吲哚布芬(美国胸科协会抗血小板药物指南)

DOI 10.1378/chest.08-0672 2008;133;199S-233S Chest Carlo Patrono, Colin Baigent, Jack Hirsh and Gerald Roth *

Antiplatelet Drugs

ull b947df727fd5360cba1adbef/content/133/6_suppl/199S.f and services can be found online on the World Wide Web at: The online version of this article, along with updated information ISSN:0012-3692

)b947df727fd5360cba1adbef/site/misc/reprints.xhtml (of the copyright holder.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

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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.

(CHEST 2008;133:199S–233S)

Key words:abciximab;antiplatelet drugs;aspirin;clopidogrel;dipyridamole;eptifibatide;platelet pharmacology;resistance;ticlopidine;tirofiban

Abbreviations:ACE ?angiotensin-converting enzyme;ADP ?adenosine diphosphate;AMP ?adenosine monophos-phate;ATT ?Antithrombotic Trialists;CAPRIE ?Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events;CHD ?coronary heart disease;CI ?confidence interval;COMMIT ?Clopidogrel and Metoprolol Myocardial Infarction Trial;COX ?cyclooxygenase;CURE ?Clopidogrel in Unstable Angina to Prevent Recurrent Events;EPIC ?Evaluation of 7E3for the Prevention of Ischemic Complications;ESPS ?European Stroke Prevention Study;ESPRIT ?European Stroke Prevention Reversible Ischemia Trial;FDA ?Food and Drug Administration;GP ?glycoprotein;INR ?international normalized ratio;MI ?myocardial infarction;NSAID ?nonsteroidal antiinflammatory drug;OR ?odds ratio;PCI ?percutaneous coronary intervention;PE ?pulmonary embolism;PG ?prostaglandin;PTCA ?percutaneous trans-luminal coronary angioplasty;RR ?rate ratio;TIA ?transient ischemic attack;TX ?thromboxane;TTP ?thrombotic 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 approximately 1011platelets are pro-duced each day under physiologic circumstances,a level of production that can increase up to 10-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 December 20,2007.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (b947df727fd5360cba1adbef/misc/reprints.shtml).

Correspondence to:Carlo Patrono,MD,Catholic University School of Medicine,Largo F.Vito 1,00168Rome,Italy;e-mail:carlo.patrono@rm.unicatt.it DOI:10.1378/chest.08-0672

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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 several 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 of?100 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 conversion of arachidonic acid to PGH2)[Fig1].PGH2is the immediate precursor of PGD2,PGE2,PGF2?,PGI2,and TXA2. COX-1and COX-2are homodimers of a?72kd 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

acid 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.DP?PGD2receptor;EP?PGE2receptor;FP?PGF2?receptor;IP?prostacyclin

receptor;TP?TX receptor.

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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 approximately 100-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 PGH 2to produce primarily TXA 2and PGI 2,respectively.11TXA 2induces platelet aggregation and vasoconstriction,whereas PGI 2inhibits platelet aggregation and induces vasodilation.11Whereas TXA 2is largely a COX-1–derived product (mostly from platelets)and thus highly sensitive to aspirin inhibition,vascular PGI 2can derive both from COX-1and,to a greater extent even under physio-logic conditions,from COX-2.16COX-1–dependent PGI 2production occurs transiently in response to agonist stimulation (eg ,bradykinin)15and is sensitive to aspirin inhibition.COX-2–mediated PGI 2produc-tion occurs long term in response to laminar shear stress 17and is largely insensitive to aspirin inhibition at conventional antiplatelet doses.This may explain the substantial residual COX-2–dependent PGI 2biosynthesis in vivo at daily doses of aspirin in the range of 30to 100mg,18despite transient suppres-sion of COX-1–dependent PGI 2release.15It is not established that more profound suppression of PGI 2formation by higher doses of aspirin is sufficient to initiate or predispose to thrombosis.However,two lines of evidence suggest that PGI 2is thrombopro-tective.The first is the observation that mice lacking the PGI 2receptor had increased susceptibility to experimental thrombosis.19The second is the obser-vation of the cardiovascular toxicity associated with

COX-2inhibitors 20that also supports the concept of PGI 2acting as an important mechanism of throm-boresistance in the setting of inadequate inhibition of platelet TXA 2biosynthesis.212.2Pharmacokinetics Aspirin is rapidly absorbed in the stomach and upper intestine.Peak plasma levels occur 30to 40min after aspirin ingestion,and inhibition of plate-let function is evident by 1h.In contrast,it can take up to 3to 4h 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-proximately 40to 50%over a wide range of doses.22A 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.23Both a controlled-release formulation 15and a trans-dermal patch 24with negligible systemic bioavailabil-ity have been developed in an attempt to achieve selective inhibition of platelet TXA 2production with-out suppressing systemic PGI 2synthesis.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 of 15to 20min.Despite the rapid clearance of aspirin from the circulation,the platelet-inhibitory effect lasts for the life span of the platelet 25because aspirin 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 approximately 8to 10days.Therefore,about 10to 12%of circulating platelets are replaced every 24h.29,30However,the recovery of TXA 2biosynthe-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-1activity and inhibition of TXA 2biosynthesis in vivo 31(Fig 2).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 b947df727fd5360cba1adbef CHEST /133/6/JUNE,2008SUPPLEMENT 201S

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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

30

60

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 .31Table 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.

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hazard ratio for the group receiving the lower dose was 0.91(95%confidence interval [CI],0.76to 1.09).42The Acetylsalicylic Acid and Carotid Endar-terectomy Trial reported that the risk of stroke,MI,or death within 3months of carotid endarterectomy is significantly lower for patients taking 81or 325mg/d aspirin than for those taking 650or 1,300mg (6.2%vs 8.4%;p ?0.03).43Thus,there is no con-vincing evidence from randomized studies that have compared different doses of aspirin that higher doses are more effective in reducing the risk of serious vascular events.In fact,both this limited set of randomized comparisons and the indirect compari-sons reported in the overview of the Antithrombotic Trialists’(ATT)Collaboration (Table 2)are compat-ible with the reverse (ie ,blunting of the antithrom-botic effect at higher doses of aspirin,consistent with dose-dependent inhibition of PGI 2).Such inhibition of PGI 2may be a potential mechanism by which COX-2inhibitors produce an excess risk of MI (see below).The antithrombotic effects of a range of doses of aspirin also have been compared with an untreated control group in a number of thrombotic vascular disorders.The doses have varied between 50and 1,500mg/d.Aspirin has been shown to be effective in the following conditions:unstable angina in which the incidence of acute MI or death was significantly reduced in four separate studies using daily doses of 75mg,32325mg,44650mg,45and 1,300mg 46;stable angina in which a dose of 75mg/d reduced the incidence of acute MI or sudden death 33;aortocoro-nary bypass surgery in which the incidence of early occlusion was similarly reduced with daily doses of 100mg,47325mg,48975mg,49and 1,200mg 49;thromboprophylaxis of patients with prosthetic heart valves who also received warfarin in whom the incidence of systemic embolism was reduced with daily doses of 100mg,50500mg,51and 1,500mg 52,53;thromboprophylaxis of patients with arterial venous shunts undergoing long-term hemodialysis in whom a dose of 160mg/d was shown to be effective 54;acute MI in which a dose of 162.5mg/d reduced early (35-day)mortality as well as nonfatal reinfarction and stroke 55;transient cerebral ischemia in which doses between 50and 1,200mg/d were effective 34,36,41,56–58;acute ischemic stroke in which doses of 160to 300mg/d were effective in reducing early mortality and stroke recurrence 59,60;and polycythemia vera in which 100mg,37but not 900mg,61was effective in reducing fatal and nonfatal vascular events.Thus,aspirin is an effective antithrombotic agent in doses between 50and 1,500mg/d.It is also possible from the results of the Dutch TIA study that 30mg/d is effective.42There is no evidence that low doses (50to 100mg/d)are less effective than high doses (650to 1,500mg/d)and,in fact,the opposite may be true.These clinical findings are consistent with saturability of platelet COX-1inactivation at doses as low as 30mg/d.62There is evidence,however,that doses of approx-imately 300mg/d produce fewer GI side effects than doses of approximately 1,200mg/d.41There is also some evidence that a dose of 30mg /d produces fewer side effects than 300mg/d.42The Clopidogrel in Unstable Angina To Prevent Recurrent Events (CURE)investigators have retrospectively investi-gated the relationship between the aspirin dose (the CURE protocol recommended 75to 325mg/d)and risk of major bleeding.63This study was a random-ized comparison of clopidogrel with placebo on a “background”of aspirin therapy.Patients with acute coronary syndromes receiving aspirin,?100mg/d,had the lowest rate of major or life-threatening bleeding complications both in the placebo (1.9%)and in the clopidogrel (3%)arms of the trial.Bleed-ing risks increased with increasing aspirin dose with or without clopidogrel.63In summary,the saturability of the antiplatelet effect of aspirin at low doses,the lack of dose-response relationship in clinical studies evaluating its antithrombotic effects,and the dose dependence of its side effects all support the use of as low a dose of aspirin as has been found to be effective in the treatment of various thromboembolic disorders (Ta-ble 1).Use of the lowest effective dose of aspirin (50to 100mg/d for long-term treatment)is currently the most appropriate strategy to maximize its efficacy and minimize its toxicity.6

2.3.2Effects of Aspirin Not Related to TXA 2:Aspirin has been reported to have effects on hemostasis that are unrelated to its ability to inactivate platelet COX-1.These include dose-dependent inhibition of platelet function,64–68enhancement of fibrinolysis,69–71

and suppression of plasma coagulation.72–75

In contrast to the saturable and well-characterized (nanomolar aspirin concentration,rapid time course,physiologic conditions,single serine modification)

Table 2—Indirect Comparison of Aspirin Doses Reducing Vascular Events in High-Risk Patients (Section 2.3.1)*Aspirin Dose,mg/d No.of Trials No.of Patients Odds Reduction 500–1,5003422,45119?3%160–3251926,51326?3%75–150126,77632?6%?7533,65513?8%*Data are from Lindemann et al 5/b947df727fd5360cba1adbef CHEST /133/6/JUNE,2008SUPPLEMENT 203S

