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Anti-platelet therapy in acute coronary syndrome
Published in K Sarat Chandra, AJ Swamy, Acute Coronary Syndromes, 2020
Kunal Mahajan, Yashasvi Rajeev, K Sarat Chandra
Adenosine diphosphate (ADP), an important platelet agonist, has P2Y1 and P2Y12 receptors on the platelet plasma membrane through which it exerts its effects. Out of these two, it is the P2Y12 pathway that plays a major contribution in sustaining and stabilising the aggregation of platelets [10]. P2Y12 receptor antagonists are therefore recommended to prevent ischaemic events both in the acute and long-term treatment of ACS. The thienopyridine, ticlopidine, which was the first P2Y12 receptor inhibitor, is seldom prescribed now following the reports of serious adverse reactions with its use, particularly neutropenia and thrombotic thrombocytopenic purpura [11]. Three oral ADP P2Y12 receptors inhibiting drugs that are currently approved for clinical use include clopidogrel, prasugrel (irreversible inhibition), and ticagrelor (reversible inhibition) (Table 11.1).
Antiplatelet therapy in interventional cardiology
Published in John Edward Boland, David W. M. Muller, Interventional Cardiology and Cardiac Catheterisation, 2019
These drugs are inactive in vitro, but active orally following hepatic metabolism via cytochrome P450 (CYP) isoforms to one or more metabolically active forms, making them indirectly-acting platelet inhibitors. The active metabolites covalently and irreversibly bind to the P2Y12 receptor for the remaining lifespan of the platelet.13 Excretion is principally renal.14,15 Like aspirin, these drugs provide irreversible platelet inhibition that persists after ceasing therapy. The effect is present for 7–10 days, equivalent to the lifespan of the platelet.16
Practical Considerations for Benefit–Risk Assessment and Implementation: Vorapaxar TRA-2°P TIMI 50 Case Study
Published in Qi Jiang, Weili He, Benefit-Risk Assessment Methods in Medical Product Development, 2017
Weili He, Daniel Bloomfield, Yabing Mai, Scott Evans
Secondary prevention of cardiovascular (CV) events in patients with atherosclerosis remains a significant medical and societal problem despite available therapies. Despite medicines for secondary prevention, patients with atherosclerotic CV disease are at substantial risk of recurrent thrombotic events. Platelets have a central role in atherothrombosis and are an important target for drug treatment. Inhibition of platelets with P2Y12 inhibitors added to aspirin for up to a year after myocardial infarction (MI) reduces recurrent thrombotic events but increases bleeding. In patients with atherosclerosis in the peripheral arteries, the benefits of P2Y12 inhibitors and aspirin are less clear. There are no known medications with an acceptable B–R profile in patients with a history of ischemic stroke. Additional therapeutic options are being evaluated on top of standard of care (with aspirin or a P2Y12 inhibitor) for long-term secondary prevention of CV events.
Pharmacodynamic and clinical efficacy of reduced ticagrelor maintenance doses in patients with coronary artery disease
Published in Current Medical Research and Opinion, 2021
Piotr Adamski, Małgorzata Ostrowska, Eliano Pio Navarese, Jacek Kubica
Patients requiring therapy with P2Y12 receptor inhibitors are often simultaneously at elevated risk of thrombotic and bleeding events. Different strategies have been proposed to optimize antiplatelet treatment in order to maintain platelet inhibition appropriate for the prevention of thrombotic complications while minimizing the occurrence of bleeding and other adverse events3–8. One of the proposed DAPT de-escalation strategies is based on temporal changes in the thrombotic risk after ACS, which accrues directly after the acute event and decreases over time9. In other words, initially, ACS patients require more aggressive antiplatelet treatment, but after stabilization occurs a less potent therapy could be sufficient to maintain the desired antiaggregatory effect7,10. It could be achieved by discontinuation of aspirin after the patient reaches the stabilization phase and maintenance of monotherapy with a potent P2Y12 receptor inhibitor afterwards7. Alternatively, DAPT could be downgraded by introducing less powerful P2Y12 receptor inhibition. Although switching from more potent agents to clopidogrel after thrombotic risk approaches the steady state failed to provide clinical benefit11, an increasing amount of pharmacodynamic and clinical data indicate that reduction of ticagrelor maintenance dose in stabilized patients might improve its safety profile and adherence to the treatment5,6,12.
Polymorphisms in the GCK gene increase the risk of clopidogrel resistance in stable coronary artery disease (SCAD) patients
Published in Hematology, 2021
Hongyu Xu, Qinglin Yu, Honglin Zhou, Jin Yang, Nan Zheng, Zhifeng Xu, Jia Su
Antiplatelet medicine could decrease the MACE risk of CAD patients; hence, it is the cornerstone of CAD treatment. By inhibiting the P2Y12 receptor, clopidogrel could reduce platelet aggregation, which was induced through adenosine diphosphate (ADP) [13]. However, approximately 10–40% of patients have suffered from clopidogrel resistance. With a higher Residual platelet reactivity (RPR) after clopidogrel loading presented larger intracoronary thrombus burden, worse post-PCI myocardial flow and perfusion [14]. With the development of new P2Y12 inhibitors, prasugrel and ticagrelor could inhibit platelet activity more rapidly, consistently, and effectively. But they cause more hemorrhagic events [15]. The COSTIC trial showed that for Chinese CAD patients, clopidogrel was more suitable compared with ticagrelor [16]. Therefore, diversiform responding to clopidogrel therapy and the underlying causes are increasingly being considered.
Clopidogrel use and smoking cessation result in lower coated-platelet levels after stroke
Published in Platelets, 2020
Angelia C. Kirkpatrick, Andrea S. Vincent, George L. Dale, Calin I. Prodan
Clopidogrel, a selective, irreversible inhibitor of the platelet P2Y12 ADP receptor, prevents ADP-mediated activation of platelets, and is commonly used for prevention of thrombotic complications in the setting of myocardial infarction and ischemic stroke. Prior in vitro experiments using cangrelor, a selective inhibitor of the platelet P2Y12 receptor, have demonstrated a significant impact on coated-platelet production [27]. Specifically, cangrelor used at physiologically relevant doses resulted in a 22% relative decrease in coated-platelet levels in normal blood donors [27]. Studies with clopidogrel conducted in patients with coronary artery disease undergoing elective coronary angiography found that a single loading dose of 300 mg resulted in a significant 17.8% relative reduction in coated-platelet levels at 24 h, but no follow-up was available after that time point [18]. The relative decrease (20.9%) in coated-platelet levels noted at 90 days after stroke in our study is similar to these prior ex vivo and in vitro results [18,27], suggesting that inhibition of the P2Y12 receptor is reproducible and sustained, at least for the 90-day timeframe used in the current study.