Lipid Lowering Therapy, Low-Density Lipoprotein Level and Risk of Intracerebral Hemorrhage – A Meta-Analysis
Introduction
Randomized controlled trials have shown that low-density lipoprotein cholesterol (LDL-C) lowering with statins (3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors) reduce the risk of ischemic stroke,1 but there is controversy about whether lipid lowering agents increase the risk of intracerebral hemorrhage (ICH).2, 3 While epidemiological studies report a positive association between high serum LDL-C and ischemic stroke,4, 5, 6 the association with LDL-C and ICH appears inverse.6, 7, 8
Prior meta-analyses, evaluating the association of statin therapy and ICH, have reported no overall increase in risk of ICH,10 although one large trial reported an increased risk of ICH among those randomized to high-dose statin therapy.11 Proposed mechanisms, through which an increased risk of ICH may be mediated, include low levels of LDL-C weakening the endothelium of intracerebral arteries, causing hemorrhagic stroke in the setting of hypertension.6 Another potential mechanism is the pleiotropic antiplatelet/antithrombotic effect of lipid lowering therapies, especially statins.12 To date, meta-analyses of randomized controlled trials evaluating statin therapy, have reported on the risk of ICH, but have not explored all lipid lowering therapies and whether baseline LDL, or cardiovascular risk changes the association of all lipid lowering therapies with ICH.
In this meta-analysis of lipid lowering phase III trials, we sought to determine whether lipid lowering therapy increased the risk of ICH overall, and within prespecified subgroups of participants (ie, those with lower baseline LDL-C level, larger magnitude of LDL reduction and prior cardiovascular disease).
Section snippets
Cumulative Meta-Analysis
We extracted data from 2 previous meta-analyses: one of randomized controlled trials of statin therapy for cardiovascular prevention, reporting ICH outcomes10 and the other of randomized controlled trials of fibrates for prevention of cardiovascular outcomes, reporting ICH.13 We limited our search to dates not included in these reviews (2012-2018) and repeated primary data extraction for all papers to confirm accuracy.
Selection Criteria
We performed a systematic review, adhering to the PRISMA guidelines,14 to
Results
In total, 39 randomized controlled trials were eligible that recruited 287,651 participants and reported 27,376 deaths, 7092 ischemic strokes, and 1035 ICHs. Our updated search results found 1026 studies, 974 were excluded after title and abstract screening, 29 were excluded after full text review including 18 studies that did not report ICH, leaving 5 studies for inclusion (Supplementary Figure 1). Thirty-one were trials of statins,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,11,28, 29, 30, 31,
Main Findings
We performed a systematic review and meta-analysis of all randomized controlled trials of lipid lowering therapy to investigate the relationship between lipid lowering and ICH. We did not find a statistically significant increased risk of ICH with lipid lowering overall (OR, 1.12; 95% CI, .98-1.28), but on subgroup analysis of trials, secondary prevention was significant for lipid lowering and ICH risk in secondary prevention trials (OR, 1.18; 95% CI, 1.00-1.38), however, the P for interaction
Contributors
C.J., S.R., M.C., and R.M. were responsible for data collection. C.J. performed the analysis. All authors contributed to data interpretation and critical revision of the report.
Acknowledgments
The corresponding author certifies that no other persons have made substantial contributions to the research and/or manuscript.
Disclosures
All authors declare no competing interests.
References (56)
- et al.
Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention
Lancet Neurol
(2009) - et al.
Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis
Lancet
(2010) - et al.
Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomized, placebo-controlled trial
Lancet
(2003) - et al.
Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial
Lancet
(2002) - et al.
Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial
The Lancet
(2003) - et al.
Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trial
Lancet
(2004) - et al.
Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomized controlled trial
Lancet
(2006) - et al.
The Japan Statin Treatment Against Recurrent Stroke (J-STARS): a multicenter, randomized, open-label, parallel-group study
EBioMedicine
(2015) - et al.
