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Cardio Aspirin
A New Evidence of ASAs
benefit in the patient at risk
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CVD: a global disease with a huge
impact and cost burden
Injuries 11.1% Musculoskeletal 13.8%
Cancer 10.1%
Respiratory disease
9.4%
Nervous system
disorders 7.4%
Mental disorders 6.0%
Digestive disorders 4.8% Diabetes 0.9%
Other 21.3%
Percentage of total healthcare cost in Canada, 1993
CVD 15.2%
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CVD is a leading cause of death
COPD = chronic obstructive pulmonary disease
Source: CDC/NCHS and the American Heart Association.
0
100
200
300
400
500
600
Deaths(th
ousands)
Men
Women
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Atherothrombosis in Asia
A high proportion of atherothromboticcardiovascular disease (CVD); epidemiologicaldata show it under-reported.
CVD accounts for 15-30% of all deaths in theAsia-Pacific region.
CVD mortality rate on the increase in someareas (China, Malaysia, Korea, Japan)
Mortality rate for stroke in East Asia is higher
than New Zealand or Australia.
Khor GL.Asia Pacific J Clin Nutr2001;10:7680
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Hypertension
CVD disease risk factors
Diabetes
Smoking
Obesity
Familial
Advancing age
Inactivity
Hyper-
cholesterolaemia
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CVD: the leading cause of premature death
among people with diabetes
Individuals with diabetes are 24 times more likely to
develop CVDthan individuals without diabetes
At least 65%of individuals with diabetes die from
coronary heart disease (CHD) or stroke
CHD decreases the life-expectancyof individuals with
diabetes by 510 years
Diabetes mellitus is associated with a risk of fatal CHDthat
is as high as the risk associated with a history of myocardial
infarction in individuals without diabetes
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Hypertension is a major risk factor
for CVD
Individuals with high blood pressure are twiceas
likely to have a myocardial infarction (MI)and
eight timesmore likely to suffer a strokethan those
with normal blood pressure
The World Health Organization has shown thathypertension causes approximately 50%of all
cases of coronary heart diseaseworldwide
Even individuals with high to normal blood
pressureare 2.5 timesmore likely to suffer an MI,a stroke or heart failurethan individuals with
optimal blood pressure
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Integrating risk assessment with
intervention
Framingham coronary prediction algorithm assesses the 10-year risk of developing coronary
heart disease (CHD) in middle-aged Caucasian menand women without known heart disease
Mnster Heart Study (PROCAM) riskcalculator assesses the risk of myocardial infarction in
Caucasian men, aged 4065 years, withoutsymptoms of CHD, over 8 years
European Society of Cardiology coronaryrisk chart assesses theabsolute risk of developing CHD over
the next 10 years
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Estimate of 10-Year Risk for Men
(Framingham Point Scores)
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Estimate of 10-Year Risk for Women
(Framingham Point Scores)
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Algorithm for making decision on the use of low dose ASA for primary
prevention of CHD
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Atherothrombosis
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Definition
Atherothrombosis is a chronic disease, characterized byunpredictable disruption of an atherosclerotic plaque,leading to platelet activation and thrombus formation.
It is the underlying condition for ischemic stroke,
myocardial infarction, transient ischemic attack, acutecoronary syndrome, and vascular death.
Affects large and medium-diameter arteries throughoutthe arterial tree.
Atherothrombosis is a leading cause of morbidityand mortality.
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Atherosclerosis begins early in life
and ultimately leads to CVD
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Myocardial infarction can be triggered
by the rupture of an atherosclerotic
plaque
Vulnerable
atherosclerotic
plaque
Physical or mental
stress triggers
plaque rupture
Coagulability increases or
vasoconstriction triggers complete
occlusion by thrombus
Minor
plaque
rupture
Non-
occlusive
thrombusOcclusive
thrombus
Majorplaque
rupture
Occlusive
thrombus
MI or
sudden
cardiacdeath
Asymptomatic,
unstable anginaor non-Q-MI
Atherosclerotic
plaque on
blood vessel
wall
MI = myocardial infarction
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Plaquerupture
Platelet activationand aggregation
Non-occlusivethrombus
Acute syndrome: coronary cerebrovascular peripheral
Occlusivethrombus
Healing andresolution
Plaque growth
The development of atherothrombosis
a generalized and progressive process
Adapted from: Drouet L. Cerebrovasc Dis2002; 13(suppl 1): 16.
