http://cvm.controlled-trials.com/content/1/2/102
`
`Review
`Low-molecular-weight heparins in the treatment of venous
`thromboembolism
`Walter Ageno and Menno V Huisman*
`University of Insubria, Varese, Italy, and *Leiden University Medical Centre, Leiden, The Netherlands
`
`Received: 9 May 2000
`Revisions requested: 18 July 2000
`Revisions received: 24 July 2000
`Accepted: 25 July 2000
`Published: 29 August 2000
`
`Abstract
`
`Curr Control Trials Cardiovasc Med 2000, 1:102–106
`The electronic version of this article can be found online at
`http://cvm.controlled-trials.com/content/1/2/102
`© Current Controlled Trials Ltd
`(Print ISSN 1468-6708; Online 1468-6694)
`
`Venous thromboembolism is a common disease that is associated with considerable
`morbidity if left untreated. Recently, low-molecular-weight heparins (LMWHs) have been
`evaluated for use in acute treatment of deep venous thrombosis and pulmonary embolism.
`Randomized studies have shown that LMWHs are as effective as unfractionated heparin in
`the prevention of recurrent venous thromboembolism, and are as safe with respect to the
`occurrence of major bleeding. A pooled analysis did not show substantial differences among
`different LMWH compounds used, but no direct comparison of the different LMWHs is
`currently available. Finally, in patients with pulmonary embolism, there is a relative lack of
`large studies of daily practice. It could be argued that large prospective studies, in patients
`who were treated with LMWHs from the moment of diagnosis, are needed.
`
`Keywords:
`
`low-molecular-weight heparins, pulmonary embolism, treatment, venous thrombosis
`
`Introduction
`Venous thromboembolism is a relatively common disease,
`and may result in death. Its average annual incidence has
`been estimated at 48 per 100 000 for deep venous throm-
`bosis and 23 per 100 000 for pulmonary embolism [1].
`The clinical significance of venous thromboembolism is
`not only because of the risk of death from pulmonary
`embolism, but also because of the high risk of recurrent
`events, the occurrence of subsequent morbidity such as
`the post-thrombotic syndrome, and the consequent eco-
`nomic impact caused by the high rate of hospitalization.
`
`Since the early 1960s, anticoagulant therapy has been
`proven to be pivotal in the treatment of venous throm-
`boembolism. With the exception of massive pulmonary
`emboli (occurring in < 5% of patients who present with
`
`pulmonary embolism, in whom thrombolytic therapy should
`be considered), treatment of established deep venous
`thrombosis and pulmonary embolism is essentially identi-
`cal, and includes the administration of heparin for 5–10
`days, and oral anticoagulants for at least 3 months [2].
`
`Until recently, unfractionated heparin was the treatment
`of choice. It can be administered by continuous intra-
`venous infusion, starting with a bolus of 5000 interna-
`tional units (IU) followed by 30 000–35 000 IU/day,
`adjusted to achieve an activated partial thromboplastin
`time (APTT) of 1.5–2.5 times the control. Alternatively,
`after the intravenous bolus injection, unfractionated
`heparin can be administered subcutaneously, with
`twice daily injections of 15 000–20 000 IU, which are
`aimed at maintaining therapeutic levels of APTT.
`
`APTT = activated partial thromboplastin time; LMWH = low-molecular-weight heparin; IU = international units.
`
`0001
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`commentary
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`review
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`reports
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`primary research
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`Careful laboratory monitoring is necessary in order to
`maintain therapeutic plasma concentrations of heparin. In
`fact, inadequate anticoagulation may be responsible for a
`high number of recurrent venous thromboembolic events
`[3]. It has been reported [4] that patients who receive
`intravenous heparin without reaching the therapeutic
`range within the first 24 h may have a rate of recurrence as
`much as 15 times higher than that in patients who had
`heparin levels within the therapeutic range.
`
`Unfractionated heparin has a number of limitations. Its
`anticoagulant effect is unpredictable and varies consider-
`ably among patients, depending on age, sex, body weight,
`smoking status and renal function. This wide variability is
`caused by heparin binding to acute-phase reactant pro-
`teins, levels of which vary among normal individuals and
`disease states. Before therapeutic plasma levels are
`achieved, the binding to plasma proteins and to receptor
`sites on the endothelium must be saturated. Moreover,
`unfractionated heparin has further effects on haemostasis,
`such as inhibition of platelet aggregation and augmenta-
`tion of vessel wall permeability, which can significantly
`enhance its potential to cause bleeding complications [5].
`Finally, as many as 3% of treated patients will develop
`heparin-induced thrombocytopenia [6].
