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J Am Coll Cardiol, 2006; 47:522-528, doi:10.1016/j.jacc.2005.11.012 (Published online 13 January 2006).
© 2006 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: PLATELET INHIBITION

Randomized Comparison of Upstream Tirofiban Versus Downstream High Bolus Dose Tirofiban or Abciximab on Tissue-Level Perfusion and Troponin Release in High-Risk Acute Coronary Syndromes Treated With Percutaneous Coronary Interventions

The EVEREST Trial

Leonardo Bolognese, MD, FESC*, Giovanni Falsini, MD, Francesco Liistro, MD, Paolo Angioli, MD, Kenneth Ducci, MD, Tamara Taddei, MD, Roberto Tarducci, MD, Franco Cosmi, MD, Silvia Baldassarre, MD and Antonio Burali, MD

Azienda Ospedaliera Arezzo, Arezzo, Italy.

Manuscript received November 26, 2004; revised manuscript received January 26, 2005, accepted February 8, 2005.

* Reprint requests and correspondence: Dr. Leonardo Bolognese, Department of Cardiovascular Diseases, Azienda Ospedaliera Arezzo Via P. Nenni n. 22, 52100 Arezzo, Italy. (Email: leonardobolognese{at}hotmail.com).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We aimed to compare the effects of upstream tirofiban versus downstream high-dose bolus (HDB) tirofiban and abciximab on tissue level perfusion and troponin I release in high-risk non–ST-segment elevation acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI).

BACKGROUND: Optimal timing and dosage of glycoprotein IIb/IIIa inhibitors for ACS remain to be explored.

METHODS: We randomized 93 high-risk ACS patients undergoing PCI to receive upstream (in the coronary care unit) tirofiban, downstream (just prior to PCI) HDB tirofiban, and downstream abciximab. We evaluated the effects of the three drug regimens on tissue-level perfusion using the corrected Thrombolysis In Myocardial Infarction (TIMI) frame count, the TIMI myocardial perfusion grade (TMPG), and intracoronary myocardial contrast echocardiography (MCE) before and immediately after PCI and after cardiac troponin I (cTnI).

RESULTS: The TMPG 0/1 perfusion was significantly less frequent with upstream tirofiban compared with HDB tirofiban and abciximab both before (28.1% vs. 66.7% vs. 71%, respectively; p = 0.0009) and after PCI (6.2% vs. 20% vs. 35.5%, respectively; p = 0.015). Upstream tirofiban was also associated with a significantly higher MCE score index (0.88 ± 0.18 vs. 0.77 ± 0.32 vs. 0.71 ± 0.30, respectively; p < 0.05). Post-procedural cTnI elevation was significantly less frequent among patients in the upstream tirofiban group compared with the HDB tirofiban and abciximab groups (9.4% vs. 30% vs. 38.7%, respectively; p = 0.018). The cTnI levels after PCI were significantly lower with upstream tirofiban compared with HDB tirofiban (3.8 ± 4.1 vs. 7.2 ± 12; p = 0.015) and abciximab (3.8 ± 4.1 vs. 9 ± 13.8; p = 0.0002)

CONCLUSIONS: Among high-risk non–ST-segment-elevation ACS patients treated with an early invasive strategy, upstream tirofiban is associated with improved tissue-level perfusion and attenuated myocardial damage.

Abbreviations and Acronyms
  ACS = acute coronary syndrome
  CAD = coronary artery disease
  CCU = coronary care unit
  cTFC = corrected TIMI frame count
  cTnI = cardiac troponin I
  GP = glycoprotein
  HDB = high-dose bolus
  MCE = myocardial contrast echocardiography
  NSTE-ACS = non–ST-segment-elevation acute coronary syndrome
  PCI = percutaneous coronary intervention
  TACTICS-TIMI 18 = Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18
  TIMI = Thrombolysis In Myocardial Infarction
  TMPG = TIMI myocardial perfusion grade

