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(Circulation. 2003;107:1497.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Adjunctive Platelet Glycoprotein IIb/IIIa Receptor Inhibition With Tirofiban Before Primary Angioplasty Improves Angiographic Outcomes

Results of the TIrofiban Given in the Emergency Room before Primary Angioplasty (TIGER-PA) Pilot Trial

David P. Lee, MD; Niall A. Herity, MD; Bonnie L. Hiatt, MD; William F. Fearon, MD; Mehrdad Rezaee, MD; Andrew J. Carter, DO; Michelle Huston, MD; Donald Schreiber, MD; Peter M. DiBattiste, MD; Alan C. Yeung, MD

From Stanford University Medical Center, Divisions of Cardiovascular Medicine (D.P.L., N.A.H., B.L.H., W.F.F., M.R., A.J.C., A.C.Y.) and Emergency Medicine (M.H., D.S.), Stanford, Calif, and Merck Research Laboratories (P.M.D.), Blue Bell, Pa.

Correspondence to Dr David P. Lee, Stanford University Medical Center, Interventional Cardiology, Room H-2103, 300 Pasteur Dr, Stanford, CA 94305. E-mail dplee{at}stanford.edu

	Abstract

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Background— Previous work has suggested that platelet glycoprotein IIb/IIIa receptor blockade may confer benefit in the treatment of acute myocardial infarction. The TIGER-PA pilot trial was a single-center randomized study to evaluate the safety, feasibility, and utility of early tirofiban administration before planned primary angioplasty in patients presenting with acute myocardial infarction.

Methods and Results— A total of 100 patients presenting with acute myocardial infarction were randomized to either early administration of tirofiban in the emergency room or later administration in the catheterization laboratory. The primary outcome measures were initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion ("blush"). Thirty-day major adverse cardiac events were also assessed. Angiographic outcomes demonstrate a significant improvement in initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion when patients are given tirofiban in the emergency room before primary angioplasty. The rate of 30-day major adverse cardiac events suggests that early administration may be beneficial.

Conclusions— This pilot study suggests that early administration of tirofiban improves angiographic outcomes and is safe and feasible in patients undergoing primary angioplasty for acute myocardial infarction.

Key Words: myocardial infarction • angioplasty • platelets

	Introduction

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Improving clinical outcomes in the treatment of acute myocardial infarction (AMI) remains a daunting clinical challenge. Decreasing time to reperfusion¹ and evolutionary breakthroughs in pharmacological and mechanical approaches to reperfusion have improved outcomes over the past 10 years.

Primary angioplasty has been adopted as the preferred initial reperfusion strategy in the treatment of AMI at many institutions. Mechanical reperfusion has shown some advantages over fibrinolytic therapy^2,3 in this setting, and important previous work has correlated initial TIMI grade flow⁴ and thrombus burden⁵ with clinical outcomes. Recent studies in advancing the treatment of AMI include the use of novel coronary stents⁶ and glycoprotein (GP) IIb/IIIa receptor inhibitors in combination with fibrinolytics⁷ or primary angioplasty.^8–13

The timing of the GP IIb/IIIa receptor inhibitor administration may be important in establishing early reperfusion. Earlier administration may yield an improvement in initial angiographic outcomes, which may result in an important clinical benefit.⁴ Tirofiban is a potent synthetic GP IIb/IIIa receptor blocker that has previously been studied in acute coronary syndromes^14–16 and in percutaneous interventions.^17,18 In the present study, we examined 100 patients presenting with AMI who received tirofiban in either the emergency room (ER) before primary angioplasty or in the catheterization laboratory after diagnostic angiography just before primary angioplasty.

	Methods

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All patients were screened per a protocol approved by the Stanford University Institutional Review Board and gave informed consent for the protocol. Patients were deemed eligible for the study if they: (1) had clinical symptoms of AMI with the initial onset of chest pain in the past 12 hours; (2) were deemed to be suitable candidates for percutaneous revascularization; and (3) had an ECG that demonstrated 0.1 mV ST-segment elevation in 2 or more contiguous leads or documented new left bundle-branch block. Important exclusion criteria included cardiogenic shock, use of an intra-aortic balloon pump (IABP), and known bleeding diathesis.

After initial screening and patient consent, open-label randomization was conferred within a 1:1 ratio of "early" administration (ie, in the ER) of tirofiban versus "late" administration in the catheterization laboratory. Computerized randomization assignments in blinded envelopes were used in a consecutive fashion in the ER. The dose of tirofiban was per the Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis (RESTORE) protocol (10 µg/kg over 3 minutes as a bolus, followed by 0.15 µg · kg^-1 · min^-1 x24 hours). The dose of unfractionated heparin administered in the ER was dictated by the time of administration. Early tirofiban administration required a heparin bolus of 70 U/kg followed by 5 U · kg^-1 · h^-1, whereas late administration mandated a 100-U/kg bolus with a maintenance dose of 10 U · kg^-1 · h^-1. Other medications, including ß-blockers, nitrates, and morphine, were administered at the discretion of the attending physician.

