More Evidence Backs LDL Below 70 to Reduce Recurrent Stroke

Damian McNamara

February 21, 2020

LOS ANGELES — In a subanalysis of the Treat Stroke to Target (TST) trial, restricting analysis to only French participants followed 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.

Amarenco presented the findings as a late-breaking abstract here at the 2020 International Stroke Conference (ISC). The trial was published simultaneously in the journal Stroke.

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

The TST cohort included both French and Korean participants. 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, an average of 5.3 years compared to 2.0 years among Korean patients. The initial study had shown "very significant results in the French patients and no apparent effect in Korean patients," Amarenco said.

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

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

The European Stroke Organization and the American Heart Association/American Stroke Association guidelines each recommend intensive statin treatment to lower serum lipids following 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 cholesterol," he said.

Aiming at Different Targets

To learn more, 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 post-stroke 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).

Amarenco and colleagues measured LDL at 3 weeks post-randomization and then every 6 months.

A smaller proportion of the lower LDL target group experienced the adverse composite outcome, 9.6%, compared with 12.9% of the higher LDL target group. 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 intracranial hemorrhage (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 following 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).

Amarenco and colleagues also tracked adverse events. They found intracranial hemorrhage occurred in 13 (1.2%) patients assigned an LDL cholesterol below 70 mg/dL and in 11 (1%) 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 intracranial hemorrhage. 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 following 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 intracranial hemorrhage 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 drugs, 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 Medscape Medical News 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 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 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 Elkind, who will begin his term as president of the American Heart Association/American Stroke Association in July.

This study was supported by a grant from the French Ministry of Health and from SOS-Attaque Cérébrale Association, with unrestricted grants from Pfizer, AstraZeneca, and Merck for French sites and from Pfizer for South Korean sites.

Amarenco receives research grant support and consulting fees from Pfizer, Merck, and AstraZeneca. Elkind had has disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2020: Late-breaking abstract 9. Presented February 20, 2020.

Stroke. Published February 20, 2020. Abstract

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