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inhibition of COX-1by aspirin,13,62,76the putative mechanisms underpinning the non-PG effects of aspirin on hemostasis are dose dependent and less clearly defined.For example,inhibition of shear-induced platelet aggregation depends on the level of aspirin provided,and enhanced fibrinolysis due to N-acetylation of lysyl residues of fibrinogen is seen in vivo with high doses of aspirin (650mg bid)69and proceeds more rapidly in vitro under nonphysiologic alkaline conditions.77Aspirin suppresses plasma co-agulation through several mechanisms.The first,initially described in 1943by Link et al and con-firmed by others,72,73is caused by an antivitamin K effect of aspirin.It requires very high doses of aspirin and does not contribute to the antithrombotic effect of aspirin when the drug is used in doses up to 1,500mg/d.The second is platelet dependent and is characterized by inhibition of thrombin generation in a whole blood system.74,75A single dose of 500mg depresses the rate of thrombin generation,whereas repeated daily dosing with 300mg of aspirin reduces the total amount of thrombin formed.78An interac-tion with platelet phospholipids,which is blunted in hypercholesterolemia,has been proposed to explain the effects of aspirin on thrombin generation.78It is possible (but unproven)that this effect occurs as a consequence of impaired platelet coagulant activity secondary to inhibition of TX-dependent platelet aggregation.It is unknown whether lower doses of aspirin are able to produce this effect.This sort of in vitro effect has been shown for other platelet inhibi-tors,such as glycoprotein (GP)-IIb/IIIa antagonists (see below).Furthermore,high-dose aspirin can cause ab-normal coagulation in vitro by direct acetylation of one or more clotting factors.This can be demonstrated in platelet-poor plasma and,thus,is not related to platelet inhibition or vitamin K antagonism.

Additional studies in both animal models and human subjects have reported antithrombotic effects of aspirin that may occur,at least in part,through mechanisms unrelated to inactivation of platelet COX-1.In animal models,Buchanan et al 66and Hanson et al 64reported that optimal antithrombotic activity of aspirin required doses in excess of those required to inhibit TXA 2.In clinical studies,the results of a subgroup analysis of the North American Symptomatic Carotid Endarterectomy Trial study 79suggested that aspirin in doses of ?650mg/d might be more effective than ?325mg/d for the preven-tion of perioperative stroke in patients having carotid artery surgery.80This retrospective observation was refuted by a second prospective study,the Acetylsal-icylic Acid and Carotid Endarterectomy Trial,43which tested the hypothesis that the wide area of collagen exposed by endarterectomy is a sufficiently strong stimulus to platelet aggregation to require a larger dose of aspirin.Approximately 3,000patients scheduled for carotid endarterectomy were ran-domly assigned 81,325,650,or 1,300mg/d aspirin,started before surgery and continued for 3months.The combined rate of stroke,MI,or death at 3months was significantly (p ?0.03)lower in the low-dose groups (6.2%)than in the high-dose groups (8.4%)[primary analysis].There were no significant differences between the 81-mg and 325-mg groups or between the 650-mg and 1,300-mg groups in any of the secondary analyses of the data.43

A subgroup analysis of the Physicians’Health Study,81based on post hoc measurements of baseline plasma C-reactive protein performed in 543appar-ently healthy men who subsequently had MI,stroke,or venous thrombosis,and in 543study participants who did not report vascular complications,has found that the reduction in the risk of a first MI associ-ated with the use of aspirin (325mg on alternate days)appears to be directly related to the level of C-reactive protein,raising the possibility of antiin-flammatory as well as antiplatelet effects of the drug in cardiovascular prophylaxis.82This hypothesis is unlikely to be correct because,as noted above,the antiinflammatory effects of aspirin and other nonste-roidal antiinflammatory drugs (NSAIDs)are largely related to their capacity to inhibit COX-2activity induced in response to inflammatory cytokines,12as these clinical effects can be fully reproduced by highly selective COX-2inhibitors (coxibs)in patients with rheumatoid arthritis.83As shown in Table 3,the dose and time dependence of the effects of aspirin on nucleated inflammatory cells expressing COX-2vs anucleated platelets expressing COX-1are mark-edly different,thus making a clinically relevant anti-inflammatory effect of the drug at 325mg every

Table 3—Dose and Time Dependence of the Effects of Aspirin on Platelets and Inflammatory Cells (Section 2.3.2)

Cellular Target Enzyme Single Dose,*mg Duration of Prostanoid

Suppression,h

Cumulative Effects Upon

Repeated Dosing

Daily Dose,?mg Platelets

COX-110024–48Yes 50–81Inflammatory cells

COX-2

?650

3–4

No

3,000–5,000

*Dose causing full suppression of prostanoid formation and/or clinically detectable functional effect after single dosing.?Range of doses shown clinically effective in long-term trials of cardiovascular protection or rheumatoid arthritis.204S

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other day pharmacologically implausible.Finally,aspirin has been reported to modify the way in which neutrophils and platelets 84or erythrocytes and plate-lets 85,86interact,to protect endothelial cells from oxidative stress,87and to improve endothelial dys-function in atherosclerotic patients.88However,nei-ther the molecular mechanism(s)nor the dose de-pendence of these effects have been clearly established.Although improved endothelial dysfunc-tion could reflect an antiinflammatory effect of aspirin of relevance to atherogenesis,it should be emphasized that the hypothesis has never been tested by an appropriately sized controlled prospec-tive study.All of the evidence detailed above suggesting dose-dependent effects for aspirin is indirect and inconsistent with the failure to show a dose effect in randomized clinical trials and in the ATT overview analysis.7This failure to show a dose effect is the critical point of the discussion because it correlates with the saturability of the aspirin effect on platelet COX-1.For example,in studies with purified en-zyme and with isolated platelets,nanomolar concen-trations of aspirin will completely block PG synthesis within 20min after exposure.89Higher concentra-tions and longer exposures will not alter the inhibi-tory effect of aspirin on PG synthesis because of this saturable quality.Exactly the same feature (maximal effect at low doses,absence of dose effect)is seen in clinical trials with aspirin as an antithrombotic agent.When one raises the dose of aspirin in this situation,no further or additional effect can be appreciated because the critical event has already taken place,namely,maximal inhibition of platelet TX synthesis.Thus,the consistency of dose requirements and saturability of the effects of aspirin in acetylating the platelet enzyme,8inhibiting TXA 2production,25,62

and preventing atherothrombotic complications 6,7

constitutes the best evidence that aspirin prevents thrombosis through inhibition of TXA 2production.It is likely,therefore,that any of the potential effects of aspirin on other determinants of arterial throm-bosis are much less important than the inhibition of platelet COX-1activity.

2.3.3Aspirin “Resistance”:The term aspirin resis-tance has been used to describe a number of differ-ent phenomena,including the inability of aspirin to (1)protect individuals from thrombotic complica-tions,(2)cause a prolongation of the bleeding time,(3)reduce TXA 2production,or (4)produce a typical effect on one or more in vitro tests of platelet function.90From a therapeutic standpoint,it is im-portant to establish whether aspirin resistance can be overcome by increasing the dose of aspirin,but unfortunately very few data bear directly on this

issue.The fact that some patients may experience recurrent vascular events despite long-term aspirin therapy should be properly labeled as treatment failure rather than aspirin resistance.Treatment failure is a common phenomenon occurring with all drugs (eg ,lipid-lowering or antihypertensive drugs).Given the multifactorial nature of atherothrombosis and the possibility that platelet-mediated thrombosis may not be responsible for all vascular events,it is not surprising that only a fraction (usually one fourth to one third)of all vascular complications can be prevented by any single preventive strategy.It has been reported that a variable proportion (up to one fourth)of patients with cerebrovascular dis-ease only achieve partial inhibition of platelet aggre-gation at initial testing,and some (up to one third)seem to develop resistance to aspirin over time,even with increasing doses.91–93The results of these long-term studies carried out by Helgason et al are at variance with those of a short-term study of Weksler et al,94showing that aspirin,40mg/d,inhibited platelet aggregation and TXA 2formation as effec-tively as higher doses of aspirin in patients who had recent cerebral ischemia.Variable platelet responses to aspirin have also been described in patients with peripheral arterial disease 95and with ischemic heart disease.96–98In the Buchanan and Brister study,96aspirin nonresponders were identified on the basis of bleeding time measurements.Approximately 40%of patients undergoing elective coronary artery bypass grafting showed no prolongation of bleeding time in response to aspirin.This finding was associated with increased platelet adhesion and 12-HETE synthe-sis.96In contrast,repeated measurements of platelet aggregation performed over 24months of placebo-controlled treatment by Berglund and Wallentin 99demonstrated that 100patients with unstable coro-nary artery disease randomized to receive aspirin,75mg/d,in the Research Group on Instability in Coronary Artery Disease in Southeast Sweden study 32had consistently reduced platelet aggregation without attenuation during long-term treatment.Based on measurements of platelet aggregation in response to arachidonate and adenosine diphosphate (ADP),5%and 24%of patients with stable cardio-vascular disease who were receiving aspirin (325mg/d for ?7days)were defined as resistant and semiresponders,respectively.97Using a variety of techniques,including conventional aggregometry,shear stress-induced activation,and the expression of platelet surface receptors,Sane et al 98recently re-ported that 57%of a group of 88patients with documented heart failure who had been treated with aspirin,325mg/d,for ?1month showed aspirin nonresponsiveness.Overall,the majority of these studies were characterized by the following major b947df727fd5360cba1adbef CHEST /133/6/JUNE,2008SUPPLEMENT 205S

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limitations:(1)biochemical or witnessed verification

of patient’s adherence to the prescribed therapy

were absent;(2)there was a single measurement of

any given test;(3)intrasubject and intersubject

variability and stability of the assay over time were

usually not reported;(4)the criteria to define the

normal vs the aspirin-resistant range and the assay

conditions differed among studies;(5)doses of aspi-

rin were heterogeneous,ranging from 75to 1,300

mg;and (6)none of these studies were properly

controlled.

