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Transcript of Bi Qi Neurology Department of Beijing Anzhen Hospital of the Capital University of Medical Sciences...
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