Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate. METHODS: CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years. FINDINGS: 19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favour of clopidogrel (95% Cl 0.3-16.5). Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group. INTERPRETATION: Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.

A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee / M. Gent, D. Beaumont, J. Blanchard, M.G. Bousser, J.C.J.D.E.J.R. Hampton, L.A.H.L. Janzon, J.J. Kusmierek, E. Panak, R.S. Roberts, J.S. Shannon, J. Sicurella, G. Tognoni, E.J. Tool, M. Verstraete, C. Warlow, M. Verstraete, J.D. Easton, M.G. Bousser, J.A. Cairns, J.H. Chesebro, J.R. Hampton, G. von der Lippe, R.W. Ross Russell, P.A. Wolf, J.P. Boissel, L. Friedman, V. Fuster, M.G. Harrison, S. Pocock, B.B. Weksler, M. Gent, G. Foster, G. Lewis, T. Lychak, H.L. Nelson, R.S. Roberts, J. Sicurella, J. Sicurella, C. Stewart, B. Szechtman, S. Chrolavicius, I. Copland, B. Jedrzojawski, F. Mccreadie, L. Wilkinson, S. Vonderveehn, J.P. Boissel, F. Boutitie, D. Beaumont, G. Perdriset, I. Thizon de Gualle, J. Hoek, M.O. Besnier, A. Boddy, D. Brooker, G. Derzko, A. Jones, C. Metzinger, J. Novack, S. Pratt, D. Roome, J.P. Schulhof, E. Vallee, D. Valtier, E. Bastida, L. Coy, R. Creek, G. Destelle, T. Döberl, N. de la Forest Divonne, G. Gallo, A. Garcia, B. Geudelin, F. Hundt, R. Hylkema, P. Vanhove, N. Amalfitano, K. Cabala, J. Caniglia, I. Duval, L. Forgie, A.C. Neiss, T. Wesseling, J.F. Plehn, S.J. Kennedy, R.M. Zwolak, A. Reeves, M.D. Mcdaniel, G.J. Macdonald, C. Murphy, P.S. Howes, L.K. Cornell, M.L. Hynes, C.M. Jackson, P.D. Lyden, J.F. Rothrock, R.J. Hye, H.C. Dittrich, N.M. Kelly, C.M. Kerridge, T. Chippendale, M. Lobatz, E. Diamond, J. Schim, M. Sadoff, W. Logan, A. Auer, W. Hamilton, R. Frere, S. Schroer, M. Wilcox, C. Naeger, J.W. Harbison, R. Makhoul, J.R. Taylor, W.L. Felton, H.M. Lee, K. Massey Makhoul, K.F. Browne, G.S. Tyson, E. Pineiro, A.S. Brenner, R.A. Ford, P.J. Reddy, P. Owens, J. Heinsimer, K. Richter, K. Markowski, T. Lentini, L. Howell, H.T. Colfer, D.J. Rynbrandt, C.D. Wendt, M. Wilmot, B. Stone, R. Touchon, D. Briley, L. Adkins, K. Roe, C. Harless, M.A. Dewood, J.A. Skidmore, J.M. Randall, J. Davenport, C. Farmer, S. Hanson, L.C. Kuo, P. Brown, J. Desjardins, N. Halpern, W. Talbot, R. Schainfeld, K. Rosenfield, J.M. Isber, E. Grall, S. Lanza, P.A. Walker, R.J. Ivanhoe, M.R. Milunski, D.J. Kereiakes, C.W. Abbottsmith, D.A. Lausten, C.M. Helgason, V. Glover, T. Gnutek, W.M. Clark, B.M. Coull, E. Harrison, J.T. Suh, J.W. Mcbride, B. Foster, K. Vittum, N.Y. Lauer, B.T. Adornato, M.K. Adornato, M. Fisher, S.F. Ameriso, A. Scicli, M.R. Starling, J.A. Petrusha, W.H. Devlin, C.C. Suter, J. Tucci, S.H. Stewart, C. Sadowsky, R. Stone, M. Tuchman, E.K. Massin, H.V. Anderson, M. Harlan, J. Abrams, C. Timm, G. Rosenberg, W.R. Hiatt, J.G. Regensteiner, T. Bauer, J.L. Frey, C. Darbonne, L. Marlor, W.D. Haire, L.C. Stephens, G.D. Kotulak, B. Iteld, A. Vanderstappen, V.N.N. Kleiman, L. Bushman, A. Fischer, W.M. Clark, E. Harrison, H. Moon, A.C. Klassen, M.E. Berman, R. Sufit, J. Biller, J.W