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Heparin Use in Acute Coronary Syndromes
By William J. Brady, MD
Heparin has been shown to have a profound synergistic effect with aspirin in preventing death, acute myocardial infarction (AMI), and refractory unstable angina. Heparin, either unfractionated or as the low-molecular-weight version, should be administered early in patients with AMI or the more severe forms of non-AMI acute coronary syndrome (ACS); patients with lower risk ACS presentations may not benefit from such therapy. The term heparin refers to a heterogenous collection of mucopolysaccharide chains of varying lengths and sizes. Unfractionated heparin (UFH) is composed of a mixture of polysaccharide chains with varying molecular weights. Low-molecular-weight heparin (LMWH) is approximately 30% of the molecular weight of UFH; the mucopolysaccharide chains of LMWH are more homogeneous in size. UFH binds to antithrombin III, forming a complex, which then inactivates both thrombin and activated factor X. The conversion to fibrin is prevented, ultimately inhibiting coagulation. UFH also potentiates the inactivation of factors XIa and IXa via antithrombin. Additional anticoagulant effects are mediated via platelet interaction. LMWH inhibits the coagulation cascade in a similar fashion to UFH with action at varying levels of the cascade, including antithrombin III, thrombin, and factor Xa. It is theorized that LMWH exerts anticoagulant effects somewhat earlier in the coagulation cascade. All LMWHs are not necessarily equivalent in efficacy. The different forms of LMWH reportedly demonstrate variable antithrombotic effects attributed to differing ratios of anti-factors Xa to IIa.
Evidence-Based Support for Heparins in ACS
The FRISC trial1 demonstrated that the combination of aspirin and LMWH significantly decreased the rate of non-fatal AMI or death at 1 week; this early beneficial effect was of a lesser magnitude later in the treatment course (40 to 150 days) coupled with an increased in minor bleeding. The FRIC study2 reported the use of LMWH or UFH in patients with unstable angina and non-STEMI. The rates of recurrent ACS, urgent revascularization, and death were similar at 1 week and in 45 days.
In the ESSENCE study,3 a benefit was found with LMWH at 30 days coupled with an increased risk of minor bleeding. The ASSENT-3 study4 compared various combinations of LMWH (enoxaparin), UFH, and abciximab with tenecteplase in patients with AMI. Early in the course of therapy (48 hours), the LMWH group demonstrated a significantly lower rate of occurrence of death and recurrent ACS when compared with UFH infusion (6.1% vs 8.8%, respectively). At 30 days, the enoxaparin group continued to outperform UFH with a lower rate of occurrence of the primary endpoint when compared with UFH (15.4% vs 11.4%). The investigators concluded that LMWH was superior, particularly early in the treatment course, when compared with UFH therapy; efficacy was similar, however, at later stages of management. The investigators stated that "...in view of the present data and the ease of administration, enoxaparin might be considered an attractive alternative anticoagulant treatment when given in combination with tenecteplase."4
The TIMI-11B study5 compared LMWH (enoxaparin) with UFH in patients with unstable angina or non-STEMI. The patients managed with LMWH fared significantly better with fewer instances of recurrent AMI, need for urgent revascularization, or death. The initial benefit observed with LMWH was sustained through day 43; beyond this time, however, no further relative decrease in events was observed. In fact, there was an increase in the rate of major hemorrhage (spontaneous and instrumented) with chronic LMWH treatment.5
Comparing UFH and LMWH
In general, it appears that the LMWHs, particularly enoxaparin with its favorable anti-factor Xa/antifactor IIa ratio, offers a short-term benefit in the unstable coronary patient, which lessens significantly beyond the first week of treatment. The advantages of LMWH over UFH are numerous. LMWH inactivates factor Xa, which is resistant to inactivation by UFH. LMWH has fewer binding characteristics to coagulation factors such as platelet factor 4, other plasma proteins, and endothelial cells, resulting in higher bioavailability. LMWH has a longer half-life and less individual variability of the anticoagulant response when compared with UFH. LMWH has a lower affinity for von Willebrand factor, increased vascular permeability, and a weak effect on platelet function. These differences could explain why LMWH produces less bleeding than UFH with equivalent or higher antithrombotic effects. The long half-life of LMWH and its predictable anticoagulant response to weight-adjusted doses allows once- or twice- daily subcutaneous administration without laboratory monitoring. LMWHs are the agents of choice when heparin is contraindicated by no availability of activated partial thromboplastin time (aPTT) measurements, but the disadvantage is expense.
Certainly, the majority of patients with AMI will require therapy with heparin, whether it be fractionated or unfractionated. Unstable angina, however, is an entirely different issue. Obviously, not all unstable angina cases are the same. For example, the stable patient with a classic description of new-onset angina who is sensation-free with a negative serum marker and a normal electrocardiogram (ECG) still is diagnosed correctly with unstable angina. Contrast this patient with the individual who presents with ongoing pain—either intermittent or constant—and a dynamic ECG; such a case clearly describes an active, unstable coronary event. The latter patient is in a higher-risk situation, and clearly will benefit from heparin therapy—more so than the patient in the former case. Heparin therapy is not without risk; it has been reported to be a major contributor to morbidity and mortality among hospitalized patients; it has been estimated that major bleeding will develop in one of every 90 patients treated and that one in 34 will develop heparin-induced thrombocytopenia.
LMWH has been found to be as effective as UFH in patients with ACS and does not increase the bleeding risk while decreasing the risk of heparin-induced thrombocytopenia. Heparin should not be given to low-risk patients with unstable angina.6
Choosing the Dose of UFH and LMWH
In patients undergoing percutaneous coronary intervention, bleeding and mortality were higher in the TIMI 14 study7 in patients receiving 80 U/kg bolus and 18 U/kg/hr infusion compared with the 60 U/kg bolus and 16 U/kg/hr infusion. Therefore, the initial recommended dose is 60 U/kg by intravenous bolus, followed by a maintenance infusion of 16 U/kg/hr. Heparin should be titrated so that the aPTT is 1.5 to 2.5 times control while using the maintenance infusion. UFH has some practical advantages over LMWH in the patient with AMI who is scheduled to undergo percutaneous coronary intervention in the immediate future; heparin infusions may be shut off should excessive bleeding complicate the situation, which is more likely as these patients receive glycoprotein IIbIIIa inhibitors also. LMWH should be administered subcutaneously in a twice-daily regimen at a dose of 1 mg/kg; doses should be reduced for patients with pronounced renal insufficiency. Absolute contraindications to heparin therapy include known allergy, history of heparin-induced thrombocytopenia (only for UFH), active ongoing life-threatening hemorrhage, or predisposition to such hemorrhage.
Dr. Brady, Associate Professor of Emergency Medicine and Internal Medicine, Vice Chair, Emergency Medicine University of Virginia, Charlottesville, is on the Editorial Board of Emergency Medicine Alert.
1. Wallentin L, et al for the FRISC group. Low molecular weight heparin during instability in coronary artery disease. Fragmin during instability in coronary artery disease (FRISC) study group. Lancet 1996;347:561-568.
2. Klein W, et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in unstable coronary artery disease study (FRIC). Circulation 1997;96:61-68.
3. Cohen M, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997;337:447-452.
4. Assessment of the Safety and Efficacy of a New Thrombolytic Regiment (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin. The ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605-613.
5. Antman EM, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 1999;100:1593.
6. Brewster GS, et al. Heparin should be administered to every patient admitted to the hospital with possible unstable angina. West J Med 2000;173:138-140.
7. Schweiger MJ, et al. Early coronary intervention following pharmacologic therapy for acute myocardial infarction (the combined TIMI 10B-TIMI 14 experience). Am J Cardiol. 2001;88:831.