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Lower LDL Targets After Ischemic Stroke Significantly Reduce Subsequent Cardiovascular Events, Study Finds

Article In Brief

After an ischemic stroke or transient ischemic attack with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg/dL had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg/dL.

Figure

LDL cholesterol levels and major cardiovascular events. Panel A shows the mean levels of LDL cholesterol over time in patients assigned to a target range of 90 mg to 110 mg/dL (higher-target group) or to a target level of less than 70 mg/dL (lower-target group). Under the graph, the row labeled “absolute difference” refers to the difference between the lower-target group and the higher-target group in the LDL cholesterol level, as measured in milligrams per deciliter. Panel B shows the cumulative incidence of the composite primary end point of major cardiovascular events (including ischemic stroke, myocardial infarction, hospitalization for symptoms resulting in urgent coronary or carotid revascularization, or cardiovascular death) in the two groups. The inset shows the same data on an expanded y axis.

The American Heart Association/American Stroke Association (AHA/ASA) currently recommends using statins to lower lipid levels in patients after a transient ischemic attack (TIA) or ischemic stroke of atherosclerotic origin, but offers limited guidance on just how intensive this therapy should be.

Now new findings from the Treat Stroke to Target (TST) trial conducted in France and South Korea offer that guidance. The study, led by Pierre Amarenco, MD, chairman of the department of neurology and Stroke Center at Bichat Hospital in Paris, and colleagues, point to a significant improvement in subsequent cardiovascular events when these patients were treated with statins until they reached target low-density lipoprotein (LDL) cholesterol levels of 70 mg/dL or lower.

Investigators randomized 2,860 patients to different LDL cholesterol target groups and followed them for an average of 3.5 years.

The results of this parallel-group trial, which was the first to compare different LDL targets in patients with atherothrombotic strokes, were published online in the New England Journal of Medicine (NEJM) on November 18.

“I think these findings are an important advance in stroke prevention—particularly for stroke neurologists, general practitioners, and cardiologists. It will be easier now to target an LDL cholesterol less than 70 mg/dL in atherothrombotic stroke—no matter the dosage of the statin they use to get to that low level,” Dr. Amarenco told Neurology Today.

Back in 2006, Dr. Amarenco was part of the group behind the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, which randomized patients with stroke to either an 80 mg dose of atorvastatin or placebo.

“We found a 16 percent relative risk reduction in recurrent stroke. In the group of patients with carotid stenosis at baseline, there was a 33 percent relative risk reduction. In the group who could achieve LDL cholesterol less than 70 mg/dl during the trial, there was a 28 percent relative risk reduction,” Dr. Amarenco said.

Based on those results, the AHA/ASA recommended intensive statin therapy in patients after thrombotic stroke but did not specify a target level for LDL cholesterol or explain “what is an intensive statin therapy,” he said.

The TST trial was designed by Dr. Amarenco and colleagues to confirm the findings from that sub-analysis. After comparing two groups of patients randomized to achieve a target LDL cholesterol level of either 70 mg/dl or a target range of 90 mg to 110 mg/dl, the investigators found that the group with a lower target of LDL cholesterol, “avoided one recurrence among five, which is quite a nice advance in secondary prevention,” Dr. Amarenco said.

“I hope that the guidelines will now change in the stroke field to mention that after an atherosclerotic stroke, we should get to an LDL level of less than 70 mg,” he added.

Study Findings

The randomized, parallel-group, event-driven trial included a total of 2860 patients from 77 sites—61 in France and 16 in South Korea—between March 2010 and December 2018.

Half of the participants were assigned to one of two target LDL groups—lower target (less than 70 mg/dL) or higher target (90 mg to 110 mg/dL). Clinicians could prescribe statins of any kind and in any dose in order to achieve these two targets. Three weeks after randomization, investigators measured levels in participants and determined whether the statin needed to be adjusted or an additional lipid-lowering agent, such as ezetimibe, needed to be prescribed in order to reach the target. Every six months, investigators met with patients and the research assistants from Bichat Hospital also contacted patients or relatives to find out the results of LDL cholesterol measurements from those visits and to record answers based on a structured questionnaire.

