Impact of Clinical Syndrome Acuity on the Differential Response to 2 Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Coronary Stenting
The TARGET Trial
Background— Although glycoprotein IIb/IIIa inhibitors have been shown to reduce periprocedural and late ischemic events in patients undergoing stent implantation, the relative safety and efficacy of different agents in this class is less established. Also unknown is whether the acuity of the presenting clinical syndrome, which may affect the degree of platelet inhibition required or achieved, influences the response to different antiplatelet agents.
Methods and Results— A prospective, multicenter, double-blind, randomized trial was performed in which 4809 patients undergoing planned stenting were randomized to receive abciximab or tirofiban. In patients with acute coronary syndromes (ACS; n=3025), abciximab resulted in lower rates of myocardial infarction at 30 days (5.8% versus 8.5%; P=0.004) and 6 months (7.2% versus 9.8%; P=0.013), although 6-month mortality rates were identical (1.39% in both groups; P=0.99). Conversely, in patients without ACS (n=1784), myocardial infarction rates were not significantly lower with tirofiban, survival was similar, and target vessel revascularization was reduced, which translated into a trend toward enhanced 6-month event-free survival with tirofiban (89.7% versus 86.6%; P=0.056).
Conclusions— In patients with ACS undergoing stent implantation, abciximab use compared with tirofiban results in greater suppression of periprocedural myonecrosis, although a survival benefit has not been demonstrated. Patients with stable coronary syndromes may have equivalent or better outcomes with tirofiban relative to abciximab, with fewer adverse hematologic and hemorrhagic events. These data raise important issues regarding the relative pharmacodynamic inhibition of platelet function required in varying clinical scenarios and have important implications for the cost-effective utilization of glycoprotein IIb/IIIa inhibitors.
Received March 11, 2002; revision received March 27, 2002; accepted March 27, 2002.
As a class, glycoprotein (GP) IIb/IIIa inhibitors have been shown to reduce the composite occurrence of death, myocardial infarction (MI), and need for target vessel revascularization (TVR) after percutaneous coronary intervention (PCI).1–7⇓⇓⇓⇓⇓⇓ Individually, different GP IIb/IIIa inhibitors vary in the extent and time course of platelet inhibition achieved and in their specificity for the αIIbβ 3 integrin receptor.8–14⇓⇓⇓⇓⇓⇓ Furthermore, because clinical syndromes characterized by plaque rupture and thrombus formation are associated with systemic platelet activation,15–17⇓⇓ a differential response to GP IIb/IIIa inhibitors of varying potency might be anticipated in patients with unstable angina compared with stable ischemic heart disease.
In the TARGET (Do Tirofiban and ReoPro Give Similar Efficacy Outcomes?) Trial, 4809 patients at 149 medical centers in 18 countries were prospectively randomized to receive intravenous abciximab or tirofiban during planned coronary stenting. Compared with tirofiban, abciximab was found to result in greater protection from periprocedural myonecrosis at 30 days.18 Notably, a significant interaction effect was present between GP IIb/IIIa inhibitor assignment and presenting clinical syndrome.18 The purpose of the present report is to explore the potential impact of clinical syndrome acuity on the differential response to abciximab versus tirofiban in patients undergoing coronary stent implantation.
The TARGET protocol and methodology have been previously described.18,19⇓ In brief, patients of any age undergoing PCI were considered for enrollment if all lesions were amenable to stent implantation. Principle exclusion criteria included acute MI, cardiogenic shock or decompensated heart failure, renal insufficiency, thrombocytopenia, and bleeding diathesis. The Human Investigational Review Board at each site approved the protocol, and all patients provided informed written consent.
