Chapter 21 Marini Acute Coronary Syndromes

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CHAPTER 21 • Acute Coronary Syndromes

revascularization. Today, most of the ACS patients receive an intravenous infusion of a Gp2b/3a recep- tor antagonist for 12 to 24 hours after PCI. They are also typically on aspirin and clopidogrel long term after PCI. In patients who are candidates for coronary bypass surgery, heparin and aspirin should be continued until surgery. In patients who are not candidates for coronary angiography and revascu- larization, heparin should be continued for 3 to 5 days. There is a risk of rebound angina when the heparin infusion is stopped. Thereafter, long-term use of aspirin alone can result in a 50% reduction in the incidence of angina recurrence. Unfractionated heparin (UFH) is a heterog- enous mixture of polysaccharides with molecular weights ranging from 3,000 to 30,000. There are several disadvantages with UFH. The antithrombin binding sites of heparin can be bound by a number of other plasma proteins, by platelet factor 4, and also by endothelial cells, thereby diminishing its therapeutic effect. Furthermore, heparin does not bind to clot-bound thrombin and to factor Xa bound to platelets inside a clot. Thus, there is the possibil- ity of clot propagation while the patient is receiving heparin. Heparin-induced thrombocytopenia (HIT) is another serious adverse effect. Perhaps surpris- ingly, in this ACS setting, the currently available low molecular weight alternatives may be more effective in selective categories but have not been shown to offer dramatic risk–benefit advantages across the entire “at-risk” population. Low Molecular Weight Heparins These are homogenous glycosaminoglycans with molecular weight ranging from 4,000 to 6,000. Low molecular weight heparins (LMWH) have greater anti–factor Xa activity and less anti–factor IIa activ- ity as compared to UFH. They act mainly by pre- venting thrombin generation and have lesser effect on a PTT as compared to UFH. Assays measuring anti–factor Xa activity are now in widespread use. Enoxaparin is the most popular of all LMWH that has been shown to be efficacious in patients with NSTE-ACS, as in acute pulmonary embolism and deep venous thrombosis. Enoxaparin has been reported in clinical trials to hold a modest advantage over UFH in reducing cardiovascular events, with risk of death, recurrent ischemia, and MI. Benefit appears more pronounced in patients with high- risk features like troponin elevation and those with higher TIMI risk scores.

In patients with ACS who have creatinine clear- ance greater than 30 mL/min, enoxaparin is used in the dosage of 1 mg/kg subcutaneously twice daily. There is little need to monitor the clotting param- eters because the therapeutic effect is quite con- sistent and predictable. The anticoagulant effect with enoxaparin is consistent because of very little binding to plasma proteins, endothelial cells, and macrophages. When thought advisable, as in mas- sively obese patients, anti–factor Xa activity can be monitored. Enoxaparin’s risk of thrombocytopenia is quite low. Major bleeding is also uncommon, but the risk may be higher in the elderly and those with renal failure. In patients requiring CABG, the drug should be stopped 12 to 24 hours prior to the operation. In patients undergoing cardiac catheter- ization and PCI, there is always a concern for bleed- ing because of concomitant use of UFH, Gp2b/3a receptor antagonists, and clopidogrel. The follow- ing rule of thumb can be used for heparin dosing in patients needing PCI: within 8 hours of having received a dose of enoxaparin, no additional UFH is needed for PCI; between 8 and 12 hours, use UFH at dose of 25 to 50 units/kg; and if greater than 12 hours after receiving enoxaparin, use 50 to 70 units/kg of UFH. Despite its proven efficacy, only a minority of patients in North America and 50% of patients in Europe receive LMWH for ACS. Direct Thrombin Inhibitors The direct thrombin inhibitor (DTI) agents avail- able are hirudin, lepirudin (recombinant hirudin), argatroban, and bivalirudin. These agents are sub- stantially more expensive than UFH and enoxa- parin. They are powerful anticoagulants and their anticoagulation effect is consistent and predictable. DTIs do not depend on antithrombin III for their activity. They bind to thrombin (factor IIa) and thus inhibit coagulation process. Because thrombin is also a powerful platelet activator, DTIs also inhibit platelet activation. In a large meta-analysis, DTIs were shown to reduce rates of recurrent ischemia and infarctions as compared to heparin in patients with NSTE-ACS, but their use was associated with increased incidence of major bleeding requiring blood transfusions. DTIs are currently only recom- mended for ongoing use in those with HIT. However, the use of bivalirudin in the setting of coronary intervention has dramatically increased, ever since the REPLACE-2 trial showed significantly reduced procedure-associated bleeding rates compared with