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Original Contribution
Use of Low-Molecular-Weight Heparins During Percutaneous Coronary Intervention
January 2011
ABSTRACT: Patients with acute coronary syndromes (ACS) may transition to percutaneous coronary intervention (PCI) after an initial phase of medical management that includes anticoagulation. When patients come to the catheterization laboratory, it is important to consider previously received anticoagulation. Enoxaparin has emerged as a more effective, yet simple, agent for use in the emergency room or upon initial encounter of the ACS patient. However, there may be uncertainty among physicians on the adequacy and way to use anticoagulation in the transition to the catheterization laboratory. Recently, new data have emerged on the use of enoxaparin in the catheterization laboratory. Dosing schedules based on pharmacodynamic and clinical data offer a seamless transition for enoxaparin from the medical management phase to PCI. In this paper, the pharmacokinetics of enoxaparin are reviewed and recommendations for anticoagulant regimens provided based upon the timing of presentation and pre-catheterization dosing.
J INVASIVE CARDIOL 2011;23:1–8
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IV doses of 1.0 mg/kg, 0.75 mg/kg, and 0.5 mg/kg were 2.1 IU/ml, 1.5 IU/ml, and 0.9 IU/ml, respectively. Anti-Xa activity levels fall below a therapeutic level (16,17 A population pharmacodynamic analysis evaluated anti-Xa activity following the administration of enoxaparin 0.5 mg/kg IV in 546 consecutive patients referred for elective PCI, with a pharmacodynamic model simulating anticoagulation levels achieved with 0.75 mg/kg and 1.0 mg/kg IV boluses. Target anticoagulation levels (> 0.5 IU/ml) were rapidly achieved by all patients at all three doses evaluated. The two higher doses of IV enoxaparin (0.75 mg/kg and 1.0 mg/kg) prolonged the duration of anticoagulation within the therapeutic window (3.4 hours and 4.1 hours, respectively) compared with the 0.5 mg/kg bolus (2.7 hours), and markedly increased the proportion of patients with anticoagulation levels above 1.5 IU/ml (48% and 79% versus 2.5%, respectively).25
Compared with UFH 60 IU/kg, IV dosing with enoxaparin 0.75 mg/kg was associated with a more gradual decrease in anti-Xa activity. At 4 hours, there was significantly higher anticoagulation observed in patients who received enoxaparin than in those who were administered IV UFH (Figure 1).21 An IV dose of enoxaparin as low as 0.5 mg/kg can provide adequate anticoagulation irrespective of patient characteristics such as
age, weight, renal function or the use of the glycoprotein (GP) IIb/IIIa inhibitor eptifibatide.17 In an analysis of 242 consecutive patients, peak anti-Xa activity levels above 0.5 IU/ml were obtained in 97.5% of patients, with 94.6% of patients having peak anti-Xa activity levels in the target range of 0.5–1.5 IU/ml. Anti-Xa activity was stable throughout the procedure, confirming a high and constant degree of anticoagulation (mean anti-Xa activity level pre-PCI, 0.88 ± 0.31 IU/ml; post-PCI, 0.83 ± 0.26 IU/ml). The percentage of patients who were not over-anticoagulated (peak anti-Xa activity levels 75 years) and those younger than 75 years (97% in both), in patients with severe renal dysfunction (creatinine clearance 100 kg) and non-overweight patients (95% versus 97%, respectively).17SC dosing. Pharmacodynamic studies show that peak anti-Xa activity levels are achieved 3–5 hours after enoxaparin SC dosing.26 In a study of 46 patients with UA who received enoxaparin 1.0 mg/kg SC twice daily for 14 days, mean peak anti-Xa levels at steady state were 1.1 IU/ml.27 Steady-state dosing is achieved within 4 days of 1.0 mg/kg SC dosing twice daily, with an average anti-Xa activity level 65% higher than that following a single SC dose, and mean peak and trough levels of 1.2 IU/ml and 0.52 IU/ml, respectively.27
In the Pharmacokinetics of Enoxaparin in PCI (PEPCI) study, two dosing strategies achieved reliable anticoagulation to support PCI, largely based on SC enoxaparin; therapeutic anti-Xa activity levels were achieved either by an initial 30 mg IV dose followed immediately by the first 1.0 mg/kg SC dose, or following steady-state dosing of 1.0 mg/kg SC twice daily without an initial IV loading dose. Steady-state dosing was defined in this study as at least five SC doses.4,28Steady-state dosing. In an evaluation of enoxaparin for UA/NSTEMI patients transitioning to PCI, enoxaparin was given at a dose of 1.0 mg/kg (100 IU) SC at 12-hour intervals for a minimum of 48 hours prior to PCI.15 All procedures were scheduled to occur within 8 hours of the morning injection of enoxaparin. This dosing approach resulted in a therapeutic level of anti-Xa activity (> 0.5 IU/ml) in the vast majority of patients (97.6%) at the time of catheterization, with a mean anti-Xa activity level of 0.98 ± 0.03 IU/ml. By measuring the anti-Xa activity level after the third SC injection and adjusting the dose of enoxaparin, if necessary, accumulation was prevented in those with chronic renal failure and/or advanced age.