Lack of biochemical assessment of compliance is a

major issue for the majority of studies assessing

platelet function in response to aspirin,and this

aspect is crucial in studies investigating aspirin

unresponsiveness.Interestingly,a recent study 100

in 190patients with a history of MI compared

arachidonate-induced platelet aggregation in pa-

tients while receiving their usual aspirin therapy,

after 7days of withdrawal,and 24h after a single

witnessed intake of aspirin of 325mg.Although 9%

of the patients who declared having taken their usual

therapy failed to show inhibition of platelet aggrega-

tion,this percentage dropped to ?1%(1patient of

190)after a witnessed dose.100Furthermore,this single patient admitted NSAID intake 12h before testing.Similar results were reported in the study by Lev et al,101where after a witnessed dose of 325mg of aspirin,the mean of arachidonic acid-induced light transmission aggregometry became ?20%(the established limit to define resistance)in formerly resistant patients.Other studies have reported up to 40%noncompliance with long-term aspirin use.102It is therefore clear that questionnaires cannot be a reliable parameter to assess the compliance to any given treatment,including aspirin,and that studies not relying on salicylate measurements or serum TXB 2have a major,intrinsic bias,seriously hamper-ing the interpretation of results.Furthermore,the few studies directly comparing different functional assays failed to find any significant agreement be-tween tests,generating the disappointing conclusion that aspirin nonresponsiveness may be highly test specific.Several relatively small studies (n ?39to 180)of stroke patients 103–105have suggested that aspirin resistance may contribute to treatment failure (ie ,recurrent ischemic events while on antiplatelet ther-apy)and that doses higher than 500mg may be more effective than lower doses in limiting this phenome-non.The uncontrolled nature and small sample size of these studies make it difficult to interpret the results.As noted above,a much larger database failed to substantiate a dose-dependent effect of aspirin in stroke prevention,7an effect that one would theoreti-

cally expect if aspirin resistance could be overcome at least in part by increasing the daily dose of the drug.Gum et al 106reported that 5%of 326stable cardiovascular patients were aspirin resistant based on the results of platelet aggregation induced by ADP and arachidonic acid.The aspirin-resistant group had an increased risk of death,MI,or cere-brovascular accident during almost 2years of follow-up.There were,however,relatively few events in this study,and the rationale for the particular definition of aspirin resistance is uncertain.Among a wide range of patients with vascular disease in whom the annual rate of serious vascular events ranges from 40to 80per 1,000,aspirin typically prevents at least 10to 20fatal and nonfatal vascular events for every 1,000patients treated for 1year.6Thus,30to 60vascular events are expected to occur for every 1,000patients treated with low-dose aspirin for 1year not because of resistance,but because of the multifactorial nature of atherothrom-bosis.Thus,we do not agree with the definition given by Wang et al,107whereby “in its broadest sense,resistance refers to the continued occurrence of ischemic events despite adequate antiplatelet therapy and compliance.”Indeed,as suggested by Hennekens et al,108“given the multiple pathways by which platelets may be activated,it is perhaps more surprising that a clinical benefit is detectable in randomized trials of cardiovascular disease than that treatment failures complicate aspirin therapy.”At least three potential mechanisms may underlie the occurrence of aspirin-resistant TXA 2biosynthe-sis.The transient expression of COX-2in newly formed platelets in clinical settings of enhanced platelet turnover 4is a potentially important mecha-nism that deserves further investigation.Extraplate-let sources of TXA 2(eg ,monocyte/macrophage COX-2)may contribute to aspirin-insensitive TXA 2biosynthesis in acute coronary syndromes.109Fur-thermore,Catella-Lawson et al 110reported that con-comitant administration of a traditional NSAID (eg ,ibuprofen)may interfere with the irreversible inac-tivation of platelet COX-1by aspirin.This is due to competition for a common docking site within the COX channel (arginine-120),which aspirin binds to with weak affinity before irreversible acetylation of Serine-529.13This pharmacodynamic interaction also has been described between naproxen and aspirin 111but does not occur with rofecoxib,110celecoxib,112or diclofenac,110drugs endowed with variable COX-2selectivity.83Thus,concomitant treatment with readily available over-the-counter NSAIDs may limit the cardioprotective effects of aspirin and contribute to aspirin resistance.Based on current analysis of available data,113–115the US Food and Drug Admin-istration (FDA)has issued a statement informing 206S Antithrombotic and Thrombolytic Therapy 8th Ed:ACCP Guidelines

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patients and health-care professionals that ibuprofen can interfere with the antiplatelet effect of low-dose aspirin (81mg/d),potentially rendering aspirin less effective when used for cardioprotection and stroke prevention (b947df727fd5360cba1adbef/cder/drug/infopage/ibuprofen/default.htm).The clinical relevance of aspirin-resistant TXA 2biosynthesis has been explored by Eikelboom et al,116who performed a nested case-control study of baseline urinary TX metabolite excretion in relation to the occurrence of major vascular events in aspirin-treated high-risk patients enrolled in the Heart Outcomes Prevention Evaluation trial.After adjustment for baseline differences,the odds for the composite outcome of MI,stroke,or cardio-vascular death increased with each increasing quartile of 11-dehydro-TXB 2excretion,with pa-tients in the upper quartile having a 1.8-times higher risk than those in the lower quartile.One limitation in this study,however,was the inability to differentiate between variable compliance in taking aspirin as prescribed (or avoiding NSAIDs)and variable occurrence of aspirin-resistant sources of TXA 2biosynthesis.Thus,in summary,both the mechanism(s)and clinical relevance of aspirin resistance,as defined by platelet aggregation measurements,remain to be established.117Until its true nature and preva-lence vis-a `-vis other antiplatelet drugs are better defined,no test of platelet function is recom-mended to assess the antiplatelet effect of aspirin in the individual patient.118,119On the other hand,additional studies on the mechanisms and clinical relevance of aspirin-resistant TXA 2biosynthesis are clearly warranted.

2.4The Antithrombotic Effect of Aspirin

2.4.1Prevention of Atherothrombosis in Different Clinical Settings:The efficacy and safety of aspirin are documented from analysis of approximately 70randomized clinical trials that included ?115,000patients at variable risk of thrombotic complications of atherosclerosis.A detailed analysis of individual trials is beyond the scope of this article.It is more appropriately dealt within specific clinical sections of this volume.Aspirin has been tested in patients demonstrating the whole spectrum of atherosclerosis,from appar-ently healthy low-risk individuals to patients present-ing with an acute MI or an acute ischemic stroke;similarly,trials have extended for as short as a few weeks’duration or as long as 10years.6,7Although aspirin has been shown consistently to be effective in preventing fatal and/or nonfatal vascular events in these trials,both the size of the proportional effects

and the absolute benefits of antiplatelet therapy are somewhat heterogeneous in different clinical settings.In the Second International Study of Infarct Sur-vival,55a single tablet of aspirin (162.5mg)started within 24h of the onset of symptoms of a suspected MI and continued daily for 5weeks produced highly significant reductions in the risk of vascular mortality (by 23%),nonfatal reinfarction (by 49%),and non-fatal stroke (by 46%).There was no increase in hemorrhagic stroke or GI bleeding in the aspirin-treated patients and only a small increase in minor bleeding.55Treatment of 1,000patients with sus-pected acute MI with aspirin for 5weeks will result in approximately 40patients in whom a vascular event is prevented,7with a proportional odds reduc-tion of 30%(see the “Acute ST-Segment Elevation Myocardial Infarction”chapter).Two separate trials with a similar protocol,the International Stroke Trial 59and the Chinese Acute Stroke Trial,60tested the efficacy and safety of early aspirin use in acute ischemic stroke.Approximately 40,000patients were randomized within 48h of the onset of symptoms to 2to 4weeks of daily aspirin therapy (300mg and 160mg,respectively)or pla-cebo.An overview of the results of both trials suggests an absolute benefit of 9fewer deaths or nonfatal strokes per 1,000patients in the first month of aspirin therapy.7The proportional odds reduction in fatal or nonfatal vascular events is only 10%in this setting.Although the background risk of hemorrhagic stroke was threefold higher in the Chinese Acute Stroke Trial than in the International Stroke Trial,the absolute increase in this risk associated with early use of aspirin was similar in the two studies (excess 2per 1,000patients).59,60The broad clinical implications of these findings are discussed in the “Antithrombotic and Thrombolytic Therapy for Ischemic Stroke”chapter.In terms of their research implications,these results are consistent with biochemical evidence of episodic plate-let activation during the first 48h after the onset of symptoms of an acute ischemic stroke and with sup-pression of in vivo TXA 2biosynthesis in patients receiv-ing low-dose aspirin in this setting.120Long-term aspirin therapy confers conclusive net benefit on risk of subsequent MI,stroke,or vascular death among subjects with high risk of vascular complications.These include patients with chronic stable angina,33patients with prior MI,7patients with unstable angina,32,44–46and patients with TIA or minor stroke 34,36,41,56–58as well as other high-risk categories.7The proportional effects of long-term aspirin therapy on vascular events in these different clinical settings are rather homogeneous,ranging between 20%and 25%odds reduction based on an overview of all randomized trials.7However,individ-ual trial data show substantial heterogeneity,ranging b947df727fd5360cba1adbef CHEST /133/6/JUNE,2008SUPPLEMENT 207S

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from no statistically significant benefits in patients with peripheral vascular disease to approximately 50%risk reduction in patients with unstable angina.7Although other factors may play a role,we interpret these findings as reflecting the variable importance of TXA 2as a mechanism amplifying the hemostatic response to plaque destabilization in different clini-cal settings.In terms of absolute benefit,these protective effects of aspirin translate into avoidance of a major vascular event in 50per 1,000patients with unstable angina treated for 6months and in 36per 1,000patients with prior MI,stroke,or TIA treated for approximately 30months.7

For patients with different manifestations of ischemic heart or brain disease,a widespread consensus exists in defining a rather narrow range of recommended daily doses (ie ,75to 160mg)for the prevention of MI,stroke,or vascular death.This is supported by separate trial data in patients randomized to treatment with low-dose aspirin or placebo as well as by an overview of all antiplatelet trials showing no obvious dose dependence,from indirect comparisons,for the protective effects of aspirin 7(Table 3).There is no convincing evidence that the dose requirement for the antithrombotic effect of aspirin varies in different clinical settings.Among most high-risk patient groups,the ex-pected number avoiding a serious vascular event by using aspirin substantially exceeds the number expe-riencing a major bleed.However,it is unclear whether aspirin might benefit people who,although apparently healthy,are at intermediate risk of serious

vascular events.The question of whether aspirin is effective for the primary prevention of vascular events has been addressed in a metaanalysis of randomized trials.332

Six primary prevention trials 81,121–125including 92,873participants were studied (Table 4).Mean follow-up was approximately 6years.There was a 15%reduction in the odds of cardiovascular events (OR,0.85;95%CI,0.79to 0.92;p ?0.001)and highly significant reductions of 23%in total coronary heart disease (CHD)[OR,0.77;95%CI,0.70to 0.86;p ?0.001]and 24%in nonfatal MI (OR,0.76;95%CI,0.67to 0.85;p ?0.001).

