Incidence, outcomes, and management of bleeding in non-ST-elevation acute coronary syndromes

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ABSTRACTAntithrombotic and antiplatelet drugs and percutaneous interventions have decreased the ischemic outcomes of non-ST-elevation acute coronary syndromes, but they pose risks of bleeding. The authors review the scope of the problem and ways to prevent and manage bleeding in this situation.


  • The reported incidence of bleeding after treatment for non-ST-elevation acute coronary syndromes ranges from less than 1% to 10%, depending on a number of factors.
  • Bleeding is strongly associated with adverse outcomes, although a causal relationship has not been established.
  • Patients should be assessed for risk of bleeding so that the antithrombotic and antiplatelet regimen can be adjusted, safer alternatives can be considered, and percutaneous interventions can be used less aggressively for those at high risk.
  • If bleeding develops and the risk of continued bleeding outweighs the risk of recurrent ischemia, antithrombotic and antiplatelet drug therapy can be interrupted and other agents given to reverse the effects of these drugs.



The medical management of non-ST-elevation acute coronary syndromes focuses on blocking the coagulation cascade and inhibiting platelets. This—plus diagnostic angiography followed, if needed, by revascularization—has reduced the rates of death and recurrent ischemic events.1 However, the combination of potent antithrombotic drugs and invasive procedures also increases the risk of bleeding.

This review discusses the incidence and complications associated with bleeding during the treatment of acute coronary syndromes and summarizes recommendations for preventing and managing bleeding in this setting.


The optimal way to detect and analyze bleeding events in clinical trials and registries is highly debated. The reported incidences of bleeding during antithrombotic and antiplatelet therapy for non-ST-elevation acute coronary syndromes depend on how bleeding was defined, how the acute coronary syndromes were treated, and on other factors such as how the study was designed.

How was bleeding defined?

The first bleeding classification schemes were the GUSTO2 and the TIMI3 scales (Table 1), both of which were developed for studies of thrombolytic therapy for ST-elevation myocardial infarction. The GUSTO classification is based on clinical events and categorizes bleeding as severe, moderate, or mild. In contrast, the TIMI classification is based on laboratory values and categorizes bleeding as major, moderate, or minor.

Since these classification schemes are based on different types of data, they yield different numbers when applied to the same study population. For instance, Rao et al4 pooled the data from the PURSUIT and PARAGON B trials (15,454 patients in all) and found that the incidence of severe bleeding (by the GUSTO criteria) was 1.2%, while the rate of major bleeding (by the TIMI criteria) was 8.2%.

What was the treatment strategy?

Another reason that the true incidence of bleeding is hard to determine is that different studies used treatment strategies that differed in the type, timing, and dose of antithrombotic agents and whether invasive procedures were used early. For example, if unfractionated heparin is used aggressively in regimens that are not adjusted for weight and with a higher target for the activated clotting time, the risk of bleeding is higher than with conservative dosing.5–7

Subherwal et al8 evaluated the effect of treatment strategy on the incidence of bleeding in patients with non-ST-elevation acute coronary syndromes who received two or more antithrombotic drugs in the CRUSADE Quality Improvement Initiative. The risk of bleeding was higher with an invasive approach (catheterization) than with a conservative approach (no catheterization), regardless of baseline bleeding risk.

What type of study was it?

Another source of variation is the design of the study. Registries differ from clinical trials in patient characteristics and in the way data are gathered (prospectively vs retrospectively).

In registries, data are often collected retrospectively, whereas in clinical trials the data are prospectively collected. For this reason, the definition of bleeding in registries is often based on events that are easily identified through chart review, such as transfusion. This may lead to a lower reported rate of bleeding, since other, less serious bleeding events such as access-site hematomas and epistaxis may not be documented in the medical record.

On the other hand, registries often include older and sicker patients, who may be more prone to bleeding and who are often excluded from clinical trials. This may lead to a higher rate of reported bleeding.9

Where the study was conducted makes a difference as well, owing to regional practice differences. For example, Moscucci et al10 reported that the incidence of major bleeding in 24,045 patients with non-ST-elevation acute coronary syndromes in the GRACE registry (in 14 countries worldwide) was 3.9%. In contrast, Yang et al11 reported that the rate of bleeding in the CRUSADE registry (in the United States) was 10.3%.

This difference was partly influenced by different definitions of bleeding. The GRACE registry defined major bleeding as life-threatening events requiring transfusion of two or more units of packed red blood cells, or resulting in an absolute decrease in the hematocrit of 10% or more or death, or hemorrhagic subdural hematoma. In contrast, the CRUSADE data reflect bleeding requiring transfusion. However, practice patterns such as greater use of invasive procedures in the United States may also be responsible.

Rao and colleagues12 examined international variation in blood transfusion rates among patients with acute coronary syndromes. Patients outside the United States were significantly less likely to receive transfusions, even after adjusting for patient and practice differences.

Taking these confounders into account, it is reasonable to estimate that the frequency of bleeding in patients with non-ST-elevation acute coronary syndromes ranges from less than 1% to 10%.13


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