Identify patients at increased risk of death or MI who would benefit most from more aggressive therapy.

ANNOTATION

GP IIb/IIIa receptor antagonists are indicated in all patients in whom an invasive management strategy is followed as well as patients being managed non-invasively with one or more high-risk features. ACS patients with one or more of the following high-risk features may benefit from the addition of a Glycoprotein IIb/IIIa receptor antagonist:

1. Patients with elevated serum troponin
2. New or presumably new ST-segment depression > 1.0 mm in two or more contiguous leads.
3. Patients with recurrent angina or other ischemic symptoms despite initial medical therapy
4. Other high risk features (see table 1).

DISCUSSION

The intravenous Glycoprotein IIb/IIIa inhibitor drugs, abciximab, eptifibatide, and tirofiban, all have shown efficacy in NSTE-ACS patients. But the efficacy of abciximab has been primarily demonstrated in patients who also received a PCI and was superior to tirofiban. In the four large trials, enrolling over 18,000 patients, in which eptifibatide or tirofiban were used as part of the primary medical management of NSTE-ACSs, an approximate 10% decrease in the relative rate of death or non-fatal MI, at 30 days was demonstrated (Bhatt, 2000). There have been no direct comparison trials between eptifibatide and tirofiban.

These trials have also demonstrated an acceptable safety profile for these drugs, even when used with concomitant aspirin and heparin. Bleeding is the principal adverse effect, but can be minimized by the use of low-dose, weight-adjusted heparin. Early pilot studies suggest that these drugs may also be used safely with LMWH. The cumulative secondary outcome of 30-day death or nonfatal MI in the INTERACT trial occurred in 5% and 9% of the enoxaparin and UFH groups, respectively (P = 0.031) (Goodman, 2003). The INTERACT investigators concluded that when compared with UFH in UA/NSTEMI patients who were also receiving aspirin and eptifibatide, enoxaparin improves outcomes. An increased risk of intracranial hemorrhage has not been shown. While significant thrombocytopenia is uncommon, -occurring in less than 1% of patients, platelet counts should be obtained 2-4 hrs after starting these drugs. Active bleeding is an absolute contraindication to the use of glycoprotein IIb/IIIa inhibitors.

The following summary of study results is included in the ACC/AHA UA/NSTWMI (2002)

Glycoprotein IIb/IIIa Antagonists in PCI
GP IIb/IIIa receptor antagonists drugs take advantage of the fact that platelets play an important role in the development of ischemic complications that may occur in patients with UA/NSTEMI during coronary revascularization procedures.

The ESPRIT trial (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) was a RCT designed to assess whether eptifibatide improved outcome in patients undergoing elective stenting although, fourteen percent of the 2064 patients enrolled in ESPRIT had UA/NSTEMI. The primary end point (the composite of death, MI, target-vessel revascularization, and "bailout" GP IIb/IIIa antagonist therapy) was reduced from 10.5% to 6.6% with treatment ( P =0.0015). There was consistency in the reduction of events in all components of the end point and in all major subgroups, including patients with UA/NSTEMI. Major bleeding occurred more frequently in patients who received eptifibatide (1.3%) than in those who received placebo (0.4%; P =0.027); however, no significant difference in the transfusion rate occurred. At 1 year of follow-up, death or MI occurred in 12.4% of patients assigned to placebo and 8.0% of eptifibatide-treated patients (hazard ratio 0.63; 95% confidence interval [CI] 0.48 to 0.83; P =0.001)(O'shea, 2001).

In, the TARGET trial (Do Tirofiban and ReoPro Give similar Efficacy? Trial) randomized 5308 patients to tirofiban or abciximab before PCI with the intent to perform stenting (Topol, 2001). The primary end point, a composite of death, nonfatal MI, and urgent target-vessel revascularization at 30 days, occurred less frequently in those given abciximab than in those given tirofiban (6.0% versus 7.6%; P =0.038). There was a similar direction and magnitude for each component of the end point. The difference in outcome between the two treatment groups may be related to a suboptimal dose of tirofiban resulting in inadequate platelet inhibition. However, by six months, the primary end point occurred in a similar percentage of patients in each group (14.9% tirofiban versus 14.3% abciximab, NS). Mortality was also similar (1.9% versus 1.7%, NS). (Roffi et al., 2002).

