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Use of Low-Molecular-Weight Heparins in the Management of Acute Coronary Artery Syndromes and Percutaneous Coronary Intervention

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Use of Low-Molecular-Weight Heparins in the Management of Acute Coronary Artery Syndromes and Percutaneous Coronary Intervention CLINICAL CARDIOLOGY Use of Low-Molecular-Weight Heparins in the Management of Acute Coronary Artery Syndromes and Percutaneous Coronary Intervention Graham C. Wong, MD Context Low-molecular-weight heparins (LMWHs) possess several potential phar- Robert P. Giugliano, MD, SM macological advantages over unfractionated heparin as an antithrombotic agent. Elliott M. Antman, MD Objective To systematically summarize the clinical data on the efficacy and safety of LMWHs compared with unfractionated heparin across the spectrum of acute coro- HE INCITING EVENT IN AN ACUTE nary syndromes (ACSs), and as an adjunct to percutaneous coronary intervention (PCI). coronary syndrome (ACS) typi- Data Sources We searched MEDLINE for articles from 1990 to 2002 using the in- cally involves disruption of a dex terms heparin, enoxaparin, dalteparin, nadroparin, tinzaparin, low molecular weight vulnerable atherosclerotic heparin, myocardial infarction, unstable angina, coronary angiography, coronary an- Tplaque with superimposed thrombosis, gioplasty, thrombolytic therapy, reperfusion, and drug therapy, combination. Addi- leading to varying degrees of occlusion tional data sources included bibliographies of articles identified on MEDLINE, inquiry of the culprit artery.1-3 ST-elevation myo- of experts and pharmaceutical companies, and data presented at recent national and cardial infarction (STEMI) is usually as- international cardiology conferences. sociated with complete thrombotic oc- Study Selection We selected for review randomized trials comparing LMWHs against clusion of the culprit artery,4 while either unfractionated heparin or placebo for treatment of ACS, as well as trials and reg- nonocclusive thrombus is the typical istries examining clinical outcomes, pharmacokinetics, and/or phamacodynamics of LMWHs finding associated with unstable angina/ in the setting of PCI. Of 39 studies identified, 31 fulfilled criteria for analysis. non–ST-elevation myocardial infarc- Data Extraction Data quality was determined by publication in the peer-reviewed tion (UA/NSTEMI).5,6 Tissue factor ex- literature or presentation at an official cardiology society–sponsored meeting. posed following plaque rupture leads to Data Synthesis The LMWHs are recommended by the American Heart Associa- activation of the coagulation cascade and tion and the American College of Cardiology for treatment of unstable angina/non– generation of factor Xa (FIGURE 1).7 ST-elevation myocardial infarction. Clinical trials have demonstrated similar safety with Thrombin is formed, which leads to fi- LMWHs compared with unfractionated heparin in the setting of PCI and in conjunc- brin deposition, platelet activation, and tion with glycoprotein IIb/IIIa inhibitors. Finally, LMWHs show promise as an anti- thrombotic agent for the treatment of ST-elevation myocardial infarction. ultimately the formation of a stable clot.8 Given the central role of thrombin in Conclusions The LMWHs could potentially replace unfractionated heparin as the the pathogenesis of ACSs, an antithrom- antithrombotic agent of choice across the spectrum of ACSs. In addition, they show botic agent is an important element in promise as a safe and efficacious antithrombotic agent for PCI. However, further study is warranted to define the benefit of LMWHs in certain high-risk subgroups before therapy, regardless of whether ST eleva- their use can be universally recommended. tion is present. However, there are im- JAMA. 2003;289:331-342 www.jama.com portant limitations associated with un- fractionated heparin (currently the most commonly used antithrombotic agent), METHODS Author Affiliations: TIMI Study Group, Brigham and which has prompted a search for alter- Studies for this review were identified Women’s Hospital, Boston, Mass. 9 Financial Disclosures: Dr Giugliano has received hono- native compounds. One promising class using MEDLINE searches, reviewing ref- raria from Aventis for educational programs. Dr Antman of agents is the low-molecular-weight erence lists, and conferring with ex- has received clinical research grants from Aventis. Corresponding Author and Reprints: Robert P. heparins (LMWHs), which offer poten- perts and pharmaceutical companies. Giugliano, MD, SM, TIMI Study Group, 350 Long- tial advantages in terms of clinical effi- The medical subject headings used were wood Ave, First Floor Offices, Boston, MA 02115 (e-mail: [email protected]). cacy, safety, and ease of use in the set- heparin, enoxaparin, dalteparin, nadro- Clinical Cardiology Section Editor: Michael S. Lauer, ting of ACS. parin, tinzaparin, low molecular