This Article  • Full text  • PDF  • Correction  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (780)  • Contact me when this article is cited  Related Content  • Related letters  • Similar articles in JAMA  Topic Collections  • Revascularization  • Surgical Interventions  • Cardiovascular/ Cardiothoracic Surgery  • Randomized Controlled Trial  • Cardiovascular Intervention  • Alert me on articles by topic

A Randomized Controlled Trial

Steven R. Steinhubl, MD; Peter B. Berger, MD; J. Tift Mann III, MD; Edward T. A. Fry, MD; Augustin DeLago, MD; Charles Wilmer, MD; Eric J. Topol, MD; for the CREDO Investigators

JAMA. 2002;288:2411-2420.

Context  Following percutaneous coronary intervention (PCI), short-term clopidogrel therapy in addition to aspirin leads to greater protection from thrombotic complications than aspirin alone. However, the optimal duration of combination oral antiplatelet therapy is unknown. Also, although current clinical data suggest a benefit for beginning therapy with a clopidogrel loading dose prior to PCI, the practical application of this therapy has not been prospectively studied.

Objectives  To evaluate the benefit of long-term (12-month) treatment with clopidogrel after PCI and to determine the benefit of initiating clopidogrel with a preprocedure loading dose, both in addition to aspirin therapy.

Design, Setting, and Participants  The Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a randomized, double-blind, placebo-controlled trial conducted among 2116 patients who were to undergo elective PCI or were deemed at high likelihood of undergoing PCI, enrolled at 99 centers in North America from June 1999 through April 2001.

Interventions  Patients were randomly assigned to receive a 300-mg clopidogrel loading dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through 12 months, patients in the loading-dose group received clopidogrel, 75 mg/d, and those in the control group received placebo. Both groups received aspirin throughout the study.

Main Outcome Measures  One-year incidence of the composite of death, myocardial infarction (MI), or stroke in the intent-to-treat population; 28-day incidence of the composite of death, MI, or urgent target vessel revascularization in the per-protocol population.

Results  At 1 year, long-term clopidogrel therapy was associated with a 26.9% relative reduction in the combined risk of death, MI, or stroke (95% confidence interval [CI], 3.9%-44.4%; P = .02; absolute reduction, 3%). Clopidogrel pretreatment did not significantly reduce the combined risk of death, MI, or urgent target vessel revascularization at 28 days (reduction, 18.5%; 95% CI, -14.2% to 41.8%; P = .23). However, in a prespecified subgroup analysis, patients who received clopidogrel at least 6 hours before PCI experienced a relative risk reduction of 38.6% (95% CI, -1.6% to 62.9%; P = .051) for this end point compared with no reduction with treatment less than 6 hours before PCI. Risk of major bleeding at 1 year increased, but not significantly (8.8% with clopidogrel vs 6.7% with placebo; P = .07).

Conclusions  Following PCI, long-term (1-year) clopidogrel therapy significantly reduced the risk of adverse ischemic events. A loading dose of clopidogrel given at least 3 hours before the procedure did not reduce events at 28 days, but subgroup analyses suggest that longer intervals between the loading dose and PCI may reduce events.

Author Affiliations: Division of Cardiology, School of Medicine, University of North Carolina at Chapel Hill (Dr Steinhubl); Cardiovascular Diseases Division, Mayo Clinic, Rochester, Minn (Dr Berger); WakeMed, Raleigh, NC (Dr Mann); Department of Cardiology, St Vincent Hospital, Indianapolis, Ind (Dr Fry); Cardiology Division, Albany Medical Center, Albany, NY (Dr DeLago); Atlanta Medical Center, Atlanta, Ga (Dr Wilmer); and Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (Dr Topol).

