cad+dm.pdf

8/14/2019 cad+dm.pdf

1/16

http://dvr.sagepub.com/Diabetes and Vascular Disease Research

http://dvr.sagepub.com/content/7/4/274The online version of this article can be found at:

DOI: 10.1177/1479164110383995

2010 7: 274 originally published online 4 October 2010Diabetes and Vascular Disease ResearchJos Luis Ferreiro, ngel R Cequier and Dominick J Angiolillo

eview article: Antithrombotic therapy in patients with diabetes mellitus and coronary artery diseas

Published by:

http://www.sagepublications.com

can be found at:Diabetes and Vascular Disease ResearchAdditional services and information for

http://dvr.sagepub.com/cgi/alertsEmail Alerts:

http://dvr.sagepub.com/subscriptionsSubscriptions:

http://www.sagepub.com/journalsReprints.navReprints:

http://www.sagepub.com/journalsPermissions.navPermissions:

http://dvr.sagepub.com/content/7/4/274.refs.htmlCitations:

What is This?

- Oct 4, 2010OnlineFirst Version of Record

- Oct 13, 2010OnlineFirst Version of Record

- Nov 29, 2010Version of Record>>

by guest on February 13, 2012dvr.sagepub.comDownloaded from
http://dvr.sagepub.com/http://dvr.sagepub.com/http://dvr.sagepub.com/http://dvr.sagepub.com/content/7/4/274http://dvr.sagepub.com/content/7/4/274http://www.sagepublications.com/http://www.sagepublications.com/http://dvr.sagepub.com/cgi/alertshttp://dvr.sagepub.com/subscriptionshttp://dvr.sagepub.com/subscriptionshttp://www.sagepub.com/journalsReprints.navhttp://www.sagepub.com/journalsReprints.navhttp://www.sagepub.com/journalsPermissions.navhttp://www.sagepub.com/journalsPermissions.navhttp://dvr.sagepub.com/content/7/4/274.refs.htmlhttp://dvr.sagepub.com/content/7/4/274.refs.htmlhttp://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://dvr.sagepub.com/content/early/2010/10/02/1479164110383995.full.pdfhttp://dvr.sagepub.com/content/early/2010/10/02/1479164110383995.full.pdfhttp://dvr.sagepub.com/content/early/2010/10/12/1479164110383995.full.pdfhttp://dvr.sagepub.com/content/early/2010/10/12/1479164110383995.full.pdfhttp://dvr.sagepub.com/content/7/4/274.full.pdfhttp://dvr.sagepub.com/content/7/4/274.full.pdfhttp://dvr.sagepub.com/http://dvr.sagepub.com/http://dvr.sagepub.com/http://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://dvr.sagepub.com/content/early/2010/10/02/1479164110383995.full.pdfhttp://dvr.sagepub.com/content/early/2010/10/12/1479164110383995.full.pdfhttp://dvr.sagepub.com/content/7/4/274.full.pdfhttp://dvr.sagepub.com/content/7/4/274.refs.htmlhttp://www.sagepub.com/journalsPermissions.navhttp://www.sagepub.com/journalsReprints.navhttp://dvr.sagepub.com/subscriptionshttp://dvr.sagepub.com/cgi/alertshttp://www.sagepublications.com/http://dvr.sagepub.com/content/7/4/274http://dvr.sagepub.com/


2/16

Review article

Diabetes & Vascular Disease Research

7(4) 274288

The Author(s) 2010

Reprints and permission: sagepub.

co.uk/journalsPermissions.nav

DOI: 10.1177/1479164110383995

dvr.sagepub.com

1IDIBELL-Hospital Universitari de Bellvitge, Department of Cardiology,

Interventional Cardiology Unit, LHospitalet de Llobregat, Barcelona,

Spain2IDIBELL-Hospital Universitari de Bellvitge, Cardiovascular Research Lab,

LHospitalet de Llobregat, Barcelona, Spain3University of Florida College of Medicine-Jacksonville, Jacksonville,

Florida, USA

Corresponding author:Dominick J Angiolillo, University of Florida College of Medicine

Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA

Email: [email protected]

Antithrombotic therapy in patientswith diabetes mellitus and coronaryartery disease

Jos Luis Ferreiro1, 2, ngel R Cequier1and Dominick J Angiolillo3

AbstractCurrently approved antiplatelet treatment strategies have proved successful for reducing cardiovascular adverse eventsin patients with CAD. However, despite the use of recommended antiplatelet treatment strategies, the presence ofDM has been consistently associated with a negative impact on outcomes and a high rate of adverse cardiovascularevents continue to occur in patients with DM. The elevated prevalence of low response to standard oral antiplateletagents contribute to these impaired outcomes. Thus, the search for more potent antiplatelet treatment strategies iswarranted in high-risk patients, such as those with DM. The present manuscript provides an overview on the current

status of knowledge on currently available antiplatelet agents, focusing on the benefits and limitations of these therapiesin DM patients, and evaluating the potential role of new antithrombotic agents and treatment strategies currently underdevelopment to overcome these limitations.

KeywordsAntithrombotic therapy, coronary artery disease, diabetes mellitus, platelets

of DM patients have dysregulation of several signallingpathways (developed in details in another manuscript of thissupplement), which leads to increased platelet reactivity.911Another important feature of DM patients is an impairedresponse to antiplatelet therapies,1214 which is well estab-lished to be associated with a higher risk of adverseischaemic outcomes.1517 In fact, despite compliance withrecommended antiplatelet treatment regimens, the negativeimpact of DM on outcomes has been consistently observedacross the spectrum of manifestations of CAD.1821

The aim of the present manuscript is to provide an over-view on the current status of knowledge on currently

Introduction

The increasing worldwide prevalence of diabetes mellitus(DM), which is currently affecting more than 150 millionpeople, mainly due to type 2 DM, has led to label this dis-ease as a global pandemic.1, 2 The burden of cardiovascu-lar disease among patients with DM is substantial and has

been confirmed in large-scale surveys, such as the EuroHeart Survey, the Can Rapid Risk Stratification of UnstableAngina Patients Suppress Adverse Outcomes with EarlyImplementation of the ACC/AHA Guidelines (CRUSADE)registry and the US-based National Registry of MyocardialInfarction, which showed a prevalence of diabetes ofapproximately 30% both in patients with stable coronaryartery disease (CAD) and in those with acute coronary syn-

dromes (ACSs), including non-ST-segment elevation acutecoronary syndrome (NSTEACS) and ST-segment myocar-dial infarction (STEMI).35 In fact, cardiovascular disease isthe leading cause of morbidity and mortality in patientswith DM, due mostly to the role played by CAD.6

Of note, subjects with DM have a 24-fold increasedrisk of cardiovascular events than non-DM subjects, and68% of deaths among DM patients over the age of 65 yearsare due to CAD.7

Platelets play a key role in the development of athero-sclerosis and its atherothrombotic complications.8Platelets

http://dvr.sagepub.com/http://dvr.sagepub.com/http://dvr.sagepub.com/


3/16

Ferreiro et al. 275

available antiplatelet agents, focusing on the benefits andlimitations of these therapies in DM patients, and evaluatingthe potential role of new antithrombotic agents and treat-ment strategies currently under development to overcomethese limitations.

Currently approved antiplatelet therapiesThree different classes of antiplatet agents are currentlyapproved for the treatment and prevention of recurrentischaemic events in patients with CAD: cyclooxigenase-1(COX-1) inhibitors (aspirin), adenosine diphosphate (ADP)P2Y

12receptor antagonists (thienopyridines) and glycopro-

tein (GP) IIb/IIIa inhibitors.2224 This section providesinsights on the benefits and limitations of these agents in

patients with DM.

