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Cardiology Research and Practice
Volume 2012 (2012), Article ID 909154, 18 pages
Increased Atherothrombotic Burden in Patients with Diabetes Mellitus and Acute Coronary Syndrome: A Review of Antiplatelet Therapy
1Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
2Institute of Cellular Medicine, Newcastle University, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK
Received 1 August 2011; Accepted 23 October 2011
Academic Editor: Bernhard Witzenbichler
Copyright © 2012 Karthik Balasubramaniam et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Patients with diabetes mellitus presenting with acute coronary syndrome have a higher risk of cardiovascular complications and recurrent ischemic events when compared to nondiabetic counterparts. Different mechanisms including endothelial dysfunction, platelet hyperactivity, and abnormalities in coagulation and fibrinolysis have been implicated for this increased atherothrombotic risk. Platelets play an important role in atherogenesis and its thrombotic complications in diabetic patients with acute coronary syndrome. Hence, potent platelet inhibition is of paramount importance in order to optimise outcomes of diabetic patients with acute coronary syndrome. The aim of this paper is to provide an overview of the increased thrombotic burden in diabetes and acute coronary syndrome, the underlying pathophysiology focussing on endothelial and platelet abnormalities, currently available antiplatelet therapies, their benefits and limitations in diabetic patients, and to describe potential future therapeutic strategies to overcome these limitations.
A PubMed (Medline) search was performed using the following terms either singly or in combination: diabetes, type 2 diabetes mellitus, cardiovascular risk, hypercoagulability, prothrombotic, acute coronary syndrome, endothelial dysfunction, antiplatelet, platelet dysfunction, aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitor. All papers relevant to platelet and endothelial abnormalities in diabetes mellitus, acute coronary syndrome, and current antiplatelet therapies were considered.
Diabetes mellitus (DM) can be described as a metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defects of insulin secretion, insulin action, or a combination of both . The world prevalence of diabetes among adults (aged 20–79 years) was approximately 6.4%, affecting 285 million adults in 2010 and is predicted to rise to 7.7%, affecting 439 million adults by 2030 . Between 2010 and 2030, there will be a 69% increase in numbers of adults with diabetes in developing countries and a 20% increase in developed countries. Globally, diabetes is likely to be the fifth leading cause of death . The most prevalent form of DM is type 2 diabetes mellitus (T2DM). Insulin resistance usually precedes the onset of T2DM and is commonly accompanied by other related metabolic abnormalities such as hyperglycaemia, dyslipidaemia, hypertension, and prothrombotic factors, all of which contribute to the increased cardiovascular risk. This condition is called metabolic syndrome [4, 5].
2. Diabetes and Cardiovascular Disease (CVD)
A large body of epidemiological and pathological data, documents that diabetes is an important independent risk factor for CVD in both men and women [6–8]. The incidence of CVD, including coronary artery disease (CAD), stroke and peripheral arterial disease, is two- to four-fold, greater in diabetic patients than in the general population . The small vessel diabetes-specific conditions of nephropathy, retinopathy, and possibly neuropathy and cardiomyopathy also contribute. In patients with T2DM, CVD is responsible for about 70% of all causes of death . CVD, particularly coronary artery disease (CAD) resulting from accelerated atherosclerosis, is the leading cause of morbidity and mortality in patients with T2DM. These patients also have a higher risk of cardiovascular complications and recurrent atherothrombotic events after an index event than non-DM patients. Premenopausal women with diabetes seem to lose most of their inherent protection against developing CVD . To make matters worse, when patients with diabetes develop clinical CVD, they have a poorer prognosis than the CVD patients without diabetes [12–14]. Cardiovascular mortality in patients with DM without a history of prior MI is comparable to mortality in nondiabetic subjects with previous MI . Hence, diabetes has been classified as a coronary “risk equivalent” .
Hyperglycaemia may play an important role in increased atherothrombotic risk in DM patients. This has been supported by the Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial. In this study, acute intensive glucose lowering therapy with insulin-glucose infusion led to a reduction in mortality after 3.4 years followup in DM patients with acute myocardial infarction . However, in longstanding T2DM patients, chronic excessive glucose lowering (glycated haemoglobin <6.0%) was associated with increased mortality in the Action of Control Cardiovascular Risk in Diabetes (ACCORD) study . This was supported by ADVANCE trial and VADT trial [18, 19].
3. Diabetes and Acute Coronary Syndrome (ACS)
Diabetes not only increases the risk of myocardial infarction (MI) but also increases the mortality associated with the acute event. The presence of DM is a strong independent predictor of short-term and long-term recurrent ischaemic events, including mortality, in patients with acute coronary syndrome (ACS). Studies have demonstrated poorer outcomes among patients with diabetes following ACS. For example, the 7-year incidence of recurrent MI in a large population-based study was 45% in diabetic patients versus 19% in nondiabetic patients. Cardiovascular mortality during that period was 42.0% and 15.4% in DM patients with and without history of acute MI, respectively . The prognosis for DM patients who undergo coronary revascularisation procedures is worse than that for nondiabetic subjects ; DM patients experience more postprocedural complications and have decreased infarct-free survival . Mortality rates for DM patients with acute MI are 1.5–2.0 times those of non-DM patients. In-hospital and 6-month mortality rates after an acute MI are highest among DM patients receiving insulin therapy. The negative impact of DM on the outcomes is maintained across the ACS spectrum, including unstable angina and non-ST elevation myocardial infarction (NSTEMI) , ST elevation myocardial infarction (STEMI) treated medically , and ACS undergoing percutaneous coronary intervention (PCI) . DM patients have more progressive, diffuse, and multivessel coronary disease compared to nondiabetic patients and have poorer outcomes after both PCI (especially with bare metal stent [BMS]) and coronary artery bypass graft surgery (CABG), compared to nondiabetic patients . The advent of drug eluting stents (DES) has improved PCI outcomes but the problem of atherothrombotic complications, including stent thrombosis, persists in diabetic patients .
The majority of acute CV events are precipitated by vascular occlusion caused by atherosclerotic plaque disruption, platelet aggregation, platelet adhesion, and the resulting intravascular thrombosis. Systems that are involved in maintaining the integrity and patency of the vasculature including endothelial and platelet function, coagulation, and fibrinolysis are impaired in diabetes, thereby shifting the balance to favour thrombus formation.
4. Endothelial Dysfunction and Inflammation in Diabetes
Endothelial dysfunction (ED) plays an important role in the pathogenesis and clinical expression of atherosclerosis. It has been linked to T2DM and insulin resistance states such as obesity in experimental and clinical studies . ED refers to an impairment of the ability of the endothelium to properly maintain vascular homeostasis. This reflects a number of abnormalities that include loss of bioavailable nitric oxide (NO), increased production of vasoconstrictors, and disturbed regulation of inflammation, thrombosis, and cell growth in the vascular wall [28, 29]. The endothelium plays a key role in the regulation of blood flow and arterial tone by orchestrating the production of vasodilators such as NO, prostacyclin (PGI2) and endothelium derived hyperpolarising factor (EDHF), and vasoconstrictors including endothelin-1 (ET-1) and angiotensin II . Vasodilators oppose the effects of vasoconstrictors and act in a homeostatic fashion to maintain normal arterial compliance and patency.
The contribution of inflammation to the pathogenesis of atherosclerosis is well recognised . NO, which is produced by a family of enzymes called endothelial NO synthase (eNOS), not only causes vasodilatation but also prevents leukocyte adhesion and maintains the endothelium in a quiescent, anti-inflammatory state . In the presence of risk factors such as DM (hyperglycaemia), endothelial cells are activated to express adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) which are required for leukocyte adhesion to the endothelial surface . Endothelial expression of chemotactic factors such as monocyte chemo-attractant protein-1 and other proinflammatory cytokines like macrophage colony stimulating factor and tumour necrosis factor-beta (TNF-β) contributes to the inflammation within the vasculature and promotes atherogenesis [31, 32]. Endothelial production of prothrombotic molecules [plasminogen activator inhibitor-1 (PAI-1), thromboxane, tissue factor (TF) and von Willibrand’s factor (vWF)] is balanced by the production of antithrombotic molecules such as NO, heparins, prostacyclin, tissue plasminogen activator and thrombomodulin. Risk factors including DM shift the balance towards a prothrombotic, antifibrinolytic state (Table 1). Selective impairment of phosphoinositide-3 kinase (PI3 kinase)/Akt kinase signalling characterises insulin resistance contributing to ED in T2DM . Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) generates superoxide anion in inflammatory cells and is also involved in normal cell signalling in endothelial cells . In DM, NADPH oxidase activity and superoxide production are increased [35, 36]. This increased oxidative stress impairs NO bioavailability leading to ED. NADPH oxidase promotes the activation of the proinflammatory transcription factor [nuclear factor kappa B (NFκB)] . Angiotensin II upregulates NADPH oxidase expression, and this could be one of the reasons for angiotensin converting enzyme inhibitors (ACEIs) having favourable vascular effects in DM [38–40].
DM is associated with a systemic inflammatory state that may contribute to ED and atherosclerosis . Increased glucose and free fatty acid concentrations has been shown to activate the endothelium in various experimental studies [37, 42, 43]. Patients with DM or obesity have increased circulating levels of inflammatory markers including C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and ICAM-1 [44–47]. Furthermore, increased levels of circulating inflammatory markers predict cardiovascular risk in DM patients .
Protein kinase C beta (PKCβ) activation may also explain the link between inflammation, ED, and insulin resistance in DM . PKCs are a type of serine/threonine kinase that act at the plasma membrane in the regulation of signal transduction in various cell types. The PKCβ isoform in the endothelial cells is activated by diacylglycerol (DAG) under the conditions of increased glucose and fatty acid concentrations [50, 51]. PKCβ reduces eNOS phosphorylation/activation by inhibiting PI3 kinase and Akt and also activates NFκB [52–55]. In humans, acute treatment with a PKCβ inhibitor prevented the development of ED following glucose infusion in the forearm of healthy volunteers and improved brachial artery flow-mediated dilatation in DM patients [56, 57].
DM and insulin resistance are strongly linked to abnormalities of mitochondrial function [58–60]. DM impairs mitochondrial biogenesis, fusion, and autophagy, leading to cells with decreased mitochondrial mass and a predominance of fragmented and dysfunctional mitochondria [60, 61]. This leads to increased amounts of reactive oxygen species and decreased amounts of ATP. Impaired mitochondrial energetics leads to increased levels of DAG which activates PKCβ and this in turn impairs NO production. Recent work has demonstrated links between ED, impaired mitochondrial biogenesis, and increased mitochondrial superoxide production in arterioles isolated from patient with DM compared to healthy controls .
