Dual Antiplatelet Therapy for Prevention of Recurrent Ischemic Events

Jean Nappi, PharmD, Fccp, Bcps; Robert Talbert, PharmD, Fccp, Bcps

Disclosures

Am J Health Syst Pharm. 2002;59(18) 

In This Article

Limitations of Oral Antiplatelet Therapy

Even in appropriately treated patients, aspirin has inconsistent anti-platelet effects. Possible explanations include aspirin resistance, the multiple routes of platelet activation, and the inhibitory effect of aspirin on prostacyclin, leading to increased platelet adhesion.[10,68,93]

The most common limitation of aspirin therapy is GI toxicity. This may be related to aspirin's apparent dose-response relationship to COX-1 in the gastric mucosa and its dose-independent inhibition of platelets, creating a situation in which gastric irritation and GI bleeding may occur at doses as low as 30-50 mg/day.[43,50,53] Aspirin is an acidic drug and may directly damage the gastric mucosa. In rare cases, aspirin allergy has been reported.[25]

The most common adverse effects associated with ticlopidine are related to GI upset, including diarrhea and nausea.[94] Ticlopidine has also been associated with life-threatening hematologic adverse reactions, including neutropenia, agranulocytosis, and thrombotic thrombocytopenic purpura (TTP). The rate of ticlopidine-associated TTP may be as high as 1 case in every 2000-4000 exposed patients. Hematologic monitoring is required for the first three months of therapy.

Common adverse reactions with clopidogrel include GI disturbances and rash. Bennett et al.[95] reported that more than 3 million people have received clopidogrel since its approval in 1998, and 11 cases of TTP have been identified by active surveillance. No cases of TTP have been reported in over 15,000 patients in completed or ongoing clinical trials with clopidogrel.[96] Because hematologic adverse events rarely occur in patients receiving clopidogrel, no hematologic monitoring is required; however, patients should still be monitored for bleeding.[97]

A major concern with dual oral antiplatelet therapy is the potential for increases in bleeding complications relative to monotherapy. Data from the CURE study showed a significant increase in minor bleeding (5.1% versus 2.4%) (p < 0.001), major bleeding (3.7% versus 2.7%) (p = 0.001), and an increase in the need for transfusions (2.8% versus 2.2%) (p = 0.02) in those patients receiving clopidogrel in combination with aspirin compared with those receiving placebo and aspirin, respectively.[79] Minor bleeding included hemorrhages other than those defined as major or life-threatening that interrupted administration of the study medication.

Some safety information has been obtained from controlled trials of clopidogrel plus aspirin or ticlopidine plus aspirin in other clinical situations, such as the prevention of stent thrombosis.[97,98,99] One clinical trial comparing three antithrombotic drug regimens (aspirin alone [325 mg/day], aspirin [325 mg/day] plus warfarin [INR of 2.0-2.5], or ticlopidine [500 mg/day] plus aspirin [325 mg/day]) after inserting a coronary artery stent found that aspirin plus ticlopidine resulted in a lower rate of stent thrombosis than the other two regimens but produced more hemorrhagic complications (i.e., the need for transfusion) than with aspirin monotherapy.[98] The randomized, controlled, double-blind Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) compared the safety of treatment with clopidogrel in combination with aspirin versus ticlopidine in combination with aspirin for 28 days after inserting a coronary stent.[99] Clopidogrel plus aspirin was associated with a lower rate (4.6%) of major peripheral or bleeding complications, neutropenia, thrombocytopenia, and early drug discontinuation for a noncardiac event than ticlopidine plus aspirin (9.1%) (relative risk = 0.50) (p = 0.005). Consistent with other clinical trials, the CLASSICS study demonstrated the safety advantage of using clopidogrel plus aspirin instead of ticlopidine plus aspirin.

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