NEW ORLEANS — Lowering low-density lipoprotein (LDL) cholesterol level to < 40 mg/dL — well beneath current post-stroke guideline targets — reduced major cardiovascular events without increasing hemorrhagic stroke risk in patients with prior ischemic stroke.
Results from the FOURIER study, which included more than 5000 patients, showed that individuals with LDL levels < 40 mg/dL had a 31% lower rate of major adverse cardiovascular events (MACEs) — including stroke, cardiovascular death, myocardial infarction, hospitalization for unstable angina, and coronary revascularization — than patients whose LDL levels were ≥ 70 mg/dL. Those with LDL levels < 40 mg/dL also experienced a 27% reduction in all strokes and a 25% reduction in subsequent ischemic strokes.
Incidence of the composite endpoint and the individual outcomes of all stroke and ischemic stroke also decreased in a stepwise manner as LDL levels decreased.
In addition, there was no association between occurrence of hemorrhagic stroke and lower LDL levels, in contrast with what some prior studies have suggested.
“The main finding is that the lower the achieved LDL in this population, the better the cardiovascular outcome; there didn’t appear to be a floor to the effect,” senior investigator Robert P. Giugliano, MD, with the TIMI Study Group at the Brigham and Women’s Hospital and professor at the Harvard Medical School, both in Boston, told Medscape Medical News.
“And no matter what LDL level patients achieved, there was really no difference in safety endpoints,” he added.
Giugliano believes the results could be practice changing. “I am already advocating to my patients with ischemic stroke that we try to get the LDL down very low, if at all possible,” he said.
The findings were presented on November 8 at the American Heart Association (AHA) Scientific Sessions 2025 and were published online on November 3 in Circulation.
An Ongoing Debate
Although patients with a history of ischemic stroke are at an increased risk for recurrence and other MACEs, debate continues over the benefits and potential safety concerns of intensive LDL lowering — and just how low is too low.
A guidance paper on the management of blood cholesterol was issued 7 years ago by the AHA, the American College of Cardiology (ACC), and 10 other organizations. The 2018 AHA/ACC/multi-society guidelines discussed an LDL threshold of 70 mg/dL in high-risk individuals.
As reported at the time by Medscape Medical News,guidelines released in 2019 from the European Society of Cardiology(ESC) and European Atherosclerosis Society suggested an LDL of < 55 mg/dL in very high-risk patients, defined as those with conditions such as atherosclerotic cardiovascular disease (ASCVD). The ESC released updated guidance in August of this year.
Although some earlier studies — including certain statin trials and a 2019 analysis in patients without prior stroke or myocardial infarction — have linked very low LDL levels to a higher risk for hemorrhagic stroke, other research has indicated that intensive LDL lowering can be safe, at least in specific patient populations.
The current investigators aimed to evaluate the effects of intensive LDL lowering specifically in patients with a history of ischemic stroke, excluding those who had experienced a stroke within the previous 30 days.
The original multinational FOURIER randomized controlled trial enrolled more than 27,000 patients with stable ASCVD to compare the PCSK9 inhibitor evolocumab with placebo, with initial results published in 2017. FOURIER-OLE was an open-label extension of the original study.
For the current analysis, the investigators analyzed data of 5291 FOURIER and FOURIER-OLE participants (mean age, 65 years; 66% men) with a prior ischemic stroke over an average of 7-8 years. The primary endpoint was the composite of the five MACE conditions.
A Reasonable Target?
At the end of follow-up, 40.1% of participants achieved LDL of ≥ 70 mg/dL — while 9.6% achieved 55 to < 70 mg/dL, 11.1% achieved 40 to < 55 mg/dL, 26.6% achieved 20 to < 40 mg/dL, and 12.6% achieved < 20 mg/dL.
Lower LDL levels to < 40 mg/dL had a “monotonic relationship” with lower adjusted annualized incidence rates of the composite primary endpoint (P for trend < .001) and all stroke and recurrent ischemic stroke (P for trend = .002 for both).
Adjusted incidence rate ratios for the composite primary endpoint, all stroke, and ischemic stroke for those with LDL levels < 40 mg/dL vs those with levels ≥ 70 mg/dL were 0.69, 0.73, and 0.75, respectively.
Hemorrhagic strokes “were infrequent and unrelated” to achieved LDL level (P for trend = .85), the researchers noted.
“These findings support the concept that more intensive [LDL] lowering in patients with prior ischemic stroke may be warranted,” they wrote, adding that a level below 40 mg/dL may represent “a reasonable target.”
The investigators noted that more randomized controlled trials are now needed to definitively determine optimal LDL goals in this patient population.
Lower Is Better
Commenting on the study for Medscape Medical News, Laurence Sperling, MD, Katz professor in preventive cardiology at the Emory University School of Medicine and founder of the Emory Center for Heart Disease Prevention in Atlanta, said the findings are particularly important given the ongoing questions and concerns about this issue within both the medical and patient communities.
“This was a well-designed study with the right population in which to examine these questions. And I think it’s strong on both ends. In showing that lower [LDL] is better for cardiovascular disease risk reduction in high-risk individuals and that lower appears to be safe,” Sperling said.
He added that the trial had a “higher strength of evidence” than some previous observational or epidemiologic studies that suggested increased risk for adverse events. “Although we can’t use a single study to be definitive,” it follows along with several recent trials that have shown no signals of increased risk for hemorrhagic stroke, he said.
Sperling, who was not involved with the research, was on the writing committee of the 2018 AHA/ACC/Multi-Organization Guideline on the Management of Blood Cholesterol.
He noted that an update to that guideline is currently in progress and estimated that it will be released sometime in 2026.
FOURIER and FOURIER-OLE were funded by Amgen. Giugliano reported receiving clinical trial or research support to Brigham and Women’s Hospital from Amgen, Anthos Therapeutics, Daiichi Sankyo, and Ionis. He also reported receiving honoraria from Amgen, Big Sky Cardiology, CADECI, Daiichi Sankyo, Dr. Reddy’s Laboratories, Medical Education Resources, Menarini, and SUMMEET and serving as a consultant for several organizations, which are fully listed in the original article. Sperling reported having no relevant financial relationships.