Overcoming poor response to standard oral antiplatelet agents

Existing practice surrounding many cardiovascular medications, including anti-hypertensive and lipid-lowering agents, is based on the evaluation of response to therapy. In cases where ideal therapeutic targets (which have been identified through several previous studies) are not met in the single individual, there is evidence to support the need to intensify standard treatment so as to achieve better control of the cardiovascular risk factor under treatment (e.g. blood pressure or cholesterol levels) as this translates into a better outcome.

No such practice currently exists for anti-platelet agents. Current treatment strategies for patients with coronary artery disease ignore the individual response to antiplatelet agent(s), and likewise fail to identify therapeutic targets for platelet reactivity necessary to evaluate the intensity of treatment.

Yet, inhibition of platelet aggregation following standard oral antiplatelet agents (i.e. aspirin or clopidogrel), has limited data from dedicated trials addressing the long-term safety and efficacy of DES in high-risk subgroups like diabetics, and patients with ST and non ST segment elevation MI or complex lesions. Reaction vary greatly among healthy subjects and patients. Many previous studies have shown that poor response to oral antiplatelet agents increases 1.8-10-fold, the risk of thrombotic events, including myocardial infarction, particularly after coronary angioplasty.

It is unknown whether this reflects suboptimal platelet inhibition per se which might benefit from alternative/more potent antiplatelet agents. Studies aiming at improving outcomes while intensifying platelet inhibition in these patients who are poor responders to standard oral antiplatelet gents are critical to establishing a causal relationship between poor response to a standard anti-platelet regimen and worse outcome. This may help identifying patients who are at high risk for cardiovascular recurrences because they are not fully protected by standard medications. In these patients, the tailored use of alternative anti-platelet agents may provide better protection from cardiovascular complications.

We selected patients, based on results of a point-of-care assay (VerifyNow produced by Accumetrics, Inc., San Diego, CA, USA), undergoing elective percutaneous coronary intervention who were presenting with suboptimal response to either aspirin and/or clopidogrel (these two medications together are crucial to make percutaneous coronary intervention both effective and safe). Poor responders to either aspirin and/or clopidogrel were then randomly treated with standard care (placebo on top of aspirin and clopidogrel) or with the addition of a potent intravenous antiplatelet agents (tirofiban). Neither the patients nor their doctors knew whether they were receiving the real or placebo treatment. We were primarily interested in evaluating the effect of treatment on the incidence of myocardial damage induced during percutaneous coronary intervention (periprocedural myocardial infarction). We showed that intensifying platelet inhibition with tailored infusion of tirofiban in this population results in a greater than 40 percent reduction of the degree of myocardial damage during percutaneous coronary intervention compared to standard care which translated into a better outcomes a 30 days in patients treated in the experimental arm versus the conventional one. Both patients being poor responsive to aspirin or to clopidogrel seem to derive the same benefit.

The University of Ferrara, Italy, was the study sponsor whereas the conduction of the study was partially supported by an unrestricted research grant from Merck, USA and Iroko, USA.

Our study provides proof of concept for a new treatment strategy in patients with coronary artery disease which, by assessing response to standard anti-platelet agents by a point-of-care assay, modulates intensity of treatment accordingly.