Abstract
Patients with diabetes mellitus (DM) are at high risk for several cardiovascular disorders such as coronary heart disease, stroke, peripheral arterial disease, and congestive heart failure. DM has reached epidemic proportions and its strong association with coronary artery disease is responsible for increased cardiovascular morbidity and mortality. DM patients are characterized by platelet hyperreactivity, which contribute to the enhanced atherothrombotic risk of these subjects. Several mechanisms are involved in the hyperreactive platelet phenotype characterizing DM patients. Furthermore, a large proportion of DM patients show inadequate response to standard antiplatelet treatments and high rate of adverse recurrent cardiovascular events despite compliance with standard antiplatelet treatment regimens. Therefore, new antiplatelet treatment regimens are warranted in DM patients to reduce their atherothrombotic risk. The present manuscript provides an overview on the current status of knowledge on platelet function profiles in patients with DM and therapeutic considerations.
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Type 2 diabetes mellitus (DM) is a complex disease, diagnosed in approximately two million persons each year in the USA and worldwide its prevalence continues to climb [1]. Patients with DM have accelerated atherosclerosis, high risk of cardiovascular disease as well as atherothrombotic complications [2, 3]. Notably, DM patients without a history of coronary artery disease (CAD) have overall the same cardiac risk as non-DM patients with a history of myocardial infarction (MI) [4]. Furthermore, the presence of DM in the setting of an acute coronary syndrome (ACS), presenting with and without ST elevation, is a strong independent predictor of short-term and long-term recurrent ischemic events, including mortality [5, 6]. Several investigations have shown that DM subjects are characterized by prothrombotic status which is attributed to numerous factors, including a pro-coagulant status, impaired fibrinolysis, endothelial dysfunction, and increased platelet reactivity. The latter is a result of multiple causes which ultimately cause dysregulation of several platelet signaling pathways leading to a hyperreactive platelet phenotype [2, 7–11] (Table 1). This may contribute to another important feature of DM which consists in an impaired response to standard antiplatelet therapy which may also explain the worse outcomes found in DM subjects when compared with non-DM subjects [9, 12, 13]. The present manuscript provides an overview on the current status of knowledge on platelet function profiles in patients with DM and therapeutic considerations.
Platelet Abnormalities in DM Patients: Mechanisms
Several studies underscore the pivotal role of platelets in atherosclerosis and its thrombotic complications [14, 15]. The intensified adhesion, activation, aggregation, and platelet-derived thrombin generation are all abnormalities which characterize DM platelets [2, 7–11] (Table 1). These findings can be attributed to several factors. In particular, it is possible to identify different metabolic and cellular mechanisms closely interrelated, which can be grouped into the following categories: hyperglycemia, insulin resistance, associated metabolic conditions and other cellular abnormalities (Fig. 1) [12].
Mechanisms of platelet dysfunction in patients with diabetes mellitus, Mechanisms contributing to platelet dysfunction in diabetes mellitus (DM) patients, including hyperglycemia, insulin deficiency, associated metabolic conditions, and other cellular abnormalities. ADP: adenosine diphosphate; CA ++: calcium; GP: glycoprotein; IRS: insulin receptor substrate; NO: nitric oxide; PGI 2 : prostacycline; PKC: protein kinase C; ROS/NOS: reactive oxygen and nitrogen species; TF: tissue factor
Hyperglycemia
Diabetes is a metabolic condition characterized by dysfunction in insulin secretion and insulin action resulting in chronic hyperglycemia and deeply affecting the cardiovascular system. Hyperglycemia per se may play an independent role in the abnormalities found in platelets of DM patients [16], in particular hyperglycemia has been identified as a causal factor for in vivo platelet activation and platelet hyperreactivity [16, 17]. DM platelets are characterized by enhanced thromboxane biosynthesis, enhanced expression of adhesion molecules and activation markers [18]. Several investigations have reported different mechanisms to explain increased platelet reactivity in hyperglycemia status. These include: (1) glycation of platelet surface proteins decreases membrane fluidity, increases platelet adhesion and thus causes incorporation of glycated proteins into thrombi [19–21]; (2) activation of protein kinase C, a mediator of platelet activation, through an increased production of the lipid second messenger diacylglycerol [22, 23]; (3) increased intracellular calcium concentration due to glycation of circulating low-density lipoproteins (LDL) [24]; (4) decreased production of endothelium-derived nitric oxide (NO), which impairs endothelium-dependent vasodilation [25]; (5) production of reactive oxygen species [26]; (6) platelet glycoprotein (GP) IIb/IIIa and P-selectin expression activated by osmotic effect of glucose [27]. In addition, hyperglycemia inhibits fibrinolysis by increasing concentrations of plasminogen activator inhibitor [28] and promoted coagulation by raising concentrations of procoagulant factors (e.g., tissue factor, von Willebrand factor) [29, 30].
