Victor C. Urrutia, MD, FAHA Assistant Professor Director, The Johns Hopkins Hospital Stroke Center

1. The Role of Statins in Prevention of Stroke Victor C. Urrutia, MD, FAHA Assistant Professor Director, The Johns Hopkins Hospital Stroke Center Department of Neurology Johns Hopkins University School of Medicine vurruti1@jhmi.edu

2. Disclosures • Atrial fibrillation advisory board (1/30/12). Janssen Pharmaceuticals • Johns Hopkins Hospital site PI for DIAS 4 (Lundbeck) and POINT (NINDS) • PI for SAIL ON, funded by Genentech • I will mention off label use of approved medications

3. Objectives • Basic understanding of statins and their effect • Evidence and guidelines for use in stroke prevention • Review risk factors and management of side effects • Discuss pleiotropic effects of statins

4. What are statins? • 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or HMG-CoAreductase inhibitors = “Statins” • HMG-CoAreductase is the rate limiting step in cholesterol biosynthesis via the Mevalonate pathway • Cholesterol is reduced in the liver, this produces upregulation of LDL receptors and reduction of circulating LDL levels

5. Cholesterol Metabolism

6. Target site and effect of statins Endras, M. Journal of Cerebral Blood Flow and Metabolism 25:1093-1110. 2005

7. Pleiotropic effects Endras, M. Journal of Cerebral Blood Flow and Metabolism 25:1093-1110. 2005

8. Cholesterol and stroke risk • Prior to statins, the association of stroke and elevated cholesterol was not clear • The Framingham and Honolulu Heart Study did not reveal an association between cholesterol and cerebrovascular disease • MRFIT with 351,000 middle aged men followed 6 years showed increased risk of stroke with elevated cholesterol • Eastern Stroke and Coronary Heart Disease Study with 70,000 patients also showed decreased risk of stroke with reduction of cholesterol Iso H, et al. N Engl J Med 320:904-10. 1989 Eastern Stroke and Coronary Heart Disease Collaborative Research group. Lancet 352:1801-7. 1998

9. Endras, M. Journal of Cerebral Blood Flow and Metabolism 25:1093-1110. 2005

10. The Statin Era • Over the last 15 years, multiple clinical trials have shown a consistent effect in reducing vascular events including first time stroke • SPARCL demonstrated the benefit of statins for secondary prevention of stroke in a stroke/TIA population

11. Clinical Trials of Statinsvs Placebo Sanossian N, Ovbiagele B. Nature Clinical Practice Neurology 4(1):43-49. January 2008

12. SPARCL • 4731 patients, randomized to Lipitor 80mg daily or placebo • 1-6 months from index event (Stroke/TIA) • 4.4 years of follow up • RRR for stroke 16% • Number Needed to Treat (NNT) for stroke in 5 years: 46 • NNT for Major Cardiovascular Event: 29 SPARCL investigators. N Engl J Med. 355:549-59. 2006

13. SPARCL Sanossian N, Ovbiagele B. Nature Clinical Practice Neurology 4(1):43-49. January 2008

14. Clinical indications in stroke • Guidelines form the AHA and ATP III • Advantage of early use • Pleiotropic effects (benefit in acute stroke?) • Initiating preventive strategies in the hospital is a predictor of subsequent use and achievement of ATP III goals Sanossian N, et al. Arch Neurol. 63:1081-1083. 2006

15. AHA Guidelines Adams RJ, Albers G, et al. Stroke 39:1647-1652. 2008

16. Risk associated with Statin use • Most common are mild • Gastrointestinal, headache, rash, insomnia • Most important are Muscle and Liver toxicity • Muscle toxicity is a continuum from asymptomatic elevation of CK to myopathy to rhabdomyolisis • Liver toxicity can be mild or severe • Intracerebral hemorrhage

17. Muscle Toxicity ChatzizisisYS, Koskinas KC. Drug Saf 33(3):171-187. 2010

18. Muscle Toxicity • Muscle complaints range from 1.5-3% in clinical trials and 0.3-33% in practice • Myopathy 0.3-2.2 per 1,000,000* • Rhabdomyolisis 0.3-13.5 per 1,000,000* • Mechanism is mediated by CoQ10 depletion and decrease of cholesterol in the cell membrane • Risk factors • Older than 80 years of age • Women • Small/frail • Renal Insuficiency • Untreated hypothyroidism • Alcohol abuse • Hepatic dysfucntion *FDA Adverse Event Reporting System Database

19. Medication interactions Chatzizisis YS, Koskinas KC. Drug Saf 33(3):171-187. 2010

20. Management algorithm Chatzizisis YS, Koskinas KC. Drug Saf 33(3):171-187. 2010

21. Risk of ICH, is it significant? • Epidemiological studies correlate low cholesterol levels with risk of ICH • In SPARCL the risk of ICH with statinvs placebo was 1.66 95%CI (1.08-2.55) • Risk factors: • Increasing age • ICH as index event for study entry • Uncontrolled hypertension Goldstein L,B, Amarenco P, et al. Neurology. 2007

22. Goldstein L,B, Amarenco P, et al. Neurology. 2007

23. Events by treatment group and entry diagnosis

24. Events by treatment group and entry diagnosis

25. Events by treatment group and entry diagnosis

26. Conclusion • Statins are indicated for secondary prevention of stroke • There is a benefit of starting Statins early after acute stroke • Dosing should be guided by cerebrovascular and cardiovascular risk and weighted against risk of side effects • It is important to be aware of potential important side effects and how to manage/prevent them • There is a small but definite increased risk for ICH, this should be balanced with the benefits, and at-risk groups avoided, i.e. patients with prior ICH