Platelets and Antiplatelet Therapy in Patients with Diabetes Mellitus

Both insulin-dependent and non-insulin dependent diabetes mellitus (DM) are powerful and independent risk factors for coronary artery disease (CAD). In patients with diabetes, the risk of CAD is increased two- to four-fold. Atherosclerotic coronary disease is the major cause of death in patients with diabetes. With increasing prevalence of DM, the burden of cardiovascular disease associated with this condition will increase dramatically.¹ Platelets play a major role in the ischemic manifestations of CAD. Patients with diabetes have heightened platelet activity, which increases their risk of cardiovascular events.¹ This article reviews the rationale and the available data on the beneficial effects of antiplatelet therapy in patients with DM and CAD. Diabetes and cardiovascular events. Diabetic patients, as compared with nondiabetic patients, are at an increased risk of cardiovascular events. In a study by Haffner et al., patients with DM had a 20% risk of first myocardial infarction (MI) or death over a 7-year period, as compared to a risk of only 3.5% for nondiabetic patients.2 History of MI increased the rate of recurrent MI or cardiovascular death for both groups (45% in diabetics and 18.8% in nondiabetics). Based on these data, the risk of subsequent coronary events for patients with diabetes but without previous MI is the same as nondiabetic patients with previous MI.² In the setting of both ST-elevation MI and non-ST elevation acute coronary syndromes (ACS), diabetic patients suffer increased mortality as compared to nondiabetic patients. In a study of diabetic patients enrolled in the GUSTO-I (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I) trial, the 30-day mortality was significantly higher in patients with diabetes [10.5% in diabetics versus 6.2% in nondiabetics; odds ratio (OR): 1.77; 95% confidence interval (CI): 1.61–1.95].³ Other clinical events, including heart failure, cardiogenic shock, recurrent ischemia and stroke occurred significantly more frequently in diabetic patients. In a pooled analysis of 5 randomized trials of thrombolytic therapy for acute MI, the 30-day mortality was 11.7% in diabetics as compared with 7.1% in nondiabetics (OR: 1.71; 95% CI: 1.60–1.83).3 Similarly, in a combined analysis of the GUSTO-I, GUSTO-III and GUSTO-V trials, diabetic patients, as compared to patients without diabetes, were at greater risk of in-hospital (9.5% versus 5.5%, respectively; p 4 However, in comparison with diabetic patients in the GUSTO-I and GUSTO-III trials, diabetic patients enrolled in the GUSTO-V trial had a better 30-day survival due to improved adjunctive therapy.⁴ There is ample evidence that diabetic patients are at higher risk of subsequent cardiac events in the setting of non-ST elevation ACS. In the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry, which involved patients with unstable angina (UA) and non-Q wave MI (NQMI), diabetes was an independent predictor of mortality at 2 years [18% in diabetics versus 10% in nondiabetics; adjusted relative risk (RR): 1.57; 95% CI: 1.38–1.81; p 5 In a more recent analysis of 4 randomized trials of non-ST elevation ACS, diabetes was again identified as an independent risk factor for mortality. In this report, 30-day mortality was 5.5% among diabetic patients compared with 3.0% among nondiabetic patients (p 6 Similarly, in the diabetic substudy of the FRISC-II (Fragmin and Fast Revascularization During Instability in Coronary Artery Disease) trial, which compared invasive versus conservative management of patients with non-ST elevation ACS, diabetes remained an independent predictor of death (RR: 5.43; 95% CI: 2.09–14.1) and death or MI (RR: 2.40; 95% CI: 1.47–3.91) even after controlling for revascularization, extent of CAD and signs of myocardial damage by serum markers.⁷ In the OASIS Registry, in addition to increased mortality, diabetic patients also had significantly increased risk of recurrent MI, stroke and new-onset heart failure. Of note, diabetic patients without prior cardiovascular disease had the same event rates for all outcomes as nondiabetics patients with previous cardiovascular disease,⁵ again confirming the increased risk conferred by diabetes as shown by Haffner et al.² Therefore, regardless of the nature and severity of the ischemic syndrome, diabetic patients, as compared with nondiabetic patients, experience significantly higher incidences of subsequent cardiovascular events.^3–10Diabetes and platelet function. At the site of spontaneous or mechanical vessel injury, platelet deposition and thrombosis take place. Disruption of atherosclerotic plaque activates the coagulation cascade, leading to thrombin generation and exposure of deeper components of the plaque, which are powerful platelet activators.