or adding ezetimibe (a cholesterol-absorption blocker) or PCSK9 inhibitors (injectable drugs that help the liver clear LDL cholesterol) to a statin, lowers both LDL cholesterol and cardiovascular risk. But those trials were designed to test drugs, not specific target numbers. No randomized trial had directly compared a target of below 55 mg per deciliter with a target of below 70 mg per deciliter in patients with ASCVD.

That gap matters in daily practice. Many patients never reach the guideline-recommended target, and doctors have lacked head-to-head proof that the stricter goal is worth the extra effort and medication.

The Ez-PAVE trial was designed to answer this question directly. Its full name is "Effects of Ezetimibe Combination Therapy for Patients with Atherosclerotic Cardiovascular Disease — Randomized Comparison of LDL Cholesterol Targeting <70 mg per Deciliter vs. <55 mg per Deciliter."

How the Study Was Conducted

Ez-PAVE was an investigator-initiated, multicenter, open-label, randomized superiority trial conducted in South Korea. "Open-label" means that patients and their doctors knew which cholesterol target had been assigned. "Randomized superiority trial" means patients were assigned to groups by chance, and the researchers set out to test whether one strategy was genuinely better than the other.

A total of 3,048 patients were enrolled at 17 sites between January 2021 and July 2022. They were assigned in a 1:1 ratio — half to each group.

• Intensive-targeting group: 1,526 patients aimed for an LDL cholesterol level below 55 mg per deciliter (1.4 mmol per liter).
• Conventional-targeting group: 1,522 patients aimed for an LDL cholesterol level below 70 mg per deciliter (1.8 mmol per liter).

The trial protocol and its amendments were approved by the institutional review board or ethics committee at every participating site. Written informed consent was obtained from all patients before randomization.

Who Was Eligible

Patients could join if they were 19 to 80 years of age and had documented atherosclerotic cardiovascular disease. That meant at least one of the following:

• A previous acute coronary syndrome (heart attack or unstable angina)
• Stable angina confirmed by imaging or functional testing
• Previous coronary revascularization (procedures to reopen arteries) or revascularization of another artery
• Stroke or transient ischemic attack (TIA — a brief "warning stroke")
• Peripheral artery disease (blocked arteries in the legs or elsewhere outside the heart)

One key exclusion criterion was an LDL cholesterol level below 70 mg per deciliter in a patient not taking a statin. Full eligibility criteria appeared in the trial's supplementary appendix.

How Randomization Was Structured

Randomization used a Web response system with permuted-block randomization (blocks of 4 or 6) at each site. Patients were sorted, or "stratified," by three factors to keep the groups balanced:

1. Previous acute coronary syndrome (yes or no)
2. Presence of diabetes (yes or no)
3. Baseline LDL cholesterol level (below 100 mg per deciliter, or 100 mg per deciliter and above)

Within each target group, patients underwent a second randomization in a 1:1 ratio to either statin monotherapy (a statin alone) or combination therapy (a statin plus ezetimibe). Patients assigned to statin monotherapy were then randomly assigned again, 1:1, to receive either rosuvastatin or atorvastatin. These extra randomizations helped patients reach their targets promptly and kept the mix of statin types balanced, while preserving the main comparison between the two cholesterol targets.

Treatment Approach and Follow-Up

Investigators received basic instructions for starting and adjusting therapy. Increasing the statin dose and adding ezetimibe were recommended before PCSK9 inhibitors were considered. However, the primary goal was to reach the target safely and effectively, so final decisions — statin dose changes and the addition of ezetimibe or a PCSK9 inhibitor — were left to the treating physicians in both groups, with the reasoning documented in detail.

Follow-up visits took place at baseline, 1 month, and 1, 2, and 3 years after randomization. At each visit, researchers recorded general health, medication use, any end-point events or adverse events, and lipid profiles including LDL cholesterol. Safety laboratory tests were done at predefined time points.

Survival status was cross-checked against the Korean National Health Insurance database.

What Was Measured

The primary end point — the main result the trial was powered to detect — was a composite (combined) measure. It counted the first occurrence of any of the following within 3 years:

• Death from cardiovascular causes
• Nonfatal myocardial infarction (heart attack)
• Nonfatal stroke
• Any revascularization procedure
• Hospitalization for unstable angina

Secondary efficacy end points included each individual component of the primary end point separately, plus additional prespecified composite measures such as the combination of cardiovascular death, nonfatal heart attack, or nonfatal stroke.