Studies have shown that a decrease in expression of platelet activation markers after improved metabolic control [31]. Even clinical studies investigated the effects of glucose-lowering therapy in patients with DM in the acute setting [32]. Moreover, there are the DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) and DIGAMI-2 trials. In the DIGAMI standard treatment plus insulin-glucose infusion for 24 h followed by multidose insulin therapy was superior to standard treatment alone in the mortality at 3.4 years (33 vs. 44 %; RR = 0.72; p = 0.011) [33]. However, in the DIGAMI-2 trial no significant differences in mortality, non-fatal reinfarction or stroke were found among three glucose-lowering strategies (group 1: glucose–insulin infusion titrated by glucose levels at least for 24 h followed by insulin-based long-term glucose control; group 2: glucose–insulin infusion titrated by glucose levels at least for 24 h followed by standard glucose control; and group 3: routine metabolic control according to local practice), which achieved similar glucose levels [34]. These results suggest that the benefit of decreasing glucose levels is independent of the way it is achieved. Moreover, the optimal blood glucose concentration for events reduction remains still unknown. In fact, the ACCORD (Action to Control Cardiovascular Risk in Diabetes Study Group) trial suggested that an excessive glucose lowering may be even dangerous. The trial, which randomized 10,251 DM patients to receive an intensive glucose-lowering regimen (glycated hemoglobin level <6.0 % as target) or a standard treatment (targeting a glycated hemoglobin level 7.0–7.9 %) had to be interrupted prematurely after 3.5 years of follow-up due to greater rate of mortality in the intensive regimen group [35]. The NICE-SUGAR (Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation) trial showed similar results. In fact, patients randomized to undergo intensive glucose control (target blood glucose range 4.5 to 6.0 mmol/l) showed higher mortality than patients on conventional glucose control (target of 10.0 mmol/l or less) [36].
Insulin Resistance and Deficient Secretion
Differences in platelet abnormalities can be attributed to the different mechanisms contributing to the DM status. In fact, type 1 DM (5–10 % of cases) is caused by a cellular-mediated autoimmune destruction of the pancreatic β-cells, resulting in an absolute deficiency of insulin secretion, while type 2 DM (90–95 %) is caused by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response (relative insulin deficiency) [37]. Deficient insulin action strongly contributes to platelet dysfunction. Platelets express both insulin receptors (IR) and insulin-like growth factor-1 (IGF-1) receptors [38, 39] and the binding of insulin to platelets increases also surface expression of adenylate cyclase-linked prostacyclin receptor [40]. Nevertheless, IR expression is relatively low because the majority of its subunits heterodimerize with those of the IGF-1 receptor to form an insulin/IGF-1 hybrid receptor, which avidly binds IGF-1 but not insulin [39]. The presence of IGF-1 in the granules of platelets and the expression of its receptor on platelets surface may contribute to the amplification of platelet responses and to the pathogenesis of cardiovascular disease. The functional and signaling pathways involved in IGF-1 modulation of platelet reactivity, however, are currently not completely known [18].
Abnormalities in insulin-mediated signaling pathways, which contribute to the hampered or abolished platelet-inhibitory effect in patients with insulin resistance, can be classified in insulin receptor substrate (IRS)-dependent and independent factors [18, 41, 42]. Angiolillo et al. showed that genetic variations of IRS-1 are associated with different patterns of platelet function profiles and can identify type 2 DM patients with a hyperreactive platelet phenotype. Notably, these patients are also at an increased risk of adverse cardiovascular events [43]. Among IRS-dependent factors, insulin resistance provokes an increase in intracellular calcium concentration, leading to enhanced platelet degranulation and aggregation [44], with a mechanism not yet fully clear. IRS-independent pathways include the reduction of platelet sensitivity to NO and prostacyclin (PGI2) which are released by the endothelium and hamper platelet activation. Therefore, an impaired response to these molecules contributed to a hyperreactive platelet phenotype [45, 46]. Moreover, restoration of platelet sensitivity to NO and PGI2 has been correlated with the improvement of insulin sensitivity [47]. This may contribute to the suggested benefits of thiazolidinediones, characterized by potent insulin sensitizing effects, on platelet function. In fact, an enhanced sensitivity to NO and partial normalization of intracellular calcium concentrations in DM patients [48], and a diminished P-selectin expression in non-DM patients with CAD has been observed while rosiglitazone treatment [49]. In the multicenter randomized PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) trial pioglitazone (an insulin sensitizer) was associated with a reduced atherosclerotic disease progression measured by intravascular ultrasonography compared with glimepiride (an insulin secretagogue) at 18 months in patients with type 2 DM and stable CAD (n = 543) [50]. In the post hoc analysis of the SIMPHONY (Sibrafiban vs Aspirin to Yield Maximun Protection from Ischemic Heart Events Post-acute Coronary Syndromes) and SIMPHONY-2 trials, therapy with biguanide and/or thiazolidinedione was associated with lower cardiovascular events at 90 days compared with insulin-providing treatment with insulin and/or sulfonylurea in DM patients after an ACS (n = 3,101) [51]. However, these results were not confirmed in the APPROACH (Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients with Cardiovascular History) trial [52]. Recently, Suryadevara et al. reported pharmacodynamic (PD) data about the impact of pioglitazone on clopidogrel-mediated P2Y12 inhibitory effects in patients with type 2 DM. In this prospective, randomized, double-blind, placebo-controlled, cross-over PD study, the adjunctive use of pioglitazone does not result in enhanced platelet inhibition [53].