`
`Pharmacology and pharmacokinetics of LMWHs
`LMWHs are obtained by chemical or enzymatic depolymer-
`ization of porcine mucosal heparin preparations [7]. Their
`reduced molecular weight (and thus their reduced number
`of saccharide units) as compared with unfractionated
`heparin leads to potential pharmacological and pharmacoki-
`netic advantages over the parent compound, which result in
`a greater clinical utility. Their antithrombotic activity is mainly
`based on inactivation of factor Xa because of a reduced
`ability to inactivate factor IIa when compared with unfrac-
`tionated heparin. Moreover, the LMWHs do not bind to the
`endothelium and have a lower affinity for plasma proteins.
`This results in a more predictable bioavailability, a substan-
`tially longer half-life, a stable dose/response relationship
`when injected subcutaneously, and potentially a more
`antithrombotic than haemorrhagic activity in comparison
`with unfractionated heparin [8]. LMWHs also have minimal
`interaction with platelets, and a reduced incidence of
`heparin-induced thrombocytopenia has been observed [6].
`Because of their properties, the LMWHs can be adminis-
`tered subcutaneously in weight-adjusted, once or twice
`daily doses without the need for laboratory monitoring.
`
`Randomized trial data
`Deep venous thrombosis
`In the early 1990s, two randomized trials assessed the
`efficacy and safety of the LMWHs in the treatment of
`deep venous thrombosis. In a multicenter, double-blind
`clinical trial, Hull et al [9•] randomized 219 patients to
`receive unfractionated heparin administered intravenously
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`
`with an initial bolus of 5000 IU followed by 30 000 IU or
`40 000 IU every 24 h (depending on the presence or
`absence of risk factors for bleeding), and 213 patients to
`receive a once daily, weight-adjusted dose of the LMWH
`tinzaparin (175 IU/kg). A nonsignificant reduction in the
`incidence of recurrent venous thromboembolism (6.9% in
`the standard heparin-treated group versus 2.8% in the
`LMWH-treated group), a significant reduction in the rate
`of major bleeding (5.0% versus 0.5%) and a significant
`reduction in the rate of deaths (9.6% versus 4.7%) in
`favour of the LMWH were observed.
`
`In the same year, Prandoni et al [10] randomized 170
`patients to a similar regimen of unfractionated heparin (a
`bolus of 100 IU/kg followed by a continous infusion of
`35 000 IU every 24 h, adjusted to achieve a target APTT of
`1.5–2.0 times control), or to a twice daily, weight-adjusted,
`subcutaneous administration of the LMWH nadroparin. The
`results were similar to those reported by Hull et al [9•]: in
`the LMWH group there was a nonsignificant reduction in
`the rate of recurrent venous thromboembolism (14% in the
`standard heparin-treated group versus 7% in the LMWH-
`treated group), a nonsignificant reduction in major bleeding
`(3.5% versus 1%) and a nonsignificant reduction in deaths
`after 6 months of follow up (14% versus 7%).
`
`Many other randomized trials subsequently compared the
`LMWHs with standard heparin in the initial treatment of
`acute proximal venous thrombosis, and their results were
`evaluated in three different meta-analyses [11–13], which
`concluded that LMWHs have greater efficacy and safety.
`The most recent meta-analysis, including the most recent
`studies [14•], found no difference between the unfraction-
`ated heparin and LMWH (Table 1). The authors of that
`report concluded that LMWHs have equal effectiveness to
`that of unfractionated heparin in the prevention of recur-
`rent episodes of venous thromboembolism, and equal
`safety with respect to the occurrence of major bleeding.
`Interestingly, a statistically significant reduction in total
`mortality in patients treated with LMWHs was also found
`in this meta-analysis. Also, a pooled analysis from the
`selected trials showed no substantial differences among
`the different LMWH products used in the studies, but, as
`correctly recognized by those authors, no direct compar-
`isons of the different LMWHs are actually available.
`Finally, it is important to note that in all of the above-men-
`tioned trials patients younger than 18 years, pregnant
`patients and patients with severe renal failure were
`excluded, and consequently the results of these studies
`cannot be extrapolated to these specific patient groups.
`
`The simple, unmonitored dosing system and the practical
`administration of the LMWHs mean that these agents
`could facilitate outpatient management of deep venous
`thrombosis. Two large trials published in 1996 have clearly
`demonstrated the safety and efficacy of such an approach.
`
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`Table 1
`
`A meta-analysis comparing LMWH in the treatment of venous thromboembolism
`
`Adverse event
`
`LMWH
`
`Unfractionated heparin
`
`RR (95% CI)
`
`Recurrent venous thromboembolism
`
`96/2212 (4.3%)
`
`115/2235 (5.1%)
`
`0.85 (0.65–1.12)
`
`Major haemorrhage
`
`Total mortality
`
`33/2212 (1.5%)
`
`98/2006 (4.9%)
`
`57/2235 (2.5%)
`
`0.63 (0.37–1.05)
`
`132/2027 (6.5%)
`
`0.76 (0.59–0.98)
`
`P
`
`0.20
`
`0.08
`
`0.03
`
`CI, confidence interval; RR, relative risk. Data from Dolovich et al [14•].
