Elsevier

American Heart Journal

Volume 162, Issue 1, July 2011, Pages 98-105.e1
American Heart Journal

Clinical Investigation
Acute Ischemic Heart Disease
Bleeding, mortality, and antiplatelet therapy: Results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial

https://doi.org/10.1016/j.ahj.2011.04.015Get rights and content

Background

The association between bleeding severity and cause of mortality in the non-acute setting is unclear. We sought to investigate the association between bleeding and mortality subtype, and assess whether this association differs in patients on dual antiplatelet therapy (DAPT) versus aspirin alone.

Methods

Using multivariable Cox proportional hazards survival regression, we examined the association between moderate or severe bleeding and all-cause, cardiovascular, and cancer mortality in 15,603 patients with cardiovascular disease or multiple risk factors enrolled in the CHARISMA trial.

Results

Patients with moderate or severe bleeding had a higher incidence of all-cause, cardiovascular, and cancer mortality (P < .001 for each). After multivariable adjustment, moderate/severe bleeding remained independently associated with not only all-cause mortality (adjusted hazard ratio [HR] 1.66; 95% confidence interval [CI] 1.24-2.21) and cardiovascular mortality (HR 2.05, 95% CI 1.38-3.04) but also cancer mortality (HR 4.76, 95% CI 2.60-8.69). However, there was a significant interaction between bleeding and potency of antiplatelet therapy for all-cause (P = .002), cardiovascular (P = .02), and cancer mortality (P = .03); in subjects on aspirin alone, moderate/severe bleeding was associated with all-cause (HR 5.27, 95% CI 3.56-7.80), cardiovascular (HR 4.33, 95% CI 2.55-7.37), and cancer mortality (HR 9.01, 95% CI 4.41-18.43), but not in subjects on DAPT (all-cause: HR 1.48, 95% CI 0.93-2.34; cardiovascular: HR 1.04, 95% CI 0.58-1.86; and cancer mortality: HR 1.79, 95% CI 0.56-5.74).

Conclusions

In stable patients, moderate or severe bleeding is associated with a significantly increased risk of all-cause, cardiovascular, and cancer mortality. However, this risk appeared different in subjects on single antiplatelet therapy versus DAPT.

Section snippets

Methods

Details of the CHARISMA trial have been previously described.17 Briefly, CHARISMA was a prospective, multicenter, double-blind, randomized, placebo-controlled trial comparing clopidogrel 75 mg/d versus placebo long term in patients 45 years or older who had either documented atherosclerotic vascular disease or were at high-risk of having vascular disease based on a combination of risk factors. All patients also received aspirin (75-162 mg/d). Patients were excluded if they were believed to be

Results

Among the 15,603 patients enrolled, 487 (3.1%) had a moderate or severe bleeding episode. The median time from enrollment to the moderate or severe bleeding episode was 362 days (mean 397 ± 266 days). Table I shows the baseline characteristics of patients who did or did not have a moderate or severe bleeding episode. Compared with those who did not, patients who bled were older and more likely to have a history of hypertension, heart failure, stroke, or atrial fibrillation.

The unadjusted

Discussion

The 2 most important findings of this study are, first, that bleeding in the outpatient setting is associated with an increased risk of all-cause mortality, cardiovascular mortality, and cancer mortality. This increased risk remains significant after adjustment for demographic characteristics, clinical risk factors, medication use, and severities present with both moderate and severe bleeding. The second major finding is that when the relationship between bleeding and mortality are analyzed in

Disclosures

Dr Jeffrey Berger has received research support and honoraria for advisory board participation from Astra Zeneca (modest).

Dr Bhatt has received research grants (to the institution) from Astra Zeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and The Medicines Company.

Dr Steg reports receiving a research grant (to the institution) from Sanofi-Aventis and having received honoraria for speaking or consulting from Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Endotis,

Acknowledgements

Dr Jeffrey Berger was partially funded by an American Heart Association Fellow to Faculty Award (0775074N). The authors are solely responsible for the design and conduct of this study, all study analyses, and the drafting and editing of the paper and its final contents.

References (30)

  • T.A. Meadows et al.

    Clinical aspects of platelet inhibitors and thrombus formation

    Circ Res

    (2007)
  • C. Baigent et al.

    Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials

    Lancet

    (2009)
  • D.L. Bhatt

    Intensifying platelet inhibition—navigating between Scylla and Charybdis

    N Engl J Med

    (2007)
  • S.J. Pocock et al.

    Prognostic modeling of individual patient risk and mortality impact of ischemic and hemorrhagic complications: assessment from the Acute Catheterization and Urgent Intervention Triage Strategy trial

    Circulation

    (2010)
  • S.D. Wiviott et al.

    Therapeutic goals for effective platelet inhibition: a consensus document

    Rev Cardiovasc Med

    (2006)
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