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J Am Coll Cardiol, 2003; 41:20-25
© 2003 by the American College of Cardiology Foundation
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CLINICAL STUDY: INTERVENTIOANL CARDIOLOGY

Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous coronary intervention: Results of the coronary revascularization using integrilin and single bolus enoxaparin study

Deepak L. Bhatt, MD*,*, Benjamin I. Lee, MD, FACC{dagger}, Peter J. Casterella, MD, FACC,{ddagger}, Mark Pulsipher, MD, FACC,§, Matthew Rogers, MD, FACC,||, Marc Cohen, MD, FACC,, Victor E. Corrigan, MD, FACC,#, Thomas J. Ryan, Jr, MD, FACC**, Jeffrey A. Breall, MD, PhD, FACC{dagger}{dagger}, Jeffrey W. Moses, MD, FACC{ddagger}{ddagger}, Gregory M. Eaton, MD, FACC§§, Mitchel A. Sklar, MD, FACC|||| and A. Michael Lincoff, MD, FACC*

* Cleveland Clinic Foundation, Cleveland, Ohio, USA
{dagger} Washington Hospital Center, Washington, DC, USA
{ddagger} Scripps Clinic, La Jolla, California, USA
§ Moses Cone Hospital, Greensboro, North Carolina, USA
|| St. Luke’s Episcopal Hospital, Houston, Texas, USA
Hahnemann Hospital, Philadelphia, Pennsylvania, USA
# St. Joseph’s Hospital of Atlanta, Atlanta, Georgia, USA
** Maine Medical Center, Portland, Maine, USA
{dagger}{dagger} Krannert Institute of Cardiology, Indianapolis, Indiana, USA
{ddagger}{ddagger} Lenox Hill Heart and Vascular Institute of New York, New York, New York, USA
§§ Mid Ohio Heart Clinic, Cardiovascular Disease Specialists, Mansfield, Ohio, USA
|||| Medical City Dallas Hospital, Dallas, Texas, USA

Manuscript received June 10, 2002; revised manuscript received August 24, 2002, accepted September 6, 2002.

* Reprint requests and correspondence: Dr. Deepak L. Bhatt, Cleveland Clinic Foundation, Department of Cardiovascular Medicine, Desk F25, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
bhattd{at}ccf.org


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: This study was designed to assess whether use of enoxaparin during percutaneous coronary intervention (PCI) increased bleeding compared with unfractionated heparin, in addition to background therapy with eptifibatide.

BACKGROUND: Data supporting the benefits of enoxaparin and the glycoprotein IIb/IIIa inhibitor eptifibatide evolved in parallel. Information on combining these two classes of medications is limited.

METHODS: A total of 261 patients undergoing elective or urgent PCI were randomized to either eptifibatide plus enoxaparin or eptifibatide plus unfractionated heparin.

RESULTS: The primary end point of the study, the bleeding index (change in hemoglobin corrected for blood transfusions), was 0.8 in the patients randomized to enoxaparin and 1.1 in patients randomized to unfractionated heparin (p = 0.15). The rate of vascular access site complications was 9.3% in the enoxaparin arm versus 9.8% in the unfractionated heparin arm (p = NS). The rate of bleeding complications was not significantly different between the two arms of the study, including in those patients who received vascular closure devices. The rate of angiographic complications was 6.3% in the enoxaparin group and 6.2% in the unfractionated heparin group (p = NS). Similarly, there were no significant differences in the composite of death, myocardial infarction, or urgent target vessel revascularization at 48 h or 30 days.

CONCLUSIONS: Compared with unfractionated heparin plus eptifibatide, the combination of enoxaparin plus eptifibatide is not associated with an excess of bleeding or vascular complications, including in those receiving closure devices. Despite no monitoring of anticoagulation activity with enoxaparin, there was no apparent increase in angiographic or clinical complications.

Abbreviations and Acronyms
  ACT
  activated clotting time
  CK
  creatine kinase
  CRUISE
  Coronary Revascularization Using Integrilin and Single bolus Enoxaparin trial
  GP
  glycoprotein
  IV
  intravenous
  PCI
  percutaneous coronary intervention
  TIMI
  Thrombolysis In Myocardial Infarction

