Platelet Receptor Blockade in Unstable Angina
ABSTRACTS & COMMENTARY
Synopsis: Patients had more severe unstable angina than in PRISM. The combination of tirofiban and heparin was effective in prevention of subsequent acute ischemic incidence.
Sources: PRISM and PRISM-PLUS Study Investigators. N Engl J Med 1998;338:1488-1505; 1539-1541.
Over the past four years, the concept of interruption of the common pathway of platelet aggregation with antagonists of the glycoprotein IIb/IIIa receptor has achieved considerable success. Inhibition of this final step of platelet aggregation involves the binding of fibrinogen and von Willbrand factor to the platelet membrane, which prevents cross-linking of fibrinogen molecules with platelets. A variety of compounds are in various phases of testing, and several are now on the market for clinical use (ReoPro, Integrelin, and Aggrastat). Two major trials in acute coronary syndromes have just been reported demonstrating the effectiveness of tirofiban (Aggrastat), a small nonpeptide IIb/IIIa receptor blocker, in patients with unstable angina and non-Q myocardial infarction (NQMI).
The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM), the larger of the two trials, used a 48-hour infusion of tirofiban compared with intravenous heparin in 3232 patients hospitalized with classic unstable angina. This was an international study involving 25 countries, conducted between 1994 and 1996. Approximately one quarter of the cohort evolved an NQMI and remained in the study. Tirofiban was infused for 48 hours and was compared to continuous intravenous heparin. All patients received aspirin; the heparin infusion was adjusted conventionally. Primary end point was a composite of death, myocardial infarction, or refractory ischemia at the end of the 48-hour infusion. Secondary end points included event assessment at seven and 30 days; refractory ischemia required repolarization changes, chest pain, or hemodynamic instability. Patients received conventional medical therapy; the large majority were taking a beta-blocker and nitrates, and almost 50% were on a calcium blocker. Invasive procedures were used infrequently during the initial 48-hour period; however, within the first month, angiography was performed in 62% of the subjects, and approximately 21% underwent PTCA and 17% CABG, with comparable numbers in both cohorts.
The primary end point was decreased by approximately one-third in the tirofiban group; both refractory ischemia and myocardial infarction alone were comparably reduced. By seven days, 10.3% of tirofiban patients vs. 11.2% of heparin patients had reached the composite end point, and at 30 days, 15.9% vs. 17.1% reached the composite end point (not significant for both time intervals). However, death was significantly less common in the tirofiban group at 30 days (2.3% vs 3.6%; P = 0.02). There were no differences in composite end points in a variety of sub-groups, including diabetics, smokers, or the elderly. There was little adverse bleeding, although thrombocytopenia was more common with tirofiban (1.1% vs 0.4%). In conclusion, tirofiban decreased the rate of early ischemic events more than heparin and resulted in a 36% lower 30-day mortality. In patients who did not undergo revascularization, the rate of death from MI was reduced by 42%. The authors believe that the decrease in refractory ischemia presumably translates into a decreased need for subsequent revascularization.
PRISM-PLUS (in Patients Limited by Unstable Signs and Symptoms), another tirofiban trial, had a more complex study design and a smaller cohort. This was a 14-country study conducted from 1994 to 1996 that enrolled 1950 patients with unstable angina or NQMI. Approximately twice as many patients had infarction (45%) compared to PRISM, and, overall, the patients appeared to have more severe ischemia. Eligible subjects were randomized within 12 hours of onset of unstable angina and had to have transient or persistent ST-T abnormalities. The design of PRISM-PLUS was to assess tirofiban infusion alone, tirofiban with heparin, or heparin alone. Double placebos were used. Two tirofiban regimens were used; a lower dose infusion was combined with heparin, whereas the higher dose (comparable to PRISM) was used without heparin. The infusion was continued a minimum of 48 hours and actually lasted more than 70 hours in all groups. Aspirin was given to all patients. Investigators were encouraged to perform angiography only after the initial 48-hour infusion. The primary end point included a composite of death, new myocardial infarction, or refractory ischemia within seven days after randomization. Revascularization for unstable angina was also included in the primary end point if it occurred within the first six months of the study. Secondary end points included all of the individual composite end points at 48 hours and 30 days, as well as outcomes among patients in whom a coronary procedure was performed during initial hospitalization. Investigators were blinded to treatment for six months. Decisions regarding revascularization were based on clinical course and anatomy and were not driven by protocol.
Results show that the baseline characteristics of the three study groups were comparable. The tirofiban alone arm was discontinued prematurely because of an increased mortality at seven days (4.6% in the tirofiban group vs 1.1% in heparin group). Follow-up of these individuals indicated no excess mortality at six months and no increase rate of myocardial infarction at any time interval. Thus, the main PRISM-PLUS trial consisted of a comparison of 797 heparin-treated patients compared to 773 tirofiban plus heparin subjects. The primary composite end point was robustly decreased by the combination therapy vs. heparin alone at seven days, with a 47% decrease in risk of myocardial infarction (P = 0.006), a 30% decrease in refractory ischemia, and a 43% reduction in a composite end point of death or MI. Mortality per se was equivalent at seven days. The primary end point survival curves continued to show a separation over a six-month period. There were no significant interactions for a variety of subgroups; benefits of tirofiban were seen in men and women, old and young.
