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Review article: Antithrombotic therapy in patients with diabetes mellitus and coronary artery disease
Jos Luis Ferreiro, ngel R Cequier and Dominick J Angiolillo Diabetes and Vascular Disease Research 2010 7: 274 originally published online 4 October 2010 DOI: 10.1177/1479164110383995 The online version of this article can be found at: http://dvr.sagepub.com/content/7/4/274

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Review article

Antithrombotic therapy in patients with diabetes mellitus and coronary artery disease
Jos Luis Ferreiro1, 2, ngel R Cequier1 and Dominick J Angiolillo3

Diabetes & Vascular Disease Research 7(4) 274 288 The Author(s) 2010 Reprints and permission: sagepub. co.uk/journalsPermissions.nav DOI: 10.1177/1479164110383995 dvr.sagepub.com

Abstract Currently approved antiplatelet treatment strategies have proved successful for reducing cardiovascular adverse events in patients with CAD. However, despite the use of recommended antiplatelet treatment strategies, the presence of DM has been consistently associated with a negative impact on outcomes and a high rate of adverse cardiovascular events continue to occur in patients with DM. The elevated prevalence of low response to standard oral antiplatelet agents contribute to these impaired outcomes. Thus, the search for more potent antiplatelet treatment strategies is warranted 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 therapies in DM patients, and evaluating the potential role of new antithrombotic agents and treatment strategies currently under development to overcome these limitations. Keywords Antithrombotic therapy, coronary artery disease, diabetes mellitus, platelets

Introduction
The increasing worldwide prevalence of diabetes mellitus (DM), which is currently affecting more than 150 million people, mainly due to type 2 DM, has led to label this disease as a global pandemic.1, 2 The burden of cardiovascular disease among patients with DM is substantial and has been confirmed in large-scale surveys, such as the Euro Heart Survey, the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) registry and the US-based National Registry of Myocardial Infarction, which showed a prevalence of diabetes of approximately 30% both in patients with stable coronary artery disease (CAD) and in those with acute coronary syndromes (ACSs), including non-ST-segment elevation acute coronary syndrome (NSTEACS) and ST-segment myocardial infarction (STEMI).35 In fact, cardiovascular disease is the leading cause of morbidity and mortality in patients with DM, due mostly to the role played by CAD.6 Of note, subjects with DM have a 24-fold increased risk of cardiovascular events than non-DM subjects, and 68% of deaths among DM patients over the age of 65years are due to CAD.7 Platelets play a key role in the development of atherosclerosis and its atherothrombotic complications.8 Platelets of DM patients have dysregulation of several signalling pathways (developed in details in another manuscript of this supplement), which leads to increased platelet reactivity.911 Another important feature of DM patients is an impaired response to antiplatelet therapies,1214 which is well established to be associated with a higher risk of adverse ischaemic outcomes.1517 In fact, despite compliance with recommended antiplatelet treatment regimens, the negative impact of DM on outcomes has been consistently observed across the spectrum of manifestations of CAD.1821 The aim of the present manuscript is to provide an overview on the current status of knowledge on currently
IDIBELL-Hospital Universitari de Bellvitge, Department of Cardiology, Interventional Cardiology Unit, LHospitalet de Llobregat, Barcelona, Spain 2 IDIBELL-Hospital Universitari de Bellvitge, Cardiovascular Research Lab, LHospitalet de Llobregat, Barcelona, Spain 3 University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
1

Corresponding author: Dominick J Angiolillo, University of Florida College of Medicine Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA Email: dominick.angiolillo@jax.ufl.edu

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Ferreiro et al. available antiplatelet agents, focusing on the benefits and limitations of these therapies in DM patients, and evaluating the potential role of new antithrombotic agents and treatment strategies currently under development to overcome these limitations.

275 recommended in DM patients at increased cardiovascular disease risk (men over age 50 years and women over age 60years with a 10-year risk of cardiovascular events over 10%) and who are not at increased risk of bleeding.40 The ongoing trials A Study of Cardiovascular Events iN Diabetes (ASCEND; NCT00135226) and Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D; ISRCTN48110081) will provide further insights into the role of aspirin as a primary prevention measure in patients with DM. Aspirin remains the antiplatelet drug of choice for secondary prevention of recurrent ischaemic events in patients with an atherothrombotic manifestation of CAD or undergoing percutaneous coronary intervention (PCI).2325, 41 The benefit of aspirin therapy in the setting of ACS has been consistently demonstrated since the earliest trials, including those evaluating NSTEACS4244 and STEMI.45, 46 As per guidelines, aspirin must be given as promptly as possible, at an initial dose of 162325mg followed by a daily dose of 75162mg,23, 24 which is also the recommended maintenance dose of aspirin for secondary prevention in DM patients with atherosclerotic disease.41 Two large metaanalyses of secon dary prevention trials performed by the Antithrombotic Trialists Collaboration, involving 212,000 high-risk patients (with acute or previous vascular disease or some other predisposing condition implying an increased risk of occlusive vascular disease), supported the use of low-dose aspirin.47, 48 These metaanalyses showed that the benefit of oral antiplatelet agents was consistent independently of DM status (38 vascular events were prevented for every 1,000 DM patients and 36 events for every 1,000 non-DM patients), even though the overall incidence of vascular events was much higher in DM patients.47 Aspirin was the most commonly evaluated antiplatelet agent, at doses ranging from 75 to 325mg daily. Importantly, the use of low-dose aspirin (75 150mg/day) was found to be at least as effective as higher daily doses, while bleeding complications were diminished with the lower doses.47, 48 The Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS (CURRENT/OASIS7; NCT00335452) trial included ACS patients (n=25,087) scheduled to undergo angiography that were randomised in a 2 2 factorial design to high or standard dose of clopidogrel for a month and in an open-label way to high (300325mg daily) versus low dose (75100 mg daily) of aspirin. This trial was the first large-scale randomised study to compare highwith low-dose aspirin and no significant differences in efficacy among aspirin doses were found. However, a trend towards a higher rate of gastrointestinal bleeds in the highdose group was reported, although the bleeding rates can be considered relatively low (0.38% vs. 0.24%; p=0.051).49 The results of this study in the DM subset regarding aspirin dosage have not yet been made available.

Currently approved antiplatelet therapies

Three different classes of antiplatet agents are currently approved for the treatment and prevention of recurrent ischaemic events in patients with CAD: cyclooxigenase-1 (COX-1) inhibitors (aspirin), adenosine diphosphate (ADP) P2Y12 receptor antagonists (thienopyridines) and glycoprotein (GP) IIb/IIIa inhibitors.2224 This section provides insights on the benefits and limitations of these agents in patients with DM.

