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J Am Coll Cardiol, 2006; 47:2364-2373, doi:10.1016/j.jacc.2005.12.077 © 2006 by the American College of Cardiology Foundation |
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* TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
University of Tennessee, Knoxville, Tennessee
APEX Cardiology, Jackson, Tennessee
|| Cardiovascular Associates, Kingsport, Tennessee
¶ Ben Taub Hospital, Houston, Texas
# Our Lady of Lourdes Medical Center, Camden, New Jersey
** Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Manuscript received May 6, 2005; revised manuscript received November 23, 2005, accepted December 1, 2005.
* Reprint requests and correspondence: Dr. C. Michael Gibson, 350 Longwood Avenue, First Floor, Boston Massachusetts 02115. (Email: mgibson{at}timi.org).
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Abstract |
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BACKGROUND: The optimal combination of antiplatelet and antithrombin regimens that maximizes efficacy and minimizes bleeding among patients with non–ST-segment elevation ACS undergoing percutaneous coronary intervention (PCI) is unclear.
METHODS: A total of 857 patients with non–ST-segment elevation ACS were assigned randomly to eptifibatide + reduced dose unfractionated heparin (n = 298), eptifibatide + reduced-dose enoxaparin (n = 275), or bivalirudin monotherapy (n = 284).
RESULTS: Among angiographically evaluable patients (n = 754), the primary end point of post-PCI coronary flow reserve was significantly greater with bivalirudin (1.43 vs. 1.33 for pooled eptifibatide arms, p = 0.036). Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade more often was normal with eptifibatide treatment compared with bivalirudin (57.9% vs. 50.9%, p = 0.048). The duration of ischemia on continuous Holter monitoring after PCI was significantly longer among patients treated with bivalirudin (169 vs. 36 min, p = 0.013). There was no excess of TIMI major bleeding among patients treated with eptifibatide compared with bivalirudin (0.7%, n = 4 vs. 0%, p = NS), but TIMI minor bleeding was increased (2.5% vs. 0.4%, p = 0.027) as was transfusion (4.4% to 0.4%, p < 0.001).
CONCLUSIONS: Among moderate- to high-risk patients with ACS undergoing PCI, coronary flow reserve was greater with bivalirudin than eptifibatide. Eptifibatide improved myocardial perfusion and reduced the duration of post-PCI ischemia but was associated with higher minor bleeding and transfusion rates. Ischemic events and biomarkers for myonecrosis, inflammation, and thrombin generation did not differ between agents.
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The goal of this study was to evaluate the relative efficacy and safety of GP IIb/IIIa inhibition with eptifibatide when administered with indirect thrombin inhibition (unfractionated heparin or enoxaparin) as compared with monotherapy with direct thrombin inhibition with bivalirudin among patients with non–ST-segment elevation acute coronary syndromes. We hypothesized that selective blockade of the platelet GP IIb/IIIa receptor with an inhibitor would produce superior results compared with a direct thrombin inhibitor on microvascular dysfunction, ischemia, and inflammation. Efficacy end points included measures of post-PCI flow, myocardial perfusion, myonecrosis, ischemia, inflammation, thrombin generation, and clinical events.
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Methods |
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To be enrolled in the study, patients had to meet the following inclusion criteria: age 18 to 80 years of age, hospitalized with unstable angina/NSTEMI with chest discomfort or an anginal equivalent at rest 
10 min consistent with acute coronary syndromes, with at least one high-risk feature (i.e., diabetes, a positive cardiac troponin T/I or creatine kinase-myocardial band (CK-MB), ST-segment deviation >0.5 mm, or TIMI risk score 3) who were anticipated to undergo PCI of a native coronary artery.
Exclusion criteria included uncontrolled hypertension with a systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg that was unresponsive to treatment for >1 h; ST-segment elevation myocardial infarction (MI) within 24 h; PCI within the previous 2 weeks; intraventricular conduction defect, pacing, left ventricular hypertrophy or any other electrocardiographic finding that could make continuous electrocardiographic monitoring uninterpretable; cardiogenic shock; history of a bleeding diathesis or evidence of active bleeding within 30 days; history of a hemorrhagic stroke at any time, stroke or transient ischemic attack of any etiology within 30 days; platelet count of <100,000/mm3; major surgery within the previous six weeks; any low-molecular weight heparin within the previous 12 h; treatment with any GP IIb/IIIa in the previous 30 days or concurrent or anticipated treatment; concurrent treatment with warfarin; estimated creatinine clearance <30 ml/min; treatment of in-stent restenosis; or anticipated or staged PCI within 48 h. Pretreatment with clopidogrel was permitted. The study protocol was approved by the institutional review boards at all participating sites, and all eligible patients were required to provide written informed consent.