RELATED LETTERS

Clopidogrel and Percutaneous Coronary Interventions
Robin P. Choudhury
JAMA. 2003;289(15):1925.
EXTRACT | FULL TEXT  

Clopidogrel and Percutaneous Coronary Interventions
John F. P. Bridges
JAMA. 2003;289(15):1925-1926.
EXTRACT | FULL TEXT  

Clopidogrel and Percutaneous Coronary Interventions
Javier Borja, Iñaki Pérez, and Guillermo De la Cruz
JAMA. 2003;289(15):1926.
EXTRACT | FULL TEXT  

Clopidogrel and Percutaneous Coronary Interventions
Brian Y. L. Wong and Eric A. Cohen
JAMA. 2003;289(15):1926.
EXTRACT | FULL TEXT  

Clopidogrel and Percutaneous Coronary Interventions
Attila Dirkali and Victor A. Umans
JAMA. 2003;289(15):1926.
EXTRACT | FULL TEXT  

Glycoprotein IIb/IIIa Inhibition in Percutaneous Coronary Interventions—Reply
A. Michael Lincoff and Eric J. Topol
JAMA. 2003;290(11):1451-1452.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Optimizing Clopidogrel Therapy Before Stent Implantation: Should Clinical Setting Be Taken Into Account?
Aradi et al.
J Am Coll Cardiol 2008;52:1349-1349.
FULL TEXT  

Reply
Bonello et al.
J Am Coll Cardiol 2008;52:1349-1350.
FULL TEXT  

Review: Recurrent stroke: where do we stand with the secondary prevention of noncardioembolic ischaemic strokes?
Talelli and Greenwood
Therapeutic Advances in Cardiovascular Disease 2008;2:387-405.
ABSTRACT  

A Novel Endovascular Device for Emboli Rerouting: Part I: Evaluation in a Swine Model
Grad et al.
Stroke 2008;39:2860-2866.
ABSTRACT | FULL TEXT  

Long-Term Impact of Drug-Eluting Stents Versus Bare-Metal Stents on All-Cause Mortality
Shishehbor et al.
J Am Coll Cardiol 2008;52:1041-1048.
ABSTRACT | FULL TEXT  

A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study
Angiolillo et al.
Eur Heart J 2008;29:2202-2211.
ABSTRACT | FULL TEXT  

Increased Major Bleeding Complications Related to Triple Antithrombotic Therapy Usage in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Artery Stenting
Manzano-Fernandez et al.
Chest 2008;134:559-567.
ABSTRACT | FULL TEXT  

Incidence and Clinical Impact of Dual Nonresponsiveness to Aspirin and Clopidogrel in Patients With Drug-Eluting Stents
Gori et al.
J Am Coll Cardiol 2008;52:734-739.
ABSTRACT | FULL TEXT  

Role of Reticulated Platelets and Platelet Size Heterogeneity on Platelet Activity After Dual Antiplatelet Therapy With Aspirin and Clopidogrel in Patients With Stable Coronary Artery Disease
Guthikonda et al.
J Am Coll Cardiol 2008;52:743-749.
ABSTRACT | FULL TEXT  

Bivalirudin versus Unfractionated Heparin during Percutaneous Coronary Intervention
Kastrati et al.
NEJM 2008;359:688-696.
ABSTRACT | FULL TEXT  

Dual Antiplatelet Therapy Monitoring for Neurointerventional Procedures Using a Point-of-Care Platelet Function Test: A Single-Center Experience
Lee et al.
Am. J. Neuroradiol. 2008;29:1389-1394.
ABSTRACT | FULL TEXT  

Progress Is Precarious
Head and Barash
Anesth. Analg. 2008;107:362-364.
FULL TEXT  

Coronary Artery Stents: Part I. Evolution of Percutaneous Coronary Intervention
Newsome et al.
Anesth. Analg. 2008;107:552-569.
ABSTRACT | FULL TEXT  

Coronary Artery Stents: II. Perioperative Considerations and Management
Newsome et al.
Anesth. Analg. 2008;107:570-590.
ABSTRACT | FULL TEXT  

Optimizing antithrombotic therapy in patients with non-ST-segment elevation acute coronary syndrome
Dobesh et al.
Am J Health Syst Pharm 2008;65:S22-S28.
ABSTRACT | FULL TEXT  

Determinants of thrombin generation, fibrinolytic activity, and endothelial dysfunction in patients on dual antiplatelet therapy: involvement of factors other than platelet aggregability in Virchow's triad
Yano et al.
Eur Heart J 2008;29:1729-1738.
ABSTRACT | FULL TEXT  

Guideline on antiplatelet and anticoagulation management in cardiac surgery.
Dunning et al.
Eur. J. Cardiothorac. Surg. 2008;34:73-92.
ABSTRACT | FULL TEXT  

Aspirin in coronary artery bypass surgery: new aspects of and alternatives for an old antithrombotic agent.
Zimmermann et al.
Eur. J. Cardiothorac. Surg. 2008;34:93-108.
ABSTRACT | FULL TEXT  