The most recent guidelines for the management of patients presenting with a non–ST-segment-elevation acute coronary syndrome (NSTE-ACS) strongly recommend the use of glycoprotein (GP) IIb/IIIa receptor antagonists for high-risk patients when percutaneous coronary intervention (PCI) is planned (1,2). Although several randomized trials with different GP IIb/IIIa antagonists have convincingly demonstrated the usefulness of this therapeutic strategy, a number of lingering unsolved issues concerning which agent should be used and the most appropriate timing and dosage remain to be explored. Patients with ACS may have decreased response to antiplatelet agents (3), and tirofiban may be less effective than abciximab within 60 min after administration (4). Recently, Schneider et al. (5) have identified a tirofiban bolus of 25 µg/kg (followed by maintenance infusion of 0.15 µg/kg/min) that achieves inhibition of platelet aggregation >85% through 60 min. Preliminary reports have documented safety and efficacy of this dose regimen in patients undergoing elective or high-risk PCI (6,7). The role of this regimen in high-risk patients with NSTE-ACS remains to be established. Furthermore, there is uncertainty about whether GP IIb/IIIa inhibitors should be given just before PCI if an early (within 48 h) invasive strategy is planned in this setting.

We sought to compare the effects of upstream tirofiban versus downstream high-dose bolus (HDB) tirofiban or abciximab on epicardial and tissue-level perfusion and cardiac troponin I (cTnI) release in high-risk NSTE-ACS treated with PCI. We hypothesized that patients who were treated with upstream tirofiban regimen would have a better tissue-level perfusion and reduced cTnI release after interventions than patients who were treated with downstream HDB tirofiban or abciximab. We also hypothesized that no significant difference would be found between the downstream HDB tirofiban and abciximab regimens.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patients and study protocol.   Between September 2003 and July 2004, 93 patients were enrolled in a single-center open-label randomized study. Patients were selected from 161 patients consecutively referred to our coronary care unit (CCU) for angina at rest. Patients were considered eligible for the enrolment if they fulfilled all of the following criteria: 1) angina at rest lasting >10 min within 12 h of hospital admission; 2) unequivocal changes on ECG during angina; and 3) cTnI elevation. No upper age limit was used. All patients were required to undergo coronary angiography within 24 to 48 h of admission, with revascularization with PCI as appropriate. Exclusion criteria were: 1) inability to provide informed consent; 2) any relative or absolute contraindication to platelet GP IIb/IIIa inhibition; 3) concomitant noncardiac life-threatening disease; 4) severe hemodynamic impairment or cardiogenic shock; and 5) significant other cardiac disease.

Patients were randomized to the three following treatment arms: CCU (upstream) tirofiban administration as a bolus dose of 0.4 µg/kg/min for a period of 30 min, followed by an infusion of 0.10 µg/kg/min up to 12 h after PCI; "in-cath lab" (downstream) high-dose bolus (HDB) tirofiban of 25 µg/kg per 3 min, 10 min before PCI, followed by an infusion of 0.15 µg/kg/min for 12 h; and "in-cath lab" (downstream) abciximab bolus of 0.25 mg/kg 10 min before PCI, followed by 0.125 µg/kg for 12 h to a maximum of 10 µg/min. Of the 161 patients initially selected for the study, 131 were randomized, but 28 were excluded at the time of coronary angiography because of three-vessel coronary artery disease (CAD) requiring coronary artery bypass grafting (10 in the upstream tirofiban group, 9 in the HDB tirofiban group, and 9 in the abciximab group) and 10 for the absence of significant CAD at the angiogram or lesions not suitable for PCI (3 in the upstream tirofiban group, 3 in the HDB tirofiban group, and 4 in the abciximab group). Even if not enrolled in the study, these patients were entered into a registry and followed up for cardiac events and bleeding complications for at least 30 days. Thus, 93 patients (70 men, 23 women; mean age 64.8 ± 11.2 years; range 35 to 83 years) represent the final study group.

All patients underwent PCI within 24 to 48 h of admission. Angiographic markers of epicardial flow and tissue-level perfusion were assessed on completion of diagnostic coronary angiography and shortly after PCI. Intracoronary myocardial contrast echocardiography (MCE) was performed on completion of PCI. Blood samples for cTnI levels were obtained on admission and every 6 h thereafter up to 48 h and at 6, 12, 18, and 24 h after PCI.

The study protocol was approved by the hospital’s ethics committee, and written informed consent was obtained from all patients before catheterization.

Troponin testing.   cTnI was measured using the commercially available Dimension RxL immunoassay (Dade-Behring Ltd., Milton Keynes, United Kingdom). The manufacturer reports the minimum detectable concentration as 0.01 ng/ml. The total imprecision determined in the laboratory was characterized by a coefficient of variation of 10% at 0.05 ng/ml. The threshold used to define a positive cTnI was 0.1 ng/ml. A post-procedural elevation in cTnI was defined as an increase by ≥50% above the highest preprocedural value in at least one of the post-procedural samples.

