Bleeding with Acute Coronary Syndrome
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Synopsis: In ACS patients without persistent ST-segment elevation, there is a strong, consistent, temporal, and dose-related association between bleeding and death.
Source: Eikelboom JW, et al. Adverse Impact of Bleeding on Prognosis in Patients with Acute Coronary Syndromes. Circulation. 2006;114:774-782.
Multiple antithrombotic drugs combined with aggressive percutaneous revascularization strategies has resulted in reports of major bleeding rates of up to 5% in acute coronary syndrome (ACS) patients. These rates are similar to the incidence of major ischemic events in these conditions, yet clinicians favor this aggressive approach to reduce the incidence of ischemia. Thus, Eikelboom and colleagues evaluated 3 large ACS trials to determine the prognostic import of major bleeding. The OASIS Registry, OASIS-2, and CURE trials had over 30,000 patients with ACS, but without ST elevation myocardial infarction (MI). Major bleeding was defined as bleeding requiring 2 or more units of blood transfused, or life-threatening bleeding. The latter was defined as fatal bleeding; intracranial; hemoglobin decrease of 5 g/dL or more; hypotension requiring pressors; surgical intervention required; or 4 or more units of blood transfused. The primary outcome was 30-day mortality. Secondary end points included MI and stroke. Associations with type of antithrombotic agent, dose, and risk of bleeding were examined.
Result: The overall incidence of major bleeding over the 3 trials was 2.3%; 2% of which occurred in the first 6 months with the biggest increment in the first 30 days. Patients who developed major bleeding were older, diabetic, had prior stroke, had lower blood pressure, higher creatinine, and ST changes on ECG. Also, they were more likely to receive glycoprotein IIb/IIIa agents, heparin, warfarin, fibrinolytics, coronary angiography, bypass surgery, or intraaortic balloon pumping. In addition, they had a higher incidence of death in the first 30 days (12.8% vs 2.5% for no major bleeding, P = .002). Finally, there was a progressive increase in risk of death going from minor to major to life-threatening bleeding. Major bleeding also increased the risk of MI and stroke. Eikelboom et al concluded that in ACS patients without ST elevation MI, there is a strong association between major bleeding and death.
The strength of this analysis is that it includes over 30,000 patients from 3 studies, with the same definition of major bleeding used. It is unlikely that a randomized trial of bleeding will ever be done because you cannot predetermine who will bleed. However, the results are robust and consistent, even after adjusting for comorbidities. Also, the risk of death increases with the severity of bleeding. Major bleeding increases mortality 5-fold and ischemic events 4-fold in the first 30 days. Herein lies the rub. Once major bleeding occurs, all antithrombotic agents are stopped, leaving the patient vulnerable to recurrent ischemic events. Thus, it is desirable to prevent major bleeding so that antithrombotic therapy can be continued. How can this be done, since major bleeding was shown to be associated with the use of these agents?
Several approaches come to mind. This study clearly showed that there is a risk profile for major bleeding. However, they are the older, sicker patients who need aggressive therapy the most. One factor associated with major bleeding was serum creatinine, and we know that certain antithrombotic agents such as low molecular weight heparin need to be adjusted for renal insufficiency. We don't have details about appropriate dosing in these trials, but I wouldn't be surprised if it was not perfect. Also, until we have more data about combinations of antithrombotic medications, it is wise to stick to current guidelines. For example, there is little data about the safety of clopidogrel and the glycoprotein IIb/IIIa inhibitors in combination. We currently do not give both together unless a coronary stent has been placed. Finally, newer agents may prove to be superior. Recent data on the direct thrombin inhibitor bivalirudin are encouraging in this regard.
The trials all excluded patients at the highest risk of major bleeding so, in actual clinical practice, the incidence of major bleeding is probably higher. In the trials, the overall risk of death due to major bleeding is < 1%, so we get lulled into a sense of security with these patients. The real world experience is not so rosy. This is clearly an area where diligence will pay off. Be sure not to overdose antithrombotics for the individual patient and use only those proven to be of benefit in a given situation.