Clinical Context

Low-density lipoprotein cholesterol (LDL-C) reduction is a treatment goal for many patients across the spectrum of cardiovascular risk, but are there potential harms with pushing the LDL-C too low? Ma and colleagues assessed the risk for intracranial hemorrhage (ICH) associated with low LDL-C levels. Their study was published in the July 30, 2019, issue of Neurology.[1]

This prospective cohort study followed 96,043 adults with an average age of 51.3 years at baseline. Diagnosis codes were used to identify cases of ICH over the course of 9 years of follow-up, and the key variable was LDL-C level. Rates of ICH were similar in comparing participants with an LDL-C from 70 to 100 mg/dL and levels above 100 mg/dL. However, participants with an LDL-C between 50 and 69 mg/dL experienced a higher risk for ICH compared with participants with LDL-C levels from 70 to 99 mg/dL (adjusted hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.32-2.05). The respective HR for LDL-C levels less than 50 mg/dL was 2.69 (95% CI, 2.03-3.57). Overall, the risk for ICH was found to become significant at levels below 75.7 mg/dL.

This data should give clinicians pause regarding pushing LDL-C to very low targets, but it does not have the power of a clinical trial. The current study compares strategies of aggressive vs standard LDL-C reduction among adults at high risk for stroke.

Study Synopsis and Perspective

In a subanalysis of the Treat Stroke to Target (TST) trial, restricting analysis to only French participants followed-up for an average of 5 years demonstrated an even more robust potential to reduce recurrent stroke and other major cardiovascular events by treating patients to an LDL target of below 70 mg/dL.

Treating LDL to a mean of 66 mg/dL vs 96 mg/dL was associated with a 26% relative risk reduction for the composite endpoint of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death in an adjusted analysis.

"The results are similar to the main paper, but even more spectacular, with no increase in hemorrhagic stroke whatsoever and positive results on any stroke," study investigator Pierre Amarenco, MD, professor and chair of the Department of Neurology and Stroke Centre, Bichat University Hospital, Paris, France, told Medscape Medical News.

Dr Amarenco presented the findings as a late-breaking abstract at the 2020 International Stroke Conference. The trial was published simultaneously in Stroke.[2]

In the full TST trial population, risk was reduced by 22% with more aggressive LDL-lowering treatment compared with the more lax 90 to 110 mg/dL target, as previously reported by Medscape Medical News.[3]

The TST cohort included both French and Korean participants. Dr Amarenco and colleagues focused on the French population in the current study because the group was larger (2148 vs 712 Korean participants) and had a longer follow-up, at an average of 5.3 years compared with 2.0 years among the Korean patients. The initial study had shown "very significant results in the French patients and no apparent effect in Korean patients," Dr Amarenco said.

The longer duration of treatment in the French cohort could have contributed to the greater risk reduction, said Dr Amarenco.

A 2017 European Atherosclerosis Society Consensus Panel statement notes that exposure time to lipid-lowering drugs correlates with outcomes.[4]

The European Stroke Organization and the American Heart Association/American Stroke Association guidelines each recommend intensive statin treatment to lower serum lipids after an ischemic stroke of atherosclerotic origin or after a transient ischemic attack (TIA). However, the current researchers note, the recommendations do not specify specific target numbers.

"Therefore, there is uncertainty about the target levels of LDL[-C]," Dr Amarenco said.

Aiming at Different Targets

To learn more, Dr Amarenco and colleagues randomly assigned 1073 of the French patients to a target LDL treatment group of 70 mg/dL and another 1075 to a target range of 90 to 110 mg/dL. They enrolled participants at 61 sites in France. Mean age was 67 years.

All participants had experienced an ischemic stroke within 3 months or a TIA within 15 days of baseline. They presented either with a modified Rankin Scale poststroke score of 0 to 3 or a TIA that included at least arm and leg motor deficit or speech disturbance lasting more than 10 minutes.

Investigators could use any type and any dose of statin to reach the respective targets. Statins could be prescribed as monotherapy or in combination with ezetimibe or other agents.

The baseline mean LDL cholesterol level was 137 mg/dL in the lower target group and 138 mg/dL in the higher target group, respectively (3.5 mmol/L in both groups).

Dr Amarenco and colleagues measured LDL at 3 weeks postrandomization and then every 6 months.

A smaller proportion (9.6%) of the lower LDL target group experienced the adverse composite outcome compared with the higher LDL target group (12.9%). This translated to a hazard ratio of 0.73 (95% confidence interval [CI], 0.57-0.94; P=.015).

The absolute risk reduction was 3.3%, with a number needed to treat of 30.

An analysis adjusted for covariates showed a hazard ratio of 0.74 (95% CI, 0.57-0.95; P=.019).

Cerebral infarction and acute cerebral artery revascularization were reduced by 27% (HR, 0.73; 95% CI, 0.54-0.99; P=.046).

Cerebral infarction or ICH (all strokes) were reduced by 28% (HR, 0.72; 95% CI, 0.54-0.98; P=.023). In this case, there was an absolute risk reduction of 2.9% and a number needed to treat of 34.

In contrast, myocardial infarction or urgent coronary revascularization after new symptoms were not significantly reduced (HR, 0.66; 95% CI, 0.67-1.20; P=.18). The investigators also reported nonsignificant results regarding vascular death (HR, 0.76; 95% CI, 0.44-1.32; P=.32) and all deaths (HR, 1.0; 95% CI, 0.74-1.35; P=.99).

