Skip to main content
Log in

Benefits and risks of P2Y12 inhibitor preloading in patients with acute coronary syndrome and stable angina

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

Abstract

Treatment with P2Y12 inhibitors is an integral part of the standard of care for patients undergoing percutaneous coronary intervention. However, the most appropriate timing for P2Y12 inhibitor administration remains unclear, and the value of “preloading” with P2Y12 inhibitors prior to cardiac catheterization is controversial. While pre-catheterization treatment with P2Y12 inhibitors is performed with the goal of decreasing adverse cardiovascular events, this potential benefit must be weighed against the increased risk of bleeding complications and operative delay if coronary artery bypass graft surgery is indicated. A number of studies have been conducted to evaluate the utility of preloading with P2Y12 inhibitors prior to cardiac catheterization for varying indications including stable angina and acute coronary syndrome (ACS). In this article, we review the literature and discuss the advantages and disadvantages of the preloading strategy. Several individual studies offer inconclusive and even conflicting findings. However, when taken in sum, these studies allow for several conclusions about the utility of P2Y12 inhibitor pretreatment. The existing literature demonstrate that preloading is associated with some degree of reduction in adverse ischemic events, although this benefit comes with an increased risk of bleeding complications. The appropriateness of preloading therefore varies based on the indication for catheterization, likely justified in patients with ACS but unlikely to benefit patients with stable angina.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Yusuf S, Bijsterveld N, Moons A (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation: the clopidogrel in unstable angina to prevent recurrent events trial investigators. New Engl J Med 345(7):494–502

    Article  CAS  PubMed  Google Scholar 

  2. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO (1998) A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. New Engl J Med 339(23):1665–1671

    Article  CAS  PubMed  Google Scholar 

  3. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H-J, Zhao F, Chrolavicius S (2001) Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 358(9281):527–533

    Article  CAS  PubMed  Google Scholar 

  4. Dörler J, Edlinger M, Alber HF, Altenberger J, Benzer W, Grimm G, Huber K, Pachinger O, Schuchlenz H, Siostrzonek P, Zenker G, Weidinger F, Altenberger J, Pichler M, Benzer W, Bonner G, Weidinger F, Brunner T, Gaul G, Gratze F, Zenker G, Juhasz M, Silberbauer H, Kerschner K, Leisch F, Krappinger H, Wimmer H, Laubreiter K, Grimm G, Siostrzonek P, Mayr H, Neunteufl T, Maurer G, Norman G, Weber H, Pachinger O, Dörler J, Alber HF, Roithinger FX, Unger G, Huber K, Wallner H, Weihs W, Schuchlenz H (2011) Clopidogrel pre-treatment is associated with reduced in-hospital mortality in primary percutaneous coronary intervention for acute ST-elevation myocardial infarction. Eur Heart J 32(23):2954–2961. doi:10.1093/eurheartj/ehr360

    Article  PubMed  Google Scholar 

  5. Bellemain-Appaix A, Kerneis M, O’Connor SA, Silvain J, Cucherat M, Beygui F, Barthélémy O, Collet J-P, Jacq L, Bernasconi F (2014) Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: a systematic review and meta-analysis. BMJ 349:g6269

    Article  PubMed  PubMed Central  Google Scholar 

  6. Di Sciascio MG, Patti G, Pasceri V, Gatto L (2010) Effectiveness of in-laboratory high-dose clopidogrel loading versus routine pre-load in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol 56(7):550–557

    Article  CAS  PubMed  Google Scholar 

  7. Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay J-F, ten Berg JM, Miller DL, Costigan TM, Goedicke J (2013) Pretreatment with prasugrel in non–ST-segment elevation acute coronary syndromes. New Engl J Med 369(11):999–1010

    Article  CAS  PubMed  Google Scholar 

  8. Montalescot G, van’t Hof AW, Lapostolle F, Silvain J, Lassen JF, Bolognese L, Cantor WJ, Cequier Á, Chettibi M, Goodman SG (2014) Prehospital ticagrelor in ST-segment elevation myocardial infarction. New Engl J Med 371(11):1016–1027

