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Original Contribution
Early Ambulation and Variability in Anticoagulation during Elective Coronary Stenting with a Single Intravenous Bolus
of Low-Do
February 2006
Low-molecular weight heparin (LMWH), especially enoxaparin, and unfractionated heparin (UFH), is recommended in the early medical management of acute coronary syndromes.1,2 Compared to intravenous UFH, subcutaneous LMWH has a more predictable effect, a higher anti-Xa/anti-IIa ratio, does not require monitoring with an activated clotting time, and is resistant to inhibition by activated platelets.3–5 Earlier work by Collet and Montalescot,6 as well as the recent, large SYNERGY trial7 documented the efficacy of transitioning high-risk acute coronary syndrome patients to percutaneous coronary intervention (PCI) after treatment with subcutaneous enoxaparin (1 mg/kg every 12 hours).
In contrast, the optimal dosing, efficacy and safety of intravenously administered enoxaparin, as opposed to UFH, which has been the antithrombotic agent of choice since the early days of PCI, has not been well established.8 The primary goal of the present study was to assess the feasibility of immediate sheath removal post-PCI in consecutive stable patients given a single low-dose intravenous (IV) bolus of enoxaparin as the sole anticoagulant for elective PCI without utilization of closing devices. In order to monitor the safety of this regimen, we also analyzed anti-Xa levels and clinical outcomes.
Methods
Patient population. Technique for PCI and hematological measurements. The study was approved by the ethics committee of the Heart Institute of the University of São Paulo Medical School, and written informed consent was obtained from all patients. A total of 53 consecutive patients with stable coronary disease who were referred for elective PCI with stenting of a native stenosis greater than or equal to 70% were prospectively enrolled in the study. Exclusion criteria were primary PCI for ST-elevation myocardial infarction (MI), administration of LMWH or UFH within the last 48 hours before PCI, or a glycoprotein (GP) IIb/IIIa receptor antagonist within the previous 2 weeks. In-hospital follow up included daily physical examination, ECG and CK-MB measurements (before PCI, 8 hours after PCI, and approximately 16 hours after PCI. In cases of CK-MB elevation, measurements were repeated at 8-hour intervals until a return to normal levels). One month after the PCI, all patients underwent clinical follow up at our out-patient clinic, with physical examination and ECG recording. Clinical outcomes including death, MI and urgent target vessel revascularization were collected for up to 30 days. Periprocedural MI was defined as chest pain and/or ECG changes with a CK-MB > 3 times the upper limit of normal, or the appearance of a new left bundle block or new Q-waves. Major and minor bleeding were defined according to the Thrombolysis In Myocardial Infarction (TIMI) criteria.9
All patients were pretreated with 100 mg of aspirin and 300 mg of clopidogrel at least 6 hours prior to intervention. PCI was performed using 7 Fr arterial sheaths via the femoral approach. IV enoxaparin, 0.5 mg/kg single IV bolus, was administered 10 minutes before the intervention in all patients, independent of body weight or serum creatinine levels. There was no in-lab monitoring of anticoagulation. GP IIb/IIIa inhibitors were not utilized. Drug-eluting stents were used in only 2 patients, while bare metal stents were utilized in 51 patients. At the end of the procedure, sheaths were removed and hemostasis was achieved with manual compression. Vascular closure devices were not used. In order not to influence the anti-Xa levels, catheters were flushed with plain saline solution without added enoxaparin or UFH. The length of the procedure and the duration of femoral compression were recorded. Patients were ambulated 6 to 8 hours after their sheath pull. Blood for anti-factor Xa activity was obtained before PCI, and then 10 minutes, 1, 2, 4 and 6 hours after IV administration of enoxaparin. For anti-Xa measurements, 9 volumes of blood were collected in 1 volume of 0.1 M trisodium citrate and centrifuged at 2,500 g for 15 minutes. Plasma was stored at -20ºC and within 1 month was thawed once at 37ºC thirty minutes before assay. Anti-factor Xa activity was measured using a chromogenic assay kit from Biopool International (Ventura, California). Calibration curves were performed with standards prepared from pooled plasma enriched with the heparin preparation used during heparin therapy. CK-MB mass was measured with an immunometric method on the Immulite 1000 system (Diagnostic Product Corporation, Los Angeles, California) in accordance with the manufacturer’s instructions. The upper reference limit was 4.0 ng/ml.