AspirinAspirin is an irreversible inhibitor of COX-1, the enzyme thatcatalyses the synthesis of thromboxane A

2 (TXA

2) from

arachidonic acid, by acetylation of the hydroxyl group ofa serine residue at position 529 (Ser529). TXA

2binds to

thromboxane/prostaglandin endoperoxide (TP) receptors,resulting in changes in platelet shape and enhancement ofrecruitment and aggregation of platelets. Therefore, aspirin

blocks platelet formation of TXA2and, as a result, diminishes

platelet aggregation mediated by the TP receptors pathway.25

The use of aspirin for primary prevention in DM patientsis controversial. In 2007, the American Diabetes Association

(ADA) and the American Heart Association (AHA) jointlyrecommended aspirin therapy (75162 mg/day) for pri-mary prevention in DM patients at increased cardiovascularrisk,26while according to European guidelines aspirin wasnot recommended in this setting.27

Among the trials that have evaluated the effect of aspirinfor primary prevention of cardiovascular events, most ofthese were population based,2833while only three of themwere focused specifically on DM patients.3436Owing to thelack of consistency of the findings, a number of metaanalyseshave been performed in order to reconcile the resultsobtained in the different trials,3740being of special interestthe metaanalysis performed with individual patient-level

data from the nine trials mentioned above by a group ofexperts of the ADA, AHA and the American College ofCardiology Foundation with the purpose of providing anexpert consensus document.40 Overall, the metaanalysesshowed that aspirin appears to cause a modest size reductionin cardiovascular events [myocardial infarction (MI) andstroke], but current evidence is not conclusive to recom-mend its use as primary prevention in all patients with DM.40This has led to the most recent recommendation in the previ-ously mentioned expert consensus document, in which low-dose (75162 mg/day) aspirin use for primary prevention is

recommended in DM patients at increased cardiovasculardisease risk (men over age 50 years and women over age60 years with a 10-year risk of cardiovascular events over10%) and who are not at increased risk of bleeding.40Theongoing trials A Study of Cardiovascular Events iN Diabetes(ASCEND; NCT00135226) and Aspirin and SimvastatinCombination for Cardiovascular Events Prevention Trial inDiabetes (ACCEPT-D; ISRCTN48110081) will provide fur-ther insights into the role of aspirin as a primary preventionmeasure in patients with DM.

Aspirin remains the antiplatelet drug of choice for sec-ondary prevention of recurrent ischaemic events in patientswith an atherothrombotic manifestation of CAD or undergo-ing percutaneous coronary intervention (PCI).2325, 41 The

benefit of aspirin therapy in the setting of ACS has been con-sistently demonstrated since the earliest tr ials, includingthose evaluating NSTEACS4244and STEMI.45, 46As perguidelines, aspirin must be given as promptly as possible, at

an initial dose of 162325 mg followed by a daily dose of75162 mg,23, 24which is also the recommended maintenancedose of aspirin for secondary prevention in DM patients withatherosclerotic disease.41Two large metaanalyses of secon-dary prevention trials performed by the AntithromboticTrialists Collaboration, involving 212,000 high-risk patients(with acute or previous vascular disease or some other pre-disposing condition implying an increased risk of occlusivevascular disease), supported the use of low-dose aspirin.47, 48These metaanalyses showed that the benefit of oral antiplate-let agents was consistent independently of DM status (38vascular events were prevented for every 1,000 DM patients

and 36 events for every 1,000 non-DM patients), eventhough the overall incidence of vascular events was muchhigher in DM patients.47Aspirin was the most commonlyevaluated antiplatelet agent, at doses ranging from 75 to325 mg daily. Importantly, the use of low-dose aspirin (75150 mg/day) was found to be at least as effective as higherdaily doses, while bleeding complications were diminishedwith the lower doses.47, 48

The Clopidogrel Optimal Loading Dose Usage toReduce Recurrent EveNTs/Optimal Antiplatelet Strategyfor InterventionS (CURRENT/OASIS7; NCT00335452)trial included ACS patients (n=25,087) scheduled toundergo angiography that were randomised in a 2 2 facto- 2 facto-2 facto-

rial design to high or standard dose of clopidogrel for amonth and in an open-label way to high (300325 mg daily)versus low dose (75100 mg daily) of aspirin. This trialwas the first large-scale randomised study to compare high-with low-dose aspirin and no significant differences in effi-cacy among aspirin doses were found. However, a trendtowards a higher rate of gastrointestinal bleeds in the high-dose group was reported, although the bleeding rates can beconsidered relatively low (0.38% vs. 0.24%; p=0.051).49The results of this study in the DM subset regarding aspirindosage have not yet been made available.

http://dvr.sagepub.com/http://dvr.sagepub.com/http://dvr.sagepub.com/http://dvr.sagepub.com/


4/16

276 Diabetes and Vascular Disease Research 7(4)

P2Y12

receptor antagonists: thienopyridines

Thienopyridines (ticlopidine, clopidogrel and prasugrel)are non-direct, orally administered and irreversible plateletADP P2Y

12 receptor inhibitors. ADP-induced effects on

platelets are mediated by the P2Y1 and P2Y

12 receptors,

which are both required for aggregation, although P2Y12

stimulation plays the principal role, leading to sustained

platelet aggregation and stabilisation of the platelet aggre-gate.5052Ticlopidine, a first-generation thienopyridine, wasthe first to be developed and approved for clinical use,although it was largely replaced by clopidogrel (a second-generation thienopyridine), which has a better safety pro-file.53 In addition, clopidogrel achieves a faster onset onaction through administration of a loading dose.54

The Clopidogrel vs Aspirin in Patients at Risk ofIschaemic Events (CAPRIE) trial compared the efficacy forsecondary prevention of clopidogrel (75 mg daily) versusaspirin (325 mg daily) in a high-risk population (n=19,185)

consisting of patients with a history of recent MI, recentischaemic stroke or established peripheral artery disease. Areduction in the risk of ischaemic outcomes in the clopi-dogrel group was observed (5.32% vs.5.83%;p=0.043).55The benefit of clopidogrel therapy was higher (15.6% vs.17.7%;p=0.042) in DM patients, despite the increased inci-dence of ischaemic outcomes in this subgroup. The abso-lute reduction in events was highest among diabetic patientsrequiring insulin therapy. On the other hand, the reductionin the rates of ischaemic outcomes in patients without DMdid not reach statistical significance.56The use of clopidog-rel should be considered in very high-risk DM patients or as

an alternative therapy in patients intolerant to aspirin.

41

The efficacy of dual antiplatelet treatment with aspirinand clopidogrel is well established and recommended in theguidelines for patients with ACS, including those with

NSTEACS23and STEMI, and for patients undergoing PCI.24Several large-scale clinical trials have shown a clear benefitof clopidogrel in addition to aspirin for preventing recurrentischaemic events, including stent thrombosis, when com-

pared to aspirin alone.18, 5761Table 1 summarises ACS/PCItrials comparing dual antiplatelet therapy with aspirin and athienopyridine versus aspirin alone, highlighting the relative

benefits in the overall population and in patients with DM.The role of dual antiplatelet therapy with aspirin and

clopidogrel for patients at high risk for ischaemic events,but not presenting with an ACS or undergoing PCI, wasevaluated in the Clopidogrel for High AtherothromboticRisk and Ischaemic Stabilization, Management andAvoidance (CHARISMA; NCT00050817) trial. This trialincluded patients (n=15,603) with either clinically evidentcardiovascular disease or multiple cardiovascular risk fac-tors. In this study, concomitant treatment with clopidogreland aspirin was not significantly more effective than aspi-rin alone in reducing the rates of cardiovascular death,MI or stroke (6.8% vs. 7.3%; p=0.22).62 Consistently,

no benefit of combined therapy was observed in patientswith DM.

The efficacy of high versus standard dose of clopidogrelwas evaluated in the CURRENT/OASIS7 trial, whichincluded ACS patients (n=25,087) scheduled to undergoangiography within 72 h of hospital arrival. In the overallstudy population, no benefit was derived from the high-doseregimen. Nevertheless, in the subgroup of patients undergo-ing PCI (n=17,232), the high clopidogrel dose strategydiminished the rates of ischaemic outcomes [3.9% vs.4.5%;hazard ratio (HR)=0.85; p=0.036) and reduced the risk ofstent thrombosis by 30%, although it was at the expense ofincreased study-defined major bleedings. There were no dif-ferences in efficacy among the subset of patients with DMundergoing PCI [4.9% vs.5.6%; HR=0.87 (0.661.15)].49

Prasugrel, as all thienopyridines, is a prodrug thatrequires hepatic biotransformation into its active metabo-lite to irreversibly block the P2Y

12 receptor.63 This third-

generation thienopyridine has a faster onset of action thanclopidogrel and reaches greater platelet inhibition due to amore efficient conversion into its active metabolite, withless interindividual variability in response, even comparedwith high-dose clopidogrel.64

The efficacy and safety of prasugrel (60 mg loadingdose followed by a 10 mg maintenance dose) versus clopi-dogrel therapy (300 mg loading dose followed by 75 mgdaily maintenance dose) was evaluated in the randomisedTrial to Assess Improvement in Therapeutic Outcomes byOptimizing Platelet Inhibition with Prasugrel-Thrombolysisin Myocardial Infarction 38 (TRITON-TIMI 38; NCT-

00097591.), performed in patients (n=13,608) with moder-ate- to high-risk ACS undergoing PCI with a follow-upperiod of 14.5 months.65In the overall population, prasug-rel therapy was associated with a significant reduction inthe rates of the primary end point (composite of cardiovas-cular death, non-fatal MI or non-fatal stroke) (9.9% vs.12.1%; HR=0.81;p


5/16
http://dvr.sagepub.com/


6/16


among DM patients in the prasugrel group (2.6% vs.2.5%;HR=1.06; p=0.81). Overall, these findings suggest thathigher platelet inhibition is associated with improvedoutcome in DM patients.