    Article  PubMed  Google Scholar 

  9. Collet J-P, Silvain J, Bellemain-Appaix A, Montalescot G (2014) Pretreatment with P2Y12 Inhibitors in non-ST-segment-elevation acute coronary syndrome: an outdated and harmful strategy. Circulation 130(21):1904–1914

    Article  PubMed  Google Scholar 

  10. Dean BB, Yu H-T, Bae JP, Fiske S, Meadows E, Xiong Y, Emons MF (2010) Pattern of clopidogrel use in hospitalized patients receiving percutaneous coronary interventions. Am J Health Syst Pharm 67(17):1430–1437

    Article  CAS  PubMed  Google Scholar 

  11. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. New Engl J Med 361(11):1045–1057

    Article  CAS  PubMed  Google Scholar 

  12. Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH, Antman EM, investigators T-T (2009) Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 373(9665):723–731

    Article  CAS  PubMed  Google Scholar 

  13. Sibbing D, Kastrati A, Berger PB (2015) Pre-treatment with P2Y12 inhibitors in ACS patients: who, when, why, and which agent? Eur Heart J 16:ehv717

    Google Scholar 

  14. Giorgi MA, Cohen Arazi H, Gonzalez CD, Di Girolamo G (2011) Beyond efficacy: pharmacokinetic differences between clopidogrel, prasugrel and ticagrelor. Expert Opin Pharmacother 12(8):1285–1295

    Article  CAS  PubMed  Google Scholar 

  15. Dobesh PP, Oestreich JH (2014) TicagrelOR pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy 34(10):1077–1090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Butler K, Teng R (2010) Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol 70(1):65–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ferreiro JL, Ueno M, Angiolillo DJ (2009) CangrelOR a review on its mechanism of action and clinical development. Expert Rev Cardiovasc Ther 7(10):1195–1201

    Article  CAS  PubMed  Google Scholar 

  18. Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Lewis BS, Murphy SA, McCabe CH, Braunwald E (2005) Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 294(10):1224–1232

    Article  CAS  PubMed  Google Scholar 

  19. Zeymer U, Arntz H-R, Mark B, Fichtlscherer S, Werner G, Schöller R, Zahn R, Diller F, Darius H, Dill T (2012) Efficacy and safety of a high loading dose of clopidogrel administered prehospitally to improve primary percutaneous coronary intervention in acute myocardial infarction: the randomized CIPAMI trial. Clin Res Cardiol 101(4):305–312

    Article  CAS  PubMed  Google Scholar 

  20. Ducci K, Grotti S, Falsini G, Angioli P, Liistro F, Mandò M, Porto I, Bolognese L (2013) Comparison of pre-hospital 600 mg or 900 mg versus peri-interventional 300 mg clopidogrel in patients with ST-elevation myocardial infarction undergoing primary coronary angioplasty. The Load&Go randomized trial. Int J Cardiol 168(5):4814

    Article  PubMed  Google Scholar 

  21. Steinhubl SR, Berger PB, Mann IJ et al (2002) Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288(19):2411–2420. doi:10.1001/jama.288.19.2411

    Article  CAS  PubMed  Google Scholar 

  22. Lev EI, Kornowski R, Vaknin-Assa H, Brosh D, Fuchs S, Battler A, Assali A (2008) Effect of clopidogrel pretreatment on angiographic and clinical outcomes in patients undergoing primary percutaneous coronary intervention for ST-elevation acute myocardial infarction. Am J Cardiol 101(4):435–439

    Article  CAS  PubMed  Google Scholar 

  23. de Waha S, Eitel I, Desch S, Fuernau G, Lurz P, Schuler G, Thiele H (2014) Association of upstream clopidogrel administration and myocardial reperfusion assessed by cardiac magnetic resonance imaging in patients with ST-elevation myocardial infarction. Eur Heart J 3(2):110–117

