The analysis showed that in patients with stroke in the context of atherosclerotic stenosis, a target LDL cholesterol below 70 mg/dL did not significantly increase the risk for ICH, compared with a target LDL cholesterol of 100 mg/dL. In addition, predictors of ICH were uncontrolled hypertension and anticoagulant treatment, but not LDL cholesterol levels achieved.
The results of the new analysis were published online in Stroke on December 29, 2021.
Lead author of the new analysis, Pierre Amarenco, MD, Bichat Hospital, Paris, explained to theheart.org | Medscape Cardiology that there has been concern about ICH risk at low LDL levels, which has come mainly from older observational studies. And trials of statins in the secondary prevention of stroke have suggested a 1.7-fold relative increase in ICH, compared with placebo.
One of these trials — SPARCL — showed an overall benefit of atorvastatin over placebo in patients with stroke, but a slight increase in ICH. In a multivariable analysis of the SPARCL data, predictors of ICH were uncontrolled hypertension and previous ICH at study entry. Although low LDL was not an independent predictor of ICH, use of atorvastatin stayed independently associated with ICH.
For more information on the relationship between LDL levels and risk for ICH in stroke patents, Amarenco and colleagues conducted the current prespecified analysis of the TST trial.
In the study, 2860 patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of less than 70 mg/dL or 100 mg/dL, using a statin or ezetimibe. The main results showed that patients in the lower target LDL group had a significantly reduced risk for major cardiovascular events, compared with the higher target LDL group.
The current analysis focuses on the risk for incident ICH in the two groups. Results show that incident ICH occurred in 31 patents over a median follow-up of 3 years.
There were 18 incident ICH events in the low target LDL group (3.21 per 1000 patient-years) and 13 in the higher LDL target group (2.32 per 1000 patient-years), giving a hazard ratio (HR) of 1.38, which was not statistically significant (95% CI, 0.68 – 2.82).
Although there were no baseline predictors of ICH, uncontrolled hypertension (HR, 2.51) and being on an anticoagulant (HR, 2.36) during the trial were significant predictors. On-treatment low LDL cholesterol was not a predictor of ICH.
In addition, among those who developed an ICH, the mean LDL lowering from baseline to the last lipid profile recorded before the ICH was 28.8 mg/dL, compared with a mean lowering of 50.9 mg/dL in the group without an ICH.
“Our results are reassuring in general; ICH risk was not significantly increased at lower LDL levels. I think we can advise that LDL can be lowered below 70 mg/dL in stroke patients without worrying about bleeding, but that tight control of blood pressure and anticoagulation treatment is even more important in stroke patients,” Amarenco commented.
He pointed out that further reassurance has come from trials of PCSK9 inhibitors, which have reached very low levels of LDL — 30 to 40 mg/dL — and have not shown any increase in ICH, even in patients with previous stroke. “Altogether low LDL is not clearly associated with ICH,” he noted.
Still Some Caution in Small-Vessel Disease
But he cautioned that there remains some uncertainty about use of statins, particularly in patients with small-vessel disease.
“In a further analysis of SPARCL, the risk of ICH was associated with intracranial small-vessel disease at baseline, lacunar stroke, or previous ICH,” he said. “There was an interaction for this suggesting that statins may increase risk of ICH in patients with small-vessel disease.”
He noted that the TST trial selected atherosclerotic disease so few patients with small-vessel disease were included.
Amarenco and colleagues are now planning another trial to investigate whether the anti-inflammatory agent colchicine can lower the risk for ICH in patients with a previous stroke, all of whom will be taking statins.
Worrying About Excessive LDL Lowering “Misguided”
In an editorial accompanying the current publication in Stroke, Seemant Chaturvedi, MD, professor of stroke neurology, University of Maryland School of Medicine, Baltimore, says these latest results from TST reinforce other information from large-scale analyses.
He reports that a Danish population-based, propensity-score-matched cohort study of more than 55,000 patients showed that, among patients with a previous ischemic stroke, the rate of ICH was reduced by about one-half in statin users compared with nonusers, and that in patients with previous ICH, there was no difference in the rate of new ICH with statin use.
“While stroke clinicians have been consumed with worries about ICH risk, the rest of the vascular world has moved on,” Chaturvedi says, noting that European guidelines now recommend an LDL target below 55 mg/dL for patients with diabetes and other high-risk patients.
He points out that the current analysis by Amarenco et al has limitations, including the fact that it was not powered to evaluate the ICH outcome in relation to intensity of LDL lowering, and the population was not broadly representative of all stroke subtypes because it was skewed toward those with atherosclerotic cerebrovascular events.
“Despite these limitations, the study provides an important message for clinicians. We should not hesitate to adopt intensive lipid lowering and we should concentrate on blood pressure control and appropriate anticoagulant use to have the greatest impact on decreasing ICH. Worrying about excessive LDL lowering is misguided,” Chaturvedi concludes.
This study was an investigator-driven initiative and received a grant from the French Ministry of Health and from SOS-Attaque Cérébrale Association (a not-for-profit organization), with unrestricted grants obtained from Pfizer, AstraZeneca, and Merck. Amarenco reports receiving research grant support from Pfizer, Sanofi, Bristol Myers-Squibb, Merck, AstraZeneca, Boston Scientific, and the French government; consulting fees from Pfizer, BMS, AstraZeneca, Bayer, Boston Scientific, Kowa, Fibrogen, Amgen, Shin Poong and Portola; and lecture fees from Bayer, Amgen, Pfizer, Viatris, and Sanofi. Chaturvedi reports that he serves as an associate editor for Stroke and is on the executive committee of the CREST 2 study (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial).