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J Am Coll Cardiol, 2003; 42:424-427, doi:10.1016/S0735-1097(03)00653-3
© 2003 by the American College of Cardiology Foundation
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CLINICAL STUDY

The impact on coagulation of an intravenous loading dose in addition to a subcutaneousregimen of low-molecular-weight heparinin the initial treatment of acute coronary syndromes

Nick R. Bijsterveld, MD*,*, Arno H. Moons, MD*, Joost C. M. Meijers, PhD{dagger}, Marcel Levi, MD{dagger}, Harry R. Büller, MD{dagger} and Ron J. G. Peters, MD*

* Departments of Cardiology, Amsterdam, The Netherlands
{dagger} Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Manuscript received December 16, 2002; revised manuscript received February 17, 2003, accepted April 24, 2003.

* Reprint requests and correspondence: Dr. Nick R. Bijsterveld, Department of Cardiology, Room F3-241, Academic Medical Center, Meibergdreef 9, 1105 AZ, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands.
n.r.bijsterveld{at}amc.uva.nl


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We sought to quantify the impact of adding an intravenous loading dose to a subcutaneous regimen of enoxaparin in patients with an acute coronary syndrome (ACS).

BACKGROUND: It is unclear whether an intravenous (IV) loading dose of enoxaparin should be added to a subcutaneous (SQ) regimen in patients with ACS.

METHODS: Patients admitted with ACS were randomized to IV+SQ (n = 14) or SQ alone (n = 11) enoxaparin treatment. Coagulation markers were measured at nine time points during the first 24 h of treatment.

RESULTS: The IV+SQ therapy immediately resulted in therapeutic anti-Xa levels, which remained significantly higher for 6 h compared with SQ alone, without reaching excessively high levels. A rapid decrease of plasma prothrombin fragments 1+2 (F1+2) levels was observed as soon as 5 min after the IV injection (33% lower; p = 0.007), and these levels remained lower up to 2 h after the start of treatment compared with SQ alone. The ex vivo thrombin generation time was maximally prolonged at 5 min post-injection in the IV+SQ group and remained significantly prolonged up to 6 h post-injection compared with SQ alone. The tissue factor pathway inhibitor plasma activity was immediately increased by 194% with IV+SQ, whereas the maximum increase with SQ alone was 47% at 3 h.

CONCLUSIONS: Therapeutic plasma levels of enoxaparin are achieved significantly earlier by an IV+SQ regimen compared with SQ alone, without leading to unacceptably high levels. As the risk of thrombotic complications is greatest early after admission, the observed differences in antithrombotic effects may translate into a clinical benefit. However, this remains to be established.

Abbreviations and Acronyms
  ACS
  acute coronary syndrome
  anti-Xa
  anti-factor Xa
  AUC
  area under the curve
  F1+2
  prothrombin fragments 1+2
  IV
  intravenous
  LMWH
  low-molecular-weight heparin
  SQ
  subcutaneous
  TFPI
  tissue factor pathway inhibitor
  TGT
  thrombin generation time

Low-molecular-weight heparins (LMWH) are now routinely used in the initial treatment of patients admitted with acute coronary syndromes (ACS). However, there is no uniformity regarding the initiation of LMWH, both in clinical trials and clinical practice. In several trials (1–3), treatment was initiated by subcutaneous (SQ) injection on hospital admission. In contrast, other trials (4,5) used a combined regimen, with an intravenous (IV) loading dose followed by SQ administration. An IV loading dose may benefit these patients, as the highest event rates are observed early after admission. However, this combined regimen results in higher initial plasma drug levels, potentially increasing the risk of bleeding. No studies have compared these regimens.

Therefore, we quantified the impact on the coagulation system in patients admitted with ACS in a randomized comparison of these two regimens.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patient selection and treatment.   Patients admitted to the Coronary Care Unit at the Academic Medical Center (Amsterdam, The Netherlands) with a diagnosis of unstable angina or non–Q-wave myocardial infarction were eligible. Patients using anticoagulants, including heparin and warfarin, or antiplatelet agents other than aspirin (i.e., clopidogrel, nonsteroidal anti-inflammatory drugs) were not included.

After written informed consent was obtained, patients were randomized to 40 mg IV enoxaparin combined with SQ enoxaparin or SQ enoxaparin alone. In the combined group, SQ enoxaparin was administered within 2 min after the IV dose.

Based on a standard dose of 1 mg/kg, the following SQ dose of enoxaparin was administered twice daily: 60 mg if the body weight was <70 kg, 80 mg for weight between 70 and 90 kg, and 100 mg if >90 kg. Aspirin was dosed at 100 mg once daily.

The study was approved by the Institutional Review Board of the Academic Medical Center in Amsterdam.

Blood sampling.   Nine blood samples were obtained during the first day of admission: before administration of enoxaparin, at 5 min, and 1, 2, 3, 4, 6, 8, and 24 h after the start of enoxaparin. Blood samples were obtained through an IV catheter, which was distal to other systems and not used for medication. The IV catheter was only flushed with 0.9% saline, performed just before and after blood sampling. At each blood sampling, the first 2 ml blood was discarded, and 9 ml blood was collected in citrated Vacutainer tubes (4.5 ml sodium-citrate 0.105 molair 0.5 ml per 4.5 ml blood). Immediately after sampling, the blood was centrifuged at 2,200 g for 20 min at 6°C. Plasma was separated and filled out in cryocups and frozen at –80°C until analysis was performed. These procedures were completed within 1 h after blood sampling.

Assays.   Anticoagulation levels were determined by an anti-factor Xa (anti-Xa) determination with a chromogenic assay (coated heparin, Chromogenix, Mölndal, Sweden) calibrated against enoxaparin.

To measure in vivo thrombin generation, prothrombin fragment 1 + 2 (F1+2) plasma concentrations were determined by sandwich-type enzyme-linked immunosorbent assay (Dade-Behring, Marburg, Germany). Additionally, the thrombin generation time (TGT) was determined, reflecting ex vivo thrombin formation using calcium and recombinant human tissue factor (Dade, Innovin). Results were measured spectrophotometrically and expressed as T max (time to reach the mid-point of clear to maximum turbid density).

Tissue factor pathway inhibitor activity (TFPI), a natural anticoagulant, was quantified by a sandwich-type enzyme-linked immunosorbent assay from Behring (Marburg, Germany).

Statistical analysis.   Differences between the groups per time point were identified using an independent samples t test.

Differences between the groups in total thrombin generation (TGT, F1+2) and TFPI plasma levels over the time period 0 to 8 h were identified using an independent samples t test over the calculated area under the curve (AUC) between time points 0 h and 8 h.

Differences within a group between time points were compared using a paired samples t test.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Baseline characteristics.   Of the 25 patients randomized, 14 received IV+SQ enoxaparin (IV+SQ group) and 11 received SQ enoxaparin alone (SQ group). The baseline characteristics of the two groups were comparable (Table 1).


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  		Table 1 Patient Characteristics

 
During the first 24 h of treatment, no bleeding complications occurred. Six patients in the IV+SQ group and two patients in the SQ group had recurrent anginal symptoms; of these eight patients, only three had accompanying ischemic electrocardiographic changes (one IV+SQ and two SQ patients). In both groups, one patient underwent coronary angiography, and one revascularization was performed (IV+SQ group).

Anticoagulation levels.   Within 5 min after IV injection of enoxaparin, the mean anti-Xa levels rose from 0 to 1.25 U/ml (Fig. 1). During the following hours, the levels gradually decreased to 0.63 U/ml after 8 h. In contrast, 5 min after SQ alone administration, the anti-Xa levels were still undetectable, increasing to 0.30 U/ml after 1 h, and remained significantly lower up to 6 h compared with the IV+SQ group. The AUC between time points 0 and 8 h was significantly higher in the IV+SQ group compared with the SQ alone group (p < 0.0005). Anti-Xa levels at steady-state (24 h after baseline) were comparable between both groups (±0.90 U/ml).



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  		Figure 1 Anti-factor Xa (anti-Xa) levels during the first 24 h of treatment with subcutaneous (SQ) alone (solid circles) or intravenous +SQ (open squares) enoxaparin. Data are presented as the mean value ± SEM. Dotted lines represent the lower and upper therapeutic range (0.5 and 1.0 U/ml, respectively). Significant differences (p < 0.05) using the t test between the two groups are marked with an asterisk.

 
In vitro thrombin generation.   Higher initial anti-Xa levels were reflected in the TGT (Fig. 2). A slow increase in TGT was observed after SQ alone injection, rising from 170 s at baseline to a maximum of 738 s at 6 h. Intravenous loading resulted in an immediate increase of TGT to ±2,000 s 5 min after injection, which remained significantly higher during the first 6 h compared with SQ alone group. This delay in thrombin generation was reflected in a significant higher AUC in the IV+SQ group compared with the SQ alone group (p < 0.0005).



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  		Figure 2 Thrombin generation time (TGT) during the first 24 h of treatment with subcutaneous (SQ) alone (solid circles) or intravenous +SQ (open squares) enoxaparin. Data are presented as the mean value ± SEM. Significant differences (p < 0.05) using the t test between the two groups are marked with an asterisk.

 
In vivo thrombin generation.   Intravenous bolus injection resulted in a rapid decrease of F1+2, with significantly lower levels compared with baseline levels, as soon as 5 min post-injection (0.76 nmol/l; p < 0.0005), which further decreased in the first 24 h to 0.58 nmol/l (Fig. 3). In the SQ alone group, 2 h after administration, F1+2 levels were significantly lower than baseline (p = 0.01) and reached the lowest level of 0.71 nmol/l at 24 h. Significantly lower F1+2 levels between in the IV+SQ group compared with the SQ alone group were observed at the 5-min, 1-h and 2-h time points. The AUC between time points 0 and 8 h was nonsignificantly reduced by 19% in the IV+SQ group compared with the SQ alone group (p = 0.2).



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  		Figure 3 Levels of prothrombin fragments 1 + 2 (F1+2) during the first 24 h of treatment with subcutaneous (SQ) alone (solid circles) or intravenous +SQ (open squares) enoxaparin. Data are presented as the mean value ± SEM. Significant differences (p < 0.05) using the t test between the two groups are marked with an asterisk.

 
In vivo natural anticoagulants.   Intravenous enoxaparin resulted in an immediate increase of plasma TFPI, tripling the mean plasma activity from 80% to 294% (Fig. 4). Subcutaneous alone administration showed a modest increase of plasma TFPI activity from 79% to a maximum of 126% at 3 h. During the first 2 h, TFPI was significantly different between the treatment groups. Six hours after the start of treatment, both groups had returned to baseline TFPI levels. A 68% higher AUC in the IV+SQ group was observed (p = 0.1).



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  		Figure 4 Activity of tissue factor pathway inhibitor (TFPI) during the first 24 h of treatment with subcutaneous (SQ) alone (solid circles) or intravenous +SQ (open squares) enoxaparin. Data are presented as the mean value ± SEM. Significant differences (p < 0.05) using the t test between the two groups are marked with an asterisk.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Our study demonstrates that combined IV and SQ enoxaparin administration, compared with SQ alone enoxaparin, in the initial treatment of patients with ACS results in a more rapid inhibition of the coagulation system. This is reflected by an immediate decrease of plasma levels of the in vivo thrombin generation marker F1+2 and of ex vivo prolongation of TGT. Intravenous initiation of enoxaparin treatment immediately resulted in therapeutic anticoagulation levels, with anti-Xa levels of 1.25 U/ml within 5 min after administration. Furthermore, an immediate release of TFPI was observed, tripling TFPI plasma activity. This rapidly induced anticoagulant effect remained significantly greater up to 6 h after the start of treatment, compared with the SQ alone enoxaparin regimen.

Whether the reduction in thrombin generation during the first hour of ACS treatment results in a reduction of ischemic events cannot be derived from our study. A retrospective comparison of trials using SQ LMWH (1–3) with those using IV+SQ LMWH (4,5) is not reliable because of the differences in patients and methods. The Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events study demonstrated that antithrombotic treatment may have an impact on clinical events as early as four hours after initiation of treatment (6). Consequently, we postulate that adequate anticoagulant drug levels are desirable as early as possible.

An immediate and significant increase of TFPI activity caused by IV enoxaparin was observed. This rapid release could be of benefit, especially in these ACS patients. Coronary plaque rupture exposes subendothelial tissue factor to the circulation (7,8), which is a strong activator of the coagulation system and local thrombus formation. The TFPI binds to the tissue factor-factor VII complex (TF-VII) and inhibits the procoagulant properties of TF-VIIa. Also, TFPI has been shown to reduce tissue factor activity, particularly in human atherosclerotic plaques (9). We observed no depletion of TFPI activity in the IV+SQ group as compared with the SQ alone group.