    Google Scholar 

  24. Fefer P, Hod H, Hammerman H, Segev A, Beinart R, Boyko V, Behar S, Matetzky S (2009) Usefulness of pretreatment with high-dose clopidogrel in patients undergoing primary angioplasty for ST-elevation myocardial infarction. Am J Cardiol 104(4):514–518

    Article  CAS  PubMed  Google Scholar 

  25. Koul S, Smith JG, Scherstén F, James S, Lagerqvist B, Erlinge D (2011) Effect of upstream clopidogrel treatment in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Eur Heart J 32(23):2989–2997

    Article  CAS  PubMed  Google Scholar 

  26. Katritsis DG, Siontis GC, Kastrati A, van’t Hof AW, Neumann F-J, Siontis KC, Ioannidis JP (2011) Optimal timing of coronary angiography and potential intervention in non-ST-elevation acute coronary syndromes. Eur Heart J 32(1):32–40

    Article  PubMed  Google Scholar 

  27. Chan AW, Moliterno DJ, Berger PB, Stone GW, DiBattiste PM, Yakubov SL, Sapp SK, Wolski K, Bhatt DL, Topol EJ (2003) Triple antiplatelet therapy during percutaneous coronary intervention is associated withimproved outcomes including one-year survival results from the do tirofiban and reoprogive similar efficacy outcome trial (TARGET). J Am Coll Cardiol 42(7):1188–1195. doi:10.1016/S0735-1097(03)00944-6

    Article  CAS  PubMed  Google Scholar 

  28. Wang TY, White JA, Tricoci P, Giugliano RP, Zeymer U, Harrington RA, Montalescot G, James SK, Van de Werf F, Armstrong PW (2011) Upstream clopidogrel use and the efficacy and safety of early eptifibatide treatment in patients with acute coronary syndrome an analysis from the early glycoprotein IIb/IIIa inhibition in patients with non-ST-segment elevation acute coronary syndrome (EARLY ACS) trial. Circulation 123(7):722–730

    Article  CAS  PubMed  Google Scholar 

  29. Saw J, Lincoff AM, DeSmet W, Betriu A, Rutsch W, Wilcox RG, Kleiman NS, Wolski K, Topol EJ (2004) Lack of clopidogrel pretreatment effect on the relative efficacy of bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to heparin with routine glycoprotein IIb/IIIa blockade: a REPLACE-2 substudy. J Am Coll Cardiol 44(6):1194–1199

    CAS  PubMed  Google Scholar 

  30. Lincoff AM, Steinhubl SR, Manoukian SV, Chew D, Pollack CV, Feit F, Ware JH, Bertrand ME, Ohman EM, Desmet W (2008) Influence of timing of clopidogrel treatment on the efficacy and safety of bivalirudin in patients with non–ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention: an analysis of the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. JACC 1(6):639–648

    PubMed  Google Scholar 

  31. Szük T, Gyöngyösi M, Homorodi N, Kristóf È, Király C, Èdes IF, Facskó A, Pavo N, Sodeck G, Strehblow C (2007) Effect of timing of clopidogrel administration on 30-day clinical outcomes: 300-mg loading dose immediately after coronary stenting versus pretreatment 6 to 24 h before stenting in a large unselected patient cohort. Am Heart J 153(2):289–295

    Article  PubMed  Google Scholar 

  32. Valgimigli M (2014) Pretreatment with P2Y12 inhibitors in non–ST-segment-elevation acute coronary syndrome is clinically justified. Circulation 130(21):1891–1903

    Article  PubMed  Google Scholar 

  33. Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot G, Kleiman NS, Goodman SG, White HD, Mahaffey KW (2009) Intravenous platelet blockade with cangrelor during PCI. New Engl J Med 361(24):2330–2341