In the PEPCI study, patients undergoing PCI within 8 hours of the last SC dose, after a minimum of 5 SC doses or an initial 30 mg IV bolus followed by at least 1 SC dose, were predicted to be in the target range for at least 2 hours after the start of PCI. For patients undergoing PCI 8–12 hours after receiving 1.0 mg/kg SC enoxaparin, pharmacodynamic modeling suggested that an additional “booster” dose of 0.3 mg/kg IV would raise and maintain anti-Xa activity levels to 0.6–1.8 IU/ml for at least 2 hours following the start of PCI.4 These proposed strategies were then tested in 55 patients in whom the 
predicted and actual (measured) serum anti-Xa activity levels were compared. Measured anti-Xa activity levels were generally within 10% of the predicted value and within the targeted range for 96% of patients (Figure 2).4
The use of this booster IV dose was also tested in patients who had received only one 1.0 mg/kg SC dose without an initial IV bolus.26 At 2 and 6 hours after the initial SC enoxaparin dose, 35% of patients had anti-Xa activity levels below 0.6 IU/ml. All patients who received a booster dose of 0.3 mg/kg IV 6 hours after the initial SC dose achieved anti-Xa 
activity levels within the therapeutic range between 5 minutes to at least 2 hours following administration of the dose (Figure 3).26IV loading dose. An IV loading dose of enoxaparin prior to SC dosing may benefit those patients at highest risk or most likely to proceed to PCI early. A pharmacodynamic study found that therapeutic plasma levels of enoxaparin are achieved significantly earlier by an IV loading dose of 40 mg enoxaparin added to a SC regimen compared with SC dosing alone. Mean anti-Xa activity levels rose to 1.25 IU/ml within 5 minutes of the IV injection of enoxaparin compared with anti-Xa activity levels first reaching 0.5 IU/ml after 2 hours with a first SC injection. At 24 hours, anti-Xa activity levels were comparable between SC dosing 
alone and IV plus SC enoxaparin (Figure 4).29 Another study found that a 30 mg enoxaparin bolus immediately followed by 1.0 mg/kg SC twice daily provided initial peak anti-Xa activity levels of 1.16 IU/ml and an average exposure of 84% of steady-state levels. Moreover, steady-state levels were achieved on the second day of treatment.27The impact of renal function on SC dosing. Although a single IV enoxaparin dose does not lead to over-anticoagulation in patients with renal dysfunction,17 renal function does influence the pharmacodynamics of multiple SC doses. Dose adjustments of SC enoxaparin are recommended in patients with severe renal failure in order to avoid drug accumulation.30 In an analysis of 445 patients who were enrolled in the TIMI 11A trial, the impact of renal function was assessed on the pharmacodynamics of anticoagulation with administration of an enoxaparin 30 mg IV bolus, followed by weight-adjusted doses of either 1.0 mg/kg or 1.25 mg/kg SC twice daily. This study showed a linear relationship between anti-Xa plasma clearance and creatinine clearance at steady state. Apparent clearance was reduced by 22% in patients with a creatinine clearance of 30 It is therefore recommended that all patients with renal impairment should be observed carefully for signs of bleeding. Dose adjustment is recommended for patients with a creatinine clearance of 27 In patients with renal impairment who are non-emergently transitioned to PCI, we recommend that anti-Xa activity levels should be used to guide the selection of a supplemental IV dose. No supplemental dose is recommended for patients in the high therapeutic range unless the procedure is anticipated to last for several hours beyond the time of anti-Xa sampling; patients at the lower end of the targeted range (Clinical Profile of Enoxaparin in PCI
Elective PCI. The STEEPLE trial is the largest trial on the use of IV enoxaparin for elective PCI and included 3,528 patients. Two doses of IV enoxaparin (0.5 or 0.75 mg/kg) were compared with IV UFH (70–100 IU/kg with no GP IIb/IIIa inhibitors; 50–70 IU/kg with GP IIb/IIIa inhibitors).12 For the enoxaparin groups, a single IV bolus was administered after sheath placement and immediately prior to PCI. Patients also received an additional bolus dose of half the original dose if PCI was delayed by more than 2 hours. The primary endpoint of non-coronary artery bypass graft-related bleeding in the first 48 hours occurred in 8.5% of the UFH group compared with 5.9% in the enoxaparin 0.5 mg/kg group (p = 0.01) and 6.5% in the enoxaparin 0.75 mg/kg group (p = 0.051). Although the trial was not designed to demonstrate differences in the efficacy endpoints, death, MI, or urgent target revascularization occurred at similar rates between UFH and enoxaparin 0.5 mg/kg (5.8% vs. 6.2%, respectively; p = 0.51) and 0.75 mg/kg (5.8% vs. 6.8%, respectively; p = 0.30). The trial data safety and monitoring committee recommended that enrollment be discontinued in the enoxaparin 0.5 mg/kg arm based on global differences in all-cause mortality between the three treatment groups. However, the final analysis of the data showed no significant mortality difference between groups.
Predefined target anticoagulation levels (anti-Xa activity levels of 0.5–1.8 IU/ml) were achieved in 78.8% and 91.8% of patients with IV enoxaparin 0.5 mg/kg and 0.75 mg/kg, respectively. By comparison, significantly fewer (19.7%) patients given IV UFH (p 12
STEMI patients on IV loading followed by SC enoxaparin transitioning to PCI. The ExTRACT–TIMI 25 trial compared the efficacy and safety profile of enoxaparin with UFH in conjunction with aspirin as adjunctive therapy for fibrinolysis in patients presenting with STEMI.2 The enoxaparin dosing strategy was adjusted according to patient age and renal function. For patients younger than 75 years, enoxaparin was given as a fixed 30 mg IV bolus followed within 15 minutes by 1.0 mg/kg SC twice daily (up to a maximum of 100 mg for the first two SC doses).2 For patients 75 years or older, the IV bolus was eliminated and the SC dose was reduced to 0.75 mg/kg twice daily (up to a maximum of 75 mg for the first two SC doses).2 For patients with severe renal impairment (creatinine clearance 14 For patients transferring to PCI, if the last SC dose of enoxaparin was given 8 hours after balloon inflation, an additional 0.3 mg/kg IV bolus dose was administered.14 UFH was administered prior to PCI according to ACT values: target of 200 seconds with concomitant use of GP IIb/IIIa inhibitors, and 250 seconds if GP IIb/IIIa inhibitors were not used. The overall incidence of the primary endpoint of death or recurrent MI at 30 days in the subgroup of patients undergoing PCI (n = 4,676) was lower with enoxaparin than with UFH (10.7% vs. 13.8%, respectively; p 31
UA/NSTEMI patients on SC enoxaparin transitioning to PCI. Enoxaparin is approved for use at a dose of 1.0 mg/kg twice daily in UA/NSTEMI patients, without the use of an initial IV bolus and in conjunction with oral aspirin. The most recent trial evaluating SC enoxaparin for use in UA/NSTEMI patients, the SYNERGY trial, randomized 10,027 high-risk patients who presented with UA/NSTEMI to receive either enoxaparin or UFH in conjunction with aspirin. Patients received either enoxaparin 1.0 mg/kg SC twice daily or IV UFH (60 IU/kg bolus [5,000 IU maximum] followed by 12 IU/kg/h infusion [1,000 IU/h max] titrated to an activated partial thromboplastin time of 1.5–2 times the institutional upper limit of normal of 50–70 seconds). Nearly half of the study population (4,687) were managed with an early invasive approach after receiving study drugs for approximately 24 hours, and 57% of patients received concomitant GP IIb/IIIa inhibition.13 Patients could be enrolled in the trial even if they had already received a LMWH or UFH by the treating physician before randomization. The randomized assignment was independent of any prior antithrombin treatment. The SYNERGY protocol called for no additional enoxaparin if the last dose was given within 8 hours of PCI, and an additional 0.3 mg/kg IV bolus of enoxaparin was given if the last SC dose had been administered > 8 hours previously. Catheterization could be performed any time after dosing for patients who received enoxaparin. Sheaths were removed 6–8 hours after the last SC enoxaparin dose or 4–6 hours after the 0.3 mg/kg IV bolus dose. For patients assigned to UFH, the infusion was stopped during PCI and the ACT was used to guide therapy. Additional UFH was given in order to achieve an ACT of ≤ 250 seconds. Sheaths were removed when the ACT was 13 The protocol-driven change in medication was carried out by a prespecified regimen based on known pharmacokinetic profiles. Importantly, nonprotocol-driven crossover (usually in the catheterization laboratory) to the alernative antithrombotic occurred in 12.7% of enoxaparin patients and 3.0% of UFH-treated patients (p 13 In the subgroup of patients in SYNERGY who underwent PCI, enoxaparin and UFH were associated with a similar incidence of death and MI at 30 days (13.1% vs. 14.2%, respectively; p = 0.289). Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-defined severe bleeding occurred at similar rates in both groups (1.5% vs. 1.6%, respectively; p = 0.688), but major bleeding, as defined by the TIMI criteria, occurred more frequently with enoxaparin (3.7% vs. 2.5%, respectively; p = 0.028).13
In patients undergoing PCI in the SYNERGY trial, it was suggested that there may be a temporal relationship between the timing of PCI from randomization and 30-day endpoints of death or nonfatal MI. While statistically nonsignificant, patients randomized to UFH as compared with enoxaparin fared better if PCI was performed within 12 hours and the reverse was the case if PCI was performed after 12 hours.13 In accordance with pharmacodynamic studies, these findings suggest that there may have been inadequate anticoagulation during PCI after only a single enoxaparin 1.0 mg/kg SC dose.
