Correspondence
Tirofiban in Unstable Coronary Disease
N Engl J Med 1998; 339:1163-1165October 15, 1998
- Article
To the Editor:
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) and Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) studies (May 21 issue)1,2 left me confused. The studies were conducted almost simultaneously, but they found different results with the use of tirofiban alone, which were not adequately explained by the editorialists.3 There was no effect of tirofiban alone in the PRISM-PLUS study (treatment in this group was in fact stopped early), whereas in the PRISM study tirofiban alone was suggested as a treatment option. Is there an explanation for these differences?
3 ReferencesMeir Liron, M.D.
Tel Aviv Medical Center, Tel Aviv 64239, Israel1
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators
Full Text | Web of Science | Medline2
The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators
Full Text | Web of Science | Medline3
Chesebro JH ,Badimon JJ . Platelet glycoprotein IIb/IIIa receptor blockade in unstable coronary disease. N Engl J Med 1998;338:1539-1541
Full Text | Web of Science | Medline
Author/Editor Response
Dr. Théroux replies:
To the Editor: Combined inhibition of platelets with aspirin and inhibition of thrombin with unfractionated heparin has become standard therapy for the management of unstable angina and non–Q-wave myocardial infarction.1 Platelet glycoprotein IIb/IIIa–receptor antagonists and low-molecular-weight heparins were recently introduced for the treatment of these syndromes.
The interactions between platelets and the coagulation factors are complex. The platelet glycoprotein IIb/IIIa–receptor blockers prevent platelet aggregation by all stimuli, including thrombin, and the platelet thrombus, in turn, serves as a template for the amplification of the coagulation cascade. In the investigation of tirofiban, it was hypothesized that inhibition of platelet aggregation could prevent thrombus formation and decrease the need for the concomitant administration of heparin. In the PRISM trial, tirofiban was directly compared with heparin; the findings suggested that this hypothesis was true and that platelet inhibition alone could prevent early recurrent cardiac ischemic events. The PRISM-PLUS trial was performed in higher-risk patients and showed that a combination of tirofiban and heparin, as well as the application of combination treatment during percutaneous cardiac procedures, was needed to prevent myocardial infarction and for sustained benefit over the six-month period of follow-up. These findings are in agreement with the experimental and clinical evidence of a major role of platelets during short periods of vascular occlusion associated with acute vessel-wall injury and a role of intravascular coagulation during more sustained occlusion that is related to the release of tissue factor from the injured plaque.1 Antiplatelet therapy targets the former and, possibly, also plaque remodeling associated with the release of active products from platelets. Antithrombotic therapy targets the prevention of fibrin-clot formation and propagation of the active thrombogenic plaque. Longer-term control of the underlying disease process, an appropriate goal, as pointed out in the editorial by Drs. Chesebro and Badimon, will probably be achieved by controlling the risk factors that render the plaque unstable and the mechanisms that control the process, with additional support in the form of therapy with an oral antiplatelet agent, an anticoagulant, or combination therapy.1
A new standard for the management of unstable angina and non–Q-wave myocardial infarction has been set with the advent of triple antithrombotic therapy combining aspirin, heparin, and a potent inhibitor of platelet aggregation such as tirofiban. Although the results of the PRISM trial support the central role of platelets, the results of the PRISM-PLUS trial underscore the need for a multifactorial approach for optimal control of a disease with many pathophysiologic mechanisms that culminate in myocardial infarction and death.
1 ReferencesPierre Théroux, M.D.
Montreal Heart Institute, Montreal, QC H1T 1C8, Canada1
Theroux P ,Fuster V . Acute coronary syndromes: unstable angina and non-Q-wave myocardial infarction. Circulation 1998;97:1195-1206
Web of Science | Medline
Author/Editor Response
Dr. White replies:
To the Editor: Dr. Liron asks whether there are inconsistencies in the results of the PRISM and PRISM-PLUS studies, two of the four trials that have involved approximately 18,000 randomized patients with unstable angina to test the efficacy and safety of glycoprotein IIb/IIIa–receptor antagonists.1-4 Overall, these trials show an 11 percent reduction in death or myocardial infarction at 30 days (P<0.01). In the trials in which these drugs were compared with heparin (the PRISM study,1 the dropped treatment group in the PRISM-PLUS study,2 and the Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network study3), death and myocardial infarction were reduced by 8 percent (P=0.37). In the trials in which the drugs were compared with placebo with background use of heparin, death and myocardial infarction were reduced by 12 percent (P=0.01).
The PRISM study used a 48-hour infusion of tirofiban and reported a 20 percent reduction (95 percent confidence interval of the odds reduction, 0.61 to 1.05) in death or myocardial infarction at 30 days as compared with heparin, whereas the PRISM-PLUS study used a 96-hour infusion and reported a 30 percent reduction (95 percent confidence interval, 0.51 to 0.96). The results of these two trials are thus very consistent with the overall results of the combined analysis.