A potential disadvantage of a combined IV and SQ regimen is an increased risk of bleeding complications. We observed maximum mean peak anti-Xa levels of 1.25 U/ml in the IV+SQ group 5 min after treatment start. These levels are comparable with those observed during steady-state SQ alone treatment in healthy volunteers (1.2 U/ml) (10) and ACS patients (1.0 U/ml [range 0.9 to 1.2]) (11). Because the therapeutic range of enoxaparin is 0.5 to 1.0 U/ml (10), patients given an IV loading dose are below this upper limit within 1 h after administration (Fig. 1). It is therefore unlikely that maximum anti-Xa levels after 40 mg IV enoxaparin will induce an unacceptable increased risk of bleeding complications. This is supported by a comparison of the data from the Thrombolysis In Myocardial Infarction-11B (TIMI-11B) and Efficacy Safety Subcutaneous Enoxaparin in Non–Q-wave Coronary Events (ESSENCE) studies, using 30 mg IV+SQ and SQ alone enoxaparin regimens, respectively (3,4). The incidence of minor bleeding during the first 24 h of treatment in the IV+SQ patients was 1.8% versus 2.1% in the SQ alone patients. Major bleedings occurred in 0.26% versus 0.31% of the patients, respectively. Both this indirect comparison and our data do not suggest that an initial IV loading dose of LMWH is associated with an excessive risk of bleeding that might offset the benefit of achieving therapeutic drug levels early.

Conclusions.   Therapeutic drug levels were achieved significantly earlier with combined IV+SQ treatment compared with SQ alone treatment. This resulted in a 2 to 6 h earlier reduction of in vivo thrombin generation marker F1+2 levels, a delay in TGT, and an early threefold increase of plasma TFPI activity, compared with SQ alone enoxaparin. The combined IV+SQ regimen did not result in unacceptably high anticoagulation levels. Clearly, this does not rule out a potential increase in the risk of bleeding complications. Our results suggest that a combined IV plus SQ start of LMWH administration in the treatment of ACS patients may result in a clinical benefit, compared with a regimen of SQ alone. However, this clinical benefit remains to be determined.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. The FRISC Investigators. Low-molecular-weight heparin during instability in coronary artery disease: FRagmin during InStability in Coronary artery disease study. Lancet. 1996;347:561–568[CrossRef][Medline]
  2. Klein W, Buchwald A, Hillis SE, et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease: FRagmin In unstable Coronary artery disease (FRIC) study. Circulation. 1997;96:61–68[Abstract/Free Full Text]
  3. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease (ESSENCE). N Engl J Med. 1997;337:447–452[Abstract/Free Full Text]
  4. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non–Q-wave myocardial infarction (TIMI 11B). Circulation. 1999;100:1593–1601[Abstract/Free Full Text]
  5. The FRAXIS Study Group. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non–Q-wave myocardial infarction: FRAXIS (FRAXiparine in Ischaemic Syndrome). Eur Heart J. 1999;20:1553–1562[Abstract/Free Full Text]
  6. The CURE Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502[Abstract/Free Full Text]
  7. Marmur JD, Thiruvikraman SV, Fyfe BS, et al. Identification of active tissue factor in human coronary atheroma. Circulation. 1996;94:1226–1232[Abstract/Free Full Text]
  8. Toschi V, Gallo R, Lettino M, et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation. 1997;95:594–599[Abstract/Free Full Text]
  9. Caplice NM, Mueske CS, Kleppe LS, et al. Presence of tissue factor pathway inhibitor in human atherosclerotic plaques is associated with reduced tissue factor activity. Circulation. 1998;98:1051–1057[Abstract/Free Full Text]
  10. Enoxaparin. Investigator Brochure Lovenox, Clexane, Klexane (enoxaparin sodium). December 18, 2001
  11. The TIMI 11A Investigators. Dose-ranging trial of enoxaparin for unstable angina: results of TIMI 11A. J Am Coll Cardiol. 1997;29:1474–1482[Abstract]



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