Metabolic Conditions Associated with DM
Metabolic conditions such as obesity, dyslipidemia, and enhanced systemic inflammatory status are commonly associated with type 2 DM and may contribute to the hyperreactive platelet phenotype observed in this population. Obesity is frequently associated with insulin resistance [18], elevated platelet count and high mean platelet volume [54], higher serum leptin concentration [55], greater cytosolic free calcium concentration [56], and increased oxidative stress [57]. Of note, in a population of subjects affected with central obesity, diet-induced weight loss showed to restore the sensitivity to NO and PGI2 and reduce platelet activation [47]. Likewise, in subjects with elevated body mass index response to antiplatelet drugs such as clopidogrel is also impaired [58–60]. Dyslipidemic patients present high levels of triglycerides and low levels of high-density lipoprotein (HDL) cholesterol [18]. Triglyceride-rich very-low-density lipoprotein (VLDL) particles impair fibrinolysis and affect coagulation cascade predisposing to atherothrombosis [61]. Hypertriglyceridemia is also known to induce platelet activation with a mechanism based on the interaction between the apoE content of VLDL particles and the platelet LDL receptor [62]. Low concentrations of HDL are associated with endothelial dysfunction [63] and recently Calkin et al. showed a reduction of platelet aggregation in a DM cohort after administration of reconstituted HDL, with a mechanism mediated by cholesterol efflux from platelets. Patients with DM have also increased systemic inflammation and platelets activation and coagulation markers compared to healthy subjects [64].
Other Cellular Abnormalities
Dysregulation of calcium metabolism, oxidative stress, upregulation of P2Y12 signaling pathway and accelerated platelet turnover are commonly present in DM patients and may contribute to the platelet hyperreactivity status. Although the exact mechanisms are not known, the increased cytosolic calcium concentration, due to impaired regulation of calcium metabolism, characterizes platelets of patients with DM. The suggested mechanisms include augmented influx of calcium through the sodium/calcium exchanger [65], altered activity of calcium ATPase [66], reduced sensitivity to insulin that diminishes sarcoplasmic reticulum calcium-ATPase (SERCA-2) [41, 48], and augmented oxidative stress, which enhances calcium signaling through increased formation of superoxide anions and reduced nitric oxide production [67]. This increased cytosolic calcium concentration creates an enhanced platelet reactivity [41, 68]. DM is associated with an overproduction of reactive oxygen and nitrogen species, as well as with reduced platelet antioxidant levels which enhance platelet activation [68–72]. The increased production of reactive oxygen species is associated with more production of advanced glycation end products (AGEs) [73], which cause atherosclerotic complications by increasing platelet aggregation through the serotonin receptor [74] and activating the receptor for AGEs [75]. In addition, oxidative stress contributes to endothelial dysfunction and thus to the prothrombotic status, which characterize DM, through an increased production of tissue factor [76, 77]. Ultimately, patients with DM are characterized by a higher number of reticulated platelets, a marker of elevated platelets turnover, which results in greater platelet reactivity [78].
Antiplatelet Therapy and Platelet Functional Profile in Patients with Diabetes Mellitus
Currently, three different classes of antiplatelet drugs are available for treatment and prevention of ischemic complications in patients with CAD: cycloxigenase-1 (COX-1) inhibitors (aspirin), GP IIb/IIIa inhibitors and adenosine diphosphate (ADP) P2Y12 receptor antagonist (Table 2). Therapy with GP IIb/IIIa inhibitors is reasonable in high-risk ACS patients undergoing PCI, which obviously include those with DM [79]. However, the use of these drugs is associated with increased risk of bleeding. Recent studies have demonstrated that bivalirudin is as effective as conventional therapy with heparin and GP IIb/IIIa inhibitors with a better safety profile in DM patients [80] and thus may be considered an important therapeutic option in this high-risk setting. The use of antithrombotic treatment strategies for acute use goes beyond the scope of this review, which is focused on long-term secondary prevention antithrombotic treatment regimens. In particular, this section provides an overview on the benefits, limitations and short and long term outcome of oral antiplatelets agents in DM (Table 3).
