1. Antiplatelet and anticoagulant therapy in stroke prevention
Dr Sepehr Shakib
Director
Clinical Pharmacology
Royal Adelaide Hospital

2. Topics Stroke basics Risk calculators Lipids and strokes Antiplatelets
Clopidogrel
Aspirin + dipyridamole
Warfarin for AF

3. What are the different types of strokes?
Ischemic
Lacunar
Thrombotic
Cardioembolic
Watershed
Hemorrhagic

4. Ischemic strokes Lacunar:
Occlusion of deep penetrating branches of arteries
Occlusion caused by microatheroma, lipohyalinosis, hypertension changes
Most caused by hypertension
Account for 20% of all ischemic strokes

5. Lacunar stroke

6. Ischemic strokes Cardioembolic Thrombotic strokes
Strokes from other parts of the vascular tree eg atrial fibrillation, recent MIs, endocarditis, aortic arch etc…
Some caused by lipid accumulation
Thrombotic strokes
Due to development of thrombosis and occlusion of blood vessels supplying brain eg middle cerebral artery

7. Middle cerebral artery stroke

8. Hemorrhagic strokes Much more rare and more catastrophic Caused by:
Hypertension
Amyloid angiopathy
Aneurysms

9. Hemorrhagic stroke

10. Hemorrhagic transformation
Development of hemorrhage in large ischemic stroke

11. Risk calculators: http://www.cvdcheck.org.au/

12. Risk 52 years old Bp 142/87 Family history of IHD LDL 6.4, HDL 0.8
Has just stopped
smoking

13. Risk Engine
Based on UKPDS follow-up data

14. Relationship between lipids and strokes
BMJ June 2003

15. Stroke reduction for 1mmol/L reduction in LDL cohort studies
ischemic strokes
19% increase in
hemorrhagic strokes

16. Association between lipids and strokes summary
As your LDL falls
 ischemic strokes
↑ hemorrhagic strokes
Overall benefit depends on the relative balance of absolute risks of ischemic vs hemorrhagic strokes
Even with ischemic strokes get smaller relative reduction in events than IHD
Cf 32% (95% CI 27-36%) reduction in ischemic heart disease events for every 1 mmol/L reduction in LDL

17. Benefits of lipid lowering in trials
Original evidence from IHD trials
Eg reduction in strokes in 4S and LIPID study
Heart Protection Study first study to demonstrate reduction in strokes in those without IHD (Lancet 2002)
25% reduction in all strokes

18. Aspirin Antithrombotic Trialists’ Collaboration BMJ 2002
287 studies involving 205,000 patients!
Most placebo controlled data related to aspirin

19. Relative Benefit

20. Absolute benefit

21. Benefits in other vascular events

22. What about risk of bleeding?

23. GI bleeding Meta-analysis 24 RCTs with 66,000 patients
0.45% annual bleeding rate
OR (95% CI )

24. Hemorrhagic stroke risk
16 trials, patients
108 hemorrhagic strokes
Risk 0.05% per year

25. What about dose of aspirin - efficacy
“There remains uncertainty about such low doses (<75mg) are as effective”
Antiplatelet Trialists Collaboration

26. Dose of aspirin - toxicity?
Opinion quite varied from there being no dose dependency to there being one
No direct comparison of doses
Small adverse event rate
Differences in background populations in different studies

27. Am J Cardiol 2005 31 trials 192,036 patients
Looked at low (<100mg), moderate (1-200mg) and high dose (>200)

28. Bleeding risk There appears to be dose dependency
Toxicity is substantial even at low dose

29. Aspirin summary Effective at reducing rate of recurrent stroke
Even small doses associated with risk of bleeding
Mainly GI bleeding but some intracerebral
Benefit outweighs risk in patients with previous stroke
There appears to be increased toxicity at increased doses

30. Aspirin Questions?

31. Clopidogrel CAPRIE study Clopidogrel 75mg vs aspirin 325mg
History of stroke, MI, or peripheral vascular disease
19,185 patients

32. Clopidogrel efficacy
5.8%
5.3%

33. Clopidogrel toxicity
* p<.05

34. Aspirin + Dipyridamole
Antithrombotic Trialists Collaboration 2002
6% non-significant reduction in strokes with addition of dipyridamole to aspirin
Systematic review of 25 studies, involving 10,404 patients

35. ESPRIT study
2700 patients randomised to any dose of aspirin +dipyridamole SR 200mg twice daily
Open label

36. Esprit results Fewer strokes with aspirin + dipyridamole
Fewer hemorrhages with aspirin + dipyridamole (??)
Systematic review of 6 studies shows reduction in recurrent events

37. Which is the ideal antiplatelet?
Antiplatelet therapy
Which is the ideal antiplatelet?
Stroke 2008 meta-analysis: addition of dipyridamole to aspirin: ‘robust benefit’
Editorial: “…considering the 40 times difference in cost and the discrepancies noted above, such benefit is uncertain and, judging by the data, far from robust”

38. What about aspirin+dipyridamole compared to clopidogrel?

39. PROFESS Recent ischemic strokes Randomised to clopidogrel or asa+dip
20,000 patients for 2.5 years
Non-inferiority design

40. Primary outcome- recurrent stroke
Hazard Ratio for Aspirin–ERDP 1.01 (0.92–1.11)

41. Safety outcomes

42. Other safety

43. Antithrombotic options
Drug
Efficacy
Adverse effects
Aspirin
22%  in risk
Bleeding risk
(0.5-1% per year)
Aspirin + dipyridamole
? more effective than aspirin
Headaches, nausea, flushing
Clopidogrel
Slightly more effective than aspirin
Similar bleeding to aspirin
Warfarin
Same as aspirin
More bleeding
Aspirin + Clopidogrel

44. Antiplatelet key messages
Aspirin is antithrombotic of choice in primary stroke prevention when CV risk is high
Aspirin, aspirin+dipyridamole or clopidogrel are main antiplatelet cfhoices in secondary stroke prevention
Choice depends on circumstances (PBS criteria, intolerances)

45. Antiplatelet questions?

46. Risk of stroke with AF Risk highest with valvular AF
All other stratification tools refer to non-valvular AF
There are numerous different risk stratification tools which rely on different risk factors

47. CHADS2 Score National Registry of Atrial Fibrillation JAMA 2001
Subsequently validated in different studies

49. Benefit of antithrombotic therapy
Warfarin reduces risk of stroke by 70%
Aspirin reduces risk by 30%
Less effect on large disabling strokes
Aspirin + dipyridamole- very limited data
Clopidogrel- no data
Aspirin + clopidogrel- not as good as warfarin ? Better than aspirin

50. Warfarin contraindications

51. Not contraindications
Co-prescription of interacting drug

52. What is risk of bleeding with warfarin?
Literature rate varies between 0.1%-50% per year
Initiation/transition period
Risk of mis-communication, new behavior
Modifiable risk
Bleeding due to underlying lesion
Eg colonic polyp, peptic ulcer, bladder lesion
“Desirable” bleeding
Not modifiable
Long term bleeding risk
Depends on risk factors of bleeding and how well managed
Partly modifiable

53. 5 point risk calculator
Only applies to patients who are suitable for warfarin
Validated in other populations
Am J Med 1998

54. 5 point bleeding scale 1 point each for :
Age > 65
History of stroke
History of gastrointestinal bleeding
1 point for any of: diabetes, recent MI, Hb<10, Creat >.13mmol/L
Score
Classifi-cation
Risk of major bleed
At 1 year
Low 3%
1 - 2
Intermediate
12%
3 - 4
High
25%+

55. Warfarin questions?