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(Stroke. 2000;31:1770.)
© 2000 American Heart Association, Inc.
Comments, Opinions, and Reviews |
Low-Molecular-Weight Heparins and Heparinoids in Acute Ischemic Stroke
A Meta-Analysis of Randomized Controlled Trials
From the Centre for Vascular Research, University of Nottingham, City Hospital Campus, Nottingham, UK.
Correspondence to Professor Philip Bath, Division of Stroke Medicine, University of Nottingham, City Hospital Campus, Hucknall Rd, Nottingham NG5 1PB, UK.
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Abstract |
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Background and Purpose—Low-molecular-weight heparins and heparinoids (LMWHs) are superior to unfractionated heparin in the prevention and treatment of venous thromboembolism and acute coronary syndromes. We performed a systematic review of randomized controlled trials (RCTs) to examine the safety and efficacy of LMWH in acute ischemic stroke.
Methods—Randomized, controlled, and nonconfounded trials of LMWH in acute ischemic stroke were identified from the Cochrane Library (version 2, 1999), previous systematic reviews, and a review of publication quality relating to acute stroke trials. The authors each independently extracted data by treatment group and assessed trial quality using Cochrane Collaboration criteria.
Results—Eleven completed RCTs involving 3048 patients were identified; data were available from 10 of these. Four trials explicitly excluded patients with presumed cardioembolic stroke. Treatment with LMWH was associated with significant reductions in prospectively identified deep vein thrombosis (OR 0.27, 95% CI 0.08 to 0.96) and symptomatic pulmonary embolism (OR 0.34, 95% CI 0.17 to 0.69) and with increased major extracranial hemorrhage (OR 2.17, 95% 1.10 to 4.28). Nonsignificant increases in end-of-treatment (OR 1.20, 95% CI 0.86 to 1.69) and end-of-trial (OR 1.05, 95% CI 0.83 to 1.32) case fatality and symptomatic intracranial hemorrhage (OR 1.77, 95% CI 0.95 to 3.31) were observed. End-of-trial death and disability was nonsignificantly reduced (OR 0.87, 95% CI 0.72 to 1.06).
Conclusions—LMWHs reduce venous thromboembolic events in patients with acute ischemic stroke and increase the risk of extracranial bleeding. A nonsignificant reduction in combined death and disability and nonsignificant increases in case fatality and symptomatic intracranial hemorrhage were also observed. On the basis of the current evidence, LMWH should not be used in the routine management of patients with ischemic stroke.
Key Words: deep vein thrombosis • embolism • heparin • stroke, ischemic
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Introduction |
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Although many drugs are used routinely in the management of acute ischemic stroke, only aspirin1 2 and possibly thrombolytics3 4 5 have been shown to have a beneficial effect on outcome. The International Stroke Trial found that many drugs, including glycerol, hemodilution drugs, and steroids, are used routinely even though there is no evidence from systematic reviews of randomized controlled trials (RCTs) that these agents improve outcome.6 7 A similar situation may exist for low-molecular-weight heparins or heparinoids (LMWHs), which are regularly used in acute ischemic stroke and yet whose safety and efficacy are uncertain. Indeed, the use of LMWHs is recommended for this indication by several consensus conferences and experts,8 9 10 although others have concluded there is no evidence to support the use of heparins (in general) in stroke.11
Low-molecular-weight heparins are derived enzymatically or chemically from unfractionated heparin (UFH) but differ relatively in their mode of action. UFH exerts its anticoagulant effect by activating antithrombin III and thereby inhibiting thrombin and, to an extent, activated factor X (factor Xa). In contrast, LMWHs preferentially inhibit factor Xa rather than thrombin. Low-molecular-weight heparinoids are glycosaminoglycans, which differ from heparins in that their anticoagulant activity is due to their components: heparan sulfate, dermatan sulfate, and chondroitin sulfate. These factors catalyze the inhibitory effect of heparin cofactor II on thrombin and have a higher anti-Xa/anti-IIa activity ratio than low-molecular-weight heparins.
Compared with UFH, LMWHs have a higher bioavailability, longer half-life, reduced protein binding, and dose-independent clearance (reviewed in Reference 12 ). Hence, LMWHs produce a more predictable anticoagulant response such that they can be given subcutaneously once or twice daily without monitoring. LMWHs also have less antiplatelet activity and do not increase vascular permeability compared with UFH. As a result, LMWHs cause less bleeding than UFH. LMWHs also cause less heparin-induced thrombocytopenia and osteoporosis.