5. Platelets in Diabetes: “Angry Diabetic” Platelets
ACS is precipitated by the ischaemic effect of an occlusive intracoronary thrombus that develops over a ruptured atheromatous plaque as a result of platelet adhesion and aggregation . Among diabetic individuals increased platelet aggregation and adhesion are due to the following.(i)Reduced platelet membrane fluidity due to changes in the lipid composition of the membrane or glycation of membrane proteins.(ii)Increased production of thromboxane A2 (TXA2) from arachidonic acid metabolism, which increases platelet sensitivity .(iii)Increased expression of platelet adhesion molecules such as CD31, CD36, CD49b, CD62P, and CD63 (when assessed by flow cytometry) .(iv)Upregulation of platelet ADP P2Y12 receptor signalling, which suppresses cAMP levels and lowers insulin responsiveness, thereby leading to increased adhesion, aggregation and pro-coagulant activity.(v)Increased expression of platelet surface receptors such as P-selectin, Glycoprotein (GP) Ib, and GP IIb/IIIa . GP Ib mediates platelet binding to vWF, an important step in platelet dependent thrombosis, and GP IIb/IIIa binds to fibrinogen resulting in platelet cross-linking as a part of the aggregation process .(vi)Increased generation of platelet dependent thrombin.(vii)Platelets are less sensitive to the effects of PGI2 and NO .(viii)Platelets in T2DM show disordered calcium and magnesium haemostasis. Intraplatelet calcium regulates a variety of activities including platelet shape change, secretion, aggregation, and TXA2 formation [41, 69]. Increased intracellular calcium and decreased intracellular magnesium has been linked to platelet hyperaggregability and adhesiveness .(ix)Active platelets in DM patients are also rich in cytokines and chemokines such as platelet factor-4, interleukin-1β and CD40L and hence contribute to inflammation and atherogenesis alongside a procoagulant milieu [30, 71–73].(x)Accelerated platelet turnover resulting in increased reticulated platelets also contributes to platelet hyperactivity .
These characteristics may play a role not only in the higher risk of developing ACS with poorer outcomes observed in DM, but also in the large proportion of DM patients with inadequate response to antiplatelet agents compared to non-DM patients. This in itself may contribute to the poorer outcomes observed in DM patients despite compliance with the recommended secondary prevention therapy with antiplatelet agents.
6. Microparticles in Diabetes
Besides platelets, microparticles (MPs) are also involved in diabetic atherothrombosis. MPs are membrane-coated vesicles that emerge by budding from their parental cells upon activation or apoptosis . They retain at least some functions of their cells of origin, which can include platelets, endothelial cells, and various leukocytes. MPs have the ability to activate the coagulation cascade with consequent thrombosis formation . Platelet-derived MPs (PMPs) expose negatively charged phospholipids which act as binding sites for activated coagulation factors . Platelet MPs also bind to the subendothelial matrix and act as a substrate for further platelet adhesion via GP IIb/IIIa fibrinogen bridging . Resting platelets express pre-mRNA for TF, and this gets converted to mature mRNA upon platelet activation . This may allow platelets to synthesize active TF for thrombus propagation and stabilization. Monocyte-derived MPs (MMPs) exposing TF have P-selectin glycoprotein ligand-1 which interacts with P-selectin on the surface of activated platelets and help in further stabilization of thrombus . Other possible pathways regulated by MPs include production of lysophosphatidic acid (a strong platelet agonist), endothelial and leukocyte activation, recruitment of monocyte within the plaque, stimulation of neoangiogenesis, induction of apoptosis in endothelial or smooth muscle cells, and increase in TXA2 release which in turn causes vasoconstriction [80, 81]. Increased levels of platelet-derived MPs and their role in macrovascular complications have been reported in DM patients . Elevated levels of TF-positive MPs have been found to correlate with components of metabolic syndrome in patients with uncomplicated T2DM [83, 84]. Levels of PMPs and MMPs have been shown to correlate with DM complications like diabetic retinopathy, which is associated with microvascular damage . Elevated endothelial cell-derived MPs (EMPs) are predictive for the presence of coronary artery lesions, and are a more significant independent risk factor than the duration of DM, lipid levels, and history of hypertension . In patients with T2DM and ACS, elevated EMPs have been linked to noncalcified atheromatous lesions as detected by multidetector computed tomography . Increased levels of procoagulant TF-positive MPs were demonstrated within the occluded coronary artery of patients with STEMI . Insulin has been found to reduce the expression of TF in monocytes and MMPs . Beneficial effects of statins in T2DM and atherothrombosis are possibly due to its effects on MPs [90–93]. All this evidence indicates that MPs are not only a reliable marker for vascular injury but they also actively participate in promoting atherothrombotic complications in T2DM . In this context, drugs that may reduce the release of MPs and/or their thrombogenicity may have the potential to improve the effects of current antiplatelet therapy, resulting in lower adverse event rates in DM patients.
7. Platelet Leukocyte Aggregates (PLAs) in Diabetes
Platelets and leukocytes from DM patients are hyperreactive and express more adhesion molecules. P-selectin is one of the markers of platelet activation and is the main link for platelet adhesion to circulating leukocytes . Platelet P-selectin interacts with leukocyte P-selectin glycoprotein ligand (PSGL-1) leading to the formation of PLA [95, 96]. Consequently, activated leukocytes secrete several pro-inflammatory cytokines and express a prothrombotic membrane phenotype. Elevated levels of circulating PLA have been reported in various prothrombotic states including DM thereby suggesting their involvement in the pathogenesis of atherothrombosis. Elevated circulating PLA levels were found to be linked with vascular injury in DM patients . A significant increase in circulating platelet-polymophonuclear aggregates (PPA) and platelet-monocyte aggregates (PMAs) percentages was demonstrated in DM patients . Interestingly, percentages of circulating PPA, and PMA were significantly higher in DM with vascular injury compared to DM without vascular injury suggesting the involvement of inflammatory leukocytes in vascular damage [97, 98]. Increased circulating PMA percentage was found to be more specifically a marker of diabetic microretinopathy . This reinforces the fact that pro-inflammatory cells are involved in microvascular complications in DM and atherothrombotic process. Circulating PLA determination using flow cytometry may be used as a simple marker of microvascular injury in DM patients.
8. Coagulation in Diabetes
Tissue Factor and Factor VII (F VII) initiate the thrombotic process, resulting in the generation of thrombin. This subsequently helps in the conversion of fibrinogen into a three-dimensional network of fibrin fibres which forms the skeleton of the blood clot . TF is an integral prothrombotic transmembrane protein expressed by both vascular and nonvascular cells, including monocytes, macrophages, and platelets . In T2DM, TF expression is upregulated due to the presence of low-grade inflammation . Levels of TF in atherosclerotic plaques in patients with unstable angina are higher compared with those who have stable angina . Plasma TF levels are raised in subjects with CAD particularly ACS further emphasising the role of TF in atherothrombosis [102, 103]. Patients with T2DM have higher circulating TF levels which are directly modulated by glucose and insulin, and the two appear to have an additive effect  (Table 2). In T2DM, increased levels of advanced glycation end products and reactive oxygen species activate NFκB which in turn leads to increased TF production .
F VII is a vitamin K dependent coagulation factor synthesised in the liver. F VII coagulant activity (F VII: c) has been associated with fatal cardiovascular events [105–107]. T2DM subjects have elevated F VII:c levels . An association between triglyceride levels and F VII:c levels has been demonstrated; this appears to be independent of obesity and insulin resistance .
Thrombin concentration influences fibrin clot formation and also determines the clot structure and stability . High thrombin concentration results in denser and less permeable clots which are more resistant to lysis. Thrombin generation is enhanced in DM secondary to low-grade coagulation system activation [104, 111].
Plasma fibrinogen is a well known independent CVD risk factor and is used as a surrogate marker for CVD risk . High fibrinogen levels predict silent myocardial ischaemia in T2DM patients . High levels of IL-6 in diabetes stimulate fibrinogen synthesis by the hepatocytes, representing a link between inflammation and the prothrombotic state . Insulin resistance is also associated with increased hepatocyte fibrinogen synthesis [115, 116].
9. Fibrinolysis in Diabetes
Fibrinolysis is initiated by the conversion of plasminogen to plasmin, and this is largely mediated by tissue plasminogen activator (tPA). Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of fibrinolysis by binding to tPA and forming PAI-1/tPA complex. In a long-term 18-year study, glycated haemoglobin (HbA1C) correlated positively with PAI-1 and negatively with tPA. This implicates hyperglycaemia as a reason for elevated PAI-1 levels . Hyperinsulinaemia also has been shown to increase PAI-1 levels, which may account for elevated PAI-1 levels in insulin-resistant states [118, 119] (Table 2).
A study indicated that clots derived from plasma purified fibrinogen in 150 diabetic subjects had a more compact structure characterised by smaller pore size, increased fibrin thickness, and number of branch points than that from 50 healthy controls . Clot lysis from diabetic patients was slower when compared to controls due to elevated PAI-1 levels.
10. Platelet Dependent Thrombus Formation
Arterial injury models which simulate in vivo coronary artery rheology have been used in various experimental studies to measure platelet-dependent thrombus formation. These provide a measure of actual thrombus which is the end point of all haemostatic functions. Work from our laboratory using the arterial injury model demonstrated increased blood thrombogenicity and platelet dependent thrombus formation in patients with T2DM and CAD, compared to patients with T2DM without CAD and nondiabetic controls, despite being on aspirin and other evidence based risk factor therapy (Figure 1) [121, 122]. An improvement in blood thrombogenicity in diabetic subjects with improved glycaemic control has been shown . In another study, we compared blood thrombogenicity and clot kinetics in 30 T2DM and 30 nondiabetic patients, one week after troponin positive non-ST elevation ACS (NSTE-ACS). In patients with T2DM, the thrombus was increased in quantity [area of thrombus: mean (SD) [16824.0(3619.1) versus 14413.9(4648.5) μ2/mm, ], weaker in tensile strength [clot index: median (range) 0.4 (−3.3 to 4.2) versus 1.6 (−1.5to 5.4), ] and more importantly resistant to clot retraction [clot lysis: median (range) 27.7 (3.8–83.4) versus 73.7 (55–191) mm/min, . This was despite the participants being prescribed currently recommended secondary prevention therapy including aspirin and clopidogrel, after a NSTE-ACS . These findings may partly explain the reason for reduced benefits of current antiplatelet therapy in patients with diabetes .
11. Antiplatelet Therapies in Diabetes
A clear benefit of antiplatelet agents in the prevention of atherothrombotic events in those at high risk is well established. Multiple genetic, iatrogenic, and environmental factors influence platelet responsiveness to these agents. Three different classes of antiplatelet agents are approved for treatment and/or prevention of ACS: cyclooxygenase-1 (COX-1) inhibitors (aspirin), ADP P2Y12 receptor antagonists (thienopyridines), and platelet GP IIb/IIIa inhibitors [126, 127] (Figure 2).
