Clopidogrel Resistance: Identifying and Overcoming a Barrier to Effective Antiplatelet Treatment

Abstract

SUMMARYClopidogrel is an inhibitor of the ADP receptor P2Y12 and platelet aggregation. It is widely used for the management of atherothrombotic disease in patients who have experienced severe vascular events such as stroke or myocardial infarction or with peripheral artery disease. However, some patients show "resistance" to clopidogrel, and show impaired inhibition of platelet aggregation. In this review, I discuss the clinical evidence of the extent of the problem, potential implications for future cardiovascular events and clinical tests to assess platelet aggregation. I also discuss the mechanisms that appear responsible for clopidogrel resistance. Clopidogrel is administered as a prodrug and the active metabolite is generated by the cytochrome P450 system. Therefore, inadequate responses to clopidogrel may be caused by polymorphisms in one or more of the cytochrome P450 enzymes and interaction/competition with other drugs metabolized by the cytochrome P450 system (e.g., statins and proton pump inhibitors). Finally, I discuss the therapeutic options available for patients with known or suspected clopidogrel resistance, including the use of drugs with alternative molecular targets (e.g., cilostazol), metabolized via different pathways (e.g., prasugrel) or administered in an active form (e.g., ticagrelor). Clopidogrel resistance is a clinically significant problem with potentially severe consequences if it is not identified or managed appropriately. The availability of point-of-care assays and novel treatments provide clinicians with an extensive array of tools that should aid in the management of atherothrombotic diseases/events, and reduce the risk of future severe events in these patients.

Low-dose Aspirin and Comorbidities are Significantly Related to Bleeding Peptic Ulcers in Elderly Patients Compared with Nonelderly Patients in Japan

“…A large number of elderly people with cardiovascular disease, cerebrovascular disease and chronic joint pain have been prescribed low-dose aspirin, antithrombotic drugs, NSAIDs and corticosteroids for primary or secondary prevention of cardiovascular disease, cerebrovascular disorders and arthralgia (18)(19)(20)(21)(22). In the present study, a univariate analysis focused on prescribed medications indicated that low-dose aspirin, antithrombotic drugs and corticosteroids are exacerbating factors for bleeding gastric and/or duodenal ulcers in elderly patients compared with nonelderly patients.…”

Association of thrombelastographic parameters with post-stenting ischemic events

“…However, some patients show resistance to clopidogrel or aspirin and impaired inhibition of platelet aggregation 12. It has been estimated that 4.2–31.0% of patients treated with clopidogrel do not achieve an appropriate level of efficacy of platelet activity,13–15 and aspirin resistance accounts for 7.8–32.0% of patients with recurrent events 16 17.…”

Effect of Premedication Method and Drug Resistance of Antiplatelet Agent on Periprocedural Thromboembolic Events During Coil Embolization of an Unruptured Intracranial Aneurysm

“…We only employed antiplatelet agent for stent-assisted procedures and aspirin with clopidogrel was given orally for three days before the procedure, referring to the guideline report of stent-assisted coil embolization 1). Individual variability of responsiveness to antiplatelet agents has been reported and the duration of antiplatelet premedication for stent-assisted coil embolization has been extended to five days with carefulness concerning about the hemorrhagic risk 4)20)25). After going through serial thromboembolic events and perceiving the low risk of hemorrhage related to antiplatelet agents, we began use of antiplatelet agent for other modes of coil embolization, which include the conventional method, multiple catheter technique, and balloon-assisted procedures 7)11)13).…”

“…However, there is no general consensus on defining aspirin and clopidogrel resistance, which hinders investigation of the prevalence. Several studies have reported a prevalence of drug resistance of 5.5-60% for aspirin and 5-44% for clopidogrel 4)5)25)…”