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Original Research |

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

Steven R. Steinhubl, MD; Deepak L. Bhatt, MD, MPH; Danielle M. Brennan, MS; Gilles Montalescot, MD; Graeme J. Hankey, MD; John W. Eikelboom, MB, BS, MSc; Peter B. Berger, MD; Eric J. Topol, MD, on behalf of the CHARISMA Investigators
[+] Article, Author, and Disclosure Information

ClinicalTrials.gov registration number: NCT00050817.

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.

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@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.

Ann Intern Med. 2009;150(6):379-386. doi:10.7326/0003-4819-150-6-200903170-00006
Text Size: A A A

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.


Grahic Jump Location
Unadjusted hazard ratios, 95% CIs, and Kaplan–Meier estimates of the primary efficacy end point (cardiovascular death, myocardial infarction, or stroke) in selected daily aspirin dose subgroups.
Grahic Jump Location




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Submit a Comment/Letter
Understanding Results of Aspirin dose and Plavix with Risk of Bleeding presented by CHARISHMA trial
Posted on July 27, 2009
Azhar Supariwala
St.Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons,New York
Conflict of Interest: None Declared

This letter is in reference to the recent article by the CHARISHMA investigators "Aspirin to Prevent Cardiovascular Disease: The Association of ASA Dose and Plavix With Thrombosis and Bleeding" Annals of Internal Medicine, March 2009, Vol. 150.

It was non-randomized study. Baseline characteristics were very different in the 3 groups with more than 20 variables in the model that may skew results. The univariate analyses shows that the risk of severe or life threatening bleeding with an absolute risk reduction (ARR) of 0.9 % in people who took plavix and aspirin (ASA) >100mg. The number need to harm (NNH) is 111 (1/ARR) for a follow-up period of 2 ½ years.

Plavix & Aspirin <_100mg column="column" a="a" th="th" /> Plavix & Aspirin >100mg (%)Column B ARR (%) Column C [B-A] NNH for ASA >100mg Column D = 1/C NNH for ASA<_100mg column="column" e="1/C
Incidence of severe or life threatening bleeding. Univariate 1.7 2.6 0.9 111 ---
Incidence of severe or life threatening bleeding. Multivariate adjusted for >20 factors HR=1.3 (95% CI 0.83 "“ 2.04) p not significant >0.05 1.7 2.21 0.51 196 ---
Upper Limit of HR 2 1.7 3.4 1.7 58 ---
Lower limit of HR 0.83 1.7 1.4 -0.3 --- 333

In individuals with plavix and ASA > 100 mg, the multivariate analyses of this post-hoc retrospective case-control study with significantly different baseline characteristics adjusted for more than 20 covariates is statistically not significant. A point estimate of 1.3 for HR with a large CI (95% CI; 0.83 "“ 2.04). Incidence of severe or life threatening bleeding being 1.7 in group with ASA <_100 mg="mg" _30="_30" of="of" hr="hr" makes="makes" the="the" arr="arr" _0.51.="_0.51." this="this" nnh="nnh" _196="_196" _1="_1" not="not" ignoring="ignoring" large="large" ci="ci" and="and" upper="upper" limit="limit" that="that" is="is" _2.04="_2.04" _1.7="_1.7" _58="_58" for="for" approx="approx" _2="_2" _="_" years.="years." investigators="investigators" mention="mention" many="many" people="people" take="take" asa="asa" hence="hence" a="a" small="small" risk="risk" effect="effect" size.="size." population="population" size="size" on="on" plavix="plavix" smaller="smaller" than="than" aspirin="aspirin" only.="only." other="other" hand="hand" it="it" shows="shows" _10="_10" reduced="reduced" harm="harm" in="in" individuals="individuals" taking="taking" _100mg="_100mg" vs.="vs." _0.90="_0.90" _95="_95" _0.61="_0.61" _1.6="_1.6" statistically="statistically" significant="significant" but="but" stressed="stressed" upon.="upon." suggests="suggests" did="did" have="have" dose-response-effect="dose-response-effect" relationship.="relationship." similarly="similarly" group="group" without="without" has="has" _29="_29" severe="severe" or="or" life="life" threatening="threatening" bleeding="bleeding" />100mg ASA group has 20% reduced risk as compared to <_100 mg="mg" aspirin="aspirin" statistically="statistically" not="not" significant.="significant." p="p" />

If we see the point estimate HR of 1.3 (95% CI, 0.83 "“ 2.04) with this large CI, we are 95% confident that the results lie between this CI (even after accepting the case-control study and >20 factors adjustments). Where it lies, we do not know. If we do a similar study, the chance of having reduced risk for bleeding with ASA >100 mg (let's say HR 0.9) is the same as the chance of increased risk (let's say HR 1.3. If the authors proposed a null hypothesis that " There is no significant difference in the risk of severe or life threatening bleeding in individuals taking plavix with ASA <100mg and ASA >100mg," we will accept the null hypothesis with these results.

With the results of this study, we conclude that the possibility of harm provided by ASA in dose of >100 mg with plavix is the same as possibility of reduced harm. A randomize study is needed to make the estimate more precise. Finally, considering both the safety and efficacy, ASA of 100 mg faired better than both <_100 mg="mg" and="and" />100 mg in individuals with and without plavix with statistically not significant p value. The CURRENT-OASIS 7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events and Optimal Antiplatelet Strategy for Interventions) will give concrete results.

Conflict of Interest:

None declared

Submit a Comment/Letter

Summary for Patients

What Aspirin Dose Is Safest and Most Effective for Preventing Heart Disease?

The summary below is from the full report titled “Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding.” It is in the 17 March 2009 issue of Annals of Internal Medicine (volume 150, pages 379-386). The authors are S.R. Steinhubl, D.L. Bhatt, D.M. Brennan, G. Montalescot, G.J. Hankey, J.W. Eikelboom, P.B. Berger, and E.J. Topol, on behalf of the CHARISMA Investigators.


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