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].