ATLANTA — Treatment of patients with moderate to high-risk acute coronary syndrome with the antithrombotic bivalirudin was as effective as regimens that also contained a glycoprotein IIb/IIIa inhibitor in a controlled study with more than 13,000 patients.
Treatment with bivalirudin without a IIb/IIIa inhibitor also led to significantly fewer major bleeding events, giving a regimen of bivalirudin alone an apparent advantage over the comparator regimens that used a IIb/IIIa inhibitor plus unfractionated heparin, the low-molecular-weight heparin enoxaparin, or bivalirudin, Dr. Gregg W. Stone reported at the annual meeting of the American College of Cardiology.
But some experts were skeptical about whether the results from this large and complex study clearly established equal efficacy and a safety advantage for bivalirudin alone in moderate to high-risk patients with acute coronary syndrome (ACS) who are scheduled for angiography that may be followed by a percutaneous coronary intervention (PCI).
“Only 58% of patients were high risk, based on a positive biomarker,” an elevated serum level of troponin, commented Dr. Eric D. Peterson, codirector of cardiovascular research at Duke University in Durham, N.C. Another indication that the study did not focus entirely on the types of high-risk patients enrolled in past studies was that their incidence of ischemic complications during the first 30 days after treatment was about 7.5%, substantially lower than the 12%–15% rates seen in high-risk patients in previous studies.
In other studies, treatment with a IIb/IIIa inhibitor involved a trade-off between a reduction in ischemic events and an increased risk of bleeding. “If 40% of the patients don't have high-risk ACS, then in those patients you get the risk [of increased bleeding] without the benefit,” said Dr. Peterson in an interview. “It's not surprising that drugs that work by reducing ischemic events didn't benefit” patients.
Dr. Peterson said that despite the new results, treatment with a IIb/IIIa inhibitor remains the standard of care for high-risk ACS patients with an elevated level of serum troponin who undergo angiography and may be treated with PCI.
The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial was designed by Dr. Stone and his associates to address two questions. First, the study compared bivalirudin alone with two other antithrombotic regimens that included a IIb/IIIa inhibitor. Also, it examined whether, in patients who received a IIb/IIIa inhibitor, it made a difference if the drug was given early, to all patients, or was deferred and given only to the roughly 55% of patients who actually underwent PCI.
The study enrolled 13,819 patients at 448 centers in 17 countries. More than half of the patients were treated in the United States. The study was sponsored by The Medicines Company, which markets the synthetic direct-thrombin inhibitor bivalirudin (Angiomax). Dr. Stone is a consultant to The Medicines Company.
All the patients were treated with aspirin; clopidogrel treatment was recommended, but was administered according to local practices. The patients were randomized equally among the three treatment groups: bivalirudin alone, bivalirudin plus a IIb/IIIa inhibitor, and unfractionated heparin or enoxaparin and a IIb/IIIa inhibitor. Patients who received a IIb/IIIa inhibitor during initial treatment were treated with either epifibatide or tirofiban. Those who had their treatment deferred until they underwent PCI primarily received either epifibatide or abciximab, with a small percentage receiving tirofiban.
Primary end points were the incidence during the next 30 days of ischemic events (death, MI, or need for revascularization due to ischemia); the rate of major bleeding events; and the composite incidence of ischemic events and major bleeds.
The results showed no significant difference in ischemic events, which occurred in 7.3%–7.8% of patients, proving that bivalirudin alone is not inferior to treatments with a IIb/IIIa inhibitor, said Dr. Stone, professor of medicine and director of cardiovascular research and education at Columbia University in New York. Major bleeding events occurred in 5.7% of patients treated with heparin or enoxaparin and a IIb/IIIa inhibitor, 5.3% of patients treated with bivalirudin and a IIb/IIIa inhibitor, and in 3.0% of patients treated with bivalirudin alone, a statistically significant reduced rate in the bivalirudin group.
The results of the second analysis, which compared upfront use of a IIb/IIIa inhibitor in all patients against deferred use only in the 55% of patients who underwent PCI, showed that the efficacy of both approaches was similar. The incidence of ischemic events was 7.1% in patients who received immediate treatment with a IIb/IIIa inhibitor, and 7.9% in patients who received the drug only before having PCI, a difference that was not statistically significant for superiority, but fell slightly short of proving that deferred use of a IIb/IIIa inhibitor was not inferior. The deferred strategy led to a 4.9% incidence of major bleeds, significantly less than the 6.1% rate in patients who got immediate treatment with a IIb/IIIa inhibitor. In the composite analysis of both major bleeds and ischemic events, the two strategies were completely equal, each producing an 11.7% event rate.