Dyspnea and Reversibility of Antiplatelet Agents: Ticagrelor, Elinogrel, Cangrelor, and BeyondSerebruany V.L. · Sibbing D. · DiNicolantonio J.J.
HeartDrug™ Research Laboratories, Johns Hopkins University, Towson, Md., USA
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Context: Oral reversible platelet P2Y12 receptor inhibitors (ticagrelor and elinogrel) cause double-digit rates of dyspnea, while irreversible oral antiplatelet drugs (aspirin, ticlopidoine, clopidogrel, and prasugrel) or intravenous glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, or tirofiban) do not increase the incidence of dyspnea in randomized trials. Dyspnea after oral reversible antiplatelet agents remains unexplained. A transfusion-related acute lung injury (TRALI) hypothesis has been proposed. The dyspnea risks after cangrelor, an intravenous reversible antiplatelet agent, are not well defined but may offer a universal mechanism linking TRALI, dyspnea, and reversible platelet inhibition. Objective: We analyzed safety data from recent head-to-head randomized trials with reversible antiplatelet agents (ticagrelor, elinogrel, and cangrelor) compared to irreversible (clopidogrel/placebo) comparators. Results: All three reversible antiplatelet agents cause excess dyspnea. In contrast to the high double-digit rates after oral ticagrelor or elinogrel, the dyspnea risks after intravenous cangrelor were smaller (<2%) but still consistently and significantly higher than in the corresponding control arms. Conclusions: The clinical utility of reversible antiplatelet strategies has been challenged. Despite a potential advantage of fewer bleeding events during heart surgery, reversible antiplatelet agents carry the risk of potential autoimmune reactions manifesting as dyspnea. Repeated binding and unbinding cycles, impaired platelet turnover, and lung sequestration or apoptosis of overloaded destructive platelets are among the potential mechanism(s) responsible for dyspnea after reversible antiplatelet agents.
© 2013 S. Karger AG, Basel
Frese T, Sobeck C, Herrmann K, Sandholzer H: Dyspnea as the reason for encounter in general practice. J Clin Med Res 2011;3:239-246.
Bonafede M, Jing Y, Gdovin Bergeson J, Liffmann D, Makenbaeva D, Graham J, Deitelzweig SB: Impact of dyspnea on medical utilization and affiliated costs in patients with acute coronary syndrome. Hosp Pract (1995) 2011;39:16-22.
- Serebruany VL, Stebbing J, Atar D: Dyspnea after antiplatelet agents: the AZD6140 controversy. Int J Clin Pract 2007;61:529-533.
Quan D, LoVecchio F, Clark B, Galagher JV: Prehospital use of aspirin rarely is associated with adverse events. Prehospital Disaster Med 2004;19:362-365.
- Kurzyna M, Fijalkowska A, Kuca P, Tomkowski W, Torbicki A: Recombinant hirudine in suspected heparin induced thrombocytopenia-case report of pulmonary embolism. Pol Arch Med 2000;104:785-789.
- Coons JC, Barcelona RA, Freedy T, Hagerty MF: Eptifibatide-associated acute, profound thrombocytopenia. Ann Pharmacother 2005;39:368-372.
- Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G: Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006;27:1038-1047.
- Cannon CP, Husted S, Harrington RA, Scrica BM, Emanuelsson H, Peters G, Storey RF: Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 2007;50:1844-1851.
- Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA: Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-1057.
- Welsh RC, Rao SV, Zeymer U, Thompson VP, Huber K, Kochman J, McClure MW, Gretler DD, Bhatt DL, Gibson CM, Angiolillo DJ, Gurbel PA, Berdan LG, Paynter G, Leonardi S, Madan M, French WJ, Harrington RA, INNOVATE-PCI Investigators: A randomized, double-blind, active-controlled phase 2 trial to evaluate a novel selective and reversible intravenous and oral P2Y12 inhibitor elinogrel versus clopidogrel in patients undergoing nonurgent percutaneous coronary intervention: the INNOVATE-PCI trial. Circ Cardiovasc Interv 2012;5:336-346.
- Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimský P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Généreux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA, CHAMPION PHOENIX Investigators: Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 2013;368:1303-1313.
FDA ticagrelor review of complete response - drug approval package. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433 Orig1s000TOC.cfm (accessed March 24, 2013).
FDA prasugrel prescribing information http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022307s007lbl.pdf (accessed March 24, 2013).
- Serebruany VL, Pokov IA, Kulizhkowski W, Vahabi J, Atar D: Incidence and causes of new-onset dyspnea in 3,719 patients treated with clopidogrel and aspirin combination after coronary stenting. Thromb Haemost 2008;100:76-82.
- CAPRIE Steering Committee: A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
- Serebruany VL: Adenosine release: a potential explanation for the benefits of ticagrelor in the PLATelet inhibition and clinical outcomes trial? Am Heart J 2011;161:1-4.
- Basoglu OK, Pelleg A, Essilfie-Quaye S, Brindicci C, Barnes PJ, Kharitonov SA: Effects of aerosolized adenosine 5′-triphosphate vs. adenosine 5′-monophosphate on dyspnea and airway caliber in healthy nonsmokers and patients with asthma. Chest 2005;128:1905-1909.
- Serebruany VL: Dyspnea after AZD6140: safety first? Eur Heart J 2006;27:1505.
- Deeks ED: Ticagrelor: a review of its use in the management of acute coronary syndromes. Drugs 2011;71:909-933.
- Serebruany VL, Atar D: The PLATO trial: do you believe in magic? Eur Heart J 2010;31:764-767.
- Ferreiro JL, Ueno M, Angiolillo DJ: Cangrelor: a review on its mechanism of action and clinical development. Expert Rev Cardiovasc Ther 2009;7:1195-1201.
- Angiolillo DJ, Firstenberg MS, Price MJ, Tummala PE, Hutyra M, Welsby IJ, Voeltz MD, Chandna H, Ramaiah C, Brtko M, Cannon L, Dyke C, Liu T, Montalescot G, Manoukian SV, Prats J, Topol EJ, BRIDGE Investigators: Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA 2012;307:265-274.
- Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM, Gibson CM, Pollack CV Jr, Montalescot G, Mahaffey KW, Kleiman NS, Goodman SG, Amine M, Angiolillo DJ, Becker RC, Chew DP, French WJ, Leisch F, Parikh KH, Skerjanec S, Bhatt DL: Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009;361:2318-2329.
- Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot G, Kleiman NS, Goodman SG, White HD, Mahaffey KW, Pollack CV Jr, Manoukian SV, Widimsky P, Chew DP, Cura F, Manukov I, Tousek F, Jafar MZ, Arneja J, Skerjanec S, Harrington RA, CHAMPION PLATFORM Investigators: Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009;361:2330-2341.
- Li G, Kojicic M, Reriani MK, Fernández Pérez ER, Thakur L, Kashyap R, Van Buskirk CM, Gajic O: Long-term survival and quality of life after transfusion-associated pulmonary edema in critically ill medical patients. Chest 2010;137:783-789.
- Holness L, Knippen MA, Simmons L, Lachenbruch PA: Fatalities caused by TRALI. Transfus Med Rev 2004;18:184-188.
- Toy P, Gajic O, Bacchetti P, et al, TRALI Study Group: Transfusion-related acute lung injury: incidence and risk factors. Blood 2012;119:1757-1767.
- Silliman CC, Bjornsen AJ, Wyman TH, Kelher M, Allard J, Bieber S, Voelkel NF: Plasma and lipids from stored platelets cause acute lung injury in an animal model. Transfusion 2003;43:633-640.
- Looney MR, Gilliss BM, Matthay MA: Pathophysiology of transfusion-related acute lung injury. Curr Opin Hematol 2010;17:418-423.
- Serebruany VL: Reversible nature of platelet binding causing transfusion-related acute lung injury (TRALI) syndrome may explain dyspnea after ticagrelor and elinogrel. Thromb Haemost 2012;108:1024-1027.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.