Assessment of Anticoagulation Using Activated ClottingTimes in Patients Receiving Intravenous Enoxaparin

During Percutaneous Coronary Intervention

Mark Lawrence,1,2* DO, Timothy A. Mixon,1,2MD, Donald Cross,1,2

MD, D. Scott Gantt,1,2DO,

and Gregory J. Dehmer,1,2MD

Enoxaparin is being used more frequently in patients undergoing percutaneous coronaryintervention (PCI). In this study, we determined the effect of intravenous enoxaparin onactivated clotting time (ACT) measurements in the setting of PCI. In 67 consecutivepatients, either 1 mg/kg intravenous enoxaparin alone was given for anticoagulation or0.75 mg/kg given in patients receiving eptifibatide. ACT was measured before and 5 minfollowing enoxaparin administration. After 1 mg/kg enoxaparin (n � 22), mean ACTincreased from 122 � 22 to 199 � 20 sec. After 0.75 mg/kg enoxaparin and eptifibatide(n � 45), mean ACT increased from 125 � 22 to 194 � 24 sec. The mean increase in ACTwas 77 � 26 sec in the 1 mg/kg group and 69 � 23 sec in the 0.75 mg/kg group (both Pvalues < 0.0001). Moreover, in a subgroup of 26 patients, there was an excellent corre-lation (r � 0.86) between ACTs and the ENOX test, a new point-of-care test for assessingenoxaparin anticoagulation. None of the patients had transient abrupt closure, thrombusformation, major bleeding, or required urgent revascularization. Intravenous enoxaparinat clinically relevant doses with and without eptifibatide increases ACT levels at 5 min inpatients undergoing PCI. These data suggest the ACT may be useful in the assessmentof anticoagulation by enoxaparin. Catheter Cardiovasc Interv 2004;61:52–55.© 2004 Wiley-Liss, Inc.

Key words: angioplasty; low-molecular-weight heparin; antithrombotic therapy

INTRODUCTION

For over 20 years, intravenous unfractionated heparin(UFH) has been used during percutaneous coronary in-terventions (PCI) to prevent thrombotic complications[1]. Monitoring the effect of UFH with an activatedclotting time (ACT) is important in balloon angioplastysince several retrospective studies defined an inverserelationship between the likelihood of a thrombotic eventand the ACT after receiving UFH [2,3]. Although recentdata, derived primarily from patients receiving stents,suggest ischemic endpoints do not increase with decreas-ing ACT values, at least to a level of 200 sec, testinganticoagulation in the catheterization laboratory is stillimportant [4].

Enoxaparin has been used successfully in patients un-dergoing PCI with and without glycoprotein IIb/IIIa re-ceptor antagonists [5,6]. Enoxaparin has several advan-tages over UFH, including greater bioavailability [7], adecreased incidence of thrombocytopenia [8–10], resis-tance to inactivation by platelet factor 4 [11,12], and lessactivation of platelets [13]. One perceived limitation ofenoxaparin therapy is the lack of a rapid point-of-caretest to assess the anticoagulant effect. Although a quali-tative test (ENOX clotting time) has recently become

available, the optimal therapeutic levels are not welldefined. Since most laboratories can measure ACTs andoperators are familiar with their interpretation, the pur-pose of this study was to determine if the ACT coulddetect the effect of intravenous enoxaparin.

MATERIALS AND METHODS

Patients and Anticoagulation Therapy

The study group comprised 67 consecutive patientsundergoing PCI treated with either 0.75 mg/kg i.v. enox-

1Department of Medicine, Division of Cardiology, Scott andWhite Memorial Hospital and Clinic, Temple, Texas2Texas A & M University System Health Science Center Collegeof Medicine, College Station, Texas

*Correspondence to: Dr. Mark Lawrence, Division of Cardiology,Scott and White Clinic, 2401 S. 31st Street, Temple, TX 76508.E-mail: mlawrence@swmail.sw.org

Received 24 April 2003; Revision accepted 5 August 2003

DOI 10.1002/ccd.10683Published online in Wiley InterScience (www.interscience.wiley.com).

Catheterization and Cardiovascular Interventions 61:52–55 (2004)

© 2004 Wiley-Liss, Inc.

aparin with concomitant eptifibatide or 1 mg/kg enox-aparin if eptifibatide was not used. Similar to the ESPRITtrial, the dose of eptifibatide was a 180 �g/kg bolus i.v.,immediately followed by a 2 �g/kg/min infusion, and asecond 180 �g/kg bolus i.v. 10 min after the first bolus[14]. ACTs were measured with a Hemochron device(International Technidyne, Edison, NJ) using arterialblood from the femoral sheath, at baseline and 5 minfollowing i.v. enoxaparin. None of the patients receivedUFH before the baseline measurements. All patients re-ceived aspirin (160–325 mg) before starting the PCI andclopidogrel (300 mg) either before or immediately afterthe PCI. Informed written consent was obtained from allsubjects.

After this investigation started, the Rapidpoint CoagEnoxaparin test card (ENOX; PharmaNetics, Morrisville,NC) became available. This is a new point-of-care testoptimized to detect the anticoagulant effect of enoxapa-rin. Accordingly, in 26 of the 67 patients, blood samplesfor both ACT and ENOX were collected before and afterenoxaparin PCI was performed from the femoral arteryapproach using 6 or 7 Fr guiding catheters. Arterialsheaths were removed either immediately following theprocedure if an arterial closure device was used or 4 hrafter the i.v. enoxaparin dose followed by 2 hr of com-pression using a Fem-Stop device.

Statistical Analysis

ACT values before and after enoxaparin were com-pared with a paired t-test. Linear regression analysis wasused to compare the relationship between ACT andENOX card values. A P value � 0.05 was consideredsignificant.

