STATINS POST STROKE: HOW MUCH IS ENOUGH?

1. STATINS POST STROKE: HOW MUCH IS ENOUGH? Case presentation General Medicine Rotation Rajwant Minhas Oct 2011

2. Outline Learning Objectives Case Background Stroke Overview of statin therapy Clinical Question Assessment Plan Monitoring Follow up

3. Learning Objectives Have an understanding of stroke and hemorrhagic transformation Discuss benefit vs. harm of using statins post stroke Review of SPARCL trial

4. Patient Information VB 58 yo (5’3”, 88.6 kg) IBW = 51.9 kg Caucasian F Admitted Oct 13, 2011 Vitals: Temp: 36.6 C, BP: 191/93 mm Hg, HR: 71 RR: 20, O2 Sat 99% C/C: Ischemic Stroke HPI: Felt unsteady for a day Left hand doing its own thing, unable to control Left arm tingling, numbness Confusion Nausea

5. Patient Information

6. Patient Information Allergies: NKDA FH: Father and mother died of stroke SH: Caffeine: 1-2 cups coffee/day No alcohol No smoking AAT Lives with husband Low fat diet

7. Current Medications

8. Review of Systems CVS: Oct 19: BP =139/83, HR = 61 GI/GU/Renal: Oct 19: SCr=84, BUN=5, eGFR=101 Liver/Spleen/Endo: Oct 16: A1C 7.1 Oct 15 Oct 21 Bilirubin 12 14 GGTP 27 35 AST 27 37 ALT 29 41 ALP 71 88 Oct 16 TG 1.1 Cholesterol 3.4 LDL 2.0 HDL 0.9 TC/HDL 3.78

9. Diagnostic Tests

10. Medical Problem List Ischemic stroke with hemorrhagic transformation HTN Diabetes Headache Dyslipidemia

11. Drug Related Problems Potential: VB is at risk of stroke recurrence secondary to not receiving high dose Atorvastatin and would benefit from reassessment of her therapy. Potential: VB is at risk of stroke recurrence secondary to not receiving anti-platelet therapy and would benefit from reassessment of her therapy once repeat CT scan shows resolution of stroke and no further bleeding. Potential: VB is at risk of stroke recurrence secondary to not receiving therapy for low HDL.

12. Background: Stroke .

13. Hemorrhagic Transformation (HT) • Could be symptomatic with clinical worsening or asymptomatic • Antithrombotics, anticoagulants & thrombolytic agents: ↑ the likelihood of serious HT • Early use of ASA: small ↑ in the risk of clinical detectable hemorrhage • HT in patients with cerebellar infarct significantly ↑ the risk of deterioration • With the use of CT, 1 prospective study determined that ≈5% of infarctions spontaneously developed symptomatic hemorrhagic transformations from frank hematomas.

14. Goals of Therapy VB’s goal: Restore functioning of her left arm Prevent another stroke, MI Healthcare team’s goal Minimize brain damage Prevent complications: aphasia, paralysis, memory loss Reduce risk of recurrence Restore baseline function of VB Minimize adverse drug events

15. Clinical Question P: In a 58 yo Caucasian female with ischemic stroke transformed to hemorrhagic stroke I: Is Atorvastatin 80 mg OD better than C: Atorvastatin 40 mg OD O: In preventing future stroke

16. What Do We Know About Statins? Meta Analysis: Statins ↓ primary stroke incidence in hyperlipidemic patients both with & without CHD (RR:0.75 & 0.77 respectively). Heart Protection Study: Simvastatin 40mg ↓ the rate of 1° and/or 2° (fatal or non-fatal) stroke in patients with CHD (4.3% vs. 5.7% placebo, NNT=72) regardless of baseline lipid levels(but not those with pre-existing stroke)

17. Benefit vs. Harm of Statins

18. SPARCL Trial: Stroke Prevention by Aggressive Reduction in Cholesterol Levels P: Patients after a recent stroke or TIA with “normal” cholesterol levels (LDL: 2.6-4.9 mmol/L) & no known hx of CHD I: Atorvastatin 80 mg OD C: Placebo O: Efficacy of high dose Atorvastatin for the prevention of stroke recurrence (fatal and non fatal)

19. SPARCL: Background Statins  stroke in patients at risk for CVD or CHD Prior stroke or TIA: ↑ risk for future CV events Prior stroke or TIA: No trials conducted to evaluate statin use for secondary prevention Goal: To evaluate whether high-dose statin treatment  risk of stroke in patients with a recent stroke or TIA & no hx of CHD