Statistics. Continuous variables are presented as mean ± standard deviation (SD). Categorical variables are expressed as percentages. Anti-Xa levels at different time points were compared using a repeated measures general linear model. Multiple comparisons among the main effects of the evaluated time points were analyzed using the Bonferroni adjustment to the confidence intervals and significance. A p-value than 3 times the upper limit of normal. There were no Q-wave MIs, stent thromboses or urgent revascularization within 30 days.
Postprocedural elevations of CK-MB levels to > 3 times the upper normal level occurred in 7 patients (13.2%). None of these 7 patients had clinical symptoms of ischemia or ECG changes post-PCI. Peak anti-Xa levels for the 7 patients with CK-MB elevation were 0.54 ± 0.22 IU/ml. There was no relationship between anti-Xa levels and CK-MB elevations. Total CK levels to > 2 times normal occurred in 15% of patients.
In 51 of the 53 patients, the sheath was removed immediately after the intervention. Two patients had their sheaths removed 6 hours post-PCI: 1) the patient in which an intracoronary thrombus was detected (and then received IV UFH), and 2) the patient in whom persistent oozing at the access site was noted throughout the intervention. The average duration of femoral compression after sheath removal was 19.1 ± 7.2 minutes.
The anti-Xa level before enoxaparin administration was 0.04 ± 0.0 IU/ml, increasing to 0.56 ± 0.16 IU/ml at 10 minutes post-bolus, and then progressively decreasing to 0.44 ± 0.15, 0.36 ± 0.13, 0.24 ± 0.11, and 0.14 ± 0.09 IU/ml, 1, 2, 4 and 6 hours after IV enoxaparin administration, respectively (Table 2 and Figure 1). All comparisons among anti-Xa levels showed that the measurements significantly differed in all time points (p 0.5 IU/ml was not achieved in 12 patients (23.5%). Mean ± SD anti-Xa levels among these 12 patients was 0.37 ± 0.11 IU/ml. Anti-Xa levels > 0.8 IU/ml were achieved in only 5 of 53 patients (4%). Although a progressive decrease was seen over the measured time points, the average anti-Xa level was still significantly higher than baseline 6 hours after the IV bolus administration (Figure 1).
Discussion
Our findings indicate that a single IV bolus of low-dose enoxaparin (0.5 mg/kg) for elective stenting allowed for immediate removal of femoral sheaths at the end of the procedure with a low incidence of vascular complications. This was achieved with the routine use of 7 Fr arterial sheaths by the femoral approach. However, a significant proportion of patients had what many cardiologists would regard as a lower than “ideal” (0.5 IU/ml) anti-Xa level during the intervention. Nevertheless, intracoronary thrombus was identified in only 1 patient, there were no Q-wave MIs and/or stent thromboses, and CK-MB levels > 3 times the upper limit of normal was detected in only 13% of patients. These CK-MB elevations occurred in a cohort that did not receive any platelet GP receptor antagonists.
The safety and efficacy of IV LMWH in PCI, using different doses of IV enoxaparin without previous subcutaneous administration, has been tested in patients with stable or unstable coronary disease undergoing PCI.8,10–16
Rabah et al.10 randomized 60 patients to receive IV enoxaparin (1 mg/kg bolus dose) or unfractionated heparin at the time of coronary intervention. Angioplasty success rates, in-hospital ischemia, bleeding and vascular complications were similar in both groups. Dudek et al.11 reported the outcomes of PCI procedures conducted after IV administration of 1 mg/kg of enoxaparin in 61 patients with CAD. No major bleeding occurred, while minor bleeding was noted in 6.5% of patients. No periprocedural major adverse cardiac events (death, Q-wave infarction, urgent revascularization) were observed. Postprocedural CK-MB > 3 times the upper reference level was detected in 5% of the patients.
