Pharmacologic Prevention of Stroke

1. Pharmacologic Prevention of Stroke Jonathan Raser-Schramm, MD, PhD Medical Director, Stroke ProgramChristiana Care Health System March 21, 2014

2. Disclosures • No financial relationships • Will discuss off-label use of a number of antithrombotic agents

3. What is a stroke? sudden onset neurological deficit attributable to a vascular cause

4. What is a stroke? infarction ICH SAH

5. What is a stroke? 80% 15% 5% infarction ICH SAH

6. Modifiable stroke risk factors hypertension tobacco abuse infarction ICH SAH

7. Modifiable stroke risk factors infarction

8. Atherothrombosis thrombus atheromatous plaque VASCULAR NEUROLOGY Lammieet al. Stroke (1999)

9. Thromboembolism thrombus atheromatous plaque Lammie et al. Stroke (1999)

10. Modifiable stroke risk factors diabetes mellitus dyslipidemia infarction

11. Outline • antihypertensives • antilipid agents • antithrombotics • other pharmacologic approaches

12. Two phases of stroke treatment acute stroke secondary prevention

13. Two phases of stroke treatment acute stroke secondary prevention weeks to months

14. Hypertension and stroke

15. Who should be treated? • All patients after stroke? • All hypertensive patients after stroke? • What about patients with non-atherosclerotic causes of stroke? • Could some patients be harmed by lowering blood pressure?

16. Causes of cerebral infarction cryptogenic other small vessel disease large vessel disease atrial fibrillation

17. Who should be treated? • All patients after stroke? Across numerous randomized studies, there has not been any subset of patients that does not clearly benefit from blood pressure reduction in stroke prevention. Yes

18. Who should be treated? • All hypertensive patients after stroke? Stroke prevention occurs with treatment in patients regardless of baseline blood pressure.

19. Who should be treated? • What about non-atherosclerotic causes of stroke? There is an argument that patients who are normotensive (120/70) and have specific causes of stroke such as atrial fibrillation, DVT with PFO, endocarditis, or hypercoagulable states may not benefit from treatment. This question is not well-studied.

20. Who should be treated? • Who might be harmed? large vessel disease concern for cerebral hypoperfusion

21. Who should be treated? • Who might be harmed? For patients with large vessel stenosis >50% (especially >70%), there is a risk of recurrent stroke with aggressive treatment. However, some studies suggest benefit with long-term, stepwise aggressive lowering of blood pressure.

22. How much to lower? • <140/90 • <130/80 • <120/70 • As much as possible • Until it causes a problem

23. How much to lower? • Some support for all these answers!! the lower, the less risk of stroke <120/70 is likely too low and associated in at least one study with worse outcomes. <130/80 if tolerated is likely the ideal range One reasonable guideline:<140/90 for all patients, and <130/80 for patients with diabetes

24. Which agents to choose? • Diuretics • Beta blockers • ACE inhibitors • Angiotension receptor blockers • Calcium channel blockers • Alpha blockers

25. Which agents to choose? • Diuretics • Beta blockers • ACE inhibitors • Angiotension receptor blockers • Calcium channel blockers • Alpha blockers Ultimately, achieving reduction in blood pressure is likely more important than specific agent required.

26. Which agents to choose? • Diuretics • Beta blockers • ACE inhibitors • Angiotension receptor blockers • Calcium channel blockers • Alpha blockers All these agents have safety/efficacy after stroke.

27. Which agents to choose? • Diuretics • Beta blockers • ACE inhibitors • Angiotension receptor blockers • Calcium channel blockers • Alpha blockers Though traditionally first-line agents, in one trial HCTZ was inferior to CaCB; indapamide and chlorthalidone may have better support.

28. Which agents to choose? • Diuretics • Beta blockers • ACE inhibitors • Angiotension receptor blockers • Calcium channel blockers • Alpha blockers Concerns about blood pressure variability and central vs peripheral effects make beta blockers not the initial preferred agents after stroke.

29. Which agents to choose? • Diuretics • Beta blockers • ACE inhibitors • Angiotension receptor blockers • Calcium channel blockers • Alpha blockers These agents may increase the risk of stroke, despite being effective in lowering blood pressure.

30. Which agents to choose? • Diuretics • Beta blockers • ACE inhibitors • Angiotension receptor blockers • Calcium channel blockers • Alpha blockers Ultimately, achieving reduction in blood pressure is likely more important than specific agent required.

31. Antilipid therapies

32. Cholesterol and stroke • Relationship between high cholesterol (high LDL) and stroke is less strong than for coronary heart disease • Low cholesterol has been associated with intracerebral hemorrhage • However, similar mechanism from CAD strongly implied for many causes of stroke, and similar benefit expected

33. Trial X treatment A treatment B stroke(vascular event) 15% 10% hemorrhage 10% 10% 5% death 10% patients enrolled

34. SPARCL (2006) atorvastatin80 mg placebo cerebral infarction* 9% 12% 1% 2% ICH* 9% 9% death *p<0.05 stroke/TIA (LDL>100)

35. ACC recommendations (2013) stroke = ASCVD

36. Statin intensity

37. Reasons to avoid high-intensity Characteristics predisposing individuals to statin adverse effects include, but are not limited to: • Multiple or serious comorbidities, including impaired renal or hepatic function. • History of previous statin intolerance or muscle disorders. • Unexplained ALT elevations >3 times ULN. • Patient characteristics or concomitant use of drugs affecting statin metabolism. • >75 years of age. Additional characteristics that may modify the decision to use higher statin intensities may include, but are not limited to: • History of hemorrhagic stroke. • Asian ancestry.

38. What about other agents? • Niacin-ER did not lower risk of cardiovascular events compared with placebo though it is effective in increasing HDL and lowering triglycerides • Ezetimibe has not been shown to have any clinical benefit though it can lower LDL • Omega-3 fatty acids have not been shown to benefit in stroke prevention

39. Antithrombotic therapies warfarin rivaroxaban aspirin apixaban thrombus clopidogrel dabigatran atheromatous plaque prasugrel dipyridamole ticagrelor

40. Antithrombotic therapies aspirin thrombus atheromatous plaque COX-inhibitor

41. Antithrombotic therapies P2Y12 (ADP-R) inhibitor thrombus clopidogrel atheromatous plaque prasugrel ticagrelor

42. Antithrombotic therapies thrombus atheromatous plaque dipyridamole PDE-inhibitor

43. Antithrombotic therapies warfarin thrombus atheromatous plaque vit K antagonist – fII, fVII, fIX, fX

44. Antithrombotic therapies rivaroxaban apixaban thrombus atheromatous plaque factor Xa inhibitor

45. Antithrombotic therapies thrombus dabigatran atheromatous plaque direct thrombin inhibitor

46. Antithrombotic therapies ANTIPLATELET - aspirin - clopidogrel - Aggrenox DUAL ANTIPLATELET - aspirin + clopidogrel ANTICOAGULANT - warfarin - dabigatran - apixaban - rivaroxaban - enoxaparin etc.

47. How do we pick the right one? • Stroke mechanism • Patient preference • Cost • Ease of compliance • Failure of prior agent • Tolerability and side effects

48. Causes of cerebral infarction cryptogenic other small vessel disease large vessel disease atrial fibrillation/cardioembolism

49. Atrial fibrillation

50. Meta-analysis (2002) warfarin aspirin 5% stroke* 2% 1% 2% major hemorrhage* 5% death 5% *p<0.05 afib