The pharmacodynamic benefit of prasugrel was recentlyobserved in the Third Optimizing Anti-Platelet Therapy inDiabetes MellitUS (OPTIMUS-3; NCT00642174) study,in which a standard prasugrel dose (60 mg loading dosefollowed by 10 mg maintenance dose daily for 1 week)achieved significantly higher platelet inhibition and betterresponse profiles compared with high-dose clopidogrel(600 mg loading dose followed by 150 mg maintenancedose) in DM patients with CAD on chronic aspirin therapy.68The ongoing trial TaRgeted platelet Inhibition to cLarify theOptimal strateGy to medicallY manage ACS. (TRILOGYACS; NCT00699998) will provide insights into the clini-cal efficacy of prasugrel in medically managed patients

with NSTEACS, which will likely comprise a large numberof DM subjects.

Glycoprotein IIb/IIIa inhibitors

Three GP IIb/IIIa antagonists are available for clinical use:abciximab, eptifibatide and tirofiban. All of them are admin-istered intravenously, have a rapid onset of action, a potentinhibitory effect on platelets and a relatively short half-life.The GP IIb/IIIa receptor is the main mediator of plateletaggregation through its binding to fibrinogen.8The efficacyof GP IIb/IIIa blockers correlates directly with the severity

and the risk of ACS, hence, using these drugs in low-mod-erate risk patients or in those managed with a conservativeapproach is generally not recommended.69Therefore, GPIIb/IIIa inhibitors are used mainly in clinical practice as anadjunctive therapy on top of aspirin and a thienopyridine forthe acute phase of therapy, due to its intravenous adminis-tration, in high-risk ACS patients undergoing PCI.

The efficacy of GP IIb/IIIa inhibitors in the ACS scenariowas evaluated in a metaanalysis of six large-scale trials.70The use of GP IIb/IIIa blockers was associated with a 26%reduction in 30-day mortality (4.6% vs.6.2%;p=0.007)in patients with DM (n=6,458), while non-DM patients(n=23,072) had no survival benefit. A statistically signifi-cant interaction between treatment with GP IIb/IIIa and DMstatus was observed. In this metaanalysis, the mortalityreduction among DM patients was of greater magnitude inthose patients (n=1,279) undergoing PCI during index hos-

pitalisation (4.01.2%;p=0.002).70However, caution on the

conclusions from these study findings is warranted as thesemay not necessarily apply to todays clinical practice sinceclopidogrel regimens commonly used in current practicewere not used in these trials (e.g. pre-treatment, high loadingdose regimens).

Two more recent studies have evaluated the efficacyof GP IIb/IIIa blockers on top of dual antiplatelet therapy.The Intracoronary Stenting and Antithrombotic Regimen:Is Abciximab a Superior Way to Eliminate ElevatedThrombotic Risk in Diabetics (ISAR-SWEET) trial did notshow a benefit of abciximab over placebo in terms of reduc-ing the 1-year risk of death and MI in DM patients (n=701)

undergoing elective PCI after pre-treatment with a clopi-dogrel loading dose of 600 mg at least 2 h before the proce-dure.71 Conversely, in the Intracoronary Stenting andAntithrombotic Regimen: Rapid Early Action for CoronaryTreatment 2 (ISAR-REACT 2) trial, which comparedabciximab treatment to placebo in patients with high-riskACS undergoing PCI after pre-treatment with 600 mg ofclopidogrel, a 25% reduction of the risk of adverse events(death, MI or urgent target vessel revascularisation within30 days) was observed in the abciximab group.72Of note,the benefit provided by abciximab was restricted to patientswith elevated troponin levels and was observed across allsubgroups, including DM patients. Overall, the results of

the last two trials performed in the clopidogrel era supportthe use of GP IIb/IIIa receptor antagonists in high-risk ACS

patients undergoing PCI, in particular those with DM, butnot for routine use in elective PCI.

The value of GP IIb/IIIa inhibitors in DM patients withSTEMI undergoing PCI has been assessed in a few small-scale studies. In a small placebo-controlled randomisedstudy performed before the clopidogrel era, abciximab usewas associated with lower mortality and reinfarction ratesacross the DM subgroup (n=54) in patients undergoing pri-mary coronary stenting for the treatment of acute MI.73 Inthe Controlled Abciximab and Device Investigation to

Figure 1. KaplanMeier curves for prasugrel versus clopidogrelin patients with diabetes mellitus from the TRITON-TIMI 38trial. Primary efficacy end point: cardiovascular death/non-fatalmyocardial infarction/non-fatal stroke.Source: Reprinted from Wiviott SD, Braunwald E, Angiolillo DJ, et al.

Greater clinical benefit of more intensive oral antiplatelet therapy withprasugrel in patients with diabetes mellitus in the trial to assessimprovement in therapeutic outcomes by optimizing platelet inhibitionwith prasugrel-Thrombolysis in Myocardial Infarction 38.67Circulation,118(16): 16261636 (2008), with permission from Lippincott Williams& Willkins.CABG: coronary artery bypass grafting, HR: hazard ratio.



7/16

Ferreiro et al. 279

Lower Late Angioplasty Complications (CADILLAC) trial,no benefit was observed with abciximab in a cohort of low-risk DM patients (n=346) with acute MI treated with balloonangioplasty or stenting.21However, a metaregression of ran-domised trials evaluating the effect of adjunctive use of anyGP IIb/IIIa inhibitor (abciximab, eptifibatide and tirofiban)on top of dual antiplatelet therapy in STEMI patients under-going primary PCI found a relationship between benefit interms of mortality of these agents and patients risk profile.74Thus, the use of GP IIb/IIIa inhibitors should be consideredin high-risk patients undergoing primary PCI, which mayinclude those with DM.

The main drawback associated with the administrationof GP IIb/IIIa inhibitors is an increased risk of bleeding,which impairs the prognosis of patients suffering fromACS, even in terms of mortality.75, 76A valid alternative may

be bivalirudin, a direct thrombin inhibitor, which was shownin the Acute Catheterization and Urgent Intervention Triage

Strategy (ACUITY; NCT00093158) trial to have similarefficacy in reducing ischaemic events and a better safety

profile with lower rates of major bleeding compared to GPIIb/IIIa antagonists in moderate-risk NSTEACS patients(n=13,819).77 In the DM subgroup (n=3,852), bivalirudintherapy was associated with a lower risk of major bleeding(3.7% vs.7.1%;p


8/16


worse clinical outcomes. Among DM patients, the presenceof moderate to severe CKD is associated with decreasedresponse to clopidogrel,95which is in line with the results of apost hocanalysis of the CHARISMA trial, which suggeststhat clopidogrel use might increase adverse outcomes in

patients with diabetic nephropathy.96These results contributeoverall to clarify why the presence of DM is a strong predictor

of recurrent ischaemic events, including stent thrombosis.

97

Several mechanisms have been involved in the impairedclopidogrel-induced effects observed in DM patients, suchas: (a) diminished platelet response to insulin;98(b) dysregu-lation of calcium metabolism;99 (c) upregulation of P2Y12receptor signalling;98(d) increased exposure to ADP;100and(e) increased platelet turnover.101

Future strategiesThe persistence of high platelet reactivity despite the use ofstandard recommended antiplatelet treatment regimens hasled to developing treatment strategies to optimise platelet

inhibitory effects, which are of special interest in high-risksubjects such as those with DM. These new approaches can

be summarised as follows: (a) increased dosing of currentlyapproved agents; (b) use of new agents; and (c) addition of athird antiplatelet drug. In this section, we provide a brief over-view of the studies that have evaluated the above-mentionedstrategies in patients with DM.

