Abstract
Objectives
To compare a loading dose of 600 mg clopidogrel given in the prehospital phase versus clopidogrel administered only after the diagnostic angiogram in patients with STEMI scheduled for primary PCI.
Background
The optimal time and dose for the initiation of clopidogrel therapy in patients with STEMI scheduled for primary PCI has not been studied in prospective randomized trials.
Methods
The primary efficacy endpoint was the TIMI 2/3 patency of the infarct-related artery in the diagnostic angiography immediately prior to PCI.
Results
We randomized 337 patients to prehospital (n = 166) loading dose versus standard therapy (n = 171). The time interval between initiation of clopidogrel therapy and diagnostic angiography was 47 min. TIMI 2/3 patency before PCI was not different between the groups (49.3 vs. 45.1%, P = 0.5). We observed a trend towards a reduction of the combined endpoint death, re-infarction, and urgent target vessel revascularization in the prehospital-treated patients (3.0 vs. 7.0%, P = 0.09), this difference was significant if patients were classified as treated (4/161 vs. 13/174; 2.5 vs. 7.5%, P < 0.05). There was no difference in TIMI major bleeding complications (9.1 vs. 8.2%, P = 0.8).
Conclusions
Early inhibition of the platelet ADP-receptor with a high loading dose of 600 mg clopidogrel given in the prehospital phase in patients with STEMI scheduled for primary PCI is safe, did not increase pre-PCI patency of the infarct vessel, but was associated with a trend towards a reduction in clinical events.
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References
Simes RJ, Topol EJ, Holmes DR Jr., White HD, Rutsch WR, Vahanian A, Simoons ML, Morris D, Betriu A, Califf RM, GUSTO-I Investigators (1995) Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. Circulation 91:1923–1928
Anderson JL, Karagounis LA, Califf RM (1996) Metaanalysis of five reported studies on the relation of early coronary patency grades with mortality and outcomes after acute myocardial infarction. Am J Cardiol 78:1–8
Weaver WD, Simes RJ, Betriu A, Grines CL, Zijlstra F, Garcia E, Grinfeld L, Gibbons RJ, Ribeiro EE, DeWood MA (1997) Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review. JAMA 278:2093–2098
Keeley EC, Boura JA, Grines CL (2003) Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 361:13–20
Claeys MJ, Bosmans J, Veenstra L, Jorens P, De Raedt H, Vrints CJ (1999) Determinants and prognostic implications of persistent ST-segment elevation after primary angioplasty for acute myocardial infarction: importance of microvascular reperfusion injury on clinical outcome. Circulation 99:1972–1977
Santoro GM, Antoniucci D, Valenti R, Bolognese L, Buonamici P, Trapani M, Boddi V, Fazzini PF (1997) Rapid reduction of ST-segment elevation after successful direct angioplasty in acute myocardial infarction. Am J Cardiol 80:685–689
Neumann FJ, Blasini R, Schmitt C, Alt E, Dirschinger J, Gawaz M, Kastrati A, Schomig A (1998) Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation 98:2695–2701
Montalescot G, Barragan P, Wittenberg O, Ecollan P, Elhadad S, Villain P, Boulenc JM, Morice MC, Maillard L, Pansieri M (2001) Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 344:1895–1903
Gyongyosi M, Domanovits H, Benzer W, Haugk M, Heinisch B, Sodeck G, Hodl R, Gaul G, Bonner G, Wojta J, Huber K (2004) Use of abciximab prior to primary angioplasty in STEMI results in early recanalization of the infarct-related artery and improved myocardial tissue reperfusion - results of the Austrian multi-centre randomized ReoPro-BRIDGING Study. Eur Heart J 25:2125–2133
Zeymer U, Zahn R, Schiele R, Jansen W, Girth E, Gitt A, Seidl K, Schroder R, Schneider S, Senges J (2005) Early eptifibatide improves TIMI 3 patency before primary percutaneous coronary intervention for acute ST elevation myocardial infarction: results of the randomized integrilin in acute myocardial infarction (INTAMI) pilot trial. Eur Heart J 26:1971–1977
Brodie BR, Stuckey TD, Hansen C, Muncy D (2000) Benefit of coronary reperfusion before intervention on outcomes after primary angioplasty for acute myocardial infarction. Am J Cardiol 85:13–18
Stone GW, Cox D, Garcia E, Brodie BR, Morice MC, Griffin J, Mattos L, Lansky AJ, O’Neill WW, Grines CL (2001) Normal flow (TIMI-3) before mechanical reperfusion therapy is an independent determinant of survival in acute myocardial infarction: analysis from the primary angioplasty in myocardial infarction trials. Circulation 104:636–641
Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, for the CLASSICS Investigators (2000) Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 102:624–629
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494–502
Steinhubl SR, Berger PB, Mann JT III, Fry ET, DeLago A, Wilmer C, Topol EJ (2002) Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288:2411–2420
Mehilli J, Kastrati A, Schulz S et al (2009) Abciximab in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention after clopidogrel loading: a randomized double-blind trial. Circulation 119:1933–1940