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Major clinical manifestations
of atherothrombosis
Adapted from: Drouet L. Cerebrovasc Dis2002; 13(suppl 1): 16.
Transientischemic attack
Angina: Stable
Unstable
Ischemicstroke
Myocardial
infarction
Peripheral arterialdisease: Intermittent claudication Rest Pain Gangrene Necrosis
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Angiogram: right coronary artery
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24.7% 29.9%
Coronary
disease7.4%
Atherothrombosis is commonly found in more than one
arterial bed in an individual patient*
Cerebrovascular
disease
Peripheral arterial disease
3.8% 11.8%
19.2%
* Data from CAPRIE study (n=19,185)Coccheri S. Eur Heart J 1998; 19(suppl): P1268.
3.3%
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Identifying those at risk of atherothrombosis
Yusuf S etal. Circulation2001; 104: 274653. 2.Drouet L. Cerebrovasc Dis2002;13(suppl 1):16.
Lifestyle
Smoking
Diet
Lack of exercise
Genetic
Genetic traits
Gender
Age
Generalizeddisorders
Obesity
Diabetes
Systemic
conditions
History of vascularevents
Hypertension
Hyperlipidemia
Hypercoagulable
states
Homocystinemia
Local factors
Elevated prothrombotic factors: fibrinogen, CRP, PAI-1
Blood flow patterns, vessel diameter, arterial wall structure
Atherothrombosismanifestations
(myocardial infarction,
stroke, vascular death)
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Thromboembolic disease
why is ASA so important?
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Therapeutic Options
The aim of therapy is to prevent thrombus formationby inhibiting platelet aggregation.
Antiplatelet therapy has been shown to reduce theodds of serious vascular events.
Four main classes of antiplatelet drug: Cyclooxygenase inhibitors (aspirin)
Thienopyridine derivatives (e.g. clopidogreland ticlopidine)
Phosphodiesterase inhibitors (e.g. cilostazol,
dipyridamole) Glycoprotein IIb/IIIa receptor blockers
(e.g. abciximab)
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The role of ASA in the inhibition of
platelet aggregation
Phospholipase
Arachidonic acid
Cyclic endoperoxides
Prostacyclin Thromboxane A2
Inhibition of plateletaggregation: vasodilation
Platelet aggregation:vasoconstriction
Phospholipase A2
Cyclo-oxygenase
(Vascularendothelium) (Platelet)
Inhibition by
ASA
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Aspirin
Irreversibly inhibits cyclooxygenase and prevents synthesis of thromboxane A2.
Effect lasts for the lifetime of the platelet (about 7-10 days)..
Partially inhibits aggregation induced by adenosine diphosphate (ADP).
CLOP
COX
ADP
ADP
C
GPllb/llla(Fibrinogen receptor)
Collagen thrombin
TXA 2Activation
TXA2
COX (cyclo-oxygenase)ADP (adenosine diphosphate)
TXA2 (thromboxane A2)
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ASA in thePRIMARY and SECONDARY
prevention of CVD
The clinical evidence:
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Healthy individuals: ASA reduces the
risk of a first myocardial infarction
Cardiovascualrendpoints
ASA
Placebo
*p=0.00001
**p=0.007
***p
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ASA reduces IHD in men at
increased risk
Cardiovascularevents/
1,0
00pat
ient-years
ASAwarfarin
ASA
Warfarin
Placebo
IHD = ischaemic heart disease; MI = myocardial infarctionThe Medical Research Councils General Practice Research Framework. Lancet 1988;352:23341.
0
2
4
6
8
10
12
14
***
***
*p=0.06 vs placebo
**p=0.005 vs placebo
***p=0.02 vs placebo
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Primary prevention: ASA reduces the
incidence of cardiovascular events in
individuals at high risk
0
20
40
60
80100
120
140
160
180
200
Cardiovascularendpoints
ASA
No ASA
MI = myocardial infarction; PAD = peripheral artery diseasede Gaetano G. Lancet 2001;357:8995.
*
***p=0.049
**p=0.014
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Primary prevention: ASA in patients
with diabetes mellitus
Cardiovascularendpoints
ove
r5years
MI = myocardial infarction
The Early Treatment Diabetic Retinopathy Study (ETDRS) Investigators. JAMA 1992;268:12921300.
0
2
4
6
8
10
12
14
16
ASA
Placebo
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ASA and the risk of intracerebral
haemorrhage
MI = myocardial infarction
He J, et al. JAMA 1998;280:19305.
