Bi Qi Neurology Department of Beijing Anzhen Hospital of the Capital University of Medical Sciences ACS Complicated Cerebrovascular Disease—— How to Choose Anti-platelet Therapy

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Dyslipidemia theory-----HDL-LDL Endothelial dysfunction theory-- NO-ET coagulation - vasomotion Chronic inflammation theory inflammation - anti-inflammatory autonomic nerve Common pathogenesis of atherosclerosis-coronary disease-cerebral stroke

Cardiovascular, cerebrovascular, peripheral vascular, metabolic syndrome Common pathological and physiological basis, pathogenesis and control method Angiopathy is a systemic disease The concept of macroangiopathy

Diagnosis: cardiovascular disease and cerebrovascular disease Angina TIA Myocardial infarction Cerebral infarction Acute coronary syndrome Acute ischemic cerebral vascular disease Posterior circulation ischemia (PCI)

Cardiogenic Embolism Stroke, CES  Summary of CES  Arrhythmia  Chronic cardiac failure  Valvular heart disease  Coronary atherosclerotic heart disease  Cardiac tumor  Congenital heart disease  Infectious endocarditis  Cardiomyopathy  Aortic disease  Pulmonary heart disease  CES grade II prevention

Relapse risk elevated for patients with ischemic history Sudden death refers to recorded death within 1 hour ; deaths induced by coronary heart disease (CHD) only include fatal MI and other CHD deaths, excluding non-fatal MI. Risk higher than regular population Myocardial infarction Cerebral stroke 5–7 times (including death) 3 3–4 times (including TIA) 1 2–3 times (including angina and sudden death*) 1 9 times 2 4 times (only including fatal MI and other CHD deaths † ) 4 2–3 times (including TIA) 2 Ischemic stroke Myocardial infarction Peripheral arterial disease 1. Kannel WB. J Cardiovasc Risk 1994; 1: 333– Wilterdink JI, Easton JD. Arch Neurol 1992; 49: 857– Adult Treatment Panel II. Circulation 1994; 89: 1333– Criqui MH et al. N Engl J Med 1992; 326: 381–386. Initial event

Risk of severe cardiac acute events is high for patients with ischemic stroke within 3 months Yuan Zhimin, Foreign Medical Sciences (Geriatrics). 2008; 29 (5) : SCAEs includes non-fatal ventricular tachycardia, ventricular fibrillation, acute myocardial infarction, pulmonary edema, severe heart failure, heart death, etc.

Long-term death risk after stroke is not limited to stroke relapse Hartmann A, et al. Neurology. 2001; 57: Hankey GJ, et al. Stroke. 2000; 31: Dennis MS, et al. Stroke. 1993; 24: StrokeStroke relapse Cardiovascular event Death* 17% 19% 8% 16% 8% 7% 29% 31% 35% 0% 5% 10% 15% 20% 25% 30% 35% 40% Perth Stroke Study 2 Oxfordshire Stroke Project 3 NOMASS 1

AHA/ASA: it is recommended for patients with TIA and ischemic stroke to evaluate coronary risks to prevent CAD  Stroke and MI have similar risk factors and pathomechanism.  CHD is an important cause of cerebrovascular diseases  TIA or ischemic stroke of patients without CHD history indicates elevation of CHD risk.

AHA/ADA states that: Stroke shall be included as a tool for prediction of cardiovascular risks Inclusion of Stroke in Cardiovascular Risk Prediction Instruments A Statement for Healthcare Professionals From the American Heart Association/ American Stroke Association Stroke. published online May 24, 2012; 1. Atherosclerotic ischemic stroke of great vessels shall be considered as CHD level crisis, (level I recommendation; level B evidence) 2. Among CVD risk prediction instruments for level I and level II prevention, ischemic stroke could be considered as relevant outcome event of CHD prognosis. (Level IIa I recommendation ; level B evidence)

Occurrence rates of ischemic events and hemorrhage events are increased for patients with stroke/TIA history Circulation. 2012; 125: PLATO’s study

According to a meta analysis of randomized clinical study including 287 subjects: ATC. BMJ Jan 12; 324 (7329) : ACS: patients with stroke or acute stroke tend to develop extracranial major bleeding induced by anti-platelet therapy

