The Combination of Enoxaparin, Glycoprotein IIb/IIIa Inhibitors and an Early Invasive Approach Among Acute Coronary Syndrome Pat

ABSTRACT: Objectives. This study was designed to assess the feasibility and safety of enoxaparin in combination with glycoprotein (GP) IIb/IIIa inhibitors during percutaneous coronary intervention (PCI) as part of an early invasive strategy in patients presenting with acute coronary syndromes (ACS). Background. Trials in patients with ACS have evaluated the utility of enoxaparin, adjuvant GP IIb/IIIa inhibitors with PCI, and an early invasive approach. Information about the combination of all three of these approaches, however, is limited. Methods. Forty-nine patients with ACS underwent cardiac catheterization, of whom 23 underwent PCI with enoxaparin and GP IIb/IIIa inhibitors. Results. The primary endpoint of the study, a composite of death, myocardial infarction or urgent revascularization at 30 days, occurred in 8% of patients undergoing PCI. There were no deaths. One patient received a blood transfusion. No other adverse events occurred. These event rates were comparable to those from the pooled EPILOG/EPISTENT database, in which intravenous unfractionated heparin was used in conjunction with GP IIb/IIIa receptor blockade. The mean anti-Xa level in patients undergoing PCI was 0.74 ± 0.48 U/ml. The majority of patients who underwent PCI within eight hours of their last dose of enoxaparin had therapeutic anti-Xa levels. Conclusion. In patients with ACS, enoxaparin in combination with GP IIb/IIIa inhibitors and an early invasive approach resulted in comparable clinical complication and bleeding rates versus historical references utilizing unfractionated heparin.

Key words: acute coronary syndromes, angioplasty, anticoagulation, antiplatelet drugs

In acute coronary syndromes (ACS), treatment with the low molecular weight heparin (LMWH) enoxaparin results in improved clinical outcomes compared with unfractionated heparin (UFH).^1–9 Possible reasons for this benefit include unfractionated heparin’s propensity to activate platelets as well as release von Willebrand factor.^10–13 In addition, enoxaparin has better pharmacokinetics than UFH, with improved bioavailability and more consistent and predictable levels of anticoagulation without the need for frequent laboratory monitoring and dose adjustment. Enoxaparin has also been shown to be cost-effective versus UFH in this setting.¹⁴ Recent clinical trials and observational studies have provided evidence for the safety of enoxaparin in cardiac catheterization and percutaneous intervention.^15,16 However, for patients with an ACS treated with percutaneous coronary intervention (PCI), concerns about sub-therapeutic levels, possible bleeding risks and incomplete reversibility have limited its use. The utility of measuring the extent of anticoagulation with enoxaparin at the time of PCI and sheath removal is also uncertain. While numerous trials have evaluated the use of glycoprotein (GP) IIb/IIIa inhibitors in both ACS and PCI,^17–26 few trials have studied the combination of LMWHs with GP IIb/IIIa inhibitors.^27,28 As such, questions remain regarding the combination of enoxaparin, GP IIb/IIIa inhibitors and an early invasive approach for ACS patients. This pilot study was designed to assess whether this combination is efficacious and safe in contemporary practice. Methods We prospectively enrolled 49 inpatients at the Cleveland Clinic Foundation (CCF) who needed anticoagulant therapy for an ACS. The inclusion criteria included ischemic chest pain in patients who were candidates for cardiac catheterization and possible PCI. Ischemic chest pain was defined as typical anginal pain lasting greater than 15 minutes in the 24 hours prior to admission, electrocardiographic changes and/or elevated cardiac markers of myonecrosis. Electrocardiographic changes included new ST-segment depression, transient ST-elevation (>= 1 mm) or T-wave inversions. Elevated cardiac markers were defined as a creatinine kinase myocardial band isoenzyme (CK-MB) or troponin T level greater than the upper limit of normal. Entrance into the study occurred in the emergency department or in the telemetry units. Exclusion criteria included a history of heparin-induced thrombocytopenia, fibrinolytic therapy within the previous 48 hours, uncontrolled hypertension, malignancy, recent or planned spinal puncture, renal insufficiency (creatinine > 2.0 mg/dl or significantly worsening function), prior stroke, bleeding diathesis, hemoglobin Study design. All enrolled patients received subcutaneous enoxaparin 1 mg/kg every twelve hours until the time of catheterization and interventional procedure. If the catheterization occurred within eight hours of the last dose of enoxaparin, no additional enoxaparin was given before the intervention. If the interventional procedure continued beyond the eight-hour mark, an additional 0.3 mg/kg of intravenous (IV) enoxaparin was given during the