There was no overall effect on stroke (OR,0.95;95%CI,0.84to 1.06;p ?0.3),but data were not available separately for hemorrhagic and nonhemor-rhagic stroke,126–128so the effects on these two stroke subtypes could not be examined in detail.Aspirin had no significant effect on the aggregate of all vascular causes of death (OR,0.89;95%CI,0.72to 1.10;p ?0.3),or on overall mortality (OR,0.94;95%CI,0.87to 1.00;p ?0.07).In summary,therefore,in primary prevention,aspirin chiefly pre-vents nonfatal MI,and appears to have little effect on fatal vascular events.2.5Balance of Benefit and Harm

Previous metaanalyses of the effects of antiplatelet therapy among people at high risk of occlusive vascular disease 7have shown that the benefits of aspirin far exceed the bleeding risks among such

Table 4—Primary Prevention Trials (Section 2.4.1)

Trial Dates of Recruitment Year of Publication Mean Duration of Follow-up,*yr

Target Population Eligible Age Range,yr Intervention Randomized Factorial Comparison Placebo Control British Doctors Study

11/1/1978to 11/1/1979

1988

5.6

Male physicians

19–90

500mg/d

None

No

US physicians

8/24/1981to 4/2/19841988 5.0Male physicians 45–73

325mg alternate days Beta-carotene (alternate days)vs placebo

Yes

Thrombosis Prevention Trial

2/6/1989to 5/18/19941998 6.7

Men with risk factors for CHD

45–69

75mg/d Warfarin vs placebo

Yes

Hypertension Optimal Treatment 10/12/1992to 5/7/19941998 3.8

Men and women with diastolic BP 100–115mm Hg

31–7575mg/d

Three target diastolic BPs (?80mm Hg,?85mm Hg,?90mm Hg)Yes

Primary

Prevention Project

6/8/1993to 4/21/19982001 3.7

Men and women with one or more risk factors for CHD

45–94100mg/d

Vitamin E vs open control

No

Women’s Health Study

9/1992to 5/1995200510.1

Female health professionals

?45

100mg alternate days

Vitamin E vs placebo

Yes

*Mean duration of follow-up among surviving participants within each trial.208S

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patients.By contrast,the majority of participants

(92%)in the primary prevention trials were at low

absolute risk of coronary disease;on average,the

annual risk of a vascular event in the primary pre-

vention trials was only about one tenth of that

occurring in the high-risk trials.Hence,although the

proportional benefits of aspirin appeared broadly

similar in primary and secondary prevention,the

absolute benefits and risks of aspirin in the primary

prevention trials were very small.Each year,fewer

than 1person in every 1,000could expect to avoid an

occlusive vascular event by taking aspirin,whereas a

comparably small number could expect to experience a

major extracranial bleed.The relative size of these

opposing effects is too imprecisely known in low-risk

people to predict the net public health consequences of widespread aspirin use in healthy people.The ATT Collaboration is currently analyzing individual partici-pant data from the six primary prevention trials,and these new analyses will help to clarify the benefits and risks of aspirin in particular groups of individuals.Until the benefits of aspirin can be defined more precisely,however,the possibility of a benefit does not seem to justify the probability of a hazard.This emphasizes the need for trials of aspirin for primary prevention among specific groups at increased risk of vascular disease,such as people ?70years of age and people with diabetes but no vascular disease.

2.5.1Atrial Fibrillation:Moderate-dose warfarin alone (international normalized ratio [INR],2.0to

3.0)is very effective in reducing the risk of stroke in patients with nonvalvular atrial fibrillation.129–131

The effectiveness of aspirin in doses between 75and 325mg has been compared with warfarin and pla-cebo in three randomized trials of patients with non-valvular atrial fibrillation.130,132,133In one study,130

aspirin was significantly more effective than placebo,whereas in the other two 132,133there was a nonsig-nificant trend in favor of aspirin.Pooled analysis of the three studies shows a relative risk reduction in favor of aspirin over placebo of about 25%(range,14to 44%).Aspirin was significantly less effective than warfarin in two studies on an intention-to-treat anal-ysis,132,133and in the third study on an efficacy analysis.130On pooled analysis,warfarin was signifi-cantly more effective than aspirin,with a 47%rela-tive risk reduction (range,28to 61%;p ?0.01).134

Moreover,adjusted-dose warfarin therapy (INR,2.0to 3.0)was more effective than fixed low-dose war-farin therapy (INR,1.2to 1.5)and aspirin,325mg/d,in high-risk patients with atrial fibrillation.135Thus,aspirin appears to be effective in preventing stroke in patients with atrial fibrillation but is substantially less effective than warfarin.136,137

2.5.2Deep Vein Thrombosis:The Pulmonary Em-bolism Prevention Trial 138has established that aspi-rin is effective in preventing venous thromboembo-lism after surgery for hip fracture.This was a double-blind multicenter study of 13,356patients undergoing surgery for hip fracture and of an addi-tional 4,088patients undergoing elective hip or knee arthroplasty.Patients were assigned 160mg of aspi-rin or placebo qd for 5weeks,with the first dose starting before surgery.Other forms of prophylaxis were allowed,and either heparin or low-molecular-weight heparin was used in about 40%of the patients.Among the 13,356patients with hip frac-ture,aspirin produced a 36%reduction in symptom-atic deep vein thrombosis or pulmonary embolism (PE)[absolute risk reduction 0.9%;p ?0.0003].A similar relative risk reduction in patients who were assigned aspirin was observed in patients who also received heparin.This important study,138therefore,clearly shows that aspirin reduces the incidence of fatal PE and symptomatic nonfatal deep vein thrombosis or PE in patients with hip fracture.The results of the Pulmo-nary Embolism Prevention trial are consistent with the meta-analysis performed by the Antiplatelet Tri-alists’Collaboration,139and supersede the findings in most of the previous trials.140–142However,in three randomized studies in major orthopedic surgery comparing aspirin with either warfarin 143or a low-molecular-weight heparin,144,145the incidence of ve-nous thrombosis was significantly higher in the aspi-rin group in all three.2.5.3Placental Insufficiency:The pathogenesis of preeclampsia and fetal growth retardation is related to reduced placental blood flow,which is believed to be caused by constriction and/or thrombosis of small placental arteries.146The initial reports that low-dose aspirin therapy reduces the risk of severe low birth weight among newborns,147and the risk of cesarean section in mothers with pregnancy-induced hyper-tension,146led to the widespread use of prophylactic aspirin to prevent preeclampsia.Subsequently,sev-eral larger trials reported no beneficial effects of aspirin.148–154A systematic review 155of data from 39trials in ?30,000women showed that antiplatelet therapy (mostly aspirin,60mg/d)is associated with a 15%decrease in the risk of preeclampsia.This effect was consistent,regardless of risk status (moderate or high),dose of aspirin,or gestation at trial entry.There was some evidence that there may be greater benefits for women given ?75mg of aspirin,al-though the numbers of women in the subgroup were small and so a potential for random error.There was also an 8%reduction in the risk of preterm birth and b947df727fd5360cba1adbef CHEST /133/6/JUNE,2008SUPPLEMENT 209S

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a 14%reduction in the risk of fetal or neonatal death for women allocated antiplatelet therapy.155Remain-ing questions are whether particular subgroups of high-risk women might have greater benefit and whether earlier treatment (ie ,before 12weeks)or aspirin doses of ?75mg would have additional benefits without an increase in adverse effects.155

The potential involvement of extra platelet sources of vasoactive eicosanoids expressing COX-2in response to a local growth-promoting milieu might contribute,at least in part,to the limited efficacy of low-dose aspirin therapy in this setting.