receive those without crossover to another anticoagulant.10 If patients have received SC enoxaparin 1.0 mg/kg twice daily without an initial IV bolus, the requirement for additional IV enoxaparin at the time of PCI depends on the number of SC doses received as well as the timing of the last dose (Table 2).13,15,26,28,36,37Scenario 1: The urgent emergency room patient. Upon presentation to the emergency room with the diagnosis of ACS, patients may either be admitted with plans for prompt catheterization or with plans for overnight observation and stabilization with eventual catheterization, typically during the same admission and 24–36 hours after admission. The urgent emergency room ACS patient who goes on to immediate catheterization without any contemporaneous enoxaparin administration may be treated with IV enoxaparin following sheath placement. Based on results from the NICE trials, a dose of 1 mg/kg or 0.75 mg/kg (with concomitant GP IIb/IIIa use) was demonstrated to be effective for PCI with a good safety profile.16 Similarly, the STEEPLE trial supported the safety and efficacy of the 0.75 mg/kg dose for PCI compared with UFH, although this trial was done in cases of elective PCI in non-ACS patients.12 The recently completed ATOLL trial randomized 910 patients to IV enoxaparin 0.5 mg/kg or IV unfractionated heparin in primary PCI. Ischemic endpoints were significantly reduced by a relative 41% with enoxaparin, but major bleeding was unchanged.
Scenario 2: ACS patients treated with a single SC dose of enoxaparin. A more common scenario is the ACS patient who arrives in the catheterization laboratory after receiving a single SC dose of enoxaparin 1 mg/kg in the emergency room. In such a patient, the use of a booster IV dose of enoxaparin 0.3 mg/kg given within 8 hours of the SC dose rapidly brings anti-Xa levels to the effective range for PCI.26 If the SC dose was 8–12 hours prior, or if the operator deems the patient to be at high thrombotic risk with evidence of angiographically detectable thrombus, an IV booster dose of 0.5 mg/kg can be considered.
Scenario 3: ACS patients treated with two SC doses of enoxaparin. This scenario involves patients treated with SC enoxaparin upon initial encounter in the ER or upon admission to the floor. They then receive a second dose 12 hours later, and some time within 12 hours following the second dose they move on to catheterization. If PCI is performed in these patients, they may be treated as in the ExTRACT and SYNERGY trials (no additional enoxaparin needed within the first 8 hours after the last dose; an additional IV bolus of 0.3 mg/kg if the last SC dose was 8–12 hours prior).13 This approach may not be adequate after a first, single SC dose as shown in the SYNERGY trial13 (see Scenario 2). An additional 0.3 mg/kg dose of IV enoxaparin may be considered within 8 hours after a second SC dose, based on operator discretion related to the nature and length of the case as well as the patient’s risk for bleeding. If the procedure is prolonged by more than 2 hours, an additional bolus of enoxaparin of half the original dose is recommended.12Scenario 4: ACS patients treated with 3 or more SC doses of enoxaparin. If a patient with ACS receives 3 or more SC doses of enoxaparin 1 mg/kg every 12 hours, pharmacokinetic studies have demonstrated that this patient is largely approaching steady state.15 Treatment will depend on the timing of the last SC dose; in the PEPCI study, patients treated with SC enoxaparin within 0–8 hours of the last dose had adequate anticoagulation to support PCI, but patients treated 8–12 hours following their last dose had anti-Xa levels that were too low.4 Thus, these patients may be treated for PCI as in the ExTRACT and SYNERGY trials; no additional enoxaparin is needed within the first 8 hours after the last dose, while an additional IV bolus of 0.3 mg/kg is needed if the last SC dose was 8–12 hours prior.13Scenario 5: The STEMI patient: A patient on 1.0 mg/kg twice-daily enoxaparin following an initial 30 mg/kg IV bolus. The ExTRACT-TIMI 25 dosing schedule of 30 mg IV enoxaparin followed by SC dosing in STEMI patients allowed easy transition to PCI.14 If patients have received enoxaparin 1.0 mg/kg SC twice daily following an initial IV bolus (30 mg), no additional enoxaparin is needed within the first 8 hours after the last dose irrespective of the number of SC doses received. This includes patients who received only 1 SC dose on top of the initial IV bolus and proceed to PCI early.28 If the last SC dose was 8–12 hours prior, an additional IV bolus (0.3 mg/kg) should be provided.2,4,14,23,27,28 In ExTRACT-TIMI 25, patients were treated with thrombolytic therapy. Clinical trial data on the use of enoxaparin for primary PCI in STEMI patients who have not received thrombolytic therapy are predominantly limited to the above-mentioned ATOLL trial, in which IV enoxaparin reduced ischemic endpoints by a relative 41%, but had no impact on major bleeding.
Scenario 6: Patients on subtherapeutic doses of enoxaparin. No data are available on optimal IV dosing for PCI in patients who received subtherapeutic doses of enoxaparin, either by mistake or because they were receiving prophylaxis against deep-vein thrombosis (DVT). Rather than switching anticoagulants, these patients should be treated with a single IV bolus of enoxaparin after sheath insertion and immediately before PCI.
In the Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) trial, patients administered prophylactic doses of enoxaparin (40 mg SC once daily) had anti-Xa activity levels of 0.41 IU/ml after 10 ± 4 days.38 Extrapolation of the data from the PEPCI study indicates that a 0.3 mg/kg IV dose would be insufficient to support PCI. Indeed, patients in the PEPCI study had anti-Xa activity levels above the 0.41 IU/ml seen in the MEDENOX trial (0.53–0.87 IU/ml), and the few patients in PEPCI who were supplemented with 0.3 mg/kg IV by protocol deviation beyond 12 hours did not reach the targeted range.
The dosing used in STEEPLE (no enoxaparin prior to elective PCI) with a bolus dose of enoxaparin 0.5 mg/kg IV could be adequate for a patient who has received multiple doses of DVT prophylaxis. For patients previously administered a single prophylactic dose or very low doses, an IV bolus dose of 0.5 mg/kg or 0.75 mg/kg can be considered at the operator’s discretion. Particularly when GP IIb/IIIa inhibitors are used or when patients are elderly or presenting with renal dysfunction, the 0.5 mg/kg dose may be favored over the 0.75 mg/kg dose. The 0.75 mg/kg dose may be preferred in a patient with very low prior doses if the patient has no features suggestive of an increased risk of bleeding.
