Lipid Lowering Therapy, Low-Density Lipoprotein Level and Risk of Intracerebral Hemorrhage – A Meta-Analysis

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Abstract

Background: The association of lipid lowering therapy and intracerebral hemorrhage risk is controversial. Methods: We performed a cumulative meta-analysis of lipid lowering trials that reported intracerebral hemorrhage. Statin, fibrate, ezetimibe, PCSK9, and CETP trials were included. We explored whether the association of lipid lowering therapy and risk of intracerebral hemorrhage may vary by baseline low-density lipoprotein (LDL) level, mean change in LDL or baseline cardiovascular risk of population. Results: Among 39 trials (287,651 participants), lipid lowering therapy was not associated with a statistically significant increased risk of intracerebral hemorrhage (ICH) in primary and secondary prevention trials combined (odds ratio [OR], 1.12; 95% confidence interval [CI], .98-1.28). Lipid lowering was associated with an increased risk of ICH in secondary prevention trials (OR, 1.18; 95% CI, 1.00-1.38), but not in primary prevention trials (OR, 1.01; 95% CI, .78-1.30), but the test for interaction was not significant (P for interaction = .31). Meta-regression of baseline LDL or difference in LDL reduction between active and control did not explain significant heterogeneity between studies for ICH risk. Of 1000 individuals treated for 1 year for secondary prevention, we estimated 9.17 (95% CI, 5.78-12.66) fewer ischemic strokes and .48 (95% CI, .06-1.02) more ICH, and a net reduction of 8.69 in all stroke per 1000 person-years. Conclusions: The benefits of lipid lowering therapy in prevention of ischemic stroke greatly exceed the risk of ICH. Concern about ICH should not discourage stroke clinicians from prescribing lipid lowering therapy for secondary prevention of ischemic stroke.

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)

  • A. Bustamante et al.

    Statin therapy should not be discontinued in patients with intracerebral hemorrhage

    Stroke

    (2013)
  • J.M. Leppala et al.

    Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants

    Stroke

    (1999)
  • S. Ebrahim et al.

    Serum cholesterol, hemorrhagic stroke, ischemic stroke, and myocardial infarction: Korean national health system prospective cohort study

    BMJ

    (2006)
  • H. Iso et al.

    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

    (1989)
  • D.M. Reed

    The paradox of high risk of stroke in populations with low risk of coronary heart disease

    Am J Epidemiol

    (1990)
  • K. Yano et al.

    Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program

    Stroke

    (1989)
  • C. Fitzgerald

    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

    (2014)
  • J.S. McKinney et al.

    Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials

    Stroke

    (2012)
  • High-dose atorvastatin after stroke or transient ischemic attack

    N Engl J Med

    (2006)
  • J.V. Mitsios et al.

    The antiplatelet and antithrombotic actions of statins

    Curr Pharm Des

    (2010)
  • D. Moher

    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

    Ann Intern Med

    (2009)
  • D.G. Altman et al.

    Interaction revisited: the difference between two estimates

    BMJ

    (2003)
  • W. Viechtbauer

    Conducting Meta-Analyses in R with the metafor Package

    J Stat Softw

    (2010)
  • H. Ito et al.

    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

    (2001)
  • C. Wanner et al.

    Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis

    N Engl J Med

    (2005)
  • S. Yusuf et al.

    Cholesterol lowering in intermediate-risk persons without cardiovascular disease

    N Engl J Med

    (2016)
  • J.A. de Lemos et al.

    Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: Phase Z of the A to Z Trial

    JAMA

    (2004)
  • C.D. Furberg et al.

    Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group

    Circulation.

    (1994)
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    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.

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