If we are lowering cholesterol (LDL) how low should it go to effectively achieve an effect?

The current guidelines of the American Heart Association and the American Stroke Association (AHA–ASA) recommend “intense” statin therapy after an ischemic stroke of atherosclerotic origin but do not stipulate a target level of LDL cholesterol because there are limited data on outcomes with different targets for LDL cholesterol. Most physicians prescribe high-intensity statin therapy after stroke, however the prescription is usually changed to a low or moderate statin dose thus only a moderate reduction in the level of LDL cholesterol is achieved. In a multicenter, multinational registry (TIAregistry.org) that enrolled patients with TIA or minor ischemic stroke who were followed in TIA clinics during a 5-year period, 70% of the patients had been prescribed a statin at the time of hospital discharge, only 63% were still taking a statin at 5 years. Among these patients, the mean (±SD) LDL cholesterol level went from 119±41 mg per deciliter (3.1±1.1 mmol per liter) at baseline to 92±32 mg per deciliter (2.4±0.8 mmol per liter) at 5 years. What was the clinical benefit achieved?

Intensive therapy to lower serum lipid levels with the use of statins is recommended after transient ischemic attack (TIA) or ischemic stroke of atherosclerotic origin. These recommendations are based on the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Level (SPARCL) trial that showed a 16% lower incidence of recurrent stroke with atorvastatin (at a dose of 80 mg per day) than with placebo in patients with stroke and no known coronary heart disease. In the group with carotid stenosis, there was a 33% lower incidence of stroke in the atorvastatin group than in the placebo group. A subsequent analysis of the data from that trial showed that patients who reached a level of low-density lipoprotein (LDL) cholesterol of less than 70 mg per deciliter (1.8 mmol per liter) had a 28% lower relative risk of stroke than those who reached a level of 100 mg per deciliter (2.6 mmol per liter). A meta-regression analysis, including results from the SPARCL trial, showed that the risk of stroke was 20% lower for every reduction of 39 mg per deciliter (1.0 mmol per liter) in the LDL cholesterol level, without any threshold effect. How did the authors do this? They used a statin and ezitamibe in both groups but changed the dosage to achieve a target of an LDL level of 70 mg/dl or 90 mg/dl. both the cardiovascular and neurovascular progression of cholesterol related injury were targeted. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. 2860 patients were followed up for three and a half years, (the South Korean patients were followed up for a shorter period as they entered the trial late) . After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875).

What exactly are we looking at?

The trial was conducted in 61 sites in France and 16 sites in South Korea. The nutritional transition in South Korea despite its gains in its economy and a transition towards western culture has not seen an equivalent increase in the use of dairy products or an increase in dietary fat. Obesity is not at the level of the West.

The age of the patients was diverse 18 years (for Koreans 20 years) and up. Was there the same degree of atherosclerosis in younger patients or for the same genetic or dietary reason?

All patients had already had a neurological adverse event and had a stable neurological deficit. Most had cardiac disease as well. All imaging was performed when the responsible clinician determined that knowledge of intracranial steno-occlusive disease or severe aortic atheroma would alter treatment. The choice of cardiovascular tests and the diagnosis of atherosclerotic stenosis were made and judged by the investigators and were not standardized or adjudicated.

Too late to lock the barn door?

All patients were treated to maintain blood pressure at a target level of 130/80 mm Hg in those with diabetes: to less than 140/90 mm Hg in all others, to maintain a glycated hemoglobin level of less than 7%, and were encouraged to stop smoking. Were these the confounding factors?

At a median of 2.7 years in the two groups, discontinuation rates were 30.3% and 28.5%, respectively.

there was a numerically higher number of intracranial hemorrhages in the lower-target group than in the higher-target group, in the SPARCL trial, than in the Heart Protection Study, but the 95% confidence interval for the hazard ratio suggested that the between-group difference was not significant in this trial. In addition, in the SPARCL trial, incident diabetes was 30% higher in the group assigned to receive atorvastatin (80 mg per day) than in the placebo group.

So what do we learn? Those with carotid artery stenosis were the ones who benefitted as their incidence of a recurrence was less when the cholesterol was lowered to 70 mg/dl. Those who already had cardio-atheroma disease also tended to do better with the lower LDL cholesterol. However the patients with the lower LDL cholesterol tended to have a higher incidence of intracranial hemorrhage. should the LDL be lowered to 50 mg/dl. What should be done about the diet? Is this low a LDL cholesterol sustainable? Let us think about that.


A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke
List of authors.
Pierre Amarenco, M.D., Jong S. Kim, M.D., Julien Labreuche, B.S.T., Hugo Charles, B.S.T., Jérémie Abtan, M.D., Yannick Béjot, M.D., Lucie Cabrejo, M.D., Jae-Kwan Cha, M.D., Grégory Ducrocq, M.D., Ph.D., Maurice Giroud, M.D., Celine Guidoux, M.D., Cristina Hobeanu, M.D., et al., for the Treat Stroke to Target Investigators*

January 2, 2020
N Engl J Med 2020; 382:9-19
DOI: 10.1056/NEJMoa1910355

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I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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