Antiplatelet and anticoagulant therapy in stroke prevention Dr Sepehr Shakib Director Clinical Pharmacology Royal 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 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

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 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 “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 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

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”

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

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 Low 3% 1 - 2 Intermediate 12% 3 - 4 High 25%+

Warfarin questions?