ST elevation myocardial infarction anticoagulant and antithrombotic therapy: Difference between revisions
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==Oral anticoagulation== | ==Oral anticoagulation== | ||
The benefits and risks of oral anticoagulation following presentation with an acute coronary syndrome were recently assessed in a large meta-analysis of 5,938 patients enrolled in trials of aspirin alone versus aspirin plus warfarin between 1990 and 2004. <ref name="pmid16103468">{{cite journal |author=Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR |title=Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit |journal=Ann. Intern. Med. |volume=143 |issue=4 |pages=241–50 |year=2005 |month=August |pmid=16103468 |doi= |url=}}</ref> The addition of warfarin | The benefits and risks of oral anticoagulation following presentation with an acute coronary syndrome were recently assessed in a large meta-analysis of 5,938 patients enrolled in trials of aspirin alone versus aspirin plus warfarin between 1990 and 2004. <ref name="pmid16103468">{{cite journal |author=Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR |title=Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit |journal=Ann. Intern. Med. |volume=143 |issue=4 |pages=241–50 |year=2005 |month=August |pmid=16103468 |doi= |url=}}</ref> 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. <ref name="pmid16103468">{{cite journal |author=Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR |title=Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit |journal=Ann. Intern. Med. |volume=143 |issue=4 |pages=241–50 |year=2005 |month=August |pmid=16103468 |doi= |url=}}</ref> It should be noted that the majority of this data was collected in the era before drug eluting stents and clopidogre. | ||
==References== | ==References== | ||
Revision as of 16:15, 24 April 2009
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] 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.
Please Join in Editing This Page and Apply to be an Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
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. [1] 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.
Parenteral Drugs Targeting Factor Xa
Indirect Inhibitors Requiring Antithrombin
Idraparinux
Direct Inhibitors Not Requiring Antithrombin
DX-9065a
Oral Drugs Targeting Factor Xa
Rivaroxaban
LY517717
YM150
DU-176b
PRT-054021
Parenteral Drugs Targeting Factor IIa
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
Specific Agents Most Commonly Administered in the Management of the STEMI Patient
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) [2] and the Third International Study of Infarct Survival (ISIS-3) [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%. [2][3]
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.[4] 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). [4] 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). [4]
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).[5]
Advanatges of Unfractionated Heparin
- Low cost and wide availability
- 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)
- For patients undergoing PCI, the dosing can be titrated based upon the activated clotting times (ACT)
- There is no need to adjust the dose of UFH in renal dysfunction
- 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:
- UFH binds to the glycoprotein IIbIIIa receptor and activates platelets
- When UFH is discontinued, there is a rebound of excess thrombin generation (i.e. Heparin rebound)[6]
- 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.
- UFH dosing requires monitoring and adjustment via the partial thromboplastin time (PTT) as a result of this variability.
- UFH can crystalize other drugs infusing in the same IV line such as the fibrinolytic rPA
- 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. [7] It should be noted, however, that approximately 8% of physicians withhold the adminstration of UFH in conjunction with SK. [8]
Bivalirudin
Bivalirudin (Hirulog) is a parenteral direct thrombin inhibitor. Bivalirudin has the following advantages over UFH:
- It is a direct thrombin inhibitor meaning that it does not require antithrombin III as a co-factor to exert its action.
- Bivalirudin acts directly on clot bound thrombin unlike UFH which acts on thrombin in the dissolved fluid phase.
- Bivalirudin does not activate platelets unlike UFH
- 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. [9] [10] 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.[10] 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. [11]
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.[12] [13] 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). [13] 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. [13]
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. [14] 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 this setting. [15]
Fondaparinux
Fondaparinux is an indirect Factor Xa inhibitor. Like UFH, this pentasacharide requires binding to antithrombin III to exert its benefit, and thus its classification 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. [16] 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. [16] 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 recieved stroptokinase). While formal interaction testing (which may be underpowered) did not demonstrate heterogenity 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
The benefits and risks of oral anticoagulation following presentation with an acute coronary syndrome were recently assessed in a large meta-analysis of 5,938 patients enrolled in trials of aspirin alone versus aspirin plus warfarin between 1990 and 2004. [17] 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. [17] It should be noted that the majority of this data was collected in the era before drug eluting stents and clopidogre.