. Olin, C.A. Pirzada, V.A. Medical, L.A. Hershey, K. Burch, J. Castaldo, D. Jenny, C. Wohlberg, K. Gaines, C. Cape, S.K. Gupta, R.A. Landa, S.R. Norcross, A. Culebras, D.C. Pastor, R.M. Fairman, S. Zakulec, J.M. Sutton, T. Mccullough, P.E. Fenster, W.M. Feinberg, R.G. Pellegrino, C. Jeffers, W.B. Smith, R. Vargas, T. Mccormick, N.M. Ramadan, S.R. Levine, A.T. Hirsch, A.G. Wasserman, A. Nys, D.J. Breslin, S.B. Labib, G. Woodhead, T.M. Matzura, S. Dunlap, M.A. Goodman, J. Cappelli, P. Stein, K. Nadamanee, E. Havranek, J. Weinberger, N.S. Lava, S. Horowitz, J. Byer, D. Wentworth, J.D. Dexter, A. Bonnett, G.W. Vetrovec, R.P. O'Brien, J.D. Easton, J.L. Wilterdink, D.A. Gelber, S. Hemberger, D. Sherman, D. Rogers, M.U. Alberts, C. Mcclenny, K.D. Weeks, D. Whisnant, J. D'Alton, H. Doolittle, K.A. Siller, W.K. Hass, C. Grines, G. Timmis, P.B. Gorelick, D. Robinson, A.B. Lumsden, J. Macdonald, R.L. Hughes, V. Noonan, G. Goldberg, R. Costello, S. Mohiuddin, L. Stengel, M.R. Frankel, J. Braimah, M.A. Creager, P. Baum, J.P. Cooke, A. Ma, V.L. Babikian, M.A. O'Neal, T. Mirsen, C. Bruegel, J.D. Coffman, D.C. Brindley, M. Mick, S.G. Korenman, L.M. Brass, S.W. Asher, J.L. Halperin, R. Schlesinger, G.M. Gacioch, J.R. Couch, B.E. Skolnick, M.S. Ware, J. Anderson, L. Knepper, M. Victor, S. Ball, J.C. Gurley, M. Jessup, U. Elkayam, W.G. Hughes, J.A. Fraser, E.A. Potvin, J. Mcmillan, J. Grierson, N. Hartwick, S. Musclow, A. Thompson, J. Mewett, R. Sivan, A.G. Turpie, S. Morino, M. Siguenza, J.A. Blakely, S. Styling, L. Balleza, D.S. Beanlands, L. Garrard, K. Morgan, T. Ruddy, A.L. Morris, B.A. Anderson, A.S. Arneja, S.A. Carter, V. Daniels, B. Mcewen, A.J. Ricci, J.H. Swan, J.E. Goode, D.A. Selby, B. Bozek, A. Shuaib, M. Yeung, M. Press, L.L. Walston, A.Y. Fung, H. Henning, D.C. Taylor, H. Abbey, C. Davies, L. Saunders, P.H. Tanser, D. Feldman, B. Sullivan, M.J. Sayles, E. Kent, S.J. Connolly, E. Coletta, V. Carruthers, W. Hui, P. Klinke, N. Brass, L. Kvill, J. Cusson, P. Van Nguyen, L. Marchand, S. Roy, J.F. Blair, J.L. Wellington, K. Rody, S. Poloni, M.G. Myers, C.D. Morgan, P. Parsons, R. Lecours, J.V. Patanaude, C. Turcotte, J.R. Gutelius, R. Pattenden, R.M. Gagnon, N. Racine, C. Roy, K. Harris, M. Lovell, P.A. Teal, J.L. Bloomer, C.R. Thompson, M. Wong, J.G. Sladen, K. Macdonald, D. Heinrich, G. Houde, C. Nadeau, P. Talbot, A. Pagé, A. Verdant, M. Smilovitch, N. Racine, O. Steinmetz, D. Simard, C. Benguigui, C. Ouellet, L.H. Lebrun, M.P. Desrochers, K. Finnie, S. Mccreery, W.J. Kostuk, P.W. Pflugfelder, R. Oskalns, J.F. Bonet, K. Ilott, J. Mcconnell, M. Ruel, L. Primeau, S. Phillips, L. Coleman Kamphuis, J.R. Leclerc, S. Solymoss, R. Côté, F. Bourque, T.K. Lee, L. Kvill, V. Bernstein, L. Doyle, J.R. Timothee, R. Chebayeb, C. Lefkowitz, P. Hambly, G.M. Klein, M. Robertson, N. Bayer, P. Couse, J.W. Norris, M.J. Medel, B. Sevitt, J. Fitzsimons, D. Fitchett, A. Serpa, D. Marr, B. Ouellet, A. Bellavance, W. Pryse Phillips, D.C. Howse, S.W. Rabkin, J. Mccans, D.P. Brandjes, H.R. Büller, A.R. Dÿkema, J.G. Kromhout, J.A. Lawson, R.J. Peters, J.J. van der