Pharmacoinvasive Management of Acute Coronary Syndrome in the Setting of Percutaneous Coronary Intervention: Evidence-Based, Sit

Part II of III - Continued TABLE 3 KEY (continued) 2) Unfractionated heparin(UFH) can be used as an alternative to enoxaparin. If UFH is used in the setting of PCI, activated clotting time (ACT) should be followed to achieve an appropriate level of anticoagulation. Use weight-based dosing according to guidelines. Weight-adjusted heparin dosing can be utilized during PCI. In those not treated with a GP IIb/IIIa inhibitor, 100 IU/kg IV should initially be administered; the target ACT is 300–350 seconds when measured by the Hemochron device. In those who are treated with a GP IIb/IIIa inhibitor, 60–70 IU/kg should initially be administered; the target ACT is generally given as 200–300 seconds, with some recommending a target ACT of 200–250 seconds. If manual compression is to be utilized, sheaths can be removed when the ACT is 65 years; D) ST-T wave segment changes; E) TIMI Risk Score greater than or equal to 5, and/or F) failure to respond to maximal medical therapy. Additional factors that may suggest the need for more intensive medical therapy or support PCI as the dominant approach include the presence of heart failure, and other co-existing risk factors, which, at the clinician’s discretion, suggest that maximally intensive pharmacotherapeutic approaches combined with interventional modalities will yield optimal patient outcomes. 4) Because clopidogrel increases the risk of bleeding in patients undergoing CABG, the decision to initiate clopidogrel therapy in the emergency department (prior to PCI) or in the peri-PCI period should be based primarily on whether the patient is likely to undergo CABG surgery. Unless contraindications exist, all patients with documented coronary heart disease should be discharged from the hospital on clopidogrel therapy for a minimum of 12 months. Clopidogrel is administered as a 300 mg loading dose, and 75 mg QD thereafter. It is the Panel’s recommendation that when clopidogrel therapy is initiated in patients who are not candidates for surgical revascularization, it should be initiated in the cath lab. 5) Enoxaparin-mediated anticoagulation for PCI is supported by pharmacokinetic modeling data showing that patients who have been receiving subcutaneously-administered enoxaparin for NSTE-ACS and who undergo PCI within 8 hours will have anti-Xa levels in the range of 0.6–1.8 IU/ml. Those who have received an IV loading dose or two or more doses of subcutaneous enoxaparin and undergo PCI 8–12 hours after the last SC dose achieve these levels with an additional “booster” dose of 0.3 mg/kg administered intravenously. Investigators have demonstrated that anti-Xa levels were generally within 10% of the predicted values, and in the targeted range in 96% of patients. If an initial 30 mg IV dose of enoxaparin has not been administered and if only one dose of SC enoxaparin has been administered (in a patient without an IV loading dose), then at the time of procedure, patient should receive a booster dose of 0.3 mg/kg prior to catheterization/PCI. The ENOX clotting time may be measured in such patients, and if it is found to be > 260 seconds, the booster dose may be withheld. 6) In conjunction with the dosing algorithm for enoxaparin presented above, interventional cardiologists may employ a point-of-care device approved for assessment of anticoagulation in patients receiving enoxaparin while undergoing PCI. Use of this tool should be considered in patients receiving subcutaneous doses, and/or in those in whom steady state levels may not have been achieved. Guidelines for its use and target values in the setting of PCI are presented (Table 5). Note: The activated clotting time (ACT) is not useful for assessing therapeutic levels or anticoagulation effects of enoxaparin and should not be monitored in patients receiving enoxaparin in the setting of PCI. 7) In patients with severe renal failure (Cr clearance Table 4. TIMI risk score • Age >= 65 years • Documented prior coronary artery stenosis > 50% • Three or more conventional cardiac risk factors (e.g., age, sex, family history, hyperlipidemia, diabetes, smoking, hypertension, obesity) • Use of aspirin in the preceding 24 hours • Two or more anginal events in the preceding 24 hours • ST-segment deviation (transient elevation or persistent depression) • Increased cardiac biomarkers Source: Antman EM, Cohen M, Bernink PJ, et al. The TIMI Risk Score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA 2000;284:835–842 PCI studies: Safety and efficacy of LMWH. The CATH Panel reviewed a number of clinical trials assessing the safety and dosing strategy for enoxaparin in the setting of PCI not associated with STEMI (Table 5). NICE-3 evaluated a strategy of continued enoxaparin use in 661 ACS patients who were brought forward to the catheterization laboratory without the use of any UFH. All received enoxaparin 1.0 mg/kg SC q 12 hr for at least 4 doses or a 30 mg IV bolus followed immediately by 1.0 mg/kg SC q 12 hr. Most of the patients (628) received concomitant GP IIb/IIIa antagonists. The choice of IIb/IIIa antagonist was at the discretion of each study site. Two hundred and eighty-three patients went on to PCI. At the time of PCI, additional enoxaparin (0.3 mg/kg IV) was administered if more than 8 hours had elapsed since the last SC dose. If PCI was performed less than 8 hours after the last steady-state dose, no additional enoxaparin (or UFH) was given. A dose of 1.0 mg/kg IV was given at PCI if the last SC dose was more than 12 hours prior. The combination of enoxaparin with different GP IIb/IIIa inhibitors resulted in similar clinical outcomes and bleeding frequency in comparison to those seen in the large GP IIb/IIIa inhibitor trials, which were conducted with UFH.13,14 The NICE-4 registry studied the combination of enoxaparin with abciximab during PCI.15 It should be noted that NICE-4 and NICE-1 (see below) were conducted without pre-treatment with enoxaparin, which was used in planned PCI as the only antithrombin. Enoxaparin was given as a 0.75 mg/kg intravenous bolus with standard bolus and 12-hour infusion of abciximab. Patients who received enoxaparin and abciximab had an incidence of major non-CABG bleeding of 0.4%, which compared favorably with an incidence of 2.0% in patients receiving abciximab and low-dose heparin (70 U/kg) in the EPILOG trial.16 Periprocedural CK elevation was less than that seen in EPISTENT, despite higher-risk patients and more frequent multivessel intervention in NICE-4. In 200 patients undergoing elective PCI after 3 days of aspirin and tirofiban, another group performed a randomized comparison of periprocedural heparin versus enoxaparin. Clinical outcomes and major bleeding were comparable between the groups at 30 days.17 While not a study in the setting of PCI, the pharmacokinetics, pharmacodynamics and safety of the combination of tirofiban with enoxaparin versus heparin in non-Q wave MI was addressed in a 55 patient series. As with most studies, more minor bleeding occurred with the enoxaparin combination, while major bleeding was comparable. The combination of tirofiban and enoxaparin resulted in a more consistent inhibition of platelet aggregation and lower adjusted bleeding time than did the combination with heparin. In NICE-1, Grines and colleagues performed an observational study treating 828 patients undergoing PCI with enoxaparin 1 mg/kg administered intravenously at the time of the PCI procedure without a GP IIb/IIIa inhibitor. The incidences of major non-CABG bleeding (0.5%) and major ischemic adverse events (7.9%) as assessed at 30 days were relatively low and comparable to those observed in the EPISTENT group of patients treated with placebo drug and coronary stents.15,18 In NICE-1 and NICE-4, sheaths were removed 4 hours after intravenous enoxaparin administration without prospective monitoring, a time frame consistent with the fall in anti-Xa activity after intravenous administration of enoxaparin. Manual compression (± Femstop) was utilized to achieve hemostasis. Enoxaparin dosing. The approach to dosing enoxaparin in PCI is supported by a pharmacokinetic model designed to anticipate serum anti-Xa levels in patients receiving supplemental doses of intravenous enoxaparin superimposed on the FDA-approved subcutaneous dosing regimen (1 mg/kg q 12 hr) for NSTEMI/unstable angina. (Table 6, pharmacokinetic model predicting serum factor anti-Xa levels.) The model predicted that in patients who had received subcutaneously-administered enoxaparin and were at steady state and who underwent PCI 8–12 hours after the last SC dose, an additional “booster” dose of 0.3 mg/kg administered intravenously would raise and maintain anti-Xa levels to a range of 0.6–1.8 IU/ml for 1–2 hours. Additional enoxaparin dosing recommendations are based on pretreatment and achieving a steady state, either with an initial 30 mg IV dose followed immediately by the first 1 mg/kg SC dose or after receiving 3 or more doses of 1 mg/kg SC q 12 hr without an