Randomization and Medications
Patients were randomized in a double-blind, double-dummy design to either tirofiban (10 μg/kg intravenous bolus followed by an infusion of 0.15 μg/kg per minute for 18 to 24 hours) or abciximab (0.25 mg/kg bolus followed by an infusion of 0.125 μg/kg per minute to a maximum of 10 μg/min for 12 hours). All patients received 250 to 500 mg of aspirin within 24 hours of the procedure and 75 to 325 mg daily thereafter. A 300 mg loading dose of clopidogrel was recommended 2 to 6 hours before the procedure, followed by 75 mg daily for 30 days after the procedure. Creatine kinase-MB levels were determined at 6 hours after the procedure, then every 6 hours for 24 hours. Hematologic indices were monitored at 6 and 24 hours after the procedure. Clinical follow-up was performed at 30 days and 6 months.
Definitions, End Points, and Statistical Analysis
The presenting clinical syndrome was categorized as either an acute coronary syndrome (ACS; unstable angina, non–ST-segment elevation MI, or recent but nonacute ST-segment elevation MI) or a non-ACS (stable exertional angina with or without a positive stress test, asymptomatic ischemia with a positive functional study, or other miscellaneous conditions). The primary end point of the study was the composite occurrence of death, MI, or urgent TVR within 30 days. Prespecified secondary clinical end points included the individual components of the primary end point; the rates of death, MI, and any TVR within 6 months; and hematologic and hemorrhagic complications (as defined by the TIMI criteria20). Angiographic success was defined as a diameter stenosis <20% with TIMI-3 flow. MI was defined as creatine kinase-MB elevation to >3× normal on 2 consecutive blood draws within 48 hours of the procedure, or a creatine phosphokinase (CPK)-MB >2× normal if occurring later, or the development of new Q waves. All primary and secondary end point events were adjudicated by an independent committee blinded to treatment allocation after review of original source documentation.
The sample size was chosen based on the assumption that tirofiban would be noninferior to abciximab, as previously described.18,19⇓ Categorical variables were compared by the likelihood ratio χ2 test or Fisher’s exact test. Continuous variables are presented as median (interquartile range) and were compared by one-way ANOVA or the Kruskal-Wallis test. Time-to-event data were analyzed using survival techniques and compared by the log-rank test. The influence of baseline demographic features, angiographic variables, and treatment assignment on 6-month outcomes were evaluated using Cox proportional hazards regression. All analyses were by intention to treat, and all probability values are two-sided. Statistical significance was determined at the P<0.05 level.
Clinical Syndrome Acuity and Outcomes
Of 4809 randomized patients undergoing PCI, 3025 (63%) had an ACS, and stable coronary syndromes were present in 1784 (Figure 1). Compared with patients with non-ACS, patients with ACS were more likely to be female, currently smoking, and have antecedent angina, prior MI, and left ventricular dysfunction (Table 1). Lesions associated with ACS were more frequently thrombotic and more commonly located in bypass grafts. Angiographic success rates, however, were similar in both groups.
Clinical results after intervention appear in Table 2. Compared with patients with stable coronary syndromes, patients with ACS had significantly higher rates of combined death or MI at 30 days and 6 months and TVR at 6 months. By multivariate analysis, the presence of ACS was an independent determinate of 6-month death, MI, or TVR among patients undergoing PCI (odds ratio, 1.4; 95% confidence interval, 1.2 to 1.6; P<0.001).
Impact of GP IIb/IIIa Inhibitor Assignment in ACS Patients
Demographic features(Table 3) and clinical syndrome type (Figure 1) were similar among patients with ACS who were randomized to abciximab versus tirofiban, except that patients assigned to abciximab were slightly older. Lesions in tirofiban-assigned patients were more likely to be located in the left anterior descending coronary artery and less likely to be located in the left circumflex artery. After the procedure, TIMI-3 flow was present in 98.7% versus 98.1% of patients randomized to abciximab versus tirofiban, respectively (P=0.15).
Compared with tirofiban, abciximab use in ACS resulted in fewer periprocedural infarctions due to a reduction in Q-wave and large and small non–Q-wave MI (Figures 2 and 3⇓). Composite death or MI rates at 30 days were higher and the relative benefit of abciximab was greater in patients presenting with recent MI (6.9% with abciximab versus 11.7% with tirofiban; P=0.02) than in those presenting with unstable angina without CPK-MB elevation (6.0% versus 7.9%, respectively; P=0.08). The relative reduction in periprocedural MI rates with abciximab compared with tirofiban was somewhat attenuated, although still significant, in patients pretreated with clopidogrel (Figure 3). Short-term rates of death and repeat TVR were similar with both GP IIb/IIIa inhibitors in patients with ACS. Abciximab use more commonly resulted in thrombocytopenia and mild hemorrhagic complications than did tirofiban, although major hemorrhage and the need for blood product transfusions were not increased (Table 4).