2.6Adverse Effects of Aspirin

Aspirin does not cause a generalized bleeding abnormality unless it is given to patients with an underlying hemostatic defect,such as hemophilia,uremia,or that induced by anticoagulant therapy.Aspirin-induced impairment of primary hemostasis cannot be separated from its antithrombotic effect and is similar at all doses ?75mg/d.6

The balance between preventing vascular occlu-sion and causing excess bleeding with aspirin de-pends critically on the absolute thrombotic vs hem-orrhagic risk of the patient.Thus,in individuals at low risk for vascular occlusion (eg ,?1%/yr),a very small absolute benefit is offset by exposure of a large number of healthy subjects to undue bleeding com-plications.In contrast,in patients at high risk of cardiovascular or cerebrovascular complications (eg ,?3%/yr),the substantial absolute benefit of aspirin prophylaxis clearly outweighs the harm (Table 5).For example,the absolute excess of major bleeds (ie ,those requiring transfusion)in acute MI is approxi-

mately 1/100th the absolute number of major vascu-lar events avoided by aspirin therapy.7The overall risk of major extracranial and intracra-nial hemorrhage associated with antiplatelet drugs is difficult to assess in individual trials because their incidence is low (ie ,?1%/yr),making detection of even a 50to 60%relative increase in risk unrealistic in most trials of a few thousand patients.Aspirin-induced GI toxicity,as detected in ran-domized clinical trials,appears to be dose related in the range of 30to 1,300mg/d.156This,along with studies of the relationship of efficacy to dose,is based largely on indirect comparisons of different trials and on a limited number of randomized,direct comparisons of different aspirin doses,as reviewed above.Such a dose-response relationship is thought to reflect at least two COX-1-dependent compo-nents,dose-dependent inhibition of COX-1in the GI mucosa and dose-independent (within the range of examined doses)inhibition of COX-1in platelets.6Thus,it is not surprising that the antithrombotic effect of aspirin can be dissociated,at least in part,from its most common side effect.However,even when administered at low doses,aspirin can cause serious GI bleeding,as reported in studies using 30to 50mg/d.36,42Because of the underlying preva-lence of gastric mucosal erosions related to concur-rent use of other NSAIDs and/or Helicobacter pylori infection in the general population,it should be expected that any antiplatelet dose of aspirin will cause more bleeding from preexisting lesions than a placebo.Consistent with this mechanistic interpre-tation,the relative risk of hospitalization due to upper-GI bleeding and/or perforation associated with low-dose aspirin therapy (mostly,100to 300mg/d)is comparable to that of other antiplatelet agents and anticoagulants (ie ,2.3[95%CI,1.7to 3.2],2.0[95%CI,1.4to 2.7],and 2.2[95%CI,1.4to 3.4],respectively)in a large population-based obser-vational study.157In the overview of the ATT Collaboration,7infor-mation was available on 787major extracranial hem-orrhages in 60trials recording at least one such hemorrhage.These were generally defined as hem-orrhages that were fatal or required transfusion;among them,159(20%)caused death.Overall,the proportional increase in risk of a major extracranial bleed with antiplatelet therapy was about one half (odds ratio [OR],1.6;95%CI,1.4to 1.8),with no significant difference between the proportional in-creases observed in each of the five high-risk cate-gories of patients.After allowing for noncompliance in the trials,they are compatible with the 2-to 2.5-fold excess observed in case-control studies.A case-control study with hospital and community controls has examined the risks of hospitalization for Table 5—Benefit and Harm of Antiplatelet Prophylaxis With Aspirin in Different Settings (Section 2.6)

Clinical Setting

Benefits *Harm?Men at low to high cardiovascular risk

1–21–2Essential hypertension

1–21–2Chronic stable angina

101–2Prior MI

201–2Unstable angina 501–2

*No.of patients in whom a major vascular event is avoided per

1,000/yr.Benefits are calculated from randomized trial data re-

viewed in this article and depicted in Figure 3.

?No.of patients in whom a major GI bleeding event is caused per

1,000/yr.Excess of upper-GI bleedings is estimated from a back-

ground rate of 1event per 1,000/yr in the general population of

nonusers 157and an RR of 2.0to 3.0associated with aspirin

prophylaxis.157–159Such an estimate assumes comparability of other

risk factors for upper-GI bleeding,such as age and concomitant use

of NSAIDs,and may actually underestimate the absolute risk in an

elderly population exposed to “primary”prevention.

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bleeding peptic ulcer associated with three different regimens of aspirin prophylaxis.158ORs were raised for all doses of aspirin taken:75mg,OR 2.3(95%CI,1.2to 4.4);150mg,OR 3.2(95%CI,1.7to 6.5);and 300mg,OR 3.9(95%CI,2.5to 6.3).Addi-tional epidemiologic studies have found a dose-response relationship between aspirin prescription and upper-GI complications,as reviewed by Garc?′a

Rodr?′guez et al.159It has been calculated that ap-proximately 900of the 10,000episodes of ulcer bleeding occurring in people ?60years of age each year in England and Wales could be associated with,and ascribed to,prophylactic aspirin use.158A gen-eral change to lower doses of aspirin (75mg)would not eliminate risks but would reduce risk by about 40%compared with 300-mg doses and by 30%compared with 150-mg doses if the assumptions from indirect comparisons are correct.158Given that the mortality rate among patients who are hospital-ized for NSAID-induced upper-GI bleeding is about 5to 10%,160,161such a strategy could save a signifi-cant number of lives.The widely held belief that enteric-coated and buffered varieties of aspirin are less likely to occasion major upper-GI bleeding than plain tablets was tested in data from a multicenter case-control study.162The relative risks of upper-GI bleeding for plain,enteric-coated,and buffered aspirin at average daily doses of ?325mg were 2.6,2.7,and 3.1,respectively.At doses ?325mg,the relative risks were 5.8for plain and 7.0for buffered aspirin;there were insufficient data to evaluate enteric-coated aspirin at this dose level.162Similar conclusions were reached by a case-control study using data from the UK General Practice Research Database.163Thus,physicians who recommend aspirin in an enteric-coated or buffered form should not assume that these formulations are less likely to cause GI tract bleeding than plain aspirin.Suppressing acid secretion is thought to reduce the risk of ulcers associated with regular use of NSAIDs.In patients who required continuous treat-ment with NSAIDs and who had ulcers or ?10erosions in either the stomach or duodenum,ome-prazole healed and prevented ulcers more effectively than did ranitidine.164In these patients,maintenance therapy with omeprazole was associated with a lower rate of relapse and was better tolerated than miso-prostol.165In high-risk patients (history of previous ulcer bleeding)taking low-dose aspirin for 6months,omeprazole and H pylori eradication were associated with similar rates of recurrent bleeding (0.9%vs 1.9%),166although clinically important differences between the two preventive strategies could not be excluded owing to the small sample size (n ?250).Two relatively small studies 167,168have challenged

current guidelines that recommend clopidogrel for patients who have major GI contraindications to aspirin,principally recent significant bleeding from a peptic ulcer or gastritis.169,170Both studies enrolled patients with ulcer bleeding after the use of low-dose aspirin.In the study of Chan et al,167after healing of ulcers and eradication of H pylori ,if present,320patients were randomly assigned to receive either clopidogrel,75mg/d,or aspirin,80mg/d,plus 20mg bid of esomeprazole for 12months.The cumulative incidence of recurrent bleeding was 8.6%(95%CI,4.1to 13.1%)among patients who received clopi-dogrel and 0.7%(95%CI,0to 2.0%)among those who received aspirin plus esomeprazole (p ?0.001).167In the study of Lai et al,168170patients with prior ulcer bleeding were randomly assigned to treatment with clopidogrel,75mg/d,or aspirin,100mg/d,and esome-prazole,20mg/d,for 1year.The cumulative incidence of recurrent ulcer complications was 13.6%and 0%,respectively (95%CI for the difference,6.3to 20.9%;p ?0.0019).168The consistent findings of two indepen-dent studies suggest that the combination of esomepra-zole and low-dose aspirin is superior to clopidogrel in preventing recurrent ulcer bleeding in patients with a history of aspirin-related ulcer bleeding.Substantially less information is available about the risk of intracranial hemorrhage associated with aspirin use.In the Nurses’Health Study 171cohort of approximately 79,000women 34to 59years of age,infrequent use of aspirin (1to 6tablets per week)was associated with reduced risk of ischemic stroke,whereas high frequency of use (?15aspirin tablets per week)was associated with increased risk of subarachnoid hemorrhage,particularly among older or hypertensive women.In the overview of the ATT Collaboration,7the overall absolute excess of intra-cranial hemorrhage due to aspirin therapy was ?1per 1,000patients per year in high-risk trials,with somewhat higher risks in patients with cerebrovas-cular disease.Low-dose aspirin therapy has not been reported to affect renal function or BP control,172consistent with its lack of effect on renal prostaglandins 173that derive primarily from constitutively expressed COX-2in the human kidney.83Moreover,aspirin,75mg/d,did not affect BP or the need for antihypertensive therapy in intensively treated hypertensive patients.122The sug-gestion that the use of aspirin and other antiplatelet agents is associated with reduced benefit from ena-lapril in patients with left ventricular systolic dys-function 174is not supported by the results of a large metaanalysis of MI trials.175Similarly,no negative interaction occurs between angiotensin-converting enzyme (ACE)inhibition and the cardiovascular benefits of low-dose aspirin in intensively treated hypertensive patients.176The ACE Inhibitors b947df727fd5360cba1adbef CHEST /133/6/JUNE,2008SUPPLEMENT 211S

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laborative Group 177has performed a systematic overview of data for 22,060patients from six long-term randomized trials of ACE inhibitors to assess whether aspirin altered the effects of ACE inhibitor therapy on major clinical outcomes.Even though results from these analyses cannot rule out the possibility of some sort of interaction,they show unequivocally that even if aspirin is given,the addi-tion of ACE inhibitor therapy produced substantial additional benefit in all major vascular outcomes.Therefore,in the absence of clear contraindications,concomitant use of aspirin and ACE inhibitors should be considered in all patients at high risk of major vascular events.177

Thus,in summary,inhibition of TXA 2-dependent platelet function by aspirin is effective for the pre-vention of thrombosis,but is also associated with excess bleeding.Assessing the net effect requires an estimation of the absolute thrombotic vs hemor-rhagic risk of the individual patient.In individuals at very low risk for vascular occlusion,a very small absolute benefit may be offset by exposure of very large numbers of healthy subjects to undue bleeding complications.As the risk of experiencing a major vascular event increases,so does the absolute benefit of antiplatelet prophylaxis with aspirin,as shown in Figure 3,for a number of clinical settings in which the efficacy of the drug has been tested in random-ized clinical trials.Based on the results of such trials,the antithrombotic effect of aspirin does not appear to be dose related over a wide range of daily doses (30to 1,300mg),an observation consistent with saturability of platelet COX inhibition at very low doses.In contrast,GI toxicity of the drug does appear to be dose related,consistent with dose-and dosing interval-dependent inhibition of COX activity in the nucleated lining cells of the GI mucosa.Thus,aspirin once daily should be considered in all clinical conditions in which antiplatelet prophylaxis has a favorable benefit/risk profile.Because of GI toxicity and its potential impact on compliance,physicians are encouraged to use the lowest dose of aspirin shown effective in each clinical setting (Table 1).2.7Reversible COX Inhibitors In the absence of definitive randomized studies,traditional NSAIDs have long been thought to pose no cardiovascular hazard or to be somewhat cardio-protective.Because of their reversible mechanism of action in inhibiting platelet COX-1and of their short half-lives,most traditional NSAIDs inhibit TXA 2-dependent platelet activation only transiently and incompletely in the vast majority of users.178A notable exception is provided by naproxen,which when administered regularly at 500mg bid,has been shown to inhibit TXA 2biosynthesis in vivo to the same extent as low-dose aspirin,179consistent with its

Annual risk of a vascular event on placebo

10

2030405060

05101520

Subjects in whom a vascular event

is prevented by aspirin

per 1,000 treated

/yr Figure 3.The absolute risk of vascular complications is the major determinant of the absolute benefit of antiplatelet prophylaxis.Data are plotted from placebo-controlled aspirin trials in different clinical settings.For each category of patients,the abscissa denotes the absolute risk of experiencing a major vascular event as recorded in the placebo arm of the trial(s).The absolute benefit of antiplatelet treatment is reported on the ordinate as the number of subjects in whom an important vascular event (nonfatal MI,nonfatal stroke,or vascular death)is actually prevented by treating 1,000subjects with aspirin for 1year.