Diagnostic angiography was performed in all patients before planned revascularization; per protocol, if there was a 50% lesion in the culprit vessel, no revascularization was performed. Revascularization was performed at the discretion of the attending physician with any US Food and Drug Administration (FDA)–approved coronary revascularization devices. If a coronary stent was placed, clopidogrel (300 mg orally, followed by 75 mg per day for at least 28 days) or ticlopidine (500 mg orally, followed by 250 mg twice per day for at least 28 days) was mandated. An FDA-approved vascular closure device was also allowed per protocol. If no vascular closure device was used, manual compression was performed when the activated clotting time was <180 seconds.

Laboratory screening included an initial complete blood count with platelet count, a serum creatinine, and total creatine phosphokinase (CPK), CPK-MB, and troponin levels. After admission, the complete blood count with platelet count and CPK were repeated every 6 hours and on a daily basis until discharge. A daily and a discharge ECG were also required.

Important recorded time intervals included time from initial onset of chest pain to arrival in the ER, time from initial arrival to tirofiban administration (door to drug), and time from initial arrival to first angioplasty balloon inflation (door to balloon).

Bleeding complications were recorded, and TIMI definitions of minor and major bleeding¹⁹ were used. Platelet counts were also monitored for thrombocytopenia, defined as a platelet count of <100 000/mm³. Post-hospital follow-up included at least one telephone conversation or clinic visit at 30 days documenting any of the clinical adverse events (death, re-MI, or rehospitalization) per the protocol.

Angiographic analysis included initial and final TIMI grade flow,²⁰ corrected TIMI frame count,²¹ and TIMI myocardial perfusion grade²² of the culprit vessel. These were performed off-line and by at least 2 blinded independent observers (N.H. and B.H.) with averaging of the TIMI scores if they were not in agreement.

Statistical analysis was performed with the use of statistical software (StatView 5, SAS Institute Cary, NC,) using a ² analysis or Fisher’s exact test for frequencies comparing the two treatment groups. A result was considered to be significant if the probability value was 0.05.

	Results

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A total of 157 patients were screened for enrollment between July 1999 and December 2001. Of these, 100 patients were enrolled in the study. The majority of excluded patients were excluded because they declined enrollment after screening (32; 38% of those screened but not enrolled). Nine (11%) were excluded after screening because of cardiogenic shock and/or placement of an IABP. The remainder were screened and not enrolled because of significant comorbidities (14; 17%) or recent administration of a GP IIb/IIIa receptor antagonist (2; 2.4%).

Of the 100 patients enrolled, 50 received early tirofiban. There were no significant differences in patient characteristics (Table 1) or in their presentation (Table 2). The mean door-to-balloon time was similar in both groups, with the early treatment group averaging 89±21 minutes and the cath laboratory group 83±20 minutes (P=NS). The early treatment group received tirofiban for an average of 33 minutes (range, 19 to 45 minutes) before angioplasty. Of the 100 patients, 94 (47 in each group) received at least 1 stent after initial angioplasty, with the remaining 6 patients undergoing PTCA alone.

View this table: [in this window] [in a new window]   TABLE 1. Patient Demographics and Presentation

View this table: [in this window] [in a new window]   TABLE 2. Procedural Findings

Angiographic analysis (Table 2) showed a statistically significant difference in initial TIMI grade 3 flow, corrected TIMI frame counts, and TIMI grade 3 myocardial perfusion scores favoring early tirofiban administration. The percentage of patients with initial TIMI grade 3 flow before angioplasty was 32% in the early group and 10% in the late group (P<0.007; Figure 1). Corrected initial TIMI frame counts were significantly lower in the early group (44±20 versus 66±23, P=0.005; Figure 2). Finally, initial TIMI grade 3 myocardial perfusion was seen in 32% of the early patients and 6% of the late patients (P<0.001; Figure 3).

View larger version (35K): [in this window] [in a new window]   Figure 1. Comparison of initial TIMI grade flow. A greater percentage of patients have initial TIMI grade 3 flow (P<0.007) when receiving tirofiban in the emergency room (Early) as compared with receiving tirofiban in the catheterization laboratory (Late).

View larger version (43K): [in this window] [in a new window]   Figure 2. Comparison of initial corrected TIMI frame count. Initial corrected TIMI frame count is lower (P=0.005) in the patients receiving tirofiban in the emergency room (Early) when compared with patients receiving tirofiban in the catheterization laboratory (Late).

