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Despite undisputed clinical benefit of platelet inhibitors in an acute interventional setting, chronic antiplatelet treatment with aspirin and clopidogrel have shown a moderate reduction of approximately 18% in the prevention of myocardial infarction and stroke. More recent data on the effect of combining the two compounds leading to an irreversible blockade of cyclooxygenase as well as the adenosine diphosphate receptor showed increased protection from cardiac events in patients with unstable angina and no significant protection from stroke. This improvement did come with the price of a significant increase in major bleeding, requiring hospitalization or transfusion. Furthermore, the most potent inhibition of platelet aggregation by blocking the binding of fibrinogen to activated platelets did not further improve the clinical outcome. All major clinical investigations of the effect of chronic administration have been recently terminated owing to an overall increased mortality rate for the entire class of drugs of orally active fibrinogen receptor antagonists. This poses the question of whether measuring platelet aggregation in vitro and ex vivo can serve as an adequate surrogate parameter to select antithrombotic therapy, particularly in the chronic setting. When evaluating the importance of other endogenous antithrombotic defense systems, the test for inhibition of platelet aggregation must fail. The importance of the endogenous defense systems is easily demonstrated by in vivo studies of thrombus formation in smaller vessels. The rapid and well-balanced interaction of local prothrombotic as well as antithrombotic factors is key in keeping the process confined. By carefully shifting this balance with antiplatelet therapy in combination with therapy to amplify the endogenous antithrombotic defense systems, a far more pronounced overall antithrombotic therapeutic effect can be demonstrated. By employing more complex antithrombotic tests performed in vivo, this balance can be studied. These studies confirm the importance of the ratio of two independent antithrombotic treatments when given together, which was not reflected in in vitro tests but was found to correlate with clinical outcome data. The attention in selecting antithrombotic treatment is to be shifted from approaches only directed toward the inhibition of platelets to an antithrombotic treatment, which includes amplification of the local therapeutic effects often mediated through the vessel wall.