“The composite primary end point of major cardiovascular events included adjudicated nonfatal cerebral infarction or stroke of undetermined origin, nonfatal myocardial infarction, hospitalization for unstable angina followed by urgent coronary-artery revascularization, TIA treated with urgent carotid revascularization, or cardiovascular death, including unexplained sudden death,” the researchers wrote.

At enrollment, mean baseline levels of the participants' LDL cholesterol measured 135 mg/dL. After 3.5 years, the lower-target group mean LDL cholesterol level was 65 mg/dl and the mean higher-target group level was 96 mg/dL.

Figure

“We found a 16 percent relative risk reduction in recurrent stroke. In the group of patients with carotid stenosis at baseline, there was a 33 percent relative risk reduction. In the group who could achieve LDL cholesterol less than 70 mg/dl during the trial, there was a 28 percent relative risk reduction.”—DR. PIERRE AMARENCO

The two groups did not show a significant difference in incidence of intracranial hemorrhage or newly diagnosed diabetes. Interestingly, patients with existing diabetes benefited most from reaching lower-target LDL levels, “with 40 percent relative risk reduction” in subsequent events, Dr. Amarenco said.

When the trial was stopped, only 277 of the anticipated 385 end-point events had occurred. In the lower-target group, 121 patients (8.5 percent) experienced the composite primary end point compared with 156 (10.9 percent) in the higher target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; p=0.04), which was significant.

“Perhaps the main limitation of this trial is that it was stopped early before we reached the target of 385 primary end points,” Dr. Amarenco said. Additionally, since Korea joined the trial later in 2015, the average follow up for those participants was only two years (compared with 5.3 years in France), “and that is something important to consider because the duration of the exposure to the statin is very important for the efficacy on vascular events.”

Another question to consider going forward, he said, is whether TIAs should be included in these studies. “When we looked at patient randomized with proven ischemic stroke—that is proven on brain MRI or CT scan, we found a 33 percent relative risk reduction. These patients with proven ischemic stroke represented 85 percent of the sample, so they had a 33 percent relative risk reduction. The TIAs had no effect from the low LDL cholesterol... Since the definition of TIA has changed, all TIA with brain lesions are now considered ischemic stroke. So the TIAs in our trial were the patients with transient neurological symptoms but no proven ischemia, but the diagnosis is very difficult and they may not be relevant for such a trial,” said Dr. Amarenco.

He added that in this trial, ezetimibe was used with a statin in one-third of cases. In the future, “I think there are new avenues to try more potent lipid-lowering drugs to try to get to less than 55mg/dL as recommended by European Society of Cardiology, for example, or even lower targets,” he said.

Expert Commentary

In addition to providing phase 3, randomized trial evidence of the superiority of an aggressive LDL target in patients with atherosclerotic cerebrovascular events, “this study supports a more finessed and physiological approach to secondary stroke prevention,” Babak Navi, MD, MS, chief of the division of stroke and hospital neurology and medical director of the stroke center at Weill Cornell Medicine, told Neurology Today.

“Most prior studies supporting cholesterol reduction after stroke, including the landmark SPARCL trial, utilized a single drug at a fixed dose or a single class of drugs at different dose ranges, while this trial targeted the cholesterol level itself and allowed investigators flexibility in which drugs or doses they could use to achieve their target,” Dr. Navi, said.

Dr. Navi prescribes high-dose statins to all of his patients with acute ischemic stroke or TIA, “regardless of mechanism because of the pleiotropic effects of statins, including their vasodilatory and anti-inflammatory properties, as well as the robust observational data suggesting that high dose statins at the time of stroke hospitalization are associated with better clinical outcomes.” But in the months following hospital discharge, he generally reduces this dose to the minimum needed to reach an LDL less than 70, “particularly in those whose strokes are not atherosclerotic.”