    Article  CAS  PubMed  Google Scholar 

  34. Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM, Gibson CM, Pollack CV Jr, Montalescot G, Mahaffey KW, Kleiman NS (2009) Platelet inhibition with cangrelor in patients undergoing PCI. New Engl J Med 361(24):2318–2329

    Article  CAS  PubMed  Google Scholar 

  35. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E (2013) Effect of platelet inhibition with cangrelor during PCI on ischemic events. New Engl J Med 368(14):1303–1313

    Article  CAS  PubMed  Google Scholar 

  36. Steinhubl SR, Berger PB, Brennan DM, Topol EJ (2006) Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol 47(5):939–943

    Article  CAS  PubMed  Google Scholar 

  37. Widimský P, Motovská Z, Šimek S, Kala P, Pudil R, Holm F, Petr R, Bílková D, Skalická H, Kuchynka P, Poloczek M, Miklík R, Malý M, Aschermann M (2008) Clopidogrel pre-treatment in stable angina: for all patients > 6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI? A randomized multicentre trial PRAGUE-8. Eur Heart J 29(12):1495–1503. doi:10.1093/eurheartj/ehn169

    Article  PubMed  PubMed Central  Google Scholar 

  38. van der Heijden DJ, Westendorp IC, Riezebos RK, Kiemeneij F, Slagboom T, van der Wieken LR, Laarman G-J (2004) Lack of efficacy of clopidogrel pre-treatment in the prevention of myocardial damage after elective stent implantation. J Am Coll Cardiol 44(1):20–24

    Article  PubMed  Google Scholar 

  39. Assali AR, Salloum J, Sdringola S, Moustapha A, Ghani M, Hale S, Schroth G, Fujise K, Anderson HV, Smalling RW (2001) Effects of clopidogrel pretreatment before percutaneous coronary intervention in patients treated with glycoprotein IIb/IIIa inhibitors (abciximab or tirofiban). Am J Cardiol 88(8):884–886

    Article  CAS  PubMed  Google Scholar 

  40. Amin AP, Kennedy KF, Pencina M, Berger P, Piana RN, Lopez J, Kleiman N, Cohen DJ, Event Investigators (2011) Effect of clopidogrel pretreatment on ischemic complications of percutaneous coronary intervention among bivalirudin-treated patients (from the EVENT registry). Am J Cardiol 107(12):1751–1756

    Article  CAS  PubMed  Google Scholar 

  41. Feldman DN, Fakorede F, Minutello RM, Bergman G, Moussa I, Wong SC (2010) Efficacy of high-dose clopidogrel treatment (600 mg) less than two hours before percutaneous coronary intervention in patients with non–ST-segment elevation acute coronary syndromes. Am J Cardiol 105(3):323–332

    Article  CAS  PubMed  Google Scholar 

  42. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann F-J, Ardissino D, De Servi S, Murphy SA (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. New Engl J Med 357(20):2001–2015

    Article  CAS  PubMed  Google Scholar 

  43. Breet N, van Donkersgoed H, van Werkum J, Bouman H, Kelder J, Zijlstra F, Hackeng C, Ten Berg J (2011) Is platelet inhibition due to thienopyridines increased in elderly patients, in patients with previous stroke and patients with low body weight as a possible explanation of an increased bleeding risk? Neth Heart J 19(6):279–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kandzari DE, Berger PB, Kastrati A, Steinhubl SR, Mehilli J, Dotzer F, Jurriën M, Neumann F-J, Bollwein H, Dirschinger J (2004) Influence of treatment duration with a 600-mg dose of clopidogrel before percutaneous coronary revascularization. J Am Coll Cardiol 44(11):2133–2136

    Article  CAS  PubMed  Google Scholar 

  45. Chew DP, Mahaffey KW, White HD, Huang Z, Hoekstra JW, Ferguson JJ, Califf RM, Aylward PE (2008) Coronary artery bypass surgery in patients with acute coronary syndromes is difficult to predict. Am Heart J 155(5):841–847