Aspirin
Aspirin selectively acetylates cyclooxygenase-1 (COX-1), thereby blocking the formation of thromboxane A2 (TXA2) in platelets [81]. This effect is irreversible, as platelets are enucleate and thus are unable to resynthesize COX-1. The role of aspirin for primary prevention in DM patients is still controversial. The ETDRS (Early Treatment Diabetic Retinopathy Study) showed a significant decrease in the relative risk of MI at 5 years (RR = 0.72; p < 0.01) with aspirin (325 mg bid) in DM patients (n = 3,711), although no significant difference in mortality was observed [82]. The POPADAD (Prevention of Progression of Arterial Disease and Diabetes) trial randomized patients (n = 1,276) with type 1 or 2 DM over the age of 40 with asymptomatic peripheral artery disease to aspirin (100 mg) or antioxidants and did not show any benefit in primary prevention of cardiovascular events [83]. In the JPAD (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes) trial the use of aspirin (81 to 100 mg) for primary prevention of cardiovascular events showed a 20 % difference between the aspirin and non-aspirin arms in the primary endpoint (atherosclerotic events) but without achieving statistical significance [84]. Nevertheless, the incidence of fatal coronary and cerebrovascular events (a secondary endpoint) was significantly reduced. Several meta-analyses have been performed in order to reconcile the results obtained in the different trials and showed that aspirin produces only a modest reduction in cardiovascular events. Therefore, present guidelines do not recommend routine use of aspirin for primary prevention in DM patients [85]. A consensus from the American Diabetes Association, the American Heart Association and the American College of Cardiology Foundation recommends low-dose aspirin (75–162 mg/day) for primary prevention in adults with DM and no previous history of vascular disease who are at increased cardiovascular disease (CVD) risk (10-year risk of CVD events over 10 %) and who are not at increased risk for bleeding. Aspirin is also recommend for DM subjects who have increased CVD risk (men over age 50 years and women over age 60 years with one or more major risk factors) [86]. The ASCEND (A Study of Cardiovascular Events in Diabetes; NCT00135226) and ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes; ISRCTN48110081) trials are studying the role of aspirin in primary prevention in DM cohort.
Conversely, aspirin is the treatment of choice in the secondary prevention of patients with CAD or undergoing PCI [79, 87]. Several studies have broadly demonstrated the efficacy of aspirin in non-ST elevation acute coronary syndromes and ST elevation myocardial infarction (STEMI) and its use is recommended in current guidelines (initial dose of 162–325 mg followed by a daily dose of 75–162 mg) [79, 87, 88]. The use of aspirin for secondary prevention is based on the results of two large meta-analyses involving 212,000 high-risk patients which showed a benefit with oral antiplatelet agents, mainly aspirin (75–325 mg/die), irrespective of DM status. The incidence of vascular events was reduced from 22.3 to 18.5 % in the cohort of DM patients (p < 0.002), and from 16.4 % to 12.8 % (p < 0.00001) in non-DM patients [89]. The use of low-dose aspirin (75–150 mg/day) was at least as effective as higher daily doses, while bleeding complications were increased with the higher doses [90].
However, aspirin treatment has some limitations in DM subjects. In fact, several investigations provided correlations between aspirin poor responsiveness and a higher risk of recurrent ischemic events [91, 92]. The prevalence of aspirin resistance varies considerably among studies [93] and the specific mechanisms of aspirin resistance in DM patients have not been entirely elucidated and likely multifactorial. These include hyperglycemia, as augmented protein glycation may be associated with decreased protein acetylation mediated by aspirin [81, 94], increased TXA2 synthesis [81], and accelerated platelet turnover [94]. Other mechanisms involved in the reduced response to aspirin are type of aspirin used [95], genetic factors [96], drug interactions [97], and low-grade inflammation that may induce an increased TXA2 synthesis [98].
Clopidogrel
Clopidogrel is a thienopyridine, which is a non-direct, oral antiplatelet agent that irreversibly blocks the platelet ADP P2Y12 receptor. P2Y1 and P2Y12 receptors mediate the role of ADP on platelets but activation of P2Y12 pathway plays the principal role, leading to sustained platelet aggregation and stabilization of the platelet aggregate [99–101]. The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial randomized 19,185 high-risk patients (history of recent MI, recent ischemic stroke, or established peripheral artery disease) with atherosclerotic vascular disease to aspirin (325 mg daily) or clopidogrel (75 mg daily) to test their efficacy for secondary prevention [102]. The global results showed that clopidogrel group had a significantly lower annual rate of the composite end-point of ischemic stroke, MI or vascular death (5.32 vs. 5.83 %; p = 0.043). In particular, the DM sub-group reached a greater benefit with clopidogrel, while the reduction in the rates of ischemic outcomes in patients without DM did not reach statistical significance [103]. The efficacy of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in primary and secondary prevention in patients at high risk for ischemic events, but not presenting with an ACS or undergoing PCI, was evaluated in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial. The results showed that DAPT was not significantly more effective than aspirin alone in reducing the rates of cardiovascular death, MI, or stroke (6.8 vs 7.3 %; p = 0.22) [104]. Consistent with the results in the overall population, no benefit of combined therapy was observed in the DM subgroup.