Currently, the approved loading and maintenancedoses for clopidogrel are 300 mg and 75 mg/daily, respec-tively, although a loading dose of 600 mg is common inclinical practice, especially in patients undergoing PCI. The

pharmacodynamic efficacy of a high (150 mg) versus stand-ard maintenance dose of clopidogrel (75 mg) in type 2 DM

patients with CAD and high platelet reactivity, while in theirmaintenance phase of clopidogrel therapy, was evaluated inthe OPTIMUS study. Patients randomised to the 150 mgdose showed a marked improvement in platelet inhibition,although a considerable number of patients remained withhigh platelet reactivity.102Results of the CURRENT/OASIS7trial, which randomised ACS patients in a 2 2 factorialdesign to high (600 mg loading dose followed by 150 mgdaily for 1 week and then 75 mg/daily until day 30) or stand-ard dose of clopidogrel (300 mg loading followed by 75 mgdaily until day 30) for a month and in an open-label way tohigh (300325 mg daily) versus low dose (75100 mg daily)of aspirin, in which no particular benefit was observed in

patients with DM, have been commented on previously.49Increasing clopidogrel dosing according to the degree ofresponsiveness of a given patient, which has been defined

as tailored or individualised treatment, has also raisedconsiderable interest. The ongoing Gauging Responsivenesswith a VerifyNow Assay-Impact on Thrombosis And Safety(GRAVITAS; NCT00645918) trial will evaluate the efficacyand safety of tailored treatment with high clopidogrel main-tenance dose for 6 months in those patients with low responseto standard clopidogrel dose in which a considerable numberof patients with DM will be enrolled.103

Several new agents that block multiple pathways involvedin platelet adhesion, activation and aggregation are currentlyat different stages of clinical development. Novel agents tar-geting the TXA

2pathway include picotamide (a combined

TXA2synthase inhibitor and TP receptor blocker), ridogrel(a combined TXA2 synthase inhibitor and TP receptor

blocker), ramatroban (a TP receptor inhibitor), NCX 4016 [anitric oxide (NO)-releasing aspirin derivative] and S18886/terutroban (a TP receptor inhibitor). These have been evalu-ated in different scenarios with variable success and might

be of future interest , although none of them appear to besuitable for replacing aspirin at the current time.104108

Novel and more potent P2Y12

receptor inhibitors (prasug-rel, ticagrelor, cangrelor, elinogrel) have emerged recentlyand may represent attractive treatment choices in high-risk

patients, such as those with DM. The pharmacodynamiceffects of the third-generation thienopyridine prasugrel and

its beneficial clinical implications specifically in patientswith DM have already been discussed in this manuscript.Ticagrelor is an orally administered cyclopentyltriazolopy-rimidine, which directly and reversibly inhibits the plateletADP P2Y

12receptor.109, 110Ticagrelor has a faster onset and

offset of action and achieves higher inhibition of plateletaggregation than clopidogrel.111, 112The phase III Study ofPlatelet Inhibition and Patient Outcomes (PLATO) trial ran-domised ACS patients (n=18,624) to receive either ticagre-lor (180 mg loading dose followed by 90 mg twice daily) orclopidogrel (300600 mg loading dose followed by 75 mg

Figure 2. Platelet aggregation after 20 mol adenosinediphosphate (ADP) stimulus.Source: Reprinted from Angiolillo DJ, Bernardo E, Ramirez C, et al. Insulintherapy is associated with platelet dysfunction in patients with type 2diabetes mellitus on dual oral antiplatelet treatment.94Journal of the

American College of Cardiology, 48: 298304 (2006), with permissionfrom Elsevier.ITDM: insulin-treated diabetes mellitus, NDM: non-diabetes mellitus(patients), NITDM: non-insulin-treated diabetes mellitus.



9/16

Ferreiro et al. 281

daily). The rate of the primary end point (death from vascu-lar causes, MI or stroke) at 12 months was significantlydecreased in the ticagrelor arm (10.2% vs.12.3%; HR=0.84;p=0.0001), as well as, remarkably, the rate of cardiovasculardeath (4.0% vs.5.1%; HR=0.79; p=0.001) and the occur-rence of definite or probable stent thrombosis (2.2% vs.2.9%; HR=0.75;p=0.02) in the subgroup of patients under-going PCI. This benefit was not hampered by an increase in

protocol-defined major bleeding (11.6% vs. 11.2%;HR=1.04;p=0.43), although ticagrelor use was associatedwith a higher rate of major bleeding not related to CABG(4.5% vs. 3.8%; HR=1.19; p=0.03).113 A predefined sub-group analysis of the DM cohort (n=4,662) showed a non-significant reduction of the rates of the primary end point[14.1% vs.16.2%; HR=0.88 (0.761.03)], while no differ-ence in major bleeding rates was found [14.1% vs.14.8%;HR=0.95 (0.811.12)]. Ticagrelor is currently pendingapproval by regulatory authorities for clinical use.

Cangrelor is an intravenous ATP analogue, which is adirect-acting, reversible, without any biotransformation,P2Y

12receptor inhibitor.109, 114Phase II trials showed prom-

ising results, as cangrelor proved to be a very potentantiplatelet agent, achieving >90% inhibition of plateletaggregation, with very rapid onset and offset of action, aswell as dose-dependent and, thus, predictable, effects.115However, the results of the phase III Cangrelor VersusStandard Therapy to Achieve Optimal Management ofPlatelet Inhibition (CHAMPION) program, which evalu-ated mostly ACS patients undergoing PCI, failed to showthe superiority of cangrelor over clopidogrel in the

CHAMPION-PCI (NCT00305162) (n=8,716), and overplacebo in the CHAMPION-PLATFORM (NCT00385138)(n=5,362) in terms of reducing ischaemic outcomes.116, 117Analysis of the DM cohort (n=2,702) from the CHAMPION-PCI trial showed results that were consistent with thoseobtained in the overall population.

Elinogrel is a novel, direct-acting and reversible P2Y12

inhibitor in the preliminary stages of development, with theimportant feature of having both oral and intravenous waysof administration.118, 119The ongoing trial INtraveNous andOral administration of elinogrel to eVAluate Tolerabilityand Efficacy in nonurgent PCI patients (INNOVATE-PCI).(INNOVATE-PCI; NCT00751231) is evaluating the effi-

cacy and safety of three different doses of elinogrel (oral50, 100 and 150 mg twice daily following an intravenous

bolus) in patients undergoing non-urgent PCI.120

Future strategies also include the use of a third antiplate-let drug that blocks pathways other than COX-1 and P2Y

12

to be used on top of aspirin and a P2Y12

inhibitor. Drugs thathave been proposed for being part of such triple therapyare: (a) cilostazol; (b) protease-activated receptor-1 (PAR-1) antagonists; and (c) new oral anticoagulants. Amongthem, cilostazol, a phosphodiesterase III inhibitor thatincreases intraplatelet cyclic adenosine monophosphate

(cAMP) concentration, has the most consistent datareporting a benefit in patients with DM. In patients withtype 2 DM, the OPTIMUS-2 study showed that adjunctiveuse of cilostazol on top of standard dual antiplatelet therapyincreases platelet inhibition.121This enhanced platelet inhib-itory effect may contribute to the better outcomes observedin patients undergoing PCI, both elective and after sufferingan ACS event.122124Interestingly, this benefit appears to behigher in high-risk patients, such as those with DM, andseems not to be hampered by an increase in bleeding.125, 126The high frequency of side effects (mainly headache, palpi-tations and gastrointestinal disturbances) may, however,limit the use of cilostazol.121 Two oral thrombin receptorantagonists, which block the platelet PAR-1 receptor sub-type, are currently under clinical development: vorapaxar(SCH 530348) and E5555 (Figure 3).109, 127, 128

Vorapaxar has shown an excellent safety profile in alarge, phase II safety and dose-ranging trial performed in

patients (n=1,030) undergoing non-urgent PCI or coronaryangiography with planned PCI, in which triple therapy wasnot associated with any significant increase of bleedingacross all doses tested.129Two ongoing large-scale phase IIItrials are evaluating the efficacy and safety of vorapaxar inACS patients: the Trial to Assess the Effects of SCH 530348in Preventing Heart Attack and Stroke in Patients WithAtherosclerosis (TRA 2P-TIMI 50; NCT00526474) trial in

patients with atherosclerosis and the Trial to Assess theEffects of SCH 530348 in Preventing Heart Attack andStroke in Patients With Acute Coronary Syndrome(TRA*CER; NCT00527943).130, 131Finally, several new

oral anticoagulants are currently under investigation andbeing tested in adjunct to standard antiplatelet treatmentregimens in high-risk settings. In fact, in high-risk settingssuch as patients with ACS, in addition to increased plateletreactivity, dysregulation of coagulation processes may alsooccur and contribute to atherothrombotic recurrences.

Novel oral anticoagulants include anti-factor IIa or gat-rans (e.g. dabigatran) and anti-factor Xa or xabans (e.g.rivaroxaban, apixaban), which are currently at differentstages of development.132

ConclusionsPatients with DM have higher rates of adverse cardiovascu-lar events compared with those without DM despite usingrecommended antiplatelet treatment regimens. A high prev-alence of impaired response to standard antiplatelet thera-

pies is characteristic of DM, which may contribute to theirworse outcomes. Therefore, more potent antiplatelet therapyis needed in such a high-risk population. Novel antiplatelettreatment strategies that are currently under investigationwill provide important insights on their safety and efficacyin high-risk settings, including patients with DM.



10/16


Funding

This work was supported by an unrestricted educationalgrant from Eli Lilly and Daiichi Sankyo to the Universityof Sheffield to fund the activities of the European PlateletAcademy.