Cardiov
ascularevents/1,00
0patients
14
12
10
8
6
4
2
0
2
The substantial clinical benefits of
low-dose ASA clearly outweigh the
low risk of haemorrhagic stroke
(1.2 events per 1,000 patients
treated)
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Annual risk of a vascular event on placebo
Subjects in whom avascular event is
prevented by aspirin
per 1,000 treated for
1 year
0
10
20
30
40
50
60
0 5 10 15 20%
Healthy Subjects
Stable Angina
Survivors of MI
Unstable
Angina
The Risk of Vascular Complications is the MajorDeterminant of the Absolute Benefit of
Antiplatelet Therapy
Patrono et al, Chest
2001;119:39S-63S
NNT
20
55
100
1000
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ASA is greatly under-used for
cardiovascular disease prevention
ARBs = angiotensin receptor blockers; ACE = angiotensin-converting enzymeCardiomonitor Database, TNS Healthcare, 2000
Percentage of patients with coronary heart disease and hypertension
receiving platelet aggregation inhibitors (PAIs)
PAIs
Lipid lowering
ACE inhibitor
Calcium channel blockers
Beta blockers (plain)
Nitrates
USA
4% 1%
26%
43%
25%14%
20%
46%
0%
France
28%
25%
31%
9%11%
52%
30%
5%
ARBs (plain)
Diuretics
Coronary
therapeutics
Germany
26%
48%
17%
12%
40%
41%
8%
4%1%
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ASA is greatly under-used for
cardiovascular disease prevention
Only 26 % of coronary artery disease patientswho could benefit
took ASA in 1996.1
Only 50 % of patients with history of acute MItook ASA regularly. 2
Furthermore, Although 86 % of hospital patients with acute MIwere
judge to be ideal for, and received ASA therapy while in hospital,only 78 % continued treatment following hospital dischargeeven
though these patients were still at high risk of further cardiovascular
events.3
Of 2,367 non users of ASA, 998 patients were eligiblefor antiplatelet
agents but did not receivethem, and 50 % of these patients hadreceived no advicefrom their physician on the benefits of ASA
therapy.4
1. Stafford R. Circulation 2000: 101:1097-101
2. Shahar E, folsom AR, Romm FJ, et al. Am Heart J 1996;131:915-22
3. OConnor G, Quinton H, Traven N, et al. JAMA 1999:281:627-33
4. Califf R, Delong E, ostbye T, et al. Am J Cardiol 2002;89:653-61
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ASA is recommended for
prevention of CVD
Secondary prevention American Heart Association/ American College of
Cardiology
European Society of Cardiology
European Atherosclerosis Society
European Society of Hypertension American Diabetes Association
American College of Phsicians
Primary prevention US preventive Services Task Force
British Hypertension Society
American Diabetes Association
American Heart Association
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Recommendations from major clinical international
organizations on the use of low-dose ASA for primary
prevention in patients at risk of cardiovascular events.
Organization Recommendation
US Preventive Services Task
Force, 2002
ASA preventive therapy with adults at increasing
risk of CHD. Men > 40 years, post menopausal
women, and younger individuals with risk factorsfor CHD(eg. Hypertension, diabetes or smoking) at
increased risk of CHD.
American Diabetes
Association, 2002 and
confirmed in 2003
ASA for primary prevention in patients with
diabetes, > 40 years with one or more risk factors
for CVD.
2 nd Joint Task Force of
European and other Societies
on Coronary Prevention, 1998
ASA (at least 75 mg/day) should be considered for
virtually all patients with CHDor other
atherosclerotic disease.
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Organisation Recommendation
AHA, 2002 Treatment with 75-160 mg/day ASA should be considered
for individuals at high risk(especially those with a 10 year
risk of CHD of 10%)
British Hypertension
Society, 1999
ASA recommended for patients with hypertension, aged
50 years, whose blood pressure satisfactorily controlled
(
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Benefit vs harm of ASA therapy for
patients at different levels of risk for
CHD events
Outcome Estimated 5-year risk for
CHD events at baseline
1% 3% 5%
CHD events avoided 3(14) 8(412) 14(620)
Haemorrhagic stroke
caused1(02) 1(02) 1(02)
Major gastrointestinal
bleeding events caused 3(24) 3(24) 3(24)
CHD = coronary heart disease; CV = cardiovascularUS Preventive Services Task Force. Ann Intern Med 2002;136:15760.
