Stable and Optimal Anticoagulation is Achieved with a Single Dose of Intravenous Enoxaparin in Patients Undergoing Percutaneous

Unfractionated heparin (UFH) has been the anticoagulant of choice for percutaneous coronary intervention (PCI) since the procedure’s inception, although few data exist regarding the optimal extent of activated partial thromboplastin time (aPTT) or of activated clotting time (ACT) prolongation. It has been shown that ACT is inversely related to the likelihood of abrupt vessel closure, but a minimum target ACT cannot be identified.1 High procedural ACTs are associated with increased bleeding risk.2,3 On the other hand, despite the use of relatively high doses of UFH together with aspirin, periprocedural ischemic events occur in 6–8% of patients.4,5 The biological response to UFH can vary considerably even though weight-adjusted doses are given.6 Moreover, UFH has the disadvantage of neutralization by platelet factor IV and the potential to cause thrombocytopenia and heparin-induced thrombocytopenia syndrome.7,8 Enoxaparin has been shown to be more efficacious than UFH in patients with non-ST elevation acute coronary syndromes (ACS).9,10 In comparison to UFH, enoxaparin has better bioavailability, a longer half-life, and dose-independent clearance that enables it to be given in a weight-adjusted dose twice daily via the subcutaneous route without the need for monitoring in the majority of cases.11 Preliminary data from the National Investigators Collaborating on Enoxaparin (NICE)-4 trial demonstrated the safety and efficacy of enoxaparin combined with abciximab in PCI.12 However, there are no data on Asian populations. We therefore sought to determine the safety, efficacy and pharmacokinetics of intravenous enoxaparin in place of UFH to achieve adequate anticoagulant effects when used in Asian patients undergoing PCI. METHODS Study patients. Sixty-one consecutive Chinese patients undergoing PCI were recruited. Patients were excluded from the study if any of the following were present: 1) inability to give informed consent; 2) contraindications to anticoagulation or aspirin; 3) history of heparin-induced thrombocytopenia; 4) serum creatinine >= 200 mmol/L; or 5) international normalized ratio >= 1.5. The protocol was approved by the local ethics committee on human research. Percutaneous coronary intervention. All patients received aspirin 100–300 mg and clopidogrel 300 mg at least 1 hour before PCI. The transfemoral approach and 7 or 8 French guiding catheters were used. Intravenous enoxaparin 1 mg/kg was given 5 minutes prior to standard angioplasty procedure with or without stenting or atherectomy. Procedural success was defined as a final diameter stenosis of Determination of anticoagulation profile. For the first 20 patients, venous blood samples were collected for assay of anti-Xa activity and aPTT before (0 minutes) and after enoxaparin administration at 5, 30, 60, 90, 120, 150, 180, 210, 240, 360 and 480 minutes. Venous blood samples for ACT were collected at 0 minutes and 5 minutes. The HemoTac (Medtronic HemoTac, Minneapolis, Minnesota) was used to measure the ACT. Blood samples for anti-Xa assay and aPTT were anticoagulated with sodium citrate (9:1 v/v) and were centrifuged at 3,000 g for 15 minutes at 4°C to collect platelet poor plasma, which was then stored at -70°C until analysis. Plasma anti-Xa activity was determined by amidolytic assay using chromogenic substrate CBS 3139 and bovine factor Xa in the presence of excess antithrombin (Diagnostica Stago 00906), so that the color intensity as detected by paranitroaniline was inversely proportional to the amount of enoxaparin present in the plasma. The system was calibrated at three levels (0, 0.4 and 0.8 IU/ml) with a commercial reagent (Stago 00517). Patient samples were assayed together with a control reagent (Stago 00537). The detection limit of the assay was 0.05 IU/ml. The Thrombosil I reagent (Ortho Diagnostic Systems, Raritan, New Jersey) using the MDA-180 automated coagulometer (Organon Technika, Durham, North Carolina) was employed to determine aPTT. Follow-up and clinical endpoints. Bleeding complications were classified according to Thrombolysis in Myocardial Infarction (TIMI) criteria.14 All patients were monitored for adverse clinical events at clinic visit 4–8 weeks after hospital discharge. Statistical analysis. Continuous variables were expressed as means ± SD and compared using students’ t-test. A significant level was defined when p was Baseline characteristics. Baseline clinical characteristics of the patients are shown in Table 1. Angiographic and procedural characteristics of the patients are summarized in Table 2. The majority of the patients underwent non-urgent single-vessel PCI involving the use of 1 or more stents. Anticoagulation profile. The anti-Xa levels and aPTT values versus time from the first 20 patients are shown in Figure 1. Five minutes after the intravenous enoxaparin bolus of 1 mg/kg, the peak anti-Xa level was 1.30 ± 0.18 IU/ml (range, 1.03–1.69 IU/ml). The ACT increased from 128 ± 13 seconds to 203 ± 20 seconds (p = 0.028) while the aPTT increased from 30 ± 2 seconds to 78 ± 9 seconds (p = 0.001). Four hours after intravenous enoxaparin, the minimum anti-Xa level was 0.55 IU/ml. Clinical outcome. Procedural success was achieved in all patients. There were no deaths and no TIMI minor or major bleeding complications during hospitalization for the PCI. One patient developed non-Q wave MI with a peak creatine kinase of 1,401 U/L (5.2 times upper limit of normal) after a PCI using balloon angioplasty. No bleeding or major adverse cardiac events (death, MI or urgent target vessel revascularization) occurred from hospital discharge to first clinic follow-up. DISCUSSION Pharmacokinetic studies of intravenous enoxaparin have been performed mostly in Caucasians.15 In the study by Rabah et al., intravenous enoxaparin 1 mg/kg was found to be safe and equal in percentage inhibition of anti-Xa when compared with UFH 10,000 U.16 In the NICE-4 trial, combined enoxaparin and abciximab were used as the antithrombotic regime for PCI. The peak anti-Xa level after intravenous enoxaparin 1 mg/kg was between 1.3 and 1.4 IU/ml.12 In our present study, we showed detailed pharmacokinetic data on intravenous enoxaparin in Asian patients. The peak anti-Xa level of ~ 1.3 IU/ml was comparable to the figure from the NICE-4 trial. The lowest anti-Xa level among the 20 patients was 0.55 IU/ml up to 4 hours after enoxaparin administration. This was above the lower limit of mean anti-Xa activity that was found to be effective for the treatment of venous17 and arterial18 thrombosis. The use of enoxaparin was associated with no major or minor bleeding complications in this cohort. This compared favorably with the results of contemporary PCI trials, in which the major and minor bleeding complications in the UFH control arms were

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