Aspirin selectively acetylates the COX-1 enzyme, thereby blocking TXA2 synthesis in platelets. This effect is irreversible since the platelets are enucleate and, therefore, unable to resynthesise COX-1. Aspirin use for primary prevention in DM patients has been controversial [129–131], but ongoing studies including 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 insight into this area. Aspirin, however, remains the antiplatelet agent of choice for secondary prevention of recurrent ischaemic events in patients with atherothrombotic disease including those with DM [126, 127, 132–134]. Benefits of aspirin in the early management of ACS patients including unstable angina/NSTEMI [135–137] and STEMI [138, 139] have been demonstrated consistently in various studies. Aspirin should be given as early as possible at an initial dose of 162 to 325 mg followed by a daily maintenance dose of 75 to 162 mg [126, 127]. The recommended dose of aspirin for secondary prevention in DM patients with atherothrombotic disease is 75 to 162 mg . Withdrawal of aspirin can lead to recurrence of ACS . Two large meta-analysis trials performed by the Antiplatelet Trialists’ Collaboration included 287 studies and involved 212000 high-risk patients (with acute or previous vascular disease or other predisposing condition increasing the risk of occlusive vascular disease) [141, 142]. Aspirin was the frequently used antiplatelet agent at doses ranging from 75 to 325 mg daily in these trials. The incidence of vascular events on aspirin was reduced from 22.3% to 18.5% in DM cohort () and from 16.4% to 12.8% () in non-DM cohort. The incidence of vascular events was much higher in DM patients but the benefit of antiplatelet therapy was consistent regardless of the DM status . Low-dose aspirin (75 to 150 mg) was as effective as higher daily doses but with significantly lower bleeding complications [141, 142]. The Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organisation to Assess Strategies in Ischaemic Syndromes (CURRENT/OASIS-7) trial is the first large-scale randomised study comparing high- and low-dose aspirin. This study randomised ACS patients who were scheduled to undergo angiography within 72 hours of hospital arrival [143, 144]. With a factorial design, patients were randomised (double blinded) to high or standard dose clopidogrel for a month and in open label fashion to high-dose (300 to 325 mg daily) or low-dose (75 to 100 mg daily) aspirin. There was no significant difference in the rates of the primary outcome (cardiovascular death, MI or stroke after 30 days) between high and low dose aspirin (4.1% versus 4.2%; hazard ratio [HR] = 0.98; ) in DM and non-DM patients. A trend towards higher gastrointestinal bleeding rates (0.38% versus 0.24%; ) in the high dose group was observed .
13. P2Y12 Receptor Antagonists
Platelet ADP signalling pathways mediated by P2Y1 and P2Y12 play an important role in platelet activation and aggregation. P2Y12 activation leads to sustained platelet aggregation and stabilisation of the aggregated platelets [145, 146]. Thienopyridines (Ticlopidine, Clopidogrel,8 and Prasugrel) which are nondirect, irreversible P2Y12 antagonists are currently approved for clinical use.
Ticlopidine was the first thienopyridine that was approved for clinical use in 1991. Ticlopidine in combination with aspirin was superior to aspirin alone or anticoagulation with aspirin in various clinical trials for the prevention of recurrent ischaemic events in patients undergoing PCI [147–150]. Ticlopidine (high rates of neutropenia) was largely replaced by clopidogrel (a second generation thienopyridine) due to its better safety profile .
Clopidogrel is the most widely used thienopyridine and has a faster onset of action through the administration of a loading dose . The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial compared the efficacy of clopidogrel (75 mg/day) and aspirin (325 mg/day) in reducing the risk of ischaemic outcomes in patients ( 185) with recent MI, recent ischaemic stroke, or established peripheral arterial disease. The results showed a significantly low annual rate of ischaemic events (ischaemic stroke, MI, or vascular death) in patients who received clopidogrel (5.32% versus 5.83%; ) . DM subgroup had a significantly higher benefit (15.6% versus 17.7%; ). For every 1000 DM patients treated with clopidogrel, 21 vascular events were prevented .
Several large scale trials have shown, clear benefit of clopidogrel in addition to aspirin in preventing recurrent ischaemic events, including stent thrombosis in the setting of ACS (including unstable angina/NSTEMI, STEMI, PCI), compared to aspirin alone [22, 155–159] (Table 3). Current guidelines recommend dual antiplatelet therapy with aspirin and clopidogrel for patients with ACS, including unstable angina/NSTEMI, STEMI, and patients undergoing PCI [126, 127, 134]. The recommended clopidogrel dose is 300 mg loading dose (up to 600 mg in PCI setting) followed by a maintenance dose of 75 mg daily. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial found no benefit of dual aspirin and clopidogrel therapy in the long-term in a wide range of non-ACS patients () with risk factors for, and established atherothrombotic disease including DM patients (; 42% of the study population) . Hence, dual antiplatelet therapy is not recommended even in DM patients outside ACS/PCI setting.
In the CURRENT/OASIS-7 trial, high-dose clopidogrel regimen (600 mg loading dose, then 150 mg/day for 7 days followed by 75 mg daily) significantly reduced the rates of cardiovascular death, MI, or stroke at 30 days (3.9% versus 4.5%; HR = 0.85; ) as well as the risk of stent thrombosis (0.7% versus 1.3%; HR = 0.54; ) in a subgroup of patients who underwent PCI () . But among DM patients, rates of the primary outcome were not significantly different with high and standard dose clopidogrel (4.9% versus 5.6%; HR = 0.89; 95% confidence interval [CI], 0.66 to 1.15; ) .
Prasugrel is a third generation thienopyridine that was recently approved for clinical use in ACS patients undergoing PCI. It is an orally administered, prodrug that requires hepatic metabolism to be converted to its active metabolite that irreversibly inhibits the P2Y12 receptor . Prasugrel has a more rapid onset of action than clopidogrel with greater platelet inhibition because it is converted to its active metabolite more effectively . The TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN With prasugrel-Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) examined the efficacy and safety of Prasugrel (60 mg loading dose followed by 10 mg daily) versus clopidogrel (300 mg loading dose followed by 75 mg daily) in patients () with ACS undergoing PCI . A significant reduction in the rates of primary end point (consisting of cardiovascular death, nonfatal MI or nonfatal stroke) favouring prasugrel (9.9% versus 12.1%; HR = 0.81; ) was found. Reduction in the rates of stent thrombosis over a follow-up period of 15 months was also found in the prasugrel treated group, but with increased risk of major bleeding . The subgroups of patients with DM or with STEMI had a higher beneficial effect. In DM patients, the risk of primary end point was reduced significantly with prasugrel (12.2% versus 17%; HR = 0.70; ). Prasugrel also improved the risk of stent thrombosis in DM subgroup (all DM patients: 2.0% versus 3.6%; HR = 0.52; ; insulin treated patients: 1.8% versus 5.7%; HR = 0.31; ) . Major bleeding was higher in DM patients over all but there was no difference among DM patients treated with either prasugrel or clopidogrel (2.6% versus 2.5%; HR = 1.06; ).
The Optimizing antiplatelet Therapy in diabetes MellitUS-3 (OPTIMUS-3) study showed that prasugrel (60 mg loading dose followed by 10 mg/day maintenance dose) achieved significantly greater platelet inhibition compared to double dose clopidogrel (600 mg loading dose followed by 150 mg/day maintenance dose) in DM patients with CAD. Verify Now P2Y12 assay demonstrated more effective platelet inhibition with prasugrel compared to clopidogrel, 4 hours after the loading dose (least squares mean, 89.3% versus 27.7%; ). This difference in platelet inhibition remained significant up to 7 days after dosing [166–168]. Higher platelet inhibition in DM patients results in greater clinical benefit as suggested by all the above observations. The clinical efficacy of prasugrel when compared to clopidogrel in medically managed patients with unstable angina/NSTEMI is being evaluated in the ongoing TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndrome (TRILOGY ACS) trial.
Ticagrelor is an orally administered, direct reversible P2Y12 inhibitor which achieves higher platelet aggregation inhibition compared to clopidogrel in ACS patients . The PLATelet inhibition and patient Outcomes (PLATO) trial compared ticagrelor (180 mg loading dose followed by 90 mg twice daily) with clopidogrel (300 to 600 mg loading dose followed by 75 mg daily) in preventing cardiovascular events in ACS patients (). The rate of primary end point (death resulting from MI or stroke) at 12 months decreased significantly in patients treated with ticagrelor (10.2% versus 12.3%; HR = 0.84; ). In the PCI subgroup the rate of CV death and stent thrombosis reduced significantly. Ticagrelor was not associated with an increase in protocol defined major bleeding. In DM patients, ticagrelor reduced the rates of the primary end point (HR = 0.88), all cause mortality (HR = 0.82) and stent thrombosis (HR = 0.65) compared to clopidogrel. Similar benefits were seen in patients with or without insulin treatment. Bleeding rates were similar (HR = 0.98) in ticagrelor and clopidogrel treated DM patients. Side effects reported included dyspnoea, ventricular pauses, and increase in creatinine and uric acid levels [170, 171]. Ticagrelor has been approved for use in Europe but not yet approved for clinical use by the FDA.
14. GP IIb/IIIa Inhibitors
Three different GP IIb/IIIa inhibitors (abciximab, tirofiban and eptifibatide) are currently approved for clinical use. All these agents can be administered only intravenously, and hence their use is limited to acute settings. A meta-analysis of 6 large clinical trials evaluating the effect of GP IIb/IIIa inhibitors in ACS patients showed a 22% reduction of mortality at 30 days in DM patients () who received GP IIb/IIIa inhibitor compared to those who did not (4.6% versus 6.2%; ). Non-DM patients () had no survival benefit . The benefit was greater among the DM patients who underwent PCI during index hospitalisation (, 1.2% versus 4%; ). Unfortunately, these trials were performed using ticlopidine or standard dose clopidogrel instead of the high loading dose of clopidogrel. A high loading dose of clopidogrel has a more potent antiplatelet effect and is the current recommendation for ACS patients who undergo PCI.
A recent study, the Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) trial, compared the effect of abciximab and placebo on the 1-year risk of death and MI in DM patients () who underwent elective PCI after pretreatment with 600 mg loading dose of clopidogrel at least 2 hours before the procedure . There was no beneficial effect from abciximab in this study, suggesting that routine use of GP IIb/IIIa inhibitor in elective PCI (non-ACS setting) is not recommended.
In the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatement-2 (ISAR-REACT 2); trial, abciximab was shown to be significantly beneficial in patients with high-risk ACS undergoing PCI after pretreatment with 600 mg of clopidogrel . These trials support the use of GP IIb/IIIa inhibitors in high-risk ACS patients, including DM patients as recommended in the current guidelines .
A meta-regression analysis of randomised trials evaluated the effect of GP IIb/IIIa inhibitors in STEMI patients treated with primary PCI. These agents showed benefit in terms of death but not re-infarction in high risk patients including DM patients . The major limitation of GP IIb/IIIa inhibitors is the increased risk of bleeding, and it is well known that bleeding has a significant impact on prognosis after an ACS, including mortality [176, 177].
15. Direct Thrombin Inhibitors
Bivalirudin, a direct thrombin inhibitor, provided similar protection from ischaemic events as GP IIb/IIIa inhibitors, but with lower bleeding rates in the Acute Catheterisation and Urgent Intervention Triage strategY (ACUITY) trial . In a subgroup analysis in DM patients, rates of primary end point (death, MI or unplanned ischaemic revascularisation) were similar on bivalirudin monotherapy and GP IIb/IIIa inhibitor plus heparin treatment (7.9% versus 8.9%; ). The rate of major bleeding was significantly lower in the bivalirudin group (3.7% versus 7.1%; ). This bleeding risk reduction is particularly important because the risk of bleeding complications is increased in diabetic patients with ACS undergoing PCI .