Conflicts of interest

Jos Luis Ferreiro and ngel R Cequier have no con-flicts of interest to report. Dominick J Angiolillo reportsreceiving honoraria for lectures from Bristol-Myers

Squibb, Sanofi-Aventis, Eli Lilly and Company andDaiichi Sankyo, Inc.; consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly and Company,Daiichi Sankyo, Inc., The Medicines Company, PortolaPharmaceuticals Inc., Novartis, Medicure, Accumetrics,Arena Pharmaceuticals, Inc., AstraZeneca and Merck &Co., Inc.; and research grants from GlaxoSmithKline,Otsuka Pharmaceutical Co., Ltd., Eli Lilly and Company,Daiichi Sankyo, Inc., The Medicines Company, PortolaPharmaceuticals Inc., Accumetrics, Schering-Plough,AstraZeneca and Eisai.

Figure 3. Currently available and novel antiplatelet drugs under development.Platelet adhesion is mediated by GP receptors, which bind to exposed extracellular matrix proteins (collagen and vWF). Severalintracellular signalling pathways contribute to platelet activation, which causes local production of thrombin and the production andrelease of multiple agonists, including TXA

2and ADP. These factors bind to G proteincoupled receptors, inducing paracrine and

autocrine mechanisms, as well as potentiating each others actions (e.g. P2Y12

signalling modulates thrombin generation). The integrinGP IIb/IIIa complex mediates the final common step of platelet activation by undergoing a conformational shape change and bindingfibrinogen and vWF, which leads to platelet aggregation. The final result of these processes is thrombus formation due to platelet/platelet interactions with fibrin. Current and emerging agents inhibiting platelet receptors, integrins and proteins involved in thisprocess include TX inhibitors, ADP receptor antagonists, GP inhibitors, adhesion antagonists and PAR antagonists. Reversible agentsare indicated by brackets.Source: Reprinted from Angiolillo DJ, Capodanno D and Goto S. Platelet thrombin receptor antagonism and atherothrombosis.128European HeartJournal, 31: 1728 (2010), with permission from Oxford University Press.5-HT2A: 5-hydroxytryptamine 2A receptor, ADP: adenosine diphosphate, COX-1: cyclooxygenase-1, GP: glycoprotein, PAR: protease-activatedreceptor, TP: thromboxane/prostaglandin endoperoxide receptors, TX: thromboxane, TXA2: thromboxane A

2, vWF: von Willebrand factor.



11/16

Ferreiro et al. 283

References

1. Zimmet P, Alberti KG and Shaw J. Global and societalimplications of the diabetes epidemic. Nature 2001; 414:782787.

2. King H, Aubert RE and Herman WH. Global burden of

diabetes, 19952025: prevalence, numerical estimates, andprojections.Diabetes Care1998; 21: 14141431.

3. Bartnik M, Rydn L, Ferrari R, et al. The prevalence ofabnormal glucose regulation in patients with coronary arterydisease across Europe. The Euro Heart Survey on diabetesand the heart.Eur Heart J2004; 25: 18801890.

4. Bhatt DL, Roe MT, Peterson ED, et al.Utilization of earlyinvasive management strategies for high-risk patients withnon-ST-segment elevation acute coronary syndromes:results from the CRUSADE Quality Improvement Initiative.JAMA2004; 292: 20962104.

5. Roe MT, Parsons LS, Pollack CV Jr, et al.Quality of care

by classification of myocardial infarction: treatment pat-terns for ST-segment elevation vs non-ST-segment eleva-tion myocardial infarction. Arch Intern Med 2005; 165:16301636.

6. Webster MW and Scott RS. What cardiologists need to knowabout diabetes.Lancet1997; 350(Suppl 1): SI23SI28.

7. Centers for Disease Control and Prevention. 2007 NationalDiabetes Fact Sheet: General Information and National

Estimates on Diabetes in the United States,www.cdc.gov/diabetes/pubs/factsheet07.htm (2007, accessed September2010).

8. Dav G and Patrono C. Platelet activation and atherothrom-bosis.N Engl J Med2007; 357: 24822494.

9. Creager MA, Lscher TF, Cosentino F and Beckman JA.Diabetes and vascular disease: pathophysiology, clinicalconsequences, and medical therapy: Part I. Circulation2003;108: 15271532.

10. Stratmann B and Tschoepe D. Pathobiology and cell interac-tions of platelets in diabetes.Diab Vasc Dis Res2005; 2: 1623.

11. Ferroni P, Basili S, Falco A and Dav G. Platelet activationin type 2 diabetes mellitus. J Thromb Haemost 2004; 2:12821291.

12. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al.Platelet function profiles in patients with type 2 diabetes and

coronary artery disease on combined aspirin and clopidogreltreatment.Diabetes2005; 54: 24302435.

13. Ferreiro JL and Angiolillo DJ. Diabetes and anti-platelettherapy in acute coronary syndrome. Circulation 2010 (inpress).

14. Geisler T, Anders N, Paterok M, et al. Platelet response

to clopidogrel is attenuated in diabetic patients undergo-ing coronary stent implantation. Diabetes Care2007; 30:372374.

15. Angiolillo DJ. Antiplatelet therapy in diabetes: efficacy andlimitations of current treatment strategies and future direc-tions.Diabetes Care2009; 32: 531540.

16. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al.Variability in individual responsiveness to clopidogrel:clinical implications, management, and future perspectives.J Am Coll Cardiol2007; 49: 15051516.

17. Ferreiro JL and Angiolillo DJ. Clopidogrel response varia-bility: current status and future directions. Thromb Haemost

2009; 102: 714. 18. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel

in addition to aspirin in patients with acute coronary syn-dromes without ST-segment elevation.N Engl J Med2001;345: 494502.

19. Mak KH, Moliterno DJ, Granger CB, et al. Influence ofdiabetes mellitus on clinical outcome in the thrombolyticera of acute myocardial infarction. GUSTO-I Investigators.Global Utilization of Streptokinase and Tissue PlasminogenActivator for Occluded Coronary Arteries. J Am CollCardiol1997; 30: 171179.

20. Roffi M and Topol EJ. Percutaneous coronary intervention

in diabetic patients with non-ST-segment elevation acutecoronary syndromes.Eur Heart J2004; 25: 190198. 21. Stuckey TD, Stone GW, Cox DA, et al.Impact of stenting

and abciximab in patients with diabetes mellitus undergo-ing primary angioplasty in acute myocardial infarction (theCADILLAC trial).Am J Cardiol2005; 95: 17.

22. Fraker TD Jr, Fihn SD, Gibbons RJ, et al. 2007 chronicangina focused update of the ACC/AHA 2002 Guidelinesfor the management of patients with chronic stable angina:a report of the American College of Cardiology/AmericanHeart Association Task Force on Practice Guidelines WritingGroup to develop the focused update of the 2002 Guidelinesfor the management of patients with chronic stable angina.

Circulation2007; 116: 27622772. 23. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA

2007 guidelines for the management of patients withunstable angina/non ST-elevation myocardial infarction:a report of the American College of Cardiology/AmericanHeart Association Task Force on Practice Guidelines(Writing Committee to Revise the 2002 Guidelines forthe Management of Patients With Unstable Angina/NonST-Elevation Myocardial Infarction): developed in col-laboration with the American College of EmergencyPhysicians, the Society for Cardiovascular Angiography

Key messages

Patients with DM have worse outcomes and impaired

response to standard antiplatelet therapies.

More potent antiplatelet agents, such as prasugrel, are

particularly beneficial in patients with DM. Several new antiplatelet treatment strategies are cur-

rently under investigation which will provide important

insights on their safety and efficacy in high-risk settings,

including patients with DM.



12/16


and Interventions, and the Society of Thoracic Surgeons:endorsed by the American Association of Cardiovascularand Pulmonary Rehabilitation and the Society for AcademicEmergency Medicine. Circulation2007; 116: e148e304.

24. Kushner FG, Hand M, Smith SC Jr, et al. 2009 FocusedUpdates: ACC/AHA Guidelines for the Management of

Patients With ST-Elevation Myocardial Infarction (updat-ing the 2004 Guideline and 2007 Focused Update) andACC/AHA/SCAI Guidelines on Percutaneous CoronaryIntervention (updating the 2005 Guideline and 2007 FocusedUpdate) a report of the American College of CardiologyFoundation/American Heart Association Task Force onPractice Guidelines. Circulation2009; 120: 22712306.

25. Patrono C, Garca Rodrguez LA, Landolfi R and Baigent C.Low-dose aspirin for the prevention of atherothrombosis.NEngl J Med2005; 353: 23732383.

26. Buse JB, Ginsberg HN, Bakris GL, et al.Primary preventionof cardiovascular diseases in people with diabetes mellitus:

a scientific statement from the American Heart Associationand the American Diabetes Association. Diabetes Care2007; 30: 162172.