At 6 months after the procedure, MI rates remained lower in patients with ACS who were treated with abciximab rather than tirofiban, although mortality was identical and rates of TVR were similar (Figure 4). Independent correlates of adverse events at 6 months in patients with ACS are shown in Table 5.
Impact of GP IIb/IIIa Inhibitor Assignment in Non-ACS Patients
Baseline characteristics (Table 3) and clinical syndrome type (Figure 1) were similar among patients with stable coronary syndromes randomized to abciximab versus tirofiban. Postprocedure TIMI-3 flow was achieved in 97.3% of patients randomized to both abciximab and tirofiban (P=0.95).
In contrast to the findings in patients with ACS, tirofiban and abciximab resulted in similar rates of periprocedural MI in those with stable coronary syndromes, with the point estimates favoring tirofiban (Figures 2 and 3⇑). Death at 30 days and 6 months was infrequent in patients with non-ACS treated with either GP IIb/IIIa inhibitor. However, TVR within 6 months was required less frequently in tirofiban-assigned non-ACS patients, which resulted in a trend toward enhanced late event-free survival with tirofiban (Figure 4 and Table 5).
Relationship Between Periprocedural Myonecrosis and Mortality
By actuarial analysis, 6-month mortality occurred in 1.0% of patients with periprocedural peak CPK-MB <3× the upper limit of normal, in 0% with peak CPK-MB 3 to 8× the upper limit of normal, and in 8.7% with peak CPK-MB >8× the upper limit of normal (P<0.001). However, of the 51 patients who died by 6 months, only 6 (12%) had periprocedural myonecrosis after PCI.
In this large, prospective, multicenter study in which a broad cross-section of patients undergoing stent implantation was randomized to abciximab or tirofiban, the acuity of the presenting clinical syndrome had the greatest impact on the relative response to these 2 agents in all the subgroups examined (interaction term P= 0.016 for the 30-day primary end point and P=0.006 for death, MI, or any TVR at 6 months).18 This observation raises important issues regarding the relationship between disease processes and the response to pharmacological agents within the same class but with varying pharmacodynamic potencies and properties, and it has potentially important implications for cost-effective medical practice.
Risk Stratification: ACS Versus Non-ACS
Surprisingly, recent studies have found similar rates of adverse events after PCI in patients with stable and unstable angina.2,3⇓ In contrast, in the present study, the presence of ACS was a powerful independent determinate of adverse events, even after differences in baseline variables were controlled for in multivariate analysis. Patients with recent MI were at an even higher risk than those with unstable angina and normal CPK-MB. Thus, identification of optimal strategies to improve outcomes in patients with ACS undergoing PCI is particularly critical. Conversely, applying cost-effective strategies in lower risk patients with non-ACS is desirable as long as outcomes are not compromised.
