Aspirin+and+vascular

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Antiplatelet Antiplatelet

Therapy Evidence and Therapy Evidence and GuidelinesGuidelines

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Ischemic heart diseaseDefinition

• An imbalance between the supply of oxygen and the myocardial demand resulting in myocardial ischaemia.

• Angina pectorisSymptom not a diseaseChest discomfort associated with abnormal

myocardial function in the absence of myocardial necrosis

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Manifestations

• Sudden death• Myocardial infarction• Acute coronary syndrome• Stable angina pectoris• Heart failure• Arrhythmia• Asymptomatic

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Epidemiology

• Commonest cause of death in the Western world. (up to 35% of total mortality)

• Over 20% males under 60 years have IHD

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Aetiology

• Fixed– Age, Male, +ve family history

• Modifiable – strong association– Dyslipidaemia, smoking, diabetes mellitus, obesity,

hypertension

• Modifiable - weak association– Lack of exercise, high alcohol consumption, type A

personality, OCP, soft water

Atherosclerosis

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Pathophysiology

• Response to injury hypothesis

• ATHEROSISAccumulation of cholesterol within the vessel wall intima. Smooth muscle cell proliferation

• SCLEROSISExpansion of fibrous tissue

• INFLAMMATIONChronic inflammatory cells migrate into wall, release cytokines

• GROWTH FACTORS/INFLAMMATORY MEDIATORS

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Pathophysiology

An atherosclerotic lesion

a

Schematic illustration

Endothelium Smooth muscle cell

Macrophage foam cellThrombus formation

Media(smooth muscle cells)

Lymphocytes

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Ischemic heart diseaseAcute coronary syndromes

AtherosclerosisAtherosclerosis

Fatal / non-fatal AMI Unstable

angina

CoronaryArtery spasm

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Acute coronary syndromes

• Fatal AMISmall, fat rich plaques. Plaque RUPTURE. Thrombus in lipid core and on plaques surface. Vessel lumen OCCLUDED.

• Non-fatal AMIPlaque EROSION rather than rupture. OCCLUSIVE thrombus.

• Unstable anginaUsually mod-severe stenosis. Multiple vessels. Collaterals often formed. Thrombus formation and vasoconstriction. Myocardial infarction may ensue.

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Ischemic heart diseaseRisk factors and prevention

• Family History• Smoking• Hypertension• Diabetes Mellitus• Hypercholesterolemia• Lack of exercise

• PRIMARY PREVENTION

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Chest PainMyocardial ischemia

• SiteJaw to navel, retrosternal, left submammary

• RadiationLeft chest, left arm, jaw….mandible, teeth, palate

• Quality/severitytightness, heaviness, compression…clenched fists

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Chest PainMyocardial ischaemia

• Precipitating/relieving factors

Physical exertion, cold windy weather, emotion

rest, sublingual nitrates

• Autonomic symptoms

Sweating, pallor, peripheral vasoconstriction, nausea and vomiting

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Chest PainDifferential diagnosis

• Cardiac pathology– Pericarditis, aortic dissection

• Pulmonary pathology– Pulmonary embolus, pneumothorax, pneumonia

• Gastrointestinal pathology– Peptic ulcer disease, reflux, pancreatitis, ‘café

coronary’• Musculoskeletal pathology

– Trauma, Tietze’s Syndrome

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Management

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Antiplatelet Therapy: TargetsAntiplatelet Therapy: Targets

CollagenThrombin

TXA2

ADP

(FibrinogenReceptor)

ADP=Adenosine diphosphate, COX=Cyclooxygenase, TXA2=Thromboxane A2

clopidogrel bisulfate

TXA2

phosphodiesterase

ADP

Gp IIb/IIIa Activation

COX

ticlopidine hydrochloride

aspirin

Gp 2b/3a Inhibitors

dipyridamole

Schafer AI. Am J Med 1996;101:199–209

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Antiplatelet Therapy: Common Oral AgentsAntiplatelet Therapy: Common Oral Agents

Acetylsalicylic acid (ASA)

