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

Main Content

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: 333–339. 2. Wilterdink JI, Easton JD. Arch Neurol 1992; 49: 857–863. 3. Adult Treatment Panel II. Circulation 1994; 89: 1333–1363. 4. 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) : 239-40.

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: 2000-2005.Hankey GJ, et al. Stroke. 2000; 31: 2080-2086.

Dennis MS, et al. Stroke. 1993; 24: 796-800.

Stroke Stroke relapse Cardiovascular event

Dea

th*

17%19%

8%

16%

8%7%

29%31%

35%

0%

5%

10%

15%

20%

25%

30%

35%

40%

Perth Stroke Study2

Oxfordshire Stroke Project3

NOMASS1

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: 2914-2921

PLATO’s study

According to a meta analysis of randomized clinical study including 287 subjects:

ATC. BMJ. 2002 Jan 12; 324 (7329) : 71-86.ATC. BMJ. 2002 Jan 12; 324 (7329) : 71-86.

ACS: patients with stroke or acute stroketend to develop extracranial major bleedinginduced by anti-platelet therapy

Increase antithrombotic efficacy and reduce hemorrhage event: sufficient balance required

出血危险 缺血危险

抗栓治疗

14

Anti-platelet therapy for ACS patients with stroke/TIA history

Main content

CREDO study design

16

n=2, 116 patients

1 yearG

rou

p A

Gro

up

BPCI 28 days

Placebo loading dose 300mg

+ ASA 325 mgPlacebo + 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

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

18

18.5 % RRR

p = 0.23

10

9

8

7

6

5

4

3

2

1

00 7 14 21 28

Number of days after randomization

6.8%

8.3%28-day result

Dea

th,

MI,

U

TV

R (

%)

Without pre-treatment

With pre-treatment

Number of risky casesWithout pre-treatment 915 839 834 834 832With pre-treatment 900 838 836 834 832

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,

str

ok

e o

r d

ea

th (

%)

Several months after randomization0 3 6 9 12

8.5%

0

5

10

15

Early efficacy

benefit of patients after good treatment increases with time

Number of risky casesClopidogrel 10, 53 931 920 909 901Placebo 1, 063 929 910 881 863

Benefit of long-term Clopidogrel therapy for PCI patients

Safety index: Severe hemorrhage event28-day result ITT

20

* On top of standard therapy including ASAITT=Intent-to-treat populationPP = 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

Prasugrel60 mg loading dose/10 mg

maintenance dose

Clopidogrel300 mg loading dose/75 mg

maintenance dose

Level I end point: cardiovascular (CV) death, myocardial infarction (MI) , strokeLevel 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 hemorrhageMajor 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: 2001-15

0

5

10

15

0 30 60 90 180 270 360 450

Prasugrel

Clopidogrel

day

En

d p

oin

t eve

nts

(%

) 12.1

9.9

Prasugrel

Clopidogrel 1.82.4

CV death/ MI / Stroke

TIMI major bleeding risk Non-CABG related hemorrhage

HR 0.81 (0.73-0.90)

P=0.0004

HR 1.32 (1.03-1.68)

P=0.03

↓138 events

↑35 events

NNT = 46

NNH = 167

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: 2001-15

N=13, , 457

Eve

nt r

ate

(%

)

HR 1.32P=0.03

NNH=167

HR 1.52P=0.01

P=0.23 P=0.74P=0.002

Clopidogrel

Prasugrel

1.8

0.9 0.9

0.10.3

2.4

1.41.1

0.4 0.3

0

2

4

TIMI major bleeding

Life-threatening hemorrhage

Non-fatal hemorrhage

Fatal hemorrhag

e

Intracranial hemorrhage

RRI32%

RRI52%

Prasugrel significantly increases hemorrhage risk

Net clinical benefit of Prasugrel for patients with stroke/TIA history is harmfulNo net clinical benefit for patients ≥75 yrs and body weight < 60 kg

Total

≥60 kg

＜ 60 kg

＜ 75岁

≥75岁

No

Yes

0.5 1 2

Stroke/TIA history

Age

Body weigh

t

Risk (%)

+ 54

-16

-1

-16

+3

-14

-13

Risk ratio

Pint = 0.006

Pint = 0.18

Pint = 0.36

Prasugrel preferred

Clopidogrelppreferred

* Combined end point of all-cause death, MI, stroke and non-CABG related TIMI severe hemorrhage

Wiviott SD et al NEJM 2007; 357: 2001-15

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 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: 599-605.

PLATO experiment design

The longest treatment period was 12 months (11 months in average)

(N=18, 624)

ASA* + Clopidogrel300-mg LD/75 mg qd†

300-mg LD before PCI operation

ASA* + Ticagrelor180-mg LD/90 mg bid†

90 mg LD for patients accepting PIC treatment more than

24 hours after randomization.

ACS patientUA/NSTEMI/STEMI

PCI, drug therapy, or CABG therapy

Treatment drug shall be administered immediately after the diagnosis is confirmed (≤ 24 h); ASA 75-100 mg/d for every patient, except for that intolerant.

Treatment drug shall be administered immediately after the diagnosis is confirmed (≤ 24 h); ASA 75-100 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)

1312

11109876

543210

累计

发生

率 (

%)

0 60 120

180

240

300

360Period after randomization (day)

HR (0.84 (95% CI 0.77–0.92) , p<0.001

ClopidogrelTicagrelor

No. at riskTicagrelor 9, 333 8, 628 8, 460 8, 219 6, 743 5, 161 4, 147Clopidogrel 9, 291 8, 521 8, 362 8, 124 6, 650 5, 096 4, 047K-M = Kaplan–Meier; HR = hazard ratio; CI = confidence interval

11.7

9.8

RRR 16%

Wallentin L et al. New Engl J Med.2009; 361

Major bleeding – main safety

end points

10

15

0

K-M

esti

mate

d r

ate

(%

per

year)

0 60 120

180

240

300

360Period after initial dose (day)

No. at riskTicagrelor 9, 235 7, 246 6, 826 6, 545 5, 129 3, 783 3, 433Clopidogrel 9, 186 7, 305 6, 930 6, 670 5, 209 3, 841 3, 479

11.6

12.1

Clopidogrel

Ticagrelor

HR 1.04 (95% CI 0.95–1.13) , p=0.43

5

Wallentin L et al. New Engl J Med.2009; 361

Risk of non-CABG related major bleeding:

significantly increased forTicagrelor

7

0

K-M

est

imate

d r

ate

(%

per

year)

9

8

6

5

4

3

2

1

Non-CABGPLATO major

bleeding

4.5

3.8

p=0.03

2.82.2

p=0.03

7.47.9

NS

5.35.8

NS

Ticagrelor

Clopidogrel

Non-CABGTIMI majorbleeding

CABGPLATO major

bleeding

CABGTIMI 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: 3409-3410

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;

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.

2012 ACCF-AHA UA-NSTEMI指南2012 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