IIb or Not IIb
abstracts & commentary
Synopsis: Intravenous IIb/IIIa infusion is appropriate and complementary to the use of PCI with or without stenting, and total deaths and MIs both before and after PCI in stented and nonstented patients are reduced. However, oral IIb/IIIa was of no benefit when compared to aspirin.
Sources: Kleiman NS, et al. Circulation 2000;101:751-757; SYMPHONY investigators. Lancet 2000;355:337-345.
Two new articles advance our knowledge of iib/iiia receptor antagonists in unstable coronary syndromes, although the results are conflicting between the intravenous trial, PURSUIT, and the oral IIb/IIIa inhibitor trial, SYMPHONY.
Several published studies have confirmed the efficacy of intravenous glycoprotein IIb/IIIa receptor blockade in individuals with acute coronary syndromes (ACS), particularly in subjects undergoing percutaneous coronary interventions (PCI). The first article reports on the use of intravenous eptifibatide (EPT) or placebo in a large number of individuals with ACS with a focus on whether there was an early PCI. The initial PURSUIT reports (N Engl J Med 1998;329:436-443) confirmed a benefit for EPT irrespective of subsequent conservative or revascularization therapy. This report used a sophisticated series of statistical analyses to determine whether there was a different outcome in patients receiving EPT than in those who had early PCI or were managed conservatively, and whether the combination of early PCI and IIb/IIIa inhibition would reduce major coronary end points compared to delayed PCI. There were 9641 patients enrolled in PURSUIT; all had ischemic chest pain of less than 24 hours with ECG changes or elevations of myocardial muscle creatine kinase isoenzyme (CK-MB), but no ST segment elevation. Randomization to placebo or intravenous EPT by bolus and continuous infusion began immediately. Of those patients who underwent PCI at the end of the first 72 hours (early PCI), the study drug infusion continued up to 96 hours. All treatment decisions, including cardiac catheterization and revascularization, were made by the treating physician. The primary end point was the composite of death or myocardial infarction (MI) within 30 days; secondary end point included death and MI in those who had PCI within 72 hours. A number of statistical modeling techniques were used, including a censored analysis using Cox regression survival modeling, as well as the use of propensity scores for likelihood of PCI and its timing.
The primary end point was reduced in individuals who received PCI within 72 hours compared to those who did not. Over the 30-day study period, when patients were censored for having PCI, there was a reduction of risk with EPT (P = < 0.03). Patients who had early PCI continued on EPT or placebo for a median of 26 hours. In placebo-treated patients with early PCI, 25% had recurrent ischemia and 5% had an acute MI, compared to 18% and 1.7% of 606 EPT-treated patients who received early PCI. The EPT-treated patients with early PCI had a significant decrease of all events when compared to the individuals who received placebo and PCI, or those who were managed conservatively with a delayed invasive strategy. Following EPT administration, the event rates were similar regardless of strategy, "indicating that EPT blunted the early hazard associated with PCI." EPT reduced the composite of MI or death both before and after early PCI, as well as in patients who received a stent (approximately half the PCI group). EPT was more effective in centers that had higher rates of early PCI. Early PCI did not predict subsequent death or all MI. However, it was associated with a lower composite rate of death or Q-wave MI (hazard ratio 0.5; P < 0.001). The EPT benefit remained after adjustment for propensity score and PCI use for the major end points; the hazard ratio for death or MI was 0.75 (P = 0.008) and approximately 0.8 for death or Q-wave infarction. Kleiman and colleagues conclude that intravenous IIb/IIIa infusion is appropriate and complementary to the use of PCI with or without stenting, and total deaths and MIs both before and after PCI in stented and nonstented patients are reduced. The drug also decreases major end points in individuals who did not undergo PCI. In individuals receiving early PCI, the hazard ratio for the primary end point is reduced 30% between 96 hours and 30 days. There is no significant difference between EPT and placebo in individuals who did not receive the PCI in less than 72 hours. The benefits of EPT with early PCI are noted in individuals who did and did not receive a stent. Because baseline characteristics between the groups were different, an attempt was made to correct the event rate through the propensity score. The adjusted benefit of the EPT did not differ between those individuals who did and did not receive PCI. In fact, the outcomes between EPT patients and those who had a PCI were comparable. The data suggest that patients with an ACS who are selected for PCI will also predict individuals who are likely to benefit from IIb/IIIa inhibition.
