Prasugrel compared with high-dose clopidogrel in acute coronary syndrome

 

 Buy Article Permissions and Reprints

Summary

Compared with the approved dose regimen of clopidogrel (300-mg loading dose [LD], 75-mg maintenance dose [MD]), prasugrel has been demonstrated to reduce ischaemic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). In ACS, antiplatelet effects of a prasugrel MD regimen have not been previously compared with either a higher clopidogrel MD or after switching from a higher clopidogrel LD. The objective of this study was to evaluate the antiplatelet effect of a prasugrel 10-mg MD versus a clopidogrel 150-mg MD in patients with ACS who had received a clopidogrel 900-mg LD. Patients with non-ST elevation ACS, treated with aspirin and a clopidogrel 900-mg LD, were randomised within 24 hours post-LD to receive a prasugrel 10-mg or clopidogrel 150-mg MD. After 14 days of the initial MD, subjects switched to the alternative treatment for 14 days. The primary endpoint compared maximum platelet aggregation (MPA, 20 μM adenosine diphosphate [ADP]) between prasugrel and clopidogrel MDs for both periods. Responder analyses between treatments were performed using several platelet-function methods. Of 56 randomised subjects, 37 underwent PCI. MPA was 26.2% for prasugrel 10 mg and 39.1% for clopidogrel 150 mg (p<0.001). The prasugrel MD regimen reduced MPA from the post-900-mg LD level (41.2% to 29.1%, p=0.003). Poor response ranged from 0% to 6% for prasugrel 10 mg and 4% to 34% for clopidogrel 150 mg. Thus, in ACS patients a prasugrel 10-mg MD regimen resulted in significantly greater platelet inhibition than clopidogrel at twice its approved MD or a 900-mg LD.