Clopidogrel bisulfate*

Ticlopidine hydrochloride*

Trade Name Aspirin Plavix® Ticlid®

Class Salicylate Thienopyridine Thienopyridine

Formulation Active Drug Pro-Drug Active Drug

Maintenance Dose 75-325 mg daily 75 mg daily 250 mg twice daily

Major Bleeding Risk (%)

2-3%1 1-4% alone2,3

3-5% w/ ASA4

1% alone5

2-6% w/ ASA6,7

1Topol EJ et al. Circulation 2003;108:399-4062Diener HC et al. Lancet 2004;364;331-73Plavix® package insert. www.sanofi-synthelabo.us4Peters RJ et al. Circulation 2003;108:1682-7 5Hass WK. NEJM 1989;321:501-7 6Urban P. Circulation 1998;98:2126-327Ticlid® package insert. www.rocheusa.com

*Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile

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The formula of aspirin is C9H8O4

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Synthesis of Acetylsalicylic acid

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Aspirin: Mechanism of ActionAspirin: Mechanism of Action

Membrane Phospholipids

Arachadonic Acid

Prostaglandin H2

COX-1

Thromboxane A2

Platelet AggregationVasoconstriction

Prostacyclin Platelet Aggregation

Vasodilation

Aspirin

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Pharmacokinetics Of Aspirin

• Aspirin is rapidly absorbed from the gastrointestinal tract and peak plasma concentration are achieved in 30 to 40 minutes.

• Significant platelet inhibition is noted within 60 minute of ingestion and a single dose of 100mg of aspirin can completely block TXA2 production for the life of the platelet in most individual.

• The plasma half-life of aspirin is only 20 minutes but the irreversible nature function makes once-daily dosing sufficient to maintain its antithrombotic benefit.

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Aspirin Evidence: Primary Prevention in MenAspirin Evidence: Primary Prevention in Men

Physicians’ Health Study (PHS)22,071 men randomized to aspirin (325mg every other day) followed for an

average of 5 years

Aspirin significantly reduces the risk of MI in men

End point Relative Risk (95% CI) P value Myocardial infarction Fatal 0.34 (0.15-0.75) 0.007 Nonfatal 0.59 (0.47-0.74) <0.00001 Total 0.56 (0.45-0.70) <0.00001 Stroke Fatal 1.51 (0.54-4.28) 0.43 Nonfatal 1.20 (0.91-1.59) 0.20 Total 1.22 (0.93-1.60) 0.15

Physicians’ Health Study Research Group. NEJM 1989;321:129-35

CI=Confidence interval, MI=Myocardial infarction

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Aspirin Evidence: Primary Prevention in WomenAspirin Evidence: Primary Prevention in Women

Womens’ Health Study (WHS)

Placebo

Aspirin

Ridker P et al. NEJM 2005;352:1293-304

MI=Myocardial infarction

39,876 women randomized to aspirin (100 mg every other day) or placebo for an average of 10 years

Aspirin did not reduce the risk of MI, CVA & CV death

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Aspirin Evidence: Primary PreventionAspirin Evidence: Primary PreventionBDT, 1988

Combined

PPP, 2001

HOT, 1998

TPT, 1998

PHS, 1989

RR of MI in Men

1.0 2.0 5.00.50.2

RR = 0.68 (0.54-0.86)P=0.001

1.0 2.0 5.00.50.2

RR = 1.13 (0.96-1.33)P=0.15

HOT, 1998

Combined

WHS, 2005

PPP, 2001

1.0 2.0 5.00.50.2

Aspirin Better Placebo Better

RR = 0.99 (0.83-1.19)P=0.95

1.0 2.0 5.00.50.2

Aspirin Better Placebo Better

RR = 0.81 (0.69-0.96)P=0.01

RR of CVA in Men

RR of MI in Women

RR of CVA in Women

Ridker P et al. NEJM 2005;352:1293-304

CVA=Cerebrovascular accident, MI=Myocardial infarction, RR=Relative risk

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Aspirin Evidence: Secondary PreventionAspirin Evidence: Secondary Prevention

Antithrombotic Trialist Collaboration. BMJ 2002;324:71–86

Category % Odds Reduction

Acute MI

Acute CVA

Prior MI

Prior CVA/TIA

Other high risk

CVD(e.g. unstable angina, heart failure)