20. Inclusion & Exclusion Criteria

21. SPARCL: Study design Stroke or TIA in ≤6 months,no known CHD, LDL-C 100–190 mg/dL Atorvastatin 80 mg daily n = 2365 Placebo n = 2366 Randomized Double blind, ITT Primary end point: Time to first fatal/nonfatal strokeSecondary end points: Major coronary or CV events Follow-up:~5 years (until >540 primary end points)

22. Baseline Characteristics .

23. Baseline Characteristics *Ischemic stroke or TIA in >97% of patients

24. Baseline Characteristics

25. High-dose Statin Treatment Reduces Fatal/nonfatal Stroke Primary outcome Placebo NNT = 46 patientsfor 5 years 16 16% RRR* HR 0.84 (0.71–0.99) P = 0.03 12 Fatal/ nonfatal stroke(%) Atorvastatin 8 4 0 0 1 2 3 4 5 6 Time since randomization (years) *Prespecified adjustment for baseline factors

26. Results

27. Magnitude of Benefit 1 less secondary stroke for q 53 patients treated X 4.9 years. Reduction in TIA: NNT= 43 Major Coronary Events: NNT=59 Major CV events: NNT=32 NO reduction in overall mortality, not powered to assess risk of death

28. Adverse Events

29. Post Hoc Analysis Atorvastatin group: ↑ Risk of hemorrhagic stroke (HR 1.66, 95% CI 1.08-2.55) ↓ Risk of ischemic stroke (HR 0.78, 95% CI 0.66-0.94). ↓ Risk unclassified stroke (HR 0.55, 95% CI 0.21 to 1.40) Statins may be associated with an↑ the risk of hemorrhagic stroke in all patients with prior stroke or prior hemorrhagic stroke Epidemiologic evidence: Inverse association b/w total cholesterol levels & brain hemorrhage

30. Magnitude of Harm 1 more hemorrhagic stroke for q 112 patients (2.3%) vs. 33 (1.4%) in placebo group treated with Atorvastatin 80mg x4.9 years. Also ↑’d in those with previous CV hx HPS: 1.3 % Simvastatin 40mg vs. 0.7% placebo

31. Investigators’ Conclusion In patients with a recent stroke or TIA, treatment with Atorvastatin 80 mg/day ↓ the overall incidence of strokes and of cardiovascular events despite a small increase in the incidence of hemorrhagic stroke.

32. Limitations Extrapolation to patients with Afib & other cardiac sources of embolism Non-significant ↓ in non-fatal stroke Comparison to lower doses of Atorvastatin? Benefit vs. harm (Atorvastatin 10mg=$800; 80mg= $1050 per yr) Difference in stroke severity? (preliminary data presented by Goldstein at the ANA 131st Meeting suggests ↓ stroke severity) Open label statin use: Atorvastatin group: 11.4%, Placebo: 25.4% Treatment assignment of 9 patients ( 3 in Atorvastatin group, 6 placebo) revealed to study physician Serious adverse events not defined

33. Assessment VB would benefit from statin therapy Benefit > risk Start anti-platelet therapy when follow-up CT scan show resolution of hemorrhage and rules out no further bleeding

34. Plan: Drug & Non-drug Measures Continue with Atorvastatin 40 mg Reinitiate ASA 81 mg once follow-up CT scan results show resolution of hemorrhage and no further bleeding Diet (↓ saturated fats & refined sugars) Weight loss (Actual weight = 88.6 kg, IBW=51.9 kg) Exercise

35. Monitoring SEs: HA, dyspepsia, N,V, diarrhea, muscle soreness, tenderness or pain Lipid level monitoring in 4 weeks Liver enzyme monitoring in 12 weeks Serum transaminases & CK monitoring q 6-12 months

36. Discharge Medications Lipitor 40 mg OD Ramipril 5 mg BID HCTZ 25 mg OD Amlodipine 10 mg OD Metformin 500 mg BID Gliclazide 80 mg OD

37. Follow up F/U with Neurologist in 6 months Repeat CT Oct 28: previous areas of hemorrhage resolving FD to initiate therapy for low HDL

38. Outline Learning Objectives Case Background Stroke Overview of statin therapy Clinical Question Assessment Plan Monitoring Follow up

39. References Mascitelli, Luca et al. Letter to the editor. Hemorrhagic stroke in the SPARCL study . Stroke. 2008;39:e180, published online before print October 2 2008, doi: 10.1161/STROKEAHA.108.532309 The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators: High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006, 355:549–559 Rx Files. An Overview of SPARCL – Stroke Prevention by Aggressive Reduction in Cholesterol Levels. [updated 2006 Nov; cited 2011 Oct 28] Available from: http://www.rxfiles.ca/rxfiles/uploads/documents/Lipid-QandA-SPARCL.pdf