Several trials have demonstrated the superiority of DAPT with aspirin and clopidogrel compared to aspirin alone for preventing recurrent ischemic events in patients with ACS and undergoing coronary stenting [105–110] and thus its use is recommended in practice guidelines [79, 88]. Despite the proven efficacy of DAPT with aspirin and clopidogrel, there is a rate (5–40 %) of patients who have recurrent ischemic events while on therapy [111, 112]. These subjects are known as “low responder” or “resistant”. Clopidogrel response variability has been explained by three different mechanisms: genetic, cellular, and clinical factors [113]. Among the clinical mechanisms, DM is considered one of the most important factors both in the acute and maintenance phase of therapy [114, 115]. In fact, platelet ADP P2Y12 receptor signaling pathway is upregulated in DM platelets [18, 116], as shown in a mechanistic study in which platelets from patients with DM were hypo-responsive to P2Y12 receptor blockade achieved by escalating concentrations of the active metabolite of clopidogrel compared with platelets from non-DM patients [117]. Reduced PD effects in patients treated with thienopyridines may also be attributed to reduced generation of the active metabolites, which has been shown for both clopidogrel and prasugrel [118]. Interestingly, smoking, which is an inducer of CYP1A2 metabolic activity involved in the first oxidation step of clopidogrel metabolism, is associated with enhanced clopidogrel-induced antiplatelet effects and reduced rates of inadequate clopidogrel response in DM patients [119]. Importantly, DM patients with poor metabolic control or at an advanced stage requiring insulin therapy have the worse response to clopidogrel [120]. In addition, DM is a strong risk factor for the development of chronic kidney disease (CKD) which is itself a cause of clopidogrel resistance. A recent analysis performed in 306 DM patients with CAD and on DAPT therapy with aspirin and clopidogrel, showed that the percentage of poor responders to clopidogrel, who also had higher levels of markers of platelet activation, was greatest among patients with moderate to severe CKD [121]. Moreover, the presence of high on-treatment platelet reactivity in DM patients with CAD while on chronic DAPT has showed to be associated with a higher risk of long-term adverse cardiovascular events [122]. The reduced responsiveness to clopidogrel contributes to explain why DM is also a strong predictor of stent thrombosis [123–125]. Other mechanisms contributing to clopidogrel resistance in DM patients are diminished platelet response to insulin, which leads to increased platelet adhesion, aggregation, and procoagulant activity on contact with collagen [117], dysregulation of calcium metabolism [65], increased exposure to ADP [126], and increased platelet turnover [127].
Novel and Future Strategies of Antiplatelet Therapy in DM Patients
Patients with DM have well-known poor responsiveness to aspirin and clopidogrel with high platelet reactivity and thus greater risk of ischemic events. In this section we will provide insights into three different strategies to optimize platelet inhibition in patients with DM: modification of dosing of commonly used agents (aspirin and clopidogrel), use of new agents and addition of a third antiplatelet drug (triple therapy).
Modification of Aspirin and Clopidogrel Dosing
Increasing the dose of aspirin has been suggested to overcome low responsiveness. A post hoc analysis of the ASPECT (Aspirin-Induced Platelet Effect) study analyzed three aspirin dosages (81, 162, or 325 mg/daily) in DM vs. non-DM patients and showed higher platelet reactivity in the 81-mg DM group compared with non-DM. However, when increasing aspirin dose (162 and 325 mg daily), there was greater platelet inhibition in patients with DM to an extent that the final rates of aspirin resistance were similar between groups [128]. The CURRENT/OASIS-7 (clopidogrel optimal loading dose usage to reduce recurrent events–organization to assess strategies in ischemic syndromes) trial was the first large-scale randomized study comparing high with low-dose aspirin in ACS patients undergoing angiography [129]. Patients were randomized in a 2 × 2 factorial design to a high or standard dose of clopidogrel for a month and in an open-label fashion to high (300–325 mg daily) versus low dose (75–100 mg daily) aspirin. The trial did not show significant differences in efficacy among aspirin doses with a trend toward an increasing in bleeding. There are no data reported specifically in the DM subset.
The hypothesis that increasing the frequency of aspirin administration (twice daily instead of once daily) has also been advocated as this may result in more effective platelet inhibition based on the fact that the accelerated platelet turnover which characterizes DM subjects may lead to an increased proportion of non-aspirin-inhibited platelets using a daily dosing interval [92, 130]. Several small studies showed a benefit of twice daily aspirin dose on platelet function profiles in DM patients [131–133]. However, it remains unknown if this translates into differences in clinical outcomes.
The recommended loading and maintenance doses for clopidogrel are 300–600 mg and 75 mg/daily, respectively [79, 88]. In the OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus) study type 2 DM patients with CAD and high platelet reactivity while in their maintenance phase of clopidogrel therapy were administered high (150 mg) versus standard maintenance dose of clopidogrel (75 mg) and a PD evaluation was performed. The 150-mg dose showed a moderate improvement in platelet inhibition, although approximately 60 % of patients remained with high platelet reactivity [134]. The CURRENT/OASIS-7 trial evaluated also the efficacy of high (600-mg loading dose followed by 150 mg daily for 1 week and then 75 mg/daily until day 30) versus standard dose (300-mg loading followed by 75 mg daily until day 30) of clopidogrel. In the subgroup of patients undergoing PCI the high-dose strategy was associated with a decrease in the rates of ischemic outcomes (3.9 vs. 4.5 %; HR = 0.85; p = 0.036), and reduced the risk of stent thrombosis by 30 %, at the expense of increased study-defined major bleedings. Consistent findings were observed across subgroups, including according to DM status (p value for interaction = 0.872) [135].
