Treating LDL to Below 70 Reduces
Recurrent Stroke

Richard Kirkner and Damian McNamara

November 21, 2019

Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events compared with a higher LDL goal, even though the international trial was stopped early because of a lack of funding.

Dr Pierre Amarenco

"In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving an LDL cholesterol between 90 and 110 mg/dL," lead author Pierre Amarenco, MD, chairman, Department of Neurology and Stroke Centre at Bichat Hospital in Paris, France, told | Medscape Cardiology.

"We avoided more than one recurrence in five," he added.

The findings of the investigator-initiated trial were reported here during a late breaking research session at the American Heart Association (AHA) 2019 Scientific Sessions and simultaneously published online November 18 in the New England Journal of Medicine.

Dr Mitchell Elkind

Discussant Mitchell S.V. Elkind, MD, MPhil, president-elect of the American Heart Association, called the TST findings "practice confirming" of a strategy many cardiologists already follow for patients who have suffered a stroke.

"The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that's what makes it a hopeful and real advance," he said in an interview.

To achieve the LDL-lowering goal, two thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower and higher target groups.

"Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin," said Amarenco, who is also a professor of neurology at Denis Diderot Paris University.

Rare Lipid Study Following Stroke

American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke, "but no target level is given to the practitioners," Amarenco said. "In reality, most patients receive a reduced dose of statin."

For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real world registry.

The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).

SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily vs placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time, however, when post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment, although subsequent analyses seemed to suggest the finding may have been a chance one.

For the TST study, Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.

Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, Amarenco said.

Amarenco and colleagues randomly assigned 1430 participants to the low-LDL-cholesterol target group, less than 70 mg/dL, and another 1430 to a high-LDL group with a target of 100 mg/dL.

Assessments were every 6 months and up to 1 year after the last patient joined the study.

Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total 55% were statin naïve at study entry.

Study Stopped Early

The trial was stopped in May of this year after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.

The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization, TIA followed by urgent carotid revascularization, or cardiovascular death, including sudden deaths.

The endpoint was experienced by 8.5% of participants in the lower target group vs 10.9% of those in the higher target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 - 0.98; P = .04).

A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33%, "meaning that we could avoid one third of recurrent major vascular events," Amarenco said.

Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.

Secondary Outcomes Not Significant

The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.

This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).

The early ending "weakened the results of the trial, and the results should be taken with caution because of that," Amarenco said.

In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower target group and 13 in the higher target cohort.

That numerical increase in intracranial hemorrhage was "driven by the Korean patients…and that is something we will report soon," Amarenco said. 

Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower LDL target group, for example, was in the therapeutic range on average during the study.

When Amarenco and colleagues looked at participants who managed to spend 50% to 100% in the target range, the relative risk reduction was 36%.

"So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size," Amarenco said.  

"Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better," Amarenco said.

"Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease," Amarenco said.

"Practice-Confirming" Findings

The findings are also in line with secondary analyses of the WASID and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Amarenco noted.

However, the TST trial, he said, didn't provide clear answers on which specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.

"What is stroke without atherosclerotic disease?" he said. "Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.

"Many, many stroke patients will fall into this category," Elkind said, "and the question is, should they be treated more aggressively with lipid lowering?"

Dr Donald Lloyd-Jones

"The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines," said Donald M. Lloyd-Jones, MD, ScM, chairman of the Department of Preventive Medicine at Northwestern University Feinberg School of Medicine, Chicago, Illinois, and chair of the AHA's 2019 Council on Scientific Sessions Programming. Lloyd-Jones was also a member of the guideline committee.

Patients who have suffered a stroke are not "garden variety coronary patients," he said. "The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us."

Consideration for Future Guidelines

The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, MPH, director, Preventive Intervention Center, Department of Epidemiology, University of Iowa in Iowa City, said in an interview.

"What was the dose intensity of statins the patients were on?" Robinson said. "Part of our struggle has been to convince people to use high-intensity statins — get the maximum from statins that are generic now and cost-saving in even very low-risk primary prevention patients."

She said that one third of patients in TST also taking ezetimibe with the statin "makes sense" because of its generic status.

Nonetheless, Robinson said TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen, and that adding a non-statin — ezetimibe in TST — can derive added benefit.

The TST findings may give guideline writers direction going forward, she said. "We really need to start thinking about the potential for net benefit from added therapy, whether it's from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or [an] SGLT2 inhibitor," she said.

"There are a lot of options," Robinson said. "We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy."

The TST trial was funded primarily by the French Government, but also with grants from Pfizer, AstraZeneca, and Merck. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Bayer, GlaxoSmithKline, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, AstraZeneca, Sanofi, Bristol-Myers Squibb, Merck, Boston Scientific, and the French Government. Robinson receives honoraria from Modest, Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. She also receives research grants from Acasti, Amarin, Amgen, AstraZeneca, Esai, Esperion, Merck, Regeneron, Sanofi, and Takeda. Elkind and Lloyd-Jones have disclosed no relevant financial relationships.

American Heart Association (AHA) Scientific Sessions 2019: Presented November 18, 2019.

N Engl J Med. Published online November 18, 2019. Abstract, Editorial

This article also appears on MDEdge/Cardiology News.

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