Unstable angina non ST elevation myocardial infarction anticoagulant therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-in-Chief: Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.; Smita Kohli, M.D.

Overview

Anticoagulation, traditionally with unfractionated heparin (UFH), is a cornerstone of therapy for patients with Unstable angina/NSTEMI. Some of the agents available in this category include:

• unfractionated heparin,
• low molecular weight heparin,
• Direct Thrombin Inhibitors (e.g.,bivalirudin)
• Factor Xa Inhibitors (e.g.,fondaparinux), and
• warfarin.

These agents are also sometimes referred to as antithrombins, although, it should be noted that they often inhibit one or more proteins in the coagulation cascade before thrombin.

Unfractionated Heparin(UFH)

Mechanism of action:

• Unfractionated heparin exerts its anticoagulant effect by potentiating the action of circulating antithrombin, a proteolytic enzyme that inactivates factor IIa (thrombin), factor IXa, and factor Xa.
• It prevents thrombus propagation but does not lyse existing thrombi.

Clinical trial data:

• A meta-analysis showed that in aspirin-treated patients with acute coronary syndrome without ST elevation, short-term unfractionated heparin or LMWH halves the risk of myocardial infarction or death.

Dosing:

• This is a short acting drug with an anticoagulation half life of 1.5hrs. Hence, frequent monitoring of the anticoagulant response using activated partial thromboplastin time (APTT) is recommended with titrations made according to a standardized nomogram aiming for an APTT range between 1.5 to 2 times control or 50 to 70 seconds .

Adverse effects:

• bleeding(specially with elevated APTT)
• heparin induced thrombocytopenia

Low Molecular Weight Heparin(LMWH)

Mechanism of benefit:

• LMWH combine factor IIa and factor Xa inhibition and thus inhibit both the action and generation of thrombin.
• It has a number of advantages over UFH such as its greater anti-factor Xa activity inhibits thrombin generation more effectively, lower rate of thrombocytopenia, high bioavailabiltiy, more consistent anticoagulant effect and no requirement of intensive lab monitoring.

Clinical trial data:

• Results from TIMI 11B study showed superiority of LMWH over UFH for reducing a composite of death and serious cardiac ischemic events during the acute management of Unstable angina/NQMI patients without causing a significant increase in the rate of major hemorrhage.
• Results from SYNERGY trial revealed noninferiority of LMWH over UFH for the treatment of high-risk patients with non-ST-segment elevation ACS. However, both trials did show increased risk of major bleeding with LMWH.
• A prospective analysis of the A to Z trial showed that enoxaparin provided significant benefit over UFH in patients managed conservatively (who are typically on heparin/LMWH for at least 48 hours) but not in those with early invasive approach(who are taken to the catheterization laboratory within 48 hours and have their heparin discontinued thereafter).

Disadvantages of LMWH:

• LMWH are more affected by renal dysfunction than UFH, and the dose should be reduced in patients with a creatinine clearance <30 mL/min.
• Also, in the event of bleeding, the anticoagulant effect of UFH can be reversed more effectively with protamine.

Direct Thrombin Inhibitors

Hirudin which is the prototype of this class of drugs has been studied in multiple trials with mixed results. Other drugs in this class include bivalirudin, argatroban, efegatran and inogatran. Bivalirudin is a synthetic analog of hirudin that binds reversibly to thrombin and inhibits clot-bound thrombin.

Indications:

• Hirudin (lepirudin) is presently indicated by the US Food and Drug Administration only for anticoagulation in patients with heparin-induced thrombocytopenia and for the prophylaxis of deep vein thrombosis in patients undergoing hip replacement surgery.

• Argatroban is another direct thrombin inhibitor that is approved for the management of patients with heparin-induced thrombocytopenia.

Clinical trial data:

• The relative benefits of hirudin versus UFH in ACS patients was evaluated in the 12,142 patient in GUSTO-IIb trial. A reduction in risk for nonfatal MI was seen without increased risk of major bleeding.
• TIMI 9B study failed to show any difference in outcomes in Hirudin verus heparin treated patients getting TPA.
• The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial randomized 13,819 patients with Unstable angina/NSTEMI to one of three treatments: UFH, or enoxaparin plus a GP IIb/IIIa inhibitor, or bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone. Patients were managed with an early invasive strategy and the primary endpoint was the composite of death, myocardial infarction, unplanned revascularization for ischemia, and major bleeding at 30 days. No differences were observed in the direct comparison of the anticoagulants i.e., between bivalirudin plus GP IIb/IIIa inhibitor and UFH/enoxaparin plus a GP IIb/IIIa inhibitor or bivalirudin alone. But for the bivalirudin alone group, when compared with the group receiving UFH/enoxaparin plus a GP IIb/IIIa inhibitor, there was decrease risk for bleeding.

