Adjunctive pharmacotherapy and coronary intervention
Ever D. Grech in Practical Interventional Cardiology, 2017
Several medications are available to inhibit platelet activity at the level of the P2Y12 ADP receptor that provides an additive anti-platelet effect to the TXA-2 inhibition by aspirin. There are three oral thienopyridines (clopidogrel, prasugrel and ticlopidine) approved by the United States Food and Drug Administration (FDA) which irreversibly inhibit ADP-mediated platelet activation and aggregation by binding to the platelet P2Y12 receptor. Non-thienopyridine agents include ticagrelor and cangrelor, which do not require metabolic activation and lead to a reversible P2Y12 receptor inhibition, in contrast to thienopyridines. Ticlopidine was the first approved agent and was used in many of the early historical trials; however, due to its delayed onset of action and unfavourable haematologic adverse events it is no longer used in contemporary treatment. Clopidogrel, considered a ‘second-generation’ agent, along with the ‘third-generation’ prasugrel and ticagrelor, is currently used as oral agents. Cangrelor was recently approved and is an intravenous medication which combines desirable properties of both a rapid onset of action with a short duration of effect. After a review of the individual agents, this section will also examine the evidence for pre-treatment with and duration of DAPT therapy in the setting of PCI.
Anti-platelet therapy in acute coronary syndrome
K Sarat Chandra, AJ Swamy in Acute Coronary Syndromes, 2020
It belongs to a new class of drugs termed as non-thienopyridine adenosine triphosphate analogues. It is an intravenous and competitive P2Y12 inhibitor and has a reversible mode of action. It has a short half-life of 5 minutes only. Cangrelor has a very rapid onset and offset of action, unlike the currently approved oral P2Y12 anti-platelet agents, which require hours to be effective. Furthermore, cangrelor does not require in vivo bioactivation. It, therefore, reaches a steady-state in plasma within a few minutes of its administration and achieves more than 90% inhibition of platelet activation resulting from the P2Y12 pathway [2,3]. Multiple randomised controlled trials, comparing the use of cangrelor with the current standard therapy, have found no significant differences in the mortality or further MI when patients were treated with either cangrelor or clopidogrel before [27] or during PCI [28]. However, in a double-blind placebo-controlled randomised trial involving 11,145 patients, cangrelor led to a significant reduction in the rate of ischaemic events during PCI, compared with clopidogrel, without any increase in severe bleeding [29]. Cangrelor was subsequently approved by US and European regulatory agencies in 2015 for use in patients undergoing PCI. It is particularly useful in patients with ACS who are unable to take oral agents due to repeated vomiting or those in a state of shock or on a ventilator. It is also very useful in patients with ACS who require urgent surgery, as its use avoids preloading with DAPT and thus permits early surgery without waiting 5–7 days for oral drug washout.
Briefing Therapeutic Approaches in Anticoagulant, Thrombolytic, and Antiplatelet Therapy
Debarshi Kar Mahapatra, Sanjay Kumar Bharti in Medicinal Chemistry with Pharmaceutical Product Development, 2019
ADP induced platelet aggregation takes place through binding of ADP to G protein-coupled P2Y purinergic receptors. Clopidogrel (Figure 7.13) is a thienopyridine that irreversibly inhibits P2Y12 on the platelet surface. It must be metabolized in the liver to generate the active metabolites that inhibit the ADP receptor [88]. New P2Y12 inhibitors include prasugrel, cangrelor, and ticagrelor (Figure 7.13). Like clopidogrel, prasugrel is a thienopyridine that requires hepatic metabolism to generate active metabolites. It is more efficient than that of clopidogrel. It produces more rapid, more consistent, and more potent inhibition of ADP-induced platelet aggregation. Cangrelor and ticagrelor are direct-acting reversible inhibitors of P2Y12. Cangrelor, which is administered intravenously, has a rapid onset and offset of action. Ticagrelor is administered orally [89, 90]. Elinogrel (Figure 7.13) is an experimental antiplatelet drug acting as a P2Y12 inhibitor. However, development was discontinued in 2012. Ticlopidine (Figure 7.13) is an antiplatelet drug in the thienopyridine family. However, because of its rare but serious side effects of neutropenia and thrombotic thrombocytopenic purpura, its use remained limited [91, 92].
Investigational drugs for the treatment of acute myocardial infarction: focus on antiplatelet and anticoagulant agents
Published in Expert Opinion on Investigational Drugs, 2019
Srikanth Yandrapalli, Gabriela Andries, Shashvat Gupta, Abdel Rahman Dajani, Wilbert S. Aronow
Of these agents, the antiplatelet agents cangrelor and vorapaxar, and anticoagulant agent rivaroxaban (at a low dose) have shown promise to reduce ischemic events when administered during and in the acute phase following ACS [10,57,95,96]. Cangrelor is a promising agent to treat AMI patients not pre-treated with other P2Y12 inhibitors, when oral route or administration is challenging or when immediate CABG is planned [10]. However, cangrelor use should be followed by loading with another antiplatelet agent. It is important to remember that if a thienopyridine will be used after cangrelor infusion, the loading dose should be given at the time of discontinuation of the cangrelor infusion. Available data make the addition of vorapaxar, as a third antiplatelet therapy, an attractive option to further reduce thrombotic events in patients post-myocardial infarction, however prospective trial data is lacking in the population for which vorapaxar is indicated. In addition, cost and increased bleeding risk are important considerations [26]. Although cangrelor may have advantages like intravenous administration, rapid onset and offset of action, and reversibility, it has not been compared directly against more potent P2Y12 inhibitors like prasugrel or ticagrelor, and so is vorapaxar [58,59].
Targeted pharmacotherapy for ischemia reperfusion injury in acute myocardial infarction
Published in Expert Opinion on Pharmacotherapy, 2020
Amit Rout, Udaya S Tantry, Marko Novakovic, Ajaypaul Sukhi, Paul A Gurbel
Cangrelor is a potent, intravenously administered, direct-acting P2Y12 antagonist with a potent antiplatelet effect, rapid onset and quick, reversible action. A cardioprotective effect of cangrelor beyond potent inhibition of platelets was demonstrated in two animal studies. Administration of cangrelor shortly before IRI in rabbits reduced infarct size by approximately 30%, and this effect was dose-dependent and correlated with platelet inhibition. However, delaying the cangrelor administration by 10 minutes after the onset of reperfusion eliminated the cardioprotective effect [74]. In a primate model, cangrelor started just prior to reperfusion, and ischemic preconditioning significantly decreased infarct to the same extent [75]. Sphingosine kinase activity is suggested as one of the pathways of cardioprotection by cangrelor [76].
Cangrelor for the treatment of patients with Arterial Thrombosis
Published in Expert Opinion on Pharmacotherapy, 2018
Udaya Tantry, Rahul Chaudhary, Jacek Kubica, Kevin Bliden, Paul A Gurbel
Bridging therapy in patients treated with antiplatelet agents to reduce the risk of thrombotic events in the phase between drug cessation and surgery may also be a role for cangrelor in the future. However, currently we do not have sufficient evidence to support this strategy. In preparation for surgery, P2Y12 inhibitors are commonly discontinued 5–7 days before surgery to minimize bleeding risk during the procedure [46,47]. The latter practice can be especially problematic in patients who have undergone recent drug-eluting stenting and who are at risk for thrombosis should antiplatelet therapy be interrupted [48]. GPIs have been used as an antiplatelet bridge to surgery, although the safety and efficacy of this approach has also not been clearly established [49,50]. Although intuitive based on pharmacodynamic properties, the clinical utility of bridging with cangrelor has never been adequately tested.
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