ST elevation myocardial infarction anticoagulant and antithrombotic therapy

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Editors-In-Chief: C. Michael Gibson, M.S., M.D.  Duke Clinical Research Institute  [mailto:mgibson@perfuse.org]; John  Alexander, M.D.  [mailto:john.h.alexander@duke.edu], Duke  Clinical Research Institute As an active clinical researcher, Dr. Gibson has received research and grant support from the majority of manufacturers of antithrombin and antiplatelet agents. You can view his complete disclosure statement here.

Overview
Management of the patient with ST elevation myocardial infarction requires inhibition of both the generation of thrombin (i.e inhibition of the coagulation cascade via antithrombins) as well as the platelet (via antiplatelet agents). Selection of the appropriate antithrombin depends upon a variety of factors including the choice of revascularization strategy. This chapter reviews data supporting the optimal selection of both parenteral antithrombotic and oral antithrombotic (anticoagulant) agents for a given patient.

Sites of Action of Antithrombins
The majority of established and investigational antithrombins target two factors in the coagulation cascade: Factor Xa and Factor IIa. Factor Xa lies higher in the coagulation cascade at the intersection of the intrinsic and extrinsic pathways. Inhibition of Factor Xa limits the initial thrombin generation irrespective of whether the coagulation cascade was triggered by activation of the intrinsic or extrinsic pathway. Factor IIa (thrombin) lies lower in the coagulation cascade and is involved in the conversion of fibrinogen to fibrin.

Indirect Inhibitors Requiring Antithrombin
Fondaparinux

Idraparinux

Direct Inhibitors Not Requiring Antithrombin
DX-9065a

Otamixaban

Oral Drugs Targeting Factor Xa
Rivaroxaban

Apixaban

LY517717

YM150

DU-176b

PRT-054021

Parenteral Drugs Targeting Factor IIa
Bivalirudin

Oral Drugs Targeting Factor IIa
Dabigatran

Ximelogatran (removed from market)

Parenteral Drugs Targeting Both Factor IIa and Factor Xa
Enoxaparin inhibits Factor Xa more than Factor IIa

Unfractionated heparin (UFH) inhibits Factor IIa more than Factor Xa

Unfractionated Heparin
By itself, unfractionated heparin (UFH) actually exerts little or no direct effect on thrombin, and for this reason UFH is not classified as a direct thrombin inhibitor. The enzymatic activity is actually achieved indirectly via antithrombin III (AT III). When UFH combines with AT III, the enzymatic activity of AT III is tremendously increased, and for this reason, UFH is classified as an indirect thrombin inhibitor. While the major target of UFH is the indirect inhibition of Factor IIa, UFH also has some anti-Factor Xa activity.

Early trial data supporting the superiority of UFH over placebo in STEMI management
Two trials conducted in the early 1990s, The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI 2) and the Third International Study of Infarct Survival (ISIS-3), provided data in over 53,000 patients regarding the relative efficacy of UFH vs placebo among STEMI patients treated with a fibrinolytic agent and aspirin. UFH in these early trials was administered by the slower acting subcutaneous (SQ) route 4 to 12 hours after the administration of fibrinolytic therapy. The delayed administration of the agent via a route that is associated with a delay in achieving therapeutic anticoagulation (the SQ route) may have accounted for the modest efficacy of this strategy: an absolute reduction in 35 day mortality of only 0.7%.

While these two early trials evaluated the efficacy of SQ UFH relatively late in the course of STEMI, 4 other trials compared the more rapidly acting preparation of intravenous (IV) UFH to placebo among patients who had been administered both a fibrinolytic agent and aspirin ASA. In a meta-analysis of these 4 trials which enrolled a total of 1,239 patients, UFH was not associated with a significant reduction in reinfarction or death (52 events (4.2%) in the UFH group vs 48 events (3.9%) in the control group, p=NS). UFH was asociated with an increase in both minor and major bleeding compared with placebo. The excess rate of minor bleeding did reach statistical significance (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.22–2.43).