The low-molecular-weight heparin enoxaparin has been shown to improve outcomes in patients with acute coronary syndromes (1–7). Enoxaparin has also been shown to be cost-effective in this setting compared with intravenous (IV) unfractionated heparin (8). However, given the current lack of point-of-care monitoring for the extent of anticoagulation with low-molecular-weight heparin, concerns about integrating enoxaparin into the catheterization laboratory and the potential for thrombosis or abrupt closure persist and have limited its use. Furthermore, enoxaparin evolved in parallel, but separately, with the platelet glycoprotein (GP) IIb/IIIa inhibitor era. While there is abundant evidence regarding the efficacy of GP IIb/IIIa inhibitors such as eptifibatide and tirofiban in acute coronary syndromes (9–13) and abciximab and eptifibatide in the catheterization laboratory (14–19), there is no guidance in combining enoxaparin use with eptifibatide. In particular, it is unclear whether an anticoagulation assay would be needed to select optimal doses of enoxaparin when used with eptifibatide. In some tertiary care centers, because over 50% of coronary interventions involve the use of GP IIb/IIIa inhibitors, the limited data on bleeding risk from combination therapy has been especially troubling and has limited the utilization of enoxaparin. The combination of enoxaparin, GP IIb/IIIa inhibitors, and vascular closure devices has raised additional concerns regarding the potential for groin complications. Only nonrandomized registry experience has been available thus far to assess the safety of combination therapy with abciximab and enoxaparin in comparison with historical data (20). Therefore, this study was performed as the first randomized trial of the safety and feasibility of combined enoxaparin with eptifibatide during percutaneous coronary revascularization.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
The Coronary Revascularization Using Integrilin and Single bolus Enoxaparin (CRUISE) trial was conducted at 12 medical centers and enrolled a total of 261 patients undergoing elective or urgent percutaneous coronary intervention (PCI). Written informed consent was obtained from all participants, and institutional review board approval was given. All patients received 325 mg of daily aspirin; patients treated with stents received clopidogrel 75 mg daily for at least 30 days, with a loading dose allowed at the operator’s discretion. All patients received eptifibatide therapy before device activation. Patients were assigned in an open-label fashion by central telephone randomization to receive IV enoxaparin or unfractionated heparin at the time of PCI.

Patients were included if they were males or nonpregnant females at least 18 years of age who were to undergo elective or urgent percutaneous coronary revascularization. Exclusion criteria included: acute myocardial infarction within the 24 h before randomization; administration of any IV unfractionated heparin within 4 h or low-molecular-weight heparin within 12 h before randomization; treatment with any parenteral or oral platelet GP IIb/IIIa inhibitor within the previous 30 days before study randomization; chronic warfarin therapy; thrombolytic therapy within 48 h before randomization; history of bleeding diathesis; evidence of active abnormal bleeding within the previous 30 days; severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) not adequately controlled on antihypertensive therapy; major surgery within the preceding 6 weeks; history of stroke within 30 days of randomization; any history of hemorrhagic stroke; concurrent or planned administration of another parenteral or oral GP IIb/IIIa inhibitor or warfarin within 30 days after randomization; platelet count <100,000 mm3; serum creatinine >2.0 mg/dl; dependency on renal dialysis; known hypersensitivity to any component of eptifibatide or heparin or porcine products; history of heparin-induced thrombocytopenia; recent or planned spinal puncture; or participation in another study of experimental therapy within 30 days.

Dosing of medications.   Eptifibatide was administered at the time of the PCI utilizing the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy double-bolus regimen (21). Eptifibatide was given as a 180 µg/kg IV bolus before PCI, followed by a 2 µg/kg/min infusion, with a second bolus of 180 µg/kg given 10 min later. The infusion was continued through intervention until 18 to 24 h after the PCI or until hospital discharge, whichever came first. Patients randomized to enoxaparin were given a dose of 0.75 mg/kg intravenously before PCI. Patients randomized to unfractionated heparin received a bolus of 60 IU/kg intravenously before PCI, with additional boluses of 10 to 20 IU/kg administered as necessary to achieve an activated clotting time (ACT) >200 s.

Sheath management
For patients randomized to unfractionated heparin, the sheath could be removed 2 to 4 h after the last administered dose of unfractionated heparin, after documenting a decline in activated partial thromboplastin time to <45 s or ACT to <150 s. For patients randomized to enoxaparin, the sheath could be removed 4 h after the bolus of enoxaparin. The use of Food and Drug Administration-approved vascular closure devices was permitted at any time after the PCI.

End points
Blood samples for creatine kinase (CK) and CK-MB were drawn at baseline (before PCI) and 6, 12, 18, and 24 h later. Hemoglobin and platelet counts were measured and electrocardiogram performed at baseline and 24 h after PCI (or at hospital discharge).

The primary end point was the bleeding index, defined as the fall in hemoglobin (g/dl) over the first 24 h, adjusted for whole blood or red blood cell transfusions (prehemoglobin – post hemoglobin + units transfused) (22).

Other safety parameters assessed included: major and minor bleeding by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria (23); major and minor bleeding by the Thrombolysis In Myocardial Infarction (TIMI) criteria (24); need for transfusion; thrombocytopenia (defined as platelet count <100 K, <50 K, <20 K, or >30% decrease); groin complications (hematoma 5 cm in diameter or bleeding requiring medical intervention, vascular repair, or leading to prolonged hospitalization); or hemorrhagic stroke at 48 h.

