Initiating Antiplatelet Therapy in Patients with

Atherothrombosis

Initiating Antiplatelet Therapy in Patients with

Atherothrombosis

Sunil V. Rao MDSunil V. Rao MD

Durham VA Medical CenterDurham VA Medical Center

Duke Clinical Research InstituteDuke Clinical Research Institute

Duke University Medical CenterDuke University Medical Center

Sunil V. Rao MDSunil V. Rao MD

Durham VA Medical CenterDurham VA Medical Center

Duke Clinical Research InstituteDuke Clinical Research Institute

Duke University Medical CenterDuke University Medical Center

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NSTE ACSNSTE ACSNSTE ACSNSTE ACS

Thrombus formationThrombus formation

Thrombin and platelets play a central roleThrombin and platelets play a central role

Collagen

TissueFactor

Thrombin

Plateletactivation

Prothrombin

ADP

TXA2

PlasmaClottingcascade

THROMBUS

Fibrinogen Fibrin

Plateletaggregation

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Clopidogrel Indications

Clopidogrel is indicated for the reduction of atherothrombotic events

Recent MI, Recent Stroke, or Established Peripheral Arterial DiseaseFor patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel has been shown to reduce the rate of a combined end point of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

Acute Coronary SyndromeFor patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, clopidogrel has been shown to decrease the rate of a combined end point of cardiovascular death, MI, or stroke as well as the rate of a combined end point of cardiovascular death, MI, stroke, or refractory ischemia.

For patients with ST-segment elevation acute myocardial infarction, clopidogrel has been shown to reduce the rate of death from any cause and the rate of a combined end point of death, reinfarction, or stroke. This benefit is not known to pertain to patients who receive primary angioplasty.

Clopidogrel prescribing information, sanofi-aventis US, LLC

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Clopidogrel Clinical Trials Overview

Clopidogrel vs aspirin

Clopidogrel + aspirinvs placebo + aspirin

Clopidogrel + aspirinvs placebo + aspirin

Clopidogrel + aspirinvs placebo + aspirin

Hours after randomizationHours after randomization

PlaceboPlacebo

ClopidogrelClopidogrel

Cum

ulat

ive

haza

rd r

ates

Cum

ulat

ive

haza

rd r

ates

RR=0.67P=0.002RR=0.67P=0.002

0

0.005

0.010

0.015

0.020

0.025

Early Benefit of Dual Antiplatelet Therapy in ACS:Early Benefit of Dual Antiplatelet Therapy in ACS:Death/MI/Ischemia Death/MI/Ischemia << 24 Hrs in CURE 24 Hrs in CURE

—Berger P, Steinhubl S. Circ 2002—Berger P, Steinhubl S. Circ 2002

Effects of Clopidogrel on Combined End Point (Death, Reinfarction, or Stroke) by Treatment Interval

Clopidogrel

Clopidogrelbetter

Effects of Clopidogrel on Bleeding Rate by Treatment Interval

Placebo + ASA

Clopidogrel + ASA

Placebo + ASA

Clopidogrel + ASA

The overall incidence of major bleeding (including life-threatening and other major bleeding) was:Clopidogrel + ASA = 3.7%Clopidogrel + ASA = 2.7%P=0.001

2007 ACC/AHA Guidelines for UA/NSTEMI2007 ACC/AHA Guidelines for UA/NSTEMI

Aspirin should be administered to UA/NSTEMI Aspirin should be administered to UA/NSTEMI patients as soonpatients as soon as possible after hospital as possible after hospital presentation and continued indefinitelypresentation and continued indefinitely in patients in patients not known to be intolerant of that medication. not known to be intolerant of that medication. (Level(Level of Evidence: A)of Evidence: A)

Clopidogrel (loadingClopidogrel (loading dose followed by daily dose followed by daily maintenance dose)maintenance dose)**

should be administeredshould be administered to to

UA/NSTEMI patients who are unableUA/NSTEMI patients who are unable to take ASA to take ASA because ofbecause of hypersensitivity or major hypersensitivity or major gastrointestinalgastrointestinal intolerance. intolerance. (Level(Level of Evidence: A)of Evidence: A)

Anderson JL et al. ACC/AHA Guideline Update. 2007. Available at:

http://www.acc.org/qualityandscience/clinical/topic/topic.htm#M Accessed August 7, 2007.

2007 ACC/AHA Guidelines for UA/NSTEMI2007 ACC/AHA Guidelines for UA/NSTEMI

For UA/NSTEMI patients in whom an initial invasive strategyFor UA/NSTEMI patients in whom an initial invasive strategy is is selected:selected: EitherEither clopidogrel (loading dose followed by daily clopidogrel (loading dose followed by daily

maintenance dose)maintenance dose)**or an intravenous GP IIb/IIIa inhibitor or an intravenous GP IIb/IIIa inhibitor

shouldshould be initiated before diagnostic angiography (upstream) be initiated before diagnostic angiography (upstream) ((Level of Evidence:Level of Evidence: AA) )

For UA/NSTEMI patients in whom anFor UA/NSTEMI patients in whom an initial conservative (i.e.,initial conservative (i.e.,

noninvasive) strategy is selected:noninvasive) strategy is selected: ClopidogrelClopidogrel (loading dose followed by daily(loading dose followed by daily maintenance maintenance

dose) should bedose) should be added to ASA and anticoagulantadded to ASA and anticoagulant therapy as therapy as soon as possible aftersoon as possible after admission and administeredadmission and administered for at for at least 1 month least 1 month (Level of Evidence:(Level of Evidence: A)A) and ideally up to and ideally up to 1 year. 1 year. (Level of Evidence: B)(Level of Evidence: B)

Anderson JL et al. ACC/AHA Guideline Update. 2007. Available at:

http://www.acc.org/qualityandscience/clinical/topic/topic.htm#M Accessed August 7, 2007.

