Regarding the new ESO guideline on pharmacological interventions for long-term secondary prevention after ischemic stroke or transient ischemic attack: Current evidence does not allow simplified recommendations

Dear Professor Kennedy Lees,

With great interest, we have read the new “European Stroke Organisation (ESO) Guideline on pharmacological interventions for long-term secondary prevention after ischemic stroke or transient ischemic attack (TIA)” published in the European Stroke Journal. ¹ The authors have gathered, analyzed and summarized current evidence in an admirably comprehensive way. Much effort has been made to accomplish straightforward, easy to use recommendations for a broad audience.

With respect to use of HMG-CoA reductase inhibitors (statins) for prevention of recurrent major adverse cardiovascular events, the authors conclude, that (1) statins should be prescribed in all individuals with ischemic stroke or TIA (Quality of evidence: high, strength of recommendation: strong for intervention), and (2) that a low-density lipoprotein (LDL) level of <1.8 mmol/L (<70 mg/dL) should be targeted (Quality of evidence: moderate, strength of recommendation: strong for intervention). Written in its present, the reader may get the impression that a target goal <1.8 mmol/L (<70 mg/dL) should be aimed at in all patients with ischemic stroke or TIA. Considering the available evidence, we feel that this recommendation may be oversimplifying a complex matter.

Evidence for the low LDL cholesterol target in secondary prevention after ischemic stroke or TIA is mainly based on the “Treat Stroke to Target trial.” Of note, evidence of atherosclerosis was a mandatory inclusion criterion in this RCT. Evidence of atherosclerosis was operationally defined as either stenosis of an extra- or intracranial cerebral artery, atherosclerotic plaques of the aortic arch (⩾4 mm in thickness), or a known history of coronary artery disease. ² Other trials investigating the effect of statins on stroke recurrence included high-risk patients whose (total or LDL-) cholesterol level was above a pre-defined threshold. Lowest cholesterol thresholds were set at 2.6–3.5 mmol/L (100–123 mg/dL) for LDL and 4.0–4.65 mmol/L (155–180 mg/dL) for total cholesterol, respectively.^3,4 In the SPARCL trial population, atherosclerotic cause of ischemic event had to be presumed whereas atrial fibrillation and other cardiac sources of embolism were explicit exclusion criteria. ³ Interestingly, in the J-STARS RCT, the risk reduction by statin treatment was seen in the subgroup of patients with stroke of atherothrombotic cause only. ⁴ The beneficial effect of statins in stroke or TIA patients without proof atherosclerotic disease or cholesterol levels above a certain threshold may be questioned. In fact, a recent meta-analysis observed that the beneficial effects of high-intensity vs. low-intensity LDL lowering for secondary stroke prevention were present in trials with all patients having evidence of atherosclerosis but not in trials with most patients not having evidence of atherosclerosis (p = 0.04 for interaction). ⁵ What is more, high-intensity versus low-intensity LDL lowering may come along with a slightly increased risk of intracerebral hemorrhage and new-onset diabetes. ⁵ Would the authors recommend statins in individuals with stroke associated with patent foramen ovale or due to cervical artery dissection without checking on cholesterol levels?

Hence, we believe that the grading of the level of evidence as “moderate” and the strength of the recommendation as “strong” for treating all stroke patients with a LDL cholesterol target <1.8 mmol (<70 mg/dL) might be premature. Although yet to be proven, benefits of individualized secondary prevention treatments may outweigh a “one size fits it all” principle.

Yours sincerely,

CH Nolte, JF Scheitz, H Erdur, HJ Audebert