Daniel G. Hackam, MD, PhD; Peter C. Austin, PhD; Anjie Huang, MSc; David N. Juurlink, MD, PhD; Muhammad M. Mamdani, PharmD, MA, MPH; J. Michael Paterson, MSc; Vladimir Hachinski, MD, DSc; Ping Li, PhD; Moira K. Kapral, MD, MSc

Arch Neurol. 2012;69(1):39-45. doi:10.1001/archneurol.2011.228
Editorial comment: Arch Neurol. 2012;69:13-16

Abstract

Background; A recent post hoc analysis of a large randomized trial in patients with cerebrovascular disease suggested that statins may increase the risk of intracerebral hemorrhage (ICH).
Objective; To examine the association between statins and ICH in patients with recent ischemic stroke in a population-based setting.
Design; Retrospective propensity-matched cohort study with accrual from July 1, 1994, to March 31, 2008.
Setting Ontario, Canada.
Participants;  A total of 17 872 patients aged 66 years and older who initiated statin therapy following acute ischemic stroke and were followed for a median of 4.2 years (interquartile range, 2.4-5.0 years). To enhance causal inference, we conducted several tests of specificity to exclude healthy user bias in this sample.
Main Outcome Measure; Hospitalization or emergency department visit for ICH defined using validated diagnosis coding.
Results Overall, 213 episodes of ICH occurred. In the primary analysis comparing statin users with nonusers, we found no association between statins and ICH (hazard ratio = 0.87; 95% confidence interval, 0.65-1.17). Subgroup and dose-response analyses yielded similar results. In tests of specificity, statin therapy was not associated with bone mineral density testing, vitamin D or B12 screening, gastrointestinal endoscopy, or elective knee arthroplasty, suggesting that results were not due to healthy user bias or differences in quality of care.
Conclusion;  Statin exposure following ischemic stroke was not associated with ICH.

Background

Patients with stroke or TIA have an increased risk for recurrent events [1].

Based on data from the SPARCL-trial (Stroke Prevention by Aggressive Lowering of Cholesterol Levels) and the Heart Protection Study, statins are recommended for most patients with a history of ischemic cerebrovascular events [2,3]. Both SPARCL and HPS suggested an increase in hemorrhagic stroke related to statin therapy in patients with a history of stroke or TIA [4,5].
There are several explanations on the cause of this association.  This study is a large retrospective population-based study to examine the association between statin therapy and ICH in patients who survive an acute ischemic stroke.

Main results

The primary outcome ICH occurred slightly less frequently in statin-treated patients than in controls, indicating no negative association. There was no interaction between statin treatment and any of the prespecified subgroup characteristics. Patients treated with either high- or low-dose statins had similar risks as controls. Patients who adhered to statin treatment and did not cross over between groups had a significantly lower risk of ICH. 

Main Results of the Study on the Association Between Statin Administration and Intracerebral Hemorrhagea

Characteristic or Analysis	Value
Baseline characteristics in statin group Age, mean, y Female sex, % Hypertension, % Diabetes mellitus, % Chronic kidney disease, % Coronary artery disease, % Transient ischemic attack, % Dementia, %	78 53 80 25 26 26 28 21
Primary outcome of ICH,b cases per 1000 patient-years Statin-treated patients Matched controls	2.94 3.71
Was there a statin exposure x prespecified subgroup characteristics interaction?	No
Risk of ICH,c HR (95% CI) Patients treated with high-dose statins vs controls Patients treated with low-dose statins vs controls	1.33 (0.30-5.96) 0.86 (0.64-1.16)
Do the findings support healthy user bias or screening bias?	No
Predictors of ICH	Hypertension, previous ICH, chronic liver disease, and exposure to oral anticoagulant or antiplatelet drugs
Protective associations	Statin use, female sex, and use of potassium-sparing diuretics

Conclusion

Patients with ischemic stroke who are prescribed statin therapy have no higher risk for cerebral bleeding than individuals not receiving statins; statin therapy therefore remains recommended for these patients, unless risks for ICH are present.

References

1. van Wijk I, Kappelle LJ, van Gijn J, et al; LiLAC Study Group. Long-term survival and vascular event risk after transient ischaemic attack or minor ischaemic stroke: a cohort study. Lancet. 2005;365(9477):2098-2104.
2. Furie KL, Kasner SE, Adams RJ, et al; American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(1):227-276.
3. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery [published online May 25, 2011]. Circulation. doi:10.1161/CIR.0b013e31820d8c98.
4. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol. 2009;8(5):453-463.
5. Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB. Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke. 2008;39(2):497-502.