Skip to main content
SpringerLink
Log in

Impact of cangrelor overdosing on bleeding complications in patients undergoing percutaneous coronary intervention: insights from the CHAMPION trials

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Overdosing of parenteral antithrombotic therapies can increase the risk of bleeding. Cangrelor is a potent intravenous platelet P2Y12 receptor antagonist with rapid onset and offset of action. In patients undergoing percutaneous coronary interventions (PCI), compared with control, cangrelor (30 µg/kg bolus, followed immediately by a 4 µg/kg per minute infusion for 2–4 h or until the conclusion of the index PCI, whichever was longer) reduces periprocedural thrombotic complications without an increase in major bleeding complications, although minor bleeding is increased. The impact of cangrelor overdosing on bleeding is unknown and represented the aim of this analysis. Patients with cangrelor overdosing were identified among safety population patients enrolled in the CHAMPION program (n = 25,107). Overdose was defined as administration of an excess >20 % of the bolus dose (30 μg/kg) and/or infusion rate (4 μg/kg per min). Bleeding complications were assessed. Among the safety analysis population in the CHAMPION program, 12,565 patients received cangrelor. A total of 36 overdosed cangrelor patients (0.29 %) were identified in this pooled analysis (20 with both bolus and infusion, 5 with bolus only, and 11 with infusion only). In the majority of patients, the dose did not exceed 2.5 times the recommended dose. Bleeding events were balanced between treatment arms and were consistent with those in the overall CHAMPION program. Only one overdosed patient experienced a serious bleed. There was no correlation between bleeding and magnitude of cangrelor overdose. In a large clinical trial program of patients undergoing PCI, cangrelor overdosing was rare and not associated with an increase in bleeding complications, an observation that may be attributed to its very short-half life and rapid offset of action.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alexander KP, Chen AY, Roe MT, Newby LK, Gibson CM, Allen-LaPointe NM, Pollack C, Gibler WB, Ohman EM, Peterson ED (2005) CRUSADE Investigators. excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA 294(24):3108–3116

    Article  CAS  PubMed  Google Scholar 

  2. Mehran R, Pocock SJ, Stone GW, Clayton TC, Dangas GD, Feit F, Manoukian SV, Nikolsky E, Lansky AJ, Kirtane A, White HD, Colombo A, Ware JH, Moses JW, Ohman EM (2009) Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial. Eur Heart J 30(12):1457–1466

    Article  PubMed Central  PubMed  Google Scholar 

  3. Chhatriwalla AK, Amin AP, Kennedy KF, House JA, Cohen DJ, Rao SV, Messenger JC, Marso SP (2013) National Cardiovascular Data Registry. Association between bleeding events and in-hospital mortality after percutaneous coronary intervention. JAMA 309(10):1022–1029

    Article  CAS  PubMed  Google Scholar 

  4. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S (2006) Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 114(8):774–782

    Article  PubMed  Google Scholar 

  5. Ndrepepa G, Berger PB, Mehilli J, Seyfarth M, Neumann FJ, Schömig A, Kastrati A (2008) Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 51(7):690–697

    Article  PubMed  Google Scholar 

  6. Halim SA, Rao SV (2011) Bleeding and acute coronary syndromes: defining, predicting, and managing risk and outcomes. Curr Drug Targets 12(12):1831–1835

    Article  CAS  PubMed  Google Scholar 

  7. Rao SV, Cohen MG, Kandzari DE, Bertrand OF, Gilchrist IC (2010) The transradial approach to percutaneous coronary intervention: historical perspective, current concepts, and future directions. J Am Coll Cardiol 55(20):2187–2195

    Article  PubMed  Google Scholar 

  8. Franchi F, Angiolillo DJ (2015) Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol 12(1):30–47

    Article  CAS  PubMed  Google Scholar 

  9. Angiolillo DJ, Schneider DJ, Bhatt DL, French WJ, Price MJ, Saucedo JF, Shaburishvili T, Huber K, Prats J, Liu T, Harrington RA, Becker RC (2012) Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 34(1):44–55

    Article  CAS  PubMed  Google Scholar 

  10. Franchi F, Rollini F, Muñiz-Lozano A, Cho JR, Angiolillo DJ (2013) Cangrelor: a review on pharmacology and clinical trial development. Expert Rev Cardiovasc Ther 11(10):1279–1291

    Article  CAS  PubMed  Google Scholar 

  11. 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 (2009) Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 361(24):2330–2341

    Article  CAS  PubMed  Google Scholar 

  12. 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 (2009) Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 361(24):2318–2329

    Article  CAS  PubMed  Google Scholar 

  13. 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 PLATFORM Investigators (2013) Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 368(14):1303–1313

