Achieving Optimal Platelet Inhibition During Percutaneous Coronary Interventions

Vascular injury leads to platelet activation and aggregation, and subsequent fibrin deposition and thrombosis. Antithrombin therapy alone without optimal platelet inhibition leads to an inferior outcome during percutaneous coronary intervention (PCI). Early experience with PCI was performed with unfractionated heparin (UFH) in patients pretreated with aspirin. Aspirin is only partially effective as an antiplatelet drug by inhibiting the cyclooxygenase enzyme and therefore partially blocking thromboxane A2 and collagen-mediated platelet activation and aggregation. However, there are several other pathways that activate platelets, among them thrombin and adenosine diphosphate (ADP). Antithrombin drugs block fibrin generation, an essential component of a thrombus. Their effect on platelets, however, is variable. Although UFH is an indirect thrombin inhibitor, it provides unpredictable anticoagulation and, in fact, has been shown to activate platelets in vivo. Therefore, the adjunctive use of the intravenous glycoprotein (Gp) IIb/IIIa inhibitors with UFH during PCI was proven to be superior to UFH alone as it provided effective inhibition of platelet aggregation by blocking the platelet GpIIb/IIIa surface receptors. Although very effective in reducing the combined endpoint of death, myocardial infarction and urgent revascularization, the combination of a GpIIb/IIIa inhibitor and UFH increased the risk of bleeding and blood transfusions. In contrast, the direct thrombin inhibitor bivalirudin is effective in inhibiting thrombin mediated platelet aggregation in vitro and does not activate platelets in vivo. The use of bivalirudin appears to be a superior replacement to UFH in PCI and its feasibility in peripheral interventions has been recently validated in the APPROVE trial. Bivalirudin and UFH, however do not block ADP-mediated platelet activation and aggregation. The use of clopidogrel-aspirin combination has become a standard treatment post-PCI, as it has clearly shown to be superior to the use of aspirin alone or aspirin-warfarin combination in preventing subacute stent thrombosis. Platelet inhibition with clopidogrel is dose- and time-dependent. After a single dose of clopidogrel 400 mg maximum, platelet inhibition is achieved in 2 to 5 hours. In contrast, clopidogrel 75 mg daily requires 3 to 7 days to reach the same level of inhibition. Blocking the ADP receptor irreversibly with clopidogrel has become an important step before PCI to reduce intermediate and long-term cardiac events. In the CREDO study, pretreatment of patients with clopidogrel 300 mg at least 15 hours pre-intervention reduced long-term adverse events. In the ISAR-REACT trial, pretreatment with clopidogrel 600 mg provided similar outcomes in low-to-intermediate risk patients, irrespective of whether they were assigned to abciximab or placebo, with maximum antiplatelet effect seen within 2–3 hours of treatment before intervention. In the ARMYDA-2 study, clopidogrel 600 mg was more effective in reducing cardiac events than clopidogrel 300 mg when given at a mean of 6 hours before PCI in both arms. ARMYDA-2 also did not exclude patients from receiving GpIIb/IIIa inhibitors, therefore also supporting the hypothesis that optimal ADP receptor antagonism before PCI might be essential even when intraprocedural optimal inhibition of platelet aggregation is achieved with GpIIb/IIIa inhibitors. It is unclear why this should be the case, but the answer might be in separating the concept of platelet aggregation from activation. ADP receptor antagonists do not only block aggregation, but also inhibit platelet activation and therefore reduce platelet-mediated inflammatory pathways. In fact, clopidogrel has been shown to alter inflammatory markers by reducing the rise in hsCRP and decreasing the expression of CD40L, P-selectin and platelet-leukocyte conjugates. Whether clopidogrel exerts its beneficial effects predominantly by inhibiting platelet aggregation or because of its additional anti-inflammatory effects needs to be further explored. At present, several effective combination treatments are being used in clinical practice in patients undergoing PCI. Optimal antiplatelet inhibition remains at the center of all these therapies, with the use of dual or triple antiplatelet agents including aspirin, clopidogrel and/or GpIIb/IIIa inhibitors. Newer and effective ADP receptor antagonists are currently in the final phase of testing. Future research will continue to focus on existing and new antiplatelet therapies in both PCI and peripheral interventions, their dosing and timing and combination with various antithrombins, and continue to explore the relationship and relative importance of these drugs in altering platelet activation, aggregation and reducing inflammation. shammas@mchsi.com