16. Antiplatelet Drug Resistance in Diabetes
“Resistance” means that the antiplatelet agent fails to block its specific target (e.g., aspirin to block the COX-1 enzyme and clopidogrel to block the P2Y12 receptor) . Aspirin resistance is associated with a higher risk of recurrent ischaemic events [181, 182]. COX-1-specific tests (urine thromboxane and assays using arachidonic acid as an agonist) and non-COX-1-specific tests are available. Poor patient compliance is the main reason for aspirin resistance when a COX-1-specific test is used . DM patients respond inadequately to aspirin when assessed by non-COX-1-specific tests [184, 185]. In the Aspirin-Induced Platelet Effect (ASPECT) study, a subanalysis showed that aspirin resistance was common in DM patients while on a low dose (81 mg daily). Increasing the aspirin dose (162 and 325 mg daily) significantly reduced the platelet activity . There has been no study designed to date to assess the implications of aspirin resistance in DM patients with ACS. Hyperglycaemia, increased TXA2 synthesis, increased platelet turnover, and TXA2 receptor (TP receptor) activation have all been proposed to play a key role in aspirin resistance in DM patients [187, 188].
Genetic, cellular, and clinical mechanisms contribute to inadequate clopidogrel responsiveness [189, 190]. DM is an important factor contributing to decreased clopidogrel effects. DM patients show lower response to clopidogrel both in the loading phase and in the maintenance phase when compared to non-DM patients [184, 191, 192]. DM patients who are on insulin have the highest degree of platelet reactivity while on dual antiplatelet therapy . Chronic kidney disease in DM patients has been associated with impaired clopidogrel response . All these findings suggest why DM is associated with higher risk of recurrent ischaemic events in patients with ACS  and is a strong predictor of stent thrombosis [195–197].
17. Future Treatment Options in Diabetic Patients with ACS
Persistent high platelet activity in DM patients despite current recommended antiplatelet therapy has raised interest in identifying strategies to optimise platelet inhibition in this high-risk population.
18. Dose Modification of Antiplatelet Agents
The OPTIMUS study showed marked improvement in platelet inhibition when 150 mg maintenance dose of clopidogrel was used in DM patients with CAD . In the Gauging Responsiveness with A VerifyNow Assay-Impact On Thrombosis And Safety (GRAVITAS) trial, high clopidogrel dose (600 mg loading dose followed by 150 mg daily maintenance dose for 6 months) was given to patients with inadequate response to standard clopidogrel dose. At six months of followup, the composite end point of cardiovascular death/MI/stent thrombosis was identical in both groups, at 2.3% (HR = 1.01; 95% CI, 0.58–1.76; ). Stent thrombosis occurred in 0.5% of the high-dose group and 0.7% of the standard-dose group, a nonsignificant difference. There was also no difference in bleeding . So there is no evidence that increase in the dose clopidogrel will improve the outcomes in patients with T2DM.
19. Newer Agents
Picotamide is an inhibitor of both TXA2 synthase and TP receptor. Increased platelet turnover in DM generates new platelets that have not been exposed to aspirin and hence continue to generate TXA2. Therefore, TP receptors may remain activated despite COX-1 inhibition, contributing to aspirin hyporesponsiveness. This suggests that TP antagonism may potentially be the future antiplatelet target for new pharmacological agents . The Drug evaluation in Atherosclerotic Vascular disease In Diabetics (DAVID) trial compared picotamide with aspirin in DM patients with peripheral arterial disease. The 2-year overall mortality was significantly lower among those treated with picotamide compared to those receiving aspirin (3.0% versus 5.5%; P=0.0474) . Other newer agents such as ridogrel (TXA2 synthase inhibitor and TP receptor blocker), NCX 4016 (NO-releasing aspirin derivative) and terutroban (TP receptor inhibitor) have been compared with aspirin in different studies and might be of interest in the future in DM patients [201–204].
This is an intravenous, direct acting and reversible P2Y12 receptor inhibitor . Phase II trials showed cangrelor to be a potent antiplatelet agent achieving a greater degree of platelet inhibition (>90%) with extremely rapid onset and offset of action . However, the Cangrelor versus Standard Therapy to Achieve Optimum Management of Platelet Inhibition (CHAMPION) study failed to show any superiority of cangrelor over clopidogrel [207, 208].
This is a phosphodiesterase III (PDE III) inhibitor that increases intraplatelet cAMP concentration. This drug may be considered in the maintenance phase of therapy along with standard dual antiplatelet therapy. A reduction in the rate of target lesion revascularisation and in-stent thrombosis has been observed in patients undergoing PCI, with this triple therapy [163, 209]. The benefit is greater in DM patients [210, 211]. The OPTIMUS-2 study also demonstrated markedly increased inhibition of platelet P2Y12 signalling in DM patients who received Cilostazol in combination with dual antiplatelet therapy . Cilostazol in addition to aspirin and clopidogrel improved long-term outcomes after PCI in patients with ACS. In this study, ACS patients () were randomised to either standard dual antiplatelet therapy or triple therapy with addition of Cilostazol for 6 months after a successful PCI. The triple therapy group had a significantly lower incidence (10.3% versus 15.1%; HR = 0.65; ) of the primary end point (cardiac death, nonfatal MI, stroke, or target vessel revascularisation at 1 year after randomisation) . No significant differences were noted in the risks for major and minor bleeding. The use, however, is limited by the side effects that include headache, palpitations, and gastrointestinal disturbances.
19.4. Thrombin Receptor Antagonists
Thrombin is an important link in the coagulation cascade and is a potent agonist of platelet aggregation. Generation of thrombin is enhanced in DM patients and hence is a potential target for treatment. Two oral thrombin receptor antagonists are in clinical development, vorapaxar, and atopaxar . Vorapaxar had an excellent safety profile when used concomitantly with aspirin and clopidogrel in a large phase II study . Two large-scale phase III trials were conducted to evaluate the safety and efficacy of vorapaxar, the Trial to Assess the Effects of vorapaxar in Preventing Heart Attack and Stroke in Patients with Atherosclerosis (TRA-2P) in atherosclerosis patients and the Trial to Assess the Effects of vorapaxar in Preventing Heart Attack and Stroke in patients with ACS (TRACER) in ACS patients. An increase in intracranial haemorrhage in patients with stroke was observed in these trials. Hence TRACER trial was discontinued earlier this year and the accumulated data are yet to be presented. In TRA-2P trial, the study drug is being given only to patients with MI and peripheral vascular disease. The study drug has been withdrawn or not being given to those with a history of stroke or who have suffered a stroke during the course of the trial. Atopaxar has also shown promising results from phase II trial . Further studies with these agents will provide an insight in to their use in the future.
20. Newer Oral Anticoagulants
In DM patients, the enhanced atherothrombotic risk is not only due to platelet reactivity but also due to dysregulation of coagulation processes. These include increased plasma coagulation factors (Factor VII and thrombin), TF, PAI-1, and decreased endogenous anticoagulants (Protein C and thrombomodulin). Several new oral anticoagulants, including antifactor IIa (Dabigatran) and antifactor Xa (Rivaroxaban, apixaban) agents, are currently being tested for long-term use in ACS patients as an adjunct to dual antiplatelet therapy, in which DM patients represent a cohort of special interest [216, 217].
21. Management of Endothelial Dysfunction in DM
In spite of the predominant role played by oxidative stress in DM and atherosclerosis, antioxidant therapy had no benefit in large randomised control trials [218–220]. ACEIs and angiotensin receptor blockers (ARB’s) decrease superoxide production by NADPH oxidase and hence are beneficial in DM patients. Statin therapy improves endothelial function, reduces free radical production, and inhibits proinflammatory mechanisms in DM patients. Practical methods to monitor endothelial function in DM patients and to help in optimising therapy accordingly might be useful in the future.
22. Further Clinical Studies in DM
Anti-inflammatory drugs, PKCβ inhibitors, and NFκB inhibitors appear to hold great promise and clinical studies using these agents are in progress. Preliminary work on drugs that have favourable effects on mitochondrial function (mitochondrial superoxide production, biogenesis, dynamics, and autophagy) has been promising.
DM patients have increased atherothrombotic risk and recurrent ischaemic events following acute coronary syndrome and PCI despite being on currently recommended dual antiplatelet therapy, when compared to the nondiabetic population. This may partly be due to abnormal endothelial function, abnormal platelet haemostasis resulting in platelet hyperactivity, and dysregulation in the coagulation processes. GP IIb/IIIa inhibitors and bivalirudin have shown to improve acute outcomes in DM patients with ACS. Current dual antiplatelet therapy has proved successful in improving the outcomes in DM patients with ACS and remains the main stay of treatment for long-term secondary prevention and reduction of stent thrombosis. However, in the presence of DM, platelet activity and recurrent thrombotic events remain significantly high in spite of the currently recommended antiplatelet and antithrombotic therapies. Therefore, more potent antithrombotic therapies are warranted for this group of high risk patients. Clinical studies with novel therapies may provide important treatment alternatives in the future to tackle this thrombotic burden.
- R. A. DeFronzo, International Textbook of Diabetes Mellitus, Wiley Reference Series in Biostatistics, John Wiley & Sons, Chichester, UK, 3rd edition, 2004.
- J. E. Shaw, R. A. Sicree, and P. Z. Zimmet, “Global estimates of the prevalence of diabetes for 2010 and 2030,” Diabetes Research and Clinical Practice, vol. 87, no. 1, pp. 4–14, 2010.
- G. Roglic, N. Unwin, P. H. Bennett et al., “The burden of mortality attributable to diabetes: realistic estimates for the year 2000,” Diabetes Care, vol. 28, no. 9, pp. 2130–2135, 2005.
- P. N. Hopkins, S. C. Hunt, L. L. Wu, G. H. Williams, and R. R. Williams, “Hypertension, dyslipidemia, and insulin resistance: links in a chain or spokes on a wheel?” Current Opinion in Lipidology, vol. 7, no. 4, pp. 241–253, 1996.
- R. S. Gray, R. R. Fabsitz, L. D. Cowan, E. T. Lee, B. V. Howard, and P. J. Savage, “Risk factor clustering in the insulin resistance syndrome. The Strong Heart Study,” American Journal of Epidemiology, vol. 148, no. 9, pp. 869–878, 1998.
- P. W. F. Wilson, R. B. D'Agostino, D. Levy, A. M. Belanger, H. Silbershatz, and W. B. Kannel, “Prediction of coronary heart disease using risk factor categories,” Circulation, vol. 97, no. 18, pp. 1837–1847, 1998.
- P. W. F. Wilson, “Diabetes mellitus and coronary heart disease,” American Journal of Kidney Diseases, vol. 32, no. 5, supplement 3, pp. S89–S100, 1998.
- H. C. McGill Jr. and C. A. McMahan, “Determinants of atherosclerosis in the young. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group,” The American Journal of Cardiology, vol. 82, no. 10B, pp. 30T–36T, 1998.
- S. M. Haffner, S. Lehto, T. Rönnemaa, K. Pyörälä, and M. Laakso, “Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction,” The New England Journal of Medicine, vol. 339, no. 4, pp. 229–234, 1998.
- M. Laakso, “Hyperglycemia and cardiovascular disease in type 2 diabetes,” Diabetes, vol. 48, no. 5, pp. 937–942, 1999.
- V. Brezinka and I. Padmos, “Coronary heart disease risk factors in women,” European Heart Journal, vol. 15, no. 11, pp. 1571–1584, 1994.
- P. H. Stone, J. E. Muller, T. Hartwell et al., “The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. The MILIS Study Group,” Journal of the American College of Cardiology, vol. 14, no. 1, pp. 49–57, 1989.