initial IV loading dose. This model was tested in 55 patients, in whom the predicted and actual (measured) serum anti-Xa levels were then compared. Measured anti-Xa level activity was generally within 10% of the predicted values, and within the targeted range for 96% of patients (Figure 1).19 Based on this and other studies, patients who have been receiving subcutaneously-administered enoxaparin receive administration of an intravenous “booster” dose of 0.3 mg/kg enoxaparin at the start of PCI, and undergo PCI 8–12 hours after the last subcutaneous dose. This has been adopted in most practices, was used in NICE-3, and is being utilized in the large, multicenter, ongoing Superior Yield of the New Strategy of Enoxaparin, Revascularization and GP IIb/IIIa Inhibitors (SYNERGY) study. This dosing regimen is endorsed by the CATH Panel. Precautions regarding enoxaparin use in “special patient groups”, such as those with renal insufficiency (Cr > 2.5 mg/dl, creatinine clearance 150 kg), and the elderly (> age 75 years), must be considered and dosage modifications made accordingly. As a rule, patients with renal dysfunction receiving less than 4 doses are at low risk for drug accumulation and bleeding. However, when more than 4 doses are required in patients with advanced renal impairment, additional dosing should be guided by anti-Xa levels or patients should be switched to UFH. Physicians should consult the enoxaparin package insert for dosing recommendations in patients with severe renal failure. Similarly, levels of activity in morbidly obese patients may be unreliable. Elderly patients treated with an initial loading dose of enoxaparin and another class of antithrombotic agent (i.e., fibrinolytics or GP IIb/IIIa inhibitors) may be at increased risk for bleeding, including ICH, and may need to be managed with alternative agents or combinations. Sheaths may be removed 6–8 hours after the last SC injection in those undergoing PCI less than 8 hours after the last SC dose and after 4 hours following IV administration. The dosing recommendations for PCI for 0–8 hours and for 8–12 hours after the last SC dose are the same with or without adjunctive GP IIb/IIIa inhibitor therapy. Table 6. Enoxaparin dosing guidelines and algorithm for NSTE-ACS patients undergoing percutaneous coronary intervention Dosing guidelines for initial enoxaparin-based anticoagulation therapy in patients with NSTE-ACS General recommendations: Enoxaparin 30 mg IV bolus (optional1) followed immediately by 1 mg/kg SC q 12 hours (until diagnostic cardiac catheterization or for 72–96 hours). An IV bolus dose should be given when cardiac catheterization is to be performed before therapeutic factor anti-Xa levels are achieved, or shortly after presentation Enoxaparin dosing guidelines and algorithm for percutaneous coronary intervention1–5 Therapeutic anti-Xa levels: To ensure that ACS patients promptly achieve therapeutic anti-Xa levels, a 30 mg IV loading dose of enoxaparin is recommended, followed immediately by administration of 1 mg/kg SC q 12 hours. Therapeutic anti-Xa levels also are achieved after >= 2 doses of enoxaparin 1 mg/kg SC q 12 hours have been administered, even in the absence of an initial loading dose.34 • If an initial 30 mg IV loading dose of enoxaparin has been administered, or >= 2 doses of SC enoxaparin have been administered (with or without IV loading dose): 1) If procedure is performed within 8 hours of the last SC dose, no additional enoxaparin needs to be administered. 2) If procedure is performed at a point within 8–12 hours of the last SC dose, 0.3 mg/kg enoxaparin IV should be administered in the catheterization laboratory. • If an initial 30 mg IV dose of enoxaparin has not been administered and if only one dose of SC enoxaparin has been administered (in a patient without an IV loading dose): 1) At time of procedure, patient should receive a booster dose of 0.3 mg/kg prior to catheterization/PCI. The ENOX clotting time may be measured in such patients, and if it is found to be > 260 seconds, the booster dose may be withheld. • If no enoxaparin has been previously administered: 1) At time of procedure, 1.0 mg/kg enoxaparin IV should be administered in the catheterization laboratory if GP IIb/IIIa inhibitor is not given; 0.75 mg/kg enoxaparin IV should be administered when a GP IIb/IIIa will be used. Sheath removal. Timing of sheath removal depends on a number of factors, among them, whether or not a closure device is employed and time and route of last enoxaparin dose: • Sheath can be removed 6–8 