ST elevation myocardial infarction anticoagulant and antithrombotic therapy
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.
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Overview
Management of the patient with ST elevation myocardial infarction requires inhibition of both the 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 II. [1] factor Xa lies higher in the coagulation cascade at the intersection of the intrisic and extrinsic pathway. Inhibition of Factor Xa limits the initial thrombin generation irrespective of whether the coagulation cascade was initiated by the intrinsic or extrinsic pathway. Factor II (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
Otamixaban
Oral Drugs Targeting Factor Xa
Rivaroxaban
Apixaban
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 inhibits Factor IIa more than Factor Xa
Specific Agents in the Management of the STEMI Patient
Unfractionated Heparin
By itself, unfractionated heparin (UFH) actually exerts little or no effect on thrombin, and for this reason UFH is not classified as a direct thrombin inhibitor. The enzymatic activity is actually achieved by antithrombin III (AT III). When UFH combines with ATIII, the activity of ATIII 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.
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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 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 1239 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. 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 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]
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)