Glycoprotein IIb/IIIa Antagonists Without Scheduled PCI
The Global Utilization of Strategies to Open Occluded Coronary Arteries IV-Acute Coronary Syndromes (GUSTO IV-ACS) trial enrolled 7800 patients with UA/NSTEMI who were admitted to the hospital with more than 5 minutes of chest pain and ST-segment depression and/or elevated troponin T or I concentration and in whom early (less than 48 hours) revascularization was not intended to be conducted. All received ASA and either unfractionated heparin (UFH) or LMWH. They were randomized to placebo, an abciximab bolus and 24-hour infusion, or an abciximab bolus and 48-hour infusion. The primary end point, death or MI at 30 days, occurred in 8.0% of patients given placebo, 8.2% given 24-hour abciximab, and 9.1% given 48-hour abciximab, differences that were not statistically significant. At 48 hours, death occurred in 0.3%, 0.7%, and 0.9% in these groups, respectively (placebo versus abciximab 48 hours, P =0.008). The lack of benefit of abciximab was observed in most subgroups, including patients with elevated concentrations of troponin who were at higher risk. Although the explanation for these results is not clear, they indicate that abciximab, at least at the dosing regimen used in GUSTO IV-ACS, is not indicated in the management of patients with UA or NSTEMI in whom an early invasive management strategy is not planned. (Simoons, 2001) In the PRISM-PLUS trial, 1069 patients did not undergo early PCI. Although tirofiban treatment was associated with a lower incidence of death, MI or death, and MI or refractory ischemia at 30 days, these reductions were not statistically significant. In a high-risk subgroup of these patients not undergoing PCI (TIMI risk score greater than or equal to 4), tirofiban appeared to be beneficial regardless of whether or not PCI was performed. (PCI: OR 0.60, 95% CI 0.35 to 1.01; No PCI: OR 0.69, 95% CI 0.49 to 0.99). However, no benefit was observed in the patients at lower risk. In the PURSUIT trial, eptifibatide reduced the incidence of death or MI from 15.7% to 14.2% (RR 0.91; 95% CI 0.79 to 1.00; P =0.032). (PRIMUS-PLUS, 1998).

Boersma et al performed a meta-analysis of GP IIb/IIIa antagonists in all 6 large, randomized, placebo-controlled trials (including GUSTO IV-ACS, which involved 31 402 patients with UA/NSTEMI who were not routinely scheduled to undergo coronary revascularization. 21 A small reduction in the odds of death or MI in the active treatment arm (11.8% versus 10.8%; OR 0.91, 95% CI 0.84 to 0.98; P=0.015) was observed. Unexpectedly, no benefit was observed in women (test for interaction between treatment assignment and gender, P less than 0.0001). However, women with positive troponins derived a treatment benefit that was similar to men. In the meta-analysis, reductions in the end points of death or nonfatal MI considered individually did not achieve statistical significance.

Although not scheduled for coronary revascularization procedures, 11 965 of the 31 402 patients (38%) actually underwent PCI or CABG within 30 days, and in this subgroup, the OR for death or MI in patients assigned to GP IIb/IIIa antagonists was 0.89 (95% CI 0.80 to 0.98). In the other 19 416 patients who did not undergo coronary revascularization, the OR for death or MI in the GP IIb/IIIa group was 0.95 (95% CI 0.86 to 1.05, P=NS). Major bleeding complications were increased in the GP IIb/IIIa antagonist-treated group compared with those who received placebo (1.4% versus 2.4%, P less than 0.0001). The authors concluded that in patients with UA/NSTEMI who were not routinely scheduled for early revascularization and who were at high risk of thrombotic complications, "treatment with a GP IIb/IIIa inhibitor might therefore be considered." Thus, GP IIb/IIIa inhibitors are of benefit in high-risk patients with UA/NSTEMI, and their administration, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned received a Class I recommendation. These agents are of questionable benefit in patients who do not undergo PCI. However, the revised guidelines recommend broader indications for a routine invasive strategy.

The ACC/AHA UA/NSTEMI 2002 recommends the following:

… Clopidogrel (in addition to aspirin and heparin or low molecular weight heparin) is recommended for patients with UA/NSTEMI in whom a noninterventional approach is planned (Class I recommendation).

In patients in whom an interventional approach is planned, a GP IIb/IIIa inhibitor (in addition to aspirin and heparin or low molecular weight heparin) is recommended (Class I recommendation).

… Addition of a GP IIb/IIIa inhibitor is recommednded for patients with UA/NSTEMI who are receiving aspirin, clopidogrel, and unfractionated or low molecular weight heparin and who are referred for an invasive strategy. (Class IIa recommendation)

GP IIb/IIIa inhibitor is recommended at the time of PCI in patients receiving heparin and aspirin. (Class I recommendation)

EVIDENCE