Cardio Aspirin

A New Evidence of ASAs

benefit in the patient at risk

CVD: a global disease with a huge

impact and cost burden
Percentage of total healthcare cost in Canada, 1993

Injuries 11.1%

Musculoskeletal 13.8%

Cancer 10.1%
CVD 15.2%
Respiratory disease
9.4%
Nervous system
disorders 7.4%
Mental disorders 6.0%
Digestive disorders 4.8%

Other 21.3%
Diabetes 0.9%

Deaths (thousands)

CVD is a leading cause of death

600

Men

500

Women

400
300
200
100
0

COPD = chronic obstructive pulmonary disease

Source: CDC/NCHS and the American Heart Association.

Atherothrombosis in Asia

A high proportion of atherothrombotic

cardiovascular disease (CVD); epidemiological
data show it under-reported.
CVD accounts for 15-30% of all deaths in the
Asia-Pacific region.
CVD mortality rate on the increase in some
areas (China, Malaysia, Korea, Japan)
Mortality rate for stroke in East Asia is higher
than New Zealand or Australia.

Khor GL. Asia Pacific J Clin Nutr 2001;10:7680

CVD disease risk factors

Diabetes
Smoking

Hypertension
Hypercholesterolaemia

Familial

Inactivity
Obesity

Advancing age

CVD: the leading cause of premature death

among people with diabetes
Individuals with diabetes are 24 times more likely to
develop CVD than individuals without diabetes
At least 65% of individuals with diabetes die from
coronary heart disease (CHD) or stroke
CHD decreases the life-expectancy of individuals with
diabetes by 510 years
Diabetes mellitus is associated with a risk of fatal CHD that
is as high as the risk associated with a history of myocardial
infarction in individuals without diabetes

Hypertension is a major risk factor

for CVD
Individuals with high blood pressure are twice as
likely to have a myocardial infarction (MI) and
eight times more likely to suffer a stroke than those
with normal blood pressure
The World Health Organization has shown that
hypertension causes approximately 50% of all
cases of coronary heart disease worldwide
Even individuals with high to normal blood
pressure are 2.5 times more likely to suffer an MI,
a stroke or heart failure than individuals with
optimal blood pressure

Integrating risk assessment with

intervention
Framingham coronary prediction algorithm
assesses the 10-year risk of developing coronary
heart disease (CHD) in middle-aged Caucasian men
and women without known heart disease

Mnster Heart Study (PROCAM) risk

calculator
assesses the risk of myocardial infarction in
Caucasian men, aged 4065 years, without
symptoms of CHD, over 8 years

European Society of Cardiology coronary

risk chart
assesses the absolute risk of developing CHD over
the next 10 years

Estimate of 10-Year Risk for Men

(Framingham Point Scores)

Estimate of 10-Year Risk for Women

(Framingham Point Scores)

Algorithm for making decision on the use of low dose ASA for primary
prevention of CHD

Atherothrombosis

Definition
Atherothrombosis is a chronic disease, characterized by
unpredictable 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, acute
coronary syndrome, and vascular death.

Affects large and medium-diameter arteries throughout

the arterial tree.
Atherothrombosis is a leading cause of morbidity
and mortality.

Atherosclerosis begins early in life

and ultimately leads to CVD

Myocardial infarction can be triggered

by the rupture of an atherosclerotic
plaque
Coagulability increases or
Physical or mental
vasoconstriction triggers complete
stress triggers
occlusion by thrombus
plaque rupture

Atherosclerotic
Vulnerable
plaque on
blood vessel atherosclerotic
plaque
wall

Minor
plaque
rupture

Major
plaque
rupture

MI = myocardial infarction

Nonocclusive
thrombus

Asymptomatic,
unstable angina
or non-Q-MI

Occlusive
thrombus

Occlusive
thrombus

MI or
sudden
cardiac
death

The development of atherothrombosis

a generalized and progressive process
Acute syndrome:
coronary
cerebrovascular
peripheral

Occlusive
thrombus

Plaque
rupture

Platelet activation
and aggregation

Non-occlusive
thrombus

Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 16.

