Bivalirudin for Acute Coronary Syndromes
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.
Source: Stone GW, et al. Bivalirudin for Patients with Acute Coronary Syndromes. N Engl J Med. 2006;355:2203-2216.
Bivalirudin has been shown to provide equivalent outcomes, but less bleeding in patients undergoing elective percutaneous coronary interventions (PCI). The Acute Catheterization and Urgent Intervention Trial Strategy (ACUITY) study was designed to compare heparin plus a glycoprotein (GP) IIb/IIIa inhibitor to bivalirudin plus GP IIb/IIIa and bivalirudin alone in patients with moderate to high-risk acute coronary syndromes (ACS) undergoing cardiac catheterization. Patients with anginal chest pain lasting > 10 minutes were eligible for enrollment if at least one of the following was present: new ECG ST depression; transient ST elevation; elevated troponin or CKMB; known CAD; or a TIMI risk score of 4 or more. Patients with ST elevation myocardial infarction (MI), shock, bleeding diathesis, thrombocytopenia, renal dysfunction or prior administration of any antithrombotic drug, thrombolytics or antiplatelet drugs were excluded. However, after randomization the control group could be on heparin. Angiography was performed within 72 hours in all patients. Almost all patients received aspirin, but clopidogrel use was left to the discretion of the local investigators. The primary end point was a composite of death, myocardial infarction or unplanned revascularization, and major bleeding or both (net clinical outcome).
Over about 2 years, 13,819 patients with ACS were enrolled at 450 centers in 17 countries. Non ST elevation MI occurred in 59% and unstable angina in 41%. Almost all had coronary angiography and two-thirds were revascularized (56% PCI, 11% CABG). Among the PCI patients, 93% had stents, of whom two-thirds got drug-eluting stents.3 The composite ischemic end point was not different between the 2 GP IIb/IIIa groups (8% with bivalirudin, 7% with heparin) nor was major bleeding (both 5% and 6%, respectively) or the net end point (both 12%). Bivalirudin alone compared to heparin plus GP IIb/IIIa showed no difference in ischemia (8% vs 7%) but less major bleeding (3% vs 6%, P < 0.001) and a reduced net adverse outcome (10% vs 12%). The results were not influenced by biomarker positivity, PCI, immediate or deferred GP IIb/IIIa or timing of PCI. Among those who did not get clopidogrel before PCI, ischemic events were more common with bivalirudin monotherapy than with heparin plus GP IIb/IIIa (9% vs 7%) but major bleeding was reduced in the bivalirudin monotherapy group regardless of clopidogrel pretreatment. In the control group outcomes were similar in the low-molecular-weight heparin vs unfractionated heparin groups. The authors concluded that in ACS patients undergoing an early invasive approach with the addition of GP IIb/IIIa agents, bivalirudin was similar to heparin with regard to ischemic outcomes and major bleeding. Bivalirudin treatment alone exhibited similar rates of ischemia, but less major bleeding as compared to heparin plus a GP IIb/IIIa inhibitor.
Commentary
Bivalirudin is a direct thrombin inhibitor that has been FDA approved for use as an alternative to heparin in patients with stable angina or ACS undergoing PCI. In the REPLACE-2 trial bivalirudin monotherapy in patients with stable angina or ACS experienced similar rates of ischemic events or death, but less bleeding on bivalirudin monotherapy as compared to unfractionated heparin plus GP IIb/IIIa. The current trial is different in that only ACS patients were included, there was a third arm of bivalirudin plus GP IIb/IIIa and the study was open label as compared to double-blind in REPLACE-2. Regardless, the results were similar overall. The substitution of bivalirudin for heparin in the combined-therapy arms showed no significant difference in any outcome, confirming the non-inferiority of bivalirudin vs heparin. Bivalirudin alone also had similar ischemic outcomes as compared to the combination-therapy groups and much less major bleeding (RR .53). Of note, about 10% of the bivalirudin monotherapy patients got unplanned GP IIb/IIIa because of PCI complications, which was similar to the REPLACE-2 trial (7%). The question is whether we should abandon heparin and GP IIb/IIIa for PCI and switch to bivalirudin alone with GP IIb/IIIa if the PCI is complicated?
Before we all switch, there are some limitations to this study to consider. It was open label so investigator bias could have influenced the softer ischemia end points. There were fewer myocardial infarctions than in other trials of ACS, eg, SYNERGY. The results do not necessarily apply to patients managed conservatively nor to those who get coronary angiography > 72 hours post admission. Only two-thirds of the patients got clopidogrel or any thienopyridine before or after PCI. Subgroup analysis showed that those who did not get a thienopyridine before PCI did better with planned GP IIb/IIIa administration plus heparin. Two-thirds of patients got heparin before randomization. This may have influenced the results in the bivalirudin alone group. Physician choice was allowed for selecting unfractionated heparin or low-molecular-weight heparin. It did not seem to make any difference in the results, but in SYNERGY, bleeding rates were higher on enoxaparin, especially if the patient was switched from enoxaparin to heparin. Whether this was the case in this study is unclear.
I do not believe we are going to see a wholesale switch to bivalirudin, but usage will increase since REPLACE-2 and now ACUITY have shown less bleeding with similar ischemic outcomes to standard therapy with heparin and GP IIb/IIIa agents. I suspect that lower-risk patients without a large thrombus burden will be the best candidates for bivalirudin alone. Whether bivalirudin will replace heparin with planned GP IIb/IIIa use is less clear at this time since no outcome was better in the combination-therapy comparisons.
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