PAD(e.g. intermittent claudication)

High risk of embolism (e.g. Afib)

Other (e.g. DM)

All trials

1.00.50.0 1.5 2.0 Control better Antiplatelet better

Effect of antiplatelet treatment* on vascular events**

*Aspirin was the predominant antiplatelet agent studied**Include MI, stroke, or death

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Aspirin Evidence: Dose and EfficacyAspirin Evidence: Dose and Efficacy

0.5 1.0 1.5 2.0

500-1500 mg 34 19

160-325 mg 19 26

75-150 mg 12 32

<75 mg 3 13

Any aspirin 65 23

Antiplatelet Better Antiplatelet Worse

Aspirin Dose No. of Trials (%)Odds Ratio for

Vascular Events

0

P<.0001

Indirect comparisons of aspirin doses on vascular events in high-risk patients

Antithrombotic Trialist Collaboration. BMJ 2002;324:71-86

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Aspirin (81 mg daily or 100 mg every other day) in at risk women >65 years of age

Aspirin in at risk women <65 years of age for ischemic stroke prevention

Aspirin in optimal risk women <65 years of age

Primary Prevention (Women)

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

CHD=Coronary heart disease



Aspirin RecommendationsAspirin Recommendations

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Aspirin RecommendationsAspirin Recommendations

Aspirin (75-162 mg daily) in those at intermediate risk (10 year risk of CHD >10%)

Primary Prevention (Men*)


CHD=Coronary heart disease

*Specific guideline recommendations for men do not exist, but these guidelines are based on previous general (not gender specific) primary prevention guidelines

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Aspirin Recommendations (Continued)Aspirin Recommendations (Continued)


Aspirin (75-162 mg daily) if known CHD/ASVD

Aspirin (162-325 mg daily) for at least 3 months after sirolimus-eluting stent implantation and at least 6 months after paclitaxel-eluting stent implantation after which aspirin (75-162 mg daily) should be continued indefinitely

Secondary Prevention

ASVD=Atherosclerotic vascular disease, CABG=Coronary artery bypass graft, CHD=Coronary heart disease


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Aspirin Recommendations (Continued)Aspirin Recommendations (Continued)

Aspirin (75-162 mg daily) as the initial dose after stent implantation in those at higher bleeding risk

Aspirin (100-325 mg daily) following CABG surgery*



*To be administered within the first 48 hours after surgery in order to reduce the risk of saphenous vein graft failure. Doses >162 mg/day may be continued for up to one year


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Definition(s) of “APT Resistance?”

• The fact that some patients may experience recurrent vascular events despite the use of APT should be properly defined as “treatment failure” rather than “APT resistance” (multiple pathways mediate thrombotic events).

• APT Resistance/Non-responsiveness=failure to inhibit the target

• APT Resistance/Non-responsiveness≠clinical failure

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Clopidogrel Evidence: Secondary PreventionClopidogrel Evidence: Secondary Prevention

Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Trial

Months Treated

Eve

nt R

ate

for

MI (

%)

(fat

al o

r no

nfat

al)

0

1

2

3

5

3 6 9 12 15 18 21 24 27 30 33 36

Aspirin

Clopidogrel

4

P = 0.008

CAPRIE Steering Committee. Lancet 1996;348:1329-39

CVA=Cerebrovascular accident, MI=Myocardial infarction, PAD=Peripheral arterial disease

19,185 patients with ischemic CVA, MI, or PAD randomized to daily aspirin (325 mg) or clopidogrel (75 mg) for 2 years

Clopidogrel provides slightly greater risk reduction

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Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

3 6 90 12

Rat

e of

dea

th,

myo

card

ial i

nfar

ctio

n,

or s

trok

e

P<0.001

Months of Follow Up

The CURE Trial Investigators. NEJM 2001;345:494-502

NSTE-ACS=Non ST-segment elevation acute coronary syndrome

Aspirin + Clopidogrel

Aspirin + Placebo

12,562 patients with a NSTE-ACS randomized to daily aspirin (75-325 mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin (75-325 mg)

for 9 months

Dual antiplatelet therapy is more efficacious in NSTE-ACS

34Steinhubl S et al. JAMA 2002;288:2411-20

Clopidogrel for the Reduction of Events during Observation (CREDO) Trial


DAP=Dual antiplatelet therapy, PCI=Percutaneous coronary intervention, RRR=Relative risk reduction

*Dual antiplatelet therapy=Aspirin (75-325 mg daily) plus Clopidogrel (300 mg load followed by 75 mg daily).