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relative COX-1selectivity and longer half-life than other commonly used NSAIDs.The only reversible COX inhibitors that have been tested in randomized clinical trials for their antithrom-botic efficacy are sulfinpyrazone,indobufen,flurbipro-fen,and triflusal.Sulfinpyrazone is a uricosuric agent structurally related to the antiinflammatory agent phe-nylbutazone.When used at the highest approved dosage of 200mg qid,the drug inhibits platelet COX activity by approximately 60%,after conversion from an inactive sulfoxide to an active sulfide metabo-lite.180The conflicting or negative results obtained in randomized clinical trials of sulfinpyrazone in pa-tients with MI or unstable angina 7(reviewed in the “Valvular and Structural Heart Disease”chapter)are not surprising in light of the drug being a weak COX inhibitor with no other established antiplatelet mechanism of action.In contrast,indobufen is a very potent inhibitor of platelet COX-1activity and has comparable bio-chemical,functional,and clinical effects to those of a standard dose of aspirin.Thus,at therapeutic plasma levels achieved after oral dosing of 200mg bid,indobufen inhibits serum TXB 2by ?95%through-out the dosing interval 181and reduces urinary TX metabolite excretion to an extent quite comparable to aspirin.182The finding that indobufen is as effec-tive as aspirin in preventing coronary graft occlusion in two randomized trials 183,184is mechanistically consistent with the concept of platelet COX-1inhi-bition largely accounting for the antithrombotic ef-fect of aspirin,as discussed above.Indobufen also has been investigated in a small placebo-controlled study of patients with heart disease at increased embolic risk 185and compared with warfarin 186and ticlopidine 187in patients with nonrheumatic atrial fibrillation and patients with recent reversible cere-bral ischemia,respectively.However,none of these studies in ?4,000patients clearly established an advantage of indobufen vs standard treatments,al-though the 95%CIs for these comparisons are wide.Indobufen has been reported to suppress in vivo TXA 2biosynthesis more effectively than low-dose aspirin in patients with unstable angina,an effect possibly related to inhibition of monocyte COX-2by therapeutic plasma levels of indobufen.14The clini-cal relevance of these findings remains to be estab-lished.Flurbiprofen has been evaluated in a single placebo-controlled,randomized trial of 461patients with acute MI.188The 6-month reinfarction rate was significantly lower in the flurbiprofen group (3%)than in the placebo group (10.5%),with an extremely low mortality rate (1.1%)in both groups.The small sample size of the study limits interpretation of these findings.

Triflusal,a salicylic acid derivative,reversibly in-hibits platelet COX activity after conversion to a long-lived metabolite,2-hydroxy-4-trifluoromethyl-benzoic acid.189Although the half-life of the parent compound is only about 30min,that of the deacety-lated metabolite approximates 2days.Although tri-flusal is claimed to have negligible effects on vascular PGI 2production,this is likely to reflect the exper-imental conditions used for the assessment of PGI 2production ex vivo .The limited sample size of head-to-head comparisons of triflusal vs aspirin in patients randomized within 24h of acute MI 190and in patients with cerebrovascular disease 191precludes unequivocal interpretation of the similar rates of major vascular events in the two treatment groups.None of these reversible COX inhibitors are approved as an antiplatelet drug in the United States,and it is unclear under which circum-stances they are prescribed instead of aspirin in other countries.2.8Coxibs and Cardiovascular Disease Coxibs were developed in an attempt to prevent the adverse GI effects of nonselective NSAIDs (by avoiding inhibition of COX-1)while maintaining equivalent antiinflammatory efficacy (by inhibiting COX-2).83Several large randomized trials 192–194have demonstrated that coxibs are associated with lower risk of serious GI events than nonselective NSAIDs,but the Vioxx GI Outcomes Research Study 193among approximately 8,000patients with rheuma-toid arthritis showed that those allocated to rofe-coxib,50mg/d,experienced a higher risk of vascular events than those allocated to naproxen 500mg bid.This excess was almost entirely accounted for by a difference in the incidence of MI (20in 2,699person-years of follow-up among rofecoxib-allocated patients,vs 4in 2,699person-years among naproxen-allocated patients).There were no significant differ-ences in stroke (11rofecoxib vs 9naproxen)or vascular deaths (7rofecoxib vs 7naproxen).193Three placebo-controlled trials have now revealed a two-fold-to threefold-increased risk of vascular events in approximately 6,000patients treated short term (10days)with valdecoxib 195or long term (up to 3years)with celecoxib 196or rofecoxib 197both with and with-out concomitant aspirin treatment.These recent findings are consistent with a mechanism-based car-diovascular hazard for the class 198and have led to the withdrawal of rofecoxib and valdecoxib from the market.A metaanalysis of tabular data from 138random-ized trials of five different coxibs in approximately 145,000patients has revealed that in placebo com-parisons,allocation to a coxib was associated with a b947df727fd5360cba1adbef CHEST /133/6/JUNE,2008SUPPLEMENT 213S

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42%increased incidence of vascular events with no statistically significant heterogeneity among the dif-ferent coxibs.20This excess risk of vascular events was derived primarily from a twofold-increased risk of MI.Overall,there was no significant difference in the incidence of vascular events between a coxib and any traditional NSAID,but there was evidence of a significant difference between naproxen and the other traditional NSAIDs.20Given the nonlinear relationship between inhibition of platelet COX-1activity and inhibition of platelet activation in vivo (Fig 2),31it is perhaps not surprising that the cardio-vascular safety profile of coxibs and some non-naproxen NSAIDs (primarily diclofenac and ibupro-fen)appears similar because these drugs fail to inhibit platelet activation adequately irrespective of their COX-2selectivity.The results of the Multina-tional Etoricoxib and Diclofenac Arthritis Long-Term study,199comparing long-term treatment with etoricoxib and diclofenac in approximately 35,000arthritis patients,are consistent with this conclusion.Whether the variable level and duration of COX-1inhibition by different NSAIDs modulate the cardio-vascular consequences of COX-2inhibition presently is unknown,given the limited utilization of NSAIDs other than ibuprofen,diclofenac,and naproxen in coxib trials.Thus,coxibs and some traditional NSAIDs moderately increase the risk of vascular events,particularly MI,but there remains considerable un-certainty about the magnitude of this hazard for particular drug regimens and patients subgroups.A metaanalysis of individual participant data from ran-domized coxib trials is currently being conducted by the Coxib Trialists’Collaboration in order to address some of the open questions related to the influence of dose,duration,and baseline characteristics,in-cluding the concomitant use of low-dose aspirin,on this cardiotoxicity.

3.0Dipyridamole

Dipyridamole is a pyrimidopyrimidine derivative with vasodilator and antiplatelet properties.The mechanism of action of dipyridamole as an antiplate-let agent has been a subject of controversy.200Both inhibition of cyclic nucleotide phosphodiesterase (the enzyme that degrades cyclic adenosine mono-phosphate ?AMP ?to 5(1)-AMP,resulting in the intraplatelet accumulation of cyclic AMP,a platelet inhibitor)and blockade of the uptake of adenosine (which acts at A 2receptors for adenosine to stimu-late platelet adenylyl cyclase and thus increase cyclic AMP)have been suggested.Moreover,direct stim-ulation of PGI 2synthesis and protection against its degradation have been reported,although the dipy-

ridamole concentrations required to produce these effects far exceed the low micromolar plasma levels achieved after oral administration of conventional doses (100to 400mg/d).200Dipyridamole also dif-ferentially inhibits the expression of critical inflam-matory genes in platelet-leukocyte aggregates.201The absorption of dipyridamole from conventional formulations is quite variable and may result in low systemic bioavailability of the drug.A modified-release formulation of dipyridamole with improved bioavailability has been developed in association with low-dose aspirin.202Dipyridamole is eliminated pri-marily by biliary excretion as a glucuronide conjugate and is subject to enterohepatic recirculation.A ter-minal half-life of 10h has been reported.This is consistent with the twice-daily regimen used in recent clinical studies.Although the clinical efficacy of dipyridamole,alone or in combination with aspirin,has been questioned on the basis of earlier randomized tri-als,2,203the whole issue has been reopened by the reformulation of the drug to improve bioavailability and the results of the ESPS-2and European Stroke Prevention Reversible Ischemia Trial (ESPRIT)studies.36,204In ESPS-2,the new preparation of dipyridamole was evaluated in 6,602patients with prior stroke or TIA.36This study showed that the addition of modified-release dipyridamole 200mg bid to aspirin 25mg bid was associated with a 22%relative risk reduction of major vascular events com-pared with aspirin alone.Headache was the most common adverse effect of dipyridamole.Bleeding at any site was almost doubled in the two aspirin arms but was surprisingly indistinguishable from placebo in the dipyridamole-treated patients.36In a post hoc analysis of cardiac events in patients with CHD or MI at entry,dipyridamole did not result in a higher number of fatal and nonfatal cardiac events.204More recently,the ESPRIT Study Group 205has performed a randomized trial in which they assigned 2,739patients within 6months of a TIA or minor stroke of presumed arterial origin to aspirin (30to 325mg/d)with or without dipyridamole (200mg bid).The primary outcome (a composite of major vascular events or major bleeding complications)was significantly reduced by the combined treatment vs aspirin alone by 20%.Patients receiving aspirin and dipyridamole discontinued trial medication almost three times more often than those receiving aspirin alone,mainly because of headache.205Addition of the ESPRIT data to the metaanalysis of previous trials resulted in an overall risk ratio of 0.82(95%CI,0.74to 0.91)for the composite of vascular death,stroke,or MI.However,based on the most recent Cochrane review,203the additional benefit of the combination over aspirin alone is not detectable in 214S Antithrombotic and Thrombolytic Therapy 8th Ed:ACCP Guidelines

