Mechanism of action: Aspirin (acetylsalicylic acid) irreversibly inhibits prostaglandin H synthase (cyclooxygenase-1) in platelets and megakaryocytes, and thereby blocks the formation of thromboxane A2 (TXA2; a potent vasoconstrictor and platelet aggregant).3 It is only the parent form, acetylsalicylic acid, which has any significant effect on platelet function. Because platelets are unable to regenerate cyclooxygenase, the immediate antithrombotic effect of aspirin remains for the lifespan of the platelet (8–10 days). As, after stopping aspirin therapy, normal haemostasis may be regained when about 20% of platelets have normal cyclooxygenase activity, daily aspirin intake is recommended.

Dose and administration: Formulations of aspirin currently available in Australia include a 100 mg enteric-coated form as well as 300 mg and 324 mg soluble tablets.

Aspirin is rapidly absorbed from the gastrointestinal (GI) tract, with peak concentrations achieved in 30–40 minutes.

When given as a single oral dose, at least 160 mg of soluble aspirin is required to maximally inhibit platelet function within 30 minutes. Thus, this dose (half 324 mg tablet) should be given as a loading dose if a rapid antiplatelet effect is required.

Soluble aspirin (40–80 mg daily) and enteric-coated aspirin (80–100 mg daily) have a cumulative effect, so that platelet TXA2 formation is maximally inhibited (by more than 95%) after 4–5 days.3,4

The evidence from randomised controlled trials (RCTs) supports daily doses of aspirin in the range 75–150 mg for the long-term prevention of serious vascular events in high risk patients (E1; Box 3).5 Higher doses of 500–1500 mg aspirin daily are no more effective (E1)5 (for an explanation of level-of-evidence codes, see Box 4).

Adverse effects: Aspirin use is associated with dose-related symptoms of upper-GI toxicity (nausea, heartburn, epigastric pain). High doses of aspirin (500–1500 mg daily) compared with medium (75–325 mg daily) or low (30 mg) doses, significantly increase the risk of upper-GI symptoms (E1).12-15 Enteric-coated aspirin may cause less gastric irritation than soluble aspirin.4

Aspirin is associated with about a 60%–70% excess of non-fatal extracranial haemorrhage (mostly from the GI tract), which corresponds to an absolute excess risk of about one or two per 1000 patients treated per year (E1).5,16 The risk of bleeding is not significantly different with different daily aspirin doses or different aspirin formulations (plain, enteric-coated and buffered aspirin).12,16 Aspirin is associated with an increased risk of intracranial haemorrhage of about one per 1000 patients treated for 3 years (E1).17 Again, there is no clear variation in risk with the dose of aspirin used (E1).17

Mechanism of action: The thienopyridine derivatives (clopidogrel and ticlopidine) are metabolised in the liver to active compounds which covalently bind to the adenosine phosphate (ADP) receptor on platelets and dramatically reduce platelet activation (see Box 1).

Dose and administration: An oral loading dose of 300–600 mg clopidogrel produces detectable inhibition of ADP-induced platelet aggregation after 2 hours, which becomes maximal after 6 hours.18,19 If a loading dose of clopidogrel is not used, repeated daily oral doses of 75 mg clopidogrel are required to achieve a steady-state maximal platelet inhibition, which is comparable with that produced by 250 mg ticlopidine orally, twice daily.20

Adverse effects: Compared with aspirin, the thienopyridines are associated with a lower risk of GI haemorrhage (odds ratio [OR], 0.71; 95% CI, 0.6–0.9) and upper-GI symptoms (OR, 0.84; 95% CI, 0.8–0.9), and an increased risk of diarrhoea and of skin rash (E1).21 Ticlopidine doubles the risk of skin rash (OR, 2.23; 95% CI, 1.7–2.9) and diarrhoea (OR, 2.27; 95% CI, 1.9–2.8) compared with aspirin (E1), whereas clopidogrel increases skin rash (OR, 1.32; 95% CI, 1.2–1.5) and diarrhoea by about a third (OR, 1.34; 95% CI, 1.2–1.6), compared with aspirin (E2).21 Clopidogrel has superseded ticlopidine because the latter is associated with an excess of neutropenia compared with aspirin (OR, 2.72; 95% CI, 1.5–4.8) (E1), particularly in the early months of therapy, whereas clopidogrel is not (OR, 0.63; 95% CI, 0.3–1.4) (E2).21 Furthermore, ticlopidine is associated with a significant excess of thrombocytopenia and of thrombotic thrombocytopenic purpura (TTP) (E3₂),22,23 whereas clopidogrel is not (E2).6,21 Although TTP has been reported in 20 patients taking clopidogrel,24,25 the association between clopidogrel and TTP is likely to be coincidental (E3₂).26 Therefore, if ticlopidine is to be used, haematological monitoring should be undertaken at commencement and every 2 weeks in the first 4 months of therapy.