Impact of GP IIb/IIIa Assignment in ACS
In the present study, despite similar rates of angiographic success, patients with ACS treated with abciximab rather than tirofiban had significantly lower rates of periprocedural MI, with the greatest relative reduction present in the highest risk patients: those with recent MI. Because protection from periprocedural events by GP IIb/IIIa receptor blockade may be dependent on the degree of platelet inhibition achieved,21 the findings of the present study are concordant with recent reports describing lesser early pharmacodynamic potency of tirofiban relative to abciximab with the drug regimens studied in this trial,10,22⇓ a condition that may be exacerbated by GP IIb/IIIa receptor up-regulation in ACS.15–17⇓⇓
A notable dissociation between periprocedural myonecrosis and 6-month mortality was observed in this large trial. Despite the fact that an additional 39 ACS patients treated with tirofiban rather than abciximab developed an MI, the 6-month mortality in these 2 groups was identical; there were 20 deaths after tirofiban versus 20 after abciximab. Although underpowered for mortality, the absence of even a weak trend toward improved survival in ACS patients treated with abciximab was surprising given that prior studies have shown that either any degree of myonecrosis after PCI23 or at least Q-wave or large non–Q-wave infarctions24 do predict subsequent mortality. Although the survival curves might possibly diverge with longer-term follow-up (as in several placebo-controlled trials of abciximab25), the nearly identical mortality in this large trial has persisted to 12 months (unpublished data). Moreover, 88% of the deaths in this trial occurred in patients without large periprocedural MI; these data are similar to the findings from a recently published meta-analysis of the controlled abciximab trials.25 In that study, however, late survival with abciximab was enhanced compared with placebo,25 suggesting a beneficial effect of the nonplatelet properties of abciximab (eg, MAC-1 and vitronectin receptor binding.8,12–14⇓⇓⇓ Tirofiban, however, as a pure antagonist of the αIIbβ3 integrin receptor, has no biological activity beyond the platelet, and thus the near identical survival with these 2 agents in the present study calls into question the clinical relevance of these nonplatelet properties, especially in the face of less myonecrosis with abciximab.
Impact of GP IIb/IIIa Assignment in Non-ACS
In contrast to those with ACS, in the lower risk non-ACS patients, tirofiban use resulted in similar 30-day outcomes as abciximab, less thrombocytopenia, and a reduction in late TVR, resulting in a strong trend for enhanced event-free survival at 6 months with tirofiban relative to abciximab, a benefit that persisted after multivariate analysis. Although these data should be viewed cautiously given the limited number of patients, the post hoc nature of the analysis, and unknown biological basis for decreased TVR rates with tirofiban compared with abciximab, this finding suggests that tirofiban may be an efficacious and safe alternative to abciximab in patients with stable coronary syndromes. Moreover, given the 3- to 4-fold difference in costs between these 2 agents, tirofiban use in this setting is likely to be cost saving, although a formal cost-effectiveness analysis is pending.
Role of Preprocedural Thienopyridine Administration
Recent studies have suggested that, compared with post-PCI initiation, thienopyridine administration before intervention results in improved procedural safety.26–28⇓⇓ The current study confirms and extends this premise; not only was preprocedural clopidogrel associated with lower rates of adverse cardiac events in both ACS and non-ACS patients, such use was of particular benefit in ACS patients treated with tirofiban; the relative reduction in periprocedural MI rates with abciximab compared with tirofiban in ACS patients was attenuated with preprocedural clopidogrel administration. Conversely, stent implantation in ACS patients with tirofiban without pretreatment with clopidogrel was associated with a striking 15.2% periprocedural MI rate. These observations may be explained by clopidogrel-mediated inhibition of stent-induced αIIbβ 3 receptor activation.29 These data also collectively suggest that maximal antiplatelet activity is required in clinical syndromes associated with heightened platelet activation15– 17⇓⇓ and that the variance in pharmacodynamic potency between abciximab and tirofiban with the drug regimens used in the present study might be mitigated by the antiplatelet effects of thienopyridines.
First, although the data were prospectively collected and adjudicated, clinical syndrome acuity was neither predefined nor prespecified for subgroup analysis.18 Nonetheless, the differential effects of abciximab versus tirofiban in acute versus non-acute syndromes are likely to be real given the significant interaction effect in this blinded study and the results of multivariate modeling. Adequately powered prospective studies performed separately in the ACS and non-ACS populations would be required, however, for confirmation. Second, serum troponin levels were not collected in this trial, and thus whether the relative benefit of abciximab versus tirofiban in preventing periprocedural MI in patients with ACS would be greatest in troponin-positive patients (as might be predicted30) cannot be answered. Third, detailed core laboratory angiographic analysis was not performed, and thus it is unknown whether the reduction in myonecrosis with abciximab compared with tirofiban in ACS would be mirrored by improved angiographic outcomes. However TIMI-3 flow rates were similar with both agents, and a recent report suggested that the prevention of most cardiac enzyme rises after stenting by GP IIb/IIIa blockade are angiographically inapparent.31 Furthermore, the lower TVR rates after tirofiban compared with abciximab in non-ACS patients may have been due either to chance or to unmeasured imbalances known to affect restenosis, such as vessel size and lesion length. Finally, the degree of platelet inhibition achieved was not measured, and thus it cannot be stated with certainty whether differences in pharmacodynamic potency between the 2 agents were truly related to the varying suppression of myonecrosis, as hypothesized. This knowledge is critical, because higher doses of tirofiban than used in the present study might theoretically be equipotent to abciximab in limiting ischemic events after stenting, a postulate currently being tested in dose-ranging studies.