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patients with other types of vascular disease.Whether this apparent discrepancy reflects a differ-ent prevalence of dipyridamole-sensitive mecha-nisms of disease or,perhaps more likely,the differ-ent types of formulation and daily dosage of the drug remains to be established.The fixed combination of modified-release dipyridamole and low-dose aspirin has been approved for stroke prevention by the FDA and other regulatory authorities.4.0Thienopyridines Ticlopidine and clopidogrel are structurally re-lated thienopyridines with platelet-inhibitory prop-erties.Both drugs selectively inhibit ADP-induced platelet aggregation with no direct effects on arachi-donic acid metabolism.206Although ticlopidine and clopidogrel also can inhibit platelet aggregation in-duced by collagen and thrombin,these inhibitory effects are abolished by increasing the agonist con-centration and,therefore,are likely to reflect block-ade of ADP-mediated amplification of the platelet response to other agonists.Neither ticlopidine nor clopidogrel affect ADP-induced platelet aggregation when added in vitro ,up to 500?mol/L,thus suggesting that in vivo hepatic transformation to an active metabolite(s)is necessary for their antiplatelet effects.In the liver,clopidogrel is metabolized into 2-oxo-clopidogrel through a cy-tochrome P450-dependent pathway.This intermedi-ate metabolite is then hydrolyzed and generates the highly labile active metabolite,207which reacts as a thiol reagent with the ADP receptors on platelets when they pass through the liver.208The active metabolite belongs to a family of eight stereoiso-mers,only one of which (bearing 7S,3Z,and 4S or 4R configuration)retains biological activity.208Experimental evidence suggests that clopidogrel and,probably,ticlopidine induce irreversible alter-ations of the platelet receptor P2Y12mediating inhibition of stimulated adenylyl cyclase activity by ADP.209,210The active metabolite of clopidogrel couples through a disulfide bridge to the P2Y12receptor,presumably to the cysteine residue in the first extracellular loop;this results in oligomers dis-sociating into dimeric receptors that are partitioned out of lipid rafts,thereby losing the ability to bind their endogenous ligand.211Interestingly,mutations in the P2Y12gene are associated with a congenital bleeding disorder and abnormality in the platelet response to ADP,resembling that induced by thienopyridines.212Permanent modification of a platelet ADP receptor by thienopyridines is con-sistent with time-dependent cumulative inhibition of ADP-induced platelet aggregation on repeated daily dosing with ticlopidine or clopidogrel and with slow recovery of platelet function after drug withdrawal.2064.1Ticlopidine Up to 90%of a single oral dose of ticlopidine is rapidly absorbed in humans.206Peak plasma concen-trations occur 1to 3h after a single oral dose of 250mg.Plasma levels of ticlopidine increase by approx-imately threefold on repeated twice-daily dosing over 2to 3weeks because of drug accumulation.Greater than 98%of ticlopidine is reversibly bound to plasma proteins,primarily albumin.Ticlopidine is metabolized rapidly and extensively.A total of 13metabolites have been identified in humans.Of these,only the 2-keto derivative of ticlopidine is more potent than the parent compound in inhibiting ADP-induced platelet aggregation.206

The apparent elimination half-life of ticlopidine is 24to 36h after a single oral dose and up to 96h after 14days of repeated dosing.206The standard regimen of ticlopidine is 250mg bid,although it is unclear how a twice-daily regimen is related to the pharma-cokinetic and pharmacodynamic features noted above.A delayed antithrombotic effect was noted in at least one clinical trial of ticlopidine in patients with unstable angina with no apparent protection during the first 2weeks of drug administration.213

Therefore,ticlopidine is not useful when a rapid antiplatelet effect is required.Ticlopidine as a single agent has been evaluated in patients with stroke,214transient cerebral isch-emia,215unstable angina,213MI,216intermittent clau-dication,217–219and aortocoronary bypass surgery.220

Ticlopidine was significantly (but marginally in abso-lute terms)more effective than aspirin in reducing stroke in patients with transient cerebral ischemia or minor stroke 215(although there was no statistically significant difference in the combined outcome of stroke,MI,or death)7;was as effective as aspirin in the treatment of patients with a recent MI 216;was more effective than placebo in reducing the risk of the combined outcome of stroke,MI,or vascular death in patients with thromboembolic stroke 214;was more effective than conventional antianginal therapy in reducing vascular death or MI in patients with unstable angina 213;was more effective than placebo in reducing acute occlusion of coronary bypass grafts 220;and was more effective than controls in improving walking distance 218and reducing vascular complications in patients with peripheral vascular disease.217–219The association of ticlopidine therapy with hypercholesterolemia and neutropenia (for which the reported rate of occurrence is 2.4%for neutrophils ?1.2?109/L and 0.8%for neutrophils

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?0.45?109/L)and its comparative expense have

reduced enthusiasm for this therapy as an alternative

to aspirin in most situations.221Ticlopidine also has been associated with thrombocytopenia,221aplastic anemia,222and thrombotic thrombocytopenic pur-pura (TTP).223Ticlopidine has been approved for clinical use in patients with cerebral ischemia when aspirin has failed,cannot be tolerated,or is contra-indicated,although this limitation does not apply to all countries where the drug is registered.Additive effects of ticlopidine and aspirin have been described in rats,in inhibition of ADP-induced platelet aggregation ex vivo ,tail bleeding time pro-longation,and protection from thrombosis in exper-imental models of platelet-dependent vascular occlu-sion.224Additive antiplatelet effects of aspirin (40mg)and ticlopidine (250mg)have been reported in healthy volunteers.225Two studies 226,227have dem-onstrated the superiority of ticlopidine with aspirin compared to aspirin alone or aspirin plus warfarin in preventing thrombotic complications after coronary artery stent placement.Ticlopidine has been rou-tinely used in combination with aspirin in patients receiving coronary artery stents,but the better safety profile of clopidogrel has resulted in the replacement of clopidogrel for ticlopidine as the standard anti-platelet regimen after stent deployment.228The risk of TTP associated with ticlopidine use has been estimated as 0.02%in patients receiving the drug after stent placement.229This risk compares with an incidence of 0.0004%in the general population.The mortality rate for this rare complication exceeds 20%.229The place of ticlopidine in the current therapeutic armamentarium is uncertain:(1)the drug is not uniformly cheaper than clopidogrel in different countries;(2)in contrast to clopidogrel,ticlopidine has no approved indication for the long-term management of post-MI patients;(3)ticlopi-dine has a higher bone-marrow toxicity than clopi-dogrel;and (4)because of safety concerns,an adequate loading dose of ticlopidine,as required in the acute setting,is unlikely to be used.

4.2Clopidogrel

The pharmacokinetics of clopidogrel are somewhat different from those of ticlopidine.Thus,after admin-istration of single oral doses (up to 200mg)or repeated doses (up to 100mg/d),unchanged clopidogrel was not detectable in peripheral venous plasma.230Concentra-tions of 1to 2ng/mL were measured in the plasma of patients who received 150mg/d of clopidogrel (twice as much as the dose used in the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events [CAPRIE]study 231and approved for clinical use)for 16days.The main systemic metabolite of clopidogrel is

the carboxylic acid derivative,SR 26334.Based on measurements of circulating levels of SR 26334,it has been inferred that clopidogrel is rapidly absorbed and extensively metabolized.230The plasma elimination half-life of SR 26334is approximately 8h.As noted above,clopidogrel,inactive in vitro ,is metabolically transformed by the liver into a short-lived active plate-let inhibitor.However,the interindividual variability in this metabolic activation is still being assessed,and to our knowledge,there are no published data on whether liver impairment decreases the ability of clopidogrel to inhibit platelet function.A pharmacokinetic/pharmacody-namic study 232of a 600-mg loading dose of clopi-dogrel in healthy subjects revealed linear correla-tions between the maximal antiplatelet effect and peak plasma concentrations of unchanged clopi-dogrel,of the carboxyl metabolite,and of the thiol metabolite as well as linear correlations between peak plasma concentration values of clopidogrel and its metabolites.These results have been interpreted to suggest that the pharmacodynamic response vari-ability is predominantly caused by individual differ-ences in clopidogrel absorption.232Because the cytochrome P450isozymes CYP3A4and 3A5metab-olize clopidogrel faster than other human P450isozymes and are the most abundant P450s in human liver,they are predicted to be predominantly respon-sible for the activation of clopidogrel in vivo .233When clopidogrel and atorvastatin,a CYP3A4sub-strate,are present at equimolar concentrations in vitro ,clopidogrel metabolism is inhibited by ?90%.233Variable metabolic activity of CYP3A4may contribute to the interindividual variability in the platelet inhibitory effect of clopidogrel.234Thus,Angiolillo et al 235recently characterized the influ-ence of CYP3A4genotype on interpatient variability in clopidogrel responsiveness.An intronic single nucleotide polymorphism in the CYP3A4gene,IVS10?12G ?A (also called CYP3A4*1G)modified platelet reactivity ex vivo as measured by GP-IIb/IIIa receptor activation in response to clopidogrel in a group of patients with stable CHD receiving long-term anti-platelet therapy.The findings were replicated in a group of clopidogrel-na?¨ve patients undergoing elective percutaneous coronary intervention (PCI)treated with a 300-mg loading dose of the drug.235Clopidogrel inhibited ADP-induced platelet ag-gregation in a dose-dependent fashion with an ap-parent ceiling effect (40%inhibition)at 400mg after single oral doses in healthy volunteers.Inhibition of platelet aggregation was detectable 2h after oral dosing of 400mg and remained relatively stable up to 48h.230On repeated daily dosing of 50to 100mg of clopidogrel to healthy volunteers,ADP-induced platelet aggregation was inhibited from the second day of treatment (25to 30%inhibition)and reached 216S Antithrombotic and Thrombolytic Therapy 8th Ed:ACCP Guidelines

