Transcript Antiplatelet and anticoagulant therapy in stroke prevention

Antiplatelet and anticoagulant
therapy in stroke prevention
Dr Sepehr Shakib
Director
Clinical Pharmacology
Royal Adelaide Hospital
Topics
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Stroke basics
Risk calculators
Lipids and strokes
Antiplatelets
– Clopidogrel
– Aspirin + dipyridamole
• Warfarin for AF
What are the different types of
strokes?
• Ischemic
–
–
–
–
Lacunar
Thrombotic
Cardioembolic
Watershed
• Hemorrhagic
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
Lacunar stroke
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
Middle cerebral artery stroke
Hemorrhagic strokes
• Much more rare and more catastrophic
• Caused by:
– Hypertension
– Amyloid angiopathy
– Aneurysms
Hemorrhagic stroke
Hemorrhagic transformation
• Development of hemorrhage in large
ischemic stroke
Risk calculators:
http://www.cvdcheck.org.au/
Risk
• 52 years old
• Bp 142/87
• Family history of
IHD
• LDL 6.4, HDL 0.8
• Has just stopped
smoking
Risk Engine
Based on UKPDS
follow-up data
Relationship between lipids and
strokes
• BMJ June 2003
Stroke reduction for 1mmol/L
reduction in LDL cohort studies
15% reduction in
ischemic strokes
19% increase in
hemorrhagic strokes
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
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
Aspirin
• Antithrombotic
Trialists’ Collaboration
• BMJ 2002
• 287 studies involving
205,000 patients!
• Most placebo
controlled data related
to aspirin
Relative Benefit
Absolute benefit
Benefits in other vascular events
What about risk of bleeding?
GI bleeding
• Meta-analysis
24 RCTs with
66,000 patients
• 0.45% annual
bleeding rate
• OR 1.68
(95% CI 1.51-1.88)
Hemorrhagic
stroke risk
• 16 trials, 66542
patients
• 108
hemorrhagic
strokes
• Risk 0.05% per
year
What about dose of aspirin
- efficacy
Antiplatelet Trialists Collaboration
“There remains uncertainty about such low doses (<75mg) are as effective”
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
Am J Cardiol
2005
• 31 trials
• 192,036 patients
• Looked at low
(<100mg),
moderate (1200mg) and high
dose (>200)
Bleeding risk
There appears to be dose dependency
Toxicity is substantial even at low dose
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
Aspirin Questions?
Clopidogrel
• CAPRIE study
• Clopidogrel 75mg
vs aspirin 325mg
• History of stroke,
MI, or peripheral
vascular disease
• 19,185 patients
Clopidogrel efficacy
5.8%
5.3%
Clopidogrel toxicity
* p<.05
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
ESPRIT study
• 2700 patients
randomised to any
dose of aspirin
+dipyridamole SR
200mg twice daily
• Open label
Esprit results
• Fewer strokes with aspirin + dipyridamole
• Fewer hemorrhages with aspirin +
dipyridamole (??)
• Systematic review of 6 studies shows
reduction in recurrent events
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”
What about aspirin+dipyridamole
compared to clopidogrel?
PROFESS
• Recent ischemic strokes
• Randomised to
clopidogrel or asa+dip
• 20,000 patients for 2.5
years
• Non-inferiority design
Primary outcome- recurrent stroke
Hazard Ratio for Aspirin–ERDP 1.01 (0.92–1.11)
Safety outcomes
Other safety
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
Warfarin
Aspirin +
Clopidogrel
Slightly more effective Similar bleeding to
than aspirin
aspirin
Same as aspirin
More bleeding
Same as aspirin
More bleeding
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)
Antiplatelet questions?
Risk of stroke with AF
• Risk highest with valvular AF
• All other stratification tools refer to nonvalvular AF
• There are numerous different risk
stratification tools which rely on different
risk factors
CHADS2
Score
• National Registry
of Atrial
Fibrillation
• JAMA 2001
• Subsequently
validated in
different studies
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
Warfarin contraindications
Not contraindications
Co-prescription of interacting drug
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
5 point risk
calculator
• Only applies to
patients who are
suitable for warfarin
• Validated in other
populations
• Am J Med 1998
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
Classification
Risk of major
bleed
At 1 year
0
Low
3%
1-2
Intermediate 12%
3-4
High
25%+
Warfarin questions?