The use of a “tailored treatment” in patients with poor clopidogrel response assessed by a platelet function assay has been suggested as a possible strategy. In the GRAVITAS (Gauging Responsiveness with a VerifyNow Assay: Impact on Thrombosis And Safety) trial high-dose clopidogrel (600-mg initial dose and 150 mg daily thereafter for 6 months) in 2,214 patients with high on-treatment reactivity, assessed by the VerifyNow system, 12 to 24 h after PCI with drug-eluting stents, demonstrated no differences in the rates of ischemic (2.3 vs. 2.3 %; HR = 1.01; p = 0.97) or bleeding outcomes (1.4 vs. 2.3 %; HR = 0.59; p = 0.10), in comparison to standard therapy [136]. However, there are not specific analyses to the DM cohort of this trial. Recently, the ARCTIC (Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption versus Continuation One Year after Stenting) trial randomized 2,440 patients scheduled for coronary stenting to a strategy of platelet-function monitoring, with drug adjustment in patients who had a poor response to antiplatelet therapy, or to a conventional strategy without monitoring and drug adjustment. In the monitoring group, high platelet reactivity in patients taking clopidogrel (34.5 % of patients) or aspirin (7.6 %) led to the administration of an additional bolus of clopidogrel, prasugrel, or aspirin along with GP IIb/IIIa inhibitors during the procedure. The trial showed no difference in the primary end-point, a composite of death, MI, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation, with the monitoring strategy (34.6 vs. 31.1 %; p = 0.10) [137]. An interaction analysis showed consistent data across various subgroups including DM (p value for interaction = 0.91).
Use of New Agents
Several new antiplatelet agents are currently in different stages of clinical development. Some of these may be considered to tailor the specific dysfunction of DM platelets. For example, DM platelets have a greater production in TXA2, which may be due to poor metabolic control, increased oxidative stress and increased platelet turnover rates. Thus, inhibition of thromboxane and prostaglandin endoperoxide receptors (TP) may be an interesting therapeutic target [94, 138, 139]. TP inhibitors include picotamide (a combined TXA2 synthase inhibitor and TP receptor blocker), ridogrel (a combined TXA2 synthase inhibitor and TP receptor blocker), ramatroban (a TP receptor inhibitor), NCX 4016 (a NO-releasing aspirin derivative), Si8886/terutroban (a TP receptor inhibitor), and EV-077 (a combined TXA2 synthase inhibitor and TP receptor blocker). These drugs have been evaluated in different clinical settings with variable success and might be of potential interest for future development in DM subjects [140–144].
Prasugrel and ticagrelor are two novel potent P2Y12 receptor blockers with important pharmacological advantages over clopidogrel and represent an attractive strategy especially in high-risk patients, such as those with DM. Prasugrel, an oral administered third-generation thienopyridine, is a prodrug which requires hepatic biotransformation into its active metabolite [145]. Compared to clopidogrel, prasugrel has a faster onset of action, greater platelet inhibition due to a more efficient conversion into its active metabolite and less interindividual variability. The OPTIMUS-3 trial showed greater platelet inhibition of prasugrel at standard dose (60-mg loading dose/10-mg maintenance dose) vs. high-dose clopidogrel (600-mg loading dose/150-mg maintenance dose) in type 2 DM patients with CAD on chronic aspirin therapy [146]. Moreover, prasugrel resulted in lower rates of poor responders [146]. The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38) examined the efficacy and safety of prasugrel (60-mg loading dose followed by 10 mg daily) versus standard clopidogrel therapy (300-mg loading dose followed by 75-mg/day maintenance dose) in 13,608 patients with moderate- to high-risk ACS undergoing PCI [147]. Prasugrel demonstrated a significant reduction in the rates of the primary end point (composite of cardiovascular death, nonfatal MI, or nonfatal stroke) (9.9 vs. 12.1 %; HR:0.81; p < 0.001), as well as a reduction in the rates of stent thrombosis over a follow-up period of 15 months, at the expense of an increased risk of major bleeding. Particular subgroups appeared to have a higher benefit with prasugrel therapy such as patients with STEMI [148], and importantly DM patients [149]. In subjects with DM the primary end point was reduced significantly with prasugrel (12.2 vs. 17.0 %; p < 0.001). This benefit was consistent in patients with and without insulin treatment. Of note, major bleeding was higher in DM patients but there were no differences in major bleeding among DM patients treated with prasugrel compared with clopidogrel.
Ticagrelor, a cyclopentyltriazolopyrimidines, is an oral, reversible, non-competitive P2Y12 receptor inhibitor with rapid onset and offset of action (requiring twice daily dosing) and provides a stronger and more consistent inhibition of platelet aggregation than clopidogrel [150–153]. The phase III PLATO (Platelet Inhibition and Patient Outcomes) trial randomized ACS patients (n = 18,624) to receive either ticagrelor (180-mg loading dose followed by 90 mg twice daily) or clopidogrel (300- to-600-mg loading dose followed by 75 mg daily). Ticagrelor showed a significant reduction in the primary end-point, the combination of death from vascular causes, MI or stroke (9.8 vs. 11.7 %; HR = 0.84; p = 0.0001), and, remarkably, of cardiovascular death (4.0 vs. 5.1 %; HR = 0.79; p = 0.001) at 12 months [154]. Moreover, the occurrence of definite or probable stent thrombosis was reduced by ticagrelor treatment in the subgroup of patients undergoing PCI (2.2 vs. 2.9 %; HR = 0.75; p = 0.02). This higher efficacy was associated with an increased rate of non-coronary artery bypass graft (CABG)-related major bleeding (4.5 vs. 3.8 %; HR = 1.19; p = 0.03). The predefined subgroup analysis of the DM cohort (n = 4,662) showed a numerical but not significant reduction of the rates of the primary end point (14.1 vs. 16.2 %), which was consistent with the overall trial results. The benefit of ticagrelor was enhanced in patients with worse metabolic control, as defined per HbA1c levels above the median (6 %), in which ticagrelor significantly reduced the rates of the primary end point, without difference in major bleeding [155]. Moreover, a new study, the MATTIS-D (Effect of Modifying Anti-platelet Treatment to Ticagrelor in Patients with Diabetes and Low Response to Clopidogrel; NCT01643031), is ongoing to evaluate clinical benefits in patients with diabetes and low response to clopidogrel after switch to ticagrelor.
