Acute dual antiplatelet therapy for minor ischaemic stroke or transient ischaemic attack

We read with interest Wang and colleagues’ article on the medical management of patients with minor ischaemic stroke or transient ischaemic attack.[1] Authors summarized the results of the large randomized clinical trials published on the field the last 5 years and highlighted future research directions.

We would like to highlight a few areas of future research on the field that might be of clinical importance. As the authors emphasized, clopidogrel resistance is mainly driven by CYP2C19 polymorphisms, which varies among populations with Asians reaching up to 62% CYP2C19 loss-of-function genotypes.[2] whereas Westerners demonstrate much lower incidence (approximately 28%) that might affect the generalization of results of some trials.[3] Of interest, clopidogrel may also be influenced by pharmacokinetic variables such as absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (e.g. CYP2C19, CYP2C9, CYP3A4, CYP3A5), bioactivation (PON1), and platelet receptors (P2RY12, P2Y1).[4] These variables were not analyzed in any trial and might be a future research consideration.

Additionally, there has been a staggering increase in the volume of literature addressing the issue of so-called "aspirin resistance". Aspirin resistance is categorized as laboratory aspirin resistance and clinical aspirin resistance. “Laboratory resistance” to aspirin is present when in vitro platelet reactivity is not properly blocked despite the use of aspirin. Clinical aspirin resistance is defined as the failure of aspirin to prevent clinical atherothrombotic events in patients who are taking aspirin. Cox-1 polymorphisms such as C50T, -A842G and -A1676G on COX-1 are considered to be related to aspirin resistance. Also polymorphisms of COX-2-765C may reduce the sensitivity of COX-2 to aspirin and contribute to aspirin resistance.[5] Also PIA1/A2 alleles reduce the antiplatelet effects of aspirin and increased the risk of aspirin resistance. In addition, ADP receptor P2Y purinoceptor 1 (P2Y1) gene polymorphism is associated with aspirin resistance, and the 1622GG genotype may weaken the antiplatelet effect of aspirin in healthy people, and may be one of the pathogenic genes of aspirin resistance.[5] Aspirin resistance was not considered and evaluated in any of the recent trials and might be another area of future research on the field.

We are entering the era of Personalized medicine where medical management may be adjusted to individual drug metabolism abilities.[6] The individual genomic profile should include not only CYP2C19 polymorphisms but also all the polymorphic genes involved in the pharmacokinetic and pharmacodynamic response to P2Y12 receptor inhibitor treatment. The precise definition of multiple genetic, cellular, and clinical determinants influencing platelet reactivity will lead to an individualized, more effective adjustment of antiplatelet treatment in carotid artery disease and to a reduction in cardiovascular-related adverse events.

References
1. Wang Y, Johnston SC, Bath PM, et al. Acute dual antiplatelet therapy for minor ischaemic stroke or transient ischaemic attack. Bmj 2019;364:l895 doi: 10.1136/bmj.l895[published Online First: Epub Date]|.
2. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. The New England journal of medicine 2009;360(4):363-75 doi: 10.1056/NEJMoa0808227[published Online First: Epub Date]|.
3. Man M, Farmen M, Dumaual C, et al. Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans. Journal of clinical pharmacology 2010;50(8):929-40 doi: 10.1177/0091270009355161[published Online First: Epub Date]|.
4. Kuliczkowski W, Witkowski A, Polonski L, et al. Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. European heart journal 2009;30(4):426-35 doi: 10.1093/eurheartj/ehn562[published Online First: Epub Date]|.
5. Cai G, Zhou W, Lu Y, et al. Aspirin resistance and other aspirin-related concerns. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2016;37(2):181-9 doi: 10.1007/s10072-015-2412-x[published Online First: Epub Date]|.
6. Pan Y, Chen W, Xu Y, et al. Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis. Circulation 2017;135(1):21-33 doi: 10.1161/CIRCULATIONAHA.116.024913[published Online First: Epub Date]|.