Resistance to Oral Antiplatelet Agents: Fact or Fantasy?

There is little question that oral antiplatelet agents have found a distinct and nearly universal role in the management of patients with atherosclerotic disease. Aspirin has proven to be an important drug that reduces the complications of virtually all manifestations of atherosclerosis in the cardiac and cerebral circulations.1 The thienopyridines, ticlopidine and clopidogrel, have been useful in managing patients who have undergone intracoronary stent placement2 as well as those suffering from acute coronary syndromes3 and ST segment elevation myocardial infarction.4•5 However, a variety of publications over the past five years have reinforced the concept that the responses of individual patients to these drugs is heterogeneous, and that this heterogeneity may have important clinical consequences. This monograph will review the evidence that such variability not only exists but is also clinically meaningful.An important point to recognize is that use of the term "resistance" is controversial and likely misleading for several reasons. First, a drug response must be defined in terms of biomarkers rather than clinical events; patients with atherosclerosis nearly always receive a variety of concomitant treatments, so a clinical event can be regarded as a failure of any or all of these treatments rather than simply an inadequate response to a specific drug. Second, a variety of in vitro tests are available to characterize the response to antiplatelet drugs. However, the responses reported by one test do not necessarily reflect responses reported by others, so categorizing a particular patient as either "responsive" or "resistant" is in part dependent on which test is used. Third, the basal reactivity of platelets before administering either drug may play a large role in determining the final degree of platelet activity after either drug is administered. Finally, relatively stringent criteria for a biomarker's adequacy have been expounded in recent years;6 however, neither the in vitro responses to aspirin nor to clopidogrel have strictly met these requirements. In addition, almost no reports exist concerning the reproducibility of determinations made with any of the tests, and very few reports exist concerning the temporal stability of these estimates. For example, it is unknown whether a patient who is classified as aspirin "resistant" on day 1 will also be "resistant" at the end of a month or a year. In fact, there is reason to suspect that this may not be the case at all.