Study protocol.
The study design is shown in Figure 1. After diagnostic catheterization, 857 patients were assigned randomly in a 1:1:1 fashion to treatment with eptifibatide + UFH, eptifibatide + enoxaparin, or bivalirudin during PCI between August 2003 and September 2004. A central randomization system was used that involved a permuted-block design in which assignment was blocked by site (block size of 12) and stratified according to thienopyridine use 6 h before randomization. All patients received aspirin (160–325 mg) before PCI, and 300 mg of clopidogrel immediately before stenting if they had not yet received a thienopyridine on the day of the procedure. For patients who were being treated with UFH at the time of screening, the UFH infusion was discontinued for 2 h before anticipated randomization to enable the transition to study anti-thrombin. It was not required to wait 2 h until randomization for patients already receiving UFH in whom the activated partial thromboplastin time was known to be <40 s or the activated clotting time (ACT) <150 s.
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Angiography was performed before and immediately after PCI. Immediately after the last balloon inflation in the culprit vessel, intracoronary adenosine was administered in the culprit artery over the course of 5 s. After the administration of adenosine, angiography was performed for the assessment of the primary end point. Immediately after completion of the PCI, a three-lead continuously recording Holter monitor was applied for 48 h. Adjunctive antiplatelet therapy with either ticlopidine 250 mg twice daily or clopidogrel 75 mg daily was administered after stent implantation.
End point assessment. The primary efficacy end point was coronary flow reserve. The primary safety end point was TIMI major bleeding. The secondary end points were: 1) the normalized duration of ischemia through 24 h after PCI among those with ischemia; 2) the composite of death, MI, and occurrence of any ischemia on the Holter recording within 48 h after randomization; and 3) the increase in troponin from baseline to its peak value by 24 h (–6/+12 hours) post-PCI based on core laboratory analysis. Other safety end points include TIMI minor bleeding and transfusion.
The coronary flow reserve is a measure of the capacity of blood flow to be augmented in response to intracoronary (IC) adenosine (hyperemic flow) and was assessed as previously described using the corrected TIMI frame count (CTFC) (20–22). Coronary flow reserve is calculated as the ratio of the post-PCI CTFC divided by the post-adenosine CTFC. The coronary flow improvement was calculated as the ratio of pre-PCI CTFC divided by the post-PCI CTFC. The TIMI flow grade (23), CTFC, and TIMI myocardial perfusion grade (TMPG) (24) were assessed as prespecified as previously defined by an angiographic core laboratory blinded to treatment assignment.
The peak increase in troponin (the increase from baseline to the peak value by 24 h) after PCI based on core laboratory analysis was a prespecified secondary end point. The myonecrosis markers troponin I and CK-MB, as well as the inflammation marker C-reactive protein, were assessed before and at 6 to 8 h and 18 to 24 h after PCI. The other inflammation markers, soluble CD40 ligand, interleukin (IL)-6 and prothrombin fragment F 1.2 all were assessed at five time points: before PCI and at 30 min, 2 h, 6 to 8 h, and 18 to 24 h after PCI.
The prespecified clinical end point was the risk of death, MI, or recurrent ischemia on Holter monitoring by 48 h or discharge. Post-PCI MI within 48 h after PCI was as defined in the . A significant episode of ischemia on Holter monitoring was defined as an episode that exceeded 0.1 mV of ST-segment deviation that persisted for 1 min. The duration of ischemia on post-PCI Holter monitoring through 24 h was an additional prespecified secondary end point.
Bleeding end points were assessed by TIMI criteria (23). The prespecified primary safety end point was TIMI major bleeding. All clinical events (recurrent ischemia, MI, and bleeding) were adjudicated by a clinical events committee or Holter Laboratory blinded to treatment allocation. Angiographic end points were assessed by the TIMI angiographic core laboratory.
Cardiac troponin I, CK-MB, and high sensitivity C-reactive protein were determined in a core laboratory (TIMI Biomarker Core Lab, Boston, Massachusetts) using established methods (Dimension RxL and Behring II Nephelometer, respectively, Dade-Behring, Deerfield, Illinois). The decision-limit for troponin I was 0.1 ng/ml based upon our previous work with this assay. Soluble CD40 ligand, prothrombin fragment 1.2, Regulated upon Activation, Normal T-cell Expressed and Secreted (i.e., RANTES), and IL-6 were measured at an independent core laboratory (Dr. Jennings, University of Tennessee, Knoxville).