procedure. If the intervention started between 8–12 hours after the last dose, 0.3 mg/kg of IV enoxaparin was given (Figure 1). All patients received 325 mg of aspirin daily, unless they had an aspirin allergy. Patients who received an intracoronary stent were given clopidogrel 75 mg daily. Patients could be started on a GP IIb/IIIa inhibitor on admission at the discretion of the treating physician. Any patient not receiving GP IIb/IIIa therapy prior to PCI was started on an agent of the operator’s choice at the time of intervention. Abciximab was given as a 0.25 mg/kg IV bolus 10–60 minutes before PCI, followed by a 0.125 µg/kg/minute infusion for twelve hours. Eptifibatide was administered as a double IV bolus of 180 µg/kg, ten minutes apart, followed by a 2 µg/kg/minute infusion for 18 hours after PCI. Tirofiban was given as a 10 µg/kg IV bolus followed by a 0.15 µg/kg/minute infusion for 18 hours after PCI (Figure 1). Sheath management. All FDA-approved closure devices were allowed. If the sheath was left in place, it was pulled at least six hours after the last dose of enoxaparin. Manual pressure was applied for at least twenty minutes. Thereafter, a pressure dressing was placed over the site, and the patient was maintained on bedrest for at least eight hours after sheath removal. Evaluation and endpoints. Pre-procedural electrocardiogram (ECG), hemoglobin level and platelet count were obtained. At the time of the procedure, samples for activated partial thromboplastin time (aPTT) and anti-Factor Xa activity were collected. The blood for the anti-Xa activity was collected in citrated tubes, and a chromogenic assay was used to measure anti-Xa activity. All patients had an ECG and measurement of cardiac enzymes, hemoglobin and platelet count the morning after the interventional procedure. In addition, the groin was examined for access site complications. The primary safety endpoints included bleeding, need for transfusion, thrombocytopenia, access site complications or stroke. The severity of bleeding was assessed by the Thombolysis in Myocardial Infarction (TIMI) criteria.²⁹ Thrombocytopenia was defined as a platelet count 3. Groin complications were defined as hematoma or bleeding requiring medical intervention, need for vascular repair or increased duration of hospitalization. The primary efficacy endpoints of the study were death, myocardial infarction or urgent revascularization (PCI or CABG) at 48 hours. Myocardial infarction was defined as new Q-waves >= 0.04 seconds in at least two contiguous leads or a CK-MB >= 3 times the upper limit of normal after PCI that was at least 50% above the previous nadir. The same efficacy endpoints at seven days and thirty days were assessed as secondary endpoints. Statistical analysis. The event rates for the different endpoints were compared with those from the pooled EPILOG/EPISTENT database in which intravenous unfractionated heparin was used in conjunction with GP IIb/IIIa receptor blockade. The goal of this pilot study was to assess the feasibility and safety of the combination of enoxaparin with a GP IIb/IIIa inhibitor in the setting of an early invasive approach. Results Study population. Forty-nine patients were enrolled and underwent cardiac catheterization, and 23 patients underwent PCI in the same setting. Baseline patient demographics and clinical characteristics are shown in Table 1. These patients were at high risk for adverse cardiac outcomes. Two-thirds of the patients had undergone previous revascularization, and one-third had diabetes mellitus. Of the patients undergoing PCI, twelve (52%) had non-ST segment elevation myocardial infarction and 11 (48%) had unstable angina. Procedural details and results are listed in Tables 2 and 3. Study drug administration. All patients received enoxaparin, and 22/23 of patients (96%) undergoing intervention received GP IIb/IIIa inhibitor. The duration of hospitalization in the PCI group was 86 ± 36 hours. The time from admission to PCI was 44 ± 30 hours. Thirty percent of patients underwent intervention within the first 24 hours, and 60% underwent intervention within the first 48 hours (Table 2). In the PCI group, the average total enoxaparin given during the hospitalization was 377 mg. Anti-Xa levels. Twenty-two PCI patients had anti-activated factor X levels drawn at the time of their catheterization, prior to additional dosing of enoxaparin if specified by protocol. The mean duration between last dose of enoxaparin and catheterization was 6.2 ± 4.2 hours. The mean anti-Xa level was 0.74 ± 0.48 U/ml (Table 4). In patients who did not undergo intervention, the mean anti-Xa level was 0.76 ± 0.33 U/ml. One of two patients who received their last dose of enoxaparin within one hour of catheterization had a therapeutic level. Seven of eight patients who received their last dose within 1–4 hours of catheterization had therapeutic values (the patient who did not have a therapeutic level suffered a protocol violation and was underdosed