Patients undergoing elective PCI were enrolled in two distinct and separate studies, NICE 1 and NICE 4, conducted by the National Investigators Collaborating on Enoxaparin study groups.12 Patients in NICE 1 received 1.0 mg/kg IV enoxaparin (without abciximab), while NICE 4 patients received 0.75 mg/kg of IV enoxaparin in combination with standard dose abciximab. Bleeding events and ischemic outcomes assessed in-hospital and at 30 days post-PCI were infrequent with either pharmacologic regimen.12
Borentain et al.8 conducted a meta-analysis of IV low-molecular-weight heparin versus unfractionated heparin in PCI. The analysis included data from eight randomized trials in which patients received either IV LMWH (n = 1,037; enoxaparin n = 571; reviparin, n = 306; dalteparin, n = 160) or UFH (n = 978). Seven additional registries were studied to assess the efficacy and safety of LMWH (enoxaparin, n = 2,504; dalteparin, n = 246) during PCI. A single IV dose of LMWH immediately before PCI was at least as efficacious as IV UFH. Patients treated with LMWH showed equivalent or less bleeding than patients treated with UFH. In particular, 0.5 mg/kg of enoxaparin had a good efficacy and safety profile.
Our study design was predicated upon the original work by Choussat et al.13 who suggested that administration of IV enoxaparin 0.5 mg/kg 10 minutes before PCI would reliably elevate the peak anti-Xa level to > 0.5 IU/ml. In their series of 242 patients, Choussat and colleagues reported peak anti-Xa levels > 0.5 IU/ml in 97.5% of their patients. In addition, there was a very low incidence of thrombotic events (only 10% had elevated cardiac markers) and vascular complications, even with immediate post-PCI sheath removal.13 Only 2.5% of their patients did not reach peak anti-Xa levels > 0.5 IU/ml. This contrasts sharply with the present study in which 23.5% of our patients did not reach peak anti-Xa levels > 0.5 IU/ml. This discrepancy may be coincidental due to the small patient population in our study, or partially influenced by several significant differences between the studies. For example, in the Choussat study13 the sheaths and catheters were flushed with a saline solution containing a low concentration of enoxaparin. In our study, flushes were done with a heparin-free saline solution. There were also differences in the adjunctive therapies including the dose of aspirin, the use of GP IIb/IIIa (26% in their study) and pretreatment with clopidogrel.
Additionally, racial differences may have contributed to the difference in anti-Xa levels among our South American patients versus the Europeans studied by Choussat et al. In particular, Chen et al.14 reported that the peak anti-Xa level was 1.3 ± 0.18 IU/ml in an Asian population, whereas Pena et al.15 reported overcoagulation (anti-Xa > 1.5 IU/ml) in 82% of patients studied in Europe.
In the present study, 13% of the patients experienced a > 3-fold elevation in cardiac markers post-PCI. This is comparable to the 10% rate observed by Choussat,13 and also to the roughly 20% observed by Cantor et al.17 It is believed that the pharmacological action of LMWHs as antithrombotics is due to the inhibition of factor Xa.16 However, some heparin fraction related to LMWHs were shown to have negligible anti-Xa activity despite potent antithrombotic properties in vivo.18,19 Similar findings were recently observed with a heparin-related molecule isolated from an algae.20 Our main interest was to check the safety of immediate sheath removal post-PCI using a low dose of IV enoxaparin. Our original intention was to enroll a larger number of patients. However, when the anti-Xa results in the first 53 patients returned with lower than expected anticoagulation levels, we opted to report our findings and wait for the publication of the STEEPLE trial, in which one of the arms involves a large number of PCI procedures performed using the same low dose of IV enoxaparin as in our study. Therefore, because of the small sample size, our data are “limited.”
Conclusions
A single, low dose of IV enoxaparin (0.5 mg/kg) for elective coronary stenting allowed immediate removal of femoral sheaths at the end of the procedure with a low incidence of bleeding complications. However, a sizeable proportion of patients reached anti-Xa levels below the recommended therapeutic targets for PCIs. These present findings warrant further investigation in larger trials in order to clarify the hematologic (anti-Xa activity), as well as clinical outcomes associated with the IV enoxaparin anticoagulation.
