Vera Sharashidze, MD

Endres M, Kernan WN. LDL (Low-Density Lipoprotein) Cholesterol Below 70: Good to Go! Stroke. 2020;51:2276–2278.

The current guidelines of the American Heart Association/American Stroke Association (AHA/ASA) recommend high-intensity statin therapy initiation or continuation with the aim of achieving a 50% or greater reduction in low-density lipoprotein cholesterol (LDL-C) levels in patients with stroke who are 75 years of age or younger. In patients who are unable to tolerate high-intensity therapy, moderate intensity statins should be started with the goal of achieving a 30% to 49% reduction in LDL-C levels.

The first evidence that stroke patients could benefit from statins came out from the Heart Protection Study that was a double-blind, randomized, placebo-controlled study in which patients received either placebo or simvastatin 40 mg daily. This study showed that in patients with high risk for cardiovascular disease, cholesterol lowering with simvastatin was associated with reduction in all-cause mortality and major vascular event risk.

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, published in 2006, was the first study to look into whether atorvastatin would reduce the risk of stroke recurrence in patients with a previous stroke or transient ischemic attack (TIA). This trial showed that daily treatment with 80 mg of atorvastatin reduced the incidence of stroke by 16%. However, translating SPARCL trial results into practice has been challenging, as some physicians are resistant to prescribe high-intensity statins due to concern for adverse effects. In 2015, IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) demonstrated that addition of ezetimibe to simvastatin in patients stabilized after coronary syndrome reduces the frequency of ischemic stroke, with particularly large effects seen in patients with a prior stroke.

Evidence was shifting toward the treat-to-target approach; however, the optimal target was still unknown. The Treat Stroke to Target (TST) trial was presented at the International Stroke Conference in 2019 and is the latest evidence with regards to stroke-specific LDL-C target-directed therapy. The study included patients with ischemic stroke or TIA who had evidence of atherosclerotic disease (stenosis of any extra- or intracranial cerebral artery, aortic arch plaque, or a history of symptomatic coronary artery disease) and LDL-C >100 mg/dL without treatment (or >70 mg/dL on treatment). Patients were randomized to either LDL-C <70 mg/dL or LDL-C 90 to 110 mg/dL. Investigators prescribed a statin, ezetimibe, or both to achieve the goal. The mean level in the higher LDL target group was 96 mg/dL, and 65 mg/dL in the <70 mg/dL group. The study results indicated that LDL-C reduction with a goal of <70 mg/dL was superior in patients with atherosclerotic cardiovascular disease and evidence of ischemic stroke/TIA.

A few limitations of this trial are also important to note. Early stoppage, lack of blinded outcome assessment, and non-adherence could have biased the findings of the TST. On the other hand, findings of TST are consistent with the other pivotal trials, including IMPROVE-IT, FOURIER, and secondary analyses from SPARCL. The latter argue in favor of TST findings being reliable.

It is important to keep in mind that these findings only apply to patients with ischemic strokes caused by atherosclerosis. What dose of statin would be appropriate to start for a patient with no vascular risk factors presenting with Embolic Stroke of Undetermined Significance? There is evidence supporting pleiotropic effects of statins including nitric oxide production and reduced inflammation that could be potentially beneficial for patients with other stroke etiologies. However, the optimal dose of statins in strokes not related to atherosclerosis is unclear.

In summary, ischemic stroke patients with atherosclerosis are likely to benefit from secondary preventive management with target-directed therapy to reduce  LDL-C to <70 mg/dL.