When the International Stroke Trial1 showed that UFH increased the risk of symptomatic intracranial hemorrhage (SICH) without improving functional outcome, it was hoped that the pharmacological advantages of LMWH over UFH would reduce the risk of bleeding while improving the potential benefit through prevention of arterial thrombus extension, early reinfarction, and the development of venous thromboembolism. Indeed, several trials13 14 15 in other areas of vascular medicine have shown that LMWHs are superior to UFH in their risk:benefit ratio. Nevertheless, several individual medium-sized studies16 17 of LMWH in acute ischemic stroke have been neutral with regard to their primary outcomes, and it remains unclear whether these drugs should be used routinely. The objectives of this systematic review were to assess the safety and efficacy of LMWHs in acute ischemic stroke. We included trials that studied patients with acute ischemic stroke, intervened with an LMWH, and recorded 1 or more outcomes relevant to stroke patients, including case fatality, combined death and disability, venous thromboembolism, and symptomatic bleeding.
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Methods |
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Study Identification
We identified studies through searches of the Cochrane Stroke Group database of trials in acute stroke, the Cochrane Library (version 2, 1999), published reviews18 19 20 21 and systematic reviews12 22 23 24 of anticoagulant treatment in acute stroke, and a recent study of publication quality of acute stroke RCTs.25 The 2 Cochrane databases are the largest and most comprehensive listings of RCTs and are based on trials present in MEDLINE and EMBASE and the results of manual journal searching. The reference lists of identified publications were also checked for additional trials. Publication language other than English was not an exclusion criteria.
Study Selection
Included trials had to be randomized, placebo or open
controlled, and completed by the end of 1998. Adult patients had to
have been included within 7 days of stroke and had to have CT exclusion
of primary intracerebral hemorrhage. Trials
were excluded if they were pseudorandomized or confounded (ie, LMWH was
tested against another active treatment).
Data Extraction
The authors independently extracted the following trial
information and data by treatment group: (1) protocol, including type
and dose of LMWH, treatment window, length of treatment, and follow-up
period; (2) numbers of patients; (3) events on treatment for each group
relating to case fatality, intracranial hemorrhage,
extracranial hemorrhage, pulmonary embolism (PE), deep
vein thrombosis (DVT), and fatal myocardial infarction; and (4)
end-of-trial case fatality and death and disability. Information on the
method used to diagnose SICH, PE, and DVT was also recorded, as was
information regarding whether patients with presumed cardioembolic
stroke could be enrolled in the study.
Where more than 1 active treatment group was compared with a single
control group, the event rate and group size for the control group were
divided between the active groups equally. This approach is recommended
by the Stroke Group of the Cochrane Collaboration because it avoids
inflating the apparent number of subjects in the trial (which would
lead to an artificial narrowing of the confidence limits). For example,
the Fraxiparine in Stroke Study (FISS) and FISS bis trials had 2 active
treatment arms, so control group event rates and patient numbers were
each divided in 2. Trial data were entered by LMWH dose with an
arbitrary cutoff of 
100 IU ·
kg-1 ·
d-1 anti-Xa for low dose
and >100 IU ·
kg-1 ·
d-1 anti-Xa for high dose,
to approximate to venous and arterial doses as defined in
the International Stroke Trial.1 This cutoff level allowed
the 2 dosing arms of the FISS and FISS bis trials to be
analyzed separately.
Data Analysis
Data were entered into and analyzed with the Cochrane
Collaboration Review Manager package (Mac version 3.1). Odds ratios
(ORs) and the 95% confidence intervals (CIs) around the ORs were
calculated with a random-effects model because
heterogeneity was expected among the trials. An OR <1
may signify a useful drug effect; conversely, an OR >1 may signify a
detrimental drug effect. Heterogeneity was assessed
with respect to protocol differences by grouping studies by their aim
(phase II or III, or DVT prophylaxis), time to treatment (within 24
hours, or longer), route of drug administration
(intravenous, intramuscular, or subcutaneous), inclusion or
exclusion of subjects with presumed cardioembolic stroke, and type of
drug used (heparin or heparinoid). Statistical
heterogeneity among trials was also assessed. We
performed sensitivity analyses by excluding trials on quality
grounds, eg, the effect of LMWH on the incidence of DVT was studied for
all trials and then separately for those trials that prospectively
assessed DVT by imaging at the end of treatment. Lack of identification
and inclusion of trials through publication or location
bias26 was assessed by a quantitative analysis of
the asymmetry of funnel plots according to Egger et
al.27
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Identification and Characteristics
Eleven completed trials were identified that fulfilled the inclusion criteria (Table 1
); 1
phase II study of danaparoid (Organon, Netherlands) was unpublished,
and data were not made available by the pharmaceutical company (Table 2). Nine studies (7 in English, 1
in French, and 1 in Italian) had been published in full or abstract
form; 1991 data on the remaining trial were obtained from Dr E.