Healing and
resolution

Plaque growth

Major clinical manifestations

of atherothrombosis

Ischemic
stroke
Myocardial
infarction

Transient
ischemic attack

Angina:
Stable
Unstable

Peripheral arterial
disease:

Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 16.

Intermittent claudication
Rest Pain
Gangrene
Necrosis

Angiogram: right coronary artery

Atherothrombosis is commonly found in more than one

arterial bed in an individual patient*

Cerebrovascular
disease

Coronary
disease

7.4%
24.7%

29.9%
3.3%
11.8%

3.8%

19.2%

Peripheral arterial disease

* Data from CAPRIE study (n=19,185)
Coccheri S. Eur Heart J 1998; 19(suppl): P1268.

Identifying those at risk of atherothrombosis

Local factors
Elevated prothrombotic factors: fibrinogen, CRP, PAI-1
Blood flow patterns, vessel diameter, arterial wall structure

Generalized
disorders
Obesity
Diabetes

Atherothrombosis
manifestations
(myocardial infarction,
stroke, vascular death)

Genetic
Genetic traits
Gender
Age

Lifestyle
Smoking
Diet
Lack of exercise

Yusuf S et al. Circulation 2001; 104: 274653. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1):16.

Systemic
conditions
History of vascular
events
Hypertension
Hyperlipidemia
Hypercoagulable
states
Homocystinemia

Thromboembolic disease
why is ASA so important?

Therapeutic Options
The aim of therapy is to prevent thrombus formation
by inhibiting platelet aggregation.
Antiplatelet therapy has been shown to reduce the
odds of serious vascular events.
Four main classes of antiplatelet drug:
Cyclooxygenase inhibitors (aspirin)
Thienopyridine derivatives (e.g. clopidogrel
and ticlopidine)
Phosphodiesterase inhibitors (e.g. cilostazol,
dipyridamole)
Glycoprotein IIb/IIIa receptor blockers
(e.g. abciximab)

The role of ASA in the inhibition of

platelet aggregation
Phospholipase
Phospholipase A2

Arachidonic acid
Cyclo-oxygenase
(Vascular
endothelium)

Cyclic endoperoxides

Prostacyclin
Inhibition of platelet
aggregation: vasodilation

Inhibition by
ASA
(Platelet)

Thromboxane A2
Platelet aggregation:
vasoconstriction

Aspirin

Irreversibly inhibits cyclooxygenase and prevents synthesis of thromboxane A 2.

Effect lasts for the lifetime of the platelet (about 7-10 days)..

Partially inhibits aggregation induced by adenosine diphosphate (ADP).

CLOP

C
ADP
ADP

GPllb/llla

Activation

(Fibrinogen receptor)

COX

COX (cyclo-oxygenase)
ADP (adenosine diphosphate)
TXA2 (thromboxane A2)

TXA2

Collagen thrombin
TXA 2

ASA in the
PRIMARY and SECONDARY
prevention of CVD
The clinical evidence:

Healthy individuals: ASA reduces the

risk of a first myocardial infarction
Cardiovascualr endpoints

250

ASA
Placebo

200
150

*p=0.00001
**p=0.007
*

***

100
50
**
0

MI = myocardial infarction
Physicians Health Study Research Group. N Engl J Med 1989;321:12935.

***p<0.00001

ASA reduces IHD in men at

increased risk

Cardiovascular events/
1,000 patient-years

14

ASAwarfarin
ASA
Warfarin
Placebo

12
10
8

***

*
**

*p=0.06 vs placebo
**p=0.005 vs placebo

6
4

***p=0.02 vs placebo

2
0

IHD = ischaemic heart disease; MI = myocardial infarction

The Medical Research Councils General Practice Research Framework. Lancet 1988;352:23341.

Cardiovascular endpoints

Primary prevention: ASA reduces the

incidence of cardiovascular events in
individuals at high risk
200

ASA

180
160
140
120
100
80
60
40
20
0

No ASA
**

*p=0.049
**p=0.014

MI = myocardial infarction; PAD = peripheral artery disease

de Gaetano G. Lancet 2001;357:8995.