- D. E. Singer, A. W. Moulton, and D. M. Nathan, “Diabetic myocardial infarction: interaction of diabetes with other preinfarction risk factors,” Diabetes, vol. 38, no. 3, pp. 350–357, 1989.
- J. W. Smith, F. I. Marcus, and R. Serokman, “Prognosis of patients with diabetes mellitus after acute myocardial infarction,” The American Journal of Cardiology, vol. 54, no. 7, pp. 718–721, 1984.
- “Third report of the National Cholestrol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholestrol in adults (adult treatment panel III) final report,” Circulation, vol. 106, pp. 3143–3421, 2002.
- K. Malmberg, “Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group,” British Medical Journal, vol. 314, no. 7093, pp. 1512–1515, 1997.
- H. C. Gerstein, M. E. Miller, R. P. Byington, et al., “Effects of intensive glucose lowering in type 2 diabetes,” The New England Journal of Medicine, vol. 358, no. 24, pp. 2545–2559, 2008.
- A. Patel, S. MacMahon, J. Chalmers et al., “Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes,” The New England Journal of Medicine, vol. 358, no. 24, pp. 2560–2572, 2008.
- W. Duckworth, C. Abraira, T. Moritz et al., “Glucose control and vascular complications in veterans with type 2 diabetes,” The New England Journal of Medicine, vol. 360, no. 2, pp. 129–139, 2009.
- K. E. Kip, D. P. Faxon, K. M. Detre, W. Yeh, S. F. Kelsey, and J. W. Currier, “Coronary angioplasty in diabetic patients. The National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry,” Circulation, vol. 94, no. 8, pp. 1818–1825, 1996.
- B. Stein, W. S. Weintraub, S. S. P. Gebhart et al., “Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty,” Circulation, vol. 91, no. 4, pp. 979–989, 1995.
- S. Yusuf, F. Zhao, S. R. Mehta, S. Chrolavicius, G. Tognoni, and K. K. Fox, “Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation,” The New England Journal of Medicine, vol. 345, no. 7, pp. 494–502, 2001.
- K.-H. Mak, D. J. Moliterno, C. B. Granger 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,” Journal of the American College of Cardiology, vol. 30, no. 1, pp. 171–179, 1997.
- M. Roffi and E. J. Topol, “Percutaneous coronary intervention in diabetic patients with non-ST-segment elevation acute coronary syndromes,” European Heart Journal, vol. 25, no. 3, pp. 190–198, 2004.
- J. D. Flaherty and C. J. Davidson, “Diabetes and coronary revascularization,” The Journal of the American Medical Association, vol. 293, no. 12, pp. 1501–1508, 2005.
- C. Cola, S. Brugaletta, V. M. Yuste, B. Campos, D. J. Angiolillo, and M. Sabaté, “Diabetes mellitus: a prothrombotic state implications for outcomes after coronary revascularization,” Vascular Health and Risk Management, vol. 5, pp. 101–119, 2009.
- M. A. Creager, T. F. Lüscher, F. Cosentino, and J. A. Beckman, “Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I,” Circulation, vol. 108, no. 12, pp. 1527–1532, 2003.
- M. E. Widlansky, N. Gokce, J. F. Keaney Jr., and J. A. Vita, “The clinical implications of endothelial dysfunction,” Journal of the American College of Cardiology, vol. 42, no. 7, pp. 1149–1160, 2003.
- J. A. Vita and J. F. Keaney Jr., “Endothelial function: a barometer for cardiovascular risk?” Circulation, vol. 106, no. 6, pp. 640–642, 2002.
- R. Ross, “Atherosclerosis—an inflammatory disease,” The New England Journal of Medicine, vol. 340, no. 2, pp. 115–126, 1999.
- P. Libby, P. M. Ridker, and A. Maseri, “Inflammation and atherosclerosis,” Circulation, vol. 105, no. 9, pp. 1135–1143, 2002.
- H. Li, M. I. Cybulsky, M. A. Gimbrone Jr., and P. Libby, “An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium,” Arteriosclerosis & Thrombosis, vol. 13, no. 2, pp. 197–204, 1993.
- S. B. Wheatcroft, I. L. Williams, A. M. Shah, and M. T. Kearney, “Pathophysiological implications of insulin resistance on vascular endothelial function,” Diabetic Medicine, vol. 20, no. 4, pp. 255–268, 2003.
- R. Stocker and J. F. Keaney Jr., “Role of oxidative modifications in atherosclerosis,” Physiological Reviews, vol. 84, no. 4, pp. 1381–1478, 2004.
- A. San Martín, P. Du, A. Dikalova et al., “Reactive oxygen species-selective regulation of aortic inflammatory gene expression in type 2 diabetes,” American Journal of Physiology, vol. 292, no. 5, pp. H2073–H2082, 2007.
- L. Gao and G. E. Mann, “Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling,” Cardiovascular Research, vol. 82, no. 1, pp. 9–20, 2009.
- E. Maloney, I. R. Sweet, D. M. Hockenbery et al., “Activation of NF-κB by palmitate in endothelial cells: a key role for NADPH oxidase-derived superoxide in response to TLR4 activation,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 9, pp. 1370–1375, 2009.
- S. Rajagopalan and D. G. Harrison, “Reversing endothelial dysfunction with ACE inhibitors: a new trend,” Circulation, vol. 94, no. 3, pp. 240–243, 1996.
- E. J. Henriksen, “Improvement of insulin sensitivity by antagonism of the renin-angiotensin system,” American Journal of Physiology, vol. 293, no. 3, pp. R974–R980, 2007.
- J. H. Oak and H. Cai, “Attenuation of angiotensin II signaling recouples eNOS and inhibits nonendothelial NOX activity in diabetic mice,” Diabetes, vol. 56, no. 1, pp. 118–126, 2007.
- J. A. Beckman, M. A. Creager, and P. Libby, “Diabetes and atherosclerosis epidemiology, pathophysiology, and management,” The Journal of the American Medical Association, vol. 287, no. 19, pp. 2570–2581, 2002.
- G. M. Pieper and H. Riaz ul, “Activation of nuclear factor-κB in cultured endothelial cells by increased glucose concentration: prevention by calphostin C,” Journal of Cardiovascular Pharmacology, vol. 30, no. 4, pp. 528–532, 1997.
- R. Piga, Y. Naito, S. Kokura, O. Handa, and T. Yoshikawa, “Short-term high glucose exposure induces monocyte-endothelial cells adhesion and transmigration by increasing VCAM-1 and MCP-1 expression in human aortic endothelial cells,” Atherosclerosis, vol. 193, no. 2, pp. 328–334, 2007.
- J. F. Keaney Jr., J. M. Massaro, M. G. Larson et al., “Heritability and correlates of intercellular adhesion molecule-1 in the Framingham Offspring Study,” Journal of the American College of Cardiology, vol. 44, no. 1, pp. 168–173, 2004.
- A. Festa, R. D'Agostino Jr., G. Howard, L. Mykkänen, R. P. Tracy, and S. M. Haffner, “Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS),” Circulation, vol. 102, no. 1, pp. 42–47, 2000.
- P. Dandona, R. Weinstock, K. Thusu, E. Abdel-Rahman, A. Aljada, and T. Wadden, “Tumor necrosis factor-α in sera of obese patients: fall with weight loss,” The Journal of Clinical Endocrinology & Metabolism, vol. 83, no. 8, pp. 2907–2910, 1998.
- B. Vozarova, C. Weyer, K. Hanson, P. A. Tataranni, C. Bogardus, and R. E. Pratley, “Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion,” Obesity Research, vol. 9, no. 7, pp. 414–417, 2001.
- M. B. Schulze, E. B. Rimm, T. Li, N. Rifai, M. J. Stampfer, and F. B. Hu, “C-reactive protein and incident cardiovascular events among men with diabetes,” Diabetes Care, vol. 27, no. 4, pp. 889–894, 2004.
- Z. He and G. L. King, “Protein kinase Cβ isoform inhibitors: a new treatment for diabetic cardiovascular diseases,” Circulation, vol. 110, no. 1, pp. 7–9, 2004.
- T. Inoguchi, R. Battan, E. Handler, J. R. Sportsman, W. Heath, and G. L. King, “Preferential elevation of protein kinase C isoform βII and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 22, pp. 11059–11063, 1992.
- P. Xia, T. Inoguchi, T. S. Kern, R. L. Engerman, P. J. Oates, and G. L. King, “Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia,” Diabetes, vol. 43, no. 9, pp. 1122–1129, 1994.
- B. Tesfamariam, M. L. Brown, and R. A. Cohen, “Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C,” Journal of Clinical Investigation, vol. 87, no. 5, pp. 1643–1648, 1991.
- A. Goel, Y. Zhang, L. Anderson, and R. Rahimian, “Gender difference in rat aorta vasodilation after acute exposure to high glucose: involvement of protein kinase C β and superoxide but not of Rho kinase,” Cardiovascular Research, vol. 76, no. 2, pp. 351–360, 2007.
- C. Rask-Madsen and G. L. King, “Proatherosclerotic mechanisms involving protein kinase C in diabetes and insulin resistance,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 3, pp. 487–496, 2005.
- S. I. Itani, N. B. Ruderman, F. Schmieder, and G. Boden, “Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α,” Diabetes, vol. 51, no. 7, pp. 2005–2011, 2002.
- J. A. Beckman, A. B. Goldfine, M. B. Gordon, L. A. Garrett, and M. A. Creager, “Inhibition of protein kinase Cβ prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans,” Circulation Research, vol. 90, no. 1, pp. 107–111, 2002.
- N. N. Mehta, M. Sheetz, K. Price et al., “Selective PKC beta inhibition with ruboxistaurin and endothelial function in type-2 diabetes mellitus,” Cardiovascular Drugs and Therapy, vol. 23, no. 1, pp. 17–24, 2009.
- B. B. Lowell and G. I. Shulman, “Mitochondrial dysfunction and type 2 diabetes,” Science, vol. 307, no. 5708, pp. 384–387, 2005.
- J. A. Kim, Y. Wei, and J. R. Sowers, “Role of mitochondrial dysfunction in insulin resistance,” Circulation Research, vol. 102, no. 4, pp. 401–414, 2008.
- A. Zorzano, M. Liesa, and M. Palacín, “Role of mitochondrial dynamics proteins in the pathophysiology of obesity and type 2 diabetes,” International Journal of Biochemistry and Cell Biology, vol. 41, no. 10, pp. 1846–1854, 2009.
- S. Goldman, Y. Zhang, and S. Jin, “Autophagy and adipogenesis: implications in obesity and type II diabetes,” Autophagy, vol. 6, no. 1, pp. 179–181, 2010.
- C. E. Tabit, W. B. Chung, N. M. Hamburg, and J. A. Vita, “Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications,” Reviews in Endocrine and Metabolic Disorders, vol. 11, no. 1, pp. 61–74, 2010.
- J. J. Badimon, A. Zaman, G. Helft, Z. Fayad, and V. Fuster, “Acute coronary syndromes: pathophysiology and preventive priorities,” Thrombosis and Haemostasis, vol. 82, no. 2, pp. 997–1004, 1999.