With the dosing regimens studied in the present trial, abciximab is more effective than tirofiban at suppressing periprocedural myonecrosis after stent implantation in patients with ACS, although a long-term survival benefit as a result has not been demonstrated. In patients with stable coronary syndromes, tirofiban use results in at least equivalent outcomes compared with abciximab, with less thrombocytopenia and bleeding, and thus may be an attractive alternative, especially when factoring in the cost differential between these agents.
This article originally appeared Online on April 22, 2002 (Circulation. 2002;105:r87– r94).
↵*The study organization and list of contributing investigators for the TARGET trial appear in reference 18.
Drs Stone and Moliterno have received grants and honoraria from Lilly and Merck. Dr Herrmann receives research funding from Merck. Dr D. Cohen has received research grants from Merck and other pharmaceutical companies. Dr E. Cohen has received research grants and honoraria from and sits on advisory boards for Lilly and Merck. Dr M. Cohen has received research grants from the pharmaceutical industry. Kathy Wolski and Dr DiBattiste are employees of Merck. Dr Topol has received research and educational grants from Lilly, Centocor, and Merck.
- ↵The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation. 1997; 96: 1445–1453.
- ↵Madan M, Berkowitz SD, Tcheng JE. Glycoprotein IIb/IIIa integrin blockade. Circulation. 1998; 98: 2629–2635.
- ↵Sweirkosz TA, Kapoor S, Tardiff DC, et al. Does greater platelet inhibition explain abciximab’s superiority in the TARGET trial? Circulation. 2001; 104: II-385.Abstract.
- ↵Scarborough RM, Kleiman NS, Phillips DR. Platelet glycoprotein IIb/IIIa antagonists. Circulation. 1999; 100: 437–444.
- ↵Thompson RD, Wakelin MW, Larbi KY, et al. Divergent effects of platelet-endothelial cell adhesion molecule-1 and B3 integrin blockade on leukocyte transmigration in vivo. J Immunol. 2000; 165: 426–434.
- ↵Rao AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction (TIMI) trial, phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol. 1988; 11: 1–11.
- ↵Steinhubl SR, Talley JD, Braden GA, et al. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study. Circulation. 2001; 103: 2572–2578.
- ↵Kabbani SS, Aggarwal A, Terrien E, et al. Inadequate early inhibition with tirofiban in conventional doses: a potential determinant of suboptimal effects after percutaneous coronary intervention. Circulation. 2001; 104: II-706.Abstract.
- ↵Stone GW, Mehran R, Dangas G, et al. Differential impact on survival of electrocardiographic Q-wave versus enzymatic myocardial infarction after percutaneous intervention: a device-specific analysis of 7147 patients. Circulation. 2001; 104: 642–647.
- ↵Steinhubl SR, Ellis SG, Wolski K, et al. Ticlopidine pretreatment before coronary stenting is associated with sustained decrease in adverse cardiac events: the EPISTENT Trial. Circulation. 2001; 103: 1403–1409.
- ↵Gurbel PA, Malinin AI, Callahan KP, et al. Loading with clopidogrel at the time of coronary artery stenting results in decreased platelet aggregation, GPIIb/IIIa expression and enhanced platelet-leukocyte microparticles formation. Circulation. 2001; 104: II-706.Abstract.