LDL-c target of <70 vs. 100 mg/mL after stroke lowers risk of CV events

Benefit of a Target LDL Cholesterol Less Than 70 mg/dl After an Ischemic Stroke of Atherosclerotic Origin, the Treat Stroke to Target Trial Results

Presented during the AHA Scientific Sessions 2019 by Pierre Amarenco (Paris Univ, Paris, France).

Introduction and methods

The SPARCL trial demonstrated a 16% relative risk reduction in stroke with atorvastatin 80 mg per day as compared to placebo, in patients with stroke and no known coronary heart disease. In the group with carotid stenosis, the relative risk reduction was 33%. In the same trial, patients achieving an LDL-c of less than 70 mg/dL (1.8 mmol/L) had a 28% relative risk reduction as compared to patients who achieved 100 mg/dL (2.4 mmol/L) or above.

Current AHA/ASA guidelines recommend “intense” statin therapy after an ischemic stroke of atherosclerotic origin, but do not stipulate an LDL-c target, because there is limited data on outcomes with different LDL-c lowering targets. Therefore, there is uncertainty about the target level of LDL-c that is appropriate to reduce CV events after stroke.

To gain insight into this, the investigator-initiated Treat Stroke to Target (TST) trial compared lowering LDL-c to a target of 100 ±10 mg/dL or of <70 mg/dL, in patients with ischemic stroke (86%) or TIA (14%) with evidence of atherosclerosis. Targets were attained by titration of lipid-lowering treatment, and investigators used statin and dose of their choice in monotherapy, or in combination with ezetimibe or other drugs. Follow-up visits were done every 6 months. Patients were contacted 3 months before the next visit, to ensure they were treated to the assigned target. The primary endpoint was a composite of non-fatal ischemic stroke or undetermined stroke, non-fatal MI, unstable angina followed by urgent coronary revascularization, TIA followed by urgent carotid revascularization and vascular death including sudden death.

2873 Patients were enrolled between March, 2010 and December, 2018 in 61 centers in France and 16 in Korea (joined in late 2015). Patients were followed until one year after inclusion of the last patients. It was an event-driven trial until accrual of 385 primary endpoints, although the trial was stopped on May 25 2019, after funding had been used, with 277 primary endpoint. Median follow-up was 3.5 years (5.3 in France, 2.0 years in Korea).

Main results

• 56.4% Of patients in the LDL-c <70 group and 54.2% in the 100 target group were statin naïve.
• In the lower target group, 66% of patients were on statin only and 33% on statin+ezetimibe and patients reached an average of 65 mg/dL (1.7 mmol/L, from 135 mg/dL, 3.5 mmol/L at baseline). In the higher target group, 94% received statin only and 5% had statin+ezetimibe, reaching 96 mg/dL (2.4 mmol/L, coming from 136 mg/dL).
• The lower target group showed a lower rate of the primary composite endpoint (8.5% vs. 10.9%), resulting in a 22% relative risk reduction (HRadj: 0.78, 95%CI: 0.61-0.98, P=0.036).
• The secondary outcome of MI and urgent coronary revascularization did not show a significant difference between target groups (1.4% vs. 2.2, HR: 0.64, 95%CI: 0.37-1.18, P=0.12). Because of this, the hierarchical testing stopped hereafter.
• There was no sign of a higher risk of intracranial haemorrhage with the lower LDL-c target (1.3% vs. 0.9%, HR: 1.38, 95%CI: 0.68-2.82).
• In subgroup analyses, the index event appeared to affect the effect of the target, as ischemic stroke showed a lower risk with the lower vs. the higher target (HR: 0.67, 95%CI: 0.52-0.87), while in those with TIA, a higher risk was observed (HR: 2.06, 95%CI: 1.03-4.12, P-interaction: 0.003).

Conclusion

Considering the limitation that the trial was stopped early after accrual of 277 primary events, as opposed to the planned 385, this trial showed that after an ischemic stroke with evidence of atherosclerosis, targeting LDL-c to less than 70 mg/dL (1.8 mmol/L) compared to 100 ±10 mg/dL (2.5 mmol/L), reduced the risk of subsequent CV events. No significant increase in intracranial haemorrhage was seen, nor an increase in newly diagnosed diabetes.

Discussion

Mitchell Elkind (Columbia University, New York City, NY, USA) was the discussant for this study. He also referred to findings of the SPARCL trial, the result of which was limited by use of a single statin, and a single dose, and no adjustment was done based on lipid or other levels. Some secondary analyses also suggested that an LDL target of <70 mg/dL reduces stroke among those with intracranial atherosclerosis. There is a persistent concern, however, that the risk of intracranial haemorrhage increases with very low LDL-c.

When interpreting the results of the current TST, Elkind noted that it is important to realize that it was an unblinded study, and multiple medications and doses were used to reach targets. It is not yet clear to whom the findings apply. Conceptual issues that arise include what exactly is ‘stroke with atherosclerotic disease’, and its dependence on baseline lipids. Future studies may focus on incidental or silent infarctions, and on intracranial haemorrhage patients who may have concomitant atherosclerotic disease.

- Our reporting is based on the information provided during AHA Scientific Sessions 2019 -

This article was simultaneously published in N Eng J Med