Primary prevention:
ASA in hypertensive patients
Major cardiovascular events/
1,000 patient-years

12
10

ASA
Control
*

*p=0.03
**p=0.002

8
6
4
**
2
0

MI = myocardial infarction
Hansson L, et al. Lancet 1998;351:175563.

Primary prevention: ASA in patients

with diabetes mellitus
Cardiovascular endpoints
over 5 years

16
14

ASA
Placebo

12
10
8
6
4
2
0

MI = myocardial infarction
The Early Treatment Diabetic Retinopathy Study (ETDRS) Investigators. JAMA 1992;268:12921300.

Cardiovascular events/1,000 patients

ASA and the risk of intracerebral

haemorrhage

2
0
2
4
6
8
10
12
14

MI = myocardial infarction
He J, et al. JAMA 1998;280:19305.

The substantial clinical benefits of

low-dose ASA clearly outweigh the
low risk of haemorrhagic stroke
(1.2 events per 1,000 patients
treated)

The Risk of Vascular Complications is the Major

Determinant of the Absolute Benefit of
Antiplatelet Therapy
60

NNT

50

Subjects in whom a
vascular event is
prevented by aspirin
per 1,000 treated for
1 year

40
30
20

55

Survivors of MI
Stable Angina

10

100
1000

Healthy Subjects

0
Patrono et al, Chest
2001;119:39S-63S

20

Unstable
Angina

10

15

20 %

Annual risk of a vascular event on placebo

ASA is greatly under-used for

cardiovascular disease prevention
Percentage of patients with coronary heart disease and hypertension
receiving platelet aggregation inhibitors (PAIs)
4% 1%

1%

0%

5%

4%

8%
26%

28%

30%

46%

26%

41%
25%

43%

48%
52%

20%

14%

25%

USA

31%

40%
17%

11% 9%

12%

France

Germany

ARBs (plain)

PAIs

Calcium channel blockers

Diuretics

Lipid lowering

Beta blockers (plain)

Coronary
therapeutics

ACE inhibitor

Nitrates

ARBs = angiotensin receptor blockers; ACE = angiotensin-converting enzyme

Cardiomonitor Database, TNS Healthcare, 2000

ASA is greatly under-used for

cardiovascular disease prevention
Only 26 % of coronary artery disease patients who could benefit
took ASA in 1996.1
Only 50 % of patients with history of acute MI took ASA regularly. 2
Furthermore, Although 86 % of hospital patients with acute MI were
judge to be ideal for, and received ASA therapy while in hospital,
only 78 % continued treatment following hospital discharge even
though these patients were still at high risk of further cardiovascular
events.3
Of 2,367 non users of ASA, 998 patients were eligible for antiplatelet
agents but did not receive them, and 50 % of these patients had
received no advice from their physician on the benefits of ASA
therapy.4
1.
2.
3.
4.

Stafford R. Circulation 2000: 101:1097-101

Shahar E, folsom AR, Romm FJ, et al. Am Heart J 1996;131:915-22
OConnor G, Quinton H, Traven N, et al. JAMA 1999:281:627-33
Califf R, Delong E, ostbye T, et al. Am J Cardiol 2002;89:653-61

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

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 factors
for 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 CHD or other
atherosclerotic disease.

Recommendations from major clinical international

organizations on the use of low-dose ASA for primary
prevention in patients at risk of cardiovascular events.
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
(<150mmHg) and who have either target organ damage,
diabetes or a 10 year risk of CHD of 15%

Third National Health and

Nutrition Examination
Survey, 2001

ASA recommended for every adult with at least one risk

factor for CVD.

Diabetes UK, 2001

ASA is recommended for patients with diagnosed diabetes

who are at least 30 years old age and have one or more risk
factors for CVD.

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
caused

1(02)

1(02)

1(02)

Major gastrointestinal
bleeding events caused

3(24)

3(24)

3(24)

CHD = coronary heart disease; CV = cardiovascular

US Preventive Services Task Force. Ann Intern Med 2002;136:15760.