with enoxaparin in the emergency room prior to catheterization). Three of four patients who had their last dose 4–8 hours prior to catheterization had therapeutic values. Only 2/5 patients who received their last dose 8–12 hours prior to catheterization had therapeutic values. One of three patients who received their last dose of enoxaparin > 12 hours prior to catheterization had therapeutic values. Per protocol, all patients who received their last dose more than eight hours prior to intervention received additional enoxaparin prior to PCI. There was no correlation between body weight and anti-Xa level, as expected, given the weight-based dosing algorithm. Also, aPTT did not accurately predict levels of anticoagulation (Table 5). Clinical ischemic events. The incidence of the composite endpoint of death, MI or urgent revascularization at 48 hours was 8% (Table 6). The patient cohort in this study was similar to the historical comparison group (Table 7). There were no deaths. One patient, who had undergone rotational atherectomy, had a peri-procedural myocardial infarction. Notably, this patient also had a subtherapeutic anti-Xa level. One patient had an urgent revascularization at thirty days. This patient developed a small hematoma at the site of enoxaparin injections and had fevers, prompting discontinuation of the enoxaparin prior to PCI. He was not treated with aspirin due to an aspirin allergy. This patient subsequently presented with a subacute stent thrombosis and unstable angina within two days of the previous intervention. At seven days and thirty days, there were no additional clinical events. However, one patient did undergo elective revascularization with PCI. Bleeding and tolerability. There was only one significant bleeding event. One patient received a blood transfusion for asymptomatic anemia, not due to a bleeding episode. No TIMI major or minor bleeding occurred. Thrombocytopenia was not observed in any patient post-intervention. Of the 23 PCI patients, sixteen received closure devices. There were no groin complications, including hematoma, arteriovenous fistula or pseudoaneurysm. No other adverse events occurred (Table 6). Discussion The TIMI 11B and ESSENCE trials have both provided ample data that enoxaparin is superior to unfractionated heparin in the medical management of ACS.^1,8,9 The results of these trials are reflected in the Class IIa recommendation in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the use of low molecular weight heparins in ACS.³⁰ However, using enoxaparin to anticoagulate patients in the catheterization laboratory has not yet been fully embraced due to concerns regarding dosing at the time of catheterization as well as safety and efficacy, especially in combination with GP IIb/IIIa inhibitors. Since the ACC/AHA guidelines for ACS also advocate an early invasive strategy for high-risk patients and adjuvant GP IIb/IIIa inhibitors for PCI as both Class I recommendations, the integration of all three of these recommendations for an individual patient with ACS remains problematic. Several trials have provided data about the safety of combining enoxaparin and GP IIb/IIIa inhibitors. The Coronary Revascularization Using Integrilin and Single Bolus Enoxaparin (CRUISE) study revealed that patients undergoing PCI treated with either enoxaparin or unfractionated heparin in combination with eptifibatide had comparable bleeding rates.¹⁶ This study, however, was conducted in patients electively undergoing PCI, not in an ACS population pretreated with enoxaparin. The National Investigators Collaboration on Enoxaparin 3 (NICE 3) trial evaluated 661 patients with unstable angina/non-ST elevation myocardial infarction (UA/NSTEMI) who were treated with a combination of aspirin, enoxaparin and GP IIb/IIIa antagonists. This was a non-randomized study with comparable bleeding rates to other published studies with unfractionated heparin.³¹ The results of the recently presented INTERACT trial revealed that the combination of eptifibatide and enoxaparin had less bleeding complications and recurrent ischemia than eptifibatide and unfractionated heparin.²⁸ More conclusive evidence about the safety and efficacy of this combination in PCI will be available upon completion of the SYNERGY trial. The issue of dosing and achieving therapeutic levels in the catheterization laboratory prior to PCI remains unsettled. The Antithrombotic Combination Using Tirofiban and Enoxaparin II (ACUTE II) study compared treatment with unfractionated heparin and tirofiban versus enoxaparin and tirofiban in patients presenting with UA/NSTEMI. In this study, enoxaparin was usually discontinued for more than ten hours prior to percutaneous intervention and anticoagulation during the intervention was achieved using unfractionated heparin in the majority of patients.