Aspirin
Aspirin is an irreversible inhibitor of COX-1, the enzyme that catalyses the synthesis of thromboxane A2 (TXA2) from arachidonic acid, by acetylation of the hydroxyl group of a serine residue at position 529 (Ser529). TXA2 binds to thromboxane/prostaglandin endoperoxide (TP) receptors, resulting in changes in platelet shape and enhancement of recruitment and aggregation of platelets. Therefore, aspirin blocks platelet formation of TXA2 and, as a result, diminishes platelet aggregation mediated by the TP receptors pathway.25 The use of aspirin for primary prevention in DM patients is controversial. In 2007, the American Diabetes Association (ADA) and the American Heart Association (AHA) jointly recommended aspirin therapy (75162 mg/day) for primary prevention in DM patients at increased cardiovascular risk,26 while according to European guidelines aspirin was not recommended in this setting.27 Among the trials that have evaluated the effect of aspirin for primary prevention of cardiovascular events, most of these were population based,2833 while only three of them were focused specifically on DM patients.3436 Owing to the lack of consistency of the findings, a number of metaanalyses have been performed in order to reconcile the results obtained in the different trials,3740 being of special interest the metaanalysis performed with individual patient-level data from the nine trials mentioned above by a group of experts of the ADA, AHA and the American College of Cardiology Foundation with the purpose of providing an expert consensus document.40 Overall, the metaanalyses showed that aspirin appears to cause a modest size reduction in cardiovascular events [myocardial infarction (MI) and stroke], but current evidence is not conclusive to recommend its use as primary prevention in all patients with DM.40 This has led to the most recent recommendation in the previously mentioned expert consensus document, in which lowdose (75162mg/day) aspirin use for primary prevention is

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Diabetes and Vascular Disease Research 7(4) no benefit of combined therapy was observed in patients with DM. The efficacy of high versus standard dose of clopidogrel was evaluated in the CURRENT/OASIS7 trial, which included ACS patients (n=25,087) scheduled to undergo angiography within 72 h of hospital arrival. In the overall study population, no benefit was derived from the high-dose regimen. Nevertheless, in the subgroup of patients undergoing PCI (n=17,232), the high clopidogrel dose strategy diminished the rates of ischaemic outcomes [3.9% vs. 4.5%; hazard ratio (HR)=0.85; p=0.036) and reduced the risk of stent thrombosis by 30%, although it was at the expense of increased study-defined major bleedings. There were no differences in efficacy among the subset of patients with DM undergoing PCI [4.9% vs. 5.6%; HR=0.87 (0.661.15)].49 Prasugrel, as all thienopyridines, is a prodrug that requires hepatic biotransformation into its active metabolite to irreversibly block the P2Y12 receptor.63 This thirdgeneration thienopyridine has a faster onset of action than clopidogrel and reaches greater platelet inhibition due to a more efficient conversion into its active metabolite, with less interindividual variability in response, even compared with high-dose clopidogrel.64 The efficacy and safety of prasugrel (60 mg loading dose followed by a 10mg maintenance dose) versus clopidogrel therapy (300 mg loading dose followed by 75 mg daily maintenance dose) was evaluated in the randomised Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38; NCT 00097591.), performed in patients (n=13,608) with moderate- to high-risk ACS undergoing PCI with a follow-up period of 14.5months.65 In the overall population, prasugrel therapy was associated with a significant reduction in the rates of the primary end point (composite of cardiovascular death, non-fatal MI or non-fatal stroke) (9.9% vs. 12.1%; HR=0.81; p<0.001), as well as with decreased rates of stent thrombosis.66 This benefit was hampered by an increased risk of TIMI major non-coronary artery bypass grafting (CABG) related bleeding in the prasugrel group. Considering together ischaemic and bleeding outcomes, no net clinical benefit was found in older patients (75years) and in those weighing less than 60kg, and even a net clinical harm was observed in patients with a history of stroke or transient ischaemic attack.65 A predefined subgroup analysis according to DM status suggested a preferential benefit of prasugrel in the DM population (Figure 1).67 The primary end point was reduced significantly with prasugrel among patients with DM (12.2% vs. 17.0%; HR=0.70; p<0.001), this benefit being consistent in patients receiving insulin (14.3% vs. 22.2%; HR=0.63; p=0.009) and in those not on insulin therapy (11.5% vs. 15.3%; HR=0.74; p=0.009). Overall, major bleeding was higher in DM patients, but remarkably, there was no increase in major bleeding rates

P2Y12 receptor antagonists: thienopyridines

Thienopyridines (ticlopidine, clopidogrel and prasugrel) are non-direct, orally administered and irreversible platelet ADP P2Y12 receptor inhibitors. ADP-induced effects on platelets are mediated by the P2Y1 and P2Y12 receptors, which are both required for aggregation, although P2Y12 stimulation plays the principal role, leading to sustained platelet aggregation and stabilisation of the platelet aggregate.5052 Ticlopidine, a first-generation thienopyridine, was the first to be developed and approved for clinical use, although it was largely replaced by clopidogrel (a secondgeneration thienopyridine), which has a better safety profile.53 In addition, clopidogrel achieves a faster onset on action through administration of a loading dose.54 The Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial compared the efficacy for secondary prevention of clopidogrel (75mg daily) versus aspirin (325mg daily) in a high-risk population (n=19,185) consisting of patients with a history of recent MI, recent ischaemic stroke or established peripheral artery disease. A reduction in the risk of ischaemic outcomes in the clopidogrel group was observed (5.32% vs. 5.83%; p=0.043).55 The benefit of clopidogrel therapy was higher (15.6% vs. 17.7%; p=0.042) in DM patients, despite the increased incidence of ischaemic outcomes in this subgroup. The absolute reduction in events was highest among diabetic patients requiring insulin therapy. On the other hand, the reduction in the rates of ischaemic outcomes in patients without DM did not reach statistical significance.56 The use of clopidogrel 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 aspirin and clopidogrel is well established and recommended in the guidelines for patients with ACS, including those with NSTEACS23 and STEMI, and for patients undergoing PCI.24 Several large-scale clinical trials have shown a clear benefit of clopidogrel in addition to aspirin for preventing recurrent ischaemic events, including stent thrombosis, when compared to aspirin alone.18, 5761 Table 1 summarises ACS/PCI trials comparing dual antiplatelet therapy with aspirin and a thienopyridine 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, was evaluated in the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management and Avoidance (CHARISMA; NCT00050817) trial. This trial included patients (n=15,603) with either clinically evident cardiovascular disease or multiple cardiovascular risk factors. In this study, concomitant treatment with clopidogrel and aspirin was not significantly more effective than aspirin alone in reducing the rates of cardiovascular death, MI or stroke (6.8% vs. 7.3%; p=0.22).62 Consistently,

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Ferreiro et al.

