Drug Information Rounds

Aspirin Dose for Prevention of Cardiovascular Disease in Diabetics Sandra N Nowak and Linda A Jaber

OBJECTIVE:

To determine whether a specific dose of aspirin can be recommended for prevention of cardiovascular disease in patients with diabetes.

DATA SOURCE:

Biomedical literature was accessed through MEDLINE (1990–February 2002). Key terms included diabetes, cardiovascular protection, and aspirin.

DATA SYNTHESIS: Pharmacologic and clinical studies focusing on the dose–response relationship of aspirin therapy were reviewed. Evidence supports the benefit of low-dose aspirin therapy in reducing vascular events in secondary and primary prevention trials in various patient populations; however, some studies suggest larger doses of aspirin may be needed in certain patients. CONCLUSIONS: Review of the evidence does not support a particular dose of aspirin for cardiovascular protection in diabetic patients. Clinical guidelines recommend aspirin therapy in the range of 81–325 mg/d. However, due to an increased prevalence of cardiovascular morbidity and disturbances in coagulation in diabetic patients, the dose of aspirin for prevention of cardiovascular disease in these individuals may be different from that in other populations and requires further evaluation. KEY WORDS: aspirin, cardiovascular protection, diabetes.

Ann Pharmacother 2003;37:116-21.

REQUEST

Does evidence support the recommendation of a particular aspirin dose (81 vs. 325 mg/d) for prevention of cardiovascular disease in patients with diabetes? RESPONSE

BACKGROUND

Patients with diabetes have a two- to fourfold increased risk of dying from cardiovascular complications than their nondiabetic counterparts. Cardiovascular disease is present at the time of diagnosis in many patients with type 2 diabetes. The prevalence of complications reported in the UKPDS 6 (United Kingdom Prospective Diabetes Study)1 in newly diagnosed diabetic patients included hypertension in 35% of patients, abnormal electrocardiogram in 18%, and previous myocardial infarction (MI), stroke, or inter-

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mittent claudication in 1–3% of patients at study entry. In addition, patients with diabetes without a history of MI have a similar risk of cardiac disease as nondiabetic individuals who have already had an MI.2 These studies provide a rationale for aggressive management of cardiovascular risk factors in patients with diabetes. A meta-analysis of 145 randomized trials of antiplatelet therapy reported a 25% reduction in the rate of events, including vascular death and nonfatal MIs or strokes in patients with a history of cardiovascular disease and in subjects at high risk of cardiovascular disease.3 These reductions were significant regardless of age, gender, and presence or absence of hypertension and diabetes. A procoagulant state exists, including an activated intrinsic coagulation system and enhanced platelet aggregation, in patients with diabetes.4 Aspirin irreversibly inhibits platelet activity by acetylation of the hydroxy group of the serine residue at position 529 within the peptide chain of prostaglandin G/H synthase (also known as cyclooxygenase), the enzyme responsible for the production of pros-

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taglandin G2 and H2 and thromboxane A2 (TXA2). TXA2 is a potent platelet proaggregant and a vasoconstrictor. Patients with diabetes have enhanced production of TXA2 and increased platelet turnover.5-7 Aspirin leads to inactivation of TXA2 synthesis almost immediately due to acetylation of prostaglandin G/H synthase in hepatic portal circulation.5,6 Since platelets do not have the ability to regenerate the enzyme, platelet activity is lost for its lifespan (8–10 d). Inhibition of platelet activity occurs in a dose-dependent manner. Low aspirin doses (300 mg/d result in more immediate inhibition of TXA2 biosynthesis and may provide additional pharmacologic benefits including reduced thrombin formation and increased plasminogen activation. Although the exact mechanism is unknown, it is postulated that aspirin’s antithrombin effects result from acetylation of platelet membrane proteins and/or proteins involved in the coagulation pathway (i.e., prothrombin).8-10 Inhibition of thrombin activity reduces the conversion of fibrinogen to a stable fibrin clot. The exact aspirin dose that inhibits thrombin formation is unclear. The American Diabetes Association recommends aspirin therapy for secondary prevention in patients with evidence of large-vessel disease and as primary prevention in high-risk patients with types 1 and 2 diabetes, which includes age >30 years, a family history of coronary heart disease, cigarette smoking, hypertension, obesity, albuminuria, or hypercholesterolemia.11 The recommended daily dose of aspirin is 81–325 mg of the enteric-coated formulation. The purpose of this review is to determine whether evidence exists to support the recommendation of a particular aspirin dose for cardiovascular protection in diabetic patients. LITERATURE REVIEW Aspirin and Thrombinogenesis

CLINICAL TRIALS

Daily aspirin doses as low as 20–50 mg administered to patients with diabetes result in inhibition of TXA2 synthesis, resulting in decreased platelet aggregation.7 Doses >300 mg/d may provide additional benefit including reduced thrombin formation.5,6 Generation of thrombin facilitates the conversion of fibrinogen to fibrin and a resultant fibrin clot.4 In vitro and ex vivo methods for evaluation of thrombin generation have been developed.9 The ex vivo method is commonly used to assess thrombinogenesis in healthy volunteers and patients with coronary heart disease (CHD) taking aspirin. This method is used to assess thrombin generation in samples of blood emerging from standardized skin incisions. Biochemical markers signaling thrombin generation include changes in the rate of formation of fibrinopeptide A, which is cleaved from fibrinogen by thrombin; thrombin–antithrombin III complex; and prothrombin fragment F1+2, which is split from prothrombin when thrombin is generated.9 Increased concentrations of any of these markers signal active thrombin formation. Rewww.theannals.com

sults from studies conducted in healthy volunteers suggest that both low- and high-dose aspirin therapy, 75 or 300 mg/d, are effective in reducing thrombinogenesis.12,13 In contrast, an in vitro study evaluating aspirin 75 versus 500 mg/d found significant reductions in the rate of formation of prothrombin fragment F1+2 in subjects taking 500 mg/d and a nonsignificant trend toward reduction in the 75-mg/d group.10 Suppression of thrombin formation in patients with CHD or status-post coronary artery bypass graft (CABG) surgery requires larger doses of aspirin (~300 mg/d). Ratnatunga et al.14 evaluated shear-induced platelet thrombus formation in 192 patients given aspirin 75 mg/d for 3 months after CABG surgery. Ninety patients were then advised to increase the dose to 300 mg/d and were retested. While antiplatelet effects were demonstrated at the higher dose, low-dose therapy did not significantly reduce platelet aggregation. The authors concluded that higher doses of aspirin are needed to produce antithrombotic effects in patients with CHD. Evaluation of patients with CHD and varying levels of hypercholesterolemia suggested that patients with elevated total cholesterol concentrations may not benefit from the antithrombotic effects at daily doses of 75 or 325 mg.9,15 However, in patients with serum cholesterol concentrations