Platelet Glycoprotein IIb/IIIa Inhibition
August 30, 1998 4 minutes read
Platelet Glycoprotein IIb/IIIa Inhibition
ABSTRACTS & COMMENTARY
Synopsis: There is little question that the available IIb/IIIa inhibiting agents have a significant potential for reducing the sequelae of thrombotic events in the coronary arteries.
Sources: The PRISM-PLUS investigators. N Engl J Med 1998;338:1488-1497; The PRISM investigators. N Engl J Med 1998;332:1498-1505.
It has become clear over the past several years that acute coronary events (i.e., acute myocardial infarctions, unstable angina pectoris, sudden cardiac death) are usually due to disruption of atherosclerotic plaques occurring more frequently than not in arteries with only minor stenotic lesions and only rarely are caused by erosion alone and/or plaque occlusion of the affected coronary artery. These culprit atherosclerotic lesions usually have large lipid cores that are statistically more likely to develop plaque disruption, an event that quite often is followed by formation of secondary occluding thrombi.
Since platelet activation and subsequent aggregation resulting in arterial thrombi formation usually occurs in acute coronary syndromes,1,2 therapeutic options for the treatment of acute thrombotic disorders have dramatically expanded with the development of drugs that inhibit fibrinogen binding to the platelet glycoprotein IIb/IIIa receptors.3,4 The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators studied 1915 patients who were randomly assigned in a double-blind fashion to receive a platelet IIb/IIIa inhibitor (tirofiban), heparin, or tirofiban plus heparin. The study was stopped prematurely by the Data and Safety Committee because the group receiving tirofiban alone demonstrated excess mortality at seven days when compared with patients treated with heparin alone. The frequency of composite primary end points at seven days was lower among the patients who received tirofiban plus heparin than among those who received heparin alone. This benefit was consistent in various subgroups of patients treated medically as well as those treated only with angioplasty.
In a second paper, the same authors described a study in which they randomly assigned 3232 patients who were already receiving aspirin to additional therapy with either intravenous tirofiban or heparin for 48 hours. Tirofiban was well tolerated and definitely reduced ischemic events during the 48-hour infusion period; in addition, the mortality rate was found to be lower among these patients at the end of 30 days, although the incidence of refractory ischemia and myocardial infarction was not significantly reduced.
COMMENT BY HAROLD L. KARPMAN, MD
Platelet-rich thrombus formation resulting in complete coronary artery occlusion is known to be the cause of acute myocardial infarctions even in patients who have only minimal to moderate degrees of coronary arterial stenosis.5,6 These thrombi affect the blood flow by narrowing the lumen, increasing the shear forces and platelet deposition, and are extremely thrombogenic. The platelet glycoprotein IIb/IIIa receptor binds fibrinogen, which promotes the aggregation of platelets-if the IIb/IIIa receptors are inhibited or blocked, platelet aggregation is inhibited, therefore diminishing the risk of vascular occlusion.
In the PRISM-PLUS study, tirofiban alone was not effective, whereas tirofiban plus heparin reduced the composite end points from 17.9% to 12.9% (32% reduction in risk) in seven days and from 32.1% to 27.7% (a 19% reduction in risk) at six months. In this group, the incidence of death or myocardial infarction was therefore reduced significantly at seven days, 30 days, and six months. In the PRISM study, primary end points (a composite of death, myocardial infarction, or refractory angina) proved to be significantly reduced at the end of the 48-hour infusion period, but reduction in these events did not occur to a significant degree at either seven days or at 30 days after the acute myocardial injury. An unanswered question is why, in the PRISM-PLUS study, tirofiban alone was not effective. In fact, it resulted in higher mortality at seven days and appeared to be no better than heparin alone; conversely, it was extremely effective in the PRISM trial.
In contrast to the results of the PRISM and PRISM-PLUS studies, the EPILOG trials reported that patients who received abciximab GP IIb/IIIa blockade demonstrated significantly reduced frequency of measured end points at 24-48 hours and at 30 days after the acute myocardial injury.7,8 In the RESTORE trial, tirofiban protected against early adverse cardiac events but had 24-66% less efficacy at 30 days after the acute injury.9 It would appear that these differences are due to the differing pharmacodynamics of tirofiban and abciximab.
An important question raised by the results of the PRISM and PRISM-PLUS studies revolved around exactly how acute revascularization procedures should be used in association with IIb/IIIa blocking agents. Also, the results of these studies clarify neither the necessary duration of drug therapy nor what combination of drugs produces the best results. The available IIb/IIIa inhibiting agents frequently appear to be ineffective from an outcome point of view as they are currently being administered; however, since there seems to be little question that these agents do have a significant potential for reducing the sequelae of thrombotic events in the coronary arteries, the results of additional well controlled studies that are now in progress should be eagerly anticipated.
References
1. Fuster V, et al. N Engl J Med 1992;326:242-250.
2. Willerson JT, et al. Circulation 1989;80:198-205.
3. Coller BS. Circulation 1995;92:2373-2380.
4. Letkivits J, et al. N Engl J Med 1995;332:1553-1559.
5. Falk E, et al. Circulation 1995;92:657-671.
6. Fuster V, et al. Haemostasis 1996;26 Suppl 4:269-284.
7. The EPIC Investigators. N Engl J Med 1994;330:956-61.
8. The EPILOG Investigators. N Engl J Med 1997;336: 1689-1696.
9. The RESTORE Investigators. Circulation 1997;96: 1445-1453.
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