teaser
A re-examination of tirofiban based on pharmacological mechanistic review sheds new light on its use in percutaneous intervention, given that it is dosed correctly to provide effective platelet inhibition
Radwane Kesserwane
Jeffrey M Sparling
Jorge F Saucedo
The Hospital Corporation of Copenhagen Denmark
The platelet membrane glycoproteins are integrins ([alpha] and [beta] subunits) that arefound on virtually all cells.[1] The glycoprotein IIb/IIIa, an integrin ([alpha]IIb/[beta]3 dimer) present on platelet surfaces, is a receptor for fibrinogen, fibronectin, vitronectin, von Willebrand factor and thrombospondin. It mediates aggregation and adhesion and participates in the spreading of platelet aggregates. The GpIIb/IIIa receptor inhibitors are antiplatelet drugs that have undergone extensive evaluation in randomised controlled clinical trials. There are three GpIIb/IIIa inhibitors commercially available today: abciximab (ReoPro), eptifibatide (Integrilin) and tirofiban (Aggrastat). Abciximab is a chimeric fragment of a monoclonal antibody to the GpIIb/IIIa receptor and is relatively nonspecific in its binding, as it also binds to other integrins. The other agents, which are smaller molecules, are specific for the GpIIb/IIIa receptor; eptifibatide, a peptide inhibitor; and tirofiban, a nonpeptide inhibitor. This review will focus on the use of tirofiban in acute coronary syndrome (ACS) and the more recent data in percutaneous coronary intervention (PCI).
Tirofiban in unstable angina and non-ST elevation myocardial infarction
Tirofiban was originally studied as an adjunctive medication in the setting of unstable angina and non-ST elevation myocardial infarction. It has traditionally been administered as a 0.4mcg/kg bolus followed by 0.1mcg/kg/min. PRISM[2] was a randomised trial of over 3,000 patients presenting with ACS without ST elevation. All patients received aspirin and were randomised to either heparin or tirofiban for 48 hours. The primary endpoint was a composite of death, MI and refractory ischemia at 48 hours. There was a 32% reduction in events at 48 hours in the tirofiban group (3.8% vs 5.9%; p=0.007), although the benefits were not significant at 30 days.
Less than 2% of patients underwent PCI at 48 hours in this trial. PRISM-PLUS [3] initially evaluated 1,570 patients with unstable angina or non-ST elevation myocardial infarction and randomised them into three arms: tirofiban (0.6mcg/kg/min for 30 minutes, followed by an infusion of 0.15mcg/kg/min) plus placebo heparin; tirofiban (0.4mcg/kg/min for 30 minutes, followed by an infusion of 0.1mcg/kg/min) plus adjusted-dose heparin; or adjusted-dose heparin plus placebo tirofiban.
PCI was discouraged during the initial 48 hours of the study unless necessitated by refractory ischemia or MI. The primary study endpoint was a composite of death, MI or refractory ischemia at 7 days. The tirofiban group was discontinued early because of increased mortality at 7 days. There was a 34% reduction in events in the tirofiban plus heparin group compared with those treated with only heparin (12.9% vs 17.9%, p=0.004). These benefits were sustained at 30 days. This discrepancy between these two parallel trials, one showing a benefit of tirofiban alone over heparin (PRISM), and the other exhibiting contrary findings with regard to tirofiban as monotherapy (PRISM-PLUS), has been attributed to the fact that PRISM-PLUS had a much higher-risk population.[4]
Almost twice as many patients in PRISM-PLUS presented with non-ST elevation MI. The design of the two trials also differed significantly; in PRISM-PLUS, virtually all patients (89.8%) underwent coronary angiography and a significant number (30.5%) underwent PCI, in direct contrast to the population in PRISM.
Tirofiban and percutaneous coronary intervention during ACS
The seeming discrepancy noted regarding the use of tirofiban in revascularisation and its proven effectiveness as a medical treatment for ACS prompted further evaluation of tirofiban as an adjunctive medication during percutaneous coronary intervention (PCI). The RESTORE trial[5] evaluated tirofiban in 2,139 patients undergoing PCI for unstable angina or acute MI. Patients were randomised to receive tirofiban and heparin for 36 hours versus placebo. The periprocedural administration of a 10mcg/kg bolus regimen of tirofiban did not significantly reduce the composite of death, MI, repeat PTCA, CABG or stent for abrupt closure as compared with placebo in patients undergoing PTCA.
