Incidence, outcomes, and management of bleeding in non-ST-elevation acute coronary syndromes
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.
TO PREVENT BLEEDING, START BY ASSESSING RISK
The CRUSADE bleeding risk score
The CRUSADE bleeding score (calculator available at https://www.crusadebleedingscore.org/) was developed and validated in more than 89,000 community-treated patients with non-ST-elevation acute coronary syndromes.8 It is based on eight variables:
- Sex (higher risk in women)
- History of diabetes (higher risk)
- Prior vascular disease (higher risk)
- Heart rate (the higher the rate, the higher the risk)
- Systolic blood pressure (higher risk with pressures above or below the 121–180 mm Hg range)
- Signs of congestive heart failure (higher risk)
- Baseline hematocrit (the lower the hematocrit, the higher the risk)
- Creatinine clearance (by the Cockcroft-Gault formula; the lower the creatinine clearance, the higher the risk).
Patients who are found to have bleeding scores suggesting a moderate or higher risk of bleeding should be considered for medications associated with a favorable bleeding profile, and for radial access at the time of coronary angiography. Scores are graded as follows8:
- < 21: Very low risk
- 21–30: Low risk
- 31–40: Moderate risk
- 41–50: High risk
- > 50: Very high risk.
The CRUSADE bleeding score is unique in that, unlike earlier risk stratification tools, it was developed in a “real world” population, not in subgroups or in a clinical trial. It can be calculated at baseline to help guide the selection of treatment.8
Adjusting the heparin regimen in patients at risk of bleeding
Both the joint American College of Cardiology/American Heart Association1 and the European Society of Cardiology guidelines31 for the treatment of non-ST-elevation acute coronary syndromes recommend taking steps to prevent bleeding, such as adjusting the dosage of unfractionated heparin, using safer drugs, reducing the duration of antithrombotic treatment, and using combinations of antithrombotic and antiplatelet agents according to proven indications.31
In the CRUSADE registry, 42% of patients with non-ST-elevation acute coronary syndromes received at least one initial dose of antithrombotic drug outside the recommended range, resulting in an estimated 15% excess of bleeding events.32 Thus, proper dosing is a target for prevention.
Appropriate antithrombotic dosing takes into account the patient’s age, weight, and renal function. However, heparin dosage in the current guidelines1 is based on weight only: a loading dose of 60 U/kg (maximum 4,000 U) by intravenous bolus, then 12 U/kg/hour (maximum 1,000 U/hour) to maintain an activated partial thromboplastin time of 50 to 70 seconds.1
Renal dysfunction is particularly worrisome in patients with non-ST-elevation acute coronary syndromes because it is associated with higher rates of major bleeding and death. In the OASIS-5 trial,33 the overall risk of death was approximately five times higher in patients in the lowest quartile of renal function (glomerular filtration rate < 58 mL/min/1.73 m2) than in the highest quartile (glomerular filtration rate ≥ 86 mL/min/1.73 m2).
Renal function must be evaluated not only on admission but also throughout the hospital stay. Patients presenting with acute coronary syndromes often experience fluctuations in renal function that would call for adjustment of heparin dosing, either increasing the dose to maximize the drug’s efficacy if renal function is recovering or decreasing the dose to prevent bleeding if renal function is deteriorating.
Clopidogrel vs prasugrel
Certain medications should be avoided when the risk of bleeding outweighs any potential benefit in terms of ischemia.
For example, in a randomized trial,34 prasugrel (Effient), a potent thienopyridine, was associated with a significantly lower rate of the composite end point of stroke, myocardial infarction, or death than clopidogrel (Plavix) in patients with acute coronary syndromes undergoing percutaneous coronary interventions. However, it did not seem to offer any advantage in patients 75 years old and older, those with prior stroke or transient ischemic attack, or those weighing less than 60 kg, and it posed a substantially higher risk of bleeding.
With clopidogrel, the risk of acute bleeding is primarily in patients who undergo coronary artery bypass grafting within 5 days of receiving a dose.35,36 Therefore, clopidogrel should be stopped 5 to 7 days before bypass surgery.1 Importantly, there is no increased risk of recurrent ischemic events during this 5-day waiting period in patients who receive clopidogrel early. Therefore, the recommendation to stop clopidogrel before surgery does not negate the benefits of early treatment.36
Lower-risk drugs: Fondaparinux and bivalirudin
At this time, only two agents have been studied in clinical trials that have specifically focused on reducing bleeding risk: fondaparinux (Arixtra) and bivalirudin (Angiomax).20,37–39
Fondaparinux
OASIS-5 was a randomized, double-blind trial that compared fondaparinux and enoxaparin (Lovenox) in patients with acute coronary syndromes.38 Fondaparinux was similar to enoxaparin in terms of the combined end point of death, myocardial infarction, or refractory ischemia at 9 days, and fewer patients on fondaparinux developed bleeding (2.2% vs 4.1%, HR 0.52; 95% CI 0.44–0.61). This difference persisted during long-term follow-up.
Importantly, fewer patients died in the fondaparinux group. At 180 days, 638 (6.5%) of the patients in the enoxaparin group had died, compared with 574 (5.8%) in the fondaparinux group, a difference of 64 deaths (P = .05). The authors found that 41 fewer patients in the fondaparinux group than in the enoxaparin group died after major bleeding, and 20 fewer patients in the fondaparinux group died after minor bleeding.38 Thus, most of the difference in mortality rates between the two groups was attributed to a lower incidence of bleeding with fondaparinux.
Unfortunately, despite its safe bleeding profile, fondaparinux has fallen out of favor for use in acute coronary syndromes, owing to a higher risk of catheter thrombosis in the fondaparinux group (0.9%) than in those undergoing percutaneous coronary interventions with enoxaparin alone (0.4%) in the OASIS-5 trial.40
