Aggrastat to Zocor - A to Z, Phase A


The goal of the "A Phase" of the Aggrastat to Zocor (A to Z) trial was to compare the efficacy and safety of unfractionated heparin (UFH) versus enoxaparin as adjunctive therapy to baseline treatment with tirofiban and aspirin in patients with non-ST elevation acute coronary syndromes (ACSs).


The primary analysis tests for noninferiority and superiority of enoxaparin in the intention-to-treat population. Noninferiority is defined as having 95% confidence (one-sided) that the odds ratio for enoxaparin relative to UFH is <1.144.

Study Design

Study Design:

Patients Enrolled: 3,987
Mean Follow Up: Seven days
Mean Patient Age: Mean age 61 years
Female: 71%

Patient Populations:

Presented within 24 hours with ≥10 minutes of ischemic symptoms at rest judged to be cardiac in origin associated with >0.5 mm of ST depression, >1 mm of transient ST elevation, or elevated cardiac markers


Prior statin or lipid-lowering therapy within prior six weeks, use of a GP IIb/IIIa inhibitor other than tirofiban within 24 hours, >24 hours of use of low molecular weight heparin or UFH prior to enrollment, high risk for bleeding, or creatinine >2 g/dl

Primary Endpoints:

Composite of all-cause mortality, new MI, and documented refractory ischemia within seven days of randomization

Secondary Endpoints:

Death, MI, documented refractory ischemia, urgent coronary revascularization, documented multiple myocardial ischemic events, and composite of these events at seven days

Drug/Procedures Used:

All patients received aspirin and tirofiban and were randomized to either open-label enoxaparin (1 mg/kg every 12 hours, n=2026) or weight-adjusted UFH (n=1961).

Concomitant Medications:

Concomitant medications and invasive or conservative management strategy were at the discretion of the local investigator.

Principal Findings:

Median duration of drug exposure was similar in the two arms. The composite of death/myocardial infarction (MI)/refractory ischemia at seven days was nonsignificantly lower for superiority of enoxaparin versus UFH (8.4% vs. 9.4%, hazard ratio [HR] 0.88, p=0.23), and the upper confidence interval (CI; HR 1.05) fell within the prespecified noninferiority boundary (HR 1.144). Similar results were observed when the analysis was based on the on-treatment population rather than the intent-to-treat population (8.5% with enoxaparin vs. 9.5% with UFH, HR 0.89, p=0.308, upper CI 1.07). Results were similar across all subgroups.

There was no difference in the individual components of the composite event: death (1.1% vs. 0.9%, HR 1.26, p=NS); MI (3.6% vs. 4.4%, HR 0.82, p=NS); and refractory ischemia (4.0% vs. 4.9%, HR 0.82, p=NS). There was no difference in the safety end points of thrombolysis in myocardial infarction (TIMI) major bleed (0.9% vs. 0.4%, p=0.076), TIMI major or minor bleed (3.1% vs. 2.2%, p=0.093), or transfusion (1% vs. 0.8%, p=0.405).


Among patients with non-ST elevation ACSs treated with aspirin and tirofiban, treatment with enoxaparin was shown to be noninferior for death, MI, or refractory ischemia compared with UFH. Earlier trials such as TIMI 11B and ESSENCE demonstrated superiority of enoxaparin versus UFH in patients with ACSs. However, not all patients in these trials received glycoprotein (GP) IIb/IIIa inhibitors.

The A to Z trial is the first large, randomized trial to examine the safety and efficacy of the combination of enoxaparin versus UFH with use of a GP IIb/IIIa inhibitor. Use of an early invasive therapy was at the discretion of the investigator in the A to Z trial. The recent SYNERGY trial addressed the efficacy of enoxaparin versus UFH in a population of patients who are all treated with an early invasive therapy.

Results of the "Z Phase" of the A to Z trial are pending; the "Z Phase" examines whether early initiation with simvastatin will reduce coronary events in ACS patients when administered as soon as patients become clinically stable.


Blazing MA, de Lemos JA, White HD, et al. Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial. JAMA 2004;292:55-64.

Presented at Late-Breaking Clinical Trials, ACC 2003.

Keywords: Acute Coronary Syndrome, Myocardial Infarction, Pyridinolcarbamate, Coronary Disease, Heparin, Simvastatin, Tyrosine, Platelet Membrane Glycoprotein IIb, Enoxaparin, Intention to Treat Analysis, Platelet Glycoprotein GPIIb-IIIa Complex

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