Sande, J. Stam, L.M. Blok, Y. Jenner, O. Ternede, J. Lens, E.C. Bollen, R.J. Welten, P. Termeulen, W.P. Hollanders, D.J. Lok, H. Groeneveld, L.H. Bouwens, F.C. Tietge, E.C. van der Velden, P.W. Bruggink André, G.J. van Iersel, J. Seegers, A.C. van Vliet, P. van der Sar, B.D. Verhoog, S.H. van der Sar de Nooijer, I. Verhoog Nijhuis, C.L. Franke, P.J. Koehler, J. van der Meer, J.S. van Os, M. van der Heijden, L.M. van Wijk, J.A. Kragten, J. de Warrimont Henquet, R. Feld, H.M. Van Gemert, D.W. Dippel, P.J. Koudstaal, J.A. Vanneste, W.H. Linssen, J.J. Kruisdijk, J. Visser, T.F. Van Gool, J. Vooges, A.C. De Vries, P. Klinkert, K.A. Bartlema, J.D. Banga, S.D. Niemeijer Kanters, M.G. de Groot, F.L. Moll, R. Sybrandy, J. Buth, F.P. Schol, R.C. Donders, A. Algra, G.A. Pop, R. van der Heijden, B. Knippenberg, J.C. Sier, D. Berqvist, S. Karacagil, I. Eriksson, S. Bowald, A. Holmberg, C. Ljungman, B. Westman, J. Sivenius, J. Puranen, A. Karinen, J. Onatsu, T. Salmenperä, M. Kalinen, M. Kaste, T. Tatlisumak, L. Soinne, M. Kallela, M. Kotila, M. Hartford, J. Herlitz, B.W. Karlson, S.O. Strömblad, B.O. Olofsson, T. Strand, B. Kristensen, J. Malm, J.H. Melin, M. Virtanen, T. Olli, F. Lindgärde, H. Pessah Rasmussen, M. Rendell, U.B. Ericsson, A. Sahlman, H. Savolainen, J. Rämö, J. Lehtonen, M.E. Hillbom, M. Reunanen, J. Turkka, K. Ylönen, T. Peltola, T. Juvonen, E. Koskela, J. Erkinheimo, K.A. Ängquist, B. Hedberg, C. Arnerlov, A. Rissanon, K. Murros, U. Idänpään Heikkilä, L. Honka, J. Heikkilä, T. Tiensuu, J. Boberg, A.L. Berggren, P.L. Thompson, E.T. Yu, P.J. Bradshaw, P.A. Cooke, S.P. Gordon, K.S. Loh, B. Mcquillan, M.M. Moshiri, D.B. Cross, W.S. Egerton, P.J. Walker, C.A. Codd, D.A. Kreuter, S. Cox, D. Naik, D.M. Cavaye, M.C. Harel, J. Horowitz, C. Rowe, S. Stewart, K. Boundy, C.F. Stringer, J.L. Anderson, D. Coller, P. Aylward, C. Anderson, R. Burns, D. Schultz, P. Waddy, J. Walsh, L. Davies, J.P. Harris, A. Wetzlar, A. Mcdougall, K. Sieunarine, P. Cremer, G.A. Donnan, A. Tonkin, C. Levi, J. Hanlan, F. Ellery, H.D. White, A.W. Hamer, V. Kapadia, K. Ramanathan, R.R. Taylor, G. Hankey, M. Brooks, T. Young, M. Mcinerney, J. Sansom, R. Thomson, C. Spaulding, R. Cutforth, A. Thomson, H.H. Salem, P. Coughlin, T.J. Campbell, R.S. Lord, D. O'Sullivan, C. Corrigan, S. D'Arcy, N.E. Anderson, A.J. Charleston, S.M. Davis, R. Gerraty, N. Bett, D.J. Hewson, R.C. Kester, D.J. Scott, D.C. Berridge, P.J. Kent, C.A. Thornton, H. Sykes, S. Bennett, D. Blakey, W.P. Brooksby, R.T. Johnston, M. Brack, J.R. Hampton, P. Vowden, M.J. Gough, R. Hooper, M. Gough, S.P. Hanley, M. Macaskill, J. Miles, C. Waywell, J.C. Mucklow, C. Davis, P. Harper, K. Cooke, G. Lowe, B. Shaw, J. Mckillop, J.A. Dormandy, H. Chaudhry, J. Evans, J.M. Bamford, S. Blundell, G. Venables, C. Doyle, C.P. Shearman, A. Crow, M. Dennis, P. Sandercock, M.M. Brown, J. Rogers, R.M. Boyle, B.S. Wiseman, P.R. Humphrey, C.R. Prentice, T. Moccetti, E. Pasotti, F. Sessa, A. Bertolini, A. Rossi, A. Del, R. Malacrida, D. Moccetti, G. Besomi, H.P. Mattle, E. Eicher Vella, D. Maurer, F. Rihs, U. Hoffmann, A. Bollinger, U.K. Franzeck, F. Mahler, D. Do, I. Baumgartner, B. Weder, L. Bönig, H.P. Ludin, J. Bogousslavsky, M. Maeder