Antiplatelet and anticoagulant therapy in stroke prevention

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
• 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
15 reduction in 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 1.68 (95 CI 1.51-1.88)

24
Hemorrhagic stroke risk

• 16 trials, 66542 patients
• 108 hemorrhagic strokes
• Risk 0.05 per year

25
What about dose of aspirin- efficacy
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 (lt100mg), moderate (1-200mg) and
  high dose (gt200)

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
plt.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
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 aspirindipyridamole compared to
clopidogrel?
39
PROFESS

• Recent ischemic strokes
• Randomised to clopidogrel or asadip
• 20,000 patients for 2.5 years
• Non-inferiority design

40
Primary outcome- recurrent stroke
Hazard Ratio for AspirinERDP 1.01 (0.921.11)
41
Safety outcomes
42
Other safety
43
Antithrombotic options
44
Antiplatelet key messages

• Aspirin is antithrombotic of choice in primary
  stroke prevention when CV risk is high
• Aspirin, aspirindipyridamole 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

48
(No Transcript)
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 gt 65
• History of stroke
• History of gastrointestinal bleeding
• 1 point for any of diabetes, recent MI, Hblt10,
  Creat gt.13mmol/L

55
Warfarin questions?