This result was possibly due to an inadequate early platelet inhibition of tirofiban on the RESTORE regimen in the trial. In the randomised comparison of platelet inhibition with abciximab, tirofiban and eptifibatide during PCI in the ACS (Comparison Of Measurements of Platelet aggregation with Aggrastat, Reopro, and Eptifibatide [COMPARE] trial[6]), platelet aggregation 15 and 30 min after drug infusion was significantly less inhibited with the tirofiban-RESTORE dose compared with abciximab and eptifibatide and, at 30 min, compared with the tirofiban–PRISM-PLUS regimen.
TARGET[7] was a double-blind study of 4,809 patients randomly assigned to either tirofiban or abciximab before undergoing angiography. Tirofiban was administered as a bolus dose of 10mcg/kg, followed by an infusion of 0.15mcg/kg/min for 18–24 hours. Abciximab was given as a bolus dose of 0.25mg/kg, followed by an infusion of 0.125mcg/kg/min (maximum 10mcg/min) for 12 hours.
The incidence of the primary endpoint was 7.6% in the tirofiban group and 6.0% in the abciximab group. Although the study was designed as a non-inferiority trial, abciximab was shown to be superior to tirofiban in patients undergoing PCI. This effect was noted to occur very early on (within the first two days). The greatest difference between the two treatments was observed in the percent of patients with MI.
This study raised the question of subtherapeutic dosage of tirofiban and triggered studies that attempted to determine whether the difference observed in TARGET reflected suboptimal inhibition of platelet aggregation during the first two hours after initiation of treatment with tirofiban. Kabani et al[8] demonstrated that the maximum inhibition of platelet aggregation was greater 15 to 60 minutes after onset of treatment with abciximab than with tirofiban when aggregation was induced by 20 μM adenosine diphosphate (abciximab 0.25mg/kg bolus followed by an 12-hour infusion of 0.125mcg/kg/min) or tirofiban (10mcg/kg bolus followed by 0.15mcg/kg/min for 18–24 hours).
The average inhibition of maximal aggregation ranged from 90% to 94% from 15 to 45 minutes after initiation of treatment with abciximab and from 61% to 66% after initiation of tirofiban (p<0.001 at 15, 30 and 45 minutes). The lower incidence of the combined endpoint in the abciximab arm compared with tirofiban was driven by a decreased incidence of periprocedural myocardial infarction. Probably this was secondary to suboptimal inhibition by tirofiban and maximal inhibition given by abciximab. This occurred prior to 12 hours and maximised by 24 hours post-PCI.[8]
High-dose bolus dosing
Following TARGET, investigators became interested in re-examining the bolus dosing of tirofiban, hypothesising that the initial dosing strategy used in TARGET might not reflect the dose needed for optimal platelet inhibition. The Danzi–High Risk PCI[9] trial attempted to determine the effect of early PCI using a high bolus dose (HDB) tirofiban regimen on clinical outcome in patients with non-ST elevation ACS.
A number of 140 consecutive patients with unstable acute coronary syndrome who underwent an immediate percutaneous coronary intervention with the administration of a high (25mcg/kg) dose bolus of tirofiban followed by an 18-hour infusion of 0.15mcg/ kg/min were compared with a matched control group of 162 patients treated with abciximab. In this study population, the beneficial effect of the HDB tirofiban regimen was similar to that of abciximab. These results suggest that HDB tirofiban is equivalent to abciximab in high-risk PCI patients, a direct refutation to TARGET.