To date, there are other novel P2Y12 inhibitors which are in different stages of development (Table 2). Cangrelor is an intravenous ATP analog with direct-acting and reversible P2Y12 receptor inhibitor binding [145, 156]. Cangrelor is characterized by dose-dependent action and can achieve a greater degree of platelet inhibition (>90 %) with extremely rapid onset and offset of action [157]. Recently, Ferreiro et al. evaluated the in vitro cangrelor PD effects in 103 clopidogrel naïve patients with CAD on aspirin therapy. The authors concluded that in vitro addition of cangrelor provides a potent and dose-dependent blockade of the platelet P2Y12 receptor, with no differential effect in patients with and without DM [158]. Despite the promising PD properties of cangrelor, the phase III CHAMPION (cangrelor versus standard therapy to achieve optimal management of platelet inhibition) trials which included CHAMPION-PCI (n = 8,716) and CHAMPION-PLATFORM (n = 5,362) did not meet the primary endpoint [159, 160], with consistent neutral findings in the DM cohort. A new phase III clinical trial, the CHAMPION-PHOENIX (NCT01156571), is evaluating the efficacy and safety of cangrelor compared to standard of care in patients undergoing PCI.
Elinogrel is another direct-acting new agent which inhibits P2Y12 inhibitor reversibly and can be administered both orally and intravenously [161, 162]. The INNOVATE-PCI (A Randomized, Double-Blind, Active-Controlled Trial to Evaluate Intravenous and Oral PRT060128, a Selective and Reversible P2Y12 Inhibitor, vs Clopidogrel, as a Novel Antiplatelet Therapy in Patients Undergoing Non-Urgent PCI) trial (NCT00751231) has provided promising results of elinogrel in terms of platelet inhibition and safety compared to clopidogrel in patients undergoing non-urgent PCI [163, 164]. There are no specific data with elinogrel in DM subjects and phase III studies with elinogrel are not planned at the current time.
Addition of a Third Antiplatelet Agent
Another strategy that has been advocated to prevent recurrent events despite the use of DAPT with aspirin and clopidogrel, in particular in DM patients, is to add a third agent which blocks pathways other than COX-1 and purinergic P2Y12. Drugs that have been suggested to be used on “triple therapy” are: cilostazol, protease-activated receptor-1 (PAR-1) antagonist and novel anticoagulants (Table 2).
Cilostazol is a potent phosphodiesterase (PDE) III inhibitor that increases intraplatelet cyclic adenosine monophosphate concentration and increases platelet inhibition when used with aspirin and clopidogrel [165]. Several investigations, including PD studies specifically conducted in DM patients, confirmed that the addition of cilostazol to standard DAPT is associated with a greater reduction of platelet reactivity, even when compared with clopidogrel 150 mg/daily [166, 167]. The magnitude of these effects appears to be greater in DM patients compared to those without DM, particularly those with high on treatment platelet reactivity [158, 168, 169]. These PD findings may explain the enhanced clinical benefit of adding cilostazol to DAPT in DM patients undergoing PCI [170].
Recently, there has been a broad interest in thrombin receptor antagonists, which block the platelet PAR-1 receptor subtype, including vorapaxar (SCH530348) and atopaxar (E5555) [138]. Vorapaxar has been evaluated in two large phase III clinical trials in CAD patients. The role of vorapaxar in the secondary prevention of patients with known atherosclerotic disease (history of MI, ischemic stroke, or peripheral arterial disease) was recently evaluated in the TRA 2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events Thrombolysis in Myocardial Infarction 50) trial [171]. In this trial, 26,449 patients were randomized to receive vorapaxar 2.5 mg daily or placebo, in addition to standard of care therapy, including aspirin (94 % of patients) and a thienopyridine (99.3 % clopidogrel). The primary efficacy end-point, a composite of death from cardiovascular causes, MI, or stroke, was significantly reduced in the vorapaxar group at 3 years (9.3 vs. 10.5 %; HR, 0.87; p < 0.001). Moderate or severe bleeding occurred in 4.2 % of patients who received vorapaxar and 2.5 % of those who received placebo (HR, 1.66; p < 0.001), with an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0 vs. 0.5 %; p < 0.001), especially in patients with a history of stroke. Of note, a composite end point termed net clinical outcome, comprising the primary efficacy and safety end points did not show any significant difference between vorapaxar and placebo (p = 0.40). The trial enrolled a total 25 % of DM patients but subgroup analysis showed no difference between DM and non-DM patients in both primary (p value for interaction = 0.61) and safety (p value for interaction = 0.79) end-points.
The TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial tested whether the addition of vorapaxar to standard therapy would be superior to placebo in reducing recurrent ischemic cardiovascular events in patients with NSTE-ACS [172]. Patients with an ACS within 24 h before hospital admission were randomized to receive vorapaxar (40-mg loading dose and a daily maintenance dose of 2.5 mg) plus standard of care or placebo plus standard of care, including a combination of aspirin (96 % of patients) and a P2Y12 inhibitor (clopidogrel in 91.8 % of patients). The TRACER trial, whose follow-up was terminated early after a safety review, showed no significant benefit of vorapaxar in the primary efficacy end-point, a composite of death from cardiovascular causes, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization (Kaplan–Meier 2-year rate, 18.5 vs. 19.9 %; HR, 0.92; p = 0.07). Vorapaxar significantly decreased the key secondary end point of death from cardiovascular causes, MI or stroke (14.7 vs. 16.4 %; HR, 0.89; p = 0.02) but significantly increased the rate of moderate or severe bleeding as compared with placebo (7.2 vs. 5.2 %; HR, 1.35; p < 0.001), in particular intracranial hemorrhage (1.1 vs. 0.2 %; HR, 3.39; p < 0.001). Primary and key secondary efficacy outcomes were consistent across subgroups. In particular, even in the 31.5 % of patients with DM the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point (p for interaction = 0.4) but significantly increased the risk of major bleeding (p for interaction = 0.8), including intracranial hemorrhage.
Triple therapy has also been evaluated with adding novel oral anticoagulants including anti-factor IIa “gatrans” (dabigatran) and direct factor Xa inhibitors or “xabans” (rivaroxaban, apixaban, darexaban) [173]. However, of the various studies only one, using rivaroxaban, completed phase III clinical testing, while others were limited by the high rates of bleeding events. The ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome 2-Thrombolysis in Myocardial Infarction 51) trial randomized 15,526 ACS patients to rivaroxaban (2.5 or 5 mg bid) or placebo in addition to standard therapy [174]. The primary efficacy outcome (composite cardiovascular death, MI, or stroke) was reduced in the rivaroxaban group with increased of non-CABG related major bleeding and intracranial hemorrhage. Moreover, the reduction in the primary efficacy end point with rivaroxaban was consistent among the subgroups, although the p for interaction for DM cohort (4,964) was not significant (p = 0.14).
Conclusions
In conclusion, DM patients are at increased atherothrombotic risk which contributes to their heightened cardiovascular morbidity and mortality. The prothrombotic status, in particular their hyperreactive platelet phenotype, plays a key role in these outcomes. Several mechanisms are involved in the hyperreactive platelet phenotype underscoring the need to define more optimal platelet inhibiting treatment regimens in these patients. The introduction of new antiplatelet agents into the armamentarium of currently available treatment regimens represents a step forward in reaching these objectives. Studies specifically designed in DM assessing the functional and clinical impact of new antithrombotic strategies are warranted to define the optimal treatment for this high-risk group of patients.
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Acknowledgments
The text and outline of the present manuscript have been adapted with permission from (1) Ferreiro JL, Angiolillo DJ (2011) Diabetes and anti-platelet therapy in acute coronary syndrome. Circulation 123:798–813 [reference 12] and (2) Ferreiro JL, Angiolillo DJ (2012) Challenges and perspectives of antiplatelet therapy in patients with diabetes mellitus and coronary artery disease. Curr Pharm Des 1:5273–5293 [reference 18].
Dr. Ana Muñiz-Lozano is recipient of the Research grant from the Spanish Society of Cardiology. (“Beca de la Sección de Cardiopatía Isquémica de la Sociedad Española de Cardiología para Formación e Investigación Post Residencia en el extranjero”): “Comparación farmacodinámica de Prasugrel versus Ticagrelor en pacientes con diabetes mellitus tipo 2 y enfermedad coronaria”.
Disclosures
Dr. Angiolillo has received honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Company, Ltd. and Eli Lilly and Company, and Sanofi-Aventis; has received consulting fees from Abbott Vascular, Accumetrics, Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Company, Ltd. and Eli Lilly and Company, Medicure, Novartis, Portola, Sanofi-Aventis and The Medicines Company; and has received research grants from Accumetrics, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Company, Ltd. and Eli Lilly and Company, Eisai, GlaxoSmithKline, Otsuka, Portola, Sanofi-Aventis, and The Medicines Company.
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All other authors have no conflict of interest to report.
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Rollini, F., Franchi, F., Muñiz-Lozano, A. et al. Platelet Function Profiles in Patients with Diabetes Mellitus. J. of Cardiovasc. Trans. Res. 6, 329–345 (2013). https://doi.org/10.1007/s12265-013-9449-0
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DOI: https://doi.org/10.1007/s12265-013-9449-0