The Dogged Search for Cryptic Effects of Ticagrelor
2016; Lippincott Williams & Wilkins; Volume: 134; Issue: 22 Linguagem: Inglês
10.1161/circulationaha.116.024710
ISSN1524-4539
AutoresPaul A. Gurbel, Young‐Hoon Jeong, Udaya S. Tantry,
Tópico(s)Platelet Disorders and Treatments
ResumoHomeCirculationVol. 134, No. 22The Dogged Search for Cryptic Effects of Ticagrelor Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Dogged Search for Cryptic Effects of TicagrelorWishful Thinking or Real Benefits Beyond P2Y12 Inhibition? Paul A. Gurbel, MD, Young-Hoon Jeong, MD and Udaya S. Tantry, PhD Paul A. GurbelPaul A. Gurbel From Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, VA (P.A.G., U.S.T.); and Cardiovascular Center, Changwon Gyeongsang National University Hospital, Gyeongsangnam-do, Republic of Korea (Y.-H.J.). , Young-Hoon JeongYoung-Hoon Jeong From Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, VA (P.A.G., U.S.T.); and Cardiovascular Center, Changwon Gyeongsang National University Hospital, Gyeongsangnam-do, Republic of Korea (Y.-H.J.). and Udaya S. TantryUdaya S. Tantry From Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, VA (P.A.G., U.S.T.); and Cardiovascular Center, Changwon Gyeongsang National University Hospital, Gyeongsangnam-do, Republic of Korea (Y.-H.J.). Originally published27 Oct 2016https://doi.org/10.1161/CIRCULATIONAHA.116.024710Circulation. 2016;134:1720–1723Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 29, 2016: Previous Version 1 Article, see p 1708Greater protection against ischemic event occurrences has been associated with lower levels of platelet reactivity to adenosine diphosphate in patients with high-risk coronary artery disease.1–3 The latter observations serve as the basis of the platelet hypothesis, ie, greater inhibition of P2Y12 equals less thrombotic event occurrence.4 Ticagrelor, a cyclopentyl-triazolo-pyrimidine, is indisputably a more potent P2Y12 inhibitor than clopidogrel5 and, when administered to patients with acute coronary syndrome in the PLATO trial (Platelet Inhibition and Patient Outcomes), it resulted in a reduction not only in myocardial infarction, but also vascular death in comparison with clopidogrel.6 The observed reduction in vascular death has provided a strong impetus to search for mechanisms of benefit beyond greater P2Y12 inhibition that are not shared by other P2Y12 inhibitors: the non–P2Y12-mediated hypothesis of ticagrelor. The latter hypothesis is largely based on the property of ticagrelor to inhibit adenosine reuptake, thereby increasing systemic and tissue adenosine levels.7 Most of the subsequent beneficial effects proceed downstream for this pivotal step, because adenosine has been proposed as an important molecule that attenuates ischemia-reperfusion injury.Indeed, there has already been significant exploration in the ticagrelor-adenosine area.Ticagrelor has been shown to inhibit adenosine reuptake in erythrocytes by inhibition of the sodium-independent equilibrative nucleoside transporter-1. Dipyridamole has 16-fold greater affinity for equilibrative nucleoside transporter-1.7No direct effect of ticagrelor on adenosine receptors has been reported, and ticagrelor is not metabolized to adenosine.7In an in vitro study, the antiplatelet effect of ticagrelor was mediated in part by increased extracellular adenosine levels and adenosine-mediated platelet inhibition via the A2A receptor.7In a canine coronary artery ligation model using 1 minute of left anterior descending coronary artery occlusion, ticagrelor and dipyridamole dose-dependently enhanced hyperemic blood flow and exhibited similar effects in augmenting flow after intracoronary adenosine administration.8In a canine coronary artery thrombosis model, ticagrelor, but not clopidogrel, significantly improved tissue plasminogen activator–induced blood flow and reduced infarct size (IS). The latter effects were importantly associated with greater ticagrelor-induced platelet inhibition.9In a rat coronary ligation model using 30 minutes of ischemia followed by 24 hours of reperfusion, 7 days of pretreatment with ticagrelor, but not clopidogrel, was associated with reduced myocardial IS. The latter was accompanied by an increase in myocardial adenosine levels, upregulation of myocardial cycloxoygenase-2 activity, and phosphorylation of Akt and endothelial nitric oxide synthase. These cardioprotective effects were reversed by adenosine-receptor antagonism and abrogated with high-dose aspirin and selective cycloxoygenase-2 inhibition.10 Using the same model, the latter investigators demonstrated that a single dose of intraperitoneally administered ticagrelor prereperfusion was associated with reduced IS at 4 hours after reperfusion and increased phosphorylation of Akt, extracellular