^11,12 Since platelets play a major role in acute vascular thrombosis, the increased risk of cardiovascular events among diabetic patients may be, in part, due to altered platelet function. There is ample evidence that platelets of diabetic patients (“diabetic platelets”) are larger and hyperreactive, showing increased adhesion and aggregation, and increased platelet-dependent thrombin generation.¹³ Patients with diabetes mellitus have increased platelet-surface expression of glycoprotein Ib (GP Ib), which mediates binding to von Willebrand factor, and GP IIb/IIIa, which mediates platelet-fibrin interaction and represents the final common pathway of platelet activation, leading to platelet aggregation.¹ In diabetic patients with stable angina, blood glucose is an independent predictor of platelet-dependent thrombosis, with higher blood glucose levels causing more severe thrombosis.¹³ Moreover, in patients with type 2 diabetes, there is an association between glycemic control and blood thrombogenicity. Osende et al., using the Badimon ex vivo perfusion chamber, showed that improved glycemic control, as indicated by >= 0.5% reduction in HbA1c, resulted in a significant decrease in blood thrombogenicity.¹⁴ In a study of diabetic patients by Davi and colleagues, there was an enhanced biosynthesis of thromboxane A-2, which causes platelet aggregation. Interestingly, tight metabolic control resulted in a significant reduction in thromboxane A-2 biosynthesis.¹⁵ Furthermore, available data indicate that calcium hemostasis is abnormal in platelets of diabetic patients.¹⁶ Since intraplatelet calcium regulates platelet shape change, thromboxane A-2 formation and platelet aggregation, disordered calcium regulation may contribute significantly to abnormal platelet activity in diabetic patients. Another hallmark of altered vascular hemostasis in diabetic patients is endothelial dysfunction, with hyperglycemia being the primary mediator of the injury. Since glucose entry into platelets does not depend on insulin, intraplatelet glucose concentration mirrors the extracellular concentration. In platelets as well as endothelial cells, elevated glucose levels leads to activation of protein kinase C, decreased production of nitric oxide and increased production of oxygen-free radicals. This ultimately results in impaired platelet-mediated, endothelium-dependent vasodilation.¹ Thus, diabetes as a “prothrombotic” state is characterized by the constellation of endothelial dysfunction, increased platelet adhesiveness and exaggerated platelet aggregation, ultimately resulting in intraluminal thrombus formation (Table 1).¹⁷ In this milieu of “diabetic heightened platelet activity”, therapy with antiplatelet agents is, therefore, expected to confer significant beneficial effects in reducing cardiovascular events. Antiplatelet drugs. There are several pathways and mediators of platelet activation and subsequent aggregation (Figure 1). Antiplatelet agents prevent platelet aggregation by inhibiting a specific pathway or mediator. In this review article, we discuss the available data on aspirin, clopidogrel (Plavix), and glycoprotein IIb/IIIa inhibitors, abciximab (ReoPro), tirofiban (Aggrastat) and eptifibatide (Integrilin). Aspirin inhibits cyclooxygenase-mediated prostaglandin synthesis, thus preventing thromboxane A2-mediated platelet aggregation. Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the GP IIb/IIIa receptor complex, thereby inhibiting platelet aggregation. Glycoprotein IIb/IIIa inhibitors prevent platelet aggregation by blocking the binding of fibrinogen to the GP IIb/IIIa receptor, which represents the “final common pathway” of platelet aggregation.¹⁸Antiplatelet therapy in the primary prevention of cardiovascular events in patients with diabetes. Several trials have evaluated the efficacy of aspirin in the prevention of cardiovascular events in asymptomatic individuals without prior history of vascular disease.¹⁸ The largest of these studies, the United States Physician Health Study, of 22,071 male physicians, revealed a 44% reduction in the risk of MI (p 19 The efficacy of aspirin in reducing MI in diabetic patients was further shown in the Early Treatment Diabetic Retinopathy Study (ETDRS), originally designed to evaluate the effects of aspirin on ocular events in 3,711 patients with diabetes and early retinopathy. In ETDRS, the 5-year event rates for fatal and nonfatal MI were 9.1% and 12.3% for patients assigned to aspirin and placebo, respectively (RR: 0.83; 99% CI: 0.66–1.04; p = 0.04).²⁰ The most recent statement from the American Diabetic Association recommends aspirin for primary prevention in diabetic individuals at high risk for cardiovascular disease.²¹Antiplatelet therapy in secondary prevention of cardiovascular events in patients with diabetes. Diabetic patients with prior vascular disease are at a high risk for recurrent cardiovascular events and, in the absence of any absolute contraindication, should be treated with aspirin.