Table 1. Large-scale randomised clinical trials evaluating the efficacy of dual antiplatelet therapy with aspirin and an orally administered P2Y12 receptor inhibitor in ACS/PCI patients in the overall study population and in the diabetes mellitus subgroup Setting UA/NSTEMI 504 560 NA 575 2,840 Primary end point Results in overall populationa N (DM) Results in DM subgroupa

Study

N (Overall) Study drugs

CURE18

12,562

PCI-CURE58 PCI patients from CURE Elective PCI

2,658

CREDO59

2,116

Cardiovascular death, nonfatal MI or stroke at 1year Cardiovascular death, MI or urgent TVR at 30days Death, MI or stroke at 1year

COMMIT60 Acute MI (93% STEMI) STEMI with fibrinolysis

45,852

14.2% vs. 16.7% RR=0.84 (0.701.02) 12.9% vs. 16.5% RR=0.77 (0.481.22) % NA RRR=11.2 [(-46.8)46.2] NA NA

CLARITY61

3,491

Aspirin+clopidogrel vs. aspirin Aspirin+clopidogrel vs. aspirin Aspirin+clopidogrel vs. aspirin Aspirin+clopidogrel vs. aspirin Aspirin+clopidogrel vs. aspirin

9.3% vs. 11.4% RR=0.80 (0.720.90) 4.5% vs. 6.4% RR=0.70 (0.500.97) 8.5% vs. 11.5% RRR=26.9% (3.9%44.4%) 9.2% vs. 10.1% OR=0.91 (0.860.97) 15.0% vs. 21.7% OR=0.64 (0.530.76)

PCI-CLARITY62

1,863

3.6% vs. 6.2% OR=0.54 (0.350.85)

282

6.0% vs. 10.1% OR=0.61 (0.241.53) 3,146 4,662

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TRITON-TIMI 3864 13,608

PLATO111

18,624

Death, reinfarction or stroke at discharge or 28days Occluded infarct-related artery on angiography, or death or recurrent MI before angiography Aspirin+clopidogrel PCI patients Cardiovascular death, vs. aspirin from CLARITY recurrent MI or stroke at 30days Aspirin+prasugrel ACS patients Cardiovascular death, nonvs. aspirin+clopidogrel undergoing PCI fatal MI or non-fatal stroke Aspirin+ticagrelor ACS patients Death from vascular causes, vs. aspirin MI or stroke

9.9% vs. 12.1% HR=0.81 (0.730.90) 10.2% vs. 12.3% HR=0.84 (0.770.92)

12.2% vs. 17.0% HR=0.70 (0.580.85) 14.1% vs. 16.2% HR=0.88 (0.761.03)

a Results are expressed as % of events and association measure (95% confidence interval). ACS: acute coronary syndrome, CLARITY: Clopidogrel as Adjunctive Reperfusion Therapy (trial), COMMIT: Clopidogrel and Metoprolol in Myocardial Infarction Trial, CREDO: Clopidogrel for the Reduction of Events During Observation (trial), CURE: Clopidogrel in Unstable angina to prevent Recurrent Events (trial), DM: diabetes mellitus; HR: hazard ratio, MI: myocardial infarction; NA: not available; NSTEMI: non-ST-segment elevation myocardial infarction; OR: odds ratio; PCI: percutaneous coronary intervention; PCI-CLARITY: percutaneous coronary intervention-Clopidogrel as Adjunctive Reperfusion Therapy (trial), PCI-CURE: percutaneous coronary intervention- Clopidogrel in Unstable angina to prevent Recurrent Events (trial), PLATO: Study of Platelet Inhibition and Patient Outcomes (trial), RR: relative risk; RRR: relative risk reduction; STEMI: ST-segment myocardial infarction; TRITON-TIMI 38: Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38, TVR: target vessel revascularisation; UA: unstable angina.

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Diabetes and Vascular Disease Research 7(4) and the risk of ACS, hence, using these drugs in low-moderate risk patients or in those managed with a conservative approach is generally not recommended.69 Therefore, GP IIb/IIIa inhibitors are used mainly in clinical practice as an adjunctive therapy on top of aspirin and a thienopyridine for the acute phase of therapy, due to its intravenous administration, in high-risk ACS patients undergoing PCI. The efficacy of GP IIb/IIIa inhibitors in the ACS scenario was evaluated in a metaanalysis of six large-scale trials.70 The 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 significant interaction between treatment with GP IIb/IIIa and DM status was observed. In this metaanalysis, the mortality reduction among DM patients was of greater magnitude in those patients (n=1,279) undergoing PCI during index hospitalisation (4.01.2%; p=0.002).70 However, caution on the conclusions from these study findings is warranted as these may not necessarily apply to todays clinical practice since clopidogrel regimens commonly used in current practice were not used in these trials (e.g. pre-treatment, high loading dose regimens). Two more recent studies have evaluated the efficacy of GP IIb/IIIa blockers on top of dual antiplatelet therapy. The Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) trial did not show a benefit of abciximab over placebo in terms of reducing the 1-year risk of death and MI in DM patients (n=701) undergoing elective PCI after pre-treatment with a clopidogrel loading dose of 600mg at least 2h before the procedure.71 Conversely, in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) trial, which compared abciximab treatment to placebo in patients with high-risk ACS undergoing PCI after pre-treatment with 600 mg of clopidogrel, a 25% reduction of the risk of adverse events (death, MI or urgent target vessel revascularisation within 30days) was observed in the abciximab group.72 Of note, the benefit provided by abciximab was restricted to patients with elevated troponin levels and was observed across all subgroups, including DM patients. Overall, the results of the last two trials performed in the clopidogrel era support the use of GP IIb/IIIa receptor antagonists in high-risk ACS patients undergoing PCI, in particular those with DM, but not for routine use in elective PCI. The value of GP IIb/IIIa inhibitors in DM patients with STEMI undergoing PCI has been assessed in a few smallscale studies. In a small placebo-controlled randomised study performed before the clopidogrel era, abciximab use was associated with lower mortality and reinfarction rates across the DM subgroup (n=54) in patients undergoing primary coronary stenting for the treatment of acute MI.73 In the Controlled Abciximab and Device Investigation to

Figure 1. KaplanMeier curves for prasugrel versus clopidogrel in patients with diabetes mellitus from the TRITON-TIMI 38 trial. Primary efficacy end point: cardiovascular death/non-fatal myocardial infarction/non-fatal stroke.
Source: Reprinted from Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38.67 Circulation, 118(16): 16261636 (2008), with permission from Lippincott Williams & Willkins. CABG: coronary artery bypass grafting, HR: hazard ratio.

among DM patients in the prasugrel group (2.6% vs. 2.5%; HR=1.06; p=0.81). Overall, these findings suggest that higher platelet inhibition is associated with improved outcome in DM patients. The pharmacodynamic benefit of prasugrel was recently observed in the Third Optimizing Anti-Platelet Therapy in Diabetes MellitUS (OPTIMUS-3; NCT00642174) study, in which a standard prasugrel dose (60mg loading dose followed by 10mg maintenance dose daily for 1week) achieved significantly higher platelet inhibition and better response profiles compared with high-dose clopidogrel (600mg loading dose followed by 150mg maintenance dose) in DM patients with CAD on chronic aspirin therapy.68 The ongoing trial TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage ACS. (TRILOGY ACS; NCT00699998) will provide insights into the clinical efficacy of prasugrel in medically managed patients with NSTEACS, which will likely comprise a large number of DM subjects.