Individuals who developed refractory ischemia after the first 48 hours had a substantially increased 30-day risk of death or myocardial infarction, with an approximate 50% decrease in this risk with combination therapy. Those subjects who underwent angioplasty within the first month had a more favorable outcome if they received tirofiban rather than heparin, with a substantial reduction in death or myocardial infarction after the procedure. A benefit of combination therapy was also seen in patients who received only medical therapy, representing approximately 50% of both cohorts. There was a 25% reduction in the rate of death and myocardial infarction at 30 days in these individuals. Bleeding was somewhat more common with combination therapy but was not a major problem. The authors conclude that tirofiban in combination with heparin added considerable additional benefits in the treatment of unstable angina by reducing the risk of refractory ischemia, new myocardial infarction, or death by one-third within the first week. The MI decrease was quite robust, although there was no reduction in total mortality. During the initial hospitalization, angioplasty was performed in approximately 30% of the patients. These individuals had a significant benefit with combination therapy, with a 46% reduction in subsequent ischemic events following PTCA and a 43% reduction in the composite end point of death or myocardial infarction.
Thus, it appears that tirofiban was useful in reducing the risk of procedures. The authors conclude that their patients had more severe unstable angina than in PRISM and that the combination of tirofiban and heparin was effective in prevention of subsequent acute ischemic incidence. The unexpected finding of an increased mortality with tirofiban alone was viewed most likely due to chance, in that other clinical end points were not increased in the tirofiban alone group, and that in the larger cohort of the PRISM trial, tirofiban, when compared to heparin, produced a significant reduction in the composite primary end points (see above). The authors conclude, "It seems reasonable that tirofiban be given along with heparin and aspirin to patients with unstable angina."
COMMENT BY JONATHAN ABRAMS, MD
The concept of platelet receptor blockade with IIb/IIIa agents appears to be a major advance in cardiovascular medicine. There are now a number of trials that document a reduction in recurrent ischemia, need for revascularization, and safety of revascularization when these agents are used. The database that already exists primarily involves individuals undergoing interventional procedures who are high risk and/or who have unstable angina. PRISM and PRISM-PLUS extends these observations to the important acute ischemia groups of unstable angina and NQMI. Recent but mostly unpublished data suggests that these agents may be beneficial when used in conjunction with thrombolytic agents or direct PTCA for acute myocardial infarction (TIMI-14, RAPPAPORT, EPISTENT), although they do not appear to be effective in the absence of thrombolytic therapy.
The role of platelet activation in the setting of plaque fissuring or rupture, with activation of the thrombotic cascade, is well known and is consistent with the variety of animal and clinical observations that have been widely emphasized over the past few years. There are many IIb/IIIa agents in various stages of development, some of which have reached the marketplace. At this point, only intravenous compounds are available, although oral IIb/IIIa blockade should be available to clinicians in the near future. Extension of infusion rates, dose ranging, comparisons of one agent to another, and the combination use of intravenous as well as oral receptor blockers, are important issues awaiting future investigation. It appears likely that platelet receptor blockade will become part of standard therapy for acute ischemic syndromes. PRISM and PRISM-PLUS clearly indicate such a benefit, at least in conjunction with heparin. The issue of tirofiban alone in the smaller cohort by PRISM-PLUS inducing an increased mortality remains unresolved; heparin rebound or excessive thrombosis burden have been suggested as possible factors.
In a useful accompanying editorial by Chesebro and Badimon, the basic pathophysiology and the mechanisms by which the IIb/IIIa blockers act are reviewed. These investigators suggest that the increased death rate in PRISM-PLUS in the tirofiban-alone subjects may be due to chance but could also be that PRISM-PLUS patients were at higher risk than PRISM (90% had ST-T segment changes vs 40% in PRISM) and, thus, may have had greater thrombin generation requiring a higher degree of glycoprotein IIb/IIIa blockade. They suggest that a longer duration of infusion and the abstinence from early procedures may be an important feature of enhancing the benefit of these agents and improving clinical outcomes. This interesting suggestion is underscored by the observation in PRISM PLUS that those individuals who underwent revascularization had high event rates, which were reduced when randomized to combination therapy.
At the present time, one may conclude that glycoprotein IIb/IIIa receptor blockade is here to stay. The use of these drugs should increase dramatically over the next several years as more agents become available and we learn more about how to use them effectively. In addition to aspirin and heparin, platelet receptor blockades will rapidly become integrated into clinical practices in treating patients with acute ischemic syndromes or who undergo high-risk percutaneous interventions.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content