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

Cleveland Clinic Journal of Medicine. 2010 June;77(6):369-379 | 10.3949/ccjm.77a.09142
June 1, 2010|Cleveland Clinic Journal of Medicine
Antonio Gutierrez, MD;Sunil V. Rao, MD
Author and Disclosure Information

Antonio Gutierrez, MD
Duke University Medical Center, Durham, NC

Sunil V. Rao, MD
Duke Clinical Research Institute, Durham, NC

Address: Antonio Gutierrez, MD, Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710; e-mail antonio.gutierrez@duke.edu

Dr. Rao has disclosed receiving consulting fees and honoraria from The Medicines Company for teaching and speaking.

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.

KEY POINTS

  • 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.

BLEEDING IS ASSOCIATED WITH POOR OUTCOMES

Regardless of the definition or the data source, hemorrhagic complications are associated with a higher risk of death and nonfatal adverse events, both in the short term and in the long term.

Short-term outcomes

A higher risk of death. In the GRACE registry study by Moscucci et al10 discussed above, patients who had major bleeding were significantly more likely to die during their hospitalization than those who did not (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.18–2.28).

Rao et al14 evaluated pooled data from the multicenter international GUSTO IIb, PURSUIT, and PARAGON A and B trials and found that the effects of bleeding in non-ST-elevation acute coronary syndromes extended beyond the hospital stay. The more severe the bleeding (by the GUSTO criteria), the greater the adjusted hazard ratio (HR) for death within 30 days:

  • With mild bleeding—HR 1.6, 95% CI 1.3–1.9
  • With moderate bleeding—HR 2.7, 95% CI 2.3–3.4
  • With severe bleeding—HR 10.6, 95% CI 8.3–13.6.

The pattern was the same for death within 6 months:

  • With mild bleeding—HR 1.4, 95% CI 1.2–1.6
  • With moderate bleeding—HR 2.1, 95% CI 1.8–2.4
  • With severe bleeding, HR 7.5, 95% CI 6.1–9.3.

These findings were confirmed by Eikelboom et al15 in 34,146 patients with acute coronary syndromes in the OASIS registry, the OASIS-2 trial, and the CURE randomized trial. In the first 30 days, five times as many patients died (12.8% vs 2.5%; P < .0009) among those who developed major bleeding compared with those who did not. These investigators defined major bleeding as bleeding that was life-threatening or significantly disabling or that required transfusion of two or more units of packed red blood cells.

A higher risk of nonfatal adverse events. Bleeding after antithrombotic therapy for non-ST-elevation acute coronary syndromes has also been associated with nonfatal adverse events such as stroke and stent thrombosis.

For example, in the study by Eikelboom et al,15 major bleeding was associated with a higher risk of recurrent ischemic events. Approximately 1 in 5 patients in the OASIS trials who developed major bleeding during the first 30 days died or had a myocardial infarction or stroke by 30 days, compared with 1 in 20 of those who did not develop major bleeding during the first 30 days. However, after events that occurred during the first 30 days were excluded, the association between major bleeding and both myocardial infarction and stroke was no longer evident between 30 days and 6 months.

Manoukian et al16 evaluated the impact of major bleeding in 13,819 patients with highrisk acute coronary syndromes undergoing treatment with an early invasive strategy in the ACUITY trial. At 30 days, patients with major bleeding had higher rates of the composite end point of death, myocardial infarction, or unplanned revascularization for ischemia (23.1% vs 6.8%, P < .0001) and of stent thrombosis (3.4% vs 0.6%, P < .0001).

Long-term outcomes

The association between bleeding and adverse outcomes persists in the long term as well, although the mechanisms underlying this association are not well studied.

Kinnaird et al17 examined the data from 10,974 unselected patients who underwent percutaneous coronary intervention. At 1 year, the following percentages of patients had died:

  • After TIMI major bleeding—17.2%
  • After TIMI minor bleeding—9.1%
  • After no bleeding—5.5%.

However, after adjustment for potential confounders, only transfusion remained a significant predictor of 1-year mortality.

Mehran et al18 evaluated 1-year mortality data from the ACUITY trial. Compared with the rate in patients who had no major bleeding and no myocardial infarction, the hazard ratios for death were:

  • After major bleeding—HR 3.5, 95% CI 2.7–4.4
  • After myocardial infarction—HR 3.1, 95% CI 2.4–3.9.

Interestingly, the risk of death associated with myocardial infarction abated after 7 days, while the risk associated with bleeding persisted beyond 30 days and remained constant throughout the first year following the bleeding event.

Similarly, Ndrepepa and colleagues19 examined pooled data from four ISAR trials using the TIMI bleeding scale and found that myocardial infarction, target vessel revascularization, and major bleeding all had similar discriminatory ability at predicting 1-year mortality.

In patients undergoing elective or urgent percutaneous coronary intervention in the REPLACE-2 trial,20 independent predictors of death by 1 year were21:

  • Major hemorrhage (OR 2.66, 95% CI 1.44–4.92)
  • Periprocedural myocardial infarction (OR 2.46, 95% CI 1.44–4.20).

THEORIES OF HOW BLEEDING MAY CAUSE ADVERSE OUTCOMES

Several mechanisms have been proposed to explain the association between bleeding during treatment for acute coronary syndromes and adverse clinical outcomes.13,22

The immediate effects of bleeding are thought to be hypotension and a reflex hyperadrenergic state to compensate for the loss of intravascular volume.23 This physiologic response is believed to contribute to myocardial ischemia by further decreasing myocardial oxygen supply in obstructive coronary disease.

Trying to minimize blood loss, physicians may withhold anticoagulation and antiplatelet therapy, which in turn may lead to further ischemia.24 To compensate for blood loss, physicians may also resort to blood transfusion. However, depletion of 2,3-diphosphoglycerate and nitric oxide in stored donor red blood cells is postulated to reduce oxygen delivery by increasing hemoglobin’s affinity for oxygen, leading to induced microvascular obstruction and adverse inflammatory reactions.15,25

Recent data have also begun to elucidate the long-term effects of bleeding during acute coronary syndrome management. Patients with anemia during the acute phase of infarction have greater neurohormonal activation.26 These adaptive responses to anemia may lead to eccentric left ventricular remodeling that may lead to higher oxygen consumption, increased diastolic wall stress, interstitial fibrosis, and accelerated myocyte loss.27–30

Nevertheless, we must point out that although strong associations between bleeding and adverse outcomes have been established, direct causality has not.

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