The Major Bleeding Rate Was Increased When Clopidogrel Was Administered <5 Days Before CABG in CURE

Major bleeding rate in patients undergoing CABG according to whether therapy is stopped or continued 5 days before CABG1

Placebo + ASAClopidogrel + ASA

Clopidogrel prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued five days prior to surgery.

* Other standard therapies were given at the physician’s discretionClopidogrel prescribing information. sanofi-aventis US, LLCCURE Trial Investigators. N Engl J Med. 2001;345;494-502.

Clopidogrel + AspirinClopidogrel + Aspirin Placebo + AspirinPlacebo + AspirinAspirin DoseAspirin Dose (+ standard therapy*)(+ standard therapy*) (+ standard therapy*)(+ standard therapy*)

*Other standard therapies were given at physician’s discretion.Clopidogrel prescribing information. sanofi-aventis U.S. LLCCURE Trial Investigators. N Engl J Med. 2001;345:494-502.

2007 ACC/AHA Guidelines for UA/NSTEMI2007 ACC/AHA Guidelines for UA/NSTEMI

For UA/NSTEMI patients inFor UA/NSTEMI patients in whom CABG is whom CABG is selected as a postangiographyselected as a postangiography management management strategy:strategy: Continue ASA. Continue ASA. (Level of Evidence:(Level of Evidence: A)A)

Discontinue clopidogrelDiscontinue clopidogrel 5 to 7 d before 5 to 7 d before elective CABG.elective CABG. (Level(Level of Evidence: B)of Evidence: B)

More urgentMore urgent surgery, if necessary, surgery, if necessary, maymay be performedbe performed by experienced by experienced surgeonssurgeons if the incremental bleedingif the incremental bleeding

risk isrisk is considered acceptable. considered acceptable. (Level(Level

of Evidence: C)of Evidence: C)

Anderson JL et al. ACC/AHA Guideline Update. 2007. Available at:

http://www.acc.org/qualityandscience/clinical/topic/topic.htm#M Accessed August 7, 2007.

Fox KAA, et. al. Fox KAA, et. al. Circulation 2004Circulation 2004Fox KAA, et. al. Fox KAA, et. al. Circulation 2004Circulation 2004

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Clopidogrel vs aspirin

Clopidogrel + aspirinvs placebo + aspirin

Clopidogrel + aspirinvs placebo + aspirin

Clopidogrel + aspirinvs placebo + aspirin

Clopidogrel Clinical Trials Overview

Acute MIAcute MI

Platelet Activation by FibrinolyticsPlatelet Activation by Fibrinolytics

Rudd and Loscalzo, CircRes ‘90Rudd and Loscalzo, CircRes ‘90Rabbit model, .05mM ADP as agonistRabbit model, .05mM ADP as agonist

Normalized Maximal Aggregation RateNormalized Maximal Aggregation Rate

Time (min)Time (min)

00 5050 100100 150150 200200 250250

1.51.5

1.01.0

0.50.5

t-PASK

SGE; 0802-3, 22

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* All treated patients received aspirin.Clopidogrel prescribing information. sanofi-aventis US, LLC

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Clopidogrel prescribing information. sanofi-aventis US, LLC

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* The total number of patients with a component event (occluded IRA, death, or recurrent MI) is greater than the number of patients with a composite event because some patients had more than a single type of component event.Clopidogrel prescribing information. sanofi-aventis US, LLC

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Major bleeding defined as intracranial bleeding or bleeding associated with a fall in hemoglobin > 5 g/dL. Subgroups of patients defined by baseline characteristics, and type of fibrinolysis or heparin therapy.Clopidogrel prescribing information, sanofi-aventis US, LLC

Clopidogrel prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 5 days prior to surgery.

LBB-left bundle branch block; UFH = unfractionated heparin; LMWH = low molecular weight heparin.American Heart Association. Circulation. 2005;112:IV-89-IV-110.

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Therapy directed at the platelet is the Therapy directed at the platelet is the cornerstone of Atherothrombosis cornerstone of Atherothrombosis managementmanagement

ASA and ClopidogrelASA and Clopidogrel CURE, COMMIT, & CLARITY Trials support CURE, COMMIT, & CLARITY Trials support

their role across the spectrum of risktheir role across the spectrum of risk Administer early and at dischargeAdminister early and at discharge

Evidence-based Antithrombotic Pharmacology:Evidence-based Antithrombotic Pharmacology:ConclusionsConclusionsEvidence-based Antithrombotic Pharmacology:Evidence-based Antithrombotic Pharmacology:ConclusionsConclusions

Bleeding is an issue with dual antiplatelet Bleeding is an issue with dual antiplatelet therapytherapy CABG – wait 5-7 days; outcomes improved if CABG – wait 5-7 days; outcomes improved if

on clopidogrelon clopidogrel Long-term – reduce ASA doseLong-term – reduce ASA dose

Guidelines are importantGuidelines are important Adherence improves survivalAdherence improves survival Don’t forget about the medically managed Don’t forget about the medically managed

patientspatients

Evidence-based Antithrombotic Pharmacology:Evidence-based Antithrombotic Pharmacology:ConclusionsConclusionsEvidence-based Antithrombotic Pharmacology:Evidence-based Antithrombotic Pharmacology:ConclusionsConclusions