INTRODUCTION

Drugs that inhibit platelet function have assumed increasing importance in the care of patients with cardiovascular and cerebrovascular disease, which are leading causes of death in the U.S. They also have uses in other settings to a lesser extent.

Aspirin - Aspirin, or acetylsalicylic acid (ASA), remains the most studied, most clinically effective, most widely used, and least expensive antiplatelet agent currently available.  ASA exerts its antiplatelet effect by acetylating the endoperoxide cyclo-oxygenase irreversibly within minutes of the ingestion of a low dose of the drug.  Thus for the life of the platelet, normally 10 days, platelet function will be inhibited.  Bleeding times may be prolonged for at least 3-5 days after ASA ingestion.  Clinically, the ASA anti-platelet effect is more important in preventing arterial thrombi, where platelets are more involved in the formation of clot, than in venous thrombi.  Numerous trials have shown ASA beneficial for:

1. prevention of primary myocardial infarction(MI),particularly in males but also in females

2. reduction of the risk of MI and death in the setting of unstable angina

3. prevention of recurrent MI after initial infarction

4. prevention of new or recurrent stroke and death after transient ischemic attacks (TIAs) or minor stroke

5. prevention of coronary artery bypass graft and stent closure.

In addition, one major study reported the addition of ASA to warfarin decreases the thrombotic risk without increasing the bleeding risk in patients with prosthetic cardiac valves.

Major side effects of ASA include increased risk of bleeding in general, GI irritation, and bleeding from ulceration of gastric mucosa in particular.  There is a slight increase in risk of hemorrhagic stroke in patients taking ASA.  Ototoxicity with tinnitus can occur; this as well as the other side effects of ASA are seen less often at low doses.

Dosing recommendations for ASA vary widely, but a dose of 325 mg/day (one standard ASA tablet) is a reasonable dose that may minimize side effects for all of the above indications except for ASA use with warfarin in cardiac valve patients where 100 mg/day is recommended (slightly more than one baby aspirin which is 81 mg).

Clopidogrel (Plavix) - Clopidogrel is an oral thienopyridine platelet antagonist that has been associated with fewer side effects to date than its structurally related predecessor, ticlopidine (Ticlid).  Clopidogrel exerts its antiplatelet action for the life of the platelet, i.e. 10 days, and may cause prolongation of the bleeding time.  For optimal reduction in bleeding risk, it should be stopped 10-14 days prior to surgery.  The mechanism of action of clopidogrel is unclear, but seems to be by inhibition of ADP-induced platelet aggregation but does not interfere with in vitro platelet function studies commonly done in the laboratory.

The indications for use of clopidogrel are evolving, but a large randomized study and other reports have shown it to be:

1. superior to ASA for prevention of stroke, myocardial infarction, and peripheral vascular disease in patients with atherosclerotic disease

2. superior to ticlopidine when used in conjunction with ASA for prevention of coronary artery stent closure.

3. probably superior for stroke prevention in combination with ASA than either agent alone

4. useful for true ASA allergic patients

Side effects include increased risk of GI bleeding at an incidence not higher than that for other antiplatelet agents.  Dosing is 75 mg once daily with or without food.  For coronary artery stents, dosing is recommended for 30 days along with ASA.

Ticlopidine (Ticlid) - Ticlopidine is an oral platelet antagonist found to be useful in patients with unstable angina and prevention of stroke in patients with transient ischemic attacks.  It is also of benefit in patients with coronary artery stents when used in conjunction with ASA.  Its higher toxicity profile relative to clopidogrel, has made it currently more difficult to recommend.

Side effects of ticlopidine include cholestatic jaundice, nausea, diarrhea, neutropenia and skin rash.  The latter may require its discontinuance.  Monitoring white blood counts every 2 weeks during the first three months of therapy is necessary.  Recent reports have clearly indicated that ticlopidine is also associated with thrombotic thrombocytopenic purpura (TTP).

The standard dose is 250 mg PO q12h.  Overdosage has not been a clinical problem, but prolonged bleeding times with ticlopidine may be normalized with methylprednisolone at a dose of 20 mg IV.

Abciximab (ReoPro) - Abciximab is a human-mouse monoclonal antibody for intravenous infusion, binding to the glycoprotein IIb/IIIa receptor on human platelets, and inhibiting platelet aggregation.  It may markedly prolong the bleeding time, and while it has a half-life of only 10 minutes, low levels of glycoprotein IIb/IIIa receptor blockade may be present for up to 10 days after infusion.  The major indication for abciximab is as adjunctive therapy with heparin and aspirin for prevention of abrupt coronary vessel closure after angioplasty.  The major side effects are bleeding and thrombocytopenia (»5%) and caution must be taken in patients with any predisposing bleeding risks.  The dose is 0.25 mg/kg IV given as a bolus 10-60 minutes prior to the start of angioplasty followed by an infusion of 10 microgram (.01 mg)/min IV for 12 hours.

Tirofiban (Aggrastat) - Tirofiban is a synthetic glycoprotein IIb/IIIa inhibitor for intravenous use indicated for unstable angina as an adjunct to heparin and aspirin therapy in coronary angioplasty and atherectomy.  For most patients, dosing is 0.4 microgram/kg/min for 30 min. followed by 0.1 microgram/kg/min.  Patients with creatinine clearance of < 30mL/min should have a dose rate reduction of 50%.

Eptifibatide (Integrelin) - Eptifibatide is a reversible inhibitor of platelet aggregation that prevents binding of fibrinogen, von Willebrand's factor, and other ligands to the glycoprotein IIb/IIIa receptor.  Safety and efficacy studies for eptifibatide have been done in-patients who received concomitant heparin and ASA.  Eptifibatide has been shown to be effective in patients with acute coronary syndromes and those undergoing percutaneous balloon angioplasty or atherectomy.  Dosing recommendations vary depending on the indication.

Dipyridamole (Persantine) - The indications for dipyridamole have narrowed in recent years with the introduction of other platelet inhibitors.  It retains an indication as an adjunct to warfarin for the prevention of postoperative thromboembolic complications of prosthetic cardiac valve replacement.  While several biochemical effects of dipyridamole are known, the exact manner in which it causes platelet inhibition is unclear.  The dose for patients with recent prosthetic valve surgery is 75-100 mg p.o. qid.  When dipyridamle is used as an adjunct with warfarin, ASA should not be administered concomitantly.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) - NSAIDS have weaker antiplatelet activity than other antiplatelet agents and are not indicated for prevention of thrombosis. NSAIDS are classified as cyclo-oxygenase-1 (COX-1) or cyclo-oxygenase-2 (COX-2) inhibitors with only the COX-1 inhibitors having antiplatelet activity. This is of clinical importance when choosing an NSAID for analgesia in a patient with a bleeding history where a COX-2 inhibitor may be preferable. In general most of the older NSAIDS have significant antiplatelet COX-1 activity except for choline magnesium trisalicylate (Trilisate) and nabumetone (Relafen). The newer NSAIDS celecoxib (Celebrex) and rofecoxib (Vioxx) are also COX-2 inhibitors and may be safer in patients with a bleeding history.

Miscellaneous - Other substances have been shown to be associated with acquired platelet dysfunction to the point of causing bleeding in some situations.  These include garlic, ginger, cumin, onions, turmeric, Chinese black tree fungus, and vitamins C and E.

REFERENCES:

1. Patrono C, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects.  Chest 1998; 114:5:470S-88S.

2. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE).  Lancet 1996; 348: 1329-39.

3. George JN, et al. The clinical importance of acquired abnormalities of platelet function.  NEJM 1991; 324: 27-29.

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