¹⁸ In the CAPRIE (Clopidogrel versus Aspirin at Risk of Ischemic Events) trial of 19,185 patients with atherosclerotic vascular disease, clopidogrel (75 mg daily) was superior to aspirin (325 mg daily) in reducing the risk of MI, ischemic stroke or vascular death (970/9599 in the clopidogrel group versus 1063/9586 in the aspirin group; p = 0.03).22 However, in the CAPRIE trial, diabetic patients received greater benefits from clopidogrel therapy than nondiabetic patients.²³ The rate of vascular events per year was 15.6% in the 1,914 diabetic patients randomized to clopidogrel and 17.7% in the 1,952 diabetic patients randomized to aspirin (p = 0.042); in the nondiabetic patients, the event rates per year were 11.8% and 12.7%, respectively (p = 0.096). It was concluded that clopidogrel is especially potent in reducing the elevated risk for recurrent ischemic events in diabetic patients with a prior history of vascular disease.²³ In the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, the effect of combination therapy with aspirin plus clopidogrel, versus aspirin alone, was evaluated in the 12,562 patients with non-ST elevation ACS.²⁴ The primary composite outcome of death, nonfatal MI or stroke occurred in 9.3% of the aspirin plus clopidogrel group and in 11.4% of the aspirin alone group (p 24 Despite treatment with aspirin and heparin, patients with non-ST elevation ACS, particularly when they are diabetic, experience high rates of recurrent ischemic events. Platelet GP IIb/IIIa inhibitors, by blocking the final common pathway of platelet aggregation, reduce composite ischemic clinical outcome in high-risk ACS patients.²⁵ In the PRISM-PLUS (Platelet Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms) study, the addition of tirofiban to aspirin and heparin was associated with a significant reduction of death, MI and refractory ischemia at 1 month (p = 0.03) and 6 months (p = 0.02).⁸ In a subgroup analysis of 362 diabetic patients in the PRISM-PLUS trial, triple therapy with aspirin, heparin and tirofiban, as compared to aspirin plus heparin, significantly reduced the incidence of MI or death at 1 month (4.7% versus 15.5%; p = 0.002) and 6 months (11.2% versus 19.2%; p = 0.03).9 In the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trial, treatment with eptifibatide, another GP IIb/IIIa inhibitor, was associated with a significant reduction in 30-day mortality in insulin-dependent diabetics (4.2% versus 8.1%; p 27 Based on the available data as well as recommendations from the American Diabetic Association, diabetic patients with prior history of cardiovascular disease should be treated with aspirin (81–325 mg daily) for secondary prevention.^18,21 In the presence of allergy or other contraindications to aspirin, clopidogrel (75 mg daily) represents a superior alternative to aspirin.²² In diabetic patients with non-ST elevation ACS, the combination of aspirin plus clopidogrel is superior to aspirin alone.²⁴ In this group of patients, intravenous GP IIb/IIIa inhibitors have been shown to significantly reduce recurrent ischemic events including MI and mortality.²⁷Antiplatelet therapy during percutaneous coronary intervention in patients with diabetes. In patients undergoing percutaneous coronary intervention (PCI), certain groups of patients, including those with unstable angina, acute MI, multivessel intervention, complex lesion morphology or diabetes, constitute high-risk groups for periprocedural cardiac events.²⁷ In diabetic patients, there is a trend toward higher rates of stent thrombosis (3.2% in diabetics versus 2.0% in nondiabetics; p = 0.06).28 Acute or subacute stent thrombosis is a catastrophic complication of coronary stenting that leads to transmural MI in 90% and death in 25% of cases.²⁹ Diabetic patients who undergo stent placement, similar to those without diabetes, should receive combination antiplatelet therapy with aspirin and clopidogrel for 4 weeks.³⁰ In the subgroup of patients undergoing PCI in the CURE trial, the PCI-CURE study,³¹ pretreatment with clopidogrel for a median of 6 days followed by long-term therapy was associated with lower rates of cardiovascular death, MI or any revascularization (p = 0.03) and of cardiovascular death or MI (p = 0.047). This strategy was also beneficial in diabetic patients, who experienced a large reduction from 16.5% to 12.9% in cardiovascular death or myocardial infarction.³¹ Another group of antiplatelet agents, that have been shown to decrease periprocedural complications are GP IIb/IIIa inhibitors. Overall, treatment with these agents has resulted in an absolute reduction of 1.5% to 6.5% in the 30-day risk of death, MI or urgent target vessel revascularization (TVR), with some variability in treatment effect among the agents tested (abciximab, eptifibatide and tirofiban).²⁵ In an analysis of 491 diabetic patients enrolled in the EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial), treatment with abciximab led to a significant reduction in the combined endpoint of death, MI and TVR at 6 months; composite endpoint occurred in 25.2% of the stent-placebo group, 23.4% of the balloon angioplasty-abciximab group, and 13.0% of the stent-abciximab group (p = 0.005).