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

<0.001

Total with bleeding

complications

8.5%

5.0%

1.69

<0.001

The CURE Trial Investigators. N Engl J Med 2001;345:494502

Safety: a lower risk of side

effects than ticlopidine
70
Ticlopidine

Incidence (%)

60

ASA
*p<0.05

50
40

30
20
10
0

0*

Hass WK, et al., for the Ticlopidine ASA Stroke Study Group. N Engl J Med 1989;321:5017

Other actions of ASA in preventing CVD

ASA improves endothelial function it

modulates tone, thrombotic potential and
atherosclerotic predisposition of the blood
vessel wall

ASA modifies platelet neutrophil interactions

ASA acts as an antioxidant and protects
against free radicals

ASA protects blood vessels from the effects of

inflammation and infection

Cardio Aspirin
The ASA of choice

Contra Indication to ASA

People with ASA allergy, bleeding tendency,
anticoagulant therapy, recent
gastrointestinal bleeding, and clinically
active hepatic disease are not candidates for
ASA therapy.
ASA should not be recommended for
patients under the age 21 years because of
increase risk of Reyes syndrome. People
under the age of 30 have generally not been
studied

Colwell JA; American Diabetes Association. Aspirin therapy in diabetes.

Diabetes Care 2004; 27(Suppl1): S72-S73

Acid resistance of Cardio Aspirin

reduces potential gastrointestinal
irritation

Acid-resistant
enteric coating

pH <3

pH >67

ASA absorption
in upper
intestine

Good GI tolerance by enteric coated aspirin

Endoscopic Comparison of Three Aspirin Preparations and Placebo
P=0.0031
N.S.

Endoscopic scores

2.33
1.60
N.S.

0.90

Methods

Plain
n=21

Buffered
n=20

Enteric coated
n=21

0.72

Placebo
n=18

Clinical Therapeutics1993;15 (2):314-320

84 patients were enrolled in a 3-month study, randomly assigned to receive either placebo or enteric coated aspirin, buffered
aspirin or plain aspirin. Each volunteer took daily 325mg tablet of one of the various aspirin preparations or placebo.

Major complications of enteric coated vs Placebo

SPAF Study
Observation
All major
period
complications
(patient-yr)

Allocation

Patients
(n)

Rate
(%/yr)

All relevant
bleeding

Enteric
coated ASA

552

720

10

1.4

Placebo

568

731

14

1.9

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.
Circulation 1991;84,2:527-539

The economic burden of

cardiovascular disease
Cost to Economy
3,270 million
Direct Medical Cost
2,498 million
Preventative strategies
25 million

ASA

Dissolution profile of various enteric-coated

tablets of ASA
120

% ASA dissolved

100

80

ThromboAspilet
Farmasal

60

Astika
40
Ascardia
20

CardioAspirin

0
10

20

30

40

50

60

Time (minutes)

70

80

90

Ref: Bayers data on file, March 2004

Note : Release of ASA from Cardio Aspirin is slower than from the other
enteric- coated tablets more salicylate & less ASA are detected in the
systemic
blood stream less gastric lesions ( tolerability)

Summary (1)
CVD is an escalating worldwide health
problem
Primary prevention is the key to reducing
the global burden of CVD in patients with
risk factors such as diabetes,
hypertension, dyslipidaemia or obesity

Summary (2)
Low-dose ASA is the first choice for
primary and secondary prophylaxis of
CVD based on
proven clinical efficacy
excellent safety and tolerability
cost-effectiveness

Prevention Always Better

than Treatment

SK

ASA is as effective and safer than

statins (HMG Co-A reductase inhibitors)
in primary prevention of CVD
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
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 costbenefits of prophylactic

low-dose ASA (1)

Atorvastatin 40mg

73.4

Simvastatin 40mg

46.3

Pravastatin 40mg

46.3
19.8

Fluvastatin 40mg
2.05

Low-dose ASA
0

20

40

60

Cost of 28 days of treatment ()

Adapted from MIMS, 2001.

80

The costbenefits of prophylactic

low-dose ASA (2)
Class of drug

Mean cost/day
19931998 ()

ACE inhibitors

0.7824

Beta-blockers

0.0324

Calcium antagonists

0.7390

Diuretics

0.3729

Low-dose ASA (100mg/day)

0.0774

Statins (lipid-lowering agents)

1.1822