Aspirin Therapy for Prevention of Cardiovascular Disease in Patients with Diabetes

Coronary artery disease is the leading cause of death in patients with diabetes. Platelets play a major role in the pathophysiology and clinical manifestations of ischemic heart disease. It is well known that platelets in diabetic patients are hyperreactive, with exaggerated adhesion, aggregation, and thrombin generation. Aspirin and other antiplatelet agents have been shown to reduce the incidence of ischemic events in patients with and without diabetes, whether or not they have a history of cardiovascular disease. This article reviews the latest recommendations for the use of antiplatelet therapy in the primary and secondary prevention of cardiovascular events in diabetic patients.

J. Roberto Duran III, MD

Oscar Aguilar, MD, FACC

Cardiology Division

Texas Tech University Health

El Paso, Tex

PRACTICE POINTS

• The ADA recommends aspirin dosages of 75 to 162 mg/day for the primary and secondary prevention of CV events in diabetic patients who have no contraindications.

Diabetes mellitus is a powerful and independent risk factor for coronary artery disease (CAD). Women and men with diabetes have a 2-to 4-fold greater risk of dying from complications of cardiovascular (CV) disease than the general population.¹ With the increasing prevalence of diabetes, the number of patients with CAD will grow dramatically in the coming years.²

Platelets in diabetic patients are often hypersensitive because of an increased production of thromboxane, a potent vasoconstrictor and stimulant of platelet aggregation. Aspirin is a powerful antiplatelet medication that inhibits cyclooxygenase (COX)-mediated prostaglandin synthesis, thus preventing thromboxane A₂-mediated platelet aggregation. Aspirin is used for primary and secondary prevention of CV events in patients who have no contraindications. The dosage of aspirin for these indications has been controversial, but substantial evidence suggests that low doses are better than higher doses.

Diabetes Increases Risk for CV Events

Compared with persons without diabetes, diabetic patients are at higher risk of CV events. In one study, patients with diabetes had a 20% risk of first myocardial infarction (MI) or death over a 7-year period, compared with only 3.5% in nondiabetics.¹ In those with a history of MI, the corresponding 7-year incidence rates of recurrent MI were 45% in diabetic patients and 19% in nondiabetics. Thus, the risk of coronary events in patients with diabetes who do not have a history of MI is about the same as nondiabetic patients who have had an MI.¹

Among patients with acute coronary syndrome (ACS), diabetic patients are at a greater risk of death than nondiabetics. The Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I (GUSTO-I) trial included almost 35,000 patients without diabetes and 6000 patients with diabetes who were treated with thrombolysis for acute MI.³ Mortality at 30 days was significantly higher in patients with diabetes than those without diabetes (10.5% vs 6.2%, respectively). Other clinical events, including heart failure, cardiogenic shock, recurrent ischemia, and stroke, were also more common in diabetic patients. Similar results emerged from GUSTO III and V, but those with diabetes in GUSTOV had a lower 30-day mortality rate (8.5%) because of improved adjunctive therapy.⁴

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The Fragmin and Fast Revascularization During Instability in Coronary Artery Disease trial⁵ and the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Registry⁶ showed that diabetic patients with non-ST-elevation ACS are at increased risk of subsequent cardiac events. In OASIS, which involved patients with unstable angina and non-Q-wave MI, diabetes was found to be an independent predictor of mortality (relative risk, 1.57) and significantly increased the risks of recurrent MI, stroke, and new-onset heart failure (<.001).⁶

Diabetes and Platelet Function

Disruption of an atherosclerotic plaque activates the coagulation cascade, leading to thrombin generation and exposure of the deeper components of the plaque that are powerful platelet activators. Since platelets play a major role in acute vascular thrombosis, the increased risk of CV events among diabetic patients may, in part, be the result of altered platelet function.

There is clear evidence that platelets in patients with diabetes ("diabetic platelets") are larger and hyperreactive, with increased adhesion and aggregation as well as increased platelet-dependent thrombin generation. Diabetic patients have increased platelet-surface expression of glycoprotein Ib. In those with stable angina, blood glucose is an independent predictor of platelet-dependent thrombosis, with higher blood glucose levels causing more severe thrombosis. Moreover, in patients with type 2 diabetes, there is an association between glycemic control and blood thrombogenicity.^7,8

Diabetic patients appear to have higher thromboxane A₂ levels. Of note, tight metabolic control can significantly reduce thromboxane A₂ biosynthesis.⁹ Available data also indicate that calcium hemostasis is abnormal in the platelets of diabetic patients. Since intraplatelet calcium regulates the shape of platelets, thromboxane A₂ formation, and platelet aggregation, disordered calcium regulation may play a significant role in this abnormal platelet activity.¹⁰

Other abnormalities in hemostasis in diabetic patients include endothelial dysfunction, decreased production of nitric oxide by platelets, reduced antithrombin III activity, and high plasminogen activator inhibitor-1 and fibrinogen levels. In platelets, as well as in endothelial cells, elevated glucose levels lead 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. As a result of these abnormalities in diabetic platelets, antiplatelet therapy would be expected to reduce CV risks in patients with diabetes.¹¹

Aspirin in Primary Prevention

Only 2 studies of the benefits of aspirin in primary prevention have included diabetic patients. The Physicians' Health Study (PHS) compared the benefit of low-dose aspirin (325 mg every other day) versus placebo in 22,071 male physicians.¹² A total of 533 (2.4%) physicians had diabetes. This diabetic subgroup was divided into 2 groups, with 275 of them receiving aspirin and 258 receiving placebo. The risk of MI was 44% lower in treated patients; among physicians with diabetes, ischemic events were reduced by 10% in the aspirin group compared with 4% in the placebo group. These results were supported by the Early Treatment Diabetic Retinopathy Study that evaluated the use of aspirin as primary and secondary prevention in 3711 patients, 48% of whom had a history of MI. Risk for fatal or nonfatal MI was significantly lower with aspirin than with placebo (relative risk, 0.83).¹³

The Hypertension Optimal Treatment (HOT) trial, which included 18,790 hypertensive patients, including 1500 patients with diabetes, confirmed the positive effects of aspirin in primary prevention in this patient population.¹⁴ Patients were randomized to receive 75 mg/day of aspirin, or placebo. In the entire study population, the addition of low-dose aspirin (75 mg/d) to antihypertensive therapy reduced CV events by 15% and MI by 36%, compared with placebo.