³² Irrespective of revascularization strategy (stent or balloon angioplasty), abciximab therapy resulted in a significant reduction in 6-month death or MI rate (p = 0.029).³² In a pooled analysis of 3 randomized trials of PCI and adjunctive therapy with abciximab, Bhatt et al. compared 1-year mortality rate for patients with and without diabetes.³³ In 1,462 diabetic patients, abciximab significantly reduced mortality from 4.5% to 2.5% (p = 0.031), while in 5,072 non-diabetic patients, the reduction in mortality (from 2.6% to 1.9%) was not statistically significant (p = 0.099). In diabetic patients who underwent multivessel intervention, 1-year mortality was reduced from 7.7% to 0.9% with the use of abciximab (p = 0.018).³³ The mortality benefit in diabetic patients undergoing PCI is not restricted to abciximab, and is also seen with other GP IIb/IIIa inhibitors, including tirofiban and eptifibatide, as shown in a recent meta-analysis by Roffi et al.²⁷ These investigators reviewed data on 6,458 diabetic patients with non-ST elevation ACS who were treated with GP IIb/IIIa inhibitors. Of these, a total of 1,279 underwent PCI during index hospitalization. In this subgroup, therapy with a GP IIb/IIIa inhibitor reduced 30-day mortality from 4.0% to 1.2% (OR: 0.30; 95% CI: 0.14–0.69; p = 0.002).²⁷ In the diabetic subgroup of TARGET (Do Tirofiban and ReoPro Give Similar Efficacy Trial), a total of 1,117 diabetic patients were randomized to tirofiban (n = 560) or abciximab (n = 557).³⁴ The incidence of death, MI or urgent TVR at 30 days was 6.2% in the tirofiban group and 5.4% in the abciximab group (p = 0.54). There was also similar event rates in the tirofiban and abciximab groups at 6 months (15.7% vs. 16.9%; p = 0.610), indicating that these 2 agents are equally effective in reducing the composite endpoint of death, MI or TVR (Figure 3). The 1-year rate of mortality of diabetic patients in the TARGET trial was 2.1% in the tirofiban group and 2.9% in the abciximab group (p = 0.43), again showing the similar efficacy of these 2 agents.³⁴ In the ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) trial, treatment with eptifibatide provided equal benefits in patients with and without diabetes undergoing elective stent placement.³⁵ Treatment with GP IIb/IIIa inhibitors has also been shown to be effective in the setting of acute ST-elevation MI.^36,37 In the ADMIRAL (Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up) trial, patients with acute MI assigned to stenting plus abciximab, as compared to stenting alone, had a lower incidence of death, reinfarction or urgent revascularization (7.4% versus 15.9%; p = 0.02) at 6-month follow-up.³⁷ In the diabetic subgroup (53/300), treatment with stent plus abciximab, as compared to stent plus placebo, significantly reduced mortality (0% versus 16.7%; p = 0.02) and TVR (13.8% versus 37.5%; p = 0.046) at 6 months. However, it should be noted that the overall number of patients is small, which prohibits any conclusive statements.³⁷Other adjunctive therapy. Diabetes mellitus is associated with a markedly increased prevalence of cardiovascular disease. Moreover, cardiovascular case fatalities remain the leading cause of death in patients with diabetes. Therefore, in addition to treatment with antiplatelet agents, more vigorous control of hyperglycemia, hyperlipidemia, hypertension and other risk factors is of crucial importance in reducing the risk of cardiovascular disease in diabetic patients.¹⁷ Improved glycemic control attenuates the heightened platelet activity seen in patients with diabetes. There is also a significant reduction in microvascular diabetes complications with intensive glucose control.³⁸ With regard to treatment of hyperlipidemia, diabetes is considered a CAD risk equivalent, and diabetic patients should be treated aggressively with lipid-lowering agents, and in particular statins, to achieve the targeted low-density lipoprotein of 38 Summary. Atherosclerotic heart disease is the major cause of mortality in diabetic patients. To a large extent, platelet inhibition with oral or intravenous agents has “normalized” the increased risk of diabetic patients with CAD. Aspirin is effective in the primary prevention of fatal and nonfatal MI in patients with diabetes, and in the absence of contraindications, should be given to all diabetic subjects at high risk for vascular disease. Clopidogrel has been proven superior to aspirin, especially in diabetic patients. Patients with diabetes and non-ST elevation ACS would benefit from combination antiplatelet therapy with aspirin and clopidogrel. There is a large body of evidence indicating the beneficial effects of GP IIb/IIIa inhibitors in reducing MI and death in diabetic patients with ACS or after PCI.

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