The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomized placebo-controlled trial
Lancet
(2011) Statin therapy should be discontinued in patients with intracerebral hemorrhage
Stroke
(2013)
Statin therapy should not be discontinued in patients with intracerebral hemorrhage
Stroke
Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants
Stroke
Serum cholesterol, hemorrhagic stroke, ischemic stroke, and myocardial infarction: Korean national health system prospective cohort study
BMJ
Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial
N Engl J Med
The paradox of high risk of stroke in populations with low risk of coronary heart disease
Am J Epidemiol
Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program
Stroke
Use of high-intensity statin in patients with ischemic stroke: observation and opinion of a clinical pharmacist in the inpatient setting
Austin J Pharmacol Ther
Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials
Stroke
High-dose atorvastatin after stroke or transient ischemic attack
N Engl J Med
The antiplatelet and antithrombotic actions of statins
Curr Pharm Des
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
Ann Intern Med
Interaction revisited: the difference between two estimates
BMJ
Conducting Meta-Analyses in R with the metafor Package
J Stat Softw
A comparison of low versus standard dose pravastatin therapy for the prevention of cardiovascular events in the elderly: the Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE)
J Atheroscler Thromb
Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis
N Engl J Med
Cholesterol lowering in intermediate-risk persons without cardiovascular disease
N Engl J Med
Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: Phase Z of the A to Z Trial
JAMA
Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group
Circulation.
Cited by (33)
LDL-C Levels Below 55 mg/dl and Risk of Hemorrhagic Stroke: A Meta-Analysis
2021, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :Recent studies with these drugs have reached very low LDL-C plasma levels that were never explored before.16,20–21 Our findings are consistent with a recently published meta-analysis that included several statin, fibrate, ezetimibe, PCSK9 inhibitors, and cholesteryl ester transfer protein (CETP) trials.28 This meta-analysis showed that lipid-lowering therapy was not associated with a statistically significant increased risk of intracerebral hemorrhage in primary and secondary prevention trials.
Statin use and mortality in atrial fibrillation: A systematic review and meta-analysis of 100,287 patients
2021, Pharmacological ResearchCitation Excerpt :Furthermore, no study reported data on the adherence or quality of anticoagulation, which are determinants of the occurrence of thromboembolic stroke (and mortality) in AF [41]. We also included a safety endpoint in our analysis as previous studies reported a marginally increase of haemorrhagic stroke in lipid lowering drugs users in secondary prevention (OR, 1.18; 95 % CI, 1.00–1.38), but not in primary prevention trials (OR, 1.01; 95 % CI, .78–1.30) [42]. However, as acknowledged by the Authors, the benefit in terms of ischemic stroke reduction greatly exceed the risk of intracranial bleeding.
Association between PNPLA3 rs738409 G variant and MRI cerebrovascular disease biomarkers
2020, Journal of the Neurological SciencesCitation Excerpt :LDL levels were not associated with WMH volume or microbleeds in NOMAS [31,33], and there is also evidence of a negative association between hyperlipidemia and these biomarkers from other cohorts [34]. Clinically, low LDL levels have been associated with an increased risk of intracerebral hemorrhage in some but not all studies [35,36]. Taken together, given the known effects of the PNPLA3 variant on lipid levels [17], these data suggest that the variant may be associated with WMH volume and microbleeds in part through effects on lipid levels.
Primary and Secondary Prevention of Ischemic Stroke and Cerebral Hemorrhage: JACC Focus Seminar
2020, Journal of the American College of CardiologyCitation Excerpt :DOACs are preferred over vitamin K antagonists due to the lower risk of ICH (23). In a meta-analysis, lipid lowering was associated with an increased risk of ICH in secondary prevention trials (OR: 1.18) (16). However, the benefit in preventing ischemic events was much higher than was the risk of bleeding.
Lipid-Lowering Therapy and Risk of Hemorrhagic Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
2024, Journal of the American Heart Association
Sources of funding: This work was performed within the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive, National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland, European Research Council (Grant Number 640580). The funding source had no role in the study design, analysis or writing of report.