`
`Table 2
`
`LMWH in the outpatient treatment of deep venous thrombosis
`
`Adverse event
`
`Recurrent venous thromboembolism
`
`Major haemorrhage
`
`Death
`
`LMWH
`
`4.45%
`
`1.00%
`
`4.55%
`
`Unfractionated heparin
`
`Risk reduction
`
`7.02%
`
`2.31%
`
`7.12%
`
`37%
`
`57%
`
`36%
`
`Pooled analysis of the studies of Koopman et al [15•] and Levine et al [16•].
`
`In the TASMAN study [15•], conducted in Europe, Aus-
`tralia and New Zealand, 198 patients were randomized to
`receive an adjusted-dose of intravenous unfractionated
`heparin in the hospital, and 202 patients to receive a fixed,
`weight-adjusted subcutaneous dose of
`the LMWH
`nadroparin, which was administered at home, if it was con-
`sidered possible. The rate of events was comparable in
`the two groups with regard to recurrent venous throm-
`boembolism (8.6 and 6.9%, respectively), major bleeding
`(2.0 and 0.5%, respectively) and death (8.1 and 6.9%,
`respectively). Importantly, the duration of hospitalization
`was reduced by 67% from 8.1 days in the unfractionated
`heparin group to 2.7 days in the LMWH group. In the
`LMWH group, 75% of the patients were discharged
`within 2 days or were not even admitted to the hospital.
`
`The second study was carried out in Canada by Levine et
`al [16•] (Table 2). The design of the trial and the sample
`size were similar to those of the TASMAN study. There
`were 253 patients randomized to the intravenous unfrac-
`tionated heparin group, and 247 patients to the LMWH
`enoxaparin group. The event rates of recurrent venous
`thromboembolism and major bleeding did not reach statis-
`tical significance and therefore it was concluded that the
`LMWH enoxaparine was not inferior to unfractionated
`heparin in the treatment of deep venous thrombosis. As in
`the previous study, the time spent in the hospital was
`remarkably reduced, from 6.5 days to 1.1 days, and 120
`out of the 247 patients randomized to the LMWH were
`never admitted to the hospital. This study and the TASMAN
`study [15•] suggest the feasibility of a significant change in
`the clinical management of patients presenting with deep
`venous thrombosis, ie treating them at home with LMWH.
`
`Two recently published reports from Canada [17,18] and
`one from The Netherlands [19] suggest that more than
`80% of patients with proximal deep venous thrombosis
`can safely be treated from the first day with LMWH at
`home without the need for hospitalization.
`
`From pharmacokinetic data it has been observed that ther-
`apeutic anti-Xa levels could be achieved over 24 h when
`LMWHs are administered once daily. Once daily dosing is
`attractive because it may be more acceptable to the patient
`and involves less nursing time. In one controlled study [20],
`once daily nadroparin was shown to have equal efficacy
`and safety as twice daily nadroparin. The primary end-point
`of a combination of venous thromboembolism and mortality
`was reported in 13 patients (4.1%) in the group that
`received daily nadroparin and in 24 patients (7.2%) who
`received twice daily nadroparin. Thus, an absolute differ-
`ence of 3.1% (95% confidence interval –6.6% to 0.5%)
`was observed in favour of the once daily therapy. Major
`bleeding occurred in four patients both in the once daily
`group (1.3%) and in the twice daily group (1.2%).
`
`Pulmonary embolism
`thrombosis and pulmonary
`Because deep venous
`embolism are considered two manifestations of the same
`disease – venous thromboembolism – the LMWHs have
`also recently been tested in the setting of patients with
`haemodynamically stable pulmonary embolism. Three trials
`were published between 1997 and 2000: one was carried
`out in a population of patients presenting with venous
`thromboembolism,
`including
`submassive pulmonary
`embolism [21]; one specifically in patients with submas-
`sive pulmonary embolism [22]; and a third was conducted
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`in patients admitted for deep venous thrombosis who also
`had objectively documented pulmonary embolism [23].