In the large GUSTO 1 trial, there was no difference in mortality outcomes among patients treated with IV vs SQ UFH in conjunction with streptokinase administration (7.2% mortality for SQ vs 7.4% mortality for IV UFH, p=NS).

Advanatges of Unfractionated Heparin

 * 1) Low cost and wide availability
 * 2) In the presence of bleeding or if there is the need for an invasive procedure, UFH can be reversed by the administration of protamine (1 mg of Protamine for every 100 Units of UFH)
 * 3) For patients undergoing PCI, the dosing can be titrated based upon the activated clotting times (ACT)
 * 4) There is no need to adjust the dose of UFH in renal dysfunction
 * 5) There is a longstanding familiarity of practitioners with its use

Limitations of Unfractionated Heparin
Despite its wide use as antithrombotic therapy in ST elevation MI (STEMI), there are several limitations to unfractionated heparin:


 * 1) UFH binds to the glycoprotein IIbIIIa receptor and activates platelets
 * 2) When UFH is discontinued, there is a rebound of excess thrombin generation (i.e. Heparin rebound)
 * 3) UFH requires the presence of antithrombin III a a cofactor to work. This is why UFH is called an indirect thrombin inhibitor. Given that the levels of antithrombin III vary from patient to patient, and given that the potency of UFH varies from manufacturing lot to lot, there is substantial variability in the pharmacodynamic response to UFH.
 * 4) UFH dosing requires monitoring and adjustment via the partial thromboplastin time (PTT) as a result of this variability.
 * 5) UFH can crystalize other drugs infusing in the same IV line such as the fibrinolytic rPA
 * 6) UFH binds non-specifically to heparin binding proteins and to other platelet factors. This non specific binding can trigger heparin induced thrombocytopenia or HIT. HIT type II is due to an autoimmune reaction with antibodies formed against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and interleukin 8 (IL8) which form complexes with heparin. The most common antigenic complex is the heparin-PF4 complex.

Current use of UFH in STEMI
As a result of its low cost, the ability to reverse UFH with protamine (1 mg of Protamine for every 100 Units of UFH), the ability to titrate the dosing based upon activated clotting times (ACT), the lack of a need to adjust the dose in renal dysfunction, and the longstanding familiarity of practitioners with its use, UFH remains the most widely administered antithrombin in conjunction with fibrinolysis worldwide. Administration of UFH carries a Class 1 recommendation in the AHA / ACC Guidelines when a fibrin specific fibrinolytic agent is administered. It should be noted, however, that approximately 8% of physicians withhold the adminstration of UFH in conjunction with SK.

Bivalirudin
Bivalirudin (Hirulog) is a parenteral direct thrombin inhibitor. Bivalirudin has the following advantages over UFH:
 * 1) It is a direct thrombin inhibitor meaning that it does not require antithrombin III as a co-factor to exert its action.
 * 2) Bivalirudin acts directly on clot bound thrombin unlike UFH which acts on thrombin in the dissolved fluid phase.
 * 3) Bivalirudin does not activate platelets unlike UFH
 * 4) Bivalirudin does not bind to platelet factor 4, and therefore does not cause heparin induced thrombocytopenia

Hirudin is another direct thrombin inhibitor, and there are several hirudin based anticoagulant pharmaceutical products such as Lepirudin (Refludan) and Desirudin (Revasc/Iprivask) that are not used as widely at present in the management of STEMI patients.

Bivalirudin use in conjunction with primary percutaneous intervention
The safety and efficacy of administering bivalirudin was compared to UFH plus glycoprotein IIbIIIa inhibition among patients undergoing primary PCI for STEMI in the The Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial. Bivalirudin was associated with a similar rate of major adverse cardiac events (MACE) and a lower rate of bleeding when compared to UFH plus glycoprotein IIbIIIa inhibition. The combination of bivalirudin plus glycoprotein IIbIIIa inhibition was not studied.

Bivalirudin was associated with a significantly higher rate of stent thrombosis in the first 24 hours of the trial. After 24 hours, there was a trend for UFH plus glycoprotein IIbIIIa inhibition to be associated with higher rates of stent thrombosis. While bivalirudin was associated with lower mortality in the HORIZONS AMI trial, a patient level meta-analysis indicates that neither bivalirudin nor direct thrombin inhibitors are in general associated with a reduction in mortality when compared to UFH.