Efficacy end points were death, myocardial infarction (defined as new Q waves of ≥0.04 s in at least two leads or CK-MB ≥3x the upper limit of normal after PCI and at least 50% above the previous nadir), or urgent revascularization (PCI or coronary artery bypass grafting) at 48 h, 7 days, and 30 days. Angiographic complications (major dissection, thrombus formation, abrupt vessel closure, side-branch closure) were recorded by the operator.

Statistical analysis
Based on prior studies of eptifibatide in PCI, the mean expected bleeding index in the unfractionated heparin group was 2.0 ± 2.6. Therefore, a sample size of 250 patients (125 per arm) was calculated to provide 83% power to detect a 50% reduction from the control rate of 2.0 in the primary end point using the Wilcoxon rank-sum test at the {alpha} = 0.05 significance level. All statistical tests were two-sided. Clinical efficacy data were analyzed using a Fisher exact test.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
The baseline characteristics of the patients in the enoxaparin and unfractionated heparin arms are listed in Table 1. Of the 129 patients randomized to enoxaparin, 126 underwent PCI; of the 132 patients randomized to unfractionated heparin, 130 underwent PCI. Stents were placed in 86.5% and 85.4% of the enoxaparin and unfractionated heparin arms, with thienopyridine pretreatment in 94.6% and 93.8%, respectively. There were no significant differences in baseline characteristics between the two randomized groups. The median maximal procedural ACT in the unfractionated heparin group was 274 (interquartile range: 241, 317).


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  		Table 1 Baseline Characteristics of the Patients Randomized to Enoxaparin Plus Eptifibatide Versus Unfractionated Heparin Plus Eptifibatide

 
There was no significant difference in the mean bleeding index, the primary end point of the study, between the patients randomized to unfractionated heparin versus enox-aparin, (1.1 vs. 0.8; p = 0.15). There were no blood transfusions within 24 h in either arm of the study; thus, the bleeding index herein represents the drop in hemoglobin. Likewise, there were no significant differences in major or minor bleeding complications (Table 2). There were no cases of severe thrombocytopenia with platelets <50 K in either arm.


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  		Table 2 Bleeding Complications

 
The proportion of patients receiving closure devices was 42.1% in the enoxaparin patients and 33.8% in the unfractionated heparin group. The median time to sheath removal in both groups was 4.4 h. Rates of vascular complications did not differ between the treatment arms in the overall population (Table 3) or in those receiving closure devices (Tables 4 and 5). In Table 5, of the 53 patients who received closure devices, 5 patients had unresolved TIMI bleeding severity and, hence, were not included in Table 4, leaving 48 patients for analysis. Similarly, 6 of the 44 patients who received closure devices had unresolved TIMI bleeding severity, leaving 38 patients for analysis.


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  		Table 3 Vascular Complications

 

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  		Table 4 Bleeding Complications in Those Receiving Closure Devices

 

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  		Table 5 Vascular Complications in Those ReceivingClosure Devices

 
There were no apparent differences in angiographic complications (Table 6). Similarly, there were no apparent differences in the rate of clinical events at 48 h (Table 7) or at 30 days. Between 48 h and 30 days, two additional patients required urgent target vessel revascularization in the enoxaparin group.


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  		Table 6 Angiographic Complications

 

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  		Table 7 Clinical End Points at 48 h

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Strong data exist supporting the use of GP IIb/IIIa inhibitors and low-molecular-weight heparin as individual drug classes. However, data are more limited regarding the combination of these two forms of antithrombotic therapy. Concerns about safety and integration with the catheterization laboratory have hampered the use of a strategy of combining these two potentially complementary forms of thrombus prevention.

The CRUISE study was designed to assess if combination therapy with enoxaparin and eptifibatide posed a bleeding hazard when compared with eptifibatide plus unfractionated heparin. The bleeding index, a sensitive metric of blood loss, was designated as the primary end point of the study. No significant difference was found in the bleeding index, which was similarly low in both arms of the study. Thus, despite concerns that enoxaparin, especially when combined with GP IIb/IIIa inhibition, may increase the rate of catheterization-related bleeding, enoxaparin plus eptifibatide appeared to be safe. Furthermore, although there was no monitoring of the anticoagulant effect of enoxaparin during PCI, we observed no increase in angiographic complications or a detectable increase in adverse clinical events.