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From the *Sharpe-Strumia Research Foundation, Bryn Mawr, Pennsylvania and §the Sarver Heart Center, University of Arizona, Tucson, Arizona.
Disclosures: The authors received editorial support in the preparation of this manuscript funded by Sanofi-Aventis, New Jersey. The authors are fully responsible for all content and editorial decisions with respect to this manuscript. Dr. Martin and Dr. Slepian report receiving speaker honoraria from Sanofi-Aventis. Dr. Martin reports receiving research support from Sanofi-Aventis.
Manuscript submitted June 15, 2010, provisional acceptance given July 28, 2010, final version accepted October 27, 2010.
Address for correspondence: Jack Martin, MD, Sharpe-Strumia Research Foundation, 130 S. Bryn Mawr Avenue, Bryn Mawr Hospital, 2nd Floor/D-Wing, Bryn Mawr, PA 19010. E-mail: MartinJ@MLHS.org
Based upon favorable clinical trial experience, low-molecular-weight heparins (LMWHs) may be used instead of unfractionated heparin (UFH) in conjunction with antiplatelet therapy to treat patients presenting with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI).1–3 Patients with acute coronary syndromes (ACS) may transition to percutaneous coronary intervention (PCI) after an initial phase of medical management. Despite the predictable and stable pharmacodynamics of LMWHs, confusion and hesitancy exist among the cardiology community regarding their seamless use as anticoagulation for PCI. However, their pharmacodynamic properties in fact eliminate the need for coagulation monitoring, simplifying the care of ACS patients, including transition to the cardiac catheterization laboratory.4
A number of LMWHs have been developed, and should be evaluated individually rather than considered as a class of interchangeable drugs.5 Although different LMWHs have been evaluated for use in ACS or PCI,3,6–8 the majority of studies, including the largest number of patients on LMWHs in ACS or PCI, have used enoxaparin. Enoxaparin is the LMWH specifically recommended in conjunction with antiplatelet therapy in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the prevention of ischemic events in UA/NSTEMI patients managed conservatively or invasively,9 and for the treatment of STEMI patients managed with fibrinolytic therapy with or without subsequent PCI.10,11 Three large-scale, multicenter, randomized clinical trials have recently been published that included populations or subpopulations of patients undergoing PCI: the Safety and Efficacy of Enoxaparin in PCI Patients, an International Randomized Evaluation (STEEPLE) trial;12 The Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial;13 and most recently, the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)-Thrombolysis in Myocardial Infarction (TIMI) 25 trial.14
This paper will review the pharmacodynamics of treatment with enoxaparin, providing specific recommendations for patients on enoxaparin transitioning to PCI. Recommendations formulated in this paper are based on best available clinical and pharmacodynamic data. As data are sometimes lacking, some recommendations have been largely based on the authors’ experience and clinical practice, and remain to be tested in clinical trials.
Pharmacodynamics of Enoxaparin
In men, enoxaparin has been administered clinically both via the subcutaneous (SC) route as well as intravenously (IV). SC enoxaparin has traditionally been administered for the prevention and treatment of venous and arterial thrombosis. To support an elective PCI procedure, enoxaparin is usually administered by the IV route; the route of administration affects the onset and duration of enoxaparin activity. SC administration provides a sustained anticoagulant effect with multiple dosing, whereas a single IV dose offers rapid onset and termination of action. A combination of both administration routes can ensure that therapeutic levels are achieved and maintained. Accordingly, SC enoxaparin, supplemented by an IV dose, has been used in non-elective cardiology patients with UA/NSTEMI or STEMI.13,14Anti-Xa activity levels in practice. The target anti-Xa activity level for therapeutic dosing of enoxaparin in PCI has been defined as a range. This range balances efficacy with safety and has been defined from a number of studies. In the work of Collet et al,15 enoxaparin provided effective anticoagulation to support PCI with a good safety profile within the range of anti-Xa levels of 0.8–1.4 IU/ml. In the NICE trials, PCI was effectively performed with enoxaparin anticoagulation in the same range.16 A number of studies have shown that target anti-Xa activity levels above 0.5 IU/ml are effective for performing PCI or for treating UA/NSTEMI.15–19 Anti-Xa activity level of at least 0.5 IU/ml is needed, as shown in a study that demonstrated a 3-fold increase in mortality in UA/NSTEMI patients with anti-Xa activity levels below 0.5 IU/ml compared with a target range of 0.5–1.2 IU/ml (p = 0.004). Anti-Xa activity up to 1.8 IU/ml did not predict major bleeding complications.20 Since no device is generally used for point-of-care determination of anti-Xa levels, current use of enoxaparin is guided by understanding the timing of enoxaparin pharmacodynamics. Monitoring of anti-Xa activity levels is generally not needed and standard dosing regimens can be used. IV dosing. The pharmacodynamics of IV enoxaparin bolus at different doses (1.0 mg/kg, 0.75 mg/kg, and 0.5 mg/kg) have been evaluated in patients undergoing elective PCI who were not pre-treated with LMWH or UFH before the catheterization laboratory (Table 1).12–17,20–22 These studies show that enoxaparin has a predictable anticoagulant effect and dose-response relationship. After IV injection, a peak anti-Xa effect is seen within 10 minutes, corresponding to the start of a PCI procedure.17,23,24 The average peak anti-Xa activities for the three different enoxaparin
IV doses of 1.0 mg/kg, 0.75 mg/kg, and 0.5 mg/kg were 2.1 IU/ml, 1.5 IU/ml, and 0.9 IU/ml, respectively. Anti-Xa activity levels fall below a therapeutic level (16,17 A population pharmacodynamic analysis evaluated anti-Xa activity following the administration of enoxaparin 0.5 mg/kg IV in 546 consecutive patients referred for elective PCI, with a pharmacodynamic model simulating anticoagulation levels achieved with 0.75 mg/kg and 1.0 mg/kg IV boluses. Target anticoagulation levels (> 0.5 IU/ml) were rapidly achieved by all patients at all three doses evaluated. The two higher doses of IV enoxaparin (0.75 mg/kg and 1.0 mg/kg) prolonged the duration of anticoagulation within the therapeutic window (3.4 hours and 4.1 hours, respectively) compared with the 0.5 mg/kg bolus (2.7 hours), and markedly increased the proportion of patients with anticoagulation levels above 1.5 IU/ml (48% and 79% versus 2.5%, respectively).25
Compared with UFH 60 IU/kg, IV dosing with enoxaparin 0.75 mg/kg was associated with a more gradual decrease in anti-Xa activity. At 4 hours, there was significantly higher anticoagulation observed in patients who received enoxaparin than in those who were administered IV UFH (Figure 1).21 An IV dose of enoxaparin as low as 0.5 mg/kg can provide adequate anticoagulation irrespective of patient characteristics such as
