NSTE, non-ST-segment elevation; PCI, percutaneous coronary intervention; ACS, acute coronary syndrome.
Pharmacology of Intravenous GP IIb/IIIa Antagonists
Three intravenous GP IIb/IIIa antagonists have undergone extensive evaluation in several large-scale clinical trials in the settings of PCI and non-ST-segment elevation myocardial ischemia, and in pharmacologic-based reperfUsion regimens for the treatment of acute myocardial infarction ("combination therapy") (91). An additional GP IIb/IIIa antagonist, lamifiban, has also been evaluated in patients presenting with ACS, but is not approved for clinical use (Table 4).
Abciximab (ReoPro™) is the human-murine chimeric Fab fragment of the monoclonal antibody directed to GP IIb/IIIa, 7E3. Owing to its affinity for the b3 (GP IIIa) subunit, abciximab also binds other b3-containing integrins, most notably the vitronectin receptor aVb3, which is involved in cell adhesion, migration, and proliferation; however, the significance of this interaction remains unknown. After intravenous administration of the standard bolus dose of abciximab (0.25 mg/kg), approximately two-thirds of the drug rapidly binds to platelets and blocks approx 80% of the GP IIb/IIIa receptors, with a corresponding 80% inhibition of platelet aggregation in response to ADP (5-20 iM). Nevertheless, there is a fair amount of variability in the degree of platelet inhibition which is attained after a bolus dose, and even more so after the standard infusion (0.125 ig/kg/min) of abciximab (92).
Free plasma levels of abciximab rapidly drop after administration. Internalization of abciximab in platelet a-granules has been documented (93) and may potentiate subsequent a-granule release (94). Several in vivo and ex vivo studies show that once administered, abciximab is redistributed from platelet to platelet (92). In fact, platelet-bound abciximab can be detected up to 3 wk after the initial administration, at a time when all of the platelets that were present during abciximab administration can be expected to have been removed from the circulation based on their 7-10 d life span. Low plasma levels of free, unbound abciximab allow rapid reversal of the drug's inhibitory effect by platelet transfusions. Nevertheless, because of abciximab's redistribution capacity, very large numbers of platelets may be needed in order to decrease GP IIb/IIIa blockade to under 50%, a level at which hemostasis should not longer be impaired.
Eptifibatide (IntegrilinTM) is a cyclic heptapeptide based on the KGD (Lys-Gly-Asp) sequence found in the venom of the southeastern pigmy rattlesnake, Sisturus m. barbouri. The molecular structure of the peptide derivative of this venom was modified by substitution of arginine for lysine (thus a KGD sequence), enhancing its specificity for GP IIb/IIIa, while cyclization of the amino acid sequence enhanced the anti-aggregatory potency of the compound (95). Therefore, unlike abciximab, eptifi-batide binds with high affinity and specificity to GP IIb/IIIa and does not cross-react with other integrins.
Renal clearance is thought to be the main elimination route of eptifibatide, which has a plasma half-life of approx 2.5 h. In contrast to abciximab, a very high number of unbound drug molecules, relative to the number of receptors, are attained after intravenous administration of eptifibatide. Therefore, platelet transfusions may not reverse eptifibatide's inhibitory effect, as the newly transfused platelets would most probably be rapidly inhibited by the unbound eptifibatide. In this regard, reversal of the antiplatelet
effect relies mainly on suspending the administration of the drug and waiting for at least 4 h for the drug to be cleared and for platelet aggregation to approx 50% of baseline levels (92).
Tirofiban (Aggrastat™) is a peptidomimetic agent with geometric, stereotactic, and charge characteristics similar to the RGD (Arg-Gly-Asp) sequence. It thus acts as a highly specific competitive antagonist of the GP IIb/IIIa receptor (96). In a similar way to eptifibatide, after intravenous administration of tirofiban, the peak molecular concentration of the drug relative to the number of receptors is high; therefore, it is also unlikely that platelet transfusions are effective in reversing the antiplatelet effects of tirofiban. Again, similarly to eptifibatide, because of tirofiban's mean half-life of approx 2 h, reversal of the drug's antiplatelet effects relies on stopping the medication and waiting for approx 4 h to achieve approx 50% of the normal platelet aggregation (92).