Bivalirudin use in conjunction with fibrinolytic administration
The safety and efficacy of bivalirudin in conjunction with fibrinolytic administration has been evaluated in the 17,073 patient Hirulog and Early Reperfusion/Occlusion (HERO-2) trial. 1.5 million units of streptokinase was the fibrinolytic agent administered in the trial and the study was open label in design. While bivalirudin is often discontinued at the completion of a PCI, in the HERO-2 trial bivalirudin was administered for 48 hours as was UFH. The primary endpoint was 30 day mortality which did not differ between patients treated with bivalirudin vs UFH ((10.8% vs 10.9%, p=NS). In the first 96 hours of the trial, bivalirudin was associated with a lower rate of reinfarction (p=0.001). While bivalirudin monotherapy has been associated with less bleeding than UFH plus glycoprotein IIbIIIa inhibition in PCI trials, bivalirudin monotherapy was associated with higher rates of moderate and mild bleeding than UFH monotherapy: the rate of moderate bleeding was 1.32 times higher (p<0.0001) and the rate of mild bleeding was 1.47 times higher (p<0.0001).  There were trends for severe bleeding (0.7% vs 0.5%, p=0.07), intracerebral bleeding (0.6% vs 0.4%, p=0.09) and transfusion (1.4% vs 1.1%, p=0.11) to be higher in the bivalirudin monotherapy vs UFH monotherapy groups.

Current Use of Bivalirudin in STEMI
Among patients undergoing primary PCI, bivalirudin appears to be a reasonable alternative to UFH plus glycoprotein IIbIIIa inhibition. It should be noted that there is a higher risk of stent thrombosis in the first 24 hours with Bivalirudin monotherapy despite treatment with clopidogrel in the majority of these patients. It should also be noted that 60% of patients received UFH prior to bivalirudin in the HORIZONS AMI trial.

The use of bivalirudin in conjunction with streptokinase administration appears to be a reasonable alternative for patients with heparin induced thrombocytopenia.

Enoxaparin
Enoxaparin inhibits Factor Xa to a greater extent than Factor IIa. UFH in contrast, inhibits Factor IIa more than Factor Xa. Unlike UFH, it requires no monitoring of the partial thromboplastin time (PTT).

Enoxaparin use in conjunction with fibrinolytic administration
The safety and efficacy of enoxaparin versus UFH in the management of STEMI patients treated with a fibrinolytic agent was most recently evaluated in the randomized double blind Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT) trial. The UFH strategy utilized a 60 U/kg bolus followed by a > 48 hour infusion of 12 U/Kg/hour. Enoxaparin was administered for the duration of the hospitalization or for a maximum of 8 days. The bolus of enoxaparin was 30 mg and the maintenance dose was 1 mg / kg subcutaneously every 12 hours. It is important to note that the dose of enoxaparin was reduced in the elderly (patients 75 years or older) from 1 mg / kg subcutaneously every 12 hours to 0.75 mg / kg every 12 hours. This strategy of enoxaparin dosing was associated with a reduction in the 30 day endpoint of death or MI from 12.0% to 9.9% (RR 0.83, p<0.001). When the efficacy is compared at 48 hours while patients in both arms are actively receiving either UFH or enoxaparin, there was a non significant trend in favor of enoxaparin in reducing death or MI (5.2% vs 4.7%, p=0.08). With respect to safety, administration of enoxaparin was associated with an increase in the risk of TIMI major bleeding (1.4% vs 2.1%, p<0.001). Among patients who sustained a TIMI major bleed, mortality was significantly higher in patients treated with enoxaparin compared with UFH (0.8% vs 0.4%, P=0.001).

Enoxaparin use in conjunction with primary percutaneous coronary intervention
There are limited data regarding the efficacy and safety of enoxaparin in the setting of primary PCI.