age, weight, renal function or the use of the glycoprotein (GP) IIb/IIIa inhibitor eptifibatide.17 In an analysis of 242 consecutive patients, peak anti-Xa activity levels above 0.5 IU/ml were obtained in 97.5% of patients, with 94.6% of patients having peak anti-Xa activity levels in the target range of 0.5–1.5 IU/ml. Anti-Xa activity was stable throughout the procedure, confirming a high and constant degree of anticoagulation (mean anti-Xa activity level pre-PCI, 0.88 ± 0.31 IU/ml; post-PCI, 0.83 ± 0.26 IU/ml). The percentage of patients who were not over-anticoagulated (peak anti-Xa activity levels 75 years) and those younger than 75 years (97% in both), in patients with severe renal dysfunction (creatinine clearance 100 kg) and non-overweight patients (95% versus 97%, respectively).17SC dosing. Pharmacodynamic studies show that peak anti-Xa activity levels are achieved 3–5 hours after enoxaparin SC dosing.26 In a study of 46 patients with UA who received enoxaparin 1.0 mg/kg SC twice daily for 14 days, mean peak anti-Xa levels at steady state were 1.1 IU/ml.27 Steady-state dosing is achieved within 4 days of 1.0 mg/kg SC dosing twice daily, with an average anti-Xa activity level 65% higher than that following a single SC dose, and mean peak and trough levels of 1.2 IU/ml and 0.52 IU/ml, respectively.27
In the Pharmacokinetics of Enoxaparin in PCI (PEPCI) study, two dosing strategies achieved reliable anticoagulation to support PCI, largely based on SC enoxaparin; therapeutic anti-Xa activity levels were achieved either by an initial 30 mg IV dose followed immediately by the first 1.0 mg/kg SC dose, or following steady-state dosing of 1.0 mg/kg SC twice daily without an initial IV loading dose. Steady-state dosing was defined in this study as at least five SC doses.4,28Steady-state dosing. In an evaluation of enoxaparin for UA/NSTEMI patients transitioning to PCI, enoxaparin was given at a dose of 1.0 mg/kg (100 IU) SC at 12-hour intervals for a minimum of 48 hours prior to PCI.15 All procedures were scheduled to occur within 8 hours of the morning injection of enoxaparin. This dosing approach resulted in a therapeutic level of anti-Xa activity (> 0.5 IU/ml) in the vast majority of patients (97.6%) at the time of catheterization, with a mean anti-Xa activity level of 0.98 ± 0.03 IU/ml. By measuring the anti-Xa activity level after the third SC injection and adjusting the dose of enoxaparin, if necessary, accumulation was prevented in those with chronic renal failure and/or advanced age.
In the PEPCI study, patients undergoing PCI within 8 hours of the last SC dose, after a minimum of 5 SC doses or an initial 30 mg IV bolus followed by at least 1 SC dose, were predicted to be in the target range for at least 2 hours after the start of PCI. For patients undergoing PCI 8–12 hours after receiving 1.0 mg/kg SC enoxaparin, pharmacodynamic modeling suggested that an additional “booster” dose of 0.3 mg/kg IV would raise and maintain anti-Xa activity levels to 0.6–1.8 IU/ml for at least 2 hours following the start of PCI.4 These proposed strategies were then tested in 55 patients in whom the 
predicted and actual (measured) serum anti-Xa activity levels were compared. Measured anti-Xa activity levels were generally within 10% of the predicted value and within the targeted range for 96% of patients (Figure 2).4
The use of this booster IV dose was also tested in patients who had received only one 1.0 mg/kg SC dose without an initial IV bolus.26 At 2 and 6 hours after the initial SC enoxaparin dose, 35% of patients had anti-Xa activity levels below 0.6 IU/ml. All patients who received a booster dose of 0.3 mg/kg IV 6 hours after the initial SC dose achieved anti-Xa 
activity levels within the therapeutic range between 5 minutes to at least 2 hours following administration of the dose (Figure 3).26IV loading dose. An IV loading dose of enoxaparin prior to SC dosing may benefit those patients at highest risk or most likely to proceed to PCI early. A pharmacodynamic study found that therapeutic plasma levels of enoxaparin are achieved significantly earlier by an IV loading dose of 40 mg enoxaparin added to a SC regimen compared with SC dosing alone. Mean anti-Xa activity levels rose to 1.25 IU/ml within 5 minutes of the IV injection of enoxaparin compared with anti-Xa activity levels first reaching 0.5 IU/ml after 2 hours with a first SC injection. At 24 hours, anti-Xa activity levels were comparable between SC dosing 
alone and IV plus SC enoxaparin (Figure 4).29 Another study found that a 30 mg enoxaparin bolus immediately followed by 1.0 mg/kg SC twice daily provided initial peak anti-Xa activity levels of 1.16 IU/ml and an average exposure of 84% of steady-state levels. Moreover, steady-state levels were achieved on the second day of treatment.27The impact of renal function on SC dosing. Although a single IV enoxaparin dose does not lead to over-anticoagulation in patients with renal dysfunction,17 renal function does influence the pharmacodynamics of multiple SC doses. Dose adjustments of SC enoxaparin are recommended in patients with severe renal failure in order to avoid drug accumulation.30 In an analysis of 445 patients who were enrolled in the TIMI 11A trial, the impact of renal function was assessed on the pharmacodynamics of anticoagulation with administration of an enoxaparin 30 mg IV bolus, followed by weight-adjusted doses of either 1.0 mg/kg or 1.25 mg/kg SC twice daily. This study showed a linear relationship between anti-Xa plasma clearance and creatinine clearance at steady state. Apparent clearance was reduced by 22% in patients with a creatinine clearance of 30 It is therefore recommended that all patients with renal impairment should be observed carefully for signs of bleeding. Dose adjustment is recommended for patients with a creatinine clearance of 27 In patients with renal impairment who are non-emergently transitioned to PCI, we recommend that anti-Xa activity levels should be used to guide the selection of a supplemental IV dose. No supplemental dose is recommended for patients in the high therapeutic range unless the procedure is anticipated to last for several hours beyond the time of anti-Xa sampling; patients at the lower end of the targeted range (Clinical Profile of Enoxaparin in PCI
Elective PCI. The STEEPLE trial is the largest trial on the use of IV enoxaparin for elective PCI and included 3,528 patients. Two doses of IV enoxaparin (0.5 or 0.75 mg/kg) were compared with IV UFH (70–100 IU/kg with no GP IIb/IIIa inhibitors; 50–70 IU/kg with GP IIb/IIIa inhibitors).12 For the enoxaparin groups, a single IV bolus was administered after sheath placement and immediately prior to PCI. Patients also received an additional bolus dose of half the original dose if PCI was delayed by more than 2 hours. The primary endpoint of non-coronary artery bypass graft-related bleeding in the first 48 hours occurred in 8.5% of the UFH group compared with 5.9% in the enoxaparin 0.5 mg/kg group (p = 0.01) and 6.5% in the enoxaparin 0.75 mg/kg group (p = 0.051). Although the trial was not designed to demonstrate differences in the efficacy endpoints, death, MI, or urgent target revascularization occurred at similar rates between UFH and enoxaparin 0.5 mg/kg (5.8% vs. 6.2%, respectively; p = 0.51) and 0.75 mg/kg (5.8% vs. 6.8%, respectively; p = 0.30). The trial data safety and monitoring committee recommended that enrollment be discontinued in the enoxaparin 0.5 mg/kg arm based on global differences in all-cause mortality between the three treatment groups. However, the final analysis of the data showed no significant mortality difference between groups.