Ingvar, F. Regli, L. Kappenberger, M. Depairon, G. Bizzini, C. Beretta Piccoli, F. Elshater Zanetti, C. Guffi, O. Bertel, T. Deseö, W. Gmuer, H. Bounameaux, J. Wicky, S. Desmarais, P. Vogt, D. Fellay, K. Rhyner, W. Wojtyna, T. Bonetti, J. Brunner, K.A. Jäger, I. von Planta, G. Noseda, A. Pugliesi, L. Pons Giudici, B. Meier, D. Evéquoz, D. Schmidt, H.S. Keel, D. Heinrich, F. Follath, H.P. Brunner, B. Caduff, M. Wirth, A. Vuilliomenet, M. Savcic, U. Hürlimann, E. Bosshard, W. Hacke, T. Brandt, S. Wildermuth, P. Ringleb, O. Busse, V. Straeten, K. Zeuner, S. Vielhaber, B. Tettenborn, G. Krämer, A. Allardt, E. Schmitt Henco, H.C. Diener, V. Schrader, J. Nebe, E. Pilger, A. Doder, B. Gürtl, C. Diehm, M. Gomer, T. Jansen, D. Kömpf, M. Kaps, M. Vidal Langwasser, M. Hennerici, M. Daffertshofer, U. Schminke, H.H. Osterhues, A. Fischer, H.J. Rupprecht, U. Borkowski, G. Rudofsky, A. Rescher, H. Schwerdt, B. Hammer, R. Voss, M. Grebe, H. Rieger, R. Grobe, W. Theiss, F. Schaub, F.J. Neumann, L. Lutilsky, F.T. Aichner, C. Schmidauer, K. Erdlenbruch, B.S. Mórsdorf, C.R. Hornig, T. Moulin, D. Chavot, A. Autret, C. Lucas, D. Leys, H. Henon, F. Chedru, A. Ameri, J.F. Dunand, P. Dambrine, A. Gabriel, F. Labaki, X. Tran Tranh, C. Jouannon, F. Durup, M. Pagès, J.M. Blard, M. Giroud, M. Menassa, M. Zuber, J.L. Mas, M. Hommel, G. Besson, C. Laurian, J.F. Mathieu, G. Geraud, V. Larrue, K. Ben Hamda, R. Fumey, B. Guiraud Chaumeil, F. Chollet, M. Pathé, D. Zannier Marzari, H. Chabriat, P. Amarenco, J.F. Pinel, J. Beaune, J.B. Pichard, A. Medvedowsky, F. Becker, B. Terriat, F. Woimant, G. Cathelineau, I. Martin Jadraque, J.L. López Sendon, I. Gonzales Maqueda, I. Roldan Rabadan, J.M. Cruz Fernández, V. López Garcia, E. Ros Die, J. Gonzáles Rios, O. Del Foco, A. Chamorro, M. Alday, J. Matias Guiu, F. Gracia, J.L. Pomar Moya Prats, C.A. Mestres, J.A. Jiménez Cossio, L. Riera de Cubas, P. Barreiro Tella, E. Diez Tejedor, L. Cunha, A.F. Goncalves, M.A. Ferro, V. Barbosa, D. Santiago, J.M. Ferro, T.P. Melo, V. Oliveira, A.N. Pinto, A.L. Bordalo Sá, D. Ferreira, J.L. Tuna, L. Providência, J. Morais, A. Pimenta, F. Van de Werf, A. Luyten, C. Luys, S.A. Blecic, N.G. Van Blercom, J.G. Hildebrand, B. Sadzot, G. Franck, C. Brohet, D. Huyberechts, M. Zicot, J. Petermans, D.A. Duprez, D.L. Clement, R. Verhaeghe, K. Peerlinck, J. De Reuck, T. Bosschaerts, J.C. Wautrecht, S. Coccheri, G. Fortunato, M. Catalano, A. Libretti, A. Carolei, S. Mearelli, P. Gresele, L. Selli, G.G. Nenci, M. Morini, M. Cortellaro, S.L. Chierchia, G. Luca Messa. - In: THE LANCET. - ISSN 0140-6736. - 348:9038(1996 Nov 16), pp. 1329-39-1339. ((windows.

A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee

M. Catalano;
1996

Abstract

Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate. METHODS: CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years. FINDINGS: 19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favour of clopidogrel (95% Cl 0.3-16.5). Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group. INTERPRETATION: Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.
Settore MED/09 - Medicina Interna
16-nov-1996
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