`
`The COLUMBUS trial [21] was an international, random-
`ized, open-label study that enrolled 1021 patients present-
`ing with acute symptomatic deep venous thrombosis,
`pulmonary embolism, or both. Patients were randomly
`assigned to one of two groups. One group receive the
`LMWH reviparin administered subcutaneously twice daily
`at fixed, weight-adjusted doses (6300 anti-Xa units if body
`weight was more than 60 kg, 4200 anti-Xa units if body
`weight was between 46 and 60 kg, and 3500 units for a
`body weight between 35 and 45 kg). The other group
`received unfractionated heparin administered
`intra-
`venously in a 5000 IU bolus followed by a dose of
`1250 IU/h, adjusted to achieve an APTT range between
`60 and 85 s. Home treatment was encouraged for patients
`assigned to reviparin. Only 12 patients were excluded
`because thrombolytic therapy was planned, and 271
`patients with pulmonary embolism were included in the
`study. The total rate of recurrences in the subgroup with
`pulmonary embolism was comparable to that of the group
`of patients with deep venous thrombosis (5.9% versus
`4.8%, respectively), and was also similar in the two treat-
`ment groups (5.8% in the reviparin group versus 6.0% in
`the unfractionated heparin group). There were six
`episodes of fatal pulmonary embolism (2.2%) during the 3
`months of follow up, all of which occurred in the subgroup
`of 271 patients enrolled with pulmonary embolism.
`
`The THÉSÉE study [22] was a randomized, multicenter,
`open-label trial. A total of 612 patients presenting with
`symptomatic pulmonary embolism were assigned to
`receive the LMWH tinzaparin administered subcuta-
`neously at a once daily dose of 175 anti-Xa units/kg body
`weight, or to receive unfractionated heparin administered
`intravenously with an initial bolus of 50 IU/kg followed by
`an initial dose of 500 IU/kg, adjusted to achieve therapeu-
`tic levels of the APTT between 2 and 3 times the control
`value. After 8 days, the occurrence of events included in
`the primary outcome (recurrent venous thromboembolism,
`major bleeding or death) was similar in the two treatment
`groups: 2.9% in the unfractionated heparin group and
`3.0% in the tinzaparin group. After 90 days this similarity
`remained, with a 7.1% and 5.9% incidence in the unfrac-
`tionated heparin and tinzaparin groups, respectively. There
`was a 1.0% rate of fatal pulmonary emboli in both groups.
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`
`of 40 320 IU/24 h (or 29 760 IU/24 h for those patients with
`risk factors for bleeding), which was adjusted to achieve a
`therapeutic APTT range between 1.5 and 2.5 times the
`control value. Of the originally included 432 patients with
`deep venous thrombosis, 200 had high-probability perfu-
`sion lung scan findings and were included in this study.
`Only 28 (14%) had presented with symptoms of pul-
`monary embolism. There were no recurrent episodes of
`venous thromboembolism in the group of patients treated
`with tinzaparin, and seven new episodes (four pulmonary
`embolisms) in the unfractionated heparin group (95% con-
`fidence
`interval
`for the difference 1.9% to 11.7%;
`P = 0.01). Death occurred in 6.2% and 8.7% of patients,
`respectively; only in one patient (in the unfractionated
`heparin group) was death related to pulmonary embolism.
`
`The LMWHs are currently considered a potentially valid
`alternative to unfractionated heparin in the treatment of
`pulmonary embolism in patients whose clinical condition
`is stable. One might argue that there is a need for more
`clinical studies, involving large groups of unselected
`patients, presenting with clinically suspected pulmonary
`embolism, who were treated with LMWHs from the
`moment of diagnosis.
`
`Conclusion
`LMWHs have replaced unfractionated heparin in the initial
`treatment of patients with deep venous thrombosis. Numer-
`ous well-designed clinical trials have demonstrated that
`LMWHs are as effective and safe as unfractionated heparin
`and, because no laboratory control is needed, they are the
`initial treatment of choice for initiating out-of-hospital antico-
`agulant treatment in patients with acute deep venous throm-
`bosis. For patients with pulmonary embolism, LMWHs are a
`potential alternative for unfractionated intravenous heparin.
`Whether all patients with pulmonary embolism can be
`treated at home from the first day with LMWHs must be
`assessed in prospective follow-up studies.
`
`References
`Articles of particular interest have been highlighted as:
`•
`of special interest
`••
`of outstanding interest
`
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`
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`The study by Hull et al [23] included a subpopulation of an
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`Patients were assigned to the LMWH tinzaparin, adminis-
`tered, as in the previous study, subcutaneously in a once
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`0004
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`Authors’ affiliations: Department of Internal Medicine, University of
`Insubria, Varese, Italy (Walter Ageno), and Department of General
`Internal Medicine, Leiden University Medical Centre, Leiden, The
`Netherlands (Menno V Huisman)
`
`Correspondence: Dr Menno V Huisman, Department of General
`Internal Medicine, Room B3 Q84, Leiden University Medical Centre,
`PO Box 9600, 2300 RC Leiden, The Netherlands.
`Tel: +31 71 526 3761; e-mail: m.v.huisman@lumc.nl
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`
`0005
`
`