Glycoprotein IIb/IIIa inhibitors

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

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Ferreiro et al. Lower Late Angioplasty Complications (CADILLAC) trial, no benefit was observed with abciximab in a cohort of lowrisk DM patients (n=346) with acute MI treated with balloon angioplasty or stenting.21 However, a metaregression of randomised trials evaluating the effect of adjunctive use of any GP IIb/IIIa inhibitor (abciximab, eptifibatide and tirofiban) on top of dual antiplatelet therapy in STEMI patients undergoing primary PCI found a relationship between benefit in terms of mortality of these agents and patients risk profile.74 Thus, the use of GP IIb/IIIa inhibitors should be considered in high-risk patients undergoing primary PCI, which may include those with DM. The main drawback associated with the administration of GP IIb/IIIa inhibitors is an increased risk of bleeding, which impairs the prognosis of patients suffering from ACS, even in terms of mortality.75, 76 A valid alternative may be bivalirudin, a direct thrombin inhibitor, which was shown in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY; NCT00093158) trial to have similar efficacy in reducing ischaemic events and a better safety profile with lower rates of major bleeding compared to GP IIb/IIIa antagonists in moderate-risk NSTEACS patients (n=13,819).77 In the DM subgroup (n=3,852), bivalirudin therapy was associated with a lower risk of major bleeding (3.7% vs. 7.1%; p<0.001) and similar efficacy in terms of ischaemic outcomes (death, MI or unplanned ischaemic revascularisation) when compared to GP IIb/IIIa plus heparin (7.9% vs. 8.9%; p=0.39).78 Recently, bivalirudin monotherapy was observed to have similar protection for ischaemic events and lower in-hospital bleeds (mainly minor) in a cohort of patients with DM undergoing elective PCI when compared to combined therapy with unfractionated heparin and tirofiban.79 Overall, the reduction of bleeding risk with bivalirudin is noteworthy, as DM is a strong predictor of bleeding in ACS and/or PCI patients.80

279 (e.g. determination of plasmatic or urinary TXA2 metabolites, tests using arachidonic acid as agonist) are used.85, 86 Conversely, the prevalence of aspirin resistance is higher when using COX-1 non-specific assays, suggesting that these results are derived not only from COX-1 degree of inhibition, but also from aspirin-induced COX-1-independent effects.81 Among the factors causing aspirin resistance assessed by COX-1 specific tests, poor patient compliance is the most important and population selection also contributes to the inadequate response.86 Importantly, reduced response to aspirin has been observed in DM patients with poor metabolic control.87 Increasing the dose of aspirin has been suggested to overcome resistance in DM patients, who have high rates of impaired response to aspirin, if assessed by COX-1 non-specific methods.12, 88 A subanalysis of the Aspirin-Induced Platelet Effect (ASPECT) study, which compared the pharmacodynamic effect of different doses of aspirin in patients with and without DM, showed a higher percentage of aspirin resistance in the DM subgroup with the lower dose (81mg daily). However, increasing the aspirin dose (162 and 325mg daily) augmented platelet inhibition in patients with DM to an extent that the final rates of aspirin resistance were similar in both groups.89 To date, few studies have investigated the specific mechanisms of aspirin resistance that are characteristic of DM patients. Some of the mechanisms that have been proposed include the following: (a) hyperglycaemia, as augmented protein glycation may be associated with decreased aspirinmediated protein acetylation; (b) increased TXA2 synthesis, which is associated with a poor metabolic control;90 and (c) accelerated platelet turnover, due to the fact that introduction into the bloodstream of newly generated platelets not exposed to aspirin may continue to generate TXA2, thereby activating the TP receptor despite COX-1 inhibition.91 Clopidogrel is the most used thienopyridine and with which there is most laboratory and clinical experience. Despite the undisputed clinical benefit of clopidogrel in addition to aspirin, the number of recurrent cardiovascular events is still relatively high.18, 5761 Variability in individual response to clopidogrel has been consistently associated with this limited efficacy.16, 17 Genetic, cellular and clinical factors have been proposed to be involved in this variability. The prevalence of clopidogrel low responsiveness varies widely (540%) and depends on differences in the type of assays used, the definition of resistance, dosage and the patient population being evaluated.16, 17 Among the clinical factors, the presence of DM has been repeatedly associated with impaired clopidogrel-induced platelet inhibition both in the acute and maintenance phases of therapy.12, 14, 15, 92 Of note, DM patients with poor metabolic control and those who require insulin therapy have the worst response to clopidogrel in patients on dual antiplatelet therapy (Figure 2).93, 94 In addition, patients with DM are at a higher risk of developing chronic kidney disease (CKD), which impairs response to antiplatelet agents and is a risk factor per se of

Limitations of oral antiplatelet drugs in patients with DM

The relationship between variability in response to antiplatelet therapy and clinical outcomes has been repeatedly and consistently reported, suggesting that poor responsiveness to oral antiplatelet drugs may play an important role in the risk of developing adverse events.16, 81, 82 The risk of recurrent ischaemic events is higher in DM patients,1821 hence, understanding antiplatelet drug response in this high-risk population is of particular interest. A number of clinical studies have observed an association between aspirin resistance and a higher risk of recurrent ischaemic events.83, 84 The prevalence of aspirin resistance varies widely among studies, due mainly to differences in the tests used, definition of resistance, aspirin dosage and population considered. In fact, aspirin resistance is a sporadic phenomenon (<5% of patients) when COX-1 specific assays