Safety end points included new-onset diabetes (among patients who did not have diabetes at the start), worsening of glycemic control (blood sugar control, among patients who did have diabetes), statin-associated muscle symptoms that led to a change in dose or regimen, a diagnosis of cancer, cataract surgery, and elevations in aminotransferase (liver enzyme), creatinine (a kidney marker), or creatine kinase (a muscle enzyme).

An independent clinical-events committee, whose members did not know the group assignments or cholesterol levels, adjudicated all cardiovascular events, cases of new-onset diabetes, and cases of worsening glycemic control.

Statistical Plan

Researchers calculated that enrolling 3,048 patients would give the trial 80% power, at a two-sided alpha level of 0.05, to detect a 24.75% lower relative risk of a primary end-point event at 3 years in the intensive group. That calculation assumed a 3-year event incidence of 15% in the conventional-targeting group and a 15% loss to follow-up.

All primary analyses used the intention-to-treat population — everyone who was randomized, analyzed in the group they were assigned to. The 3-year cumulative incidence of events was estimated with the Kaplan–Meier method and compared with a log-rank test. Hazard ratios and 95% confidence intervals came from a Cox proportional-hazards regression model. The proportional-hazards assumption was tested with Schoenfeld residuals (P=0.92), meaning the assumption held up. A per-protocol analysis excluded patients with major protocol deviations. Competing-risk sensitivity analyses used the Fine–Gray subdistribution hazard model.

Subgroup analyses were prespecified for age, sex, body-mass index, previous acute coronary syndrome, coronary or other arterial revascularization, stroke or TIA, peripheral artery disease, hypertension, diabetes, chronic kidney disease, and baseline LDL cholesterol level. Importantly, the confidence intervals for secondary end points and subgroups were not adjusted for multiple comparisons, so those intervals should not be used to draw firm conclusions about treatment effects. No interim analyses were performed, and no values were imputed for missing data. A two-sided P value below 0.05 was considered statistically significant.

Who Took Part in the Study

The two groups were well balanced at the start. The mean age was 64.4±9.0 years, and 638 patients (20.9%) were women. The median baseline LDL cholesterol level was 76 mg per deciliter (interquartile range, 61 to 96), or 2.0 mmol per liter (interquartile range, 1.6 to 2.5).

Participants' cardiovascular histories were substantial:

• 1,694 patients (55.6%) had a previous acute coronary syndrome
• 1,474 patients (48.4%) had stable angina with imaging or functional studies
• 2,049 patients (67.2%) had undergone coronary or other arterial revascularization
• 117 patients (3.8%) had had a stroke or transient ischemic attack
• 266 patients (8.7%) had peripheral artery disease

Other baseline characteristics were similar between groups. About three quarters had hypertension (74.4% intensive vs. 72.5% conventional). Nearly 40% had diabetes in each group (39.6% vs. 39.6%). Chronic kidney disease was present in 6.0% versus 5.7%. Current smokers made up 22.8% versus 25.5%. Just under 80% of patients in each group were men (78.9% vs. 79.2%). Median body-mass index was 24.9 versus 24.7.

At enrollment, statin use was comparable: high-intensity statins in 23.1% versus 22.9%, moderate-intensity statins in 67.9% versus 68.2%, low-intensity statins in 0.7% versus 0.1%, and no statin in 8.4% versus 8.8%. Ezetimibe was already being taken by 29.8% versus 27.7%. Median baseline lipid values were also similar: LDL cholesterol 77 mg per deciliter (IQR 60 to 96) versus 75 (IQR 61 to 97); HDL cholesterol 46 (40 to 55) versus 47 (39 to 54); total cholesterol 143 (123 to 167) in both groups; and triglycerides 117 (87 to 159) versus 115 (83 to 163).

What Treatments Patients Received

More patients in the intensive group were treated with high-intensity statins — as expected, since reaching a lower target takes stronger therapy.

• High-intensity statin use at 1 month: 53.5% in the intensive group vs. 35.9% in the conventional group
• At 1 year: 54.0% vs. 34.3%
• At 2 years: 50.8% vs. 32.7%
• At 3 years: 48.4% vs. 32.3%

Ezetimibe use started out nearly identical — 49.7% vs. 50.0% at 1 month — then rose faster in the intensive group: 56.0% vs. 53.1% at 1 year, 61.2% vs. 52.5% at 2 years, and 66.6% vs. 56.7% at 3 years.

