Dosage

ASA should be dosed at 75 to 162 mg once daily for prevention of vascular ischemic events. Doses above 162 mg daily do not provide increased benefit and are associated with significantly increased bleeding rates. No dosing adjustment is required in patients with mild to moderate renal or hepatic dysfunction.

Mechanism of Action

ASA exerts its antithrombotic effect by inhibition of platelet cyclooxygenase-1 (COX-1), also known as prostaglandin H-synthase-1. COX-1 catalyzes the first committed step in prostanoid biosynthesis, the conversion of arachidonic acid to prostaglandin H2 (PGH2 ) which is subsequently converted to thromboxane A2 (TXA2), a powerful inducer of platelet aggregation and vasoconstriction. Inhibition of COX-1 is due to permanent acetylation of serine 529, blocking substrate (arachadonic acid) access to the catalytic site of the enzyme. The anucleate platelet is unable to synthesize COX-1, thus low dose ASA administered once daily is able to permanently inhibit individual platelet function. Although ASA also inhibits COX-2, also known as prostaglandin H-synthase-2 by a similar mechanism, this enzyme, found in nucleated cells can be rapidly replenished. This results in far higher doses of ASA, administered more frequently, to inhibit COX-2 function responsible for non-platelet homeostatic cellular processes.

Recommendations in Vascular Prevention

Primary Prevention

Although ASA has been demonstrated to reduce the relative of primary vascular events the absolute benefit is small and largely negated by adverse bleeding events.

Recommendation

For men and women without evidence of manifest vascular disease, the use of ASA at any dose is not recommend for routine use to prevent ischemic vascular events (Class III, Level A).

Secondary CAD prevention

ASA has demonstrated benefit in the secondary prevention of coronary vascular ischemic events both acutely and with long term use. Benefit has also been demonstrated for the use of ASA following percutaneous intervention or coronary artery bypass grafting.

Recommendations

For all patients with ACS who survive to hospital discharge, indefinite therapy with low-dose ASA (75 to 162 mg daily) is recommended (Class I, Level A).

Indefinite therapy with ASA 75 to 162 mg daily should be used in all patients with acute or chronic ischemic heart disease without contraindications to its therapy (Class I, Level A). This includes patients who have undergone PCI.

For all patients who undergo saphenous vein CABG surgery, ASA 75 to 162 mg daily is recommended as lifelong therapy unless contraindicated (Class I, Level A).

Secondary Prevention of Cerebrovascular Disease

ASA has demonstrated benefit in the secondary prevention of cerebral vascular ischemic events both acutely and with long term use.

Recommendation

Patients who suffer a TIA or ischemic stroke of noncardiac origin should be treated with an antiplatelet agent (Class I, Level A). Initial therapy should be ASA 75 to 162 mg once daily, clopidogrel 75 mg once daily, or ER dipyridamole 200 mg twice daily plus ASA 25 mg twice daily (Class I, Level A).

Vascular Prevention in Patients With PAD

Evidence for a benefit of ASA in patients with symptomatic PAD is far more convincing than in those with asymptomatic disease ie. Ankle Brachial Index ≤ 0.9. Benefit has also been demonstrated for the use of ASA following peripheral vascular reconstruction. There are no randomized trials that have examined the role of antiplatelet agents in the prevention of MI, stroke, or cardiovascular death in patients with AAA. However, significantly increased rates of cardiovascular deaths and hospitalizations for atherothrombotic events, including coronary, carotid, and peripheral vascular interventions and surgical revascularizations, were observed in patients with AAA.

Recommendations

For patients with asymptomatic PAD with an ankle brachial index ≤0.9, low-dose ASA (75-162 mg daily) may be considered for those at high risk because of associated atherosclerotic risk factors in the absence of risk factors for bleeding (Class IIb, Level C).

For patients with symptomatic PAD without overt CAD or cerebrovascular disease, low-dose ASA (75-162 mg daily) or clopidogrel 75 mg daily is recommended, providing the risk for bleeding is low (Class IIb, Level B).

Long-term antiplatelet therapy with ASA 75 to 162 mg daily should be given to patients who undergo lower-extremity balloon angioplasty with or without stenting for chronic symptomatic PAD (Class IIa, Level C).

Low-dose ASA (75-162 mg daily) may be considered for all patients with an AAA, particularly those with clinical or subclinical PAD (Class IIb, Level C).

Vascular Prevention in Patients with Diabetes

The results of several observational studies subgroup analyses of randomized clinical trials, trials conducted specifically in patients with diabetes, and several meta-analyses suggest that ASA therapy for primary prevention may confer similar, or even less, benefit for cardiovascular event reduction in individuals with diabetes than in those without.

Recommendation

There is currently no evidence to recommend routine use of ASA at any dose for the primary prevention of vascular ischemic events in patients with diabetes (Class III, Level A).

Vascular Prevention in Patients with Chronic Kidney Disease

There is little high-quality evidence to guide the use of ASA or other antiplatelet agents in patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD). A meta-analysis of studies of antiplatelet therapy for maintenance of access patency among dialysis patients demonstrated a significant reduction in the relative risk of serious vascular events associated with antiplatelet therapy, mainly ASA.

Recommendation

ASA 75 to 162 mg daily may be considered for primary prevention of ischemic vascular events in patients with ESRD and a low risk of bleeding (Class IIb, Level C).

Vascular Prevention in Women Who Are Pregnant or Breastfeeding

There are no clinical trials demonstrating the efficacy of antiplatelet therapy or relative superiority of types of antiplatelet therapy in pregnant women with coexisting cardio- or cerebrovascular diseases. Data from randomized trials in which the benefits of ASA were investigated for primary and secondary prevention of preeclampsia and improved pregnancy rates in women who undertake assisted reproductive technology suggest that ASA use does not increase maternal or fetal bleeding risks, placenta abruption, or congenital defects.

Recommendations

For cardio- or cerebrovascular disease in which antiplatelet therapy would be indicated in non-pregnant women, there should be similar considerations for its use in pregnancy (Class IIa, Level A).

Low-dose ASA (75 to 162 mg daily) is likely safe for use during the first trimester of pregnancy (Class IIa, Level A). Low-dose ASA can be used safely during the second and third trimesters of pregnancy (Class I, Level of Evidence A).

Low-dose ASA (75 to 162 mg daily) may be considered for use in breastfeeding women (Class I, Level C).

Warnings & Special Considerations

Management of Patients on ASA Therapy Who Require a Surgical or Other Invasive Procedure

Patients who are receiving ASA and undergoing a diagnostic test associated with a low risk for bleeding may continue ASA without interruption, whereas patients undergoing a noncardiac procedure associated with a high risk for bleeding should discontinue ASA 7 to 10 days before the procedure (Class IIa, Level C).

Interaction Between ASA and Nonsteroidal Anti-Inflammatory Drugs

Although no randomized trials examining the clinical effect of an interaction between ASA and nonsteroidal anti-inflammatory drugs (NSAIDs) have been completed, laboratory studies and observational and epidemiologic data have suggested an adverse effect. This interaction has important clinical consequences because, unlike coxibs, traditional NSAIDs may inhibit ASA binding to platelet cyclooxygenase-1.

Recommendations

Individuals taking low-dose ASA (75 to 162 mg daily) for vascular protection should avoid the concomitant use of traditional NSAIDs (Class III, Level C).

If a patient taking low dose ASA (75 to 162 mg daily) for vascular protection requires an anti-inflammatory drug, specific cyclooxygenase-2 inhibitors should be chosen over traditional NSAIDS (Class IIb, Level C).