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Diabetes and Vascular Disease Research 7(4) pharmacodynamic efficacy of a high (150mg) versus standard maintenance dose of clopidogrel (75mg) in type 2 DM patients with CAD and high platelet reactivity, while in their maintenance phase of clopidogrel therapy, was evaluated in the OPTIMUS study. Patients randomised to the 150 mg dose showed a marked improvement in platelet inhibition, although a considerable number of patients remained with high platelet reactivity.102 Results of the CURRENT/OASIS7 trial, which randomised ACS patients in a 2 2 factorial design to high (600 mg loading dose followed by 150 mg daily for 1week and then 75mg/daily until day 30) or standard dose of clopidogrel (300mg loading followed by 75mg daily until day 30) for a month and in an open-label way to high (300325mg daily) versus low dose (75100mg daily) of aspirin, in which no particular benefit was observed in patients with DM, have been commented on previously.49 Increasing clopidogrel dosing according to the degree of responsiveness of a given patient, which has been defined as tailored or individualised treatment, has also raised considerable interest. The ongoing Gauging Responsiveness with a VerifyNow Assay-Impact on Thrombosis And Safety (GRAVITAS; NCT00645918) trial will evaluate the efficacy and safety of tailored treatment with high clopidogrel maintenance dose for 6months in those patients with low response to standard clopidogrel dose in which a considerable number of patients with DM will be enrolled.103 Several new agents that block multiple pathways involved in platelet adhesion, activation and aggregation are currently at different stages of clinical development. Novel agents targeting the TXA2 pathway include picotamide (a combined TXA2 synthase inhibitor and TP receptor blocker), ridogrel (a combined TXA2 synthase inhibitor and TP receptor blocker), ramatroban (a TP receptor inhibitor), NCX 4016 [a nitric oxide (NO)-releasing aspirin derivative] and S18886/ terutroban (a TP receptor inhibitor). These have been evaluated in different scenarios with variable success and might be of future interest, although none of them appear to be suitable for replacing aspirin at the current time.104108 Novel and more potent P2Y12 receptor inhibitors (prasugrel, ticagrelor, cangrelor, elinogrel) have emerged recently and may represent attractive treatment choices in high-risk patients, such as those with DM. The pharmacodynamic effects of the third-generation thienopyridine prasugrel and its beneficial clinical implications specifically in patients with DM have already been discussed in this manuscript. Ticagrelor is an orally administered cyclopentyltriazolopyrimidine, which directly and reversibly inhibits the platelet ADP P2Y12 receptor.109, 110 Ticagrelor has a faster onset and offset of action and achieves higher inhibition of platelet aggregation than clopidogrel.111, 112 The phase III Study of Platelet Inhibition and Patient Outcomes (PLATO) trial randomised ACS patients (n=18,624) to receive either ticagrelor (180mg loading dose followed by 90mg twice daily) or clopidogrel (300600mg loading dose followed by 75mg

Figure 2. Platelet aggregation after 20 mol adenosine diphosphate (ADP) stimulus.

Source: Reprinted from Angiolillo DJ, Bernardo E, Ramirez C, et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment.94 Journal of the American College of Cardiology, 48: 298304 (2006), with permission from Elsevier. ITDM: insulin-treated diabetes mellitus, NDM: non-diabetes mellitus (patients), NITDM: non-insulin-treated diabetes mellitus.

worse clinical outcomes. Among DM patients, the presence of moderate to severe CKD is associated with decreased response to clopidogrel,95 which is in line with the results of a post hoc analysis of the CHARISMA trial, which suggests that clopidogrel use might increase adverse outcomes in patients with diabetic nephropathy.96 These results contribute overall 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 impaired clopidogrel-induced effects observed in DM patients, such as: (a) diminished platelet response to insulin;98 (b) dysregulation of calcium metabolism;99 (c) upregulation of P2Y12 receptor signalling;98 (d) increased exposure to ADP;100 and (e) increased platelet turnover.101

Future strategies
The persistence of high platelet reactivity despite the use of standard recommended antiplatelet treatment regimens has led to developing treatment strategies to optimise platelet inhibitory effects, which are of special interest in high-risk subjects such as those with DM. These new approaches can be summarised as follows: (a) increased dosing of currently approved agents; (b) use of new agents; and (c) addition of a third antiplatelet drug. In this section, we provide a brief overview of the studies that have evaluated the above-mentioned strategies in patients with DM. Currently, the approved loading and maintenance doses for clopidogrel are 300mg and 75mg/daily, respectively, although a loading dose of 600 mg is common in clinical practice, especially in patients undergoing PCI. The

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Ferreiro et al. daily). The rate of the primary end point (death from vascular causes, MI or stroke) at 12 months was significantly decreased in the ticagrelor arm (10.2% vs. 12.3%; HR=0.84; p=0.0001), as well as, remarkably, the rate of cardiovascular death (4.0% vs. 5.1%; HR=0.79; p=0.001) and the occurrence of definite or probable stent thrombosis (2.2% vs. 2.9%; HR=0.75; p=0.02) in the subgroup of patients undergoing 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 associated with a higher rate of major bleeding not related to CABG (4.5% vs. 3.8%; HR=1.19; p=0.03).113 A predefined subgroup analysis of the DM cohort (n=4,662) showed a nonsignificant reduction of the rates of the primary end point [14.1% vs. 16.2%; HR=0.88 (0.761.03)], while no difference in major bleeding rates was found [14.1% vs. 14.8%; HR=0.95 (0.811.12)]. Ticagrelor is currently pending approval by regulatory authorities for clinical use. Cangrelor is an intravenous ATP analogue, which is a direct-acting, reversible, without any biotransformation, P2Y12 receptor inhibitor.109, 114 Phase II trials showed promising results, as cangrelor proved to be a very potent antiplatelet agent, achieving >90% inhibition of platelet aggregation, with very rapid onset and offset of action, as well as dose-dependent and, thus, predictable, effects.115 However, the results of the phase III Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) program, which evaluated mostly ACS patients undergoing PCI, failed to show the superiority of cangrelor over clopidogrel in the CHAMPION-PCI (NCT00305162) (n=8,716), and over placebo in the CHAMPION-PLATFORM (NCT00385138) (n=5,362) in terms of reducing ischaemic outcomes.116, 117 Analysis of the DM cohort (n=2,702) from the CHAMPIONPCI trial showed results that were consistent with those obtained in the overall population. Elinogrel is a novel, direct-acting and reversible P2Y12 inhibitor in the preliminary stages of development, with the important feature of having both oral and intravenous ways of administration.118, 119 The ongoing trial INtraveNous and Oral administration of elinogrel to eVAluate Tolerability and Efficacy in nonurgent PCI patients (INNOVATE-PCI). (INNOVATE-PCI; NCT00751231) is evaluating the efficacy and safety of three different doses of elinogrel (oral 50, 100 and 150mg twice daily following an intravenous bolus) in patients undergoing non-urgent PCI.120 Future strategies also include the use of a third antiplatelet drug that blocks pathways other than COX-1 and P2Y12 to be used on top of aspirin and a P2Y12 inhibitor. Drugs that have been proposed for being part of such triple therapy are: (a) cilostazol; (b) protease-activated receptor-1 (PAR1) antagonists; and (c) new oral anticoagulants. Among them, cilostazol, a phosphodiesterase III inhibitor that increases intraplatelet cyclic adenosine monophosphate