PCSK9 inhibitors were used by very few patients. In the intensive group, use was 0.2% at 1 month and 0.8%, 1.4%, and 2.3% at 1, 2, and 3 years. In the conventional group, use was 0.1% at 1 month and 0.5%, 0.5%, and 0.9% at 1, 2, and 3 years.

Over a median follow-up of 3.0 years (interquartile range, 3.0 to 3.0), 110 patients (3.6%) stopped LDL-lowering therapy or reduced its intensity despite not reaching their target. That included 62 patients in the intensive group and 48 in the conventional group. The main reason was an adverse event, reported in 85 patients (2.8%) overall — 50 in the intensive group and 35 in the conventional group. In addition, 14 patients (0.5%) withdrew consent and 5 patients (0.2%) were lost to follow-up.

Key Finding 1: How Low Did Cholesterol Actually Go?

LDL cholesterol fell in both groups and stayed separated throughout the trial.

• Intensive-targeting group: median LDL cholesterol during the trial of 56 mg per deciliter (IQR 48 to 67), or 1.4 mmol per liter (IQR 1.2 to 1.7)
• Conventional-targeting group: median LDL cholesterol of 66 mg per deciliter (IQR 58 to 76), or 1.7 mmol per liter (IQR 1.5 to 2.0)

The gap between groups stayed consistent throughout follow-up. That said, not everyone hit the assigned number. At 1 month, 31.2% of the intensive group and 59.4% of the conventional group had reached their target. At 1, 2, and 3 years, the percentages were 42.9%, 53.3%, and 60.8% in the intensive group, and 67.2%, 67.7%, and 68.1% in the conventional group.

A post hoc analysis (an analysis done after the trial was designed) showed something important: 74.1% of patients in the intensive group had an LDL cholesterol level below 70 mg per deciliter at 1 month, and 78.5%, 82.6%, and 85.2% did so at 1, 2, and 3 years. In other words, most intensive-group patients reached at least the old target, even if they did not reach the newer, tougher one.

Key Finding 2: Fewer Heart Attacks, Strokes, and Procedures

This is the headline result. Over a median follow-up of 3.0 years, a primary end-point event occurred in 100 patients in the intensive-targeting group — a Kaplan–Meier cumulative incidence of 6.6%, or roughly 1 in 15 patients.

In the conventional-targeting group, 147 patients had an event — a cumulative incidence of 9.7%, or roughly 1 in 10 patients.

The hazard ratio was 0.67 (95% confidence interval, 0.52 to 0.86; P=0.002 by log-rank test). In plain terms, the intensive strategy reduced the relative risk of these events by about 33%. The absolute difference was 3.1 percentage points, which translates to roughly 3 fewer events for every 100 patients treated to the lower target.

P=0.002 means there is about a 0.2% probability — 2 in 1,000 — that a difference this large arose by chance alone. The finding held up in the per-protocol analysis, which excluded patients with major protocol deviations.

Two individual components of the composite drove much of the benefit:

• Nonfatal heart attack: 0.8% in the intensive group vs. 1.7% in the conventional group (hazard ratio, 0.46; 95% CI, 0.23 to 0.91) — a 54% lower relative risk
• Any revascularization procedure: 4.8% vs. 7.5% (hazard ratio, 0.63; 95% CI, 0.47 to 0.84) — a 37% lower relative risk

Results for the other individual components — death from cardiovascular causes, nonfatal stroke, and hospitalization for unstable angina — were also reported in the trial publication. Because the trial was designed primarily to test the combined end point, the individual component results should be interpreted with the understanding that they were not adjusted for multiple comparisons.

Safety Results

Safety was a core part of the trial, and the news was reassuring. The incidence of prespecified safety end points was similar in the two groups, with one exception: fewer patients in the intensive-targeting group had a rise in creatinine, a marker used to monitor kidney function.

The safety end points the trial tracked included:

• New-onset diabetes in patients who did not have diabetes at enrollment
• Worsening blood sugar control in patients who already had diabetes
• Statin-associated muscle symptoms serious enough to prompt a dose or regimen change
• A diagnosis of cancer
• Cataract surgery
• Elevations in liver enzymes (aminotransferase), kidney markers (creatinine), or muscle enzymes (creatine kinase)

Roughly 2.8% of all patients (85 people) stopped or reduced their cholesterol-lowering therapy because of an adverse event, with 50 of those in the intensive group and 35 in the conventional group. This difference is modest and reflects the fact that the intensive group was generally on stronger treatment.