Predefined target anticoagulation levels (anti-Xa activity levels of 0.5–1.8 IU/ml) were achieved in 78.8% and 91.8% of patients with IV enoxaparin 0.5 mg/kg and 0.75 mg/kg, respectively. By comparison, significantly fewer (19.7%) patients given IV UFH (p 12
STEMI patients on IV loading followed by SC enoxaparin transitioning to PCI. The ExTRACT–TIMI 25 trial compared the efficacy and safety profile of enoxaparin with UFH in conjunction with aspirin as adjunctive therapy for fibrinolysis in patients presenting with STEMI.2 The enoxaparin dosing strategy was adjusted according to patient age and renal function. For patients younger than 75 years, enoxaparin was given as a fixed 30 mg IV bolus followed within 15 minutes by 1.0 mg/kg SC twice daily (up to a maximum of 100 mg for the first two SC doses).2 For patients 75 years or older, the IV bolus was eliminated and the SC dose was reduced to 0.75 mg/kg twice daily (up to a maximum of 75 mg for the first two SC doses).2 For patients with severe renal impairment (creatinine clearance 14 For patients transferring to PCI, if the last SC dose of enoxaparin was given 8 hours after balloon inflation, an additional 0.3 mg/kg IV bolus dose was administered.14 UFH was administered prior to PCI according to ACT values: target of 200 seconds with concomitant use of GP IIb/IIIa inhibitors, and 250 seconds if GP IIb/IIIa inhibitors were not used. The overall incidence of the primary endpoint of death or recurrent MI at 30 days in the subgroup of patients undergoing PCI (n = 4,676) was lower with enoxaparin than with UFH (10.7% vs. 13.8%, respectively; p 31
UA/NSTEMI patients on SC enoxaparin transitioning to PCI. Enoxaparin is approved for use at a dose of 1.0 mg/kg twice daily in UA/NSTEMI patients, without the use of an initial IV bolus and in conjunction with oral aspirin. The most recent trial evaluating SC enoxaparin for use in UA/NSTEMI patients, the SYNERGY trial, randomized 10,027 high-risk patients who presented with UA/NSTEMI to receive either enoxaparin or UFH in conjunction with aspirin. Patients received either enoxaparin 1.0 mg/kg SC twice daily or IV UFH (60 IU/kg bolus [5,000 IU maximum] followed by 12 IU/kg/h infusion [1,000 IU/h max] titrated to an activated partial thromboplastin time of 1.5–2 times the institutional upper limit of normal of 50–70 seconds). Nearly half of the study population (4,687) were managed with an early invasive approach after receiving study drugs for approximately 24 hours, and 57% of patients received concomitant GP IIb/IIIa inhibition.13 Patients could be enrolled in the trial even if they had already received a LMWH or UFH by the treating physician before randomization. The randomized assignment was independent of any prior antithrombin treatment. The SYNERGY protocol called for no additional enoxaparin if the last dose was given within 8 hours of PCI, and an additional 0.3 mg/kg IV bolus of enoxaparin was given if the last SC dose had been administered > 8 hours previously. Catheterization could be performed any time after dosing for patients who received enoxaparin. Sheaths were removed 6–8 hours after the last SC enoxaparin dose or 4–6 hours after the 0.3 mg/kg IV bolus dose. For patients assigned to UFH, the infusion was stopped during PCI and the ACT was used to guide therapy. Additional UFH was given in order to achieve an ACT of ≤ 250 seconds. Sheaths were removed when the ACT was 13 The protocol-driven change in medication was carried out by a prespecified regimen based on known pharmacokinetic profiles. Importantly, nonprotocol-driven crossover (usually in the catheterization laboratory) to the alernative antithrombotic occurred in 12.7% of enoxaparin patients and 3.0% of UFH-treated patients (p 13 In the subgroup of patients in SYNERGY who underwent PCI, enoxaparin and UFH were associated with a similar incidence of death and MI at 30 days (13.1% vs. 14.2%, respectively; p = 0.289). Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-defined severe bleeding occurred at similar rates in both groups (1.5% vs. 1.6%, respectively; p = 0.688), but major bleeding, as defined by the TIMI criteria, occurred more frequently with enoxaparin (3.7% vs. 2.5%, respectively; p = 0.028).13
In patients undergoing PCI in the SYNERGY trial, it was suggested that there may be a temporal relationship between the timing of PCI from randomization and 30-day endpoints of death or nonfatal MI. While statistically nonsignificant, patients randomized to UFH as compared with enoxaparin fared better if PCI was performed within 12 hours and the reverse was the case if PCI was performed after 12 hours.13 In accordance with pharmacodynamic studies, these findings suggest that there may have been inadequate anticoagulation during PCI after only a single enoxaparin 1.0 mg/kg SC dose.
The Importance of Consistent Anticoagulation
Switching between UFH and enoxaparin or stacking UFH therapy on top of enoxaparin can be of particular concern with respect to bleeding. Bleeding is a predictor of poor long-term outcomes.32,33 The result of the SYNERGY trial showed that switching antithrombin agents at the time of randomization or PCI influences clinical outcome in UA/NSTEMI patients.34 The favorable bleeding rates reported in the ExTRACT-TIMI 25 trial may be explained, at least in part, by the fact that few patients were switched between antithrombins from pre- to post-randomization or during PCI.14 The common practice of holding the morning dose of enoxaparin prior to PCI and then using UFH during the procedure is different from the switching that occurred in the SYNERGY trial because of the timing of the previous dose. Adding UFH in patients already anticoagulated with SC enoxaparin may result in excessive and prolonged anticoagulation not detected by the ACT, as demonstrated in the STACK-on to ENOXaparin (STACKENOX) study.35Conclusion: Enoxaparin Dosing Recommendations for Patients Transitioning to PCI
We have attempted to provide practical dosing recommendations to allow for simple utilization of enoxaparin as the primary antithrombotic agent for PCI. We have provided recommendations based on clinical scenarios likely to be encountered in real-world practice. Recommendations formulated in this paper are based on best available clinical and pharmacodynamic data. As data are sometimes lacking, some recommendations are based largely on the authors’ experiences and clinical practices, and remain to be tested in clinical trials. When patients come to the catheterization laboratory, it is important to consider the anticoagulation that was previously administered in order to provide optimal patient care.32 Patients who received UFH or enoxaparin upstream can continue to
receive those without crossover to another anticoagulant.10 If patients have received SC enoxaparin 1.0 mg/kg twice daily without an initial IV bolus, the requirement for additional IV enoxaparin at the time of PCI depends on the number of SC doses received as well as the timing of the last dose (Table 2).13,15,26,28,36,37Scenario 1: The urgent emergency room patient. Upon presentation to the emergency room with the diagnosis of ACS, patients may either be admitted with plans for prompt catheterization or with plans for overnight observation and stabilization with eventual catheterization, typically during the same admission and 24–36 hours after admission. The urgent emergency room ACS patient who goes on to immediate catheterization without any contemporaneous enoxaparin administration may be treated with IV enoxaparin following sheath placement. Based on results from the NICE trials, a dose of 1 mg/kg or 0.75 mg/kg (with concomitant GP IIb/IIIa use) was demonstrated to be effective for PCI with a good safety profile.16 Similarly, the STEEPLE trial supported the safety and efficacy of the 0.75 mg/kg dose for PCI compared with UFH, although this trial was done in cases of elective PCI in non-ACS patients.12 The recently completed ATOLL trial randomized 910 patients to IV enoxaparin 0.5 mg/kg or IV unfractionated heparin in primary PCI. Ischemic endpoints were significantly reduced by a relative 41% with enoxaparin, but major bleeding was unchanged.