Clinical Trials of Intravenous GP IIb/IIIa Antagonists in Non-ST Elevation ACS
The role of intravenous GP IIb/IIIa antagonists in the treatment of non-ST-elevation ACS has been studied in six large prospective randomized trials involving approx 30,000 patients. Unlike the clear-cut positive results of the GP IIb/IIIa antagonists in the interventional arena, there has been considerable heterogeneity in the efficacy of these drugs in reducing cardiovascular events among patients presenting with non-ST-elevation ACS (91). This heterogeneity may stem from several differences inherent to the ACS popu lation. For example, as opposed to the "planned" vessel injury in patients undergoing elective PCI, patients with unstable angina or non-ST-elevation myocardial infarction present with spontaneously ruptured plaques and have ongoing coronary thrombosis. Therefore, maximal platelet inhibition cannot be afforded at the time of injury and onset of the ACS. In spite of these observations, the results of several clinical trials support the use of GP IIb/IIIa antagonists in patents suffering non-ST-elevation ACS (Fig. 7).
The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) (97), Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) (98), Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON) (99), and Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) (100) trials, collectively known as the "4P's," are the basis for the use of GP IIb/IIIa antagonists for the treatment of ACS. Entry criteria were similar in these trials, although the PRISM study had a lower-risk population compared to the other trials. Indeed, 25% of patients enrolled in the PRISM study were diagnosed with non-Q wave myocardial infarction, compared to 45% in the higher risk populations enrolled in PRISM-PLUS and PURSUIT.
There were considerable differences between the trials regarding the therapeutic strategy to be followed. While PRISM and PARAGON focused primarily on the medical management of patients, discouraging early coronary catheterization and revascularization, PRISM-PLUS encouraged angiography and revascularization after an initial 48-h drug pretreatment period, maintaining drug therapy at the time of the procedure. PURSUIT, on the other hand, was a megatrial carried out in 28 countries and did not mandate any particular invasive or pharmacologic strategy apart from the study medication.
Regarding adjunctive pharmacotherapy, all patients received aspirin. Nevertheless, the use of heparin varied among the trials. In PURSUIT, heparin was encouraged during the active drug infusion, but was not protocol-mandated. Heparin co-administration to patients receiving GP IIb/IIIa inhibitor therapy was specifically tested in a randomized manner in the PRISM-PLUS and PARAGON-A studies. In the PRISM study, patients assigned to tirofiban did not receive adjunctive heparin. Table 5 summarizes the design of these four clinical trials.
The PARAGON-B trial enrolled 5225 high-risk patients with ischemic chest pain in the preceding 12 h, and either changes in the ST-segment or T wave, or positive cardiac enzymes (creatine kinase isoenzyme-cardiac muscle subunit [CK-MB] or troponins) (101). Patients were randomized to either lamifiban (500 mg iv bolus, followed by various infusion doses based on their estimated creatinine clearance over 72 h) or placebo for up to 120 h after any PCI.
The most recent of the GP IIb/IIIa antagonist in ACS trials is Global Use of Strategies to Open Occluded Arteries (GUSTO)-IV (102). Seven thousand eight hundred patients presenting with ischemic chest pain lasting more than 5 min in the preceding 24 h, and either positive troponins or at least 0.5 mm of ST-segment depression, randomly received either abciximab for 24 h, abciximab for 48 h, or a matching placebo. Abciximab was administered at the standard bolus and infusion doses. Early angiogra-phy and revascularization were strongly discouraged.
Design of the Major Trials Evaluating GP IIb/IIIa Antagonists in ACS
Design of the Major Trials Evaluating GP IIb/IIIa Antagonists in ACS
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