Dipyridamole inhibits phosphodiesterase, which inactivates cyclic AMP (Box 1). Increased intraplatelet concentrations of cyclic AMP reduce the activation of cytoplasmic second messengers. Dipyridamole also stimulates prostacyclin release and inhibits thromboxane A2 formation. Because the effect is short-lasting, repeated dosing or slow-release preparations are required to inhibit platelet function for 24 hours.

Mechanism of action: Glycoprotein IIb/IIIa receptor antagonists block the final common pathway for platelet aggregation (Box 1). Abciximab is a humanised mouse antibody fragment with a high binding affinity for the glycoprotein IIb/IIIa receptor. Tirofiban (a non-peptide derivative of tyrosine) and eptifibatide (a synthetic heptapeptide) mimic part of the structure of fibrinogen that interacts with the glycoprotein IIb/IIIa receptor and thus compete with ligand binding of fibrinogen to the glycoprotein IIb/IIIa receptor. Eptifibatide is not currently approved for use in Australia.

Dose and administration: Glycoprotein IIb/IIIa receptor antagonists are given intravenously as a bolus injection, followed by a continuous infusion for up to 72 hours. At 24 hours after cessation of an infusion of abciximab, there is persistent blockade of more than 50% of platelet glycoprotein IIb/IIIa receptors, but platelet function recovers after 2 days. By contrast, the antiplatelet effects of tirofiban rapidly dissipate after cessation of the infusion.

Adverse effects: Thrombocytopenia is relatively common (1.6% compared with 0.7% for placebo), and can be delayed for up to 5 days (E2). Acute severe thrombocytopenia (< 20 x 109/L in 24 hours) occurs in 0.6% of patients, and needs to be differentiated from other causes such as immune heparin-induced thrombocytopenia (E2). The risk of recurrent thrombocytopenia is increased with re-exposure to abciximab.27

Aspirin (75–150 mg/day) decreases the incidence of coronary heart disease in adults who are at increased risk (> 0.6% per year) of heart disease, but it increases the incidence of gastrointestinal bleeding (E1).36-39 For every 1000 patients with a 3% risk of a coronary event over 5 years, long-term aspirin therapy prevents 4–12 coronary events and causes 0–2 haemorrhagic strokes and 2–4 major gastrointestinal bleeding events (E1). This is a benefit-to-harm ratio of about 2.0.

Individuals at increased cardiovascular risk who may wish to consider long-term aspirin therapy (with 75–150 mg/day) are men older than 40 years of age, postmenopausal women, and younger people with risk factors for cardiovascular disease.36-39 Risk factors for cardiovascular disease include increasing age, male sex, cigarette smoking, increasing blood pressure, increasing blood total cholesterol concentration, decreasing high-density lipoprotein cholesterol concentration, raised fasting blood glucose concentration (ie, diabetes mellitus), and a positive family history of cardiovascular disease (in younger adults).36-39

Risk factors for haemorrhagic complications of aspirin include increasing age, any bleeding diathesis, uncontrolled hypertension, and concomitant use of other non-steroidal anti-inflammatory agents or anticoagulants. Enteric-coated or buffered preparations of aspirin do not clearly reduce adverse haemorrhagic effects.

Antiplatelet therapy for high-risk patients reduces the odds of deep-vein thrombosis by 37% (95% CI, 29%–44%) and fatal or non-fatal pulmonary embolism by 53% (95% CI, 41%–63%) among surgical and medical patients.40,41 However, anticoagulants such as heparin or low-molecular-weight heparin are still the preferred method of thromboprophylaxis in most patients, because they are likely to be more effective than aspirin.