PCI, concomitant drugs, and angiographic analysis.   Coronary angioplasty and stent implantation were performed according to institutional standards. All patients received aspirin (100 to 300 mg) before and after PCI. Ticlopidine (500 mg) or clopidogrel (300 mg loading dose, followed by 75 mg/day) was administered before PCI and daily thereafter for at least 30 days.

All coronary angiograms were evaluated by two readers without knowledge of clinical status and treatment modality. Flow in the epicardial arteries was assessed for Thrombolysis In Myocardial Infarction (TIMI) flow grade and corrected TIMI frame count (cTFC) by use of previously described methods (8,9). The TIMI myocardial perfusion grade (TMPG) was used to assess myocardial tissue-level perfusion (10). A "closed" microvasculature was defined as either TMPG 0 or 1, with TMPG 2 or 3 representative of an "open" microvasculature (10). TMPG was assessed only in the area supplied by the culprit vessel.

Myocardial contrast echocardiography.   Intracoronary MCE was performed on completion of coronary angioplasty. A score of 1 within a segment of the area of interest after angioplasty was interpreted as adequate perfusion. A patient was considered to have adequate perfusion if ≥50% of the segments in the area of interest had a homogeneous contrast effect (score = 1). In each patient, an MCE score index was derived. Details pertaining to acquisition and analyses of echocardiographic data are available elsewhere (11).

Bleeding complications.   Major bleeding was defined as a fall in hemoglobin of ≥2.0 mmol/l and the need for transfusion of ≥2 U of blood, corrective groin surgery, or both, or as bleeding that resulted in documented intracranial, gastrointestinal, or retroperitoneal hemorrhage. Minor bleeding was defined as a fall in hemoglobin of ≤2.0 mmol/l without the need for a transfusion (12).

Statistical analysis.   The primary end point of the study was the difference in the TMPG before PCI. Assuming a 40% lower TMPG 0/1 rate in the upstream tirofiban group compared with HDB tirofiban and abciximab groups, we estimated that 90 patients would provide ≥80% statistical power (1 – ß ≥0.80; {alpha} = 0.05) to detect such difference. The secondary end points were evaluations of TIMI grade flow, cTFC, and TMPG before and after PCI, and MCE contrast enhancement and cTnI release after PCI in the three groups. Continuous data are expressed as mean values ± SD. Analysis of variance was used to compare continuous variables and Fisher exact tests for categorical variables.

A value of p < 0.05 was considered statistically significant. Statistical analyses were performed with SPSS 8.0 for Windows (SPSS Inc., Chicago, Illinois).


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
In the 131 randomized patients, drug infusion was discontinued in advance in 4 patients in the upstream tirofiban, in 1 in the HDB tirofiban, and in 3 in the abciximab group, mainly for groin hematoma. Minor bleeding was observed in 5, 4, and 5 patients, respectively. Major bleeding due to gastrointestinal hemorrhage occurred in 1 patient (abciximab group). Of note, of the 13 patients randomized to upstream tirofiban but not enrolled to the study, 2 had just minor bleeding; no major bleeding was observed in the 10 patients who required urgent CABG.

Clinical characteristics of the 93 patients enrolled in the study stratified according to the treatment modality are summarized in Table 1. The incidence of diabetes mellitus was significantly higher in the upstream tirofiban group than in the other two groups. No other statistically significant differences in the baseline distribution of clinical and demographic characteristics between groups were found. Overall, 69 patients received clopidogrel; no significant difference was observed in the clopidogrel usage between groups (78% in the upstream tirofiban, 77% in the downstream HDB tirofiban, and 68% in the downstream abciximab group).


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  		Table 1. Baseline Clinical Characteristics
 
Angiographic findings and treatment modality.   Overall, 47 patients (50%) had a TIMI flow grade of 0 to 2, and 51 (55%) had a closed microvasculature as assessed by TMPG (0/1) before PCI. All patients underwent successful PCI with a TIMI flow grade of 3 after the procedure. Of the 51 patients with TMPG 0/1 before PCI, 32 had a TMPG of 2/3 after PCI. No patient with an open microvasculature before PCI (TMPG 2/3) had a closed microvasculature after PCI (TMPG 0/1). No significant difference in TMPG 2/3 perfusion was observed between clopidogrel and ticlopidine treatment both before and after PCI (46% vs. 44% before PCI, and 78% vs. 84% after PCI, respectively; p = NS).