What This Means for Patients

The trial answers a question that patients and doctors have been asking for years: is the newer, stricter cholesterol target actually better, or is it just a number on a guideline page? The answer, from this randomized trial, is that it is better — at least over 3 years in patients with established cardiovascular disease.

The benefit was not trivial. Patients aiming for below 55 mg per deciliter had about one-third fewer cardiovascular events, including fewer heart attacks and fewer repeat procedures to open blocked arteries. The safety profile was comparable, which matters because many patients worry that "more aggressive" automatically means "more side effects."

Equally important is the practical message about how the target was reached. Most of the extra benefit came from ordinary, widely available treatments — higher doses of statins and the addition of ezetimibe — not from expensive injectable drugs. PCSK9 inhibitors were used by fewer than 2.5% of patients in either group. This means the strategy is feasible for most patients, not just those with access to costly medications.

There is also a reassuring detail for patients who find it hard to hit a tough number. Nearly three quarters of intensive-group patients were below 70 mg per deciliter at 1 month, and that proportion climbed to 85.2% by 3 years. Progress toward the target counts.

Limitations: What the Study Could Not Prove

Every trial has boundaries, and understanding them helps patients and doctors judge how to apply the results.

• The trial was open-label. Patients and doctors knew which target was assigned. This can influence behavior, such as how aggressively medications get adjusted. An independent committee adjudicated the cardiovascular events and diabetes outcomes without knowing group assignments, which reduces — but does not eliminate — this concern.
• Treatment decisions were left to physicians. Statin doses and the addition of ezetimibe or PCSK9 inhibitors were not rigidly fixed, so the comparison is between strategies (target numbers), not between specific drug regimens.
• Follow-up was relatively short. The median was 3.0 years. Longer-term effects of very low LDL cholesterol levels — on cognition, muscle, liver, and diabetes risk over decades — remain incompletely understood.
• Subgroup results are exploratory. The investigators explicitly noted that confidence intervals for subgroup and secondary analyses were not adjusted for multiple comparisons. So a striking result in one subgroup (say, patients with diabetes) cannot be treated as proven.
• The groups did not separate perfectly. The achieved median LDL levels were 56 mg per deciliter and 66 mg per deciliter — a real difference, but not the full 15 mg per deciliter gap the targets imply. The true benefit of fully achieving a below-55 target could be larger or smaller than what was observed.
• The population was specific. All patients were enrolled in South Korea, mean age was 64.4 years, and roughly 79% were men. Benefits and risks may differ in other populations, in women, and in older or younger patients.

Practical Recommendations

If you have atherosclerotic cardiovascular disease, here is how to use this information in conversation with your care team.

1. Ask for your LDL cholesterol number and your target. Current guidelines for patients with ASCVD recommend a target below 55 mg per deciliter (1.4 mmol per liter). It helps to know where you stand and how far you are from that goal.
2. Know that reaching the target usually does not require exotic drugs. In this trial, the strategy relied mainly on stronger statin doses plus ezetimibe. PCSK9 inhibitors were used in fewer than 2.5% of patients.
3. Do not stop or reduce your medication on your own. In the trial, fewer than 3% of patients stopped therapy because of side effects. If you have muscle aches or other symptoms, tell your doctor — regimens can often be adjusted rather than abandoned.
4. Keep your follow-up appointments. This trial checked cholesterol and safety labs at 1 month and then annually for 3 years. Regular monitoring is how targets get reached safely.
5. Treat cholesterol as one part of a bigger picture. In this trial, about 73% of patients had high blood pressure, 40% had diabetes, and about a quarter smoked. Controlling blood pressure, blood sugar, and tobacco use all matter.
6. Be patient with the process. Only about 31% of patients in the intensive group hit below 55 mg per deciliter at 1 month. By 3 years, 60.8% had. Treatment is a marathon, not a sprint.

Frequently Asked Questions

What was the main finding of the Ez-PAVE trial?

In a trial of 3,048 patients with established atherosclerotic cardiovascular disease, aiming for an LDL cholesterol below 55 mg/dL reduced the risk of cardiovascular death, heart attack, stroke, repeat revascularization, or hospitalization for unstable angina by 33% compared with aiming below 70 mg/dL over a median of 3 years. Safety outcomes were similar between groups.