Fondaparinux
Fondaparinux is an indirect Factor Xa inhibitor. Like UFH, this pentasacharide requires binding to antithrombin III to exert its benefit, and therefor it is classified as an indirect inhibitor.

Fondaparinux use in conjunction with primary percutaneous intervention
In the setting of primary PCI, Fondaparinux administration has been associated with higher rates of clot formation on wires and catheters. For this reason, fondaparinux may not be an optimal agent for use among patients undergoing primary PCI, and if it is used, supplemental use of a Factor IIa inhibitor such as UFH is recommended.

Fondaparinux use in conjunction with fibrinolytic administration
The safety and efficacy of fondaparinux administered for 8 days was compared to either placebo (Stratum 1: patients who could not receive UFH) or therapy with UFH for 48 hours (Stratum II) in the randomized, double blind multicenter OASIS-6 trial of 12,092 STEMI patients. The primary endpoint of death or reinfarction at 30 days was signifcantly reduced among patients treated fondaparinux (11.2% vs 9.7%, p=0.008). The secondary endpoint of mortality was also significantly reduced among fondaparinux patients. The primary endpoint was reduced among patients treated with fibrinolytic therapy (HR =0.79 p=0.003). An important caveat is the fact that most patients who received a fibrinolytic agent were in Stratum 1 (patients not deemed appropriate for UFH and largely received streptokinase). While formal interaction testing (which may be underpowered) did not demonstrate heterogeneity between stratum 1 and stratum 2, the magnitude of the benefits of fondaparinux were numerically greater in stratum 1 than in stratum 2 (in whom patients received UFH). Likewise, while the benefits in the primary endpoint were statistically significant for both strata combined, there was no significant benefit of fondaparinux over UFH at 30 days in the primary endpoint.

Oral anticoagulation
Following an acute coronary syndrome, there is persistent activation of the coagulation cascade as manifested by persistently elevated levels of prothrombin fragments 1 + 2 (F1 +2). F1+2 is released from the end of the prothrombin molecule when prothrombin is converted to thrombin, and its levels are a surrogate of Factor Xa activity. Furthermore, clot remains visible on angioscopy in the infarct artery of 70%-80% of patients one month following fibrinolytic therapy for STEMI. Persistent activation of the coagulation cascade and the ubiquitous presence of chronic thrombus provides in part the basis for chronic anticoagulation therapy following an acute coronary syndrome.

The benefits and risks of oral anticoagulation following presentation with an acute coronary syndrome have been assessed in a large meta-analysis of 5,938 patients enrolled in trials of aspirin alone versus aspirin plus warfarin between 1990 and 2004. Many large trials of oral anticoagulation such as WARIS II, OASIS , and CARS were included. The addition of warfarin titrated to an INR of 2.0 was associated with a halving of the annual risk of myocardial infarction (rate ratio, of 0.56 [95% CI, 0.46 to 0.69]). Similarly, the annual risk of ischemic stroke was cut in half (rate ratio, 0.46 [CI, 0.27 to 0.77]). The annual rate of bleeding was increased over two fold (rate ratio, 2.5 [CI, 1.7 to 3.7]). Mortality did not differ between the two strategies. Taking all the data together you would need to tree 16 patients for 3 months to prevent one MI, and you would need to treet 333 patients to cause one major bleed. With respect to the risk of intracranial hemmorhage, warfarin was associated with only 1 ICH per 1,800 patient years of exposure. The above results are for all patients in the studies, and it should be noted that patients at higher risk of ischemic events would have a greater net clinical benefit, while those at higher risk of bleeding would have a lower net clinical benefit. It should be noted that the majority of this data was collected in the era prior to drug eluting stents and clopidogrel.

While the addition of warfarin to aspirin is efficacious, there is a 20% rate of discontinuation for both warfarin monotherapy, and the combination of warfarin plus aspirin. This high rate of discontinuation is critical in so far as only those patients who are compliant with warfarin over 70% of the time derived a clinical benefit.

