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Circulation. 2003;108:1682-1687
Published online before print September 22, 2003, doi: 10.1161/01.CIR.0000091201.39590.CB
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(Circulation. 2003;108:1682.)
© 2003 American Heart Association, Inc.

Clinical Investigations

Effects of Aspirin Dose When Used Alone or in Combination With Clopidogrel in Patients With Acute Coronary Syndromes

Observations From the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study

Ron J.G. Peters, MD; Shamir R. Mehta, MD; Keith A.A. Fox, MD; Feng Zhao, MSc; Basil S. Lewis, MD; Steven L. Kopecky, MD; Rafael Diaz, MD; Patrick J. Commerford, MD; Vicent Valentin, MD; Salim Yusuf, DPhil, for the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Trial Investigators

From the Department of Cardiology (P.J.G.P.), Academic Medical Center, Amsterdam, the Netherlands; Canadian Cardiovascular Collaboration Project Office (S.R.M., F.Z., S.Y.), McMaster University, Hamilton, Ontario, Canada; Royal Infirmary of Edinburgh (K.A.A.F.), Edinburgh, UK; Lady Davis Carmel Medical Center (B.S.L.), Haifa, Israel; Division of Cardiovascular Diseases (S.L.K.), Mayo Clinic and Foundation, Rochester, Minn; Estudios Cardiologicos Latinoamerica (R.D.), Instituto Cardiovascular de Rosario, Argentina; Department of Medicine (P.J.C.), University of Cape Town, South Africa; and Unidad Coronaria (V.V.), Hospital Universitario Dr Peset, Valencia, Spain.

Correspondence to Salim Yusuf, Canadian Cardiovascular Collaboration Project Office, Population Health Research Institute, McMaster University, Hamilton General Hospital, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada. E-mail yusufs{at}mcmaster.ca

Received November 22, 2002; de novo received March 6, 2003; revision received July 11, 2003; accepted July 11, 2003.

Abstract

Background— We studied the benefits and risks of adding clopidogrel to different doses of aspirin in the treatment of patients with acute coronary syndrome (ACS).

Methods and Results— In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, 12 562 patients with ACS using aspirin, 75 to 325 mg daily, were randomized to clopidogrel or placebo for up to 1 year. In this analysis, patients were divided into the following 3 aspirin dose groups: <=100 mg, 101 through 199 mg, and >=200 mg. The combined incidence of cardiovascular death, myocardial infarction, or stroke was reduced by clopidogrel regardless of aspirin dose, as follows: <=100 mg, 10.5% versus 8.6% (relative risk [RR], 0.81 [95% CI, 0.68 to 0.97]); 101 to 199 mg, 9.8% versus 9.5% (RR, 0.97 [95% CI 0.77 to 1.22]); and >=200 mg, 13.6% versus 9.8% (RR, 0.71 [95% CI, 0.59 to 0.85]). The incidence of major bleeding increased with increasing aspirin dose both in the placebo group (1.9%, 2.8%, and 3.7%, respectively; P=0.0001) and the clopidogrel group (3.0%, 3.4%, and 4.9%, respectively; P=0.0009); thus, the excess risk with clopidogrel was 1.1%, 1.2%, and 1.2%, respectively. The adjusted hazard ratio for major bleeding for the highest versus the lowest dose of aspirin was 1.9 (95% CI 1.29 to 2.72) in the placebo group, 1.6 (95% CI 1.19 to 2.23) in the clopidogrel group, and 1.7 (95% CI 1.36 to 2.20) in the combined group.

Conclusions— In patients with ACS, adding clopidogrel to aspirin is beneficial regardless of aspirin dose. Bleeding risks increase with increasing aspirin dose, with or without clopidogrel, without any increase in efficacy. Our findings suggest that the optimal daily dose of aspirin may be between 75 and 100 mg, with or without clopidogrel.


Key Words: aspirin • coronary disease • angina • platelets • thrombosis




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 Ann. Thorac. Surg.Home page
C. P. Cannon, S. R. Mehta, and S. F. Aranki
Balancing the Benefit and Risk of Oral Antiplatelet Agents in Coronary Artery Bypass Surgery
Ann. Thorac. Surg., August 1, 2005; 80(2): 768 - 779.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
J. W. Moses, R. Mehran, E. Nikolsky, J. M. Lasala, W. Corey, G. Albin, C. Hirsch, M. B. Leon, M. E. Russell, S. G. Ellis, et al.
Outcomes with the paclitaxel-eluting stent in patients with acute coronary syndromes: Analysis from the TAXUS-IV trial
J. Am. Coll. Cardiol., April 19, 2005; 45(8): 1165 - 1171.
[Abstract] [Full Text] [PDF]

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 Eur Heart JHome page
Authors/Task Force Members, S. Silber, P. Albertsson, F. F. Aviles, P. G. Camici, A. Colombo, C. Hamm, E. Jorgensen, J. Marco, J.-E. Nordrehaug, et al.
Guidelines for Percutaneous Coronary Interventions: The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology
Eur. Heart J., April 2, 2005; 26(8): 804 - 847.
[Full Text] [PDF]

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 CirculationHome page
A. J. Lansky, J. S. Hochman, P. A. Ward, G. S. Mintz, R. Fabunmi, P. B. Berger, G. New, C. L. Grines, C. G. Pietras, M. J. Kern, et al.
Percutaneous Coronary Intervention and Adjunctive Pharmacotherapy in Women: A Statement for Healthcare Professionals From the American Heart Association
Circulation, February 22, 2005; 111(7): 940 - 953.
[Abstract] [Full Text] [PDF]