hours after the last SC dose of enoxaparin without a closure device, or immediately if a closure device has been employed. • Sheath can be removed 4 hours after the 0.3 mg/kg IV supplemental dose for the 8–12 hour group, as well as after the 1.0 mg/kg IV (0.75 mg/kg with a GP IIb/IIIa inhibitor) for the group undergoing PCI > 12 hours after their last SC dose or who have not received any pretreatment. Enoxaparin clotting time.3 An alternative and adjunctive monitoring-based strategy using a point-of-care device Times cited for the Pharmanetics® ENOX coag assay should be used only as guidelines for efficacy, based on clinical judgment and other factors. These parameters are based on corresponding anti-Xa activity and the results of the ELECT trial. It also should be emphasized that because of the predictable pharmacokinetic properties of enoxaparin, such monitoring is generally unnecessary, provided the time from last administration is known accurately. Clinicians should consult the ENOX® package insert for additional, detailed information.22 1) From a pharmacodynamic perspective, administration of a 30 mg IV bolus immediately prior to the first 1 mg/kg SC dose of enoxaparin permits the patient to promptly achieve therapeutic factor anti-Xa levels; therefore, when prompt/immediate PCI is possible, administration of 30 mg IV enoxaparin bolus (followed by 1 mg/kg SC q 12 hours) is recommended by the CATH Consensus Panel. When PCI is likely to be delayed, the possible advantages of a 30 mg IV bolus of enoxaparin are less well defined. It should be noted that the risk of bleeding associated with administration of an IV enoxaparin (30 mg) bolus dose plus a GP IIb/IIIa inhibitor is not known; however, the risk of bleeding associated with combined use of enoxaparin 1 mg/kg SC 12 hours (i.e., no IV bolus) plus GP IIb/IIIa inhibitors has been shown to be comparable, and in some studies lower than, bleeding resulting from combined use of unfractionated heparin (UFH) plus GP IIb/IIIa receptor antagonists. Use of an initial enoxaparin 30 mg IV bolus is not recommended in patients > 75 years of age who are concomitantly being treated with thrombolytic drugs. 2) This dosing regimen for enoxaparin-mediated anticoagulation for PCI is supported by pharmacokinetic modeling data showing that patients who have been receiving subcutaneously-administered enoxaparin for ACS for > 24 hours and who undergo PCI within 8 hours will have anti-Xa levels in the currently recommended range of 0.6–1.8 IU/ml. Those who undergo PCI 8–12 hours after the last SC dose achieve these levels with an additional “booster” dose of 0.3 mg/kg administered intravenously. Investigators have demonstrated that anti-Xa levels were generally within 10% of the predicted values, and in the targeted range in 96% of patients.19 3) In conjunction with the dosing algorithm for enoxaparin, interventional cardiologists may employ a point-of-care device approved for assessment of anticoagulation in patients receiving enoxaparin while undergoing PCI. Use of this tool may be considered in patients receiving SC doses, in whom steady state levels and/or therapeutic anti-Xa levels may not have been achieved. The device generates an ENOX clotting time. Guidelines for its use are presented in the table. Clinicians should consult the ENOX® package insert for additional, detailed information. The activated clotting time (ACT) is not useful for assessing therapeutic levels or anticoagulation effects of enoxaparin and should not be monitored in patients receiving enoxaparin in the setting of PCI. 4) In patients with severe renal failure (Cr clearance 2.5 mg/dl, creatinine clearance 150 kg), and the elderly (> 75 years) must be considered and dosage modifications should be made accordingly. As a rule, patients with renal dysfunction receiving 4 doses are required in patients with severe renal impairment, additional dosing should be guided by anti-Xa levels or patients should be switched to UFH. Similarly, levels of activity in morbidly obese patients may be unreliable. Elderly patients treated with an initial loading dose of enoxaparin and another class of antithrombotic agent (i.e., fibrinolytics or GP IIb/IIIa inhibitors) may be at increased risk for bleeding, including ICH, and may need to be managed with alternative agents or combinations. A recent clinical trial evaluated both anti-Xa levels and clinical outcomes in patients who had been treated for at least 48 hours with subcutaneously administered enoxaparin for ACS and who subsequently underwent PCI.20 