There was no significant difference in the distribution of the culprit lesion, the frequency of angiographic thrombus, the angiographic morphology of the culprit lesion, the extent of CAD, and pre- and post-PCI TIMI grade flow, cTFC, and {Delta}cTFC between groups (Table 2).


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  		Table 2. Angiographic Characteristics
 
Before PCI, TMPG 0/1 perfusion was significantly less frequent with upstream tirofiban than with HDB tirofiban and abciximab (28.1% vs. 66.7% vs. 71%, respectively; p = 0.0009 by Fisher exact test) (Fig. 1A). Also after PCI, TMPG 0/1 perfusion was observed less frequently with upstream tirofiban compared with HDB tirofiban and abciximab (6.2% vs. 20% vs. 35.5%, respectively; p = 0.015) (Fig. 1B). No significant difference was found in terms of pre- and post-PCI TMPG perfusion between the HDB tirofiban and abciximab regimens.


Figure 1
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  		Figure 1 Rate of Thrombolysis In Myocardial Infarction myocardial perfusion grade (TMPG) 0/1 flow stratified by glycoprotein IIb/IIIa inhibitor treatment pre-percutaneous coronary intervention (PCI) (A) and post-PCI (B). p = 0.0009 by Fisher exact test upstream tirofiban vs. high-dose bolus (HDB) vs. abciximab before PCI. p = 0.015 by Fisher exact test upstream tirofiban vs. HDB vs. abciximab after PCI.

 
Perfusion by MCE and treatment modality.   Intracoronary MCE analysis was performed in 83 patients (26 of the upstream tirofiban, 28 of the HDB tirofiban, and 29 of the abciximab group), because 10 were excluded owing to inadequate image quality. Intracoronary MCE was evaluated in a total of 249 segments; of these, 178 (71.5%) showed homogeneous contrast effect (score = 1). A trend toward a higher number of perfused segments (score = 1) was observed with upstream tirofiban compared with HDB tirofiban and abciximab, but it did not reach a statistical significance (78.2% vs. 70.2% vs 66.7%; p = 0.6). MCE score index was significantly higher with upstream tirofiban than with HDB tirofiban and abciximab (0.87 ± 0.19 vs. 0.77 ± 0.32 vs. 0.71 ± 0.35, respectively; p < 0.05 by analysis of variance [ANOVA]) (Fig. 2A). Analysis by patient showed that patients treated with the upstream tirofiban more frequently had a normal tissue-level perfusion by MCE than those treated with HDB tirofiban or abciximab (96.2% vs. 75% vs. 72.4%, respectively; p = 0.04) (Fig. 2B).


Figure 2
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  		Figure 2 (A) Myocardial contrast echocardiography score index (MCSEI) as a semiquantitative index of impaired tissue perfusion in the three groups of patients. p < 0.05 by analysis of variance (ANOVA) upstream tirofiban versus high-dose bolus (HDB) versus abciximab. (B) Patients perfused by myocardial contrast echocardiography (MCE) among the three therapeutic regimen groups. p = 0.04 by ANOVA upstream tirofiban vs. HDB vs. abciximab.

 
Troponin I release.   By design, all patients had elevated preprocedural cTnI levels. No significant difference in peak pre-PCI cTnI levels was found between groups (6.5 ± 6.8 for upstream tirofiban regimen vs. 4.5 ± 5.7 for HDB tirofiban vs. 5.0 ± 6.6 for abciximab; p = 0.45 by ANOVA).

Twenty-four patients (26%) had a post-procedural cTnI elevation that was significantly less frequent among patients in the upstream tirofiban group compared with the HDB tirofiban and abciximab groups (9.4% vs. 30% vs. 38.7, respectively; p = 0.018).

Quantitatively, cTnI levels after PCI were significantly lower with upstream tirofiban than with HDB tirofiban (3.8 ± 4.1 vs. 7.2 ± 12; p = 0.015) and abciximab (3.8 ± 4.1 vs. 9 ± 13.8; p = 0.0002).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This pilot study shows that in high-risk NSTE-ACS treated with early PCI, an upstream tirofiban regimen is associated with better tissue-level perfusion, both before and after intervention, and less post-procedural cTnI release compared with downstream HDB tirofiban and abciximab. On the other hand, no significant difference was found on tissue-level perfusion and cTnI release between downstream HDB tirofiban and abciximab.