signal–regulated kinase 1/2, and endothelial nitric oxide synthase. Moreover, 4 weeks administration of ticagrelor was associated with reduced inflammation and fibrosis and improved remodeling. These effects were hypothesized to be independent of the antiplatelet properties of ticagrelor, because the clopidogrel-treated animals had a similar degree of platelet inhibition and had fewer myocardial protective effects.11In the current issue of Circulation, Vilahur et al12 provide more evidence to support the non–P2Y12-mediated hypothesis in a large animal model, a closed chest swine preparation of ischemia/reperfusion (n=32). Myocardial infarction was induced by 1-hour balloon occlusion of the mid left anterior descending coronary artery followed by 24 hours of reflow. Before occlusion, animals were randomly assigned to receive either placebo (n=9), a loading dose of clopidogrel (4 hours before, n=8), a loading dose of ticagrelor (2 hours before, n=8), or a loading dose of ticagrelor followed by an A1/A2 receptor antagonist (8-(p-sulfophenyl)theophylline, n=7). Edema, IS, left ventricular size, and left ventricular function were assessed by 3T-cardiac MRI. Infarct size was also assessed histologically and by troponin release. The survival rate was surprisingly high despite ≈50% jeopardized myocardium as demonstrated by Evans blue dye injection; 2 animals with left anterior descending coronary artery thrombosis in the placebo group died and 30 completed the protocol. There was no report of arrhythmia. The authors also reported the results of a crossover pilot dose–finding study conducted in 4 animals on which they based the dosing of clopidogrel and ticagrelor with similar levels of platelet aggregation.Inhibition of platelet aggregation in the current study was reported to be the same between the groups receiving a P2Y12 inhibitor. In the placebo control group, the investigators reported no changes in inhibition of platelet aggregation. However, their results differ somewhat from earlier work by others in a swine model of reperfusion using 15 minutes of left anterior descending coronary artery occlusion followed by 90 minutes of reflow where platelet function was dynamic during ischemia-reperfusion, and aggregation in the systemic circulation increased 56% at 90 minutes postreflow in comparison with preocclusion.Myocardial viability was enhanced 24 hours after infarction in animals receiving ticagrelor and clopidogrel in comparison with placebo, whereas cardiac injury (necrosis and edema) was reduced to a greater extent with ticagrelor versus clopidogrel, and these results correlated with histopathologic findings and troponin levels. Importantly, the beneficial effects of ticagrelor versus clopidogrel on IS were blocked by the A1/A2 receptor antagonist. Finally, the investigators, in laudable extensive tissue studies, explored adenosine-related modulation of pathways potentially involved in ischemia-reperfusion that provide mechanisms to explain cardioprotective effects of ticagrelor (Figure).Download figureDownload PowerPointFigure. The P2Y12- and non–P2Y12-mediated effects of ticagrelor. P2Y12 is a pivotal amplifier of platelet activation stimulated by multiple agonists. The latter central property translates to powerful inhibition of thrombosis, subsequently affecting the occurrence of myocardial infarction and possibly cardiovascular death. Myocardial ischemia-reperfusion releases adenosine triphosphate (ATP) that is ultimately converted to adenosine through specific hydrolases, CD 39 (ectonucleoside triphosphate diphosphohydrolase-1) and CD 73(ecto-5′-nucleotidase). Ticagrelor inhibits equilibrative nucleoside transporter-1 (ENT1), a major transporter of adenosine leading to higher endogenous adenosine levels. Adenosine attenuates ischemia-reperfusion injury through multiple mechanisms that may influence the occurrence of cardiovascular death following acute coronary syndrome. ADP indicates adenosine diphosphate; AMPK, adenosine monophosphate–activated kinase; COX, cyclooxygenase; eNOS, endothelial nitric oxide synthase; G, glycoprotein; IL, interleukin; mRNA, messenger ribonucleic acid; and TNF-α, tumor necrosis factor-α.All the above evidence lends strong support of the non–P2Y12-mediated effects of ticagrelor. But what evidence do we have from human data? A significantly higher plasma concentration of adenosine in blood collected from patients who have acute coronary syndrome treated with ticagrelor in comparison with clopidogrel was reported, and in vitro uptake of exogenous adenosine by erythrocytes was inhibited when incubated with serum from patients treated with ticagrelor but not clopidogrel.13 With incremental doses of adenosine coadministration in patients with non–ST-segment–elevation