- P. V. Halushka, R. C. Rogers, C. B. Loadholt, and J. A. Colwell, “Increased platelet thromboxane synthesis in diabetes mellitus,” Journal of Laboratory and Clinical Medicine, vol. 97, no. 1, pp. 87–96, 1981.
- N. Eibl, W. Krugluger, G. Streit, K. Schrattbauer, P. Hopmeier, and G. Schernthaner, “Improved metabolic control decreases platelet activation markers in patients with type-2 diabetes,” European Journal of Clinical Investigation, vol. 34, no. 3, pp. 205–209, 2004.
- J. Lefkovits, E. F. Plow, and E. J. Topol, “Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine,” The New England Journal of Medicine, vol. 332, no. 23, pp. 1553–1559, 1995.
- J. A. Colwell and R. W. Nesto, “The platelet in diabetes: focus on prevention of ischemic events,” Diabetes Care, vol. 26, no. 7, pp. 2181–2188, 2003.
- P. Ferroni, S. Basili, A. Falco, and G. Davì, “Platelet activation in type 2 diabetes mellitus,” Journal of Thrombosis and Haemostasis, vol. 2, no. 8, pp. 1282–1291, 2004.
- Y. Li, V. Woo, and R. Bose, “Platelet hyperactivity and abnormal Ca2+ homeostasis in diabetes mellitus,” American Journal of Physiology, vol. 280, no. 4, pp. H1480–H1489, 2001.
- M. Gawaz, I. Ott, A. J. Reininger, and F. J. Neumann, “Effects of magnesium on platelet aggregation and adhesion. Magnesium modulates surface expression of glycoproteins on platelets in vitro and ex vivo,” Thrombosis and Haemostasis, vol. 72, no. 6, pp. 912–918, 1994.
- S. Lindemann, N. D. Tolley, D. A. Dixon et al., “Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis,” Journal of Cell Biology, vol. 154, no. 3, pp. 485–490, 2001.
- F. Cipollone, A. Mezzetti, E. Porreca et al., “Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy,” Circulation, vol. 106, no. 4, pp. 399–402, 2002.
- A. S. Weyrich, S. Lindemann, and G. A. Zimmerman, “The evolving role of platelets in inflammation,” Journal of Thrombosis and Haemostasis, vol. 1, no. 9, pp. 1897–1905, 2003.
- J. L. Ferreiro and D. J. Angiolillo, “Diabetes and antiplatelet therapy in acute coronary syndrome,” Circulation, vol. 123, no. 7, pp. 798–813, 2011.
- L. Burnier, P. Fontana, B. R. Kwak, and A. Angelillo-Scherrer, “Cell-derived microparticles in haemostasis and vascular medicine,” Thrombosis and Haemostasis, vol. 101, no. 3, pp. 439–451, 2009.
- O. Morel, L. Kessler, P. Ohlmann, and P. Bareiss, “Diabetes and the platelet: toward new therapeutic paradigms for diabetic atherothrombosis,” Atherosclerosis, vol. 212, no. 2, pp. 367–376, 2010.
- F. D. George, “Microparticles in vascular diseases,” Thrombosis Research, vol. 122, supplement 1, pp. S55–S59, 2008.
- O. Morel, N. Morel, J. M. Freyssinet, and F. Toti, “Platelet microparticles and vascular cells interactions: a checkpoint between the haemostatic and thrombotic responses,” Platelets, vol. 19, no. 1, pp. 9–23, 2008.
- H. Schwertz, N. D. Tolley, J. M. Foulks et al., “Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenecity of human platelets,” Journal of Experimental Medicine, vol. 203, no. 11, pp. 2433–2440, 2006.
- A. S. Leroyer, A. Tedgui, and C. M. Boulanger, “Role of microparticles in atherothrombosis,” Journal of Internal Medicine, vol. 263, no. 5, pp. 528–537, 2008.
- S. P. Ardoin, J. C. Shanahan, and D. S. Pisetsky, “The role of microparticles in inflammation and thrombosis,” Scandinavian Journal of Immunology, vol. 66, no. 2-3, pp. 159–165, 2007.
- S. Nomura, M. Suzuki, K. Katsura et al., “Platelet-derived microparticles may influence the development of atherosclerosis in diabetes mellitus,” Atherosclerosis, vol. 116, no. 2, pp. 235–240, 1995.
- M. Diamant, R. Nieuwland, R. F. Pablo, A. Sturk, J. W. A. Smit, and J. K. Radder, “Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus,” Circulation, vol. 106, no. 19, pp. 2442–2447, 2002.
- T. Ueba, T. Haze, M. Sugiyama et al., “Level, distribution and correlates of platelet-derived microparticles in healthy individuals with special reference to the metabolic syndrome,” Thrombosis and Haemostasis, vol. 100, no. 2, pp. 280–285, 2008.
- S. Omoto, S. Nomura, A. Shouzu, M. Nishikawa, S. Fukuhara, and T. Iwasaka, “Detection of monocyte-derived microparticles in patients with type II diabetes mellitus,” Diabetologia, vol. 45, no. 4, pp. 550–555, 2002.
- S. Nomura, A. Shouzu, S. Omoto, M. Nishikawa, T. Iwasaka, and S. Fukuhara, “Activated platelet and oxidized LDL induce endothelial membrane vesiculation: clinical significance of endothelial cell-derived microparticles in patients with type 2 diabetes,” Clinical and Applied Thrombosis/Hemostasis, vol. 10, no. 3, pp. 205–215, 2004.
- S. Bernard, R. Loffroy, A. Sérusclat et al., “Increased levels of endothelial microparticles CD144 (VE-Cadherin) positives in type 2 diabetic patients with coronary noncalcified plaques evaluated by multidetector computed tomography (MDCT),” Atherosclerosis, vol. 203, no. 2, pp. 429–435, 2009.
- O. Morel, B. Pereira, G. Averous et al., “Increased levels of procoagulant tissue factor-bearing microparticles within the occluded coronary artery of patients with ST-segment elevation myocardial infarction: role of endothelial damage and leukocyte activation,” Atherosclerosis, vol. 204, no. 2, pp. 636–641, 2009.
- A. J. Gerrits, C. A. Koekman, C. Yildirim, R. Nieuwland, and J. W. N. Akkerman, “Insulin inhibits tissue factor expression in monocytes,” Journal of Thrombosis and Haemostasis, vol. 7, no. 1, pp. 198–205, 2009.
- D. W. Sommeijer, K. Joop, A. Leyte, P. H. Reitsma, and H. Ten Cate, “Pravastatin reduces fibrinogen receptor gpIIIa on platelet-derived microparticles in patients with type 2 diabetes,” Journal of Thrombosis and Haemostasis, vol. 3, no. 6, pp. 1168–1171, 2005.
- S. Nomura, N. Inami, A. Shouzu et al., “The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients,” Platelets, vol. 20, no. 1, pp. 16–22, 2009.
- K. K. Koh, M. J. Quon, S. H. Han, J. Y. Ahn, Y. Lee, and E. K. Shin, “Combined therapy with ramipril and simvastatin has beneficial additive effects on tissue factor activity and prothrombin fragment 1 + 2 in patients with type 2 diabetes,” Atherosclerosis, vol. 194, no. 1, pp. 230–237, 2007.
- M. Diamant, M. E. Tushuizen, M. N. Abid-Hussein et al., “Simvastatin-induced endothelial cell detachment and microparticle release are prenylation dependent,” Thrombosis and Haemostasis, vol. 100, no. 3, pp. 489–497, 2008.
- E. R. Vandendries, B. C. Furie, and B. Furie, “Role of P-selectin and PSGL-I in coagulation and thrombosis,” Thrombosis and Haemostasis, vol. 92, no. 3, pp. 459–466, 2004.
- H. M. Rinder, J. L. Bonan, C. S. Rinder, K. A. Ault, and B. R. Smith, “Activated and unactivated platelet adhesion to monocytes and neutrophils,” Blood, vol. 78, no. 7, pp. 1760–1769, 1991.
- K. I. Hidari, A. S. Weyrich, G. A. Zimmerman, and R. P. McEver, “Engagement of P-selectin glycoprotein ligand, 1 enhances tyrosine phosphorylation and activates mitogen-activated protein kinases in human neutrophils,” Journal of Biological Chemistry, vol. 272, no. 45, pp. 28750–28756, 1997.
- I. Elalamy, T. Chakroun, G. T. Gerotziafas et al., “Circulating platelet-leukocyte aggregates: a marker of microvascular injury in diabetic patients,” Thrombosis Research, vol. 121, no. 6, pp. 843–848, 2008.
- H. Hu, N. Li, M. Yngen, C.-G. Östenson, N. H. Wallén, and P. Hjemdahl, “Enhanced leukocyte-platelet cross-talk in type 1 diabetes mellitus: relationship to microangiopathy,” Journal of Thrombosis and Haemostasis, vol. 2, no. 1, pp. 58–64, 2004.
- S. H. Alzahrani and R. A. Ajjan, “Coagulation and fibrinolysis in diabetes,” Diabetes and Vascular Disease Research, vol. 7, no. 4, pp. 260–273, 2010.
- A. Breitenstein, F. C. Tanner, and T. F. Lüscher, “Tissue factor and cardiovascular disease: quo vadis?” Circulation, vol. 74, no. 1, pp. 3–12, 2010.
- B. H. Annex, S. M. Denning, K. M. Channon et al., “Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes,” Circulation, vol. 91, no. 3, pp. 619–622, 1995.
- H. Suefuji, H. Ogawa, H. Yasue et al., “Increased plasma tissue factor levels in acute myocardial infarction,” American Heart Journal, vol. 134, no. 2, part 1, pp. 253–259, 1997.
- H. Soejima, H. Ogawa, H. Yasue et al., “Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina,” Circulation, vol. 99, no. 22, pp. 2908–2913, 1999.
- G. Boden, V. R. Vaidyula, C. Homko, P. Cheung, and A. K. Rao, “Circulating tissue factor procoagulant activity and thrombin generation in patients with type 2 diabetes: effects of insulin and glucose,” The Journal of Clinical Endocrinology & Metabolism, vol. 92, no. 11, pp. 4352–4358, 2007.
- J. Heinrich, L. Balleisen, H. Schulte, G. Assmann, and J. van de Loo, “Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM study in healthy men,” Arteriosclerosis & Thrombosis, vol. 14, no. 1, pp. 54–59, 1994.
- A. R. Folsom, K. K. Wu, C. E. Davis, M. G. Conlan, P. D. Sorlie, and M. Szklo, “Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors,” Atherosclerosis, vol. 91, no. 3, pp. 191–205, 1991.
- P.-Y. Scarabin, M.-F. Aillaud, P. Amouyel et al., “Associations of fibrinogen, factor VII and PAI-1 with baseline findings among 10,500 male participants in a prospective study of myocardial infarction—the PRIME Study. Prospective Epidemiological Study of Myocardial Infarction.,” Thrombosis and Haemostasis, vol. 80, no. 5, pp. 749–756, 1998.
- D. M. Heywood, M. W. Mansfield, and P. J. Grant, “Factor VII gene polymorphisms, factor VII:C levels and features of insulin resistance in non-insulin-dependent diabetes mellitus,” Thrombosis and Haemostasis, vol. 75, no. 3, pp. 401–406, 1996.