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Clopidogrel: risk of bleeding
Variable Clopidogrel +
ASA
(n=6,259)
Placebo + ASA
(n=6,303)
Relative
risk
P value
Major bleeding 3.7% 2.7% 1.38 0.01
Necessitating
transfusion of
>2 units of blood
2.8% 2.2% 1.30 0.02
Life-threatening 2.2% 1.8% 1.21 0.13
Minor bleeding 5.1% 2.4% 2.12
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Safety: a lower risk of side
effects than ticlopidine
0
10
20
30
40
50
60
70
Incidenc
e(%)
Ticlopidine
ASA
Hass WK, et al., for the Ticlopidine ASA Stroke Study Group. N Engl J Med 1989;321:5017
*
* *
*p
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Other actions of ASA in preventing CVD
ASA improves endothelial functionitmodulates tone, thrombotic potential and
atherosclerotic predisposition of the blood
vessel wallASA modifies plateletneutrophil interactions
ASA acts as an antioxidantand protectsagainst free radicals
ASA protectsblood vessels from the effects ofinflammation and infection
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Cardio Aspirin
The ASA of choice
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Contra Indication to ASA
People with ASA allergy, bleeding tendency,
anticoagulant therapy, recent
gastrointestinal bleeding, and clinically
active hepatic diseaseare not candidates for
ASA therapy.
ASA should not be recommended for
patients under the age 21 yearsbecause of
increase risk of Reyes syndrome. People
under the age of 30 have generally not beenstudied
Colwell JA; American Diabetes Association. Aspirin therapy in diabetes.
Diabetes Care 2004; 27(Suppl1): S72-S73
A id i t f C di A i i
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Acid resistance of Cardio Aspirin
reduces potential gastrointestinal
irritation
pH >67
pH
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Methods
84 patients were enrolled in a 3-month study, randomly assigned to receive either placebo or enteric coated aspirin, bufferedaspirin or plain aspirin. Each volunteer took daily 325mg tablet of one of the various aspirin preparations or placebo.
Clinical Therapeutics1993;15 (2):314-320
Good GI tolerance by enteric coated aspirinEndoscopic Comparison of Three Aspirin Preparations and Placebo
Endoscopicsco
res
1.60
0.900.72
Plain Buffered Enteric coated Placebo
n=21 n=20 n=21 n=18
P=0.0031
N.S.
2.33
N.S.
M j li ti f t i t d Pl b
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Enteric coated aspirin 325mg/day(double-blind) or placebo used for ischemic
stroke prevention to 1,330 patients with atrial fibrillation during an mean
follow-up of 1.3 years.
Enteric
coated ASA 552 720 10 1.4 5
Placebo 568 731 14 1.9 4
All relevant
bleedingAllocation
Rate
(%/yr)
Patients
(n)
Observation
period
(patient-yr)
All major
complications
Major complications of enteric coated vs Placebo
Circulation 1991;84,2:527-539
SPAF Study
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Summary (1)
CVD is an escalating worldwide health
problem
Primary prevention is the keyto reducing
the global burden of CVD in patients withrisk factors such as diabetes,
hypertension, dyslipidaemia or obesity
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Summary (2)
Low-dose ASAis the first choice forprimary and secondary prophylaxisofCVD based on
proven clinical efficacy
excellent safety and tolerability
cost-effectiveness
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Prevention Always Better
than Treatment
SK
ASA is as effective and safer than
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ASA is as effective and safer than
statins (HMG Co-A reductase inhibitors)
in primary prevention of CVD
1. The Medical Research Council's General Practice Research Framework. Lancet 1998;351:23341.
2. Shepherd J, et al. N Engl J Med 1995;333:13017.
The yearly rate of nonfatal MIs was lower in
patients receiving ASA treatment (0.9/year)
compared with those receiving statin treatment
(1.3/year)1,2
Statins are expensive compared with low-dose
ASA
Statins have been linked to hepatotoxicity
and myositis Clinical monitoring is required
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The cost benefits of prophylactic
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The costbenefits of prophylactic
low-dose ASA (2)
Class of drug Mean cost/day
19931998 ()
ACE inhibitors 0.7824
Beta-blockers 0.0324Calcium antagonists 0.7390
Diuretics 0.3729
Low-dose ASA (100mg/day) 0.0774
Statins (lipid-lowering agents) 1.1822