Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding

  1. Steven R. Steinhubl, MD;
  2. Deepak L. Bhatt, MD, MPH;
  3. Danielle M. Brennan, MS;
  4. Gilles Montalescot, MD;
  5. Graeme J. Hankey, MD;
  6. John W. Eikelboom, MB, BS, MSc;
  7. Peter B. Berger, MD;
  8. Eric J. Topol, MD; and
  9. on behalf of the CHARISMA Investigators
  1. From the Geisinger Clinic, Danville, Pennsylvania; The Medicines Company, Zurich, Switzerland; Veterans Affairs Boston Healthcare System and Brigham and Women's Hospital, Boston, Massachusetts; The Cleveland Clinic Foundation, Cleveland, Ohio; Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France; Royal Perth Hospital, Perth, Western Australia, Australia; McMaster University, Hamilton, Ontario, Canada; and Scripps Translational Science Institute, Scripps Clinic, La Jolla, California.

    Abstract

    Background: The optimal aspirin dose for the prevention of cardiovascular events remains controversial.

    Objective: To assess the incidence of and risk factors for adverse clinical outcomes by investigator-determined aspirin dose in a primary prevention trial.

    Design: Post hoc observational analyses of data from a double-blind, placebo-controlled, randomized trial.

    Setting: Outpatient.

    Patients: 15 595 patients with cardiovascular disease or multiple risk factors.

    Intervention: Clopidogrel, 75 mg/d, or placebo, with aspirin, 75 to 162 mg/d, as selected by the investigators.

    Measurements: Incidence of the composite outcome of myocardial infarction, stroke, or cardiovascular death (efficacy end point), and incidence of severe or life-threatening bleeding (safety end point), at a median of 28 months (interquartile range, 23 to 31 months) of follow-up.

    Results: Daily aspirin doses were categorized as less than 100 mg (75 or 81 mg) (n = 7180), 100 mg (n = 4961), and greater than 100 mg (150 or 162 mg) (n = 3454). The hazard of the primary efficacy end point was the same regardless of dose (adjusted hazard ratio, 0.95 [95% CI, 0.80 to 1.13] for 100 mg vs. less than 100 mg, and 1.0 [CI, 0.85 to 1.18] for greater than 100 mg vs. less than 100 mg). The hazard of the primary safety end point also did not depend on dose (adjusted hazard ratio, 0.85 [CI, 0.57 to 1.26] for 100 mg vs. less than 100 mg and 1.05 [CI, 0.74 to 1.48] for greater than 100 mg vs. less than 100 mg). In patients also receiving clopidogrel, daily aspirin doses greater than 100 mg seemed to be non–statistically significantly associated with reduced efficacy (adjusted hazard ratio, 1.16 [CI, 0.93 to 1.44]) and increased harm (adjusted hazard ratio, 1.30 [CI, 0.83 to 2.04]).

    Limitation: The analysis was post hoc, and aspirin use was not randomized or blinded.

    Conclusion: Daily aspirin doses of 100 mg or greater were associated with no clear benefit in patients taking aspirin only and possibly with harm in patients taking clopidogrel. Daily doses of 75 to 81 mg may optimize efficacy and safety for patients requiring aspirin for long-term prevention, especially for those receiving dual antiplatelet therapy.

    Primary Funding Source: None.

    Article and Author Information

    • Acknowledgment: The authors acknowledge Pat French of Left Lane Communications for her editorial assistance.

    • Grant Support: The CHARISMA study was funded by Sanofi-Aventis and Bristol-Myers Squibb.

    • Potential Financial Conflicts of Interest: Employment: S.R. Steinhubl (The Medicines Company), D.L. Bhatt (The Cleveland Clinic). Consultancies: P.B. Berger (PlaCor, Accumetrics, The Medicines Company, Eli Lilly/Daiichi-Sankyo). Honoraria: P.B. Berger (BMS/Sanofi-Aventis, The Medicines Company, AstraZeneca, Medtronic, Eli Lilly/Daiichi-Sankyo). Stock ownership or options (other than mutual funds): P.B. Berger (Lumen). Expert testimony: D.L. Bhatt (regarding clopidogrel). Grants received: G. Montalescot (Sanofi-Aventis).

    • Reproducible Research Statement: Study protocol, statistical code, and data set: Not available.

    • Requests for Single Reprints: Steven R. Steinhubl, MD, The Medicines Company, Balsberg, 8058 Zurich-Flughafen, Switzerland; e-mail, steven.steinhubl{at}themedco.com.

    • Current Author Addresses: Dr. Steinhubl: The Medicines Company, Balsberg, 8058 Zurich-Flughafen, Switzerland.

    • Dr. Bhatt: Veterans Affairs Boston Healthcare System and Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

    • Ms. Brennan: Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.

    • Dr. Montalescot: Institut de Cardiologie, Centre Hospitalier Universi-taire Pitié-Salpêtrière, 47-83 Boulevard de l'Hôpital, Paris Cedex 13, 75651, France.

    • Dr. Hankey: Neurology Department, Royal Perth Hospital, GPO Box X2213, Perth, Western Australia 6000, Australia.

    • Dr. Eikelboom: McMaster University, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

    • Dr. Berger: Geisinger Clinic, Department of Cardiology, 100 North Academy Avenue, Danville, PA 17822.

    • Dr. Topol: Scripps Translational Science Institute, 10550 North Torrey Pines Road, SGM-300, La Jolla, CA 92037.

    • Author Contributions: Conception and design: S.R. Steinhubl, D.L. Bhatt, G. Montalescot, G.J. Hankey, P.B. Berger.

    • Analysis and interpretation of the data: S.R. Steinhubl, D.L. Bhatt, D.M. Brennan, G. Montalescot, J.W. Eikelboom, P.B. Berger, E.J. Topol.

    • Drafting of the article: S.R. Steinhubl, D.L. Bhatt, P.B. Berger, E.J. Topol.

    • Critical revision of the article for important intellectual content: S.R. Steinhubl, D.L. Bhatt, D.M. Brennan, G. Montalescot, G.J. Hankey, J.W. Eikelboom, P.B. Berger, E.J. Topol.

    • Final approval of the article: S.R. Steinhubl, D.L. Bhatt, D.M. Brennan, G. Montalescot, G.J. Hankey, J.W. Eikelboom, P.B. Berger, E.J. Topol.

    • Provision of study materials or patients: D.L. Bhatt, G.J. Hankey, E.J. Topol.

    • Statistical expertise: D.M. Brennan.

    • Obtaining of funding: D.L. Bhatt, E.J. Topol.

    • Administrative, technical, or logistic support: D.L. Bhatt, P.B. Berger, E.J. Topol.

    • Collection and assembly of data: S.R. Steinhubl, D.L. Bhatt, D.M. Brennan, G.J. Hankey, P.B. Berger, E.J. Topol.

    • ClinicalTrials.gov registration number: NCT00050817.

    Responses to this article

    • Understanding Results of Aspirin dose and Plavix with Risk of Bleeding presented by CHARISHMA trial
      • Azhar Supariwala and
      • Brenda Matti, MD
      Ann Intern Med published online October 26, 2009

    Summary for Patients

    • Summaries for Patients:What Aspirin Dose Is Safest and Most Effective for Preventing Heart Disease? Ann Intern Med March 17, 2009 150:I-22; doi:10.1059/0003-4819-150-6-200903170-00001
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