Who was eligible to participate in the Ez-PAVE trial?

Patients aged 19 to 80 with documented atherosclerotic cardiovascular disease, including a previous heart attack or unstable angina, stable angina confirmed by testing, prior revascularization, stroke or transient ischemic attack, or peripheral artery disease. One key exclusion was an LDL cholesterol below 70 mg/dL in a patient not taking a statin.

What treatments were used to reach the lower cholesterol target?

The strategy relied mainly on higher doses of statins and adding ezetimibe. In the intensive group, high-intensity statin use was about 54% at 1 year versus 34% in the conventional group, and ezetimibe use rose to 66.6% versus 56.7% at 3 years. PCSK9 inhibitors were used by fewer than 2.5% of patients in either group.

What were the risks or side effects of aiming for the lower LDL target?

Safety outcomes were similar between the two groups, except fewer patients in the intensive group had a rise in creatinine, a kidney marker. About 2.8% of all patients stopped or reduced cholesterol-lowering therapy because of an adverse event—50 in the intensive group and 35 in the conventional group. This difference was modest.

How low did LDL cholesterol actually go in each group?

During the trial, the intensive group had a median LDL cholesterol of 56 mg/dL, while the conventional group had a median of 66 mg/dL. The gap stayed consistent. At 3 years, 60.8% of the intensive group and 68.1% of the conventional group reached their assigned target, but 85.2% of the intensive group were below 70 mg/dL.

What does a 33% relative risk reduction mean for me?

It means that over a median of 3 years, patients aiming for the lower target had about one-third fewer cardiovascular events compared with those aiming for the higher target. The absolute difference was 3.1 percentage points, or roughly 3 fewer events for every 100 patients treated to the lower target.

What are the limitations of this trial?

The trial was open-label, so patients and doctors knew the assigned target. Follow-up was relatively short at a median of 3 years, and long-term effects of very low LDL cholesterol remain incompletely understood. The population was specific—all in South Korea, mean age 64.4 years, and about 79% men—so results may differ in other groups.

If I have clogged arteries and my doctor says an LDL below 70 mg/dL is fine, when should I get a second opinion about aiming below 55 mg/dL?

A second opinion is reasonable when your LDL target is set at below 70 mg/dL despite established atherosclerotic cardiovascular disease. In a randomized trial of 3,048 such patients, aiming below 55 mg/dL lowered the relative risk of cardiovascular death, heart attack, stroke, revascularization, or hospitalization for unstable angina by about 33% over a median of 3.0 years (6.6% vs. 9.7%), with similar safety. Most of that benefit came from higher statin doses plus ezetimibe, not injectable drugs. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Intensive LDL Cholesterol Targeting in Atherosclerotic Cardiovascular Disease

Authors: Yong-Joon Lee, M.D.; Seung-Jun Lee, M.D.; Jin Won Kim, M.D.; Sang-Hyup Lee, M.D.; Gwang-Sil Kim, M.D.; Jae Hyoung Park, M.D.; Jin-Man Cho, M.D.; Woong Chol Kang, M.D.; Hyuck-Jun Yoon, M.D.; Won Ho Kim, M.D.; Seung-Jin Lee, M.D.; Jin Bae Lee, M.D.; Ji-Yong Jang, M.D.; Sanghoon Shin, M.D.; Ik Hyun Park, M.D.; Sung Uk Kwon, M.D.; Sunwon Kim, M.D.; Sung-Jin Hong, M.D.; Chul-Min Ahn, M.D.; Jung-Sun Kim, M.D.; Young-Guk Ko, M.D.; Donghoon Choi, M.D.; Myeong-Ki Hong, M.D.; Yangsoo Jang, M.D.; and Byeong-Keuk Kim, M.D., for the Ez-PAVE Investigators.

Publication: The New England Journal of Medicine, April 9, 2026, Volume 394, Number 14, pages 1365–1375. Published online March 28, 2026. DOI: 10.1056/NEJMoa2600283. Copyright © 2026 Massachusetts Medical Society.

Trial registration: Ez-PAVE, ClinicalTrials.gov number NCT04626973.

Funding: The Cardiovascular Research Center (South Korea) and Yuhan. The funders had no role in trial design, data collection or analysis, interpretation of results, or manuscript writing.

This patient-friendly article is based on peer-reviewed research. It summarizes a single randomized clinical trial and does not replace personalized medical advice. Please discuss any changes to your cholesterol treatment with your own clinician.