During contemporary PCI, a large proportion of patients receive stents and pretreatment with clopidogrel before the procedure, practices that were reflected in the CRUISE study. Despite treatment with aspirin, clopidogrel, enoxaparin, and eptifibatide, blood loss in the CRUISE study was not significantly higher than in other studies of antithrombotic therapy in PCI. Additionally, the use of closure devices did not appear to be associated with a bleeding excess. Some interventional cardiologists have expressed concerns about using low-molecular-weight heparin in patients receiving a closure device if it ultimately does not deploy appropriately and obtain hemostasis; unlike unfractionated heparin, the activity of enoxaparin is only partially reversed by protamine. While these concerns may be valid, in the CRUISE population, there was no excess of bleeding or vascular complications with the combination of enoxaparin and eptifibatide with either suture-based or collagen closure devices.

Prior studies of enoxaparin in PCI have consisted only of nonrandomized registries. The National Investigators Collaborating on Enoxaparin (NICE)-1 registry established that a dose of 1 mg/kg of IV enoxaparin could be used during PCI, while the NICE-4 registry established the feasibility of 0.75 mg/kg of enoxaparin with abciximab in that setting (20). The NICE-3 registry combined enoxaparin and GP IIb/IIIa inhibition during the medical phase of therapy in patients presenting with acute coronary syndromes, continuing these agents through the time of PCI. While these observational studies supported in concept the integration of enoxaparin and GP IIb/IIIa inhibition, with safety outcomes comparable to historical controls, they did not provide direct randomized evidence showing equivalent safety. In this context, the CRUISE trial provides the first randomized experience of enoxaparin versus unfractionated heparin with background therapy including eptifibatide, confirming the safety experience inferred from prior registry data. While an equivalent degree of safety and efficacy in conjunction with greater ease of administration may be sufficient to justify the use of enoxaparin instead of unfractionated heparin, there are also data to suggest that enoxaparin may be synergistic with GP IIb/IIIa inhibition in reducing platelet activation and, thus, superior to unfractionated heparin (25,26). Enoxaparin prevents release of von Willebrand factor, a property not shared by unfractionated heparin (27). The Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial will randomize a large cohort of patients with acute coronary syndromes to either unfractionated heparin or enoxaparin in the setting of unstable angina, with a sizable proportion of patients continuing on to PCI, thus permitting definitive assessment of the relative efficacy of these two thrombin inhibitors in both the medical and revascularization phases of treatment.

Study limitations.   This study was only powered for differences in the bleeding index between enoxaparin and unfractionated heparin for patients receiving concomitant GP IIb/IIIa inhibition. The observed rate of blood loss as reflected in the bleeding index was lower than expected based upon prior data, thus limiting the statistical power of our study. Furthermore, this study, although randomized, was not double-blinded, in order to limit complexity and facilitate rapid enrollment in this pilot. Therefore, end points such as access site bleeding could have potentially been influenced by investigator bias. However, at the time of this study, there was bias against enoxaparin among interventional cardiologists, not in favor of it. Moreover, this trial was not powered to examine potential differences in efficacy, as such a trial would have required several thousand patients. While there was no apparent difference in angiographic complications between the enoxaparin and unfractionated heparin arms, all patients received eptifibatide. Therefore, the results of this study should not be extrapolated to patients not receiving GP IIb/IIIa antagonists. While there is a large body of data supporting the use of enoxaparin in patients with an acute coronary syndrome, this study does not specifically address the issue of giving IV enoxaparin at the time of PCI in patients who are already therapeutic on subcutaneous enoxaparin. However, such dosing algorithms are being developed at several centers and used in the ongoing SYNERGY trial.

Conclusions
The use of enoxaparin instead of unfractionated heparin with concomitant GP IIb/IIIa inhibition with eptifibatide during elective or urgent PCI does not lead to an increase in bleeding, including minor degrees of blood loss as measured by the sensitive bleeding index. Furthermore, there is no apparent loss of efficacy with the substitution of enoxaparin in place of unfractionated heparin in this setting. Definitive assessment of the role of enoxaparin is underway in large randomized clinical trials spanning the continuum of care of patients with acute ischemic syndromes.


   Footnotes
 
The CRUISE trial was funded by Millennium Pharmaceuticals (Cambridge, Massachusetts, USA).


   References
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 Methods
 Results
 Discussion
 References
 

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D. J. Moliterno, J. B. Hermiller, D. J. Kereiakes, E. Yow, R. J. Applegate, G. A. Braden, E. J. Dippel, M. I. Furman, C. L. Grines, N. S. Kleiman, et al.
A novel point-of-care enoxaparin monitor for use during percutaneous coronary intervention: Results of the Evaluating Enoxaparin Clotting Times (ELECT) Study
J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1132 - 1139.
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Safe to Combine Enoxaparin with Eptifibatide During PCI
Journal Watch Cardiology, March 28, 2003; 2003(328): 3 - 3.
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