Acknowledgements. We would like to thank Helena Nader and the late Carl Peter Von Dietrich for teaching us about low-molecular weight heparins and for their invaluable assistance in helping us pursue this study.
1. Braunwald E, Antman EM, Beasley JW, et al. American College of Cardiology/American Heart Association. Committee on the Management of Patients with Unstable Angina. J Am Coll Cardiol 2002;40:1366–1374.
2. Wong GC, Giugliano RP, Antman EM. Use of low-molecular-weight heparins in the management of acute coronary syndromes and percutaneous coronary intervention. JAMA 2003;289:331–342.
3. Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992;79:1–17.
4. Samama MM, Bara L, Gerotziafas GT. Mechanisms for the antithrombotic activity of low molecular weight heparins (LMWH). Haemostasis 1994;24:105–117.
5. Weitz JI. Low-molecular-weight heparin. N Engl J Med 1997;332:1330–1335.
6. Collet JPh, Montalescot G, Lison L, et al. Percutaneous coronary intervention after subcutaneous enoxaparin pretreatment in patients with unstable angina pectoris. Circulation 2001;103:658–663.
7. Ferguson JJ, Califf RM, Antman EM, et al. for the SYNERGY Trial Investigators. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: Primary results of the SYNERGY randomized trial. JAMA 2004;292:45–54.
8. Borentain M, Montalescot G, Bouzamondo A, et al. Intravenous low-molecular-weight heparin versus unfractionated heparin in percutaneous coronary angioplasty: A meta-analysis. Eur Heart J 2003;24(Abstr, Suppl):541.
9. Rao AK, Pratt C, Berke A, et al. Thrombolysis in myocardial infarction (TIMI) trial-phase I: Hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11:1–11.
10. Rabah MM, Premmereur J, Graham M, et al. Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris. Am J Cardiol 1999;84:1392–1395.
11. Dudek D, Zymek P, Bartus S, Dubiel JS. The assessment of safety of enoxaparin administration during percutaneous transluminal coronary angioplasty after ticlopidine pretreatment. Application of low molecular weight heparins in prevention of coronary micro-embolization. Przegl 2001;58:484–486.
12. Kereiakes DJ, Grines C, Fry E, et al. for the NICE 1 and NICE 4 Investigators. National Investigators Collaborating on Enoxaparin. J Invasive Cardiol 2001;13:272–278.
13. Choussat R, Montalescot G, Collet JP, et al. A unique, low dose of intravenous enoxaparin in elective percutaneous coronary intervention. J Am Coll Cardiol 2002;40:1943–1950.
14. Chen WH, Lau CP, Lau YK, et al. Stable and optimal anticoagulation is achieved with a single dose of intravenous enoxaparin in patients undergoing percutaneous coronary intervention. J Invasive Cardiol 2002;14:439–442.
15. Pena PS, Montalescot G, Hulot JS, et al. Intravenous enoxaparin in patients undergoing percutaneous coronary intervention. Circulation 2004(Suppl);110:III–616.
16. Korovesis S, Karvouni E, Karabinos I, et al. Comparison of enoxaparin and unfractionated heparin in coronary angioplasty. Hellenic J Cardiol 2005;46:46–51.
17. Cantor WJ, Newby LK, Christenson RH, et al. Prognostic significance of elevated troponin I after percutaneous coronary intervention. J Am Coll Cardiol 2002;39:1738–1744.
18. Bianchini P, Osima B, Parma B, et al. Structural studies “in vivo” and “in vitro” pharmacological activities of heparin fractions fragments prepared by chemical enzymic depolimerization. Thromb Res 1985;40:49–58.
19. Bianchini P, Osima B, Parma B, et al. Lack of correlation between “in vitro” and “in vivo” antithrombotic activity of heparin fractions related compounds: Heparin sulfate as an antithrombotic agent “in vivo”. Thromb Res 1985;40:597–607.
20. Nader HB, Lopes CC, Rocha HAO, et al. Heparins and heparinoids: Occurrence, structure and mechanism of antithrombotic and hemorrhagic activities. Curr Pharm Design 2004;10:951–966.