281 (cAMP) concentration, has the most consistent data reporting a benefit in patients with DM. In patients with type 2 DM, the OPTIMUS-2 study showed that adjunctive use of cilostazol on top of standard dual antiplatelet therapy increases platelet inhibition.121 This enhanced platelet inhibitory effect may contribute to the better outcomes observed in patients undergoing PCI, both elective and after suffering an ACS event.122124 Interestingly, this benefit appears to be higher in high-risk patients, such as those with DM, and seems not to be hampered by an increase in bleeding.125, 126 The high frequency of side effects (mainly headache, palpitations and gastrointestinal disturbances) may, however, limit the use of cilostazol.121 Two oral thrombin receptor antagonists, which block the platelet PAR-1 receptor subtype, are currently under clinical development: vorapaxar (SCH 530348) and E5555 (Figure 3). 109, 127, 128 Vorapaxar has shown an excellent safety profile in a large, phase II safety and dose-ranging trial performed in patients (n=1,030) undergoing non-urgent PCI or coronary angiography with planned PCI, in which triple therapy was not associated with any significant increase of bleeding across all doses tested.129 Two ongoing large-scale phase III trials are evaluating the efficacy and safety of vorapaxar in ACS patients: the Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA 2P-TIMI 50; NCT00526474) trial in patients with atherosclerosis and the Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome (TRA*CER; NCT00527943).130, 131 Finally, several new oral anticoagulants are currently under investigation and being tested in adjunct to standard antiplatelet treatment regimens in high-risk settings. In fact, in high-risk settings such as patients with ACS, in addition to increased platelet reactivity, dysregulation of coagulation processes may also occur and contribute to atherothrombotic recurrences. Novel oral anticoagulants include anti-factor IIa or gatrans (e.g. dabigatran) and anti-factor Xa or xabans (e.g. rivaroxaban, apixaban), which are currently at different stages of development.132

Conclusions
Patients with DM have higher rates of adverse cardiovascular events compared with those without DM despite using recommended antiplatelet treatment regimens. A high prevalence of impaired response to standard antiplatelet therapies is characteristic of DM, which may contribute to their worse outcomes. Therefore, more potent antiplatelet therapy is needed in such a high-risk population. Novel antiplatelet treatment strategies that are currently under investigation will provide important insights on their safety and efficacy in high-risk settings, including patients with DM.

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Diabetes and Vascular Disease Research 7(4)

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). Several intracellular signalling pathways contribute to platelet activation, which causes local production of thrombin and the production and release of multiple agonists, including TXA2 and 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 integrin GP IIb/IIIa complex mediates the final common step of platelet activation by undergoing a conformational shape change and binding fibrinogen 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 this process include TX inhibitors, ADP receptor antagonists, GP inhibitors, adhesion antagonists and PAR antagonists. Reversible agents are indicated by brackets.
Source: Reprinted from Angiolillo DJ, Capodanno D and Goto S. Platelet thrombin receptor antagonism and atherothrombosis.128 European Heart Journal, 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-activated receptor, TP: thromboxane/prostaglandin endoperoxide receptors, TX: thromboxane, TXA2: thromboxane A2, vWF: von Willebrand factor.

Funding This work was supported by an unrestricted educational grant from Eli Lilly and Daiichi Sankyo to the University of Sheffield to fund the activities of the European Platelet Academy. Conflicts of interest Jos Luis Ferreiro and ngel R Cequier have no conflicts of interest to report. Dominick J Angiolillo reports receiving honoraria for lectures from Bristol-Myers

Squibb, Sanofi-Aventis, Eli Lilly and Company and Daiichi Sankyo, Inc.; consulting fees from BristolMyers Squibb, Sanofi-Aventis, Eli Lilly and Company, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals 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, Portola Pharmaceuticals Inc., Accumetrics, Schering-Plough, AstraZeneca and Eisai.

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coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005; 54: 24302435. Ferreiro JL and Angiolillo DJ. Diabetes and anti-platelet therapy in acute coronary syndrome. Circulation 2010 (in press). Geisler T, Anders N, Paterok M, et al. Platelet response to clopidogrel is attenuated in diabetic patients undergoing coronary stent implantation. Diabetes Care 2007; 30: 372374. Angiolillo DJ. Antiplatelet therapy in diabetes: efficacy and limitations of current treatment strategies and future directions. Diabetes Care 2009; 32: 531540. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007; 49: 15051516. Ferreiro JL and Angiolillo DJ. Clopidogrel response variability: current status and future directions. Thromb Haemost 2009; 102: 714. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494502. Mak KH, Moliterno DJ, Granger CB, et al. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. GUSTO-I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol 1997; 30: 171179. Roffi M and Topol EJ. Percutaneous coronary intervention in diabetic patients with non-ST-segment elevation acute coronary syndromes. Eur Heart J 2004; 25: 190198. Stuckey TD, Stone GW, Cox DA, et al. Impact of stenting and abciximab in patients with diabetes mellitus undergoing primary angioplasty in acute myocardial infarction (the CADILLAC trial). Am J Cardiol 2005; 95: 17. Fraker TD Jr, Fihn SD, Gibbons RJ, et al. 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation 2007; 116: 27622772. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography

Key messages

 Patients with DM have worse outcomes and impaired  More potent antiplatelet agents, such as prasugrel, are  Several new antiplatelet treatment strategies are currently under investigation which will provide important insights on their safety and efcacy in high-risk settings, including patients with DM. particularly benecial in patients with DM. response to standard antiplatelet therapies.

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References
1. Zimmet P, Alberti KG and Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001; 414: 782787. 2. King H, Aubert RE and Herman WH. Global burden of diabetes, 19952025: prevalence, numerical estimates, and projections. Diabetes Care 1998; 21: 14141431. 3. Bartnik M, Rydn L, Ferrari R, et al. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on diabetes and the heart. Eur Heart J 2004; 25: 18801890. 4. Bhatt DL, Roe MT, Peterson ED, et al. Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. JAMA 2004; 292: 20962104. 5. Roe MT, Parsons LS, Pollack CV Jr, et al. Quality of care by classification of myocardial infarction: treatment patterns for ST-segment elevation vs non-ST-segment elevation myocardial infarction. Arch Intern Med 2005; 165: 16301636. 6. Webster MW and Scott RS. What cardiologists need to know about diabetes. Lancet 1997; 350(Suppl 1): SI23SI28. 7. Centers for Disease Control and Prevention. 2007 National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, www.cdc.gov/ diabetes/pubs/factsheet07.htm (2007, accessed September 2010). 8. Dav G and Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357: 24822494. 9. Creager MA, Lscher TF, Cosentino F and Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation 2003; 108: 15271532. 10. Stratmann B and Tschoepe D. Pathobiology and cell interactions of platelets in diabetes. Diab Vasc Dis Res 2005; 2: 1623. 11. Ferroni P, Basili S, Falco A and Dav G. Platelet activation in 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

16.

17.

18.

19.

20.

21.

22.

23.

Downloaded from dvr.sagepub.com by guest on February 13, 2012

284
and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007; 116: e148e304. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009; 120: 22712306. Patrono C, Garca Rodrguez LA, Landolfi R and Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353: 23732383. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2007; 30: 162172. Rydn L, Standl E, Bartnik M, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007; 28: 88136. Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res Ed) 1988; 296: 313316. Anon. Final report on the aspirin component of the ongoing Physicians Health Study. Steering Committee of the Physicians Health Study Research Group. N Engl J Med 1989; 321: 129135. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351: 17551762. Anon.Thrombosis prevention trial: randomised trial of lowintensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Councils General Practice Research Framework. Lancet 1998; 351: 233241. Sacco M, Pellegrini F, Roncaglioni MC, et al. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Diabetes Care 2003; 26: 32643272. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352: 12931304.