    Article  CAS  PubMed  Google Scholar 

  14. Steg PG, Bhatt DL, Hamm CW, Stone GW, Gibson CM, Mahaffey KW, Leonardi S, Liu T, Skerjanec S, Day JR, Iwaoka RS, Stuckey TD, Gogia HS, Gruberg L, French WJ, White HD, Harrington RA, CHAMPION PLATFORM Investigators (2013) Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet 382(9909):1981–1992

    Article  CAS  PubMed  Google Scholar 

  15. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500143294.pdf Accessed 29 Mar 2014)

  16. The GUSTO investigators (1993) An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 329(10):673–682

    Article  Google Scholar 

  17. Antman EM, Morrow DA, McCabe CH, Jiang F, White HD, Fox KA, Sharma D, Chew P, Braunwald E, ExTRACT-TIMI 25 Investigators (2005) Enoxaparin versus unfractionated heparin as antithrombin therapy in patients receiving fibrinolysis for ST-elevation myocardial infarction. Design and rationale for the enoxaparin and thrombolysis reperfusion for acute myocardial infarction treatment-thrombolysis in myocardial infarction study 25 (ExTRACT-TIMI 25). Am Heart J 149(2):217–226

    Article  CAS  PubMed  Google Scholar 

  18. Stone GW, Bertrand M, Colombo A, Dangas G, Farkouh ME, Feit F, Lansky AJ, Lincoff AM, Mehran R, Moses JW, Ohman M, White HD (2004) Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J 148(5):764–775

    Article  PubMed  Google Scholar 

  19. Cavender MA, Rao SV (2010) Bleeding associated with current therapies for acute coronary syndrome: what are the mechanisms? J Thromb Thrombolysis 30(3):332–339

    Article  CAS  PubMed  Google Scholar 

  20. Capodanno D, Angiolillo DJ (2010) Antithrombotic therapy in the elderly. J Am Coll Cardiol 56(21):1683–1692

    Article  CAS  PubMed  Google Scholar 

  21. Capodanno D, Angiolillo DJ (2012) Antithrombotic therapy in patients with chronic kidney disease. Circulation 125(21):2649–2661

    Article  PubMed  Google Scholar 

  22. Wang TY, Angiolillo DJ, Cushman M, Sabatine MS, Bray PF, Smyth SS, Dauerman HL, French PA, Becker RC (2012) Platelet biology and response to antiplatelet therapy in women: implications for the development and use of antiplatelet pharmacotherapies for cardiovascular disease. J Am Coll Cardiol 59(10):891–900

    Article  CAS  PubMed  Google Scholar 

  23. Capodanno D, Angiolillo DJ (2010) Impact of race and gender on antithrombotic therapy. Thromb Haemost 104(3):471–484

    Article  CAS  PubMed  Google Scholar 

  24. Cattaneo M, Schulz R, Nylander S (2014) Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance. J Am Coll Cardiol 63(23):2503–2509

    Article  CAS  PubMed  Google Scholar 

  25. 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, French WJ, Harrington RA, INNOVATE-PCI Investigators (2012) 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 5(3):336–346

    Article  CAS  PubMed  Google Scholar 

  26. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Ophuis TO, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS; PEGASUS-TIMI 54 Steering Committee and Investigators (2015) Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med

  27. Green CL, Whellan DJ, Lambe L, Bellibas SE, Wijngaard P, Prats J, Krucoff MW (2013) Electrocardiographic safety of cangrelor, a new intravenous antiplatelet agent: a randomized, double-blind, placebo- and moxifloxacin-controlled thorough QT study. J Cardiovasc Pharmacol 62(5):466–478

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The CHAMPION trial program was funded by The Medicines Company. Independent statistical analysis was performed by Harvard Clinical Research Institute (Lanyu Lei, M.Sc. and Yuyin Liu, M.Sc.).

