Elsevier

The Lancet

Volume 355, Issue 9219, 3 June 2000, Pages 1936-1942
The Lancet

Articles
Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis

https://doi.org/10.1016/S0140-6736(00)02324-2Get rights and content

Summary

Background

In acute coronary syndrome without ST elevation, the role of unfractionated and low-molecular-weight heparin in aspirin-treated patients remains unclear, and there is conflicting evidence regarding the efficacy and safety of low-molecular-weight heparin (LMWH) relative to unfractionated heparin. We did a systematic overview of the randomised trials to assess the effect of unfractionated heparin and LMWH on death, myocardial infarction, and major bleeding.

Methods

Randomised trials comparing unfractionated heparin or LMWH with placebo or untreated control, or comparing unfractionated heparin with LMWH, for the short-term and long-term management of patients with acute coronary syndrome without ST elevation, were identified by electronic and manual searches and through contact with experts and industry representatives. Odds ratios for death, myocardial infarction, and major bleeding were calculated for each trial, and results for the individual trials were combined by a modification of the Mantel-Haenszel method.

Findings

12 trials, involving a total of 17 157 patients, were included. The summary odds ratio (OR) for myocardial infarction or death during short-term (up to 7 days) unfractionated heparin or LMWH compared with placebo or untreated control was 0·53 (95% Cl 0·38–0·73; p=0·0001) or 29 events prevented per 1000 patients treated; during short-term LMWH compared with unfractionated heparin was 0·88 (0·69–1·12; p=0·34); and during long-term LMWH (up to 3 months) compared with placebo or untreated control was 0·98 (0·81–1·17; p=0·80). Long-term LMWH was associated with a significantly increased risk of major bleeding (OR 2·26, [95% Cl 1·63–3·14], p<0·0001), which is equivalent to 12 major bleeds per 1000 patients treated.

Interpretation

In aspirin-treated patients with acute coronary syndrome without ST elevation, short-term unfractionated heparin or LMWH halves the risk of myocardial infarction or death. There is no convincing difference in efficacy or safety between LMWH and unfractionated heparin. Long-term LMWH has not been proven to confer benefit additional to aspirin and there is no evidence to support its use after the first 7 days.

Introduction

Short-term unfractionated heparin or low-molecular-weight heparin (LMWH) is widely used in the management of acute coronary syndrome without ST elevation (unstable angina and non-Q-wave myocardial infarction). Selective emphasis on trials comparing the efficacy and safety of unfractionated heparin with LMWH has led clinicians to believe that LMWH should be used for the treatment of unstable angina or non-Q-wave myocardial infarction. However, individual trials have provided conflicting results as to whether heparin provides additive benefit in patients treated with aspirin, or whether there are clinically important differences in the efficacy and safety of unfractionated heparin relative to LMWH. Furthermore, although acute coronary syndrome without ST elevation is now recognised as a chronic condition that confers a persistently increased risk of recurrent ischaemic events for at least several months,1 the role of long-term LMWH remains to be clarified.

The goal of antithrombotic therapy in acute coronary syndrome is to prevent progression of intracoronary thrombus and promote stabilisation of the atherosclerotic plaque, thereby reducing myocardial ischaemia and preventing further complications such as myocardial infarction or death.2, 3, 4 Aspirin remains a mainstay of therapy, reducing the risk of myocardial infarction, stroke, or vascular death by about 25% in a broad spectrum of patients with arterial vascular disease.5 Despite the use of aspirin, however, the risk of recurrent ischaemic events (myocardial infarction, death, or urgent revascularisation) in patients with unstable angina or non-Q-wave myocardial infarction remains between 5% and 10% during the first week, about 20% at 40 days, and 40% at 150 days.6 Unregulated thrombin generation may be an important trigger for recurrent ischaemic events, and because aspirin incompletely blocks thrombin-mediated platelet activation, unfractionated heparin or LMWH is used to inhibit thrombin generation and block thrombin activity.7