Diabetes and Vascular Disease Research 7(4)

34. Anon. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. JAMA 1992; 268: 12921300. 35. Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008; 300: 21342141. 36. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008; 337: a1840. 37. Antithrombotic Trialists (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009; 373: 18491860. 38. De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ 2009; 339: b4531. 39. Calvin AD, Aggarwal NR, Murad MH, et al. Aspirin for the primary prevention of cardiovascular events: a systematic review and meta-analysis comparing patients with and without diabetes. Diabetes Care 2009; 32: 23002306. 40. Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes. J Am Coll Cardiol 2010; 55: 28782886. 41. Colwell JA, American Diabetes Association. Aspirin therapy in diabetes. Diabetes Care 2004; 27(Suppl 1): S72S73. 42. Lewis HD Jr, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 1983; 309: 396403. 43. Throux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319: 11051111. 44. Anon. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet 1990; 336: 827830. 45. Anon. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988; 2: 349360. 46. Roux S, Christeller S and Ldin E. Effects of aspirin on coronary reocclusion and recurrent ischemia after thrombolysis: a meta-analysis. J Am Coll Cardiol 1992; 19: 671677. 47. Anon. Collaborative overview of randomised trials of antiplatelet therapyI: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

Downloaded from dvr.sagepub.com by guest on February 13, 2012

Ferreiro et al.
categories of patients. Antiplatelet Trialists Collaboration. BMJ 1994; 308: 81106. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 7186. Mehta SR and the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Event/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS7) trial. A 2x2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients With ACS Undergoing An Early Invasive Strategy With Intent For PCI. Late breaking clinical trial. Paper presented at: European Society of Cardiology Congress; 2009 August 30September 2; Barcelona, Spain. Storey RF, Newby LJ and Heptinstall S. Effects of P2Y(1) and P2Y(12) receptor antagonists on platelet aggregation induced by different agonists in human whole blood. Platelets 2001; 12: 443447. Gachet C. ADP receptors of platelets and their inhibition. Thromb Haemost 2001; 86: 222232. Turner NA, Moake JL and McIntire LV. Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow. Blood 2001; 98: 33403345. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH and CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000; 102: 624629. Cadroy Y, Bossavy JP, Thalamas C, Sagnard L, Sakariassen K and Boneu B. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation 2000; 101: 28232828. Anon. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348: 13291339. Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W and Topol EJ. Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 2002; 90: 625628. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527533. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288: 24112420. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 16071621.

285
60. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 11791189. 61. Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 2005; 294: 12241232. 62. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354: 17061717. 63. Capranzano P, Ferreiro JL and Angiolillo DJ. Prasugrel in acute coronary syndrome patients undergoing percutaneous coronary intervention. Expert Rev Cardiovasc Ther 2009; 7: 361369. 64. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007; 116: 29232932. 65. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 20012015. 66. Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008; 371: 13531363. 67. Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation 2008; 118: 16261636. 68. Angiolillo DJ, Badimon J, Saucedo JF, et al. Comparison of Prasugel With Clopidogrel on Platelet Function in Coronary Artery Disease Patients With Type 2 Diabetes Mellitus Third Optimizing Anti-Platelet Therapy in Diabetes MellitUS (OPTIMUS-3). Circulation 2009; 120: S1027 [abstract 4946]. 69. Roffi M, Chew DP, Mukherjee D, et al. Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Gradient of benefit related to the revascularization strategy. Eur Heart J 2002; 23:14411448. 70. Roffi M, Chew DP, Mukherjee D, et al. Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes. Circulation 2001; 104: 27672771. 71. Mehilli J, Kastrati A, Schhlen H, et al. Randomized clinical trial of abciximab in diabetic patients undergoing elective

48.

49.

50.

51. 52.

53.

54.

55.

56.

57.

58.

59.

Downloaded from dvr.sagepub.com by guest on February 13, 2012

286
percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation 2004; 110: 36273635. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 2006; 295: 15311538. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001; 344: 18951903. De Luca G, Navarese E and Marino P. Risk profile and benefits from Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-regression analysis of randomized trials. Eur Heart J 2009; 30: 27052713. Rao SV, Eikelboom JA, Granger CB, Harrington RA, Califf RM and Bassand JP. Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28: 11931204. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA and Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774782. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 22032216. Feit F, Manoukian SV, Ebrahimi R, et al. Safety and efficacy of bivalirudin monotherapy in patients with diabetes mellitus and acute coronary syndromes: a report from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol 2008; 51: 16451652. Tavano D, Visconti G, DAndrea D, et al. Comparison of bivalirudin monotherapy versus unfractionated heparin plus tirofiban in patients with diabetes mellitus undergoing elective percutaneous coronary intervention. Am J Cardiol 2009; 104: 12221228. Manoukian SV. Predictors and impact of bleeding complications in percutaneous coronary intervention, acute coronary syndromes, and ST-segment elevation myocardial infarction. Am J Cardiol 2009; 104(Suppl): 9C15C. Angiolillo DJ. Variability in responsiveness to oral antiplatelet therapy. Am J Cardiol 2009; 103(Suppl): 27A34A. Michelson AD, Cattaneo M, Eikelboom JW, et al. Aspirin resistance: position paper of the Working Group on Aspirin Resistance. J Thromb Haemost 2005; 3: 13091311. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG and Huisman MV. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med 2007; 167: 15931599. Krasopoulos G, Brister SJ, Beattie WS and Buchanan MR. Aspirin resistance and risk of cardiovascular morbidity:

Diabetes and Vascular Disease Research 7(4)

