Copyright © 2000 by the European Society of Cardiology.
The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme. Rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease
Received September 11, 2000; accepted October 4, 2000Abstract
Background Other than aspirin, there are few oral antithrombotic treatments with proven efficacy in patients with acute coronary syndrome. In this report, we present the rationale, design and baseline characteristics of the Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) trial, which includes a meta-analysis of the effects of thienopyridines in patients with vascular disease.
Methods and Results Combined data from randomized trials of thienopyrindines in patients with atherosclerotic disease demonstrated a 29% reduction in vascular events when compared with placebo/control (n=2392) (OR 0·71, 95% CI 0·58–0·86, P=0·0006) and a 10% reduction in vascular events when compared with aspirin (n=22254) (OR 0·91, 95% Cl 0·84–0·99, P=0·039). Similarly, randomized trials of aspirin plus thienopyridines in patients undergoing intracoronary stenting, demonstrated a marked benefit of aspirin plus ticlopidine in reducing death or myocardial infarction compared with aspirin alone (OR 0·23, 95% CI 0·11–0·49, P=0·0001) or aspirin plus warfarin (OR 0·51, 95% CI 0·33–0·78, P=0·002). Whether these benefits extend to the much larger population of patients with acute coronary syndrome is unknown. CURE is an international, randomized, double-blind trial, in which patients with acute coronary syndrome will be randomized to receive either a bolus dose of clopidogrel (300mg) followed by 75mg per day for 3–12 months, or matching placebo. Both groups will receive aspirin. The co-primary efficacy end-points of CURE are: (1) the composite of cardiovascular death, myocardial infarction or stroke; and (2) the composite of cardiovascular death, myocardial infarction, stroke or refractory ischaemia. CURE will recruit approximately 12500 patients with acute coronary syndrome (from 28 countries) and its power to detect moderate treatment benefits will be in the region of 80–90%, while maintaining an overall type I error (
) of 0·05. The baseline characteristics of the study population are consistent with at least a moderate risk group of patients with acute coronary syndrome.
Conclusions Randomized trials of thienopyridines in patients with vascular disease demonstrate that thienopyridines are effective in reducing vascular events when compared with placebo/control or aspirin, as well as when used in combination with aspirin in patients undergoing intracoronary stent implantation. The CURE trial is a large international study to determine if acute and long-term treatment with the combination of clopidogrel and aspirin is superior to aspirin alone in patients with acute coronary syndrome.
Key Words: Thienopyridines, unstable angina, meta-analysis, clinical trial
References
- Theroux P, Fuster V. Acute coronary syndromes. Unstable angina and non-Q-wave myocardial infarction. Circulation. 1998;97:1195–1206
[Free Full Text] - Yusuf S, Flather M, Pogue J. Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina. Lancet. 1998;352:507–514[CrossRef][Web of Science][Medline]
- Mehta SR, Eikelboom JW, Yusuf S. Long term management of unstable angina. Eur Heart J. 2000;2:E6–E12
- N Engl J Med. 1998;338:1488–1497
[Abstract/Free Full Text] - N Engl J Med. 1998;339:436–443
[Abstract/Free Full Text] - Lancet. 2000;355:337–345[CrossRef][Web of Science][Medline]
- Cannon CP, McCabe CH, Wilcox RG. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation. 2000;102:149–156
[Abstract/Free Full Text] - Lancet. 1999;354:701–707[CrossRef][Web of Science][Medline]
- Antman EM, McCabe CH, Gurfinkel EP. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Circulation. 1999;100:1593–1601
[Abstract/Free Full Text] - Abbracchio MP, Burnstock G. Purinoceptors: are they families of P2X and P2Y purinoceptors? Pharmacol Ther. 1994;64:445–475[CrossRef][Web of Science][Medline]
- Hechler B, Leon C, Vial C. The P2Y1 receptor is necessary for adenosine 5'-diphosphate-induced platelet aggregation. Blood. 1998;92:152–159
[Abstract/Free Full Text] - Leon C, Hechler B, Vial C, Leray C, Cazenave JP, Gachet C. The P2Y1 receptor is an ADP receptor antagonized by ATP and expressed in platelets and megakaryoblastic cells. FEBS Lett. 1997;403:26–30[CrossRef][Web of Science][Medline]
- Defreyn G, Gachet C, Savi P, Driot F, Cazenave JP, Maffrand JP. Ticlopidine and clopidogrel (SR 25990C) selectively neutralize ADP inhibition of PGE 1-activated platelet adenylate cyclase in rats and rabbits. Thromb Haemost. 1991;65:186–190[Web of Science][Medline]
- Geiger J, Brich J, Honig-Liedl P. Thienopyridine-based antiplatelet drugs inhibit ADP effects on prostaglandin-stimulated, cAMP/PKA-mediated phosphorylation of the cytosckeletal protein VASP in human platelets (Abstr). Circulation. 1998;98:I-595
- Gachet C, Savi P, Ohlman P, Maffrand JP, Jakobs KH, Cazenave JP. ADP receptor induced activation of guanine nucleotide binding proteins in rat platelet membranes: an effect selectively blocked by the thienopyridine clopidogrel. Thromb Haemost. 1992;68:79–83[Web of Science][Medline]
- Gent M, Blakely JA, Easton JD. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet. 1989;1:1215–1220[Web of Science][Medline]
- Gill S, Majumdar S, Brown NE, Armstrong PW. Ticlopidine-associated pancytopenia: implications of an acetylsalicylatc acid alternative. Can J Cardiol. 1997;13:909–913[Web of Science][Medline]