2007 Guideline Update for Unstable Angina/Non-ST-Segment Elevation Myocardial Infarction: Focus on Antiplatelet and Anticoagulant Therapies
Coons and Battistone
The Annals of Pharmacotherapy 2008;42:989-1001.
ABSTRACT | FULL TEXT  

Benefits and limitations of current antiplatelet therapies
Nappi
Am J Health Syst Pharm 2008;65:S5-S10.
ABSTRACT | FULL TEXT  

Dual antiplatelet therapy with clopidogrel and aspirin
Sullivan and Amarshi
Am J Health Syst Pharm 2008;65:1134-1143.
ABSTRACT | FULL TEXT  

Long-term outcomes by clopidogrel duration and stent type in a diabetic population with de novo coronary artery lesions.
Brar et al.
J Am Coll Cardiol 2008;51:2220-2227.
ABSTRACT | FULL TEXT  

Clopidogrel pre-treatment in stable angina: for all patients >6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI? A randomized multicentre trial PRAGUE-8
Widimsky et al.
Eur Heart J 2008;29:1495-1503.
ABSTRACT | FULL TEXT  

Impact of bivalirudin or unfractionated heparin on platelet aggregation in patients pretreated with 600 mg clopidogrel undergoing elective percutaneous coronary intervention
Sibbing et al.
Eur Heart J 2008;29:1504-1509.
ABSTRACT | FULL TEXT  

Routine pre-treatment with clopidogrel before diagnostic coronary angiography: the question is right, but what about the answer?
Schiele et al.
Eur Heart J 2008;29:1475-1477.
FULL TEXT  

Pharmacoeconomic Concepts in Antiplatelet Therapy: Understanding Cost-Effectiveness Analyses Using Clopidogrel as an Example
Weintraub
J CARDIOVASC PHARMACOL THER 2008;13:107-119.
ABSTRACT  

Aspirin, Clopidogrel, and Warfarin: Is the Combination Appropriate and Effective or Inappropriate and Too Dangerous?
Hermosillo and Spinler
The Annals of Pharmacotherapy 2008;42:790-805.
ABSTRACT | FULL TEXT  

Antiplatelet Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Patrono et al.
Chest 2008;133:199S-233S.
ABSTRACT | FULL TEXT  

Antithrombotic Therapy for Non-ST-Segment Elevation Acute Coronary Syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Harrington et al.
Chest 2008;133:670S-707S.
ABSTRACT | FULL TEXT  

Acute ST-Segment Elevation Myocardial Infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Goodman et al.
Chest 2008;133:708S-775S.
ABSTRACT | FULL TEXT  

The Primary and Secondary Prevention of Coronary Artery Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Becker et al.
Chest 2008;133:776S-814S.
ABSTRACT | FULL TEXT  

Dual Antithrombotic Therapy Increases Severe Bleeding Events in Patients With Stroke and Cardiovascular Disease: A Prospective, Multicenter, Observational Study
Toyoda et al.
Stroke 2008;39:1740-1745.
ABSTRACT | FULL TEXT  

Early and Late Benefits of Prasugrel in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: A TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) Analysis
Antman et al.
J Am Coll Cardiol 2008;51:2028-2033.
ABSTRACT | FULL TEXT  

The Role of Aspirin in Cardiovascular Prevention: Implications of Aspirin Resistance
Gasparyan et al.
J Am Coll Cardiol 2008;51:1829-1843.
ABSTRACT | FULL TEXT  

Unmet needs in antiplatelet therapy
Bassand
Eur Heart J Suppl 2008;10:D3-D11.
ABSTRACT | FULL TEXT  

Dual antiplatelet therapy in the drug-eluting stent era
Wallentin
Eur Heart J Suppl 2008;10:D38-D44.
ABSTRACT | FULL TEXT  

Platelet Activation and Atherothrombosis
Kapoor et al.
NEJM 2008;358:1638-1639.
FULL TEXT  

INTERPRETING THE CHARISMA STUDY: What is the role of dual antiplatelet therapy with clopidogrel and aspirin?
BAKHRU and BHATT
Cleveland Clinic Journal of Medicine 2008;75:289-295.
ABSTRACT | FULL TEXT  

