Pharmacoinvasive Management of Acute Coronary Syndrome in the Setting of Percutaneous Coronary Intervention: Evidence-Based, Sit
- Volume 15 - Issue 11 - November, 2003
- Posted on: 8/1/08
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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 < 150–180 seconds. (Popma JJ, Ohman EM, Weitz J, et al. Antithrombotic therapy in patients undergoing percutaneous coronary intervention. Chest 2001;119(Suppl):321S–336S; Smith SC, Dove JT, Jacobs AK, et al. ACC/AHA guidelines for percutaneous coronary intervention. J Am Coll Cardiol 2001;37:1–66).
3) High-risk criteria that support more aggressive medical therapy (i.e., addition of small molecule GP IIb/IIIa inhibitor to aspirin, enoxaparin, and in most cases, clopidogrel) and/or support invasive (mechanical or surgical) revascularization include, but are not limited to the presence of one or more of the following: A) elevated troponin level (or elevated CK-MB); B) elevated C-reactive protein (CRP); C) age > 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 < 30 ml/min) receiving enoxaparin, dose adjustment may be required. Consult the package insert for detailed dosing information.
8) If the patient is not on GP IIb/IIIa inhibitor prior to PCI, use abciximab [0.25 mg/kg bolus IV, followed by 0.125 µg/kg/min (max 10 µg/min) infusion for 12 hr) or eptifibatide (180 µg/kg IV bolus x 2, 10 minutes apart, followed by 2.0 µg/kg/min infusion for 18 hr).
ISAR-COOL, presented at the AHA 2002 Scientific Sessions, randomized 410 patients with NSTEMI scheduled to undergo PCI to either immediate intervention or a “cooling-off” period in which they were treated with aspirin, clopidogrel, tirofiban and heparin for 72–120 hours before the procedure was conducted. The early (immediate) intervention group received the same medications, but no delay in PCI. The primary endpoint of death/MI at 30 days in the “cooling-off” group was 11.6% versus 5.9% (p = 0.04), driven by a reduction in non-fatal MI (10.1% versus 5.9%). The authors concluded that deferral of intervention to passivate the vessel does not improve outcome but seems to be associated with an increased event rate.11
The role of enoxaparin and other LMWHs in ACS: Spectrum- and site-of-care considerations in patients undergoing medical management or PCI. The revised 2002 AHA/ACC Guidelines for ACS recommend that anticoagulation with subcutaneous LMWH or intravenous UFH be added to antiplatelet therapy with aspirin, clopidogrel or both (Class I, Level A). In addition, enoxaparin was categorized as preferable to UFH as an anticoagulant in patients with unstable angina/NSTEMI, unless CABG is planned within 24 hours (Class IIa, Level A). The upgrade of the anticoagulation recommendation and the unusual step of singling out a specific agent within the LMWH class came from the ESSENCE3 and TIMI-11B trial results.2
In the ESSENCE study, patients with ACS were randomly assigned to receive enoxaparin or UFH. The need for revascularization procedures at 30 days was significantly less frequent with enoxaparin compared with UFH (27.0% compared with 32.2%; p = 0.001). In the TIMI-11B study, patients (n = 3,910) with unstable angina/non-Q wave MI were randomized to intravenous UFH for 3 days or more followed by subcutaneous (SC) placebo injections or uninterrupted antithrombin therapy with enoxaparin during both the acute and outpatient phases. In TIMI-IIB, urgent revascularization was required in 10.7% of patients who received enoxaparin and 12.6% of patients who received UFH at 43 days (p = 0.05). The incidence of cardiac and hemorrhagic events in patients undergoing PCI in the ESSENCE and TIMI-11B clinical studies was similar, irrespective of the initial type of anticoagulation (enoxaparin or UFH) and the timing of the intervention (PCI on treatment/within 12 hours of final dose or at any time during initial hospitalization).2,3
Because of increasing emphasis on prompt administration of enoxaparin in the ED (along with aspirin, and when appropriate clopidogrel), interventional cardiologists are more likely to encounter patients receiving subcutaneously administered enoxaparin for initial treatment of their ACS. NSTE-ACS has been recognized as a thrombosis instability state that warrants immediate administration of an anticoagulant such as enoxaparin (along with aspirin), even when the timing of intervention is uncertain. Moreover, in the setting of upstream GP IIb/IIIa receptor antagonists (especially eptifibatide in high-risk ACS patients), the interventional cardiologist must evaluate and account for the results of dosing and time-of-administration studies assessing the efficacy and safety for transitioning patients on LMWH from the medical stabilization phase to the invasive (mechanical intervention) phase of care.
The EVET study randomly compared the efficacy of enoxaparin versus tinzaparin, two different LMWH preparations, in the management of ACS. In this prospective study, a total of 438 patients with unstable angina or non-Q wave MI were randomized to receive either SC injections of 1 mg/kg enoxaparin twice daily (n = 220) or 175 IU/kg tinzaparin once daily (n = 218) for 7 days. The primary endpoints were death, MI, refractory angina and recurrence of unstable angina. Secondary endpoints were rehospitalization due to unstable angina or MI, death and the need for revascularization at 30 days.12 At 7 days, recurrence of unstable angina occurred significantly less frequently with enoxaparin than in the tinzaparin group (24/220 versus 41/218; p = 0.029). No significant differences were observed between these 2 groups with respect to the composite of death, MI or refractory angina at 7 days. At 30 days, there were no differences between the 2 groups regarding rehospitalization and death, but the need for revascularization occurred significantly less frequently in the patients assigned to enoxaparin (36/220 versus 57/218; p = 0.019). Bleeding complication rates were similar in the 2 groups. These investigators concluded that antithrombotic treatment with enoxaparin for 7 days was more effective than with tinzaparin for reducing the incidence of recurrent angina in patients with unstable angina or non-Q wave MI in the early phase.12
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