- R. A. Karatela and G. S. Sainani, “Interrelationship between coagulation factor VII and obesity in diabetes mellitus (type 2),” Diabetes Research and Clinical Practice, vol. 84, no. 3, pp. e41–e44, 2009.
- A. S. Wolberg and R. A. Campbell, “Thrombin generation, fibrin clot formation and hemostasis,” Transfusion and Apheresis Science, vol. 38, no. 1, pp. 15–23, 2008.
- A. Ceriello, K. Esposito, M. Ihnat, J. Zhang, and D. Giugliano, “Simultaneous control of hyperglycemia and oxidative stress normalizes enhanced thrombin generation in type 1 diabetes,” Journal of Thrombosis and Haemostasis, vol. 7, no. 7, pp. 1228–1230, 2009.
- E. Corrado, M. Rizzo, G. Coppola et al., “An update on the role of markers of inflammation in atherosclerosis,” Journal of Atherosclerosis and Thrombosis, vol. 17, no. 1, pp. 1–11, 2010.
- R. Guardado-Mendoza, L. Jimenez-Ceja, M. F. Pacheco-Carrasco et al., “Fibrinogen is associated with silent myocardial ischaemia in type 2 diabetes mellitus,” Acta Cardiologica, vol. 64, no. 4, pp. 523–530, 2009.
- R. Ajjan and P. J. Grant, “Coagulation and atherothrombotic disease,” Atherosclerosis, vol. 186, no. 2, pp. 240–259, 2006.
- R. Barazzoni, E. Kiwanuka, M. Zanetti, M. Cristini, M. Vettore, and P. Tessari, “Insulin acutely increases fibrinogen production in individuals with type 2 diabetes but not in individuals without diabetes,” Diabetes, vol. 52, no. 7, pp. 1851–1856, 2003.
- P. Tessari, E. Kiwanuka, R. Millioni et al., “Albumin and fibrinogen synthesis and insulin effect in type 2 diabetic patients with normoalbuminuria,” Diabetes Care, vol. 29, no. 2, pp. 323–328, 2006.
- I. Seljeflot, J. R. Larseb, K. Dahl-Jørgensen, K. F. Hanssen, and H. Arnesen, “Fibrinolytic activity is highly influenced by long-term glycemic control in type 1 diabetic patients,” Journal of Thrombosis and Haemostasis, vol. 4, no. 3, pp. 686–688, 2006.
- M. E. Stegenga, S. N. van der Crabben, M. C. Dessing et al., “Effect of acute hyperglycaemia and/or hyperinsulinaemia on proinflammatory gene expression, cytokine production and neutrophil function in humans,” Diabetic Medicine, vol. 25, no. 2, pp. 157–164, 2008.
- M.-C. Alessi and I. Juhan-Vague, “Metabolic syndrome, haemostasis and thrombosis,” Thrombosis and Haemostasis, vol. 99, no. 6, pp. 995–1000, 2008.
- E. J. Dunn, R. A. S. Ariëns, and P. J. Grant, “The influence of type 2 diabetes on fibrin structure and function,” Diabetologia, vol. 48, no. 6, pp. 1198–1206, 2005.
- A. Natarajan, A. G. Zaman, J. J. Badimon, and S. M. Marshall, “Platelet-dependent thrombosis in patients with type 2 diabetes and coronary artery disease,” Diabetes, vol. 56, Article ID A181, 2007.
- A. Natarajan, S. M. Marshall, S. G. Worthley, J. J. Badimon, and A. G. Zaman, “The presence of coronary artery disease increases platelet-dependent thrombosis in patients with type 2 diabetes mellitus,” Journal of Thrombosis and Haemostasis, vol. 6, no. 12, pp. 2210–2213, 2008.
- J. I. Osende, J. J. Badimon, V. Fuster et al., “Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control,” Journal of the American College of Cardiology, vol. 38, no. 5, pp. 1307–1312, 2001.
- G. N. Viswanathan, A. Natarajan, S. M. Marshall, J. J. Badimon, and A. G. Zaman, “Higher thrombus burden and impaired clot kinetics in patients with type 2 diabetes mellitus following non St-elevation acute coronary syndrome,” Circulation, vol. 122, Article ID A17675, 2010.
- G. N. Viswanathan, A. G. Zaman, and S. M. Marshall, “Thrombus burden, clot kinetics and response to anti-platelet therapy in type 2 diabetes,” Diabetic Medicine, vol. 28, supplement 1, pp. 1–2, 2011.
- J. L. Anderson, C. D. Adams, E. M. Antman 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 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, vol. 116, no. 7, pp. e148–e304, 2007.
- E. M. Antman, D. T. Anbe, P. W. Armstrong et al., “ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction),” Circulation, vol. 110, no. 5, pp. 588–636, 2004.
- A. I. Schafer, “Antiplatelet therapy,” American Journal of Medicine, vol. 101, pp. 199–209, 1996.
- H. Ogawa, M. Nakayama, T. Morimoto et al., “Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial,” The Journal of the American Medical Association, vol. 300, no. 18, pp. 2134–2141, 2008.
- G. De Berardis, M. Sacco, G. F. Strippoli et al., “Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials,” British Medical Journal, vol. 339, Article ID b4531, 2009.
- C. Baigent, L. Blackwell, R. Collins, et al., “Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials,” The Lancet, vol. 373, no. 9678, pp. 1849–1860, 2009.
- C. Patrono, L. A. García Rodríguez, R. Landolfi, and C. Baigent, “Low-dose aspirin for the prevention of atherothrombosis,” The New England Journal of Medicine, vol. 353, no. 22, pp. 2373–2383, 2005.
- J. A. Colwell, “Aspirin therapy in diabetes,” Diabetes Care, vol. 27, supplement 1, pp. S72–S73, 2004.
- S. B. King III, S. C. Smith Jr., J. W. Hirshfeld Jr. et al., “2007 Focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee,” Circulation, vol. 117, no. 2, pp. 261–295, 2008.
- “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,” The Lancet, vol. 336, no. 8719, pp. 827–830, 1990.
- P. Theroux, H. Ouimet, J. McCans et al., “Aspirin, heparin, or both to treat acute unstable angina,” The New England Journal of Medicine, vol. 319, no. 17, pp. 1105–1111, 1988.
- H. D. Lewis Jr., J. W. Davis, D. G. Archibald, et al., “Protective effects of aspirin against acute myocardial infarction and death in mean with unstable angina. Results of a Veterans Administration Cooperative Study,” The New England Journal of Medicine, vol. 309, no. 7, pp. 396–403, 1983.
- S. Roux, S. Christeller, and E. Ludin, “Effects of aspirin on coronary reocclusion and recurrent ischemia after thrombolysis: a meta-analysis,” Journal of the American College of Cardiology, vol. 19, no. 3, pp. 671–677, 1992.
- “Randomized 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,” The Lancet, vol. 2, no. 8607, pp. 349–360, 1988.
- K. Senior, “Aspirin withdrawal increases risk of heart problems,” The Lancet, vol. 362, no. 9395, p. 1558, 2003.
- “Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration,” British Medical Journal, vol. 308, no. 6921, pp. 81–106, 1994.
- “Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients,” British Medical Journal, vol. 324, no. 7329, pp. 71–86, 2002.
- S. R. Mehta, J. P. Bassand, S. Chrolavicius et al., “Dose comparisons of clopidogrel and aspirin in acute coronary syndromes,” The New England Journal of Medicine, vol. 363, no. 10, pp. 930–942, 2010.
- S. R. Mehta, J. F. Tanguay, J. W. Eikelboom et al., “Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial,” The Lancet, vol. 376, no. 9748, pp. 1233–1243, 2010.
- R. F. Storey, L. J. Newby, and S. Heptinstall, “Effects of P2Y 1 and P2Y 12 receptor antagonists on platelet aggregation induced by different agonists in human whole blood,” Platelets, vol. 12, no. 7, pp. 443–447, 2001.
- C. Gachet, “ADP receptors of platelets and their inhibition,” Journal of Thrombosis and Haemostasis, vol. 86, no. 1, pp. 222–232, 2001.
- A. Schomig, F. J. Neumann, A. Kastrati, et al., “A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents,” The New England Journal of Medicine, vol. 334, no. 17, pp. 1084–1089, 1996.
- M. B. Leon, D. S. Baim, J. J. Popma, et al., “A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators,” The New England Journal of Medicine, vol. 339, no. 23, pp. 1665–1671, 1998.
- M. E. Bertrand, V. Legrand, J. Boland et al., “Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study,” Circulation, vol. 98, no. 16, pp. 1597–1603, 1998.
- P. Urban, C. Macaya, H. J. Rupprecht et al., “Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS),” Circulation, vol. 98, no. 20, pp. 2126–2132, 1998.
- M. E. Bertrand, H. J. Rupprecht, P. Urban, and A. H. Gershlick, “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, vol. 102, no. 6, pp. 624–629, 2000.
- Y. Cadroy, J. P. Bossavy, C. Thalamas, L. Sagnard, K. Sakariassen, and B. Boneu, “Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans,” Circulation, vol. 101, no. 24, pp. 2823–2828, 2000.
- “A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee,” The Lancet, vol. 348, no. 9038, pp. 1329–1339, 1996.
- D. L. Bhatt, S. P. Marso, A. T. Hirsch, P. A. Ringleb, W. Hacke, and E. J. Topol, “Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus,” The American Journal of Cardiology, vol. 90, no. 6, pp. 625–628, 2002.
- M. S. Sabatine, C. P. Cannon, C. M. Gibson et al., “Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study,” The Journal of the American Medical Association, vol. 294, no. 10, pp. 1224–1232, 2005.
- M. S. Sabatine, C. P. Cannon, C. M. Gibson et al., “Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation,” The New England Journal of Medicine, vol. 352, no. 12, pp. 1179–1189, 2005.
- Z. Chen and L. Jiang, “Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial,” The Lancet, vol. 366, no. 9497, pp. 1607–1621, 2005.
- S. R. Steinhubl, P. B. Berger, J. T. Mann III et al., “Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial,” The Journal of the American Medical Association, vol. 288, no. 19, pp. 2411–2420, 2002.
- S. R. Mehta, S. Yusuf, R. J. G. Peters et al., “Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study,” The Lancet, vol. 358, no. 9281, pp. 527–533, 2001.
- D. L. Bhatt, K. A. A. Fox, W. Hacke et al., “Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events,” The New England Journal of Medicine, vol. 354, no. 16, pp. 1706–1717, 2006.
- D. J. Angiolillo and P. Capranzano, “Pharmacology of emerging novel platelet inhibitors,” American Heart Journal, vol. 156, no. 2, supplement, pp. 10S–15S, 2008.
- S. D. Wiviott, D. Trenk, A. L. Frelinger 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, vol. 116, no. 25, pp. 2923–2932, 2007.
- S. D. Wiviott, E. Braunwald, C. H. McCabe et al., “Prasugrel versus clopidogrel in patients with acute coronary syndromes,” The New England Journal of Medicine, vol. 357, no. 20, pp. 2001–2015, 2007.
- S. D. Wiviott, E. Braunwald, C. H. McCabe 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,” The Lancet, vol. 371, no. 9621, pp. 1353–1363, 2008.