Disadvantage of Direct Thrombin Inhibitors:

• Direct thrombin inhibitors lack a protamine-binding domain, hence it is not possible to reverse the effect with protamine. In the event of bleeding,discontinuation of their administration and, if needed, transfusion of coagulation factors (e.g., fresh frozen plasma)is required.
• In ACS, the monovalent direct thrombin inhibitors(including argatroban) are ineffective anti-thrombotic agents compared with UFH, and thus, argatroban should generally not be used in management of ACS.

Factor Xa Inhibitors

Fondaparinux is the prototype in this class of drug which is an indirect Xa inhibitor that requires antithrombin for its action.

Clinical trial data:

• The OASIS 5 and 6 trials evaluated the use of fondaparinux in ACS and compared it with a heparin-based strategy. Results showed that compared to heparin based strategy, fondaparinux reduced mortality, ischemic events, and major bleeding across the full spectrum of acute coronary syndromes and was associated with a more favorable net clinical outcome in patients undergoing either an invasive or a conservative management strategy.
• The OASIS-5 trial specifically compared fondaparinux, administered at a relatively low dose, 2.5 mg subcutaneously, once daily with standard-dose enoxaparin in 20,078 patients with high-risk UA/NSTEMI. The rates of death, MI, or refractory ischemia throughout the first 9 days were similar with fondaparinux and enoxaparin. Of note, however, the rate of major bleeding was almost 50 percent lower in the fondaparinux arm. By 30 days, mortality was significantly lower in the fondaparinux arm. However, in the subset of patients undergoing PCI, fondaparinux was associated with more than a threefold increased risk of catheter-related thrombi.

Disadvantage of Factor Xa Inhibitors:

• fondaparinux lacks a protamine-binding domain, hence it is not possible to reverse the effect with protamine. In the event of bleeding,discontinuation of their administration and, if needed, transfusion of coagulation factors (e.g., fresh-frozen plasma)is required.

Long Term Anticoagulation

Warfarin is the typical drug used for long term anticoagulation. However, its role, if any, in patients with UA/NSTEMI has not been clearly defined.

Clinical trial data:

• ASPECT 2 trial showed that in patients recently admitted with ACS, treatment with high-intensity oral anticoagulants or aspirin with medium-intensity oral anticoagulants was more effective than aspirin alone in reduction of subsequent cardiovascular events and death. However, similar benefit is seen with clopidogrel plus aspirin over aspirin alone, the lack of need for monitoring of the INR, and the frequent use of PCI and stenting in the patient population in whom the need for clopidogrel is well established, the clinical use of aspirin plus warfarin is limited. Among patients without a coronary stent but with another indication for warfarin, such as chronic atrial fibrillation, mechanical valve or severe left ventricular dysfunction who are at high risk of systemic embolization, the combination of aspirin plus warfarin would be preferable as the long-term antithrombotic strategy.

ACC / AHA Guidelines for Anticoagulation Therapy (DO NOT EDIT)

“

Class I Anticoagulant therapy should be added to antiplatelet therapy in UA / NSTEMI patients as soon as possible after presentation. a. For patients in whom an invasive strategy is selected, regimens with established efficacy at a Level of Evidence: A include enoxaparin and UFH, and those with established efficacy at a Level of Evidence: B include bivalirudin and fondaparinux. b. For patients in whom a conservative strategy is selected, regimens using either enoxaparin or UFH (Level of Evidence: A) or fondaparinux (Level of Evidence: B) have established efficacy. c. In patients in whom a conservative strategy is selected and who have an increased risk of bleeding, fondaparinux is preferable. (Level of Evidence: B) Class IIa For UA / NSTEMI patients in whom an initial conservative strategy is selected, enoxaparin or fondaparinux is preferable to UFH as anticoagulant therapy, unless CABG is planned within 24 h. (Level of Evidence: B)

”

See Also

• The UA / NSTEMI Living Guidelines: Vote on current recommendations and suggest revisions to the guidelines

Sources

• The ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction