DOI 10.1378/chest.08-0672
2008;133;199S-233S Chest
Carlo Patrono, Colin Baigent, Jack Hirsh and Gerald Roth
*
Antiplatelet Drugs
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may be reproduced or distributed without the prior written permission Northbrook, IL 60062. All rights reserved. No part of this article or PDF by the American College of Chest Physicians, 3300 Dundee Road, 2008Physicians. It has been published monthly since 1935. Copyright CHEST is the official journal of the American College of Chest
Antiplatelet Drugs*
American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines
(8th Edition)
Carlo Patrono,MD;Colin Baigent,MD;Jack Hirsh,MD,FCCP;
and Gerald Roth,MD
This article about currently available antiplatelet drugs is part of the Antithrombotic and Thrombo-lytic Therapy:American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).It describes the mechanism of action,pharmacokinetics,and pharmacodynamics of aspirin,reversible cyclooxygenase inhibitors,thienopyridines,and integrin␣IIb␤3receptor antago-nists.The relationships among dose,efficacy,and safety are thoroughly discussed,with a mechanistic overview of randomized clinical trials.The article does not provide specific management recommen-dations;however,it does highlight important practical aspects related to antiplatelet therapy, including the optimal dose of aspirin,the variable balance of benefits and hazards in different clinical settings,and the issue of interindividual variability in response to antiplatelet drugs.
(CHEST2008;133:199S–233S)
Key words:abciximab;antiplatelet drugs;aspirin;clopidogrel;dipyridamole;eptifibatide;platelet pharmacology;resistance; ticlopidine;tirofiban
Abbreviations:ACEϭangiotensin-converting enzyme;ADPϭadenosine diphosphate;AMPϭadenosine monophos-phate;ATTϭAntithrombotic Trialists;CAPRIEϭClopidogrel vs Aspirin in Patients at Risk of Ischemic Events; CHDϭcoronary heart disease;CIϭconfidence interval;COMMITϭClopidogrel and Metoprolol Myocardial Infarction Trial;COXϭcyclooxygenase;CUREϭClopidogrel in Unstable Angina to Prevent Recurrent Events;EPICϭEvaluation of 7E3for the Prevention of Ischemic Complications;ESPSϭEuropean Stroke Prevention Study;ESPRITϭEuropean Stroke Prevention Reversible Ischemia Trial;FDAϭFood and Drug Administration;GPϭglycoprotein;INRϭinternational normalized ratio;MIϭmyocardial infarction;NSAIDϭnonsteroidal antiinflammatory drug;ORϭodds ratio; PCIϭpercutaneous coronary intervention;PEϭpulmonary embolism;PGϭprostaglandin;PTCAϭpercutaneous trans-luminal coronary angioplasty;RRϭrate ratio;TIAϭtransient ischemic attack;TXϭthromboxane;TTPϭthrombotic thrombocytopenic purpura
P latelets are vital components of normal hemosta-sis and key participants in atherothrombosis by virtue of their capacity to adhere to injured blood vessels and to accumulate at sites of injury.1Al-though platelet adhesion and activation can be viewed as a physiologic repair response to the sud-den fissuring or rupture of an atherosclerotic plaque, uncontrolled progression of such a process through a series of self-sustaining amplification loops can lead to intraluminal thrombus formation,vascular occlu-
sion,and transient ischemia or infarction.Currently available antiplatelet drugs interfere with some steps in the activation process,including adhesion,release, and/or aggregation,1and have a measurable impact on the risk of arterial thrombosis that cannot be dissociated from an increased risk of bleeding.2
In discussing antiplatelet drugs,it is important to appreciate that approximately1011platelets are pro-duced each day under physiologic circumstances,a level of production that can increase up to10-fold at
*From the Catholic University School of Medicine(Dr.Patrono), Rome,Italy;Clinical Trial Service Unit(Dr.Baigent),University of Oxford,Oxford,UK;Hamilton Civic Hospitals(Dr.Hirsh), Henderson Research Centre,Hamilton,ON,Canada;and Seattle VA Medical Center(Dr.Roth),Seattle,WA.
Dr.Patrono was supported in part by a grant from the European Commission FP6(LSHM-CT-2004-005033).
Manauscript accepted December20,2007.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians(www.chestjournal. org/misc/reprints.shtml).
Correspondence to:Carlo Patrono,MD,Catholic University School of Medicine,Largo F.Vito1,00168Rome,Italy;e-mail: carlo.patrono@rm.unicatt.it
DOI:10.1378/chest.08-0672Supplement
ANTITHROMBOTIC AND THROMBOLYTIC THERAPY8TH ED:ACCP GUIDELINES CHEST/133/6/JUNE,2008SUPPLEMENT199S
times of increased need.3Platelets are anucleate blood cells that form by fragmentation of megakaryo-cyte cytoplasm and have a maximum circulating life span of about10days in humans.3Platelets provide a circulating source of chemokines,cytokines,and growth factors,which are preformed and packaged in storage granules.Moreover,activated platelets can synthesize prostanoids(primarily,thromboxane[TX] A2)from arachidonic acid released from membrane phospholipids through rapid coordinated activation of phospholipase(s),cyclooxygenase(COX)-1and TX synthase(Fig1).Newly formed platelets also express the inducible isoforms of COX(COX-2)and prosta-glandin(PG)E synthase,and this phenomenon is markedly amplified in association with accelerated platelet regeneration.4Although activated platelets are not thought to synthesize proteins de novo,they can translate constitutive messenger RNAs into pro-teins,including interleukin-1␤,over s
everal hours.5 Thus,platelets may play previously unrecognized roles in inflammation and vascular injury,and anti-platelet strategies may be expected to affect platelet-derived protein signals for inflammatory and/or pro-liferative responses.1
Negative modulation of platelet adhesion and aggre-gation is exerted by a variety of physiologic mecha-nisms,including endothelium-derived prostacyclin (PGI2),nitric oxide,CD39/ecto-ADPase,and platelet endothelial cell adhesion molecule-1.Some drugs may interfere with these regulatory pathways,as exempli-fied by the dose-dependent inhibition of PGI2produc-tion by aspirin and other COX inhibitors.2
2.0Aspirin and Other COX Inhibitors Aspirin has been thoroughly evaluated as an anti-platelet drug6and was found to prevent vascular death by approximately15%and nonfatal vascular events by about30%in a metaanalysis ofϾ100 randomized trials in high-risk patients.7
2.1Mechanism of Action of Aspirin
The best characterized mechanism of action of the drug is related to its capacity to inactivate permanently the COX activity of prostaglandin H-synthase-1and-2 (also referred to as COX-1and COX-2).8–12These isozymes catalyze the first committed step in prosta-noid biosynthesis(ie,the conv
ersion of arachidonic acid to PGH2)[Fig1].PGH2is the immediate precursor of PGD2,PGE2,PGF2␣,PGI2,and TXA2. COX-1and COX-2are homodimers of aϳ72kd monomeric unit.Each dimer has three independent folding units:an epidermal growth factor-like do-main;a membrane-binding domain;and an
enzy-
Figure1.Arachidonic acid metabolism and mechanism of action of aspirin.Arachidonic acid,a
20-carbon fatty acid containing four double bonds,is liberated from the sn2position in membrane
phospholipids by several forms of phospholipase,which are activated by diverse stimuli.Arachidonic
oddsacid is converted by cytosolic PGH synthases,which have both COX and hydroperoxidase activity,to
the unstable intermediate PGH2.The synthases are colloquially termed COXs and exist in two forms,
COX-1and COX-2.Low-dose aspirin selectively inhibits COX-1,and high-dose aspirin inhibits both
COX-1and COX-2.PGH2is converted by tissue-specific isomerases to multiple prostanoids.These
bioactive lipids activate specific cell membrane receptors of the superfamily of G-protein-coupled
receptors.DPϭPGD2receptor;EPϭPGE2receptor;FPϭPGF2␣receptor;IPϭprostacyclin
receptor;TPϭTX receptor.
200S Antithrombotic and Thrombolytic Therapy8th Ed:ACCP Guidelines
matic domain.12Within the enzymatic domain,there is the peroxidase catalytic site and a separate,but adjacent site for COX activity at the apex of a narrow, hydrophobic channel.
The molecular mechanism of permanent inactiva-tion of COX activity by aspirin is related to blockade of the COX channel as a consequence of acetylation of a strategically located serine residue(Ser529in the human COX-1,Ser516in the human COX-2) that prevents access of the substrate to the catalytic site of the enzyme.13The hydrophobic environment of the COX channel stabilizes the modified serine side-chain against hydrolysis.13Thus,inhibition of COX-1–dependent platelet function can be achieved with low doses of aspirin given once daily.In con-trast,inhibition of COX-2–dependent pathophysio-logic processes(eg,hyperalgesia and inflammation) requires larger doses of aspirin(probably because acetylation is determined by the oxidative state of the enzyme and is inhibited in cells with high peroxide tone)14and a much shorter dosing interval(because nucleated cells rapidly resynthesize the enzyme).Thus, there is an approximately100-fold variation in daily doses of aspirin when used as an antiinflammatory rather than as an antiplatelet agent.Furthermore, the benefit/risk profile of the drug depends on the dose and indication because its GI toxicity is dose dependent(see below).
Human platelets and vascular endothelial cells process PGH2to produce primarily TXA2and PGI2, respectively.11TXA2induces platelet aggregation and vasoconstriction,whereas PGI2inhibits platelet aggregation and induces vasodilation.11Whereas TXA2is largely a COX-1–derived product(mostly from platelets)and thus highly sensitive to aspirin inhibition,vascular PGI2can derive both from COX-1and,to a greater extent even under physio-logic conditions,from COX-2.16COX-1–dependent PGI2production occurs transiently in response to agonist stimulation(eg,bradykinin)15and is sensitive to aspirin inhibition.COX-2–mediated PGI2produc-tion occurs long term in response to laminar shear stress17and is largely insensitive to aspirin inhibition at conventional antiplatelet doses.This may explain the substantial residual COX-2–dependent PGI2 biosynthesis in vivo at daily doses of aspirin in the range of30to100mg,18despite transient suppres-sion of COX-1–dependent PGI2release.15It is not established that more profound suppression of PGI2 formation by higher doses of aspirin is sufficient to initiate or predispose to thrombosis.However,two lines of evidence suggest that PGI2is thrombopro-tective.The first is the observation that mice lacking the PGI2receptor had increased susceptibility to experimental thrombosis.19The second is the obser-vation of the cardiovascular toxicity associated with COX-2inhibitors20that also supports the concept of PGI2acting as an important mechanism of throm-boresistance in the setting of inadequate inhibition of platelet TXA2biosynthesis.21
2.2Pharmacokinetics
Aspirin is rapidly absorbed in the stomach and upper intestine.Peak plasma levels occur30to40 min after aspirin ingestion,and inhibition of plate-let function is evident by1h.In contrast,it can take up to3to4h to reach peak plasma levels after administration of enteric-coated aspirin.If only enteric-coated tablets are available,and a rapid effect is required,the tablets should be chewed.The oral bioavailability of regular aspirin tablets is ap-proximately40to50%over a wide range of doses.22 A considerably lower bioavailability has been re-ported for enteric-coated tablets and sustained-release,microencapsulated preparations.22Lower bioavailability of some enteric-coated preparations and poor absorption from the higher pH environ-ment of the small intestine may result in inadequate platelet inhibition,particularly in heavier subjects.23 Both a controlled-release formulation15and a trans-dermal patch24with negligible systemic bioavailabil-ity have been developed in an attempt to achieve selective inhibition of platelet TXA2production with-out suppressing systemic PGI2synthesis.The former was used successfully in the Thrombosis Prevention Trial(see below),but it remains unknown whether there is any advantage to the controlled-release formulation vis-a`-vis plain aspirin.
The plasma concentration of aspirin decays with a half-life of15to20min.Despite the rapid clearance of aspirin from the circulation,the platelet-inhibitory effect lasts for the life span of the platelet25because a
spirin irreversibly inactivates platelet COX-1.8,9As-pirin also acetylates the enzyme in megakaryocytes before new platelets are released into the circula-tion.10,26–28The mean life span of human platelets is approximately8to10days.Therefore,about10to 12%of circulating platelets are replaced every 24h.29,30However,the recovery of TXA2biosynthe-sis in vivo following prolonged aspirin administration is somewhat faster than predicted by the rate of platelet turnover,18possibly because of the nonlinear relationship between inhibition of platelet COX-1 activity and inhibition of TXA2biosynthesis in vivo31 (Fig2).
2.3Issues Concerning the Antithrombotic Effects of Aspirin
A number of issues related to the clinical efficacy of aspirin continue to be debated.These include the following:(1)the optimal dose of aspirin in order to
CHEST/133/6/JUNE,2008SUPPLEMENT201S
maximize efficacy and minimize toxicity;(2)the suggestion that part of the antithrombotic effect of aspirin is unrelated to inhibition of platelet TXA 2;and (3)the possibility that some patients may be aspirin “resistant.”
2.3.1The Optimal Dose of Aspirin:Well-designed,placebo-controlled randomized trials have shown that aspirin is an effective antithrombotic agent when used long term in doses ranging from 50to 100mg/d,and there is a suggestion that it is effective in doses as low as 30mg/d.6,7Aspirin,75mg/d,was shown to be effective in reducing the risk of acute myocardial infarction (MI)or death in patients with unstable angina 32and chronic stable angina,33as well as in reducing stroke or death in patients with transient cerebral ischemia 34and the risk of postoperative stroke after carotid endarterectomy.35In the Euro-pean Stroke Prevention Study (ESPS)-2,aspirin 25mg bid was effective in reducing the risks of stroke and of the composite outcome stroke or death in patients with prior stroke or transient ischemic attack (TIA).36Moreover,in the European Collaboration on Low-Dose Aspirin in Polycythemia vera Trial,37aspirin,100mg/d,was effective in preventing throm-botic complications in patients with polycythemia vera,despite a higher-than-normal platelet count.
The lowest effective dose of aspirin for these various indications is shown in Table 1.
The clinical effects of different doses of aspirin have been compared directly in a relatively small number of randomized trials.38–43In the United Kingdom TIA study,41no difference in efficacy was found between 300and 1,200mg/d of aspirin (see below).In a study of 3,131patients after a TIA or minor ischemic stroke,aspirin in a dose of 30mg/d was compared with a dose of 283mg/d,and the
Extra Platelet Sources
Platelet Synthesis
TXA 2
TXB 22,3-dinor-TXB 2
& other metabolites
Urine
TXB 2Production In Vivo
Enzymes
Liver H 2O
Calculated Rate of TXB 2
Production In Vivo :          0.1 ng/kg/min
P e r c e n t a g e I n h i b i t i o n o f  U r i n a r y 2,3-d i n o r -T X B 2E x c r e t i o n I n  V i v o
Percentage Inhibition of Serum
TXB 2Ex Vivo
Pharmacologic Inhibition
Ex Vivo vs In Vivo
TXB 2Production Ex Vivo
100
200
3000
3060 min
S e r u m T X B 2n g /m l
Time
Whole Blood Clotting at 37°C
Maximal Biosynthetic Capacity 300-400 ng/ml in 1 hr
Figure 2.Maximal capacity of human platelets to synthesize TXB 2,rate of TXB 2production in healthy subjects,and relationship between the inhibition of platelet COX activity and TXB 2biosynthesis in vivo .Left panel:The level of TXB 2production stimulated by endogenous thrombin during whole-blood clotting at 37°C.62Center panel:The metabolic fate of TXA 2in vivo and the calculated rate of its production in healthy subjects on the basis of TXB 2infusions and measurement of its major urinary metabolite.Right panel:The nonlinear relationship between inhibition of serum TXB 2measured ex vivo and the reduction in the excretion of TX metabolite measured in vivo .31
Table 1—Vascular Disorders for Which Aspirin Has Been Shown To Be Effective and Lowest Effective Dose
(Section 2.3.1)
Disorder
Lowest Effective Daily Dose,mg
TIA and ischemic stroke *
50Men at high cardiovascular risk 75Hypertension 75Stable angina 75Unstable angina *
75Severe carotid artery stenosis *75Polycythemia vera 100Acute MI
160Acute ischemic stroke *
160
*Higher doses have been tested in other trials and were not found to confer any greater risk reduction.
202S
Antithrombotic and Thrombolytic Therapy 8th Ed:ACCP Guidelines

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