0 123 6 90

Ris

k of

MI,

Str

oke,

or

Dea

th (

%)

27% RRR, P=0.02

10

5

15 4 weeks of DAP1 year of DAP

Months from Randomization

2,116 patients undergoing PCI randomized to 4 weeks of DAP* followed by aspirin (75-325 mg) monotherapy vs persistent DAP* for 1 year

DAP* produces continued benefit when used for 1 year

35Bhatt DL et al. NEJM 2006;354:1706-17

Months

8

6

4

2

00 6 12 18 24 30

PlaceboClopidogrel

Inci

den

ce

of

CV

D

eath

, M

I, o

r C

VA

(%

)

Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial


P = 0.22

CV=Cardiovascular, CVA=Cerebrovascular accident, CVD=Cardiovascular disease, DAP=Dual antiplatelet MI=Myocardial infarction

15,603 patients with multiple CV risk factors or known CVD randomized to aspirin (75-162 mg) or aspirin (75-162 mg) & clopidogrel (75 mg) for a

mean of 30 months

Routine DAP therapy offers little long-term benefit

36Bhatt DL et al. NEJM 2006;354:1706-17

Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial


15,603 patients with multiple CV risk factors or known CVD randomized to aspirin (75-162 mg) or aspirin (75-162 mg) & clopidogrel (75 mg) for a

mean of 30 months

Long-term DAP provides benefit to those with CV disease

Population RR (95% CI) p value Qualifying CAD, CVD or PAD 0.88 (0.77, 0.998) 0.04

Multiple Risk Factors 1.20 (0.91, 1.59) 0.20

Overall Population 0.93 (0.83, 1.05) 0.22

0.6 0.8 1.41.2 1.60.4

CV=Cardiovascular, CVA=Cerebrovascular accident, CVD=Cardiovascular disease, DAP=Dual antiplatelet MI=Myocardial infarction

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Thienopyridine RecommendationsThienopyridine Recommendations


No data to support the use of thienopyridines in primary prevention

Clopidogrel (75 mg daily) if aspirin intolerance or a true aspirin allergy (Class I, Level A following a NSTE-ACS; Class I, Level C following a STEMI; Class IIa, Level B in those with stable angina)



Primary PreventionIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII


NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI

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Ticlopidine* (250 mg twice daily) for aspirin intolerance or a true aspirin allergy (Class I, Level A following a NSTE-ACS; Class I, Level C following a STEMI)

Clopidogrel* (75 mg daily) in addition to aspirin for a minimum of 1 month (Class I, Level A) and ideally 1 year (Class I, Level B) after a NSTE-ACS




NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI


Thienopyridine Recommendations (Continued)Thienopyridine Recommendations (Continued)

*Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile


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Clopidogrel (75 mg daily) in addition to aspirin for a minimum of 14 days (Class I, Level A) and up to 1 year (Class IIa, Level C) in those treated with fibrinolytic therapy or no reperfusion therapy after a STEMI

Clopidogrel (75 mg daily) in addition to aspirin for a minimum of 1 month and ideally for 12 months after bare metal stent implantation and for at least 12 months after drug-eluting stent implantation in those at low bleeding risk


STEMI=ST-segment elevation myocardial infarction


Thienopyridine Recommendations (Continued)Thienopyridine Recommendations (Continued)



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Summary

• Variability in individual responsiveness to antiplatelet agents is an emerging clinical problem: poor responsiveness has been associated with an increased risk of ischemic events, including stent thrombosis.

• WHAT and HOW to measure antiplatelet drug responsiveness still needs to be fully defined.

• Responsiveness to antiplatelet therapy should be evaluated for mainly investigation purposes!!!

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Thank You

Aspirin+and+vascular

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