Dr Amarenco and colleagues also tracked adverse events. They found that ICH occurred in 13 (1.2%) patients assigned an LDL cholesterol below 70 mg/dL and in 11 (1.0%) patients assigned an LDL cholesterol of 100±10 mg/dL. In this analysis, the hazard ratio was 1.17 (95% CI, 0.53-2.62; P=.70), and the absolute difference was 0.2%.

The investigators also reported that 10.3% of the lower LDL target group vs 13.6% of the higher LDL target group experienced either the primary outcome or ICH. This translated to a 25% relative risk reduction (HR, 0.75; 95% CI, 0.58-0.96; P = .021), an absolute risk reduction of 3.3%, and a number needed to treat of 30.

Avoiding 1 in 4 Events

Assessing the French participants in the TST trial showed that targeting LDL below 70 mg/dL for more than 5 years avoided more than 1 in 4 subsequent major cardiovascular events among adults who experienced a recent ischemic stroke or TIA.

Furthermore, more intense LDL lowering also avoided more than 1 in 4 recurrent cerebral infarctions or urgent carotid revascularizations after a TIA, as well as 1 in 4 recurrent cerebral infarctions or hemorrhages (all strokes) compared with the higher LDL target.

"This was obtained without increasing the risk of [ICH] with a number needed to treat of 30," the researchers note.

"In the context of all randomized clinical trials with statin and other lipid-lowering drug, there is no reason to think that Asian patients do not benefit from statin treatment and from a lower target LDL cholesterol," the researchers add.

Therefore, they plan to continue assessing the 712 Korean participants until they reach a median of 5 years of follow-up.

Clinically Validating Results

"My feeling is that these data are highly supportive of a practice that many of us have been using for years without this level of evidence," Mitchell Elkind, MD, told when asked to comment on the study.

Prior secondary analyses of studies, including research into patients with intracranial atherosclerosis, demonstrated benefit from treating to this lower LDL target. "These studies were suggestive enough that many of us were treating patients aggressively with statins," added Dr Elkind, professor of neurology and epidemiology and chief of the Division of Neurology Clinical Outcomes Research and Population Sciences at Columbia University in New York City.

"But this really confirms that [fact] with clinical trial evidence," said Dr Elkind, "and I think will be very useful to us as clinicians."

The results could be used to counsel patients about the potential benefits of statin therapy or to motivate primary care providers to treat patients more aggressively, said Dr Elkind

Study Highlights

Adults aged 18 years and older were eligible to participate in this randomized trial. All participants had history of ischemic stroke in the 3 months before enrollment, with minimal functional deficit, or they had a transient ischemic attack (TIA) in the past 15 days that involved a motor deficit or speech disturbance. Participants also had to have evidence of atherosclerotic disease that might have caused the stroke or TIA.
Participants were randomly assigned to treatment strategies with a target LDL-C of less than 70 mg/dL or target of 100 mg/dL. LDL-C was measured every 6 months, and treatment was adjusted on the basis of the intervention group.
The primary end point was a composite of stroke, myocardial infarction, unstable angina requiring urgent revascularization, TIA requiring urgent revascularization, or cardiovascular death. Researchers also assessed these outcomes separately and followed rates of ICH and incident diabetes.
The trial was designed to be conducted entirely in France. Because of slow enrollment, research centers in South Korea were added midway through the enrollment period.
2148 patients were randomly assigned in France, and 712 entered the trial in South Korea. The mean age of the French cohort was 67 years, and 68% were male; 83% of participants entered the study after having suffered a stroke.
The average LDL-C level during follow-up in the target lower than 70 mg/dL group was 66 mg/dL, whereas the respective level in the target 100 mg/dL group was 96 mg/dL. Ezetimibe was added to treatment in up to 44.0% of the LDL-C lower than 70 mg/dL cohort, but just up to 7.8% of participants in the LDL target 100 mg/dL cohort.
The median follow-up periods for both countries were 5.3 years and 2.0 years, respectively. The composite cardiovascular outcome occurred in 9.6% and 12.9% of participants in the LDL-C lower than 70 mg/dL and LDL-C target 100 mg/dL groups, respectively (adjusted HR, 0.73; 95% CI, 0.57-0.94).
Regarding specific outcomes, the lower LDL-C target demonstrated a significant improvement in the risk for stroke, but rates of myocardial infarction, vascular death, and all-cause mortality were similar between groups.
The rates of ICH were 1.2% in the LDL lower than 70 mg/dL cohort and 1.0% in the LDL target 100 mg/dL group, a nonsignificant difference.
Incident diabetes occurred in 8.1% and 6.1% of participants in the LDL lower than 70 mg/dL and LDL target 100 mg/dL groups, respectively, a nonsignificant difference.

Clinical Implications

In a previous prospective cohort study, LDL-C levels below 75 mg/dL were associated with a significantly higher risk for ICH.
The current study suggests that an LDL-C target less than 70 mg/dL can improve cardiovascular outcomes as secondary prevention after stroke or TIA, led by an improvement in the risk for another stroke. Rates of ICH were similar in the LDL lower than 70 mg/dL and LDL-C target 100 mg/dL groups.
Implications for the Healthcare Team: The healthcare team should encourage intensive statin therapy and lower targets for LDL-C among adults with a history of stroke or TIA.

LDL Target - How Low Should We Push ?

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