27. Rydn L, Standl E, Bartnik M, et al.Guidelines on diabe-tes, pre-diabetes, and cardiovascular diseases: executivesummary. The Task Force on Diabetes and CardiovascularDiseases of the European Society of Cardiology (ESC)and of the European Association for the Study of Diabetes(EASD).Eur Heart J 2007; 28: 88136.

28. Peto R, Gray R, Collins R, et al.Randomised trial of pro-phylactic daily aspirin in British male doctors. Br Med J(Clin Res Ed)1988; 296: 313316.

29. Anon. Final report on the aspirin component of the ongo-ing Physicians Health Study. Steering Committee of thePhysicians Health Study Research Group. N Engl J Med1989; 321: 129135.

30. Hansson L, Zanchetti A, Carruthers SG, et al. Effects ofintensive blood-pressure lowering and low-dose aspi-rin in patients with hypertension: principal results of theHypertension Optimal Treatment (HOT) randomised trial.HOT Study Group.Lancet1998; 351: 17551762.

31. Anon.Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-doseaspirin in the primary prevention of ischaemic heart diseasein men at increased risk. The Medical Research Councils

General Practice Research Framework. Lancet 1998; 351:233241.

32. Sacco M, Pellegrini F, Roncaglioni MC, et al.Primary pre-vention of cardiovascular events with low-dose aspirin andvitamin E in type 2 diabetic patients: results of the PrimaryPrevention Project (PPP) trial. Diabetes Care 2003; 26:32643272.

33. Ridker PM, Cook NR, Lee IM, et al.A randomized trialof low-dose aspirin in the primary prevention of cardio-vascular disease in women. N Engl J Med 2005; 352:12931304.

34. Anon. Aspirin effects on mortality and morbidity inpatients with diabetes mel litus. Early Treatment DiabeticRetinopathy Study report 14. ETDRS Investigators. JAMA1992; 268: 12921300.

35. Ogawa H, Nakayama M, Morimoto T, et al. Low-doseaspirin for primary prevention of atherosclerotic events in

patients with type 2 diabetes: a randomized controlled trial.JAMA2008; 300: 21342141.

36. Belch J, MacCuish A, Campbell I, et al.The prevention ofprogression of arterial disease and diabetes (POPADAD)trial: factorial randomised placebo controlled trial of aspirinand antioxidants in patients with diabetes and asymptomaticperipheral arterial disease.BMJ2008; 337: a1840.

37. Antithrombotic Trialists (ATT) Collaboration, Baigent C,Blackwell L, et al. Aspirin in the primary and secondaryprevention of vascular disease: collaborative meta-anal-ysis of individual participant data from randomised trials.Lancet. 2009; 373: 18491860.

38. De Berardis G, Sacco M, Strippoli GF, et al.Aspirin forprimary prevention of cardiovascular events in people withdiabetes: meta-analysis of randomised controlled trials.BMJ2009; 339: b4531.

39. Calvin AD, Aggarwal NR, Murad MH, et al.Aspirin for theprimary prevention of cardiovascular events: a systematicreview and meta-analysis comparing patients with and with-out diabetes.Diabetes Care2009; 32: 23002306.

40. Pignone M, Alberts MJ, Colwell JA, et al.Aspirin for pri-mary prevention of cardiovascular events in people withdiabetes.J Am Coll Cardiol2010; 55: 28782886.

41. Colwell JA, American Diabetes Association. Aspirin ther-

apy in diabetes.Diabetes Care2004; 27(Suppl 1): S72S73. 42. Lewis HD Jr, Davis JW, Archibald DG, et al. Protectiveeffects of aspirin against acute myocardial infarction anddeath in men with unstable angina. Results of a VeteransAdministration Cooperative Study. N Engl J Med 1983;309: 396403.

43. Throux P, Ouimet H, McCans J, et al.Aspirin, heparin, orboth to treat acute unstable angina.N Engl J Med1988; 319:11051111.

44. Anon. Risk of myocardial infarction and death during treat-ment with low dose aspirin and intravenous heparin in menwith unstable coronary artery disease. The RISC Group.Lancet1990; 336: 827830.

45. Anon. Randomised trial of intravenous streptokinase,oral aspirin, both, or neither among 17,187 cases of sus-pected acute myocardial infarction: ISIS-2. ISIS-2 (SecondInternational Study of Infarct Survival) CollaborativeGroup.Lancet1988; 2: 349360.

46. Roux S, Christeller S and Ldin E. Effects of aspirin on cor-onary reocclusion and recurrent ischemia after thromboly-sis: a meta-analysis.J Am Coll Cardiol1992; 19: 671677.

47. Anon. Collaborative overview of randomised trials ofantiplatelet therapyI: Prevention of death, myocardial infarc-tion, and stroke by prolonged antiplatelet therapy in various



13/16

Ferreiro et al. 285

categories of patients. Antiplatelet Trialists Collaboration.BMJ1994; 308: 81106.

48. Antithrombotic Trialists Collaboration. Collaborativemeta-analysis of randomised trials of antiplatelet therapyfor prevention of death, myocardial infarction, and stroke inhigh risk patients.BMJ2002; 324: 7186.

49. Mehta SR and the Clopidogrel Optimal Loading DoseUsage to Reduce Recurrent Event/Optimal AntiplateletStrategy for Interventions (CURRENT/OASIS7) trial. A2x2 Factorial Randomized Trial of Optimal Clopidogrel andAspirin Dosing in Patients With ACS Undergoing An EarlyInvasive Strategy With Intent For PCI. Late breaking clini-cal trial. Paper presented at: European Society of CardiologyCongress; 2009 August 30September 2; Barcelona, Spain.

50. Storey RF, Newby LJ and Heptinstall S. Effects of P2Y(1)and P2Y(12) receptor antagonists on platelet aggrega-tion induced by different agonists in human whole blood.Platelets2001; 12: 443447.

51. Gachet C. ADP receptors of platelets and their inhibition.Thromb Haemost2001; 86: 222232.

52. Turner NA, Moake JL and McIntire LV. Blockade of adeno-sine diphosphate receptors P2Y(12) and P2Y(1) is requiredto inhibit platelet aggregation in whole blood under flow.Blood2001; 98: 33403345.

53. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH andCLASSICS Investigators. Double-blind study of the safetyof clopidogrel with and without a loading dose in combi-nation with aspirin compared with ticlopidine in combina-tion with aspirin after coronary stenting: the clopidogrelaspirin stent international cooperative study (CLASSICS).

Circulation2000; 102: 624629. 54. Cadroy Y, Bossavy JP, Thalamas C, Sagnard L, SakariassenK and Boneu B. Early potent antithrombotic effect with com-bined aspirin and a loading dose of clopidogrel on experi-mental arterial thrombogenesis in humans. Circulation2000; 101: 28232828.

55. Anon. A randomised, blinded, trial of clopidogrel versusaspirin in patients at risk of ischaemic events (CAPRIE).CAPRIE Steering Committee.Lancet1996; 348: 13291339.

56. Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W andTopol EJ. Amplified benefit of clopidogrel versus aspirin inpatients with diabetes mellitus.Am J Cardiol2002; 90: 625628.

57. Mehta SR, Yusuf S, Peters RJ, et al.Effects of pretreatment

with clopidogrel and aspirin followed by long-term therapyin patients undergoing percutaneous coronary intervention:the PCI-CURE study.Lancet2001; 358: 527533.

58. Steinhubl SR, Berger PB, Mann JT 3rd, et al.Early and sus-tained dual oral antiplatelet therapy following percutaneouscoronary intervention: a randomized controlled trial.JAMA2002; 288: 24112420.

59. Chen ZM, Jiang LX, Chen YP, et al.Addition of clopidogrelto aspirin in 45,852 patients with acute myocardial infarc-tion: randomised placebo-controlled trial.Lancet2005; 366:16071621.

60. Sabatine MS, Cannon CP, Gibson CM, et al.Addition ofclopidogrel to aspirin and fibrinolytic therapy for myocar-dial infarction with ST-segment elevation. N Engl J Med2005; 352: 11791189.

61. Sabatine MS, Cannon CP, Gibson CM, et al.Effect of clopi-dogrel pretreatment before percutaneous coronary interven-

tion in patients with ST-elevation myocardial infarctiontreated with fibrinolytics: the PCI-CLARITY study.JAMA2005; 294: 12241232.

62. Bhatt DL, Fox KA, Hacke W, et al.Clopidogrel and aspirinversus aspirin alone for the prevention of atherothromboticevents.N Engl J Med2006; 354: 17061717.

63. Capranzano P, Ferreiro JL and Angiolillo DJ. Prasugrel inacute coronary syndrome patients undergoing percutaneouscoronary intervention.Expert Rev Cardiovasc Ther2009; 7:361369.

