Glycoprotein IIbIIIa Receptor Antagonists

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The use of intravenous platelet GP IIb/IIIa receptor inhibitors and stents has markedly reduced the early hazard in diabetic patients undergoing PCI. In the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial, abciximab halved the risk of death, MI, or urgent revascularization at 30 days among diabetic patients undergoing stenting compared with placebo (12.1% versus 5.6%, respectively). The observed event rate was comparable to that of abcix-imab-treated nondiabetic patients (5.2%). A pooled analysis of three early abciximab trials demonstrated a significant 1-year mortality rate reduction among diabetic patients randomized to the drug compared with placebo (2.5% versus 4.5%).117 The Intracoro-nary Stenting and Antithrombotic Regimen: is abciximab a Superior Way to Eliminate Elevated Thrombotic risk in diabetics (ISAR-SWEET) study demonstrated that, among 701 low-risk diabetic patients, abcix-imab did not confer additional benefit on top of aspirin and a high clopidogrel loading dose (i.e., 600 mg > 2 hours before PCI).118 However, the study excluded ACS and insulin-treated diabetic patients. The question whether one GP IIb/IIIa inhibitor rather than another may be preferable in diabetic patients was addressed in a subgroup analysis of the TARGET trial, the only head-to-head comparison thus far performed. Among the 1117 diabetic patients enrolled, randomization to abciximab or tirofiban at the time of PCI led to comparable outcomes for up to 1 year.46 In particular, no difference was observed in terms of TVR or late mortality, suggesting that the non-GP IIb/IIIa properties of abciximab (such as vitronectin and aMp2 [Mac-1] receptor inhibition) do not translate into a long-term clinical benefit among diabetic patients.

In the setting of non-ST-segment elevation ACS, although the overall impact of GP IIb/IIIa receptor inhibitors used in a conservative setting has been modest,119 a mortality benefit was detected among diabetic patients. Accordingly, the meta-analysis of the diabetic populations (n = 6458) enrolled in the six large-scale trials of GP IIb/IIIa inhibitors in ACS detected a highly significant 26% mortality reduction associated with the use of these agents at 30 days, compared with placebo (Fig. 2-15).120 These findings were reinforced by a statistically significant interaction between treatment and diabetic status. The use of these potent platelet inhibitors was associated with a similar proportionate reduction in mortality for patients treated with insulin and for those treated with diet or with oral hypoglycemic drugs. Even more striking was the mortality reduction (70%) associated with the use of GP IIb/IIIa inhibitors among the diabetic patients who underwent PCI (see Fig. 2-15).

Figure 2-15. Meta-analysis of six randomized, placebo-controlled trials demonstrating the effect of platelet glycoprotein IIb/IIIa inhibitors (IIb/IIIa) on 30-day mortality among diabetic patients with acute coronary syndromes (ACS): A, overall benefit; B, efficacy among patients who underwent inhospital percutaneous coronary intervention (PCI). The data are reported as odds ratios with 95% confidence intervals (CI) and corresponding probability (P) values. Values lower than 1.0 indicate a survival benefit of IIb/IIIa. (From Roffi M, Chew DP, Mukherjee D, et al: Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes. Circulation 2001;104:2767-2771.)

Trial PURSUIT PRISM PRISM-PLUS GUSTO IV PARAGON A PARAGON B Pooled

Trial PURSUIT PRISM PRISM-PLUS GUSTO IV PARAGON A PARAGON B Pooled

2163 687 362 1677 412 1157 6458

Diabetic patients with ACS: 30 day-mortality

Odds ratio and 95% CI

OR 0.74

IIb/IIIa better

Placebo better

Diabetic patients with ACS undergoing PCI: 30 day-mortality

457 147 107 239 45 284 1279

Odds ratio and 95% CI

OR 0.30

IIb/IIIa better

Placebo better

Odds ratio and 95% CI

Placebo

IIb/IIIa

-►

3.3%

2.4%

P =

.57

P =

.50

2.5%

0.0%

P =

1.00

1.8%

0.0%

P =

.037

6.5%

1.2%

P =

.31

7.1%

0.0%

P =

.06

4.3%

0.7%

P =

.002

4.0%

1.2%

With respect to putative mechanisms underlying the preferential benefit of GP IIb/IIIa inhibitors observed among diabetic patients, an hypothesis was generated by an in vitro study in which the blood of diabetic (n = 35) and nondiabetic (n = 38) individuals was exposed to pharmacologic concentrations of abciximab, tirofiban, and eptifibatide.121 The assessment of fibrinogen-binding capacity with flow cytometry after exposure to 1 ^mol/L ADP showed that GP IIb-IIIa antagonists inhibited platelet activation to a greater extent in blood from the diabetic patients. The decreased rate of fibrinogen binding after platelet activation was thought to be a consequence of glycation of the GP IIb/IIIa receptor, which may subsequently enhance the inhibitory function of GP IIb-IIIa antagonists.121 Despite the preferential benefit from GP IIb/IIIa antagonists in the setting of non-ST-elevation ACS, data from the US NRMI registry including more than 60,000 patients with NSTEMI showed that diabetic patients had a significantly lesser chance to be treated with these potent platelet inhibitors than did nondiabetic individuals.122

The value of GP IIb/IIIa inhibitors for diabetic patients at the time of mechanical revascularization for STEMI cannot be adequately assessed, because few data are available. In a small, placebo-controlled, randomized trial with abciximab for stent-based primary PCI, the use of the GP IIb/IIIa antagonists among diabetic patients (n = 53) led to a significantly lower mortality rate at 6 months (0% versus 16.7%), as well as a reduced rate of reinfarction.123 Within the previously mentioned CADILLAC trial, no benefit of abciximab in terms of morbidity or mortality was observed among 346 lower-risk diabetic patients treated with either PTCA or stents for acute MI.104

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