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a steady state (50to 60%inhibition)after 4to 7days.Such level of maximal inhibition was comparable to that achieved with ticlopidine,500mg/d,although the latter showed a slower onset of the antiplatelet effect than the clopidogrel.No appreciable differ-ences in the maximum inhibitory effects of 50,75,and 100mg of clopidogrel were noted in this study.230As would be expected from these pharma-cokinetic and pharmacodynamic features,a loading dose (eg ,300mg)of clopidogrel results in a much more rapid onset of platelet inhibition than is achieved with the 75-mg dose.236

Several recent studies have examined the ade-quacy of a 300-mg loading dose of clopidogrel in patients scheduled for cardiac catheterization as potential candidates for PCI.237–240After loading with 600mg of clopidogrel,the full antiplatelet effect of the drug was achieved after 2h.237More-over,a loading dose of 600mg resulted in higher plasma concentrations of the active metabolite,clo-pidogrel,and the carboxyl metabolite than did a loading dose of 300mg.238ADP-induced platelet aggregation also was significantly lower in patients receiving 600mg than in those receiving 300mg.238–240The incremental antiplatelet effect of 900mg over 600mg of clopidogrel appears mar-ginal,238,239possibly because of limited drug ab-sorption.238

Clopidogrel treatment exhibited marked interindi-vidual variability in inhibiting platelet function in three different studies 241–243of patients undergoing elective PCI and stenting.A variable proportion of these patients were considered to be clopidogrel nonresponders or to have clopidogrel resistance based on ADP-induced platelet aggregation.Three separate studies 241,244,245suggested that concurrent treatment with lipophilic statins that are substrates of CYP3A4(eg ,atorvastatin and simvastatin)may inter-fere with the inhibitory effects of clopidogrel on platelet function.In the study of Lau et al,244

atorvastatin,but not pravastatin,attenuated the an-tiplatelet effect of clopidogrel in a dose-dependent manner.Because many drugs are metabolized by CYP3A4,246it is likely that other drugs may modify the systemic bioavailability of the active metabolite of clopidogrel and affect its clinical efficacy.More-over,variable metabolic activity of CYP3A4may contribute to the interindividual variability in the platelet inhibitory effects of clopidogrel,as noted above.Although ex vivo measurements of ADP-in-duced platelet aggregation have suggested a pharma-cokinetic interaction between a CYP3A4-metabolized statin and clopidogrel,post hoc analyses of placebo-controlled studies 247,248of clopidogrel,a single center cohort study,249and data from a large multinational registry 250have failed to detect a statistically signifi-

cant clinical interaction between the two.However,it should be emphasized that retrospective post hoc analyses have limitations that preclude definitive conclusions.Moreover,the lack of information on statin daily doses used in trials notably restricts our ability to assess the dose dependence of potential drug interactions.As with aspirin,both the mechanism(s)and the clinical relevance of clopidogrel resistance or nonre-sponsiveness 251remain to be established.Thus,no test of platelet function can currently be recom-mended to assess the effects of clopidogrel in the individual patient,as there is no uniformly estab-lished method for quantification of ex vivo platelet reactivity after clopidogrel treatment and to what extent platelet activity is inhibited by the drug.251Thus,the active metabolite of clopidogrel has a pharmacodynamic pattern quite similar to that of aspirin in causing cumulative inhibition of platelet function on repeated daily administration of low doses.As in the case of aspirin,platelet function returns to normal 7days after the last dose of clopidogrel.Both the cumulative nature of the in-hibitory effects and the slow rate of recovery of platelet function are consistent with the active moi-eties of aspirin (acetylsalicylic acid)and clopidogrel (active metabolite),causing a permanent defect in a platelet protein that cannot be repaired during the 24-h dosing interval and can only be replaced as a function of platelet turnover.This consideration also justifies the once-daily regimen of both drugs,de-spite their short half-life in the human circulation.It should be noted,however,that although aspirin currently is used at doses that represent a 2.5-to 10-fold excess over the dose of 30mg necessary and sufficient to fully inactivate platelet COX-1activity on repeated daily dosing,25,62clopidogrel is used at doses causing only partial inactivation of P2Y12.Thus,the main determinants of the inter-individual variability in the antiplatelet effects of the two drugs are substantially different (Table 6).Bleeding time measurements performed in the same multiple dose study 230described above showed a comparable prolongation (by 1.5-to 2.0-fold over control)at 50to 100mg/d of clopidogrel or 500mg/d ticlopidine.Clopidogrel has undergone a quite unusual clinical development,with very limited phase II studies and a single,very large phase III trial (ie ,CAPRIE,to test its efficacy and safety at 75mg/d vs aspirin at 325mg/d).231CAPRIE is unique among the studies that have directly compared antiplatelet agents against aspirin in that it incorporated three groups of pa-tients,all of whom are recognized to be at an increased risk of recurrent ischemic events:those who have experienced a recent stroke or recent MI b947df727fd5360cba1adbef CHEST /133/6/JUNE,2008SUPPLEMENT 217S

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and those presenting with symptomatic peripheral arterial disease.Overall,CAPRIE showed a modest difference in effectiveness between aspirin and clo-pidogrel that did not result in regulatory approval of a superiority claim.What is particularly interesting,however,are the results obtained when the effects of aspirin and clopidogrel in the three groups are compared.Each comparison between clopidogrel and aspirin involved approximately 6,400patients and,therefore,represents the largest head-to-head comparison between aspirin and another antiplatelet agent in that particular clinical setting,although the statistical power of such comparison is inadequate to detect a modest difference between the two.This analysis shows that the majority of the difference in effectiveness occurred in the patients who entered the trial because of symptomatic peripheral arterial disease.A formal test of heterogeneity of these three treatment effects was statistically significant (p ?0.042),suggesting that the true benefit of clopidogrel may not be identical across the three clinical settings.Both clopidogrel and medium-dose aspirin ther-apy were well tolerated in the CAPRIE study.231The incidence of early permanent discontinuation of the study drug due to adverse events was practically identical in the two treatment groups (12%).Simi-larly,the overall incidence of hemorrhagic events was identical in the aspirin and clopidogrel groups (9.3%).The frequency of severe rash and severe diarrhea was higher with clopidogrel than with aspi-rin,whereas GI discomfort and hemorrhage were more frequent with aspirin than with clopidogrel.No excess neutropenia was found in the clopidogrel group,and thrombocytopenia was identical in the clopidogrel and aspirin groups.Based on these find-ings,clopidogrel has been approved for the reduc-tion of atherosclerotic events in patients with recent stroke,recent MI,or established peripheral arterial disease.TTP can occur within the first 2weeks after the initiation of clopidogrel therapy.252

The complementary mechanisms of action of clo-pidogrel and low-dose aspirin has led to testing the efficacy and safety of their combination in high-risk clinical settings.253The CURE trial 253randomly assigned 12,562patients with acute coronary syn-dromes without ST-segment elevation who pre-sented within 24h after the onset of symptoms to receive clopidogrel (300-mg loading dose followed by 75mg qd)or placebo in addition to aspirin (75to 325mg/d)for 3to 12months.After a mean duration of treatment of 9months,the primary outcome (a composite of cardiovascular death,nonfatal MI,or stroke)occurred in 9.3%of the patients in the clopidogrel group and 11.4%of the patients in the placebo group (RR,0.80;95%CI,0.72to 0.90;p ?0.001).The benefit of clopidogrel was apparent within the first 30days after randomization and remained constant during the 12months of the study.There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7%vs 2.7%;p ?0.001).The clinical benefit of dual antiplatelet therapy vs aspirin alone has been confirmed in patients under-going PCI,254and in those presenting with an acute MI with ST-segment elevation within 12h 256to 24h 257after the onset of symptoms.In the Clopidogrel and Metoprolol Myocardial Infarction Trial 257(COMMIT),addition of 75mg/d of clopidogrel to 162mg/d of aspirin reduced mortality and major vascular events in the hospital by 9%(95%CI,3to 14%),corresponding to nine fewer events per 1,000MI patients treated for about 2weeks.Overall,when all transfused,fatal,or cerebral bleeds were consid-ered together,there was no significant excess risk associated with the use of clopidogrel during the scheduled treatment period (0.58%clopidogrel plus aspirin vs 0.55%aspirin alone;p ?0.59),nor was there any excess of major bleeds in patients ?70years of age or in those given fibrinolytic therapy before randomization.257Clopidogrel was,however,associated with a small,but significant,excess of 4.7(95%CI,1.4to 8.0)reported minor bleeds per 1,000patients treated.Taking major and minor bleeds together,there was no apparent trend with respect to age in the excess risk.257Factors that may have contributed to the remarkable safety of dual anti-platelet therapy in the COMMIT trial include the lack of a loading dose of clopidogrel,the uniform use of 162mg of aspirin,and the short duration of treatment.In contrast to the consistent finding of a favorable benefit/risk profile of dual antiplatelet therapy in patients with acute coronary syndromes,253,256,257the same strategy was not proven successful when com-pared to clopidogrel alone in patients after a recent ischemic stroke or TIA,255when compared to aspirin Table 6—Main Determinants of the Interindividual Variability in the Antiplatelet Effects of Aspirin and Clopidogrel (Section 4.2)

Determinant

Aspirin Clopidogrel Dependence on systemic bioavailability

No Yes Dependence on liver metabolism to

active moiety

No Yes Recommended dose:minimum

effective dose for full

pharmacodynamic effect

2–31Relevance of pharmacodynamic

interactions at the target site

Yes ?Relevance of extraplatelet sources of

the platelet agonist Yes No

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