The dropped treatment group in the PRISM-PLUS study used a randomization strategy similar to that of the PRISM trial, but this treatment was discontinued when an increase in mortality was noted at seven days (16 deaths [4.6 percent] with tirofiban, as compared with 4 deaths [1.1 percent] with heparin) after only 345 patients had been assigned to this group. There was no increase in mortality at 30 days or at 6 months (7.2 percent with tirofiban vs. 6.9 percent with heparin), nor was there any consistency with respect to other ischemic end points. Also, 70 percent of the patients who were randomly assigned to receive tirofiban alone had previously been receiving intravenous heparin, which was stopped at randomization. Seven deaths (44 percent) occurred within 24 hours after tirofiban was discontinued, and 10 deaths (62 percent) occurred within 48 hours. Heparin rebound, which increases ischemic events, has been observed up to 150 hours after the cessation of heparin.5 This is thus one possible explanation, along with chance, for the isolated finding of increased mortality at one time point.
Of particular interest in the PRISM study are the 1999 patients who did not undergo interventions and were treated medically. A post hoc analysis of this group showed that tirofiban reduced death and myocardial infarction by 42 percent at 30 days (6.2 percent in the heparin group, as compared with 3.6 percent in the tirofiban group; P<0.01).
Further studies are required to evaluate these agents together with low-molecular-weight heparin and as background therapy in a comparison of invasive and conservative treatment.
5 ReferencesHarvey D. White, D.Sc.
Green Lane Hospital, Auckland 1030, New Zealandfor the PRISM Study Investigators
1
The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators
Full Text | Web of Science | Medline2
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators
Full Text | Web of Science | Medline3
The PARAGON Investigators
Web of Science | Medline4
The PURSUIT Trial Investigators
Full Text | Web of Science | Medline5
Granger CB ,Miller JM ,Bovill EG , et al. Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes. Circulation 1995;91:1929-1935
Web of Science | Medline
Author/Editor Response
Drs. Chesebro and Badimon reply:
To the Editor: Dr. Liron's question cannot be answered with certainty and was not intended to be addressed by the PRISM and PRISM-PLUS trials. The investigators in both trials and the editorialists all offered speculative answers; however, certain points need emphasis and amplification.
Most discrepancies in the outcomes of drug trials are usually explained by differences in the patient populations, trial designs, or both. The patient populations in the PRISM and PRISM-PLUS studies differed greatly with respect to the short-term (30-day) risk of myocardial infarction or death. The presence of ST-segment changes of ≥1 mm on the base-line electrocardiogram conveys a high risk for patients presenting with unstable angina.1 A subgroup analysis of such patients enrolled in recent trials of low-molecular-weight heparin2,3 (and Wallentin L and Cohen M: personal communications) shows that these ST-segment changes were the best single predictor of high risk. In the PRISM study, 39 percent of patients, as compared with over 90 percent in the PRISM-PLUS study, had these base-line ST changes. Consistent with this greater risk was the greater proportion of patients who presented with non–Q-wave myocardial infarction in the PRISM-PLUS study than in the PRISM study (46 percent vs. 25 percent). Thus, it appears that tirofiban plus heparin is needed for these higher-risk patients.
The trial designs differed significantly between the PRISM study (48-hour infusion of heparin or tirofiban; 48-hour primary composite end point; percutaneous revascularization in only 1.9 percent during the first 48 hours) and the PRISM-PLUS study (mean of 71 hours of study-drug infusion including during angiography and coronary procedures; 7-day primary composite end point; 90 percent of patients underwent angiography and only 45 percent of patients received medical therapy alone without revascularization). Likewise, the incidence of composite end points in the PRISM-PLUS study increased greatly in all treatment groups from 48 hours to 7 days, the time at which tirofiban therapy was discontinued (increase in incidence: from 7.5 percent to 17.1 percent in the tirofiban group, from 6.9 percent to 16.9 percent in the heparin group, and from 5.7 percent to 11.6 percent in the tirofiban-plus-heparin group). Most procedures were done between two and seven days, and the procedures appeared to increase event rates in all treatment groups throughout the study.
Thus, with respect to the higher-risk patients in the PRISM-PLUS study and the higher risk associated with the use of angiography and revascularization procedures, more potent antithrombotic therapy with tirofiban plus heparin, for a longer duration, appears to be required.
3 ReferencesJames H. Chesebro, M.D.
Juan J. Badimon, Ph.D.
Mount Sinai Medical Center, New York, NY 10029-65741
Braunwald E, Mark DB, Jones RH, et al. Unstable angina: diagnosis and management. Clinical practice guideline no. 10. Rockville, Md.: Department of Health and Human Services, 1994. (AHCPR publication no. 94-0602.)
2
The FRISC Study Group
Web of Science | Medline3
Cohen M ,Demers C ,Gurfinkel EP , et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447-452
Full Text | Web of Science | Medline