RESULTS

After 0.75 mg/kg of enoxaparin plus eptifibatide, meanACT increased from 125 � 22 to 194 � 24 sec. After 1mg/kg of enoxaparin, ACT increased from 122 � 22 to199 � 20 sec. The mean increase in ACT was 69 � 23sec (range, 10–132) in the 0.75 mg/kg group (n � 45;P � 0.0001) and 77 � 26 sec (range, 25–120) in the 1mg/kg group (n � 22; P � 0.0001; Fig. 1). There was astrong linear relationship between the ACT and ENOXvalues (r � 0.86; P � 0.0001; Fig. 2). None of thepatients developed transient abrupt closure, thrombusformation, major bleeding, or required urgent revascular-ization.

DISCUSSION

Because of the consequences of thrombosis duringPCI, most operators monitor the state of anticoagulationthroughout the procedure [2,3]. The usefulness of ACT

measurements in the setting of balloon angioplasty hasbeen shown in several trials and target values for anti-coagulation with and without glycoprotein IIb/IIIa inhib-itors are defined. Because of the limitations of UFH as ananticoagulant, low-molecular-weight heparins are beingused more frequently during PCI. However, the ability tomonitor quickly the status of anticoagulation after low-molecular-weight heparin is still under development. Theanticoagulant effect of low-molecular-weight heparinscan be assessed by measuring anti-Xa levels. For venous

Fig. 1. Pretreatment and posttreatment (5 min) activated co-agulation times in seconds. Each line is the value from anindividual patient, with the bold line indicating the change inmean values.

Fig. 2. Linear regression of the relationship between the ENOXtest (vertical axis) and ACTs (horizontal axis). Both the ACTsand ENOX test results are measured in seconds.

Monitoring Enoxaparin With ACT 53

indications, anti-Xa levels of � 0.6 IU/ml are felt to betherapeutic, whereas for arterial indications, such asacute coronary syndromes, levels between 0.6 and 1.8IU/ml are appropriate [15–17]. Although anti-Xa assayscan be performed in many hospital laboratories, the timerequired makes it impractical for decision-making duringPCI. Since most laboratories have the equipment andexperience to measure ACTs, it would be useful to un-derstand if the ACT is an acceptable test in patientsreceiving enoxaparin.

Our data show that ACT measurements may be usefulfor monitoring anticoagulation after i.v. enoxaparin.Mean ACT increased from 122 � 22 to 199 � 20 secafter 1 mg/kg i.v. enoxaparin and from 125 � 22 to194 � 24 sec after 0.75 mg/kg enoxaparin in patientsreceiving concomitant eptifibatide therapy. Althoughsome previous reports have stated that enoxaparin haslittle effect on ACTs, other small studies have shownresults similar to ours [18]. For example, in a study of 60patients, 5 min after 1 mg/kg intravenous enoxaparinmean ACT increased from 130 to 188 sec [19]. A morerecent study showed a mean ACT increase from 128 to203 sec after 1 mg/kg i.v. enoxaparin with a mean peakanti-Xa level of 1.30 � 0.18 IU/ml [20]. In a study using60 or 80 IU/kg i.v. daltaparin, a different low-molecular-weight heparin with distinct pharmacokinetics, meanACT increased from 125 to 184 sec [21]. The differencesin ACT prolongation between various low-molecular-weight heparins is likely due to the differences in theIIa/Xa ratio. While this ratio may be important in clinicalefficacy, no direct comparisons have been performedbetween the low-molecular-weight heparins in the settingof PCI.

Recently, a rapid point-of-care assay, the ENOX clot-ting time, has become available with times � 260 sec,indicating anti-Xa levels � 1.0 IU/ml and times of 450sec corresponding with anti-Xa levels of 1.9–2.0 IU/ml.The test costs approximately $25 per sample and large-scale trials to evaluate the appropriate therapeutic rangeduring PCI are underway. We found a significant corre-lation (r � 0.86) between ACTs and ENOX clotting timein a subgroup of 26 patients, suggesting that the ACTmay be an acceptable surrogate.

Point-of-care monitoring with either ACT or ENOXcoagulation time has several potential advantages. It mayhelp confirm adequate anticoagulation in patients receiv-ing an earlier subcutaneous dose of enoxaparin. Further-more, it could identify the presence or lack of a thera-peutic effect in patients with morbid obesity, renalinsufficiency, and in those receiving enoxaparin withfibrinolytic therapy, or smaller i.v. doses of enoxaparin[22–27].

Study Limitations

This study is limited by its size and we did not corre-late ACT values with anti-Xa levels. We did not evaluatethe relationship between increasing doses of enoxaparinand ACT levels in the same patient, nor did we determinethe duration of ACT prolongation after i.v. administra-tion. We evaluated only enoxaparin and eptifibatide anddid not study other low-molecular-weight heparins orplatelet glycoprotein IIb/IIIa antagonists. Moreover, it isunknown if the same magnitude of effect will occur aftersubcutaneous dosing. Finally, the purpose of this studywas to demonstrate that ACTs were affected by i.v.enoxaparin and the study was not powered to determinethe efficacy of i.v. enoxaparin use in PCI or the appro-priate therapeutic range as established by ACT monitor-ing.

CONCLUSIONS

The ACT is prolonged in patients 5 min after receivingi.v. enoxaparin and may be useful in monitoring theanticoagulant effect of this drug. Moreover, ACT levelsin this setting correlate with the ENOX clotting times.The relationship between ACT level and clinical efficacyusing i.v. enoxaparin will require a larger trial.

ACKNOWLEDGMENTS

The authors express their gratitude to the staff of thecardiac catheterization laboratory at the Scott and WhiteHospital for their assistance in the performance of thisstudy and to Mark Riggs for his help in the analysis ofthese data.

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