GUSTO-IV ACS GUSTO IV ACS evaluated the safety and efficacy of abciximab given as first line medical therapy in a broad population of patients with non-ST elevation acute coronary syndrome specifically when PCI was not planned. GUSTO IV ACS, was a multinational, multicenter, randomized, double blind, placebo-controlled trial in patients with ACS without ST-segment elevation. The primary hypothesis was that both 24- and 48-hour infusions of abciximab when compared to placebo (aspirin and heparin alone) would reduce the composite endpoint of death or MI at 30 days. 7800 patients were enrolled. Patients were diagnosed with cardiac ischemic chest pain lasting at least 5 minutes within the previous 24 hours and had either transient or persistent ST segment depression of > 0.5 mm or positive levels of troponin T or I above the upper limit of normal for the assay used.

Current Management of ACS with Advent of Abciximab Therapy Abciximab is currently approved for a broad range of patients with ACS undergoing PCI. Upon presentation, ACS patients are quickly triaged into ST elevation and non-ST elevation populations. Once diagnosed with ST elevation, two major treatment strategies are employed: fibrinolytic therapy or primary PCI. Patients undergoing primary PCI are already indicated to receive abciximab. Patients undergoing rescue angioplasty for failed fibrinolysis are also indicated for abciximab therapy (with appropriate risk/benefit analysis). Patients receiving fibrinolysis are not currently indicated to receive concomitant abciximab medical therapy, although this has been studied in 2 phase II clinical trials and is being investigated further in GUSTO IV AMI. As with ST elevation patients, non-ST elevation patients are also treated with two major strategies: early conservative therapy or early invasive therapy. Patients undergoing early invasive therapy are indicated to receive abciximab. Patients who are unresponsive to conventional medical therapy and are planned to undergo angioplasty within 24 hours are also indicated for abciximab therapy. Not studied, until this trial, was the role of abciximab as pure medical therapy in patients in whom PCI was not planned.

Major Study Objectives The GUSTO IV ACS trial has two major objectives: - To compare the effects of abciximab as a medical therapy vs. placebo on the incidence of death or MI within 30 days in patients with non-ST elevation ACS in whom PCI is not planned. - To evaluate the safety of abciximab in this setting.

Inclusion Criteria for GUSTO IV ACS 1. Patients must be diagnosed with cardiac ischemic chest pain lasting at least 5 minutes within the previous 24 hours 2. Patients must also have demonstrated one of the following two diagnostic criteria: a) ST segment depression of 0.5 mm or greater not known to be pre-existing or b) positive levels of troponin T or I, based upon each individual assay If the patient had been diagnosed with MI within the past 10 days, then the CK-MB value (or CK if CK-MB not available) must have returned to normal since the previous cardiac episode. These inclusion criteria were meant to be tighter than those of previous trials evaluating GP IIb/IIIa inhibition in this setting in order to ensure enrolling a population with ongoing disease likely to experience an observable, meaningful benefit. As a point of reference, the inclusion criteria for similar trials were: PURSUIT: ischemic pain lasting > 10 min within 24h and ST seg  or  of > 0.5 mm, T wave inversion of > 1 mm within 12h. or CKMB above normal PRISM: ischemic pain within 24h and: ST seg  or  of > 0.1 mV, T-wave inversion, elevated cardiac enzymes, or a history of risk factors (MI, PCI within 6 months, CABG w/in 1 month), positive stress or dipyridamole test, or > 50 % stenosis PRISM Plus: ischemic pain within 12 h and ST seg  or  of > 0.1 mV, T wave inversion of > 0.3 mm, pseudonormalization of > 0.1 mV within 12h. or CKMB/CK above normal PARAGON: ischemic pain lasting w/in 12h and ST seg  or  of > 0.5 mm, T wave inversion

Exclusion Criteria The major exclusion criteria in the GUSTO IV trial were as follows: Planned PCI or CABG within 30 days after enrollment. Myocardial ischemia precipitated by a condition other than atherosclerotic coronary artery disease ECG evidence of acute ST segment elevation myocardial infarction Use of thrombolytic agent within the previous 48 hours or planned use of a thrombolytic Contraindication to heparin or abciximab. Patients with standard bleeding risks. For logistical reasons, patients weighing above 120 kg were excluded: the study agent kits do not contain enough abciximab for these patients.