Statistical analysis. On the basis of data from the placebo arm of the Novel Dosing Regimen of Eptifibatide in Planned Coronary Stent Implantation Trial (ESPRIT) (8), a coronary flow reserve of 1.28 to 0.70 was anticipated in the bivalirudin arm. On the basis of these assumptions, a sample size of 267 evaluable patients per treatment group would provide 98% power to detect a 20% increase in coronary flow reserve with eptifibatide in the comparison of each eptifibatide treatment group with the bivalirudin treatment group.
The prespecified efficacy analyses were based on the intention to-treat principle. The primary end point (coronary flow reserve) was analyzed as a randomized, intent-to-treat basis in angiographically evaluable patients and compared with the pooled eptifibatide arms with the bivalirudin arm as prespecified in the protocol. The analysis of efficacy end points was prespecified to include stratification by the duration of clopidogrel use (
6 h vs. >6h) before randomization. All safety analyses were based on treatment received. Analyses were performed using two-sided tests at the 0.05 level of significance. If the pooled eptifibatide treatment comparison was significant at the specified significance level, then each of the two eptifibatide groups were individually compared with bivalirudin at the same alpha level as prespecified in the protocol.
For the continuous efficacy end points, the analyses were performed using analysis of variance models with treatment group as a covariate. Because the coronary flow reserve and the biomarker data were not normally distributed, these data were rank transformed for the analysis. For categorical efficacy variables, analyses were performed using logistic regression models with treatment group as a covariate. Data analysis was performed independently by the TIMI Data Coordinating Center (Brigham and Women’s Hospital, Boston, Massachusetts). Three interim assessments of safety were conducted by an independent data and safety monitoring board.
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Results |
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The other prespecified angiographic end point was the TMPG, which evaluates blood flow directly into and out of the myocardium in the territory supplied by the culprit artery. The frequency of normal TMPG 3 after PCI was significantly greater in the eptifibatide arms compared with the bivalirudin arm (Fig. 3). Randomization to eptifibatide (vs. bivalirudin) remained independently associated with normal TMPG in a multivariate analysis that adjusted for all potential confounders identified in univariate analyses (Table 3). When the efficacy end points were analyzed using an as treated population, the overall results were minimally different, with no major shift in results.
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Discussion |
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It is notable that the CFR results and the myocardial perfusion results are divergent. This mismatch of improved epicardial flow and reduced myocardial performance after embolization has been noted in prior studies (25–27). In animal models, microembolization has been associated with hyperemia as surrounding territories increase their release of endogenous adenosine (25,27). A progressive decline in left ventricular performance with each episode of embolization has been noted despite sustained hyperemia after each embolic episode (25–27). Given that zones surrounding the embolic territory can become hyperemic while at the same time the injured zone has impaired perfusion, a perplexing scenario can result: heterogeneity can exist in the velocity of dye within a given epicardial artery. In these scenarios, some regions of the epicardial artery are hyperemic (usually the proximal territory), whereas other regions have slower velocity (usually the distal territory that has sustained embolization). This heterogeneity in the velocity of dye is not captured with the use of either a Doppler velocity wire or the corrected TIMI frame count and warrants further investigation.
Although the coronary flow reserve assesses the improvement in epicardial flow after adenosine administration, the post-PCI TMPG assesses the entrance and exit of dye directly into the muscle itself in the area supplied by the culprit artery (24,28). The administration of eptifibatide was associated with greater rates of normal TMPG, even after adjustment for all identified confounders in a multivariate model. This finding builds upon several previous angiographic observations in which GP IIb/IIIa inhibition has been associated with improved myocardial perfusion. (29–33).
Although the incidence of post-PCI Holter ischemia did not differ between treatment groups, the duration of ischemia on the post-PCI Holter (a prespecified secondary end point) was significantly shorter with eptifibatide. This is similar to the trend that was observed in favor of abciximab compared with heparin in the Chimeric 7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment (CAPTURE) trial (9 vs. 61 min, p = 0.10) (34). There was no difference between treatment strategies with respect to the increase in biomarkers after PCI. The trial population in the PROTECT–TIMI-30 trial included a greater proportion of patients with elevated markers of myonecrosis at baseline than did previous studies using troponin or CK-MB elevations after PCI as an end point. It is possible that any difference in the extent of necrosis after MI was masked by ongoing biomarker release from the index event. Among patients with no CK increase at baseline in whom an increase in CK-MB after PCI more likely reflects myonecrosis accompanying the PCI, it is notable that the risk of an increase in CK-MB after PCI was increased significantly less among patients treated with eptifibatide. These findings are consistent with the potential benefit of antiplatelet therapy at the time of the PCI procedure and are consistent with data demonstrating reduced myonecrosis with greater platelet inhibition, as shown in the recent Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study (35).