- S. D. Wiviott, E. Braunwald, D. J. Angiolillo 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, vol. 118, no. 16, pp. 1626–1636, 2008.
- D. J. Angiolillo, J. J. Badimon, J. F. Saucedo et al., “A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy in diabetes MellitUS (OPTIMUS)-3 Trial,” European Heart Journal, vol. 32, no. 7, pp. 838–846, 2011.
- D. J. Angiolillo, S. B. Shoemaker, B. Desai 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, vol. 115, no. 6, pp. 708–716, 2007.
- D. J. Angiolillo, P. Capranzano, S. Goto 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,” European Heart Journal, vol. 29, no. 18, pp. 2202–2211, 2008.
- R. F. Storey, S. Husted, R. A. Harrington et al., “Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes,” Journal of the American College of Cardiology, vol. 50, no. 19, pp. 1852–1856, 2007.
- L. Wallentin, R. C. Becker, A. Budaj, et al., “Ticagrelor versus clopidogrel in patients with acute coronary syndromes,” The New England Journal of Medicine, vol. 361, no. 11, pp. 1045–1057, 2009.
- S. James, D. J. Angiolillo, J. H. Cornel et al., “Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial,” European Heart Journal, vol. 31, no. 24, pp. 3006–3016, 2010.
- M. Roffi, D. P. Chew, D. Mukherjee et al., “Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes,” Circulation, vol. 104, no. 23, pp. 2767–2771, 2001.
- J. Mehilli, A. Kastrati, H. Schuhlen, et al., “Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel,” Circulation, vol. 110, no. 24, pp. 3627–3635, 2004.
- A. Kastrati, J. Mehilli, F. J. Neumann, et al., “Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial,” The Journal of the American Medical Association, vol. 295, no. 13, pp. 1531–1538, 2006.
- G. De Luca, E. Navarese, and P. Marino, “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,” European Heart Journal, vol. 30, no. 22, pp. 2705–2713, 2009.
- S. V. Rao, J. A. Eikelboom, C. B. Granger, R. A. Harrington, R. M. Califf, and J. P. Bassand, “Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes,” European Heart Journal, vol. 28, no. 10, pp. 1193–1204, 2007.
- J. W. Eikelboom, S. R. Mehta, S. S. Anand, C. Xie, K. A. A. Fox, and S. Yusuf, “Adverse impact of bleeding on prognosis in patients with acute coronary syndromes,” Circulation, vol. 114, no. 8, pp. 774–782, 2006.
- G. W. Stone, B. T. McLaurin, D. A. Cox et al., “Bivalirudin for patients with acute coronary syndromes,” The New England Journal of Medicine, vol. 355, no. 21, pp. 2203–2216, 2006.
- S. V. Manoukian, “Predictors and impact of bleeding complications in percutaneous coronary intervention, acute coronary syndromes, and ST-segment elevation myocardial infarction,” The American Journal of Cardiology, vol. 104, no. 5, supplement, pp. 9C–15C, 2009.
- D. J. Angiolillo, “Variability in responsiveness to oral antiplatelet therapy,” The American Journal of Cardiology, vol. 103, no. 3, supplement, pp. 27A–34A, 2009.
- J. D. Snoep, M. M. C. Hovens, J. C. J. Eikenboom, J. G. van der Bom, and M. V. Huisman, “Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis,” Archives of Internal Medicine, vol. 167, no. 15, pp. 1593–1599, 2007.
- G. Krasopoulos, S. J. Brister, W. S. Beattie, and M. R. Buchanan, “Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis,” British Medical Journal, vol. 336, no. 7637, pp. 195–198, 2008.
- A. D. Michelson, M. Cattaneo, J. W. Eikelboom, et al., “Aspirin resistance: position paper of the Working Group on Aspirin Resistance,” Journal of Thrombosis and Haemostasis, vol. 3, no. 6, pp. 1309–1311, 2005.
- D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo, et al., “Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment,” Diabetes, vol. 54, no. 8, pp. 2430–2435, 2005.
- D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo, et al., “Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention,” The American Journal of Cardiology, vol. 97, no. 1, pp. 38–43, 2006.
- A. L. Frelinger III, M. I. Furman, M. D. Linden 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, vol. 113, no. 25, pp. 2888–2896, 2006.
- C. Watala, J. Pluta, J. Golanski et al., “Increased protein glycation in diabetes mellitus is associated with decreased aspirin-mediated protein acetylation and reduced sensitivity of blood platelets to aspirin,” Journal of Molecular Medicine, vol. 83, no. 2, pp. 148–158, 2005.
- G. Davi, I. Catalano, M. Averna et al., “Thromboxane biosynthesis and platelet function in type II diabetes mellitus,” The New England Journal of Medicine, vol. 322, no. 25, pp. 1769–1774, 1990.
- D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo et al., “Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives,” Journal of the American College of Cardiology, vol. 49, no. 14, pp. 1505–1516, 2007.
- J. L. Ferreiro and D. J. Angiolillo, “Clopidogrel response variability: current status and future directions,” Journal of Thrombosis and Haemostasis, vol. 102, no. 1, pp. 7–14, 2009.
- T. Geisler, N. Anders, M. Paterok et al., “Platelet response to clopidogrel is attenuated in diabetic patients undergoing coronary stent implantation,” Diabetes Care, vol. 30, no. 2, pp. 372–374, 2007.
- V. Serebruany, I. Pokov, W. Kuliczkowski, J. Chesebro, and J. Badimon, “Baseline platelet activity and response after clopidogrel in 257 diabetics among 822 patients with coronary artery disease,” Thrombosis and Haemostasis, vol. 100, no. 1, pp. 76–82, 2008.
- D. J. Angiolillo, E. Bernardo, C. Ramirez, et al., “Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment,” Journal of the American College of Cardiology, vol. 48, no. 2, pp. 298–304, 2006.
- D. J. Angiolillo, E. Bernardo, D. Capodanno et al., “Impact of chronic kidney disease on platelet function profiles in diabetes mellitus patients with coronary artery disease taking dual antiplatelet therapy,” Journal of the American College of Cardiology, vol. 55, no. 11, pp. 1139–1146, 2010.
- I. Iakovou, T. Schmidt, E. Bonizzoni et al., “Incidence, predictors and outcome of thrombosis after succesful implantation of drug-eluting stents,” The Journal of the American Medical Association, vol. 293, no. 17, pp. 2126–2130, 2005.
- P. Urban, A. H. Gershlick, G. Guagliumi et al., “Safety of coronary sirolimus-eluting stents in daily clinical practice: one-year follow-up of the e-Cypher registry,” Circulation, vol. 113, no. 11, pp. 1434–1441, 2006.
- P. K. Kuchulakanti, W. W. Chu, R. Torguson et al., “Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents,” Circulation, vol. 113, no. 8, pp. 1108–1113, 2006.
- M. J. Price, P. B. Berger, P. S. Teirstein et al., “Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial,” The Journal of the American Medical Association, vol. 305, no. 11, pp. 1097–1105, 2011.
- D. J. Angiolillo, M. Roffi, and A. Fernandez-Ortiz, “Tackling the thrombotic burden in patients with acute coronary syndrome and diabetes mellitus,” Expert Review of Cardiovascular Therapy, vol. 9, no. 6, pp. 697–710, 2011.
- G. G. Neri Serneri, S. Coccheri, E. Marubini, and F. Violi, “Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study,” European Heart Journal, vol. 25, no. 20, pp. 1845–1852, 2004.
- “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, vol. 89, no. 2, pp. 588–595, 1994.
- P. Gresele, R. Migliacci, A. Procacci, P. De Monte, and E. Bonizzoni, “Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication,” Thrombosis and Haemostasis, vol. 97, no. 3, pp. 444–450, 2007.
- H. Kariyazono, K. Nakamura, J. Arima et al., “Evaluation of anti-platelet aggregatory effects of aspirin, cilostazol and ramatroban on platelet-rich plasma and whole blood,” Blood Coagulation and Fibrinolysis, vol. 15, no. 2, pp. 157–167, 2004.
- A. Chamorro, “TP receptor antagonism: a new concept in atherothrombosis and stroke prevention,” Cerebrovascular Diseases, vol. 27, supplement 3, pp. 20–27, 2009.
- D. J. Angiolillo and L. A. Guzman, “Clinical overview of promising nonthienopyridine antiplatelet agents,” American Heart Journal, vol. 156, no. 2, supplement, pp. S23–S28, 2008.
- R. F. Storey, R. G. Wilcox, and S. Heptinstall, “Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease,” Platelets, vol. 13, no. 7, pp. 407–413, 2002.
- R. A. Harrington, G. W. Stone, S. McNulty et al., “Platelet inhibition with cangrelor in patients undergoing PCI,” The New England Journal of Medicine, vol. 361, no. 24, pp. 2318–2329, 2009.
- D. L. Bhatt, A. M. Lincoff, C. M. Gibson et al., “Intravenous platelet blockade with cangrelor during PCI,” The New England Journal of Medicine, vol. 361, no. 24, pp. 2330–2341, 2009.
- S. W. Lee, S. W. Park, M. K. Hong et al., “Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis,” Journal of the American College of Cardiology, vol. 46, no. 10, pp. 1833–1837, 2005.
- S. W. Lee, S. W. Park, Y. H. Kim 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 Stent Implantation in Diabetic Patients),” Journal of the American College of Cardiology, vol. 51, no. 12, pp. 1181–1187, 2008.
- G. G. L. Biondi-Zoccai, M. Lotrionte, M. Anselmino et al., “Systematic review and meta-analysis of randomized clinical trials appraising the impact of cilostazol after percutaneous coronary intervention,” American Heart Journal, vol. 155, no. 6, pp. 1081–1089, 2008.
- Y. Han, Y. Li, S. Wang 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,” American Heart Journal, vol. 157, no. 4, pp. 733–739, 2009.
- D. J. Angiolillo, D. Capodanno, and S. Goto, “Platelet thrombin receptor antagonism and atherothrombosis,” European Heart Journal, vol. 31, no. 1, pp. 17–28, 2010.
- R. C. Becker, D. J. Moliterno, L. K. Jennings et al., “Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study,” The Lancet, vol. 373, no. 9667, pp. 919–928, 2009.
- S. Goto, H. Ogawa, M. Takeuchi, M. D. Flather, and D. L. Bhatt, “Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease,” European Heart Journal, vol. 31, no. 21, pp. 2601–2613, 2010.
- A. K. Wittkowsky, “New oral anticoagulants: a practical guide for clinicians,” Journal of Thrombosis and Thrombolysis, vol. 29, no. 2, pp. 182–191, 2010.
- S. J. Connolly, M. D. Ezekowitz, S. Yusuf et al., “Dabigatran versus warfarin in patients with atrial fibrillation,” The New England Journal of Medicine, vol. 361, no. 12, pp. 1139–1151, 2009.
- E. Lonn, S. Yusuf, B. Hoogwerf et al., “Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy,” Diabetes Care, vol. 25, no. 11, pp. 1919–1927, 2002.
- “MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial,” The Lancet, vol. 360, no. 9326, pp. 23–33, 2002.
- T. Münzel and J. F. Keaney Jr., “Are ACE inhibitors a “magic bullet” against oxidative stress?” Circulation, vol. 104, no. 13, pp. 1571–1574, 2001.