==ACC/AHA Guidelines- Recommendations for Parenteral Anticoagulants (DO NOT EDIT) ==

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Class I
1. 1. For patients proceeding to primary PCI who have been treated with ASA and a thienopyridine, recommended supportive anticoagulant regimens include the following:


 * a. For prior treatment with UFH, additional boluses of UFH should be administered as needed to maintain therapeutic activated clotting time levels, taking into account whether GP IIb/IIIa receptor antagonists have been administered. (Level of Evidence: C)
 * b. Bivalirudin is useful as a supportive measure for primary PCI with or without prior treatment with UFH. (Level of Evidence: B)

Class IIa
1. In STEMI patients undergoing PCI who are at high risk of bleeding, bivalirudin anticoagulation is reasonable. (Level of Evidence: B)}}

==ACC/AHA Guidelines- Recommendations for Anticoagulants as Ancillary Therapy to Reperfusion Therapy (DO NOT EDIT) ==

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Class I
1. Patients undergoing reperfusion with fibrinolytics should receive anticoagulant therapy for a minimum of 48 hours (Level of Evidence: C) and preferably for the duration of the index hospitalization, up to 8 days (regimens other than UFH are recommended if anticoagulant therapy is given for more than 48 hours because of the risk of heparin-induced thrombocytopenia with prolonged UFH treatment). (Level of Evidence: A) Anticoagulant regimens with established efficacy include:
 * a. UFH (initial intravenous bolus 60 U per kg [maximum 4000 U]) followed by an intravenous infusion of 12 U per kg per hour (maximum 1000 U per hour) initially, adjusted to maintain the activated partial thromboplastin time at 1.5 to 2.0 times control (approximately 50 to 70 seconds) (Level of Evidence: C). (Note: the available data do not suggest a benefit of prolonging the duration of the infusion of UFH beyond 48 hours in the absence of ongoing indications for anticoagulation; more prolonged infusions of UFH increase the risk of development of heparin-induced thrombocytopenia.)
 * b. Enoxaparin (provided the serum creatinine is less than 2.5 mg per dL in men and 2.0 mg per dL in women): for patients less than 75 years of age, an initial 30 mg intravenous bolus is given, followed 15 minutes later by subcutaneous injections of 1.0 mg per kg every 12 hours; for patients at least 75 years of age, the initial intravenous bolus is eliminated and the subcutaneous dose is reduced to 0.75 mg per kg every 12 hours. Regardless of age, if the creatinine clearance (using the Cockroft-Gault formula) during the course of treatment is estimated to be less than 30 mL per minute, the subcutaneous regimen is 1.0 mg per kg every 24 hours. Maintenance dosing with enoxaparin should be continued for the duration of the index hospitalization, up to 8 days. (Level of Evidence: A)
 * c. Fondaparinux (provided the serum creatinine is less than 3.0 mg per dL): initial dose 2.5 mg intravenously; subsequently subcutaneous injections of 2.5 mg once daily. Maintenance dosing with fondaparinux should be continued for the duration of the index hospitalization, up to 8 days. (Level of Evidence: B)

2. For patients undergoing PCI after having received an anticoagulant regimen, the following dosing recommendations should be followed:
 * a. For prior treatment with UFH, administer additional boluses of UFH as needed to support the procedure, taking into account whether GP IIb/IIIa receptor antagonists have been administered. (Level of Evidence: C) Bivalirudin may also be used in patients treated previously with UFH. (Level of Evidence: C)
 * b. For prior treatment with enoxaparin, if the last subcutaneous dose was administered within the prior 8 hours, no additional enoxaparin should be given; if the last subcutaneous dose was administered at least 8 to 12 hours earlier, an intravenous dose of 0.3 mg per kg of enoxaparin should be given. (Level of Evidence: B)
 * c. For prior treatment with fondaparinux, administer additional intravenous treatment with an anticoagulant possessing anti-IIa activity taking into account whether GP IIb/IIIa receptor antagonists have been administered. (Level of Evidence: C)

Class III
1. Because of the risk of catheter thrombosis, fondaparinux should not be used as the sole anticoagulant to support PCI. An additional anticoagulant with anti-IIa activity should be administered. (Level of Evidence: C)}}