Upstream versus downstream GP IIb/IIIa inhibitors.   The contribution of GP IIb/IIIa inhibition in NSTE-ACS is shown in placebo-controlled trials in which upstream GP IIb/IIIa inhibition was initiated upon admission (13). Although these results are encouraging, there are few other data to support the use of upstream GP IIb/IIIa inhibitors (14). In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) trial (15), all patients received upstream GP IIb/IIIa inhibitors and were randomized to either early invasive or conservative treatment, so the design did not permit a definitive statement to be made as to whether upstream GP IIb/IIIa inhibition is helpful in patients who progress to an early invasive strategy. Also, there has been no randomized trial in which patients were actually randomized to receive upstream or downstream GP IIb/IIIa inhibitors. To our knowledge, the present pilot study is the first experience comparing in a randomized manner upstream versus downstream GP IIb/IIIa inhibitors in the setting of an early invasive strategy for high-risk NSTE-ACS. The results show that patients treated with upstream tirofiban had improved pre- and post-PCI tissue level perfusion and attenuation of myocardial damage. These mechanistic findings confirm and expand previous experimental data (16) and coupled with the clinical findings from the TACTICS-TIMI 18 trial (15,17) suggest that the earlier initiation of tirofiban for patients with NSTE-ACS, followed by routine angiography within 48 h and PCI as appropriate, may yield more favorable outcomes.

Timing and dosage of GP IIb/IIIa inhibitors.   The presumed benefits of early therapy with GP IIb/IIIa inhibitors raise the question of whether there are differences among the available agents. The Tirofiban and Reopro Give Similar Efficacy Outcomes Trial (TARGET) (18) demonstrated the superiority of PCI in combination with abciximab instead of tirofiban at 30 days. The reasons for these results are currently speculative and possibly due to an inadequate early platelet inhibition with tirofiban in the TARGET regimen. In a randomized comparison of platelet inhibition with abciximab, tirofiban, and eptifibatide during PCI in the ACS (19), platelet aggregation 15 and 30 min after drug infusion was significantly less inhibited with the tirofiban-TARGET regimen compared with abciximab and eptifibatide. Therefore, the two-compartment model of treating ACS patients (20)—"upstream" versus "downstream"—might only remain separated by the adequacy of time allowed for steady-state concentrations in plasma of small-molecule agents to be reached before PCI. Thus, a possible way to remove the compartmentation might be with an adequately high-dose bolus of tirofiban to maintain at least 90% inhibition of platelet aggregation until steady state is reached with the infusion. Although preliminary reports have documented safety and efficacy of this dose regimen in patients undergoing elective or high-risk PCI (6,7), its role in NSTE-ACS remains to be addressed. In the present study, upstream tirofiban was associated with a better angiographic outcome than HDB tirofiban, suggesting that early treatment in CCU is better than a high dosage in the catheterization laboratory for achieving an improvement in tissue-level reperfusion and attenuation of myocardial damage. On the other hand, we also found no significant difference in angiographic outcome and post-procedural cTnI release between downstream HDB tirofiban and abciximab. These findings confirm and expand recent observations showing similar effects of HDB tirofiban and abciximab on the extent of platelet inhibition as well as on angiographic outcome and left ventricular function recovery in ST-segment elevation ACS (12,21).

Study limitations.   Although timing of coronary angiography and PCI was similar between groups (within 48 h of admission), the beneficial effects of upstream tirofiban in the present study might partly depend on the delay itself, because downstream groups did not receive GP IIb/IIIa inhibitors until PCI was performed. Further studies comparing early (within 48 h) invasive strategy with upstream GP IIb/IIIa inhibitor treatment with fast-track (within a few hours) invasive strategy with downstream treatment are needed to resolve this issue.

The effects of the different drug regimens on the extent of platelet inhibition were not investigated. Such data might have provided additional insights into the relationship between the degree of platelet inhibition and perfusion and enzymatic outcome.

Conclusions.   This pilot study shows that in high-risk NSTE-ACS, an early invasive strategy with upstream tirofiban is associated with improved tissue-level perfusion and attenuated myocardial damage, compared with an early invasive strategy with downstream HDB tirofiban or abciximab. High-dose bolus tirofiban or abciximab administered just before PCI achieved similar effects on angiographic outcome and cTnI release. Further studies are needed to clarify if the strategy and dose regimens have a clinical impact.


   Footnotes
 
This study was supported by a grant from the Andrea Cesalpino Foundation, Arezzo, Italy.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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Journal Watch Cardiology, March 16, 2006; 2006(316): 3 - 3.
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