³² Therefore, the investigators were unable to answer the question of whether enoxaparin can be used as the sole anticoagulant in combination with GP IIb/IIIa antagonists during PCI. The National Investigators Collaborating on Enoxaparin (NICE)-4 trial used a combination of a bolus of intravenous enoxaparin (0.75 mg/kg) and abciximab prior to PCI and found the combination resulted in low rates of ischemic events and bleeding, albeit without an active comparator.¹⁵ Collet et al. studied patients with UA/NSTEMI who were treated with subcutaneous enoxaparin (1 mg/kg every 12 hours). Virtually all patients who underwent intervention in this cohort were initially treated with medical therapy for at least 48 hours prior to catheterization and were scheduled to undergo intervention within eight hours of the last dose of enoxaparin, with no additional dosing of enoxaparin at the time of intervention. This trial was one of the first that measured anti-Xa levels at the time of catheterization and found that the vast majority of patients had therapeutic levels.²⁷ However, this trial does not specify which, if any, patients had co-administration of GP IIb/IIIa inhibitors at the time of PCI. Furthermore, it provides no guidance about patients who are taken to the catheterization lab sooner than 48 hours or who present to the catheterization lab more than 8 hours after their last dose of enoxaparin. Martin et al. measured anti-Xa levels in ACS patients undergoing PCI last treated with subcutaneous enoxaparin 8–12 hours prior to the procedure and after an additional IV bolus of 0.3 mg/kg had been given. They found that the anti-Xa levels were in the therapeutic range in 45/47 patients (96%).³³ Our trial found that the majority of patients (3/5) had subtherapeutic levels at 8–12 hours after the last dose if no additional IV dose was given. This trial provides corroboration that an additional IV bolus given in this subset of patients results in the vast majority reaching therapeutic levels. In our observational series of patients presenting with UA/NSTEMI undergoing percutaneous intervention, the combination of enoxaparin, GP IIb/IIIa inhibitors and an early invasive approach was safe and efficacious, with little bleeding and comparable clinical ischemic event rates to standard therapy with unfractionated heparin (Table 6). There were very few clinical events in our study, with 4% periprocedural myocardial infarction rate and 4% urgent revascularization rate. Notably, the composite endpoints occurred in patients predisposed to events. Only one patient received a blood transfusion, and there were no vascular or groin complications and no TIMI bleeding events. Our study provides support for the hypothesis that therapeutic anticoagulation can be achieved with enoxaparin at the time of percutaneous intervention, with a protocol that utilizes additional intravenous dosing in patients likely to be sub-therapeutic at the time of their catheterization. The anti-Xa levels measured in this study substantiate this conclusion and suggest that patients should receive additional IV enoxaparin if their catheterization occurs more than eight hours after their last dose. In addition, patients scheduled to receive enoxaparin within 1 hour of their catheterization may benefit from withholding enoxaparin until the time of the catheterization, at which time it can be given intravenously to ensure therapeutic levels at the start of the intervention; alternatively, in addition to the subcutaneous dose, a 30 mg intravenous bolus (or 0.5 mg/kg) may be given at the start of PCI to ensure a therapeutic effect. Recently, an enoxaparin-specific point-of-care monitor was FDA approved, and the Evaluating ENOX Clotting Times (ELECT) trial found that there was a trend toward lower ischemic events when the clotting time was between 250–450 seconds.³⁴ Until a point of care assay for low molecular weight heparins becomes readily accepted for use prior to PCI or until the need for such testing is proven unnecessary, algorithms such as the one used in this study can be used to predict and manage anticoagulation at the time of intervention (Figure 2). Study limitations. This was an observational study with a relatively small number of patients that used historical references. In addition, the anti-Xa levels were drawn at the beginning of catheterization before administration of any additional IV enoxaparin, as indicated by the algorithm. The efficacy of the dosing algorithm would have been better demonstrated by a repeat measurement of the anti-Xa level immediately prior to intervention. Finally, anti-Xa levels have not yet been adequately studied in correlation with ischemic or bleeding outcomes. Conclusion. Enoxaparin use in patients presenting with ACS treated with an early invasive approach who undergo PCI with adjuvant GP IIb/IIIa blockade appears well tolerated, safe and efficacious. A dosing algorithm that utilizes additional IV dosing in patients likely to be sub-therapeutic at the time of their catheterization may be beneficial to ensure adequate anticoagulation. Further trials to confirm these results are ongoing.