Indications for Dual Antiplatelet Therapy with Aspirin and Clopidogrel: Evidence-Based Recommendations for Use
Reaume et al.
The Annals of Pharmacotherapy 2008;42:550-557.
ABSTRACT | FULL TEXT  

Trends in Usage of Alternative Antiplatelet Therapy After Stroke and Transient Ischemic Attack
Hills and Johnston
Stroke 2008;39:1228-1232.
ABSTRACT | FULL TEXT  

Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: results from the PREPAIR randomized study.
L'Allier et al.
J Am Coll Cardiol 2008;51:1066-1072.
ABSTRACT | FULL TEXT  

Prescribing Practice of General Practitioners in Northern Ireland for Peripheral Arterial Disease
Badger et al.
ANGIOLOGY 2008;59:57-63.
ABSTRACT  

Commentary on "Antiplatelet Therapy for Vascular Interventions"
Srivastava
PERSPECT VASC SURG ENDOVASC THER 2008;20:36-37.
 

Antiplatelet Therapy for Vascular Interventions
Comerota and Thakur
PERSPECT VASC SURG ENDOVASC THER 2008;20:28-35.
ABSTRACT  

Which patients receiving warfarin can be treated safely with a drug-eluting stent?
Ryding and Banning
Heart 2008;94:275-277.
FULL TEXT  

P2Y12 Antagonism: Promises and Challenges
Michelson
Arterioscler. Thromb. Vasc. Bio. 2008;28:s33-s38.
ABSTRACT | FULL TEXT  

Restrictive access to clopidogrel and mortality following coronary stent implantation
Sheehy et al.
CMAJ 2008;178:413-420.
ABSTRACT | FULL TEXT  

Incidence of Death and Acute Myocardial Infarction Associated With Stopping Clopidogrel After Acute Coronary Syndrome
Ho et al.
JAMA 2008;299:532-539.
ABSTRACT | FULL TEXT  

Ensuring appropriate use of antiplatelet agents in the treatment of acute coronary syndromes have cardiovascular physicians been given enough grace in getting it right?
Gershlick
Heart 2008;94:135-137.
FULL TEXT  

Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated With Aspirin: The Randomized, Double-Blind OCLA (Omeprazole CLopidogrel Aspirin) Study
Gilard et al.
J Am Coll Cardiol 2008;51:256-260.
ABSTRACT | FULL TEXT  

2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention
American College of Cardiology/American Heart Asso et al.
J Am Coll Cardiol 2008;51:172-209.
FULL TEXT  

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: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee
King et al.
Circulation 2008;117:261-295.
FULL TEXT  

Myocardial Revascularization with Percutaneous Devices
Wilson and Willerson
Card Surg Adult 2008;3:573-598.
FULL TEXT  

Antiplatelet therapy in acute coronary syndromes
Gitt and Betriu
Eur Heart J Suppl 2008;10:A4-A12.
ABSTRACT | FULL TEXT  

Antiplatelet therapy in percutaneous coronary intervention
Bode and Huber
Eur Heart J Suppl 2008;10:A13-A20.
ABSTRACT | FULL TEXT  

When and how to discontinue antiplatelet therapy
Bertrand
Eur Heart J Suppl 2008;10:A35-A41.
ABSTRACT | FULL TEXT  

Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes
Wiviott et al.
NEJM 2007;357:2001-2015.
ABSTRACT | FULL TEXT  

Safety, Tolerability, and Initial Efficacy of AZD6140, the First Reversible Oral Adenosine Diphosphate Receptor Antagonist, Compared With Clopidogrel, in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome: Primary Results of the DISPERSE-2 Trial
Cannon et al.
J Am Coll Cardiol 2007;50:1844-1851.
ABSTRACT | FULL TEXT  

A comparison between coronary artery bypass grafting surgery and drug eluting stent for the treatment of unprotected left main coronary artery disease in elderly patients (aged >=75 years)
Palmerini et al.
Eur Heart J 2007;28:2714-2719.
ABSTRACT | FULL TEXT  

Late Coronary Stent Thrombosis
Windecker and Meier
Circulation 2007;116:1952-1965.
FULL TEXT  

Effect of Antiplatelet Therapy on Thromboembolic Complications of Elective Coil Embolization of Cerebral Aneurysms
Yamada et al.
Am. J. Neuroradiol. 2007;28:1778-1782.
ABSTRACT | FULL TEXT  

