Low-Molecular-Weight Heparins in Conjunction with Thrombolysis for ST-Elevation Acute Myocardial Infarction

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Abstract

Background: Intravenous unfractionated heparin (UFH) is recommended in ST-elevation acute myocardial infarction (STEMI), following thrombolysis with fibrin-specific agents. Subcutaneous low-molecular-weight heparins (LMWH), previously proven effective in non-ST-elevation acute coronary syndromes, have been recently investigated in the setting of STEMI. We aimed at evaluating the current level of evidence supporting the use of LMWH in STEMI. Methods: A Medline search of the English language literature between January 1995 and December 2005 was performed and randomized clinical trials comparing LMWH to either placebo or UFH in conjunction with thrombolysis were selected. Results: About 26,800 patients treated with various thrombolytic regimens were included in 12 randomized clinical trials. Dalteparin was superior to placebo on left ventricular thrombosis/arterial thromboembolism, with no significant effect on the early patency rate of the infarct-related artery (IRA). Compared to UFH, dalteparin had no significant effect on clinical events and on the IRA late patency, although less thrombus was present. Enoxaparin was superior to placebo on the medium-term death/reinfarction/angina rate and late IRA patency, and superior also to UFH on in-hospital and medium-term occurrence of death/reinfarction/angina. The effect of enoxaparin on IRA patency rate was not univocal. Compared to placebo, reviparin significantly reduced early and medium-term mortality and reinfarction rates, without a substantial increase in overall stroke rate. As regards safety, bleedings were more frequent than placebo and comparable to UFH in LMWH groups, with the exception of the pre-hospital ASSENT-3 PLUS trial, where in elderly patients, enoxaparin had an incidence of intracranial hemorrhage twice higher than UFH. Conclusions: In-hospital subcutaneous administration of dalteparin, enoxaparin or reviparin, as an adjunct to various thrombolytics in STEMI, appears feasible and at least as effective and safe as intravenous UFH. Before LMWH might be recommended, however, some yet unresolved issues (i.e. use in elderly patients, in severe renal insufficiency, in association with glycoprotein IIb/IIIa inhibitors and during interventional procedures), need to be addressed.

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Most cited references 26

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The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. The GUSTO Angiographic Investigators.

(1993)

Although it is known that thrombolytic therapy improves survival after acute myocardial infarction, it has been debated whether the speed with which coronary-artery patency is restored after the initiation of therapy further affects outcome. To study this question, we randomly assigned 2431 patients to one of four treatment strategies for reperfusion: streptokinase with subcutaneous heparin; streptokinase with intravenous heparin; accelerated-dose tissue plasminogen activator (t-PA) with intravenous heparin; or a combination of both activators plus intravenous heparin. Patients were also randomly assigned to cardiac angiography at one of four times after the initiation of thrombolytic therapy: 90 minutes, 180 minutes, 24 hours, or 5 to 7 days. The group that underwent angiography at 90 minutes underwent it again after 5 to 7 days. The rate of patency of the infarct-related artery at 90 minutes was highest in the group given accelerated-dose t-PA and heparin (81 percent), as compared with the group given streptokinase and subcutaneous heparin (54 percent, P < 0.001), the group given streptokinase and intravenous heparin (60 percent, P < 0.001), and the group given combination therapy (73 percent, P = 0.032). Flow through the infarct-related artery at 90 minutes was normal in 54 percent of the group given t-PA and heparin but in less than 40 percent in the three other groups (P < 0.001). By 180 minutes, the patency rates were the same in the four treatment groups. Reocclusion was infrequent and was similar in all four groups (range, 4.9 to 6.4 percent). Measures of left ventricular function paralleled the rate of patency at 90 minutes; ventricular function was best in the group given t-PA with heparin and in patients with normal flow through the infarct-related artery irrespective of treatment group. Mortality at 30 days was lowest (4.4 percent) among patients with normal coronary flow at 90 minutes and highest (8.9 percent) among patients with no flow (P = 0.009). This study supports the hypothesis that more rapid and complete restoration of coronary flow through the infarct-related artery results in improved ventricular performance and lower mortality among patients with myocardial infarction. This would appear to be the mechanism by which accelerated t-PA therapy produced the most favorable outcome in the GUSTO trial.

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A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group.

Lewis Cohen, G J Fromell, Melody Goodman … (1997)

Antithrombotic therapy with heparin plus aspirin reduces the rate of ischemic events in patients with unstable coronary artery disease. Low-molecular-weight heparin has a more predictable anticoagulant effect than standard unfractionated heparin, is easier to administer, and does not require monitoring. In a double-blind, placebo-controlled study, we randomly assigned 3171 patients with angina at rest or non-Q-wave myocardial infarction to receive either 1 mg of enoxaparin (low-molecular-weight heparin) per kilogram of body weight, administered subcutaneously twice daily, or continuous intravenous unfractionated heparin. Therapy was continued for a minimum of 48 hours to a maximum of 8 days, and we collected data on important coronary end points over a period of 30 days. At 14 days the risk of death, myocardial infarction, or recurrent angina was significantly lower in the patients assigned to enoxaparin than in those assigned to unfractionated heparin (16.6 percent vs. 19.8 percent, P=0.019). At 30 days, the risk of this composite end point remained significantly lower in the enoxaparin group (19.8 percent vs. 23.3 percent, P=0.016). The need for revascularization procedures at 30 days was also significantly less frequent in the patients assigned to enoxaparin (27.1 percent vs. 32.2 percent, P=0.001). The 30-day incidence of major bleeding complications was 6.5 percent in the enoxaparin group and 7.0 percent in the unfractionated-heparin group, but the incidence of bleeding overall was significantly higher in the enoxaparin group (18.4 percent vs. 14.2 percent, P=0.001), primarily because of ecchymoses at injection sites. Antithrombotic therapy with enoxaparin plus aspirin was more effective than unfractionated heparin plus aspirin in reducing the incidence of ischemic events in patients with unstable angina or non-Q-wave myocardial infarction in the early phase. This benefit of enoxaparin was achieved with an increase in minor but not in major bleeding.

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Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.

M Bertrand (2002)

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Author and article information

Journal

Journal ID (publisher-id): CRD

Journal ID (nlm-ta): Cardiology

Journal ID (doi): 10.1159/issn.0008-6312

Title: Cardiology

Publisher: S. Karger AG

ISSN (Print): 0008-6312

ISSN (Electronic): 1421-9751

Publication date Subscription-year: 2007

Publication date (Print): February 2007

Publication date (Electronic): 21 July 2006

Volume: 107

Issue: 2

Pages: 132-139

Affiliations

^aDivision of Cardiology, Maggiore Hospital, Bologna, and ^bDivision of Cardiology, ‘G.B. Morgagni’ Hospital, Forlì, Italy; ^cLinköping Heart Center, University of Linköping, Linköping, Sweden

Article

Publisher ID: 94659 Other ID: Cardiology 2007;107:132–139

DOI: 10.1159/000094659

PubMed ID: 16864962

SO-VID: db7c07ed-ca39-40fd-b59d-9645ff84d755

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