View larger version (33K): [in this window] [in a new window]   Figure 3. Comparison of initial TIMI myocardial perfusion grade. The percentage of patients with initial TIMI myocardial perfusion grade 3 is higher (P<0.001) in the patients receiving tirofiban in the emergency room (Early) when compared with patients receiving tirofiban in the catheterization laboratory (Late).

Ninety-two percent of patients in both groups had postprocedural TIMI grade 3 flow. This was also reflected in the corrected TIMI frame counts (18±8 and 16±8, respectively; P=NS), as well as in the percentage of patients with a final TIMI myocardial perfusion grade of 3 (50% versus 40%, respectively; P=NS).

Between the independent observers, there were no differences in estimating TIMI grade flow at the initial and final angiograms in all cases. The corrected TIMI frame count varied <5% between them for all cases, and the TIMI myocardial perfusion grade also had only 2 cases with a difference in score of 1.

The peak CPK was measured in all patients while in the hospital (Table 3). The early treatment group had a mean peak CPK of 1924±1699 IU/L, whereas the late cath laboratory group had a mean of 2260±1959 (P=NS). The mean time to peak CPK was slightly lower in the early group (10.0±7.1 hours) than in the late group (11.7±6.5; P=NS).

View this table: [in this window] [in a new window]   TABLE 3. Complications and Outcomes

No differences were noted between the two groups with regard to bleeding complications (Table 3), although the sample size was too small to detect modest differences in these low-frequency events. TIMI-defined minor and major bleeding was not statistically different, with 5 minor bleeds (10%) in the early group and 3 (6%) in the late group (P=0.47) and 1 major bleed in each group (2%). Five transfusions (10%) were given in the early group and 4 (8%) in the late group. Thrombocytopenia, as defined by a platelet count of <100 000/mm³ after tirofiban administration, was seen in only 2 patients (4%), both in the early administration arm. Neither of these patients had a drop in their platelet counts below 50 000/mm³ (severe thrombocytopenia).

The 30-day clinical outcomes (Table 3) revealed a lower number of clinical adverse events (combined outcome of death, recurrent MI, or rehospitalization) favoring the early treatment group (6% early; 10% late; P=0.47). No significant differences were seen with each individual outcome, with a low death rate (2% in both groups) and low re-MI (0% in the early group and 2% in the late group) and rehospitalization rates (4% and 6%, respectively) favoring the early treatment group. The patient in the late group who had a re-MI was the only patient in the study who underwent target vessel revascularization within the 30-day follow-up.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The benefit of a platelet GP IIb/IIIa receptor inhibitor has been previously shown in a variety of clinical situations, including high-risk angioplasty,^17,23 elective stenting,^24,25 and non–ST-elevation acute coronary syndromes.^14,15,26 Previous work has suggested at least a modest clinical benefit with abciximab^8–12 or eptifibatide¹³ in the setting of AMI and primary angioplasty. With regard to previous trial data in the setting of AMI with the use of tirofiban, 6% of patients in RESTORE underwent primary angioplasty for a diagnosis of AMI and were given tirofiban or placebo in the catheterization laboratory after the lesion was crossed with a guidewire. Although the overall data showed a trend favoring the tirofiban group, no data from this trial have been reported with regard to the subset of patients undergoing percutaneous coronary intervention for AMI.

The angiographic findings of this pilot trial suggest that early administration of tirofiban, ie, in the ER on AMI presentation, significantly improves initial TIMI flow grade, including the percentage of patients with initial TIMI grade 3 flow, corrected frame counts, and myocardial perfusion when compared with administration at the time of the primary angioplasty. This result was seen with 33-minute earlier initiation of platelet GP IIb/IIIa inhibition and with a lower dose of heparin than in the late administration arm, suggesting that tirofiban was the primary agent responsible for the improvement in flow.

Our positive clinical findings are most likely due to the effect of GP IIb/IIIa blockade on prevention of microembolization and further impairment of the coronary microcirculation. This is reflected not only in the improved TIMI flow grade and corrected frame counts but also in the myocardial perfusion grade, which is thought to reflect the functionality of the coronary microvascular circulation.²²

An early pilot trial, ReoPro in acute MI (ReoMI),⁸ in which abciximab was administered in the ER, showed only a 9% TIMI grade 3 flow rate using a weight-based bolus and infusion scheme and a similar lower dose of heparin as used in our study. The mean time from abciximab administration to angiography was also similar to our study. The differences in the TIMI grade 3 flow may be related to the small sample size or possibly the wide range of drug-to-PTCA times (3 to 96 minutes) seen in ReoMI.