• References

• 1 Yusuf S, Zhao F, Mehta SR. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
  CrossrefPubMedGoogle Scholar
• 2 Hochholzer W, Trenk D, Frundi D. et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005; 111: 2560-2564.
  CrossrefPubMedGoogle Scholar
• 3 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J 2004; 25: 1903-1910.
  CrossrefPubMedGoogle Scholar
• 4 Montalescot G, Sideris G, Meuleman C. et al, ALBION Trial Investigators. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006; 48: 931-938.
  CrossrefPubMedGoogle Scholar
• 5 Cuisset T, Frere C, Quilici J. et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006; 48: 1339-1345.
  CrossrefPubMedGoogle Scholar
• 6 Lotrionte M, Biondi-Zoccai GG, Agostoni P. et al. Meta-analysis appraising high clopidogrel loading in patients undergoing percutaneous coronary intervention. Am J Cardiol 2007; 100: 1199-1206.
  CrossrefPubMedGoogle Scholar
• 7 von Beckerath N, Taubert D, Pogatsa-Murray G. et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE Trial. Circulation 2005; 112: 2946-2950.
  PubMedGoogle Scholar
• 8 L’Allier PL, Ducrocq G, Pranno N. et al, PREPAIR Study Investigators.. Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: results from the PREPAIR randomized study. J Am Coll Cardiol 2008; 51: 1066-1072.
  CrossrefPubMedGoogle Scholar
• 9 Bonello L, Camoin-Jau L, Arques S. et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized, prospective study. J Am Coll Cardiol 2008; 51: 1404-1411.
  CrossrefPubMedGoogle Scholar
• 10 Kastrati A, von Beckerath N, Joost A. et al. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation 2004; 110: 1916-1919.
  CrossrefPubMedGoogle Scholar
• 11 Collet JP, Silvain JP, Landivier A. et al. Dose-effect of clopidogrel reloading in patients already on 75-mg maintenance dose: the reload with clopidogrel before coronary angioplasty in subjects treated long term with dual antiplatelet therapy (RELOAD) study. Circulation 2008; 118: 1225-1233.
  CrossrefPubMedGoogle Scholar
• 12 Patti G, Colonna G, Pasceri V. et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 Study. Circulation 2005; 111: 2099-2106.
  CrossrefPubMedGoogle Scholar
• 13 Gurbel PA, Tantry US. Clopidogrel resistance?. Thromb Res 2007; 120: 311-321.
  CrossrefPubMedGoogle Scholar
• 14 Bliden KP, DiChiara J, Tantry US. et al. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?. J Am Coll Cardiol 2007; 49: 657-666.
  CrossrefPubMedGoogle Scholar
• 15 Angiolillo DJ, Bernardo E, Sabaté M. et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2007; 50: 1541-1547.
  CrossrefPubMedGoogle Scholar
• 16 Angiolillo DJ, Shoemaker SB, Desai B. et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the OPTIMUS study. Circulation 2007; 115: 708-716.
  CrossrefPubMedGoogle Scholar
• 17 American College of Cardiology/American Heart Association Task Force.. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol 2008; 51: 172-209.
  CrossrefPubMedGoogle Scholar
• 18 Jakubowski JA, Winters KJ, Naganuma H. et al. Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev 2007; 25: 357-374.
  CrossrefPubMedGoogle Scholar
• 19 Jernberg T, Payne CD, Winters KJ. et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006; 27: 1166-1173.
  CrossrefPubMedGoogle Scholar
• 20 Brandt JT, Payne CD, Wiviott SD. et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007; 153: 66.e9-16.
  CrossrefPubMedGoogle Scholar
• 21 Wiviott SD, Braunwald E, McCabe CH. et al, TRITON-TIMI 38 Investigators.. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
  CrossrefPubMedGoogle Scholar
• 22 Wallentin L, Varenhorst C, James S. et al. Prasugrel achieves greater and faster P2Y₁₂receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29: 21-30.
  PubMedGoogle Scholar
• 23 Wiviott SD, Trenk D, Frelinger AL. et al, PRINCIPLE-TIMI 44 Investigators.. Prasugrel compared to high loading and maintenance dose clopidogrel in patients with planned percutaneous coronary Intervention: The PRINCIPLE-TIMI 44 Trial. Circulation 2007; 116: 2923-2932.
  CrossrefPubMedGoogle Scholar
• 24 Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology.. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28: 1598-1660.
  CrossrefPubMedGoogle Scholar
• 25 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742-1750.
  CrossrefPubMedGoogle Scholar
• 26 Barragan P, Bouvier JL, Roquebert PO. et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003; 59: 295-302.
  CrossrefPubMedGoogle Scholar
• 27 Patti G, Nusca A, Mangiacapra F. et al. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention: results of the ARMYDA-PRO (antiplatelet therapy for reduction of myocardial damage during angioplasty-platelet reactivity predicts outcome) study. J Am Coll Cardiol 2008; 52: 1128-1133.
  CrossrefPubMedGoogle Scholar
• 28 Bovill EG, Terrin ML, Stump DC. et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med 1991; 115: 256-265.
  CrossrefPubMedGoogle Scholar
• 29 The GUSTO Investigators.. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-682.
  CrossrefPubMedGoogle Scholar
• 30 Casterella PJ, Tcheng JE. Review of the 2005 American College of Cardiology, American Heart Association, and Society for Cardiovascular Interventions guidelines for adjunctive pharmacologic therapy during percutaneous coronary interventions: practical implications, new clinical data, and recommended guideline revisions. Am Heart J 2008; 155: 781-790.
  CrossrefPubMedGoogle Scholar
• 31 Labarthe B, Théroux P, Angioï M. et al. Matching the evaluation of the clinical efficacy of clopidogrel to platelet function tests relevant to the biological properties of the drug. J Am Coll Cardiol 2005; 46: 638-645.
  CrossrefPubMedGoogle Scholar
• 32 Aleil B, Ravanat C, Cazenave JP. et al. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 2005; 03: 85-92.
  CrossrefPubMedGoogle Scholar
• 33 Jakubowski JA, Payne CD, Li YG. et al. The use of the VerifyNow P2Y₁₂ point of care device to monitor platelet function across a range of P2Y₁₂ inhibition levels following prasugrel and clopidogrel administration. Thromb Haemost 2008; 99: 409-415.
  Article in Thieme ConnectPubMedGoogle Scholar
• 34 Jakubowski JA, Payne CD, Li YG. et al. A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry. Thromb Haemost 2008; 99: 215-222.
  Article in Thieme ConnectPubMedGoogle Scholar
• 35 von Beckerath N, Kastrati A, Wieczorek A. et al. A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J 2007; 28: 1814-1819.
  CrossrefPubMedGoogle Scholar
• 36 Angiolillo DJ, Bernardo E, Palazuelos J. et al. Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous coronary interventions: Results from a randomized study. Thromb Haemost 2008; 99: 161-168.
  Article in Thieme ConnectPubMedGoogle Scholar
• 37 Mehta SR. Clopidogrel in non-ST-segment elevation acute coronary syndromes. Eur Heart J 2006; 08 Suppl G G25-G3.
  CrossrefPubMedGoogle Scholar
• 38 Mehta SR, Bassand J-P, Chrolavicius S. et al, CURRENT-OASIS 7 Steering Committee.. Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J 2008; 156: 1080-1088.
  CrossrefPubMedGoogle Scholar
• 39 Mehta SR for the CURRENT-OASIS 7 Investigators.. A randomized comparison of a clopidogrel high loading and maintenance dose regimen versus standard dose and high versus low dose aspirin in 25,000 patients with acute coronary syndromes: Results of the CURRENT OASIS 7 Trial. Presented at: European Society of Cardiology; 30 August, 2009; Barcelona, Spain. Available at: http://assets.esc/ardio.org/webcasts/default.aspx?id=ESC2009/177. Accessed 7 September, 2009.
  PubMedGoogle Scholar
• 40 Snoep JD, Hovens MMC, Eikenboom JCJ. et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007; 154: 221-231.
  CrossrefPubMedGoogle Scholar
• 41 Price MJ, Endemann S, Gollapudi RR. et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000.
  CrossrefPubMedGoogle Scholar
• 42 Cuisset T, Frere C, Quilici J. et al. High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-ST elevation acute coronary syndromes. Thromb Haemost 2007; 97: 282-287.
  Article in Thieme ConnectPubMedGoogle Scholar
• 43 Frere C, Cuisset T, Quilici J. et al. Determination of prognostic values of ADP-induced platelet aggregation and platelet reactivity index VASP for clinical outcomes in non-ST-elevation acute coronary syndrome. Thromb Haemost 2007; 98: 838-843.
  Article in Thieme ConnectPubMedGoogle Scholar
• 44 Angiolillo DJ, Alfonso F. Platelet function testing and cardiovascular outcomes: steps forward in identifying the best predictive measure. Thromb Haemost 2007; 98: 707-709.
  Article in Thieme ConnectPubMedGoogle Scholar
• 45 Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome P-450 polymorphisms and response to clopidogrel. New Engl J Med 2009; 360: 354-362.
  CrossrefPubMedGoogle Scholar
• 46 Simon T, Verstuyft C, Mary-Krause M. et al, French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators.. Genetic determinants of response to clopidogrel and cardiovascular events. New Engl J Med 2009; 360: 363-375.
  CrossrefPubMedGoogle Scholar
• 47 Collet JP, Hulot JS, Pena A. et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373: 309-317.
  CrossrefPubMedGoogle Scholar
• 48 Giusti B, Gori AM, Marcucci R. et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y₁₂ T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics 2007; 17: 1057-1064.
  CrossrefPubMedGoogle Scholar
• 49 Pena A, Collet J-P, Hulot J-S. et al. Can we override clopidogrel resistance?. Circulation 2009; 119: 2854-2857.
  CrossrefPubMedGoogle Scholar
• 50 Montalescot G, Bal-dit-Sollier C, Chibedi D. et al.; ARMADA Investigators. Comparison of effects on markers of blood cell activation of enoxaparin, dalteparin, and unfractionated heparin in patients with unstable angina pectoris or non-ST-segment elevation acute myocardial infarction. Am J Cardiol 2003; 91: 925-930.
  CrossrefPubMedGoogle Scholar