Scenario 2: ACS patients treated with a single SC dose of enoxaparin. A more common scenario is the ACS patient who arrives in the catheterization laboratory after receiving a single SC dose of enoxaparin 1 mg/kg in the emergency room. In such a patient, the use of a booster IV dose of enoxaparin 0.3 mg/kg given within 8 hours of the SC dose rapidly brings anti-Xa levels to the effective range for PCI.26 If the SC dose was 8–12 hours prior, or if the operator deems the patient to be at high thrombotic risk with evidence of angiographically detectable thrombus, an IV booster dose of 0.5 mg/kg can be considered.
Scenario 3: ACS patients treated with two SC doses of enoxaparin. This scenario involves patients treated with SC enoxaparin upon initial encounter in the ER or upon admission to the floor. They then receive a second dose 12 hours later, and some time within 12 hours following the second dose they move on to catheterization. If PCI is performed in these patients, they may be treated as in the ExTRACT and SYNERGY trials (no additional enoxaparin needed within the first 8 hours after the last dose; an additional IV bolus of 0.3 mg/kg if the last SC dose was 8–12 hours prior).13 This approach may not be adequate after a first, single SC dose as shown in the SYNERGY trial13 (see Scenario 2). An additional 0.3 mg/kg dose of IV enoxaparin may be considered within 8 hours after a second SC dose, based on operator discretion related to the nature and length of the case as well as the patient’s risk for bleeding. If the procedure is prolonged by more than 2 hours, an additional bolus of enoxaparin of half the original dose is recommended.12Scenario 4: ACS patients treated with 3 or more SC doses of enoxaparin. If a patient with ACS receives 3 or more SC doses of enoxaparin 1 mg/kg every 12 hours, pharmacokinetic studies have demonstrated that this patient is largely approaching steady state.15 Treatment will depend on the timing of the last SC dose; in the PEPCI study, patients treated with SC enoxaparin within 0–8 hours of the last dose had adequate anticoagulation to support PCI, but patients treated 8–12 hours following their last dose had anti-Xa levels that were too low.4 Thus, these patients may be treated for PCI as in the ExTRACT and SYNERGY trials; no additional enoxaparin is needed within the first 8 hours after the last dose, while an additional IV bolus of 0.3 mg/kg is needed if the last SC dose was 8–12 hours prior.13Scenario 5: The STEMI patient: A patient on 1.0 mg/kg twice-daily enoxaparin following an initial 30 mg/kg IV bolus. The ExTRACT-TIMI 25 dosing schedule of 30 mg IV enoxaparin followed by SC dosing in STEMI patients allowed easy transition to PCI.14 If patients have received enoxaparin 1.0 mg/kg SC twice daily following an initial IV bolus (30 mg), no additional enoxaparin is needed within the first 8 hours after the last dose irrespective of the number of SC doses received. This includes patients who received only 1 SC dose on top of the initial IV bolus and proceed to PCI early.28 If the last SC dose was 8–12 hours prior, an additional IV bolus (0.3 mg/kg) should be provided.2,4,14,23,27,28 In ExTRACT-TIMI 25, patients were treated with thrombolytic therapy. Clinical trial data on the use of enoxaparin for primary PCI in STEMI patients who have not received thrombolytic therapy are predominantly limited to the above-mentioned ATOLL trial, in which IV enoxaparin reduced ischemic endpoints by a relative 41%, but had no impact on major bleeding.
Scenario 6: Patients on subtherapeutic doses of enoxaparin. No data are available on optimal IV dosing for PCI in patients who received subtherapeutic doses of enoxaparin, either by mistake or because they were receiving prophylaxis against deep-vein thrombosis (DVT). Rather than switching anticoagulants, these patients should be treated with a single IV bolus of enoxaparin after sheath insertion and immediately before PCI.
In the Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) trial, patients administered prophylactic doses of enoxaparin (40 mg SC once daily) had anti-Xa activity levels of 0.41 IU/ml after 10 ± 4 days.38 Extrapolation of the data from the PEPCI study indicates that a 0.3 mg/kg IV dose would be insufficient to support PCI. Indeed, patients in the PEPCI study had anti-Xa activity levels above the 0.41 IU/ml seen in the MEDENOX trial (0.53–0.87 IU/ml), and the few patients in PEPCI who were supplemented with 0.3 mg/kg IV by protocol deviation beyond 12 hours did not reach the targeted range.
The dosing used in STEEPLE (no enoxaparin prior to elective PCI) with a bolus dose of enoxaparin 0.5 mg/kg IV could be adequate for a patient who has received multiple doses of DVT prophylaxis. For patients previously administered a single prophylactic dose or very low doses, an IV bolus dose of 0.5 mg/kg or 0.75 mg/kg can be considered at the operator’s discretion. Particularly when GP IIb/IIIa inhibitors are used or when patients are elderly or presenting with renal dysfunction, the 0.5 mg/kg dose may be favored over the 0.75 mg/kg dose. The 0.75 mg/kg dose may be preferred in a patient with very low prior doses if the patient has no features suggestive of an increased risk of bleeding.