A total of 132 patients among 451 consecutively treated ACS patients underwent PCI. By protocol, patients received their morning dose of enoxaparin and underwent PCI within 8 hours (average, 5.6 ± 1.9 hours) of the last morning dose. At PCI, anti-Xa activity was greater than 0.5 IU in 97.6% of patients, averaging 0.98 ± 0.03 IU. (Figure 2). Abrupt coronary closures or urgent revascularization were not observed in-hospital or at 30-day follow-up. The incidence of death or MI at 30 days was only 3.0% and the incidence of major bleeding only 0.8%. This study demonstrates that patients at steady state arrive in the cardiac catheterization laboratory with a predictably high level of anticoagulation when PCI is performed within 8 hours of subcutaneous enoxaparin (1.0 mg/kg). In addition, it suggests that initiating enoxaparin therapy in the ED setting does not adversely affect clinical outcome, or preclude early catheterization or increase hemorrhagic complications in PCI.20 The Coronary Revascularization Using Integrilin and Single Bolus Enoxaparin (CRUISE) trial was a randomized, open-label trial evaluating ACS patients undergoing PCI who had not previously received anticoagulation therapy. Patients (n = 261) were randomized to receive either enoxaparin (0.75 mg/kg IV) or UFH (60 IU/kg IV) at the time of PCI.21 All patients were treated with eptifibatide using the ESPRIT double-bolus regimen (180 mg/kg IV bolus x 2, 10 minutes apart, and 2.0 mg/kg/min infusion for 16 hours). Removal of femoral sheaths and achievement of hemostasis were managed by either manual compression or by use of a vascular closure device. Bleeding, assessed by several parameters, was comparable between the 2 groups. Interestingly, no bleeding complications were noted in the 48 patients treated with enoxaparin who were managed with a vascular closure device. No significant differences in clinical events were noted, although this relatively small trial had limited statistical power. A point-of-care device (The Rapidpoint® Coag Enoxaparin Test card) recently has been approved for the assessment of anticoagulation in patients receiving enoxaparin. The precise role of this device in managing patients treated with enoxaparin and undergoing PCI remains unclear and is in need of further clarification. The device generates an “ENOX clotting time”, which, when it exceeds a value of 260 seconds, correlates with a serum anti-Xa level of 1.0 IU or greater. The sensitivity and specificity point estimates for this 260 second clotting time are 96.3% (95% CI, 89.4–99.2) and 25% (95% CI, 3.2–65.1), respectively. Patients with clotting times less than 260 seconds are considered to have results consistent with an anti-Xa level less than 1.0 IU/ml. Clinicians are referred to the ENOX® package insert for additional, detailed information.22 Much of enoxaparin’s pharmacodynamic and clinical benefits stem from its greater inhibition of activated factor X (Xa) as compared to activated thrombin (or activated factor II; IIa). Accordingly, its effect is not readily detected by activated clotting time (ACT). Dalteparin and other LMWHs with less specificity for Xa inhibition do prolong ACT because of the greater relative effect on IIa similar to UFH.23 The aforementioned investigations support the safe and effective use of enoxaparin in PCI in the setting of ACS, and its use in combination with GP IIb/IIIa inhibitors. The greatest number of studies supporting the advantages of a LMWH anticoagulant plus a GP IIb/IIIa antagonist have evaluated the use of enoxaparin in combination with eptifibatide or abciximab.9,18,20,21,24–28 Although there has been initial reluctance among some cardiac interventionalists to use enoxaparin in combination with GP IIb/IIIa antagonists, due primarily to concerns about hemorrhagic risk, a number of studies examining this issue in the interventional setting have confirmed that the combination of LMWH and GP IIb/IIIa agents is not associated with excessive bleeding.9,15,29–31 Retrospective analysis of data from ESSENCE and TIMI-11B revealed that 201 patients from these 2 studies underwent PCI while receiving treatment with enoxaparin. A minority of these patients received some dose of supplemental UFH for the PCI procedure. Major bleeding and ischemic complication rates were comparable between those undergoing PCI on enoxaparin and those undergoing PCI on UFH.32 In addition, risk of death or MI at 1-year follow-up was reduced 51% in those randomized to initial treatment with enoxaparin.33 (Continued in PART III of III)