“There are still risks involved in taking statins and other cholesterol lowering agents, he said, “so I closely monitor for side effects and periodically follow patients' liver function tests and CPK.”

He also does not prescribe high-dose statins to individuals with known liver disease. Following the results of the TST trial, he continued, “I think that clinicians should aggressively target LDL levels in patients with atherosclerotic cerebrovascular events and that this focus should persist even years after patients' index stroke.”

“Secondary analysis of the SPARCL trial suggested that an inverse association between achieved LDL levels and recurrent cardiovascular events and there was no evidence for a ‘floor’ or ‘threshold’ effect. Furthermore, trials of PCSK9 inhibitors, which are potent cholesterol lowering agents that frequently reduce LDL levels to below 30, have reported similar findings,” Dr. Navi said.

He said he would like to see future trials use PSK9 inhibitors target even lower levels of cholesterol reduction after stroke, “akin to what has transpired in patients with coronary artery disease.”

Lawrence R. Wechsler, MD, FAAN, Henry B. Higman Professor of Neurology and chairman of the department of neurology at the University of Pittsburgh Medical School, who authored the accompanying editorial in NEJM, said that although the TST trial shows that lower LDL is better for preventing cardiovascular events, it does not specifically discuss prevention of subsequent stroke events, which “is of most interest to neurologists.”

Currently, based on the SPARCL results, some neurologists give high dose statins to all stroke patients, Dr. Wechsler said, “rather than titrating dose to specific LDL targets. Others aim for LDL less than 100 mg/dL or LDL less than 70 mg/dL. This study suggests titrating dose to achieve an LDL of 70 mg/dL is a better target.”

The commentators agreed there needs to be more research into the effects of even lower LDL targets in this group of patients in the future. They also wondered whether the TST trial findings would be relevant for patients with non-atherosclerotic cardiovascular events.

Dr. Wechsler told Neurology Today that he still has many questions after the TST trial: For example: Is the improvement attributable to the statins or the cholesterol reduction? “The use of ezetimibe to achieve the lower target suggests the latter but we don't know if the same result could be achieved without statins.

“Other remaining questions include the risk of hemorrhagic stroke with aggressive LDL reduction and whether all stroke subtypes benefit. Does aggressively lowering LDL cholesterol reduce the risk of recurrent stroke? Is it safe to continue statins in patients with ICH?”

Disclosures

The study was funded by the French Ministry of Health, by SOS–Attaque Cérébrale Association, and by grants from Pfizer, AstraZeneca, and Merck for the French sites and from Pfizer for the South Korean sites. Dr. Pierre Amarenco reports receipt of research grant support from Pfizer, Sanofi, Bristol-Myers-Squibb, Merck, AstraZeneca, Boston Scientific, from the French government and consulting fees from Pfizer, BMS, Merck, Boehringer-Ingelheim, AstraZeneca, Bayer, Daiichi-Sankyo, Lundbeck, Edwards, Boston Scientific, Kowa, GSK, Fibrogen, Amgen, Shin Poong, Gilead, and lecture fees from Bayer, St-Jude Medical, Amgen, Pfizer. Dr. Navi serves as a member of the DSMB for the PCORI-funded TRAVERSE trial and has received personal fees for medicolegal consulting on stroke. Dr. Wechsler had no relevant disclosures.

Link Up for More Information

• Amarenco P, Kim JS, Labreuche J, et al. A comparison of two LDL cholesterol targets after ischemic stroke https://www.nejm.org/doi/full/10.1056/NEJMoa1910355. N Engl J Med 2019; Epub 2019 Nov 18.
    • Wechsler LR. Editorial: Statins and stroke — it's complicated https://www.nejm.org/doi/full/10.1056/NEJMe1914757. N Engl J Med 2019; Epub 2019 Nov 18.