Antiplatelet and anticoagulant therapy in stroke prevention

Dr Sepehr ShakibDirector

Clinical PharmacologyRoyal Adelaide Hospital

Topics

• 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 strokesOverall 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

“There remains uncertainty about such low doses (<75mg) are as effective”

Antiplatelet Trialists Collaboration

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 (1-200mg) and high dose (>200)

Bleeding risk

There appears to be dose dependencyToxicity 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 Slightly more effective than aspirin

Similar bleeding to aspirin

Warfarin Same as aspirin More bleeding

Aspirin + Clopidogrel

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 non-valvular 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

Classifi-cation

Risk of major bleed

At 1 year

0 Low 3%

1 - 2 Intermediate 12%

3 - 4 High 25%+

Warfarin questions?