- Bennet C, Weinberg P, Rozenberg-Ben-Dror K, Yarnold P, Kwaan H, Green D. Thrombotic thrombocyopenic purpura associated with ticlopidine: a review of 60 cases. Ann Int Med. 1998;128:541–544
[Abstract/Free Full Text] - Kupfer Y, Tessler S. Ticlopidine and thrombotic thrombocytopenic purpura. N Engl J Med. 1997;337:1245
[Free Full Text] - Page Y, Tardy B, Zeni F, Comtet C, Terrana R, Bertrand JC. Thrombotic thrombocytopenic purpura related to ticlopidine. Lancet. 1991;337:774–776[CrossRef][Web of Science][Medline]
- Bennett CL, Connors JM, Carwile JM. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med. 2000;342:1773–1777
[Abstract/Free Full Text] - Herbert JM, Frechel D, Vallee E, Kieffer G, Gouy D, Berger Y. Clopidogrel, a novel antithrombotic agent. Cardiovasc Drug Rev. 1993;11:180–198[CrossRef][Web of Science]
- Balsano F, Rizzon P, Violi F. Antiplatelet treatment with ticlopidine in unstable angina: a controlled multicenter trial: the Studio della Ticlopidina nell'Angina Instabile Group. Circulation. 1990;82:17–26
[Abstract/Free Full Text] - Balsano F, Coccheri S, Libretti A. Ticlopidine in the treatment of intermittent claudication: a 21-month double-blind trial. J Lab Clin Med. 1989;114:84–91[Web of Science][Medline]
- Janzon, L, Bergqvist, D, Boberg, J, Prevention of myocardial infarction and stroke in patients with intermittent claudication: effects of ticlopidine: results from STIMS, the Swedish Ticlopidine Multicentre Study, J Intern Med, 227, 1990, 308
- Hass WK, Easton JD, Adams HP. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients: Ticlopidine Aspirin Stroke Study Group. N Engl J Med. 1989;321:501–507[Abstract]
- Lancet. 1996;348:1329–1339[CrossRef][Web of Science][Medline]
- Bossavy JP, Thalamas C, Sagnard L. A double-blind randomized comparison of combined aspirin and ticlopidine therapy versus aspirin or ticlopidine alone on experimental arterial thrombogenesis in humans. Blood. 1998;92:1518–1525
[Abstract/Free Full Text] - Herbert J, Dol F, Bernat A, Falotico R, Lale A, Savi P. The antiaggregating and antithrombotic activity of clopidrogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost. 1998;80:512–518[Web of Science][Medline]
- Schomig A, Neumann FJ, Kastrati A. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996;334:1084–1089
[Abstract/Free Full Text] - Hall P, Nakamura S, Maiello L. A randomized comparison of combined ticlopidine and aspirin therapy versus aspirin therapy alone after successful intravascular ultrasound-guided stent implantation. Circulation. 1996;93:215–222
[Abstract/Free Full Text] - Urban P, Macaya C, Rupprecht H. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin and Ticlopidine Trial after Intracoronary Stenting (MATTIS). Circulation. 1998;98:2126–2132
[Abstract/Free Full Text] - Bertrand M, Legrand V, Boland J. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: the Full Anticoagulation versus Aspirin and Ticlopidine (FANTASTIC) study. Circulation. 1998;98:1597–1603
[Abstract/Free Full Text] - Leon M, Baim D, Popma J. A clinical trial comparing three antithrombotic drug regimens after coronary-artery stenting. N Engl J Med. 1998;339:1671
- Moussa I, Oetgen M, Roubin G. Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation. Circulation. 1999;99:2364–2366
[Abstract/Free Full Text] - Muller C, Buttner HJ, Petersen J, Roskamm H. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after placement of coronary-artery stents. Circulation. 2000;101:590–593
[Abstract/Free Full Text] - Bertand ME, Rupprecht H-J, Urban P, Gershlick AH. 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 international cooperative study (CLASSICS). Circulation. 2000;102:624–629
[Abstract/Free Full Text] - Berger PB, Bell MR, Grill DE, Melby S, Holmes DR. Frequency of adverse clinical events in the 12 months following successful intracoronary stent placement in patients treated with aspirin and ticlopidine (without warfarin). Am J Cardiol. 1998;81:713–718[CrossRef][Web of Science][Medline]
- Mishkel GJ, Aguirre FV, Ligon RW, Rocha-Sing KJ, Lucore CL. Clopidogrel as adjunctive antiplatelet therapy during coronary artery stenting. J Am Coll Cardiol. 1999;34:1884–1890
[Abstract/Free Full Text] - Gregorini L, Marco J, Fajadet J. Ticlopidine and aspirin pretreatment reduces coagulation and platelet activation during coronary dilation procedures. J Am Coll Cardiol. 1997;29:13–20[Abstract]
- Bergqvist D, Almgren B, Dickinson JP. Reduction of requirement for leg vascular surgery during long-term treatment of claudicant patients with ticlopidine: results from the Swedish Ticlopidine Multicentre Study (STIMS). Eur J Vasc Endovasc Surg. 1995;10:69–76[CrossRef][Web of Science][Medline]
- Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–748[Web of Science][Medline]
- Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Betablockade during and after myocardial infarction:an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335–371[Web of Science][Medline]
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|
|
|
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|
|
|
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|
|
|
|
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|
|
|
|
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|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
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