Although the PHS and the HOT trials did not focus exclusively on diabetic patients, their findings clearly demonstrate the benefits of aspirin in this patient population.

Aspirin in Secondary Prevention

Multiple studies have supported the benefit of aspirin in the secondary prevention of CV events. A meta-analysis of 287 randomized trials of antiplatelet therapy in men and women at high risk of CV events (eg, acute or previous MI, stroke, transient ischemic attack, vascular surgery, angioplasty, angina) found that antiplatelet therapy reduced the risk of a serious vascular event?nonfatal MI, nonfatal stroke, or CV death?by about 25% in diabetics and nondiabetics.¹⁵

What Is the Optimal Dose of Aspirin for Prevention of CV Events?

The platelet release of thromboxane A₂ is very sensitive to aspirin. Several studies have concluded that low-dose (75 mg/d) aspirin is as effective as higher doses of either plain or enteric-coated aspirin in inhibiting thromboxane synthesis. Enteric-coated aspirin may be a better choice in patients with rapid platelet turnover, which occurs with diabetes, secondary to a steady plasma concentration that allows constant suppression of thromboxane A₂ synthesis.^16,17

Different doses of aspirin have been used in secondary prevention (Table 1). Within a few days of using 75 mg/day of aspirin in nondiabetic patients, the COX enzyme is almost completely inhibited in platelets, producing an antithrombotic effect.¹⁵ High doses ranging from 500 to 1500 mg/day are not only more gastrotoxic, they are no more effective than medium (160-325 mg/day) or low doses (75-150 mg/day). Thus available evidence supports daily doses of approximately 75 to 150 mg for the long-term prevention of serious vascular events in high-risk patients (which includes those with diabetes). The American Diabetes Association (ADA) recommends doses of 75 to 162 mg/day for patients with diabetes.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial compared the benefit of combination therapy with aspirin and clopidogrel (Plavix) to aspirin alone in patients with ACS.¹⁷ The addition of clopidogrel to aspirin reduced the incidence of CV death, MI, or stroke regardless of aspirin dose, ranging from about 11% for combination therapy compared with 9% for aspirin alone with aspirin doses of 100 mg/day or lower to 14% versus 10% with aspirin doses of 200 mg/day or higher.^17,18 In patients treated with aspirin alone, no major differences in efficacy were seen among the various doses (Table 2).

Most of the bleeding events observed in CURE were associated with use of aspirin, not clopidogrel. However, risk of bleeding with aspirin was lower with low doses, without any apparent reduction in efficacy (Table 3). The investigators concluded that bleeding could increase when aspirin was combined with another antiplatelet agent, such as clopidogrel.¹⁸

Available evidence suggests that the full antiplatelet effect of aspirin is seen at low doses. There are no data showing that higher doses are any more effective in preventing secondary events.¹⁹ In contrast, the gastrointestinal (GI) bleeding and irritation associated with aspirin seem to be dose related, which is why the ADA recommends dosages of 75 to 162 mg/day for primary and secondary prevention in diabetic patients without contraindications (Table 4).²⁰

Conclusion

Atherosclerotic heart disease is the major cause of mortality in diabetic patients. Aspirin is effective in the primary and secondary prevention of CV disease and should be given to any diabetic patient with a history of MI or with CV risk factors.

Lower doses of aspirin offer the same benefit as higher doses but with fewer GI complications. Enteric- coated aspirin may have advantages in producing a sustained-release on the medication.

There is no single study of aspirin in the primary or secondary prevention of CV events involving only diabetic patients. Most of the information we have is based on large studies in predominantly nondiabetic populations. We know that diabetic patients have hypersensitive platelets and secrete more thromboxane A₂. Since they are very sensitive to aspirin, it would be reasonable to assume that they may need higher doses of aspirin than nondiabetics, although there are no data to support this assumption. A large-scale trial comparing high-and low-dose aspirin in this patient population is urgently needed.

SELF-ASSESSMENT TEST

1. Which of these statements about the risk of CV events is true?

• Risk in diabetic patients without past MI is the same as in nondiabetics without past MI
• Risk in diabetic patients without past MI is twice that of nondiabetics with past MI

2. All these are features of platelets in diabetic patients, except:

• Disordered calcium hemostasis
• Increased production of oxygen free radicals

3. Randomized, controlled studies have demonstrated all the following facts, except:

• In patients with unstable angina and non-Q-wave MI, diabetic patients are at greater risk of newonset heart failure than nondiabetics
• Aspirin reduces risk of recurrent MI in diabetics with a history of MI

4. Which of the following doses of aspirin is appropriate for the primary prevention of CV events in a diabetic patient?

• 100 mg/day
• 250 mg/day

5. Aspirin therapy is contraindicated in all these diabetic patients, except:

• A45-year-old woman taking warfarin
• A75-year-old woman with a history of claudication

(Answers at end of reference list)

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Answers:

1. C; 2. C; 3. C; 4. B; 5. D