Unfractionated heparin is a heterogeneous mixture of polysaccharide chains with a mean molecular weight of 15 000. LMWH consists of fragments of unfractionated heparin with a mean molecular weight of 5000. Both bind to antithrombin via a unique pentasaccharide sequence that is randomly dispersed on one-third and one-fifth of the chains of unfractionated heparin and LMWH, respectively. Binding of heparin to antithrombin accelerates the rate at which antithrombin inhibits factor Xa and thrombin in the order of 1000-fold. Pentasaccharide-containing heparin chains of any length can enhance antithrombin-mediated inactivation of factor Xa. By contrast, to catalyse thrombin inhibition, heparin must bind to both thrombin and antithrombin to bridge them together. This bridging reaction can only be effected by pentasaccharide-containing chains comprised of at least 18 saccharide units. Because almost all the chains of unfractionated heparin contain at least 18 saccharide units, it has equivalent inhibitory activity against thrombin and factor Xa. By contrast, less than half of the chains of LMWH are of sufficient length to bridge antithrombin to thrombin. Consequently, LMWH preparations have greater activity against factor Xa than thrombin, with anti-Xa:anti-IIa ratios that range from 2:1 to 4:1.8, 9

Although in-vitro studies show that inhibition of either factor Xa or thrombin confers antithrombotic activity,8, 10 thrombin may be a more important therapeutic target because of its ability to amplify its own generation through activation of factor V and VIII.11, 12 However, in the clinical setting, the relative importance of factor Xa and thrombin inhibition remains unclear.

LMWH has pharmacokinetic advantages over unfractionated heparin. LMWH produces a more predictable anticoagulant response and has a longer plasma half-life than unfractionated heparin. This permits once or twice subcutaneous dosing and obviates the need for laboratory monitoring. The incidence of heparin-induced thrombocytopenia is lower with LMWH than with unfractionated heparin, which may offer a safety advantage.13 Individual LMWH preparations exhibit distinct pharmacological and biochemical profiles,8, 14 and may not be clinically interchangeable. As yet, however, there have been no direct comparisons between individual agents in acute coronary syndrome. LMWH is more convenient to use than unfractionated heparin and this factor alone has led to the widespread use of LMWH in both arterial and venous thrombosis.

Given the importance of thrombin in the pathogenesis of acute coronary syndrome, the addition of unfractionated heparin or LMWH to aspirin has the potential to confer additional benefit. However, when comparing unfractionated heparin with LMWH, only moderate benefit of one agent over the other (eg, 15% or 20% risk reduction) is expected, particularly in aspirin-treated patients. To achieve sufficient power to detect moderate differences, most trials have used a composite outcome that includes not only “hard” outcomes (death or myocardial infarction) but also less well defined outcomes such as recurrent angina or need for revascularisation. The results of a trial may be largely influenced by the frequency of this reversible “anginal” component of the composite outcome, rather than the irreversible and more important components of death and myocardial infarction. Further, when several small trials have been done, the play of chance may lead to spurious claims of efficacy (type I error) or lack of a difference (type II error).

Meta-analytical techniques try to overcome some of the problems inherent in examining trials in isolation. A meta-analysis of all relevant trials can provide sufficient power to detect differences in outcomes with a lower incidence such as death or myocardial infarction (ie, avoid type II error) and they overcome type I error by avoiding selection biases resulting from overemphasis on individual trials whose results appear more extreme. By the use of the most robust endpoints differences in outcome definitions can be minimised. By obtaining information from all the trials at a consistent time point, especially at, or close to, the end of treatment, further variation between trials is reduced.

Section snippets

Methods

We attempted to obtain data on major cardiovascular complications, particularly death and myocardial infarction, from completed, published and unpublished, unconfounded randomised trials of unfractionated heparin or LMWH in acute coronary syndrome without ST elevation. The literature was scanned by formal searches of electronic databases (MEDLINE, EMBASE) and informal searches for studies that were known to ourselves or our colleagues. Reference lists of published papers were also scanned, and

Studies excluded

Our search yielded 23 studies,6, 16, 37 of which 12, involving a total of 17 157 patients, met our inclusion criteria.6, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 Studies were excluded that fitted the following criteria: randomised comparison heparin versus aspirin,27, 28, 29 heparin plus aspirin versus combined antiplatelet therapy,30 or heparin versus non-aspirin control;31, 32, 33 non-randomised comparison reported;34 dose-ranging uncontrolled study;35 patients alternately allocated to LMWH

Discussion

Addition of unfractionated heparin or LMWH to aspirin for up to 7 days reduces the incidence of non-fatal myocardial infarction or death by about 50%. This analysis included data on 2900 aspirin-treated patients with acute coronary syndrome without ST elevation; 1300 patients in trials of unfractionated heparin, and 1600 patients in trials of LMWH. About 30 major vascular events are prevented for every 1000 patients treated with either unfractionated heparin or LMWH. A similar reduction in

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