weight MD, Contributing Editor. ©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, January 15, 2003—Vol 289, No. 3 331 Downloaded From: https://jamanetwork.com/ on 09/23/2021 LMWH IN ACS AND PCI reviewed journal or presentation at an Figure 1. Differential Effects of Unfractionated Heparin and Low-Molecular-Weight Heparin official cardiology society–sponsored meeting. Of 39 studies identified, 31 ful- Tissue Factor Tissue Factor filled criteria for analysis. - Pathway Inhibitor Factor VIIa RESULTS Endothelial Cells Understanding of the pharmacological + + + characteristics of LMWHs has evolved Factor IX Factor IXa 10,11 Activation since previous reviews. The LMWHs LMWH UFH act more proximally on the coagula- - + + tion cascade than unfractionated hepa- rin and more effectively inhibit throm- Factor X Factor Xa Activation bin generation (Figure 1). Increasing evidence also suggests that LMWHs may LMWH differ from unfractionated heparin in other thrombin-dependent and throm- bin-independent mechanisms (TABLE 1). Antithrombin III - These differences may explain the dif- ferent pharmacological profiles of UFH LMWH and unfractionated heparin in Prothrombinase Complex the setting of ACSs and PCI. + Although anti-Xa monitoring is not Prothrombin Thrombin commonly performed nor recom- mended in routine clinical practice,12,13 it has been suggested that monitoring of LMWH LMWH activity may be of benefit in cer- tain high-risk patient subgroups in Antithrombin III - which the optimal dose of LMWH has not been established.14 These include pa- tients at weight extremes, patients with UFH + renal insufficiency (prolongation of Fibrinogen Fibrin anti-Xa activity),15 and patients who are pregnant (lower than normal anti-Xa ac- In acute coronary syndromes, thrombosis is typically initiated via exposure of tissue factor at the site of a dis- 16 rupted plaque. The complex of tissue factor and Factor VIIa activates Factor X to Xa. Factor Xa subsequently tivity for a given LMWH). participates in the prothrombinase complex (Factor Xa, Factor Va, Ca++, and a phospholipid membrane, usu- ally from an activated platelet). The tissue factor/VIIa complex also activates Factor IX to IXa, which helps Non–ST-Elevation ACSs maintain the thrombotic process. Both unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) act by complexing with antithrombin III. LMWHs have a relatively greater inhibitory effect on Factor Xa than (UA/NSTEMI) on factor IIa (thrombin), such that the anti-Xa:IIa inhibitory ratio is greater than 1. This produces greater up- The LMWHs have been compared with stream inhibition of the coagulation cascade and relatively greater reduction of thrombin generation than when unfractionated heparin is administered. Unfractionated heparin has an anti-Xa:IIa inhibitory ratio of 1. While unfractionated heparin for the treat- it is theoretically possible to achieve similar anti-Xa activity with unfractionated heparin as with LMWH, be- ment of UA/NSTEMI in 4 large, pro- cause of poor bioavailability very high doses of unfractionated heparin are required that would result in un- 17-20 acceptably high anti-IIa levels and an increased risk of bleeding. Both unfractionated heparin and LMWHs also spective randomized trials. Several inhibit coagulation through release of tissue factor pathway inhibitor (TFPI) from endothelial cells. However, meta-analyses comparing unfraction- unlike unfractionated heparin, LMWHs do not cause TFPI depletion, which has been associated with a para- ated heparin with LMWH have al- doxical prothrombotic state during anticoagulant therapy in the setting of acute coronary syndromes. ready demonstrated the superiority of LMWH over placebo21-23 and the supe- heparin, myocardial infarction, unstable als that compared a LMWH with either riority of enoxaparin over unfraction- angina, coronary angioplasty, thrombo- unfractionated heparin or placebo for the ated heparin21,22 (FIGURE 2). lytic therapy, reperfusion, and drug treatment of STEMI and UA/NSTEMI. Key differences in clinical trial de- therapy, combination. In addition, rel- We also included nonrandomized tri- sign, patient selection, and character- evant abstracts from the annual meet- als and registries of LMWH that exam- istics of the preparations make com- ings of the American Heart Association ined clinical outcomes, and/or pharma- parisons among LMWHs difficult. Only (AHA), American College of Cardiol- cokinetics and phamacodynamics in the 1 trial has compared 2 LMWH prepa- ogy (ACC), and European Society of setting of percutaneous coronary inter- rations in the setting of UA/NSTEMI. Cardiology were reviewed. We se- vention (PCI). Data quality was deter- The Enoxaparin Versus Tinzaparin lected for review randomized clinical tri- mined by publication in a peer- (EVET) trial randomized 438 patients 332 JAMA, January 15, 2003—Vol 289, No. 3 (Reprinted) ©2003 American Medical Association.
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