cardioaspirin presentation - summary

8/10/2019 CardioAspirin Presentation - Summary

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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


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


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

cardioaspirin presentation - summary

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