systematic review and meta-analysis. BMJ 2008; 336: 195198. Gurbel PA, Bliden KP, DiChiara J, et al. Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation 2007; 115: 31563164. Frelinger AL 3rd, Furman MI, Linden MD, et al. Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance. Circulation 2006; 113: 28882896. Watala C, Golanski J, Pluta J, et al. Reduced sensitivity of platelets from type 2 diabetic patients to acetylsalicylic acid (aspirin)-its relation to metabolic control. Thromb Res 2004; 113: 101113. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention. Am J Cardiol 2006; 97: 3843. DiChiara J, Bliden KP, Tantry US, et al. The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the aspirin-induced platelet effect (ASPECT) study. Diabetes 2007; 56: 30143019. Dav G, Catalano I, Averna M, et al. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 1990; 322: 17691774. Guthikonda S, Lev EI, Patel R, et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost 2007; 5: 490496. Serebruany V, Pokov I, Kuliczkowski W, Chesebro J and Badimon J. Baseline platelet activity and response after clopidogrel in 257 diabetics among 822 patients with coronary artery disease. Thromb Haemost 2008; 100: 7682. Singla A, Antonino MJ, Bliden KP, Tantry US and Gurbel PA. The relation between platelet reactivity and glycemic control in diabetic patients with cardiovascular disease on maintenance aspirin and clopidogrel therapy. Am Heart J 2009; 158: 784.e16. Angiolillo DJ, Bernardo E, Ramrez C, et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. J Am Coll Cardiol 2006; 48: 298304. Angiolillo DJ, Bernardo E, Capodanno D, et al. Impact of chronic kidney disease on platelet function profiles in diabetes mellitus patients with coronary artery disease on dual antiplatelet therapy. J Am Coll Cardiol 2010; 55: 11391146. Dasgupta A, Steinhubl SR, Bhatt DL, et al. Clinical outcomes of patients with diabetic nephropathy randomized to clopidogrel plus aspirin versus aspirin alone (a post hoc analysis of the clopidogrel for high atherothrombotic risk and ischemic stabilization, management, and avoidance [CHARISMA] trial). Am J Cardiol 2009; 103: 13591363.

85.

72.

86.

73.

87.

74.

88.

75.

89.

76.

90.

77.

91.

78.

92.

79.

93.

80.

94.

81. 82.

95.

83.

96.

84.

Downloaded from dvr.sagepub.com by guest on February 13, 2012

Ferreiro et al.
97. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005; 293: 21262130. 98. Ferreira IA, Mocking AI, Feijge MA, et al. Platelet inhibition by insulin is absent in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol 2006; 26: 417422. 99. Li Y, Woo V and Bose R. Platelet hyperactivity and abnormal Ca(2+) homeostasis in diabetes mellitus. Am J Physiol Heart Circ Physiol 2001; 280: H1480H1489. 100. Michno A, Bielarczyk H, Paweczyk T, Jankowska-Kulawy A, Klimaszewska J and Szutowicz A. Alterations of adenine nucleotide metabolism and function of blood platelets in patients with diabetes. Diabetes 2007; 56: 462467. 101. Guthikonda S, Alviar CL, Vaduganathan M, et al. Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. J Am Coll Cardiol 2008; 52: 743749. 102. Angiolillo DJ, Shoemaker SB, Desai B, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 2007; 115: 708716. 103. Price MJ, Berger PB, Angiolillo DJ, et al. Evaluation of individualized clopidogrel therapy after drug-eluting stent implantation in patients with high residual platelet reactivity: design and rationale of the GRAVITAS trial. Am Heart J 2009; 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 inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study. Eur Heart J 2004; 25: 18451852. 105. Anon. Randomized trial of ridogrel, a combined thromboxane A2 synthase inhibitor and thromboxane A2/prostaglandin endoperoxide receptor antagonist, versus aspirin as adjunct to thrombolysis in patients with acute myocardial infarction. The Ridogrel Versus Aspirin Patency Trial (RAPT). Circulation 1994; 89: 588595. 106. Gresele P, Migliacci R, Procacci A, De Monte P and Bonizzoni E. Prevention by NCX 4016, a nitric oxidedonating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication. Thromb Haemost 2007; 97: 444450. 107. Kariyazono H, Nakamura K, Arima J, et al. Evaluation of anti-platelet aggregatory effects of aspirin, cilostazol and ramatroban on platelet-rich plasma and whole blood. Blood Coagul Fibrinolysis 2004; 15: 157167. 108. Chamorro A. TP receptor antagonism: a new concept in atherothrombosis and stroke prevention. Cerebrovasc Dis 2009; 27(Suppl 3): 2027.

287
109. Angiolillo DJ and Guzman LA. Clinical overview of promising nonthienopyridine antiplatelet agents. Am Heart J 2008; 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 Rev Cardiovasc Ther 2010; 8: 151158. 111. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/ OFFSET study. Circulation 2009; 120: 25772585. 112. Storey RF, Husted S, Harrington RA, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with 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 Med 2009; 361: 10451057. 114. Ferreiro JL, Ueno M and Angiolillo DJ. Cangrelor: a review on its mechanism of action and clinical development. Expert Rev Cardiovasc Ther 2009; 7: 11951201. 115. Storey RF, Wilcox RG and Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets 2002; 13: 407413. 116. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009; 361: 23182329. 117. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009; 361: 23302341. 118. Berger JS, Roe MT, Gibson CM, et al. Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: the Early Rapid ReversAl of platelet thromboSis with intravenous Elinogrel before PCI to optimize reperfusion in acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J 2009;158: 9981004. 119. Ueno M, Rao SV and Angiolillo DJ. Elinogrel: pharmacological principles, preclinical and early phase clinical testing. Future Cardiol 2010; 6: 445453. 120. Leonardi S, Rao SV, Harrington RA, et al. Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y(12)-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATEPCI). Am Heart J 2010; 160: 6572.

Downloaded from dvr.sagepub.com by guest on February 13, 2012

288
121. Angiolillo DJ, Capranzano P, Goto S, et al. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study. Eur Heart J 2008; 29: 22022211. 122. Douglas JS Jr, Holmes DR Jr, Kereiakes DJ, et al. Coronary stent restenosis in patients treated with cilostazol. Circulation 2005; 112: 28262832. 123. Lee SW, Park SW, Hong MK, et al. Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis. J Am Coll Cardiol 2005; 46: 18331837. 124. Han Y, Li Y, Wang S, et al. Cilostazol in addition to aspirin and clopidogrel improves long-term outcomes after percutaneous coronary intervention in patients with acute coronary syndromes: a randomized, controlled study. Am Heart J 2009; 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 percutaneous coronary intervention. Am Heart J 2008; 155: 10811089. 126. Lee SW, Park SW, Kim YH, et al. Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus the DECLARE-DIABETES Trial (A Randomized Comparison of Triple Antiplatelet Therapy with Dual Antiplatelet Therapy After Drug-Eluting

Diabetes and Vascular Disease Research 7(4)

Stent Implantation in Diabetic Patients). J Am Coll Cardiol 2008; 51: 11811187. Ueno M, Ferreiro JL and Angiolillo DJ. Mechanism of action and clinical development of platelet thrombin receptor antagonists. Expert Rev Cardiovasc Ther 2010; 8: 11911200. Angiolillo DJ, Capodanno D and Goto S. Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J 2010; 31: 1728. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing nonurgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet 2009; 373: 919928. Morrow DA, Scirica BM, Fox KA, et al. Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial. Am Heart J 2009; 158: 335341.e3. TRA*CER Executive and Steering Committees. The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA*CER) trial: study design and rationale. Am Heart J 2009; 158: 327334.e4. Wittkowsky AK. New oral anticoagulants: a practical guide for clinicians. J Thromb Thrombolysis 2010; 29: 182191.

127.

128.

129.

130.

131.

132.

Downloaded from dvr.sagepub.com by guest on February 13, 2012