Kleiman et al stress that selection bias was a major issue in PURSUIT, as the choice of PCI and its timing was relegated to the general physician. The PURSUIT data are hypothesis generating, raising the question as to whether early PCI with IIb/IIIa inhibition may be the best approach to ACS. Because EPT treatment prevented events both before and after PCI, Kleiman et al conclude that early treatment with the IIb/IIIa antagonist "most likely forms a useful part of a larger comprehensive strategy."
SYMPHONY
The second report is from the SYMPHONY trial, another large study enrolling 9233 patients with an acute chest syndrome (ACS) who had no further chest pain for at least 12 hours after admission. To be eligible, participants had to have protracted chest pain, elevated enzymes, or ST segment shifts. Ongoing ischemia was an exclusion, as was Killip class III or greater. SYMPHONY was carried out in 33 countries, enrolling patients within seven days of admission for an ACS. The study treatment included low- and high-dose sibrafiban (SIB) compared to aspirin (80 mg BID). Dosage for SIB was calculated on the basis of weight and serum creatine in an attempt to achieve predefined target drug concentrations. Procedure use and treatment with other medications was the decision of the attending physician. Individuals who underwent stent placement received ticlopidine for 2-4 weeks in the placebo group, but not in the SIB cohort. Primary end point of SYMPHONY was the 90-day composite of all-cause mortality, nonfatal MI or re-MI, or severe current ishcemia. The treatment groups were comparable, with approximately 3100 segments in each cell, 50% had hypertension, 17% had diabetes, almost 50% had high cholesterol, and one-third were current smokers. Twenty percent of the overall cohort had had a current MI, and 20% had received previous revascularization.
The results indicate that there was no difference in the primary end point among the three treatment groups, thus indicating that oral SIB was of no benefit when compared to aspirin. The outcomes were similar for secondary end points as well. Overall, the 90-day rates of revascularization were approximately 23% for bypass surgery and 16% for PCI, whereas another 22% of patients had a PCI between qualifying and randomization. Bleeding was a problem with SIB, particularly at the higher doses. There was a dose-related excess of bleeding complications with SIB and aspirin. Thus, the use of the oral glycoprotein IIb/IIIa inhibitors sibrafiban provided no significant benefits in this cohort. Discussion of other oral IIb/IIIa trials, including OPUS (orbofiban) and EXCITE (xemilogiban), indicated that these trials with oral inhibitors were unsuccessful in reducing morbidity and mortality. In all three trials—SYMPHONY, OPUS, and EXCITE—the odds ratio for mortality favored aspirin. While the investigators suggest that SYMPHONY, OPUS, and EXCITE may not have been continued for a long enough period, other questions have been raised regarding the efficacy of oral IIb/IIIa blockade. They conclude that "these agents have neither met expectations nor matched the consistent track record of efficacy shown with the intravenous administration of such agents."
Comment by Jonathan Abrams, MD
There is increasing evidence as well as enthusiasm for the use of intravenous glycoprotein IIb/IIIa receptor antagonist in patients hospitalized with unstable angina or non-Q-wave infarction, particularly if early PCI is likely. A variety of studies have suggested that these agents would be beneficial in individuals with unstable angina or non-Q infarction who did or did not receive an angioplasty. This analysis of PURSUIT suggests that an early invasive strategy plus a platelet antagonist appear to significantly decrease early morbidity and mortality; in contradistinction, placebo infusion did not confer any benefits.
The use of the oral agent sibrafiban was a disappointment, in that there was no obvious benefit in the two SIB groups over aspirin alone. Another SYMPHONY trial is now under way that will test aspirin plus low-dose as well as high-dose SIB therapy.
In conclusion, platelet receptor antagonism is a proven therapy in ACS, with or without PCI. An assessment of which subjects will benefit the most is still being conducted. Currently, only intravenous agents have been shown to be safe and effective. The promise of oral therapy remains unfulfilled.
Editor’s Note: At the American College of Cardiology scientific sessions in Anaheim, CA, March 12-15, SYMPHONY TWO was reported. This trial used sibrafiban in two doses, along with aspirin at the lowest dose. The results were no different from aspirin alone, and slightly worse with the highest dose of SIB, which was not given in conjunction with aspirin. Thus, there is a real problem with the oral IIb/IIIa receptor blockers, and it does not look promising right now for this approach to be available in the near future.
Oral IIb/IIIa agents are of proven benefit in patients with:
a. acute coronary syndromes.
b. acute MI.
c. cardiogenic shock.
d. None of the above
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