Conflict of interest

Dominick J. Angiolillo: has received payment as an individual for: a) Consulting fee or honorarium from Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Merck, Abbott Vascular, Bayer and PLx Pharma; and b) Participation in review activities from CeloNova, Johnson & Johnson, St. Jude, and Sunovion. He has received institutional payments for grants from Gilead, GlaxoSmithKline, Eli Lilly, Daiichi Sankyo, The Medicines Company, and AstraZeneca. Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Get With The Guidelines Steering Committee; Data Monitoring Committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor); Research Funding: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, St. Jude Medical, The Medicines Company (including for his role as co-Chair of the CHAMPION trials); Trustee: American College of Cardiology; Unfunded Research: FlowCo, PLx Pharma, Takeda. Ph. Gabriel Steg discloses the following relationships: Research grants (to INSERM U1148): Servier, Sanofi; Speaker or consultant (including steering committee, DMC and CEC memberships) : Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, BristolMyersSquibb, Daiichi-Sankyo-Lilly, GlaxoSmithKline, Janssen, Medtronic, Merck-Sharpe Dohme, Novartis, Otsuka, Pfizer, Regado, Regeneron, Sanofi, Servier, The Medicines Company; Stockholder: Aterovax. Gregg W. Stone has served as a past consultant for Eli Lilly, Daiichi-Sankyo and Astra Zeneca. Harvey D. White discloses the following relationships: Research Grants >$10,000 received from (Significant): Sanofi Aventis; Eli Lilly, NIH, Merck Sharpe & Dohme, Astra Zeneca, GSK, Daiichi Sankyo Pharma Development; Advisory boards <$10,000 (Modest): Astra Zeneca;; Consulting Fees <$10,000 (Modest): Daiichi Sankyo Pharma Development Michael Gibson has received funding from or been a consultant to Angel Medical Corporation, AstraZeneca, Atrium Medical Systems, Baxter Healthcare, Bayer, Cardiovascular Research Foundation, Consensus Medical Communications, CSL Behring, Cytori Therapeutics, Daiichi Sankyo Company, Eli Lilly and Company, Exeter Group, Genentech, GlaxoSmithKline, Ikaria, Janssen Pharmaceuticals, Johnson & Johnson, Lantheus Medical Imaging, Merck, Ortho-McNeil, Portola Pharmaceuticals, Roche Diagnostics, Sanofi-Aventis, Stealth Peptides, St Jude Medical, The Medicines Company, UpToDate in Cardiovascular Medicine Volcano Corp, and Walk Vascular. Christian W. Hamm has received honoraria from Abbott, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Merck-Sharpe-Dohme, Bristol-Myers Squibb, BRAHMS, Daiichi Sankyo, Essex, GlaxoSmithKline, Medtronic, Lilly, Sanofi-Aventis, Correvio, Pfizer, Roche, The Medicines Company, Boston Scientific, and Gilead. Matthew J. Price has received consulting honoraria from Daiichi Sankyo/Eli Lilly & Co., AstraZeneca, The Medicines Company, Medtronic, St Jude Medical, and Boston Scientific; and speaking honoraria from Daiichi Sankyo/Eli Lilly & Co. and AstraZeneca Jayne Prats and Tiepu Liu are employees of The Medicines Company. Kenneth W. Mahaffey: Dr. Mahaffey’s financial disclosures prior to August 1, 2013, can be viewed at https://www.dcri.org/about-us/conflict-of-interest/Mahaffey-COI_2011-2013.pdf; disclosures after August 1, 2013, can be viewed at http://med.stanford.edu/profiles/kenneth_mahaffey. Robert A. Harrington has received research grants from Astra Zeneca, Bristol-Myers Squibb, Sanofi, The Medicines Company, Lilly, Daiichi Sankyo, GlaxoSmithKline, Johnson & Johnson, Portola, Merck, and Regado, and has been a consultant for Sanofi, Bristol-Myers Squibb, Merck, Johnson & Johnson, and Gilead.

Author information

Authors and Affiliations

  1. University of Florida College of Medicine–Jacksonville, 655 West 8th Street, Jacksonville, FL, 32209, USA

    Dominick J. Angiolillo

  2. Brigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA, USA

    Deepak L. Bhatt

  3. Université Paris-Diderot, DHU FIRE, Hôpital Bichat, AP-HP, INSERM U1148, Paris, France

    Ph. Gabriel Steg

  4. NHLI, Imperial College, Royal Brompton Hospital, London, UK

    Ph. Gabriel Steg

  5. Columbia University Medical Center and the Cardiovascular Research Foundation, New York, NY, USA

    Gregg W. Stone

  6. Auckland City Hospital and Green Lane Cardiovascular Service, Auckland, New Zealand

    Harvey D. White

  7. Beth Israel Deaconess Medical Center, Boston, MA, USA

    C. Michael Gibson

  8. Kerckhoff Heart Center, Bad Nauheim, Germany

    Christian W. Hamm

  9. Scripps Clinic, La Jolla, CA, USA

    Matthew J. Price

  10. The Medicines Company, Parsippany, NJ, USA

    Jayne Prats & Tiepu Liu

  11. Stanford University Medical School, Stanford, CA, USA

    Kenneth W. Mahaffey & Robert A. Harrington

Authors
  1. Dominick J. Angiolillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deepak L. Bhatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ph. Gabriel Steg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gregg W. Stone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Harvey D. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Michael Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christian W. Hamm
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Matthew J. Price
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jayne Prats
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tiepu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kenneth W. Mahaffey
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Robert A. Harrington
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dominick J. Angiolillo.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Angiolillo, D.J., Bhatt, D.L., Steg, P.G. et al. Impact of cangrelor overdosing on bleeding complications in patients undergoing percutaneous coronary intervention: insights from the CHAMPION trials. J Thromb Thrombolysis 40, 317–322 (2015). https://doi.org/10.1007/s11239-015-1233-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-015-1233-3

Keywords

Search

Navigation