Curriculum in Cardiology
Variation in the definitions of bleeding in clinical trials of patients with acute coronary syndromes and undergoing percutaneous coronary interventions and its impact on the apparent safety of antithrombotic drugs

https://doi.org/10.1016/j.ahj.2007.04.009Get rights and content

Background

This review compares and contrasts the various criteria used to characterize bleeding (particularly major bleeding) during recent studies of antithrombotic therapies in acute coronary syndromes (ACSs) and/or percutaneous coronary intervention (PCI).

Methods

This review includes an analysis of recent large randomized clinical trials (published between January 2000 and September 2006; n > 3000 patients) evaluating antithrombotic drugs in patients with ACS or patients undergoing PCI who were identified using Medline searches.

Results

Bleeding has been shown to correlate with patient mortality and major cardiovascular events. Different definitions of bleeding, other than Thrombolysis In Myocardial Infarction or Global Utilization of Streptokinase and t-PA for Occluded coronary arteries bleeding criteria, were used in 9 of the 13 randomized trials that were identified and enrolled over 178,000 patients in total. These definitions overlapped to a degree but differed substantially. Bleeding rates according to several bleeding criteria within one trial illustrate that different bleeding definitions can lead to markedly different conclusions about the safety of an antithrombotic regimen. The shift toward identifying therapies that specifically attempt to reduce bleeding while maintaining efficacy at reducing ischemic complications increases the need of standardized bleeding definitions.

Conclusions

A task force should be initiated to formulate an internationally accepted, meaningful, and standardized approach for reporting bleeding events. A fixed definition may not work for all disease states throughout ACS and PCI. Rather, a predefined scale of bleeding can be proposed, which moves from a more liberal definition of bleeding for elective PCI to a more conservative definition in other settings such as rescue angioplasty.

Section snippets

Methods

We performed searches on Medline to identify all randomized controlled trials (RCTs) published between January 2000 and September 2006 that evaluated an antithrombotic drug and enrolled more than 3000 patients with an ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), or undergoing PCI. Searches were performed for the following drugs: dalteparin; tinzaparin; enoxaparin; fondaparinux; clopidogrel; bivalirudin; lepirudin; hirudin;

Differences in bleeding definitions in clinical trials

The trials reviewed evaluated 7 different antithrombotic drugs in over 178,000 patients. The incidence of major bleeding in these trials ranged from as low as 0.2% to as high as 9.1% (Table II).10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 The risk of bleeding is not the same for fibrinolytics, antithrombins, or antiplatelets and is influenced by the use of glycoprotein IIb/IIIa inhibitors and the clinical situation. Notwithstanding that there are important differences between

Need for standardized bleeding definitions

A number of recent trials in patients with NSTEMI, such as the OASIS-515 and ACUITY13 trials, have shown the clinical value of antithrombotic therapies that have a lower risk of bleeding compared with older strategies and the favorable impact this has on late clinical outcome. A similar advantage of new antithrombotic regimens is seen in recent PCI trials, namely the STEEPLE17 and REPLACE-216 trials, which both demonstrated a lower bleeding risk at similar antithrombotic efficacy compared with

References (35)

  • J.W. Eikelboom et al.

    Adverse impact of bleeding on prognosis in patients with acute coronary syndromes

    Circulation

    (2006)
  • S.V. Rao et al.

    Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes

    JAMA

    (2004)
  • E.G. Bovill et al.

    Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis In Myocardial Infarction (TIMI), phase II trial

    Ann Intern Med

    (1991)
  • An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO Investigators

    N Engl J Med

    (1993)
  • Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT) -3 Investigators

    Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction

    Lancet

    (2001)
  • H. White et al.

    Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial

    Lancet

    (2001)
  • Z.M. Chen et al.

    Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial

    Lancet

    (2005)
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    Disclosures: Dr Steinhubl received research support from and served as a consultant for Bristol-Myers Squibb, Sanofi-Aventis, and The Medicines Company and served as a consultant for AstraZeneca. Doctor Berger received consulting and lecture fees from Bristol-Myers Squibb, Sanofi-Aventis, Johnson & Johnson, Genentech, Guilford, Arginox, Schering-Plough, and Boston Scientific and is the medical director and owns equity in Lumen. Doctor Kastrati received lecture fees from Bristol-Myers Squibb, Lilly, and Sanofi-Aventis.

    Disclosures: Financial and editorial support for this publication has been provided by Sanofi-Aventis US Inc.

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