Increase antithrombotic efficacy and reduce hemorrhage event: sufficient balance required 出血危险 缺血危险 14 Anti-platelet therapy for ACS patients with stroke/TIA history

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CREDO study design 16 n=2, 116 patients 1 year Group A Group B PCI 28 days Placebo loading dose 300mg + ASA 325 mg Placebo + ASA 81–325 mg Plavix75 mg + ASA 81–325 mg 3-24 hours before PCI Plavix loading dose 300 mg + ASA 325 mg Plavix75 mg + ASA 325 mg R 2, 116 patients grouped at random

Research results: Baseline characteristics 17 * * On top of standard therapy including ASA Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

Research results: 28-day end point Clopidogrel group and placebo group 28-day combined end point % RRR p = Number of days after randomization 6.8% 8.3% 28-day result Death, MI, UTVR (%) Without pre-treatment With pre-treatment Number of risky cases Without pre-treatment With pre-treatment Occurrence rate of 28-day death, MI or UTVR in the treatment group and the control group (groups implemented the program)

Research results: Clopidogrel group and placebo group combined 1-year end point 19 27% RRR p = 0.02 Placebo 11.5% MI, stroke or death (%) Several months after randomization % Early efficacy benefit of patients after good treatment increases with time Number of risky cases Clopidogrel 10, Placebo 1, Benefit of long-term Clopidogrel therapy for PCI patients

Safety index: Severe hemorrhage event 28-day result ITT 20 * On top of standard therapy including ASA ITT=Intent-to-treat population PP = Per Protocol population Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420 Severe hemorrhage

Overall safety result  No fatal hemorrhage or intracranial hemorrhage cases were found  Increase of severe hemorrhage after 1-year Clopidogrel treatment was not statistically significant (8.8% vs. 6.7 %, p=0.07), and occurrence rates of mild hemorrhage were very similar in the two groups.  There is lack of sub-group analysis on Clopidogrel combined with ASA in early treatment and long-term treatment for stroke patients in CREDO study. 21

TRITON-TIMI38 research design Double blind ACS (STEMI or UA/NSTEMI), to perform PCI Aspirin Prasugrel 60 mg loading dose/10 mg maintenance dose Clopidogrel 300 mg loading dose/75 mg maintenance dose Level I end point: cardiovascular (CV) death, myocardial infarction (MI), stroke Level II end point : CV death, MI, sudden death, readmission due to ischemia relapse CV death, MI, UTVR Stent thrombosis(ARC confirmed/very likely) Safety end point: TIMI major bleeding, life-threatening hemorrhage Major subgroup study: pharmacokinetics, genomics Lasting period median treatment – 12 months N=13, 608 Wiviott SD et al AHJ 152: 627, 2006

Prasugrel: anti-therapy efficacy enhanced, Hemorrhage risk significantly increased Wiviott SD et al NEJM 2007; 357:

Intracranial hemorrhage cases among patients with stroke/TIA history (N=518) Clopidogre group 0 (0%) Prasugrel group 6 (2.3%) (P=0.02) Wiviott SD et al NEJM 2007; 357: , N=13, 457 Event rate (%) HR 1.32 P=0.03 NNH=167 HR 1.52 P=0.01 P=0.23P=0.74P=0.002 Clopidogrel Prasugrel TIMI major bleeding Life-threatening hemorrhage Non-fatal hemorrhage Fatal hemorrhage Intracranial hemorrhage RRI 32% RRI 52% Prasugrel significantly increases hemorrhage risk

Net clinical benefit of Prasugrel for patients with stroke/TIA history is harmful No net clinical benefit for patients ≥75 yrs and body weight < 60 kg Total ≥60 kg ＜ 60 kg ＜ 75 岁 ≥75 岁 No Yes Stroke/TIA history Age Body weight Risk (%) Risk ratio P int = P int = 0.18 P int = 0.36 Prasugrel preferred Clopidogrelp preferred * Combined end point of all-cause death, MI, stroke and non- CABG related TIMI severe hemorrhage Wiviott SD et al NEJM 2007; 357:

FDA issued a warning in black box along with Prasugrel approval, and it is not recommended to use Prasugrel on specific groups.