acute coronary syndrome undergoing percutaneous coronary intervention, ticagrelor but not prasugrel was associated with greater coronary blood flow velocity.14With respect to cardioprotective benefits of adenosine itself, intravenous infusion of high-dose adenosine started before reperfusion significantly reduced IS in patients with anterior wall ST-segment–elevation myocardial infarction in the AMISTAD trials (Acute Myocardial Infarction Study of Adenosine). In the AMISTAD II trial, the primary end point of new congestive heart failure beginning >24 hours after randomization, the first rehospitalization for heart failure, or death from any cause within 6 months was not reduced by adenosine, and there was a trend toward increasing adverse end points associated with adenosine in the AMISTAD I trial.11 In addition, in a rat model using photochemical-induced thrombosis, prasugrel, another potent P2Y12 inhibitor administered 2 hours before coronary artery photoirradiation, resulted in lower mortality, and necrosis area/total left ventricular area at 24 hours in surviving animals was smaller than in controls.15Thus, while acknowledging the non–P2Y12-mediated effect of ticagrelor on adenosine reuptake inhibition, some other questions arise from the results of study by Vilahur et al: (1) How certain are we that better platelet inhibition does not explain the effects on IS? The current study included a small number of animals for comparison of pharmacodynamic effects. Also, intramyocardial platelet function may be more inhibited because of the effects of local adenosine on A2A receptors. (2) Clinical outcomes in PLATO do not diverge until late, a pattern that may not be expected based on the authors' observations.6 (3) The experimental model of infarction was not a thrombus model and involved a nonatherosclerotic animal with presumed healthy endothelial function. Therefore, its relevance to the human myocardial infarction has limitations.Despite controversies regarding the clinical relevance of the non–P2Y12-mediated hypothesis of ticagrelor, Vilahur et al should be acknowledged for their labor-intensive and complex analysis of the acute effects of clopidogrel and ticagrelor on myocardial injury and the potential underlying downstream mechanisms. Longer-term studies of myocardial infarction using other known equilibrative nucleoside transporter-1 inhibitors with and without accompanying P2Y12 inhibition may strengthen the authors' conclusions suggesting that adenosine is an important independent mediator of clinical benefits of ticagrelor.DisclosuresDr Gurbel reports serving as a consultant, receiving honoraria from Daiichi Sankyo, Bayer, AstraZeneca, Merck, New Haven Pharmaceuticals, Janssen, and MedImmune, and receiving grants from the National Institutes of Health, Daiichi Sankyo, CSL, AstraZeneca, Harvard Clinical Research Institute, Haemonetics, New Haven Pharmaceuticals, Duke Clinical Research Institute, Sinnowa, and Coramed. Dr Gurbel has patents in the field of platelet function testing. Dr Jeong has received honoraria for lectures from AstraZeneca, Sanofi-Aventis, Daiichi Sankyo/Lilly, Haemonetics, Otsuka, and Yuhan Pharmaceuticals; and research grants or support from AstraZeneca, Korean Society of Interventional Cardiology, Han-mi Pharmaceuticals, and Haemonetics. Dr Tantry reports no conflicts of interest.FootnotesCirculation is available at http://circ.ahajournals.org.The opinions in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Paul A. Gurbel, MD, Inova Center for Thrombosis Research and Drug Development IHVI, 3300 Gallows Rd, Falls Church, VA 22042. E-mail [email protected]References1. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. 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Simard T, Jung R, Labinaz A, Faraz M, Ramirez F, Di Santo P, Pitcher I, Motazedian P, Gaudet C, Rochman R, Marbach J, Boland P, Sarathy K, Alghofaili S, Russo J, Couture E, Beanlands R and Hibbert B Adenosine as a Marker and Mediator of Cardiovascular Homeostasis: A Translational Perspective, Cardiovascular & Hematological Disorders-Drug Targets, 10.2174/1871529X18666181011103719, 19:2, (109-131) Tantry U, Jeong Y and Gurbel P (2017) More Evidence for Non-P2Y12-Mediated Effects of Ticagrelor, JACC: Cardiovascular Interventions, 10.1016/j.jcin.2017.06.014, 10:16, (1659-1661), Online publication date: 1-Aug-2017. November 29, 2016Vol 134, Issue 22 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.116.024710PMID: 27789557 Originally publishedOctober 27, 2016 Keywordsclopidogrelreperfusion injuryplatelet aggregation inhibitorpurinergic P2Y receptor antagonistsEditorialsPDF download Advertisement SubjectsAnimal Models of Human DiseaseMyocardial BiologyPlatelets
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