Patients in this study were not assigned randomly to a pretreatment strategy with clopidogrel but, as pre-specified, randomization was stratified and the results were analyzed by the duration of clopidogrel pre-treatment. The risk of death and MI was significantly reduced among eptifibatide patients who were pretreated for <6 h with clopidogrel before PCI. Although there was no difference in the risk of death and MI among those patients pretreated for longer than 6 h, these findings point to the importance of inhibition of platelet function in these patients, with the benefit of blockade of the platelet GP IIb/IIIa receptor apparent in patients "unprotected" by blockade of the P2Y12 receptor. The observed benefit among patients who were not pretreated with clopidogrel is congruent with the results of the CLEAR PLATELETS study, in which patients who were not pretreated with clopidogrel before the procedure sustained an improvement in platelet inhibition and a reduced the risk of myonecrosis with the addition of eptifibatide (35).
The treatment strategies did not differ with respect to the primary safety end point, i.e., TIMI major bleeding. This confirms what was observed in the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 study, where the rates of TIMI major bleeding were 0.9% in the GP IIb/IIIa inhibitor arm and 0.6% in the bivalirudin arm (p = NS) (18). However, both the number of TIMI minor bleeds and the number of transfusions were substantially and significantly higher among patients treated with eptifibatide. A reduced dose of enoxaparin was used in the study but did not reduce the bleeding risk of GP IIb/IIIa inhibition compared with bivalirudin, in contrast to the results of the recently completed Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients: An International Randomized Evaluation (STEEPLE) trial of 0.5 mg/kg or 0.75 mg/kg of enoxaparin demonstrated lower rates of non-coronary artery bypass grafting-related major or minor bleeding by 48 h after PCI and no difference in death, MI, or urgent target vessel revascularization compared with treatment with ACT-driven UFH. Additional information will be provided by the results of the ongoing Acute Catheterization and Urgent Intervention Triage Strategy Trial (ACUITY) regarding the efficacy and safety of upstream inhibition, but these results were not available at the time the manuscript was submitted.
Greater ACTs after the administration of unfractionated heparin have been associated with greater rates of bleeding (36). In an effort to reduce the risk of bleeding, the heparin bolus in the present study was reduced as was the ACT target for the maintenance infusion. Despite these reductions in the unfractionated heparin dosing and despite the fact that the ACT values among bivalirudin patients was 75 s longer, bleeding among bivalirudin patients was reduced. The present analysis adds to the body of literature that demonstrates an uncoupling between the risk of bleeding and ACT values with bivalirudin. In a recent study in which the mean ACT paralleled that reported in the REPLACE-2 trial, no association was identified between the ACT after bivalirudin and either efficacy or safety (37).
Bivalirudin has numerous advantages over UFH, which include a lack of activation of platelets, absence of circulating inhibitors, and inhibition of clot-bound thrombin. The rapid return to normal hemostasis following bivalirudin administration may explain at least in part the favorable bleeding profile observed in this study as well as others (38).
Study limitations. This trial was a mechanistic one and was not designed with sufficient power to evaluate clinical events. The patients enrolled in the trial were moderate- to high-risk patients, and the results observed may not be applicable to all patients in clinical practice. Previous concomitant medication use may have modulated the baseline inflammatory biomarker measures.
Conclusions. Compared with bivalirudin, eptifibatide was associated with lower coronary flow reserve but improved myocardial perfusion as well as a reduction in the duration of ischemia after PCI. However, these benefits came at the expense of an increase in TIMI minor bleeding and transfusion, although not TIMI major bleeding.
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Footnotes |
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1 Dr. Palabrica is an employee of Millennium Pharmaceuticals. 
2 David J. Cohen has received grant support from the Medicines Company, Millennium Pharmaceuticals, and Schering-Plough.
3 Dr. Gibson has received grant support and honorarium and has served as a consultant for the Medicines Company, Millennium Pharmaceuticals, and Schering-Plough.
4 Dr. Jennings has received grant support and honorarium and has served as a consultant for Millennium Pharmaceuticals and Schering-Plough.
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