Additional Considerations
Method of dilution and administration. In order to ensure correct IV administration of small doses of enoxaparin, it is recommended that the enoxaparin dose be diluted into a larger volume, which is easier to administer. Injection should be into a line and not directly into a vein. Flushing of the tubing immediately and thoroughly ensures that the full dose is given and nothing is lost in the tubing. Sheath management. In ACS patients undergoing PCI, sheaths can be removed immediately if a closure device is used. If a manual compression method is used, the sheath should be removed 6 hours after the last enoxaparin dose (SC or IV).27 In patients undergoing elective PCI, sheaths can be removed immediately after PCI with a single IV dose of 0.5 mg/kg or when a closure device is used.12,39 Anticoagulation monitoring is not generally required before sheath removal in patients receiving enoxaparin.12 If treatment with enoxaparin is continued, the next scheduled dose should be given no sooner than 6–8 hours after sheath removal.27References
1. Ferguson JJ, Califf RM, Antman EM, et al. 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. 2. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006;354:1477–1488. 3. Yusuf S, Mehta SR, Xie C, et al. Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation. JAMA 2005;293:427–435. 4. Martin JL, Fry ET, Sanderink GJ, et al. Reliable anticoagulation with enoxaparin in patients undergoing percutaneous coronary intervention: The pharmacokinetics of enoxaparin in PCI (PEPCI) study. Catheter Cardiovasc Interv 2004;61:163–170. 5. Nightingale SL. From the Food and Drug Administration. JAMA 1993;270:1672. 6. Natarajan MK, Velianou JL, Turpie AG, et al. A randomized pilot study of dalteparin versus unfractionated heparin during percutaneous coronary interventions. Am Heart J 2006;151:175. 7. Kereiakes DJ, Kleiman NS, Fry E, et al. Dalteparin in combination with abciximab during percutaneous coronary intervention. Am Heart J 2001;141:348–352. 8. Karsch KR, Preisack MB, Baildon R, et al. Low molecular weight heparin (reviparin) in percutaneous transluminal coronary angioplasty. Results of a randomized, double-blind, unfractionated heparin and placebo-controlled, multicenter trial (REDUCE trial). Reduction of Restenosis After PTCA, Early Administration of Reviparin in a Double-Blind Unfractionated Heparin and Placebo-Controlled Evaluation. J Am Coll Cardiol 1996;28:1437–1443. 9. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non ST-Elevation Myocardial Infarction): Developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148–e304. 10. King SB 3rd, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: A report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol. 2008;51:172–209. 11. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 2008;117:296–329. 12. Montalescot G, White HD, Gallo R, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med 2006;355:1006–1017. 13. White HD, Kleiman NS, Mahaffey KW, et al. Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Am Heart J 2006;152:1042–1050. 14. Gibson CM, Murphy SA, Montalescot G, et al. Percutaneous coronary intervention in patients receiving enoxaparin or unfractionated heparin after fibrinolytic therapy for ST-segment elevation myocardial infarction in the ExTRACT-TIMI 25 trial. J Am Coll Cardiol 2007;49:2238–2246. 15. Collet JP, Montalescot G, Lison L, et al. Percutaneous coronary intervention after subcutaneous enoxaparin pretreatment in patients with unstable angina pectoris. Circulation 2001;103:658–663. 16. Kereiakes DJ, Grines C, Fry E, et al. Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention. J Invasive Cardiol 2001;13:272–278. 17. 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. 18. The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators. Dose-ranging trial of enoxaparin for unstable angina: results of TIMI 11A. J Am Coll Cardiol 1997;29:1474–1482. 19. Montalescot G, Collet JP, Tanguy ML, et al. Anti-Xa activity relates to survival and efficacy in unselected acute coronary syndrome patients treated with enoxaparin. Circulation 2004;110:392–398. 20. Moliterno DJ, Hermiller JB, Kereiakes DJ, 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 2003;42:1132–1139. 21. Madan M, Radhakrishnan S, Reis M, et al. Comparison of enoxaparin versus heparin during elective percutaneous coronary intervention performed with either eptifibatide or tirofiban (the ACTION Trial). Am J Cardiol 2005;95:1295–1301. 22. Bhatt DL, Lee BI, Casterella PJ, et al. 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. J Am Coll Cardiol 2003;41:20–25. 23. Aslam MS, Sundberg S, Sabri MN, et al. Pharmacokinetics of intravenous/subcutaneous Enoxaparin in patients with acute coronary syndrome undergoing percutaneous coronary interventions. Catheter Cardiovasc Interv 2002;57:187–190. 24. Zalc S, Lemos PA, Esteves A, et al. Early ambulation and variability in anticoagulation during elective coronary stenting with a single intravenous bolus of low-dose, low-molecular weight heparin enoxaparin. J Invasive Cardiol 2006;18:45–48. 25. Sanchez-Pena P, Hulot JS, Urien S, et al. Anti-factor Xa kinetics after intravenous enoxaparin in patients undergoing percutaneous coronary intervention: A population model analysis. Br J Clin Pharmacol 2005;60:364–373. 26. Levine GN, Ferrando T. Degree of anticoagulation after one subcutaneous and one subsequent intravenous booster dose of enoxaparin: Implications for patients with acute coronary syndromes undergoing early percutaneous coronary intervention. J Thromb Thrombolysis 2004;17:167–171. 27. Lovenox® (enoxaparin sodium injection). Sanofi-Aventis U.S., LLC, 2007. Available: https://products.sanofi-aventis.us/lovenox/lovenox.pdf. [Accessed July 4, 2008] 28. Martin JL, Fry ET, Martin T, et al. The pharmacodynamics of enoxaparin in percutaneous coronary intervention with precise rapid enoxaparin loading (PEPCI-PRE study). J Thromb Thrombolysis 2009;28:224–228. 29. Bijsterveld NR, Moons AH, Meijers JC, et al. The impact on coagulation of an intravenous loading dose in addition to a subcutaneous regimen of low-molecular-weight heparin in the initial treatment of acute coronary syndromes. J Am Coll Cardiol 2003;42:424–427. 30. Becker RC, Spencer FA, Gibson M, et al. Influence of patient characteristics and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in non-ST-segment elevation acute coronary syndromes. Am Heart J 2002;143:753–759. 31. Montalescot G, Cohen M, Goldstein P, et al, for the ATOLL investigators. ATOLL An international randomized study comparing IV enoxaparin to IV UFH in primary PCI. ESC, Stockholm – Hotline session August 30, 2010. 32. Manoukian SV, Feit F, Mehan R, et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: An analysis from the ACUITY trial. J Am Coll Cardiol 2007;49:1362–1368. 33. Montalescot G, Gallo R, White HD, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention 1-year results from the STEEPLE (SafeTy and efficacy of enoxaparin in percutaneous coronary intervention patients, an international randomized evaluation) trial. JACC Cardiovasc Interv 2009;2:1083–1091. 34. Cohen M, Mahaffey KW, Pieper K, et al. A subgroup analysis of the impact of prerandomization antithrombin therapy on outcomes in the SYNERGY trial: Enoxaparin versus unfractionated heparin in non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol 2006;48:1346–1354.
35. Drouet L, Bal dit Sollier C, Martin J. Adding intravenous unfractionated heparin to standard enoxaparin causes excessive anticoagulation not detected by activated clotting time: Results of the STACK-on to ENOXaparin (STACKENOX) study. Am Heart J 2009;158:177–184. 36. Díez JG, Cheong BY, O’Meallie LP, Alt EU. Monitoring of enoxaparin level using citrated clotting time during percutaneous coronary intervention. J Interv Cardiol 2004;17:307–313. 37. Welsh RC, Gordon P, Westerhout CM, et al. A novel enoxaparin regime for ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: A WEST sub-study. Catheter Cardiovasc Interv 2007;70:341–348. 38. Desjardins L, Bara L, Boutitie F, et al. Correlation of plasma coagulation parameters with thromboprophylaxis, patient characteristics, and outcome in the MEDENOX study. Arch Pathol Lab Med 2004;128:519–526. 39. Gallo R, Steinhubl SR, White HD, Montalescot G, on behalf of the STEEPLE Investigators. Impact of anticoagulation regimens on sheath management and bleeding in patients undergoing elective percutaneous coronary intervention in the STEEPLE trial. Catheter Cardiovasc Interv 2009;73:319–325.
