Introduction
As of the latest Global Burden of Disease (GBD) estimates for 2019, stroke ranks as the second largest global cause of death, significantly impacting public health, especially in low and middle-income countries [1]. GBD 2017 data indicates that the number of stroke-related deaths in China is approximately 2 million [2]. Effective management strategies for carotid artery stenosis encompass percutaneous transluminal angioplasty, stent implantation, post-surgery dual antiplatelet therapy with aspirin and clopidogrel, and proactive risk factor management to prevent recurrent ischemic events in stroke patients [3,4]. Concurrently, high therapeutic platelet reactivity has emerged as a predictor of major adverse cardiovascular events, influenced by factors including metabolism, genetics, clinical complications, and patient compliance [5].
The venerable drug, aspirin, cuts the relative risk of recurrent stroke by around 22% [6]. However, not all patients experience its antithrombotic effects, leading to a phenomenon known as ”aspirin resistance,” where platelet aggregation inhibition remains incomplete, potentially resulting in cardiovascular events post-administration [7]. In China, studies on cardiovascular and cerebrovascular diseases indicate that the rates of aspirin resistance, semi-resistance, and sensitivity stand at 15.4%, 4.6%, and 64.6% respectively [8], with some analyses reporting resistance rates up to 60% [7]. Clopidogrel, a prodrug, undergoes variable absorption and metabolism due to distinct bodily enzymes [6,8]. Consequently, gene mutations tied to these pathways can lead to differential patient reactions, flagging concerns of ”clopidogrel resistance” [8,9]. Research has documented individual variability in clopidogrel’s antiplatelet response, wherein inadequate or excessive response escalates the risks of ischemia and bleeding, respectively [9].
Post-absorption in the intestinal tract, aspirin swiftly hydrolyzes into salicylic acid and other compounds. It then undergoes an irreversible acetylation reaction with the active portion of the platelet COX serine residue, deactivating the enzyme and curtailing the arachidonic acid AA metabolism. This suppresses TXA2 generation, a known inducer of platelet aggregation, exerting an anticoagulant effect [7,10]. Clopidogrel’s metabolic activation hinges on the hepatic cytochrome P450 system. Gene mutations such as ABCB1, CYP2C19 [11], CYP3A4, CYP3A5, PON1 [11], P2Y12 [11] and CES1[12], which play roles in its pharmacokinetic and pharmacodynamic pathways, influence its antiplatelet efficacy. Particularly, the CYP2C19 enzyme activity prominently affects clopidogrel’s activation [13,14], with its intestinal absorption chiefly restrained by the activity of the P-glycoprotein intestinal efflux pump, encoded by the ABCB1 gene [15]. Grasping the ramifications of gene polymorphisms on dual antiplatelet therapy can bolster personalized clinical treatments.
Patients less responsive in producing anti-platelet aggregation effects tend to be more susceptible to drug resistance. In such cases, clinicians often advise switching to alternative medications or combining drugs [13]. With the pervasive utilization of dual antiplatelet therapy in combating cardiovascular and cerebrovascular diseases, and in the absence of alternative medicines, continuous monitoring of disease progression in potential resistance-risk individuals becomes imperative [9,16]. The expanding knowledge on the genetic underpinnings of stroke and cardiovascular ailments, powered by advances in genomic technologies, heralds the prospect of precision drug treatments. Pharmacogenetics offers a vision wherein a patient’s genetic makeup guides clinicians in choosing the most effective therapy [17].