64. Wiviott SD, Trenk D, Frelinger AL, et al.Prasugrel com-pared with high loading- and maintenance-dose clopidogrel

in patients with planned percutaneous coronary intervention:the Prasugrel in Comparison to Clopidogrel for Inhibitionof Platelet Activation and Aggregation-Thrombolysis inMyocardial Infarction 44 trial. Circulation 2007; 116:29232932.

65. Wiviott SD, Braunwald E, McCabe CH, et al.Prasugrel ver-sus clopidogrel in patients with acute coronary syndromes.N Engl J Med2007; 357: 20012015.

66. Wiviott SD, Braunwald E, McCabe CH, et al. Intensiveoral antiplatelet therapy for reduction of ischaemic eventsincluding stent thrombosis in patients with acute coronarysyndromes treated with percutaneous coronary intervention

and stenting in the TRITON-TIMI 38 trial: a subanalysis ofa randomised trial.Lancet2008; 371: 13531363. 67. Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater

clinical benefit of more intensive oral antiplatelet therapywith prasugrel in patients with diabetes mellitus in the trialto assess improvement in therapeutic outcomes by opti-mizing platelet inhibition with prasugrel-Thrombolysis inMyocardial Infarction 38. Circulation2008; 118: 16261636.

68. Angiolillo DJ, Badimon J, Saucedo JF, et al.Comparison ofPrasugel With Clopidogrel on Platelet Function in CoronaryArtery Disease Patients With Type 2 Diabetes Mellitus Third Optimizing Anti-Platelet Therapy in DiabetesMellitUS (OPTIMUS-3). Circulation2009; 120: S1027

[abstract 4946]. 69. Roffi M, Chew DP, Mukherjee D, et al.Platelet glycoprotein

IIb/IIIa inhibition in acute coronary syndromes. Gradient ofbenefit related to the revascularization strategy.Eur Heart J2002; 23:14411448.

70. Roffi M, Chew DP, Mukherjee D, et al.Platelet glycopro-tein IIb/IIIa inhibitors reduce mortality in diabetic patientswith non-ST-segment-elevation acute coronary syndromes.Circulation2001; 104: 27672771.

71. Mehilli J, Kastrati A, Schhlen H, et al.Randomized clinicaltrial of abciximab in diabetic patients undergoing elective



14/16


percutaneous coronary interventions after treatment witha high loading dose of clopidogrel. Circulation2004; 110:36273635.

72. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab inpatients with acute coronary syndromes undergoing per-cutaneous coronary intervention after clopidogrel pretreat-

ment: the ISAR-REACT 2 randomized trial. JAMA 2006;295: 15311538.

73. Montalescot G, Barragan P, Wittenberg O, et al. Plateletglycoprotein IIb/IIIa inhibition with coronary stentingfor acute myocardial infarction. N Engl J Med2001; 344:18951903.

74. De Luca G, Navarese E and Marino P. Risk profile andbenefits from Gp IIb-IIIa inhibitors among patients withST-segment elevation myocardial infarction treated withprimary angioplasty: a meta-regression analysis of rand-omized trials.Eur Heart J2009; 30: 27052713.

75. Rao SV, Eikelboom JA, Granger CB, Harrington RA, Califf

RM and Bassand JP. Bleeding and blood transfusion issuesin patients with non-ST-segment elevation acute coronarysyndromes.Eur Heart J2007; 28: 11931204.

76. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KAand Yusuf S. Adverse impact of bleeding on prognosis inpatients with acute coronary syndromes. Circulation2006;114: 774782.

77. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin forpatients with acute coronary syndromes. N Engl J Med2006; 355: 22032216.

78. Feit F, Manoukian SV, Ebrahimi R, et al.Safety and efficacyof bivalirudin monotherapy in patients with diabetes mellitus

and acute coronary syndromes: a report from the ACUITY(Acute Catheterization and Urgent Intervention TriageStrategy) trial.J Am Coll Cardiol2008; 51: 16451652.

79. Tavano D, Visconti G, DAndrea D, et al.Comparison ofbivalirudin monotherapy versus unfractionated heparinplus tirofiban in patients with diabetes mellitus undergoingelective percutaneous coronary intervention. Am J Cardiol2009; 104: 12221228.

80. Manoukian SV. Predictors and impact of bleeding complica-tions in percutaneous coronary intervention, acute coronarysyndromes, and ST-segment elevation myocardial infarc-tion.Am J Cardiol2009; 104(Suppl): 9C15C.

81. Angiolillo DJ. Variability in responsiveness to oral antiplate-

let therapy.Am J Cardiol2009; 103(Suppl): 27A34A. 82. Michelson AD, Cattaneo M, Eikelboom JW, et al.Aspirin

resistance: position paper of the Working Group on AspirinResistance.J Thromb Haemost2005; 3: 13091311.

83. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JGand Huisman MV. Association of laboratory-defined aspi-rin resistance with a higher risk of recurrent cardiovascularevents: a systematic review and meta-analysis. Arch InternMed2007; 167: 15931599.

84. Krasopoulos G, Brister SJ, Beattie WS and Buchanan MR.Aspirin resistance and risk of cardiovascular morbidity:

systematic review and meta-analysis. BMJ 2008; 336:195198.

85. Gurbel PA, Bliden KP, DiChiara J, et al. Evaluation ofdose-related effects of aspirin on platelet function: resultsfrom the Aspirin-Induced Platelet Effect (ASPECT) study.Circulation2007; 115: 31563164.

86. Frelinger AL 3rd, Furman MI, Linden MD, et al.Residualarachidonic acid-induced platelet activation via an adeno-sine diphosphate-dependent but cyclooxygenase-1- andcyclooxygenase-2-independent pathway: a 700-patient studyof aspirin resistance. Circulation2006; 113: 28882896.

87. Watala C, Golanski J, Pluta J, et al.Reduced sensitivity ofplatelets from type 2 diabetic patients to acetylsalicylic acid(aspirin)-its relation to metabolic control. Thromb Res2004;113: 101113.

88. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al.Influence of aspirin resistance on platelet function profilesin patients on long-term aspirin and clopidogrel after per-

cutaneous coronary intervention. Am J Cardiol 2006; 97:3843.

89. DiChiara J, Bliden KP, Tantry US, et al.The effect of aspi-rin dosing on platelet function in diabetic and nondiabeticpatients: an analysis from the aspirin-induced platelet effect(ASPECT) study.Diabetes2007; 56: 30143019.

90. Dav G, Catalano I, Averna M, et al.Thromboxane bio-synthesis and platelet function in type II diabetes mellitus.N Engl J Med1990; 322: 17691774.

91. Guthikonda S, Lev EI, Patel R, et al.Reticulated plateletsand uninhibited COX-1 and COX-2 decrease the antiplateleteffects of aspirin.J Thromb Haemost2007; 5: 490496.

92. Serebruany V, Pokov I, Kuliczkowski W, Chesebro J andBadimon J. Baseline platelet activity and response afterclopidogrel in 257 diabetics among 822 patients with coro-nary artery disease. Thromb Haemost2008; 100: 7682.

93. Singla A, Antonino MJ, Bliden KP, Tantry US and GurbelPA. The relation between platelet reactivity and glycemiccontrol in diabetic patients with cardiovascular disease onmaintenance aspirin and clopidogrel therapy. Am Heart J2009; 158: 784.e16.

94. Angiolillo DJ, Bernardo E, Ramrez C, et al.Insulin therapyis associated with platelet dysfunction in patients with type2 diabetes mellitus on dual oral antiplatelet treatment.J AmColl Cardiol2006; 48: 298304.

95. Angiolillo DJ, Bernardo E, Capodanno D, et al. Impactof chronic kidney disease on platelet function profiles indiabetes mellitus patients with coronary artery diseaseon dual antiplatelet therapy.J Am Coll Cardiol2010; 55:11391146.

96. Dasgupta A, Steinhubl SR, Bhatt DL, et al. Clinical out-comes of patients with diabetic nephropathy randomizedto clopidogrel plus aspirin versus aspirin alone (a post hocanalysis of the clopidogrel for high atherothrombotic riskand ischemic stabilization, management, and avoidance[CHARISMA] trial).Am J Cardiol2009; 103: 13591363.



15/16

Ferreiro et al. 287

97. Iakovou I, Schmidt T, Bonizzoni E, et al.Incidence, predic-tors, and outcome of thrombosis after successful implanta-tion of drug-eluting stents.JAMA2005; 293: 21262130.

98. Ferreira IA, Mocking AI, Feijge MA, et al. Platelet inhi-bition by insulin is absent in type 2 diabetes mellitus.Arterioscler Thromb Vasc Biol2006; 26: 417422.