ADVANCE[10] enrolled a total of 202 patients undergoing high-risk PCI pretreated with thienopyridines, consecutively randomising them to HDB tirofiban (25 mcg/kg/3 min followed by infusion of 0.15mcg/kg/min for 24–48 hours) or placebo immediately before the procedure. Subjects were then followed for 185 days for the occurrence of the primary composite endpoint of death, myocardial infarction, target vessel revascularization (TVR) and bailout use of glycoprotein GpIIb/
IIIa inhibitors. The cumulative incidence of the primary endpoint was 35% and 20% in the placebo and HDB tirofiban groups (p=0.01). HDB tirofiban plus heparin significantly reduced MACE in high-risk ACS patients undergoing PCI as compared with heparin alone without increasing complications.
The EVEREST trial[11] was designed to compare HDB tirofiban with abciximab administered immediately prior to intervention. The investigators also wanted to study “upstream” tirofiban use, hypothesising that early administration of tirofiban would result in improved tissue perfusion. A total of 93 patients with high-risk NSTEMI were randomised to one of three regimens: tirofiban administered “upstream” (in the coronary care unit) at the traditional dosing levels used in PRISM; HDB tirofiban (25mcg/kg bolus for 3 min followed by 0.15mcg/kg/min infusion) initiated at the time of intervention; or abciximab at the time of intervention. Upstream tirofiban was significantly better than in-lab abciximab. Upstream tirofiban was also noted to be significantly better than both in-lab HDB tirofiban and in-lab abciximab with regard to reducing peak cardiac troponin I levels post-PCI.
Tirofiban and ST-elevation myocardial infarction
Given the previous positive experience with HDB tirofiban in the setting of PCI, a number of trials studied the effect of HDB tirofiban with or without subsequent infusion in patients with STEMI.
STRATEGY[12] was a prospective, single-blind, randomised controlled study of 175 patients comparing HDB tirofiban plus drug-eluting stent with abciximab plus bare-metal stent in the setting of STEMI. HDB tirofiban plus DES significantly reduced major cardiac and cerebrovascular events as compared with abciximab plus BMS, as followed through 8 months. There were no differences between the two groups with regard to bleeding events.
In the Danzi–Primary PCI trial,[13] 100 patients who underwent primary coronary angioplasty for STEMI were randomised to receive a standard dose of abciximab or HDB tirofiban. HDB tirofiban and abciximab had similar effect on recovery of LV function as well as on TIMI flow grade and myocardial perfusion. HDB tirofiban and abciximab had similar safety profiles.
The MULTISTRATEGY trial[14] randomised patients with STEMI or new left bundle branch block to abciximab with uncoated stent versus tirofiban with a sirolimus-coated stent. In patients with STEMI being managed with primary PCI, HDB tirofiban was shown to be non-inferior to abciximab in its effect on ST-segment resolution 90 minutes postprocedure. At 30 days
and at 8 months, rates of MACE were similar between the HDB tirofiban and abciximab groups, independent of the use of SES or BMS.
On-TIME 2[15] was designed to test the safety of HDB tirofiban in the prehospital setting. A double-blind, randomised, placebo-controlled trial in 24 centres in Europe, 984 patients with STEMI who were candidates to undergo PCI were randomly assigned to either HDB tirofiban or placebo in addition to aspirin, heparin and clopidogrel (600mg). Prehospital administration of HDB tirofiban, in conjunction with adjunctive antithrombotic therapy, was shown to be a safe and effective management strategy for patients with STEMI undergoing primary PCI, resulting in a significantly greater percentage of patients with ST-segment resolution at 60 minutes. Bailout use of tirofiban was encountered significantly less frequently in patients receiving prehospital administration of HDB tirofiban. The addition of prehospital administration of HDB tirofiban also resulted in a significantly lower incidence of abrupt closure as measured by TIMI flow post-PCI.
Conclusion
Despite the theoretical class advantages of platelet IIb/ IIIa inhibition, trial data indicate that not all IIb/IIIa inhibitors are similarly effective. This is no more evident than via a historical examination of tirofiban, which initially was dismissed as an adjunctive medication during PCI despite its validated advantages in the medical management of ACS. However, a re-examination of tirofiban based on pharmacological mechanistic review sheds new light on its use in percutaneous intervention, given that it is dosed correctly to provide effective platelet inhibition. In this setting, it has proven therapeutic advantage and should be considered for routine use.
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