Outcomes of Coronary Artery Bypass Grafting Versus Percutaneous Coronary Intervention With Drug-Eluting Stents for Patients With Multivessel Coronary Artery Disease
Javaid et al.
Circulation 2007;116:I-200-I-206.
ABSTRACT | FULL TEXT  

An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial
Wang et al.
Eur Heart J 2007;28:2200-2207.
ABSTRACT | FULL TEXT  

Aggressive antiplatelet strategies: time to reconsider?
Serebruany
Eur Heart J 2007;28:2183-2184.
FULL TEXT  

Perioperative antiplatelet therapy: the case for continuing therapy in patients at risk of myocardial infarction
Chassot et al.
Br J Anaesth 2007;99:316-328.
ABSTRACT | FULL TEXT  

Therapeutic Benefit of Low-Dose Clopidogrel in Patients Undergoing Carotid Surgery Is Linked to Variability in the Platelet Adenosine Diphosphate Response and Patients' Weight
Payne et al.
Stroke 2007;38:2464-2469.
ABSTRACT | FULL TEXT  

Drug-Eluting Stent Update 2007: Part II: Unsettled Issues
Daemen and Serruys
Circulation 2007;116:961-968.
FULL TEXT  

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine
Anderson et al.
J Am Coll Cardiol 2007;50:e1-e157.
FULL TEXT  

Incidence and Predictors of Drug-Eluting Stent Thrombosis During and After Discontinuation of Thienopyridine Treatment
Airoldi et al.
Circulation 2007;116:745-754.
ABSTRACT | FULL TEXT  

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
von Beckerath et al.
Eur Heart J 2007;28:1814-1819.
ABSTRACT | FULL TEXT  

Dual antiplatelet therapy in high-risk patients
Van de Werf
Eur Heart J Suppl 2007;9:D3-D9.
ABSTRACT | FULL TEXT  

The use of antiplatelet agents following percutaneous coronary intervention: focus on late stent thrombosis
Bode and Zehender
Eur Heart J Suppl 2007;9:D10-D19.
ABSTRACT | FULL TEXT  

PCI for Stable Coronary Disease
Katritsis et al.
NEJM 2007;357:414-418.
FULL TEXT  

Combining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events: is it safe and effective to use just one antiplatelet agent?
Nguyen et al.
Eur Heart J 2007;28:1717-1722.
ABSTRACT | FULL TEXT  

Effects of preoperative aspirin and clopidogrel therapy on perioperative blood loss and blood transfusion requirements in patients undergoing off-pump coronary artery bypass graft surgery
Shim et al.
J. Thorac. Cardiovasc. Surg. 2007;134:59-64.
ABSTRACT | FULL TEXT  

Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology
Authors/Task Force Members et al.
Eur Heart J 2007;28:1598-1660.
FULL TEXT  

Impact of Platelet Reactivity After Clopidogrel Administration on Drug-Eluting Stent Thrombosis
Buonamici et al.
J Am Coll Cardiol 2007;49:2312-2317.
ABSTRACT | FULL TEXT  

Patients With Prior Myocardial Infarction, Stroke, or Symptomatic Peripheral Arterial Disease in the CHARISMA Trial
Bhatt et al.
J Am Coll Cardiol 2007;49:1982-1988.
ABSTRACT | FULL TEXT  

Clinical Aspects of Platelet Inhibitors and Thrombus Formation
Meadows and Bhatt
Circ. Res. 2007;100:1261-1275.
ABSTRACT | FULL TEXT  

Coronary artery stents and non-cardiac surgery
Howard-Alpe et al.
Br J Anaesth 2007;98:560-574.
ABSTRACT | FULL TEXT  

Use of Antiplatelet Drugs in Secondary Prevention in Older Persons With Atherothrombotic Disease
Aronow
J. Gerontol. A Biol. Sci. Med. Sci. 2007;62:518-524.
ABSTRACT | FULL TEXT  

Clopidogrel and Long-term Outcomes After Drug-Eluting Stent Implantation
Falcone and Tangri
JAMA 2007;297:1770-1770.
FULL TEXT  

Variable Platelet Response to Aspirin and Clopidogrel in Atherothrombotic Disease
Maree and Fitzgerald
Circulation 2007;115:2196-2207.
FULL TEXT