References
- ↑ Weitz JI (2006). "Emerging anticoagulants for the treatment of venous thromboembolism". Thromb. Haemost. 96 (3): 274–84. doi:10.1160/TH06-05-0234. PMID 16953267. Unknown parameter
|month=ignored (help) - ↑ 2.0 2.1 "GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico". Lancet. 336 (8707): 65–71. 1990. PMID 1975321. Unknown parameter
|month=ignored (help) - ↑ 3.0 3.1 "ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group". Lancet. 339 (8796): 753–70. 1992. PMID 1347801. Unknown parameter
|month=ignored (help) - ↑ 4.0 4.1 4.2 Eikelboom JW, Quinlan DJ, Mehta SR, Turpie AG, Menown IB, Yusuf S (2005). "Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirin-treated patients with ST-elevation acute myocardial infarction: a meta-analysis of the randomized trials". Circulation. 112 (25): 3855–67. doi:10.1161/CIRCULATIONAHA.105.573550. PMID 16344381. Unknown parameter
|month=ignored (help) - ↑ "An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators". N. Engl. J. Med. 329 (10): 673–82. 1993. PMID 8204123. Unknown parameter
|month=ignored (help) - ↑ Granger CB, Miller JM, Bovill EG; et al. (1995). "Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes". Circulation. 91 (7): 1929–35. PMID 7895349. Unknown parameter
|month=ignored (help) - ↑ Antman EM, Hand M, Armstrong PW; et al. (2008). "2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee". Circulation. 117 (2): 296–329. doi:10.1161/CIRCULATIONAHA.107.188209. PMID 18071078. Unknown parameter
|month=ignored (help) - ↑ Berdan LG, Kleiman NS, Woodlief LH, Harrington RA, Granger CB, Califf RM (1997). "Physicians' Use of Heparin Following Thrombolytic Therapy: An International Perspective" (PDF). J. Thromb. Thrombolysis. 4 (3/4): 415–423. PMID 10639646.
- ↑ Mehran R, Brodie B, Cox DA; et al. (2008). "The Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial: study design and rationale". Am. Heart J. 156 (1): 44–56. doi:10.1016/j.ahj.2008.02.008. PMID 18585496. Unknown parameter
|month=ignored (help) - ↑ 10.0 10.1 Stone GW, Witzenbichler B, Guagliumi G; et al. (2008). "Bivalirudin during primary PCI in acute myocardial infarction". N. Engl. J. Med. 358 (21): 2218–30. doi:10.1056/NEJMoa0708191. PMID 18499566. Unknown parameter
|month=ignored (help) - ↑ "Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients' data". Lancet. 359 (9303): 294–302. 2002. doi:10.1016/S0140-6736(02)07495-0. PMID 11830196. Unknown parameter
|month=ignored (help) - ↑ White HD (1998). "Direct thrombin inhibition and thrombolytic therapy: rationale for the Hirulog and Early Reperfusion/Occlusion (HERO-2) trial". Am. J. Cardiol. 82 (8B): 57P–62P. PMID 9809893. Unknown parameter
|month=ignored (help) - ↑ 13.0 13.1 13.2 White H (2001). "Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial". Lancet. 358 (9296): 1855–63. PMID 11741625. Unknown parameter
|month=ignored (help) - ↑ Antman EM, Morrow DA, McCabe CH; et al. (2006). "Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction". N. Engl. J. Med. 354 (14): 1477–88. doi:10.1056/NEJMoa060898. PMID 16537665. Unknown parameter
|month=ignored (help) - ↑ Labèque JN, Jaïs C, Dubos O; et al. (2006). "Prehospital administration of enoxaparin before primary angioplasty for ST-elevation acute myocardial infarction". Catheter Cardiovasc Interv. 67 (2): 207–13. doi:10.1002/ccd.20549. PMID 16416473. Unknown parameter
|month=ignored (help) - ↑ 16.0 16.1 Yusuf S, Mehta SR, Chrolavicius S; et al. (2006). "Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial". JAMA. 295 (13): 1519–30. doi:10.1001/jama.295.13.joc60038. PMID 16537725. Unknown parameter
|month=ignored (help) - ↑ 17.0 17.1 Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR (2005). "Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit". Ann. Intern. Med. 143 (4): 241–50. PMID 16103468. Unknown parameter
|month=ignored (help)