Vlaar PJ, Svilaas T, Damman K, de Smet BJGL, Tijsen JGP, Hillege HL, Zijlstra F (2008) Impact of pretreatment with clopidogrel on initial patency and outcome of patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. A systematic review. Circulation 118:1828–1836
Zeymer U, Arntz HR, Darius H, Huber K, Senges J (2007) Efficacy and safety of clopidogrel 600 mg administered pre-hospitally to improve primary percutaneous coronary intervention in patients with acute myocardial infarction (CIPAMI): study rationale and design. Cardiology 108:265–272
Schröder R, Zeymer U, Wegscheider K, Neuhaus KL, for the HIT-4 trial group (1999) Comparison of the predictive value of ST segment elevation resolution 90 and 180 minutes after start of streptokinase in acute myocardial infarction. A substudy of the Hirudin for Improvement of Thrombolysis (HIT)-4 Study. Eur Heart J 20:1563–1571
De Luca G, Gibson M, Bellandi F, Murphy S, Maioli M, Noc M, Zeymer U, Dudek D, Arntz HR, Zorman S, Gabriel M, Emre A, Cutlip D, Biondi-Zoccai G, Rakowski T, Gyongyosi M, Marino P, Huber K, Van’t Hof A (2008) Early Glycoprotein IIb–IIIa inhibitors in primary angioplasty (EGYPT) cooperation. An individual patients’ data meta-analysis. Heart 94:1548–1558
Van’t Hof AWJ, ten Berg J, Heestermans T, Dill T, Funck RC, van Werkum W, Dambrink JH, Suryapranata H, van Houwelingen G, Ottervanger JP, Stella P, Giannitsis E, Hamm C (2008) Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2: a multicentre, double-blind, randomised controlled trial). Lancet 372:537–546
Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, Jorgensen E, Marco J, Nordrehaug JE, Ruzyllo W (2005) Guidelines for percutaneous coronary interventions. The Task Force for percutaneous coronary interventions of the European Society of Cardiology. Eur Heart J 26:804–847
Muller I, Seyfarth M, Rudiger S, Wolf B, Pogatsa-Murray G, Schomig A, Gawaz M (2001) Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 85:92–93
Montalescot G, Sideris G, Meulemann C, Bal-dit Sollie RC (2006) A randomized comparison of high clopidogrel loading doses in patients with non-ST segment elevation acute coronary syndromes. The ALBION trial. J Am Coll Cardiol 48:931–938
Larson DM, Duval S, Sharkey SS, Solie C, Tschautscher C, Lips DL, Burke MN, Steinhubl S, Henry TD (2010) Clopidogrel pretreatment in ST-elevation myocardial infarction transferred for percutaneous coronary intervention. Am Heart J 160:202–207
Koul S, Smith JG, Scherstein F, James S, Lagerquist B, Erlinge D (2011) Effect of upstream clopidogrel treatment in patients with ST-segment elevation myocardial infarction undergoing primary PCI. Eur Heart J
American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care (2005) Part 4: adult basic life support. Circulation 112 (Suppl):IV-19–34
Montalescot G, Wiviott SD, Braunwald E et al (2009) Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIM 38). Lancet 373:723–731
Steg PG, James S, Harrington RA et al (2010) Ticagrelor versus clopidogrel in patients with ST-elevations acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a PLATO trial subgroup analysis. Circulation 122:2131–2141
Acknowledgments
The study has been supported by an unrestricted grant of Bristol Myers Squibb (BMS). Munich, and Sanofi-Aventis, Berlin, Germany.
Study chairmen: Uwe Zeymer; Steering committee: Hans-Richard Arntz, Harald Darius, Kurt Huber. Angiographic Core laboratory: Walter Desmet, University of Leuven, Belgium. ECG Core laboratory: Rolf Schröder, Berlin, Germany. Project leader Institut für Herzinfarktforschung Ludwigshafen, Germany: Frank Diller. Participating Centers appearing in the order of the number of enrolled patients: Charité Campus Benjamin Franklin, Berlin: Hans-Richard Arntz; Herzzentrum Ludwigshafen: Bernd Mark, Uwe Zeymer; Universitätsklinikum Frankfurt: Andreas Zeiher, Stephan Fichtschlerer; Klinikum Darmstadt: Gerald Werner; DRK-Klinikum Westend, Berlin: Ralph Schöller, Dietlind Glöckner; Klinikum Leverkusen: Peter Schwimmbeck, Wolfgang Jansen; Caritas-Klinik Pankow, Berlin: Heiko Lehmann; Kreiskrankenhaus Bergstraße, Heppenheim: Wolfgang Auch-Schwelk, Thomas Schnebelt; Städtisches Klinikum Brandenburg: Michael Oeff, Claudia Sprenger; Universitätsklinikum Rostock: Christoph Nienaber, Hendrik Schneider; Klinikum Lüneburg: Wolfram Kupper; Wilhelminenspital, Wien: Kurt Huber; Klinikum Saarbrücken: Günter Görge; Kerckhoff-Klinik, Bad Nauheim: Thorsten Dill; Sana Klinikum Lichtenberg, Berlin: Sven Tessin; Vivantes Klinikum Neukölln, Berlin: Harald Darius; Universitätsklinikum Innsbruck: Otmar Pachinger; KMG Kliniken/Klinikum Wittstock: Volker Hitz; Universitätsklinikum Gießen: Ali Erdogan; Allgemeines Krankenhaus Celle: Uwe Klotz; Universität Leipzig - Herzzentrum: Holger Thiele; St. Vincenz Krankenhaus, Limburg: Jörg Kreuzer; Hanusch-Krankenhaus, Wien: Georg Gaul; Evangelisches Krankenhaus, Holzminden: Christian Beythien
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Zeymer, U., Arntz, HR., Mark, B. et al. 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, 305–312 (2012). https://doi.org/10.1007/s00392-011-0393-1
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DOI: https://doi.org/10.1007/s00392-011-0393-1