99. Li Y, Woo V and Bose R. Platelet hyperactivity and abnor-mal Ca(2+) homeostasis in diabetes mellitus.Am J PhysiolHeart Circ Physiol2001; 280: H1480H1489.

100. Michno A, Bielarczyk H, Paweczyk T, Jankowska-KulawyA, Klimaszewska J and Szutowicz A. Alterations of adeninenucleotide metabolism and function of blood platelets inpatients with diabetes.Diabetes2007; 56: 462467.

101. Guthikonda S, Alviar CL, Vaduganathan M, et al.Role ofreticulated platelets and platelet size heterogeneity on plate-let activity after dual antiplatelet therapy with aspirin andclopidogrel in patients with stable coronary artery disease.J Am Coll Cardiol2008; 52: 743749.

102. Angiolillo DJ, Shoemaker SB, Desai B, et al.Randomizedcomparison of a high clopidogrel maintenance dose inpatients with diabetes mellitus and coronary artery dis-ease: results of the Optimizing Antiplatelet Therapy inDiabetes Mellitus (OPTIMUS) study. Circulation 2007;115: 708716.

103. Price MJ, Berger PB, Angiolillo DJ, et al. Evaluation ofindividualized clopidogrel therapy after drug-eluting stentimplantation in patients with high residual platelet reactiv-ity: design and rationale of the GRAVITAS trial.Am Heart J2009; 157: 818824.

104. Neri Serneri GG, Coccheri S, Marubini E, Violi F and Drug

Evaluation in Atherosclerotic Vascular Disease in Diabetics(DAVID) Study Group. Picotamide, a combined inhibitorof thromboxane A2 synthase and receptor, reduces 2-yearmortality in diabetics with peripheral arterial disease: theDAVID study.Eur Heart J2004; 25: 18451852.

105. Anon. Randomized trial of ridogrel, a combined thrombox-ane A2 synthase inhibitor and thromboxane A2/prostaglandinendoperoxide receptor antagonist, versus aspirin as adjunctto thrombolysis in patients with acute myocardial infarc-tion. The Ridogrel Versus Aspirin Patency Trial (RAPT).Circulation1994; 89: 588595.

106. Gresele P, Migliacci R, Procacci A, De Monte P andBonizzoni E. Prevention by NCX 4016, a nitric oxide-

donating aspirin, but not by aspirin, of the acute endothelialdysfunction induced by exercise in patients with intermit-tent claudication. Thromb Haemost2007; 97: 444450.

107. Kariyazono H, Nakamura K, Arima J, et al.Evaluation ofanti-platelet aggregatory effects of aspirin, cilostazol andramatroban on platelet-rich plasma and whole blood.BloodCoagul Fibrinolysis2004; 15: 157167.

108. Chamorro A. TP receptor antagonism: a new concept inatherothrombosis and stroke prevention. Cerebrovasc Dis2009; 27(Suppl 3): 2027.

109. Angiolillo DJ and Guzman LA. Clinical overview of prom-ising nonthienopyridine antiplatelet agents. Am Heart J2008; 156: S23S28.

110. Capodanno D, Dharmashankar K and Angiolillo DJ.Mechanism of action and clinical development of ticagrelor,a novel platelet ADP P2Y12 receptor antagonist.Expert RevCardiovasc Ther2010; 8: 151158.

111. Gurbel PA, Bliden KP, Butler K, et al. Randomized dou-ble-blind assessment of the ONSET and OFFSET of theantiplatelet effects of ticagrelor versus clopidogrel inpatients with stable coronary artery disease: the ONSET/OFFSET study. Circulation2009; 120: 25772585.

112. Storey RF, Husted S, Harrington RA, et al. Inhibition ofplatelet aggregation by AZD6140, a reversible oral P2Y12receptor antagonist, compared with clopidogrel in patientswith acute coronary syndromes. J Am Coll Cardiol 2007;50: 18521856.

113. Wallentin L, Becker RC, Budaj A, et al.Ticagrelor versus

clopidogrel in patients with acute coronary syndromes.N Engl J Med2009; 361: 10451057.

114. Ferreiro JL, Ueno M and Angiolillo DJ. Cangrelor: a reviewon its mechanism of action and clinical development.ExpertRev Cardiovasc Ther2009; 7: 11951201.

115. Storey RF, Wilcox RG and Heptinstall S. Comparisonof the pharmacodynamic effects of the platelet ADPreceptor antagonists clopidogrel and AR-C69931MX inpatients with ischaemic hear t disease.Platelets2002; 13:407413.

116. Harrington RA, Stone GW, McNulty S, et al.Platelet inhi-bition with cangrelor in patients undergoing PCI.N Engl J

Med2009; 361: 23182329.117. Bhatt DL, Lincoff AM, Gibson CM, et al.Intravenous plate-let blockade with cangrelor during PCI.N Engl J Med2009;361: 23302341.

118. Berger JS, Roe MT, Gibson CM, et al.Safety and feasibilityof adjunctive antiplatelet therapy with intravenous elinogrel,a direct-acting and reversible P2Y12 ADP-receptor antago-nist, before primary percutaneous intervention in patientswith ST-elevation myocardial infarction: the Early RapidReversAl of platelet thromboSis with intravenous Elinogrelbefore PCI to optimize reperfusion in acute MyocardialInfarction (ERASE MI) pilot trial. Am Heart J 2009;158:9981004.

119. Ueno M, Rao SV and Angiolillo DJ. Elinogrel: pharmaco-logical principles, preclinical and early phase clinical test-ing.Future Cardiol2010; 6: 445453.

120. Leonardi S, Rao SV, Harrington RA, et al. Rationaleand design of the randomized, double-blind trial testingINtraveNous and Oral administration of elinogrel, a selec-tive and reversible P2Y(12)-receptor inhibitor, versus clopi-dogrel to eVAluate Tolerability and Efficacy in nonurgentPercutaneous Coronary Interventions patients (INNOVATE-PCI).Am Heart J 2010; 160: 6572.



16/16


121. Angiolillo DJ, Capranzano P, Goto S, et al.A randomizedstudy assessing the impact of cilostazol on platelet func-tion profiles in patients with diabetes mellitus and coronaryartery disease on dual antiplatelet therapy: results of theOPTIMUS-2 study.Eur Heart J2008; 29: 22022211.

122. Douglas JS Jr, Holmes DR Jr, Kereiakes DJ, et al.

Coronary stent restenosis in patients treated with cilostazol.Circulation2005; 112: 28262832.

123. Lee SW, Park SW, Hong MK, et al. Triple versus dualantiplatelet therapy after coronary stenting: impact on stentthrombosis.J Am Coll Cardiol2005; 46: 18331837.

124. Han Y, Li Y, Wang S, et al.Cilostazol in addition to aspirinand clopidogrel improves long-term outcomes after percu-taneous coronary intervention in patients with acute coro-nary syndromes: a randomized, controlled study. Am HeartJ2009; 157: 733739.

125. Biondi-Zoccai GG, Lotrionte M, Anselmino M, et al.Systematic review and meta-analysis of randomized clinical

trials appraising the impact of cilostazol after percutaneouscoronary intervention.Am Heart J2008; 155: 10811089.

126. Lee SW, Park SW, Kim YH, et al. Drug-eluting stentingfollowed by cilostazol treatment reduces late restenosis inpatients with diabetes mellitus the DECLARE-DIABETESTrial (A Randomized Comparison of Triple AntiplateletTherapy with Dual Antiplatelet Therapy After Drug-Eluting

Stent Implantation in Diabetic Patients).J Am Coll Cardiol2008; 51: 11811187.

127. Ueno M, Ferreiro JL and Angiolillo DJ. Mechanism of actionand clinical development of platelet thrombin receptor antago-nists.Expert Rev Cardiovasc Ther2010; 8: 11911200.

128. Angiolillo DJ, Capodanno D and Goto S. Platelet thrombin

receptor antagonism and atherothrombosis. Eur Heart J2010; 31: 1728.

129. Becker RC, Moliterno DJ, Jennings LK, et al.Safety andtolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised,double-blind, placebo-controlled phase II study. Lancet2009; 373: 919928.

130. Morrow DA, Scirica BM, Fox KA,et al.Evaluation of a novelantiplatelet agent for secondary prevention in patients with ahistory of atherosclerotic disease: design and rationale for theThrombin-Receptor Antagonist in Secondary Prevention ofAtherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI

50 trial.Am Heart J2009; 158: 335341.e3.131. TRA*CER Executive and Steering Committees. The

Thrombin Receptor Antagonist for Clinical Event Reductionin Acute Coronary Syndrome (TRA*CER) trial: studydesign and rationale.Am Heart J2009; 158: 327334.e4.

132. Wittkowsky AK. New oral anticoagulants: a practical guidefor clinicians.J Thromb Thrombolysis2010; 29: 182191.

cad+dm.pdf

Documents