Both UA/NSTEMI guideline and STEMI guideline point out that Prasugrel shall not be used on patients with stroke/TIA history( Ⅲ B) 2012 ACCF-AHA UA-NSTEMI guideline 2011 年 ACCF/AHA/SCAI PCI guideline 2012 ACCF/AHA NSTEMI/UA guideline: 2013 ACCF/AHA STEMI guideline: Prasugrel shall not be used on patients with stroke/TIA history

James S et al. Am Heart J. 2009; 157: PLATO experiment design The longest treatment period was 12 months (11 months in average) (N=18, 624) ASA* + Clopidogrel 300-mg LD/75 mg qd † 300-mg LD before PCI operation ASA* + Ticagrelor 180-mg LD/90 mg bid † 90 mg LD for patients accepting PIC treatment more than 24 hours after randomization. ACS patient UA/NSTEMI/STEMI PCI, drug therapy, or CABG therapy Treatment drug shall be administered immediately after the diagnosis is confirmed (≤ 24 h); ASA mg/d for every patient, except for that intolerant. Level I efficacy end point: vascular death/MI/stroke Level II efficacy end point: vascular death/MI/stroke of PCI patients; all-cause death/MI/stroke, vascular death/MI/stroke/severe recurrent ischemic event/TIA/ arterial thromboembolism; stent thrombogenesis; all-cause death rate Primary safety end point: PLATO defined major bleeding ASA: Aspirin; LD: loading dose; PLATO = PLATelet inhibition and patient Outcomes trial.

Baseline group with medical history in PLATO study

Main efficacy end points (CV death, MI or stroke) 累计发生率 ( %) Period after randomization (day) HR (0.84 (95% CI 0.77–0.92), p<0.001 Clopidogrel Ticagrelor No. at risk Ticagrelor9, 3338, 6288, 4608, 2196, 743 5, 161 4, 147 Clopidogrel9, 2918, 5218, 3628, 1246, 650 5, 096 4, 047 K-M = Kaplan–Meier; HR = hazard ratio; CI = confidence interval RRR 16% Wallentin L et al. New Engl J Med.2009; 361

Major bleeding – main safety end points K-M estimated rate (% per year) Period after initial dose (day) No. at risk Ticagrelor9, 2357, 246 6, 826 6, 5455, 129 3, 783 3, 433 Clopidogrel9, 1867, 305 6, 9306, 6705, 209 3, 841 3, Clopidogrel Ticagrelor HR 1.04 (95% CI 0.95–1.13), p= Wallentin L et al. New Engl J Med.2009; 361

Risk of non-CABG related major bleeding: significantly increased forTicagrelor 7 0 K-M estimated rate (% per year) Non-CABG PLATO major bleeding p= p= NS NS Ticagrelor Clopidogrel Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding Wallentin L et al. New Engl J Med.2009; 361

Safety end points: Ticagrelor vs. Clopidogrel Wallentin L et al. New Engl J Med.2009; 361

FDA issued a warning in black box along with Ticagrelor approval.

Stroke. 2012; 43: In consideration that in PLATO study, Ticagrelor did not lower the occurrence rate of stroke compared with Clopidogrel, Ticagrelor seemed to cause net harm for patients with cerebrovascular disease history; PLATO study Patients with cerebrovascular disease history have higher occurrence rate of stroke/TIA or hemorrhage events in Ticagrelor group than that in Clopidogrel group

2012 ACCF/AHA updated NSTEMI/UA guideline, and stressed about the newly added P2Y12 receptor antagonist Ticagrelor that: Attention shall be paid to the risk of intracranial hemorrhage when Ticagrelor is used on patients with stroke/TIA ACCF-AHA UA-NSTEMI 指南 Ticagrelor shall be used with care on patients with storke/TIA hsitory

 There is a close and inseparable relationship between cardiovascular and cerebrovascular diseases.  Heart disease is one of the important causes of cerebral stroke death, esp. long-term death.  Attention shall be paid to hemorrhagic tendency and drug selection when anti-platelet therapy is administered on ACS patients with stroke/TIA history.  With reference to comprehensive assessment of efficacy and hemorrhage risk, Clopidogrel has a lower hemorrhage risk while maintaining relevant efficacy. Summary

Bi Qi Neurology Department of Beijing Anzhen Hospital of the Capital University of Medical Sciences Thank you