ACS Without ST Segment Elevation The schematic of the protocol is as follows: A total of 7800 patients meeting the entry criteria were randomized to one of three treatment arms, 2600 to each arm: (1) Placebo bolus plus two consecutive 24 hour placebo infusions (2) Abciximab bolus followed by a 24 hour abciximab infusion, followed by a 24 hour placebo infusion (3) Abciximab bolus followed by two consecutive 24 hour abciximab infusions The abciximab bolus was administered at 0.25 mg/kg, which is the same as has been used in previous trials. The abciximab infusion was administered at 0.125 g/kg/min to a maximum of 10 g/min. The primary endpoint of the trial was the incidence of death or non-fatal MI at 30 days. MI was defined as an increase in CK-MB levels greater than or equal to three times normal. Concomitant Therapy Heparin was administered in the following manner: 70 U/kg IV bolus (to a maximum of 5000 U) after initiation of study agent (if patient was already on heparin, titrate to maintain an aPTT between 50 - 70 seconds) Then a heparin infusion of 10 U/kg/hr (to a maximum of 800 U/hr), titrated to an aPTT of 50-70 seconds for 48 hours. Use of low molecular weight heparin during these first 48 hours was discouraged unless in substudy Use of heparin after the first 48 hours if clinically indicated Aspirin, when not contraindicated, was administered in the following manner: 150-325 mg orally (non-enteric coated) or 250-500 mg IV as soon as possible after randomization Then 75-325 mg orally once daily for at least 30 days post randomization

Primary and Secondary Efficacy Endpoints The outcome of this landmark trial was clear, striking, and remarkable: there was no difference in endpoint events between placebo and abciximab at 30 days in patients with non-ST elevation ACS receiving active treatment for either 24 or 48 hours with abciximab. No pre-specified subgroup, with the exception of patients with diabetes, showed a difference between either abciximab arm and placebo in this trial. The results, as described in detail below, are nearly uniformly neutral with the expected low incidence of statistical variation and/or outliers.

Primary and Secondary Efficacy Endpoints. The primary end-point of the study demonstrates that rates of death and MI at 30 days in the two active treatment arms are no different statistically from that in the placebo control arm. There is a non-significant trend for increased event rates in the 48-hour treatment arm. There was no dose-response of the treatment effect from 0 to 24 to 48 hours.

Rates of revascularization Rates of revascularization during the 24-48 hour abciximab infusion were quite low. Only 154 patients (2%) underwent any revascularization through 48 hours; there were no differences among the placebo and either of the two active treatment groups. Through 7 days, the rate increased to 13.7%, again with no differences among the three randomized groups. Rates through 30 days were 28.9-30.7% in the 24 and 48 hour treatment arms (p=ns). Rates of PCI through 30 days were 18.2 - 20.1%, with corresponding rates of CABG of 10.8 - 11.2%. Rates of cardiac catheterization were low through 48 hours (3.4% overall), but increased to 30.6% through 7 days, and 48.3% through 30 days without statistically significant differences between placebo and either of the active treatment groups at any time point. PCI, when performed, was undertaken following cessation of abciximab therapy in ~93% of the patients who underwent PCI (total of 1381 patients or 17.7% of total enrolled patients); the use of abciximab during cardiac catherization in these patients was quite low (< 3.3%), indicating that the use of abciximab during PCI in this trial was quite low.

Secondary Efficacy Endpoints Of the multiple secondary endpoints, there was no difference in event rates within 48 hours, 7 days and 30 days on the composite of a) death or (re) MI; b) death or (re) MI or revascularization; c) MI or reinfarction; d) cardiac catheterization; e) PCI; f) CABG; g) any revascularization (PCI or CABG); or h) death or MI (or reinfarction) within 30 days among patients with and without revascularization.

Secondary Efficacy Endpoints Of the multiple secondary endpoints, there was no difference in event rates within 48 hours, 7 days and 30 days on the composite of a) death or (re) MI; b) death or (re) MI or revascularization; c) MI or reinfarction; d) cardiac catheterization; e) PCI; f) CABG; g) any revascularization (PCI or CABG); or h) death or MI (or reinfarction) within 30 days among patients with and without revascularization.

Secondary Efficacy Endpoints (Troponin +/-) Previous analyses of troponin levels in patients with ACS suggested that elevated troponin levels would identify a patient population who would derive particular benefit from medical treatment with abciximab by identifying patients with active and embolic atherosclerotic lesions. Thus, positive troponins were utilized as one of the entry criteria for this study. Troponins measured at enrolling sites were rerun in a central laboratory. Troponin levels at sites were measured using a number of assays; one standard assay was used in the central laboratory. By measurements performed at sites, 51-52% of enrolled patients had a positive troponin at baseline; this contrasted with 41-42% positive troponins as measured in the central laboratory. As shown in the figure, event rates for troponin positive patients were elevated compared to those in troponin negative patients. Rates of death or MI through 30 days were no different among the treatment groups except for the expected higher event rates in patients with positive troponin assays.

Secondary Efficacy Endpoints (ST depression) ST depression is a known risk factor for the increased occurrence of death and / or myocardial infarction in patients with NQMI and USA. Patients were diagnosed with cardiac ischemic chest pain lasting at least 5 minutes within the previous 24 hours and had either transient or persistent ST segment depression of > 0.5 mm as entrance into the study . 80 % of all patients in GUSTO IV ACS had ST depression on entry No treatment effect of either 24 or 48 hour abciximab was seen based upon ST depression.

Safety Analyses Adverse events, including bleeding, need for transfusion, thrombocytopenia, intracranial hemorrhage, or stroke all occurred at very low rates in the active treatment and placebo arms. Major bleeding occurred in 0.3% of placebo treated patients, 0.6% in patients treated for 24 hours, and 1.0%(p<0.001) in patients treated for 48 hours. Minor bleeding occurred in 1.5% of placebo, 2.5% (p<0.05) of 24 hour, and 3.6% (p<0.001) of 48 hour treated patients. Thrombocytopenia in general reflected rates seen in previous trials with abciximab (data not shown). Intracranial hemorrhage occurred in a total of 11 patients overall in the trial, yielding low rates in all arms; any stroke or intracranial hemorrhage occurred in 51 patients at rates that were 0.73% +/- 0.16% in all arms (data not shown).

CK-MB critera PURSUIT > 1x ULN PRISM + > 2x ULN PARAGON-B > 2x ULN CAPTURE > 3x ULN GUSTO-IV > 3x ULN

GUSTO-IV ACS: Low-Molecular Weight Substudy Unfractionated heparin has been shown to reduce the occurrence of symptomatic and silent ischemia, myocardial infarction, and death in patients with ACS. However, one of the drawbacks of unfractionated heparin is its practical limitation in maintaining a constant and predictable anticoagulant effect. Unfractionated heparin administration needs to be monitored by aPPT to ensure that it is reaching (but not exceeding) and maintaining a level of clinical efficacy. Low-molecular weight heparins offer better bioavailability and therefore a more predictable pharmacokinetic profile, which eliminates the need for repeated laboratory monitoring. In the coming years, it is expected that the advantages of LMWH’s will ultimately lead to the replacement of unfractionated heparin by low molecular weight heparin for the treatment of unstable angina as has already occurred in several European countries. For this reason, GUSTO IV ACS evaluated the use of dalteparin in conjunction with abciximab for the treatment of unstable angina.

GUSTO-IV ACS: Low-Molecular Weight Substudy Unfractionated heparin has been shown to reduce the occurrence of symptomatic and silent ischemia, myocardial infarction, and death in patients with ACS. However, one of the difficulties with unfractionated heparin is its practical limitation in maintaining a constant and predictable anticoagulant effect. Unfractionated heparin administration needs to be monitored by aPTT to ensure that it is reaching and maintaining a level of clinical efficacy. Low-molecular weight heparins offer better bioavailability and therefore a more predictable pharmacokinetic profile, which eliminates the need for repeated laboratory monitoring. For this reason, GUSTO IV ACS evaluated the use of dalteparin in conjunction with abciximab for the treatment of unstable angina.

GUSTO IV ACS-LMWH Substudy The low molecular weight heparin (LMWH) substudy was performed in 974 of the propsed 1500 patients enrolled in GUSTO IV ACS. There was no significant difference in the composite of death or MI between abciximab/LMWH (n=646) and placebo/LMWH treated patients (n=328) at 48 hours (data not shown) though there was a trend towards improved outcomes in the abciximab/LMWH treated patients at both 7 (data not shown) and 30 days. Rates of stroke or intracranial hemorrhage, intracranial hemorrhage alone, or non-hemorrhagic stroke were not significantly different between abciximab and placebo treated patients. Similarly, non-CABG TIMI major bleeding was not significantly different between abciximab and placebo treated patients, though there was a statistically significant increase in minor bleeding (4.0% vs. 1.3%, p=0.029). There were no significant differences in the occurrence of post-medication thrombocytopenia to either <100,000/L or <50,000/L between abciximab and placebo patients.