    Article  PubMed  Google Scholar 

  46. McLean DS, Sabatine MS, Guo W, McCabe CH, Cannon CP (2007) Benefits and risks of clopidogrel pretreatment before coronary artery bypass grafting in patients with ST-elevation myocardial infarction treated with fibrinolytics in CLARITY-TIMI 28. J Thromb Thrombolysis 24(2):85–91

    Article  CAS  PubMed  Google Scholar 

  47. Fox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, Yusuf S (2004) Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome the clopidogrel in unstable angina to prevent recurrent ischemic events (CURE) trial. Circulation 110(10):1202–1208

    Article  CAS  PubMed  Google Scholar 

  48. Mehta RH, Roe MT, Mulgund J, Ohman EM, Cannon CP, Gibler WB, Pollack CV, Smith SC, Ferguson TB, Peterson ED (2006) Acute clopidogrel use and outcomes in patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass surgery. J Am Coll Cardiol 48(2):281–286

    Article  CAS  PubMed  Google Scholar 

  49. Ebrahimi R, Dyke C, Mehran R, Manoukian SV, Feit F, Cox DA, Gersh BJ, Ohman EM, White HD, Moses JW (2009) Outcomes following pre-operative clopidogrel administration in patients with acute coronary syndromes undergoing coronary artery bypass surgery: the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol 53(21):1965–1972

    Article  CAS  PubMed  Google Scholar 

  50. Biancari F, Airaksinen KJ, Lip GY (2012) Benefits and risks of using clopidogrel before coronary artery bypass surgery: systematic review and meta-analysis of randomized trials and observational studies. J Thorac Cardiovasc Surg 143(3):665–675

    Article  CAS  PubMed  Google Scholar 

  51. Peterson ED, Dai D, DeLong ER, Brennan JM, Singh M, Rao SV, Shaw RE, Roe MT, Ho KK, Klein LW (2010) Contemporary mortality risk prediction for percutaneous coronary intervention: results from 588,398 procedures in the National Cardiovascular Data Registry. J Am Coll Cardiol 55(18):1923–1932

    Article  PubMed  PubMed Central  Google Scholar 

  52. Diercks DB, Kontos MC, Chen AY, Pollack CV, Wiviott SD, Rumsfeld JS, Magid DJ, Gibler WB, Cannon CP, Peterson ED (2009) Utilization and impact of pre-hospital electrocardiograms for patients with acute ST-segment elevation myocardial infarction: data from the NCDR (National Cardiovascular Data Registry) ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry. J Am Coll Cardiol 53(2):161–166

    Article  PubMed  Google Scholar 

  53. O’Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX (2013) 2013 ACCF/AHA Guideline for the management of ST-elevation myocardial Infarction a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 61(4):e78–e140. doi:10.1016/j.jacc.2012.11.019

    Article  PubMed  Google Scholar 

  54. Falk E (1983) Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 50(2):127–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV, Brindis RG, Douglas PS (2010) Low diagnostic yield of elective coronary angiography. New Engl J Med 362(10):886–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Good CW, Berger PB (2011) P2Y12 antagonists in acute coronary syndrome: in whom should they be started, and when? Curr Cardiol Rep 13(4):320–326

    Article  PubMed  Google Scholar 

  57. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, Jaffe AS, Jneid H, Kelly RF, Kontos MC (2014) 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 64(24):e139–e228

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Taylor C. Bazemore.

Ethics declarations

Conflict of interest

Dr. Taylor C. Bazemore and Dr. Michael G. Nanna report no disclosures; Dr. Sunil V. Rao reports consulting honoraria from Terumo Interventional Systems Inc and Medtronic Inc.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bazemore, T.C., Nanna, M.G. & Rao, S.V. Benefits and risks of P2Y12 inhibitor preloading in patients with acute coronary syndrome and stable angina. J Thromb Thrombolysis 44, 303–315 (2017). https://doi.org/10.1007/s11239-017-1529-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-017-1529-6

Keywords

Navigation