Our results are more consistent with the Abciximab before Direct angioplasty and stenting Myocardial Infarction Registering Acute Long-term follow-up (ADMIRAL) trial,¹¹ which found a slightly lower overall TIMI grade 3 flow rate (21%) with abciximab, but this was in the setting of only 26% of AMI patients receiving abciximab in either the ER or ambulance before primary angioplasty. In that trial, a 30-day follow-up angiogram with left ventricular (LV) function was performed, suggesting improved LV ejection fraction and a lower composite event rate of death, reinfarction, or revascularization in those who had received abciximab in combination with primary angioplasty when compared with placebo control. This improved outcome with a greater number of patients with normal TIMI grade flow is consistent with previous findings.⁴ Another study combining abciximab and a percutaneous coronary intervention in the setting of AMI, Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC),¹² also suggested a clinical benefit for abciximab but did not include patients with preintervention administration of the glycoprotein IIb/IIIa receptor inhibitor.

One potential price of earlier administration of tirofiban could be increased bleeding, but in the present trial no significant differences were detected in bleeding rates as defined by TIMI criteria. The rate of minor bleeding in this trial with early administration of tirofiban (10%) or in the overall cohort (8%) is very similar to the minor bleeding rate in ADMIRAL patients receiving abciximab (12.1%). Major bleeding rates were also low in TIGER-PA (2%), with blood transfusions seen in 9% of patients. Thrombocytopenia was also rare in the overall cohort (2%), with no cases of severe thrombocytopenia. These results are consistent with ADMIRAL and other recent elective GP IIb/IIIa receptor inhibitor stenting trials.^24,25

It is interesting to speculate about the potential for further optimizing the dosing of tirofiban in the setting of PCI. Data from the do Tirofiban And ReoPro Give similar Efficacy outcomes Trial (TARGET),¹⁸ in which tirofiban was found to be inferior to abciximab with regard to its primary end point of 30-day major adverse cardiac events in the setting of coronary stenting, has led some investigators to believe that suboptimal dosing of tirofiban was at least partly responsible for the result. Indeed, early inhibition of platelet aggregation using the RESTORE dosing is lower than with the standard abciximab dosing regimen.²⁷ However, Neumann et al²⁸ also studied inhibition of platelet aggregation with all 3 FDA-approved GP IIb/IIIa receptor inhibitors and found that with the dose of tirofiban used in the present trial, similar levels of platelet inhibition were achieved by all 3 agents at time points >2 hours after drug initiation. Interestingly, 6-month major adverse cardiac event results from TARGET suggested no significant difference between the tirofiban- and abciximab-treated groups.²⁹ If a higher dose of tirofiban was used in the ER in this pilot study, there probably would be a greater level of platelet inhibition with a possible improvement in initial TIMI grade 3 flow rates and myocardial perfusion. This, however, could potentially come at the cost of an increase in bleeding events. It is also unknown whether a new, higher dosing scheme³⁰ would necessarily translate into better clinical outcomes, although, at least in theory, earlier reperfusion should lead to less myocardial damage and its sequelae.

The main limitation of this trial is that the study was underpowered to show a significant difference in clinical events, both from an efficacy standpoint and a safety standpoint. It is unknown whether the earlier reperfusion seen in our study would necessarily translate into a better mortality outcome, although previous data with 60- and 90-minute restoration of normal TIMI grade angiographic parameters have shown reduced mortality.^31,32 Further study is required to fully assess the clinical impact of the early initiation strategy tested here. In addition, the exclusion criteria included cardiogenic shock or use of an IABP, which in this report excluded 11% of the initially screened patients. As a result, these data may not apply to those situations in which an IABP is used for cardiogenic shock or to augment coronary perfusion.

At many hospitals, the current mainstay of reperfusion for patients presenting with AMI is primary angioplasty. It has been shown to be superior to fibrinolytic therapy, as long as the door-to-balloon time remains short and an experienced operator is involved.^1,2 The present study suggests that, in centers where primary angioplasty is the preferred reperfusion strategy, the administration of tirofiban in the ER for AMI is safe and feasible while augmenting reperfusion even before reaching the catheterization laboratory. This study was underpowered to show a significant difference in clinical end points, but on the basis of the documented association of TIMI grade 3 flow and myocardial perfusion grade with improved clinical outcomes, it does suggest that earlier initiation of reperfusion with tirofiban in combination with primary angioplasty may translate into improved patient outcomes. Larger investigations with administration of GP IIb/IIIa receptor antagonists in the ER for AMI in combination with primary angioplasty should confirm our findings from this pilot trial and likely show an improved clinical outcome.

	Acknowledgments

 
This work was supported by a grant from Merck & Co.

	Footnotes

 
Drs Lee and Yeung serve on the Speaker’s Bureau of Merck & Co. Dr DiBattiste is employed by Merck & Co.

Received November 14, 2002; revision received December 18, 2002; accepted December 19, 2002.

	References

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