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 NEJMHome page
F. K. Chan, J. Y.L. Ching, L. C.T. Hung, V. W.S. Wong, V. K.S. Leung, N. N.S. Kung, A. J. Hui, J. C.Y. Wu, W. K. Leung, V. W.Y. Lee, et al.
Clopidogrel versus Aspirin and Esomeprazole to Prevent Recurrent Ulcer Bleeding
N. Engl. J. Med., January 20, 2005; 352(3): 238 - 244.
[Abstract] [Full Text] [PDF]

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 NEJMHome page
B. Cryer
Reducing the Risks of Gastrointestinal Bleeding with Antiplatelet Therapies
N. Engl. J. Med., January 20, 2005; 352(3): 287 - 289.
[Full Text] [PDF]

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T. J. Gluckman, M. Sachdev, S. P. Schulman, and R. S. Blumenthal
A Simplified Approach to the Management of Non-ST-Segment Elevation Acute Coronary Syndromes
JAMA, January 19, 2005; 293(3): 349 - 357.
[Abstract] [Full Text] [PDF]

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 Eur Heart JHome page
M. Gyongyosi, H. Domanovits, W. Benzer, M. Haugk, B. Heinisch, G. Sodeck, R. Hodl, G. Gaul, G. Bonner, J. Wojta, et al.
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., December 1, 2004; 25(23): 2125 - 2133.
[Abstract] [Full Text] [PDF]

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P. Eriksson
Reply: Long-term clopidogrel following PCI: marginal antithrombotic effects are offset by increased bleeding risks
Eur. Heart J., December 1, 2004; 25(23): 2170 - 2171.
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 PediatricsHome page
J. W. Newburger, M. Takahashi, M. A. Gerber, M. H. Gewitz, L. Y. Tani, J. C. Burns, S. T. Shulman, A. F. Bolger, P. Ferrieri, R. S. Baltimore, et al.
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association
Pediatrics, December 1, 2004; 114(6): 1708 - 1733.
[Abstract] [Full Text] [PDF]

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 Eur Heart JHome page
C. M. Gibson, R. L. Dumaine, E. V. Gelfand, S. A. Murphy, D. A. Morrow, S. D. Wiviott, R. P. Giugliano, C. P. Cannon, E. M. Antman, E. Braunwald, et al.
Association of glomerular filtration rate on presentation with subsequent mortality in non-ST-segment elevation acute coronary syndrome; observations in 13307 patients in five TIMI trials
Eur. Heart J., November 2, 2004; 25(22): 1998 - 2005.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
S. Gruner, M. Prostredna, B. Aktas, A. Moers, V. Schulte, T. Krieg, S. Offermanns, B. Eckes, and B. Nieswandt
Anti-Glycoprotein VI Treatment Severely Compromises Hemostasis in Mice With Reduced {alpha}2{beta}1 Levels or Concomitant Aspirin Therapy
Circulation, November 2, 2004; 110(18): 2946 - 2951.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
J. W. Newburger, M. Takahashi, M. A. Gerber, M. H. Gewitz, L. Y. Tani, J. C. Burns, S. T. Shulman, A. F. Bolger, P. Ferrieri, R. S. Baltimore, et al.
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association
Circulation, October 26, 2004; 110(17): 2747 - 2771.
[Abstract] [Full Text] [PDF]

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S. P. Schulman
Antiplatelet Therapy in Non-ST-Segment Elevation Acute Coronary Syndromes
JAMA, October 20, 2004; 292(15): 1875 - 1882.
[Abstract] [Full Text] [PDF]

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 Journal of Pharmacy PracticeHome page
B. S. Wiggins and S. Spinler
Antiplatelet and Antithrombin Therapy for Early Management of Acute Coronary Syndromes
Journal of Pharmacy Practice, October 1, 2004; 17(5): 347 - 369.
[Abstract] [PDF]

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 ChestHome page
C. Patrono, B. Coller, G. A. FitzGerald, J. Hirsh, and G. Roth
Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Chest, September 1, 2004; 126(3_suppl): 234S - 264S.
[Abstract] [Full Text] [PDF]

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J. J. Popma, P. Berger, E. M. Ohman, R. A. Harrington, C. Grines, and J. I. Weitz
Antithrombotic Therapy During Percutaneous Coronary Intervention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Chest, September 1, 2004; 126(3_suppl): 576S - 599S.
[Abstract] [Full Text] [PDF]

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 StrokeHome page
J. S. Varanasi and S. R. Steinhubl
Antiplatelet Effect of Aspirin in Patients With Cerebrovascular Disease
Stroke, June 1, 2004; 35(6): e144 - e145.
[Full Text] [PDF]

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 Eur Heart J SupplHome page
E. M Antman
The re-emergence of anticoagulation in coronary disease
Eur. Heart J. Suppl., April 1, 2004; 6(suppl_B): B2 - B8.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
D. L. Bhatt
Aspirin resistance: more than just a laboratory curiosity
J. Am. Coll. Cardiol., March 17, 2004; 43(6): 1127 - 1129.
[Full Text] [PDF]

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 J Am Coll CardiolHome page
D. L. Connolly, A. Choudhury, R. C. Davis, and G. Y. H. Lip
A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis
J. Am. Coll. Cardiol., March 17, 2004; 43(6): 1134 - 1135.
[Full Text] [PDF]

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 Journal Watch CardiologyHome page
Optimal Aspirin Dosage for ACS Patients
Journal Watch Cardiology, December 19, 2003; 2003(1219): 1 - 1.
[Full Text]

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 BMJHome page
Minerva
BMJ, October 18, 2003; 327(7420): 938 - 938.
[Full Text] [PDF]


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