Lindenstrom of Leo Pharmaceuticals. The available 10 trials had studied
2855 patients. Another 11 studies (
3400 patients) involving an LMWH
were excluded, 3 because they were not randomized, 7 because they were
confounded (LMWH was compared with another active therapy, either UFH
23 or aspirin), and 1 because there was no control
untreated group (Table 2).
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Trial Designs
Each of the studies was randomized, and all recruited patients
after CT exclusion of primary intracerebral
hemorrhage. The primary aims of each of the studies fell into 3
groups: (1) 5 small trials prospectively assessed the effect of LMWH on
the development of DVT (Dr E. Lindenstrom, unpublished data, 1991, and
References 28 29 30 31 ; (2) 2 small phase II studies
assessed safety, tolerability, and feasibility of
LMWH32 33 ; and (3) 3 medium-sized phase III trials
assessed the safety and efficacy of LMWH.16 17 34 LMWHs
were administered intravenously in 2
studies,16 28 intramuscularly in 1,32 and
subcutaneously in the remaining studies (Table 1
). Treatment was
started within 24 to 72 hours in all but 1 study28 and was
given for between 7 and 30 days (median and mode 14 days). Follow-up
ranged between 2 weeks and 6 months. Four studies explicitly excluded
patients with presumed cardioembolic stroke (Dr E. Lindenstrom,
unpublished data, 1991, and References 28 ,
30 , and 31 ; the remaining trials
recruited between 14.0% and 29.8% (median 20.9%) of subjects with
presumed cardioembolic stroke.
Death, and Death and Disability
Case-fatality rates at the end of the treatment and follow-up
periods were nonsignificantly increased in patients who received LMWH
(Table 3; Figures 1A and 3). Conversely, LMWH therapy was
associated with a nonsignificant decrease in combined death and
disability (Figure 1B). There was no evidence of
heterogeneity among the trials for death or death and
disability, and no dose-dependent effects of LMWH were observed. When
assessed by stroke subtype, no particular group of patients appeared to
benefit with respect to death and disability (Figure 2). Analysis of a funnel plot did
not reveal asymmetry (P=0.2), which suggests that few, if
any, trials were missed by the search process.
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Intracranial and Extracranial Bleeding
Five trials prospectively assessed the incidence of intracranial
hemorrhage by performing a second CT scan at the end of the
treatment period; LMWH had no effect on the rate of all intracranial
hemorrhages (Table 3). Other studies only performed a
second CT scan if patients deteriorated and there was clinical
suspicion of SICH. The risk of SICH was low in the control groups and
was nonsignificantly increased by 75% during treatment with LMWH
(Figures 1C and 3). Although the definition of major
extracranial hemorrhage varied between studies, the overall
rate was low across the control groups (Table 3). However, the
odds of major extracranial hemorrhagic events were significantly raised
by >2-fold in patients receiving LMWH. The effect of LMWH on both
intracranial and extracranial hemorrhage appeared to be dose
dependent.
Venous Thromboembolic Events
LMWH significantly reduced the incidence of DVT in those 5 trials
that prospectively assessed this outcome using venography (Dr E.
Lindenstrom, unpublished data, 1991, and Reference 30 )
or fibrinogen-labeled imaging28 29 31 during or at the end
of treatment (Table 3). A nonsignificant reduction in proximal
thrombi was also observed with LMWH therapy. The remaining studies
diagnosed DVT on the basis of clinical suspicion confirmed by an
imaging modality; DVT rates tended to be lower in patients receiving
LMWH, an effect that was not significant owing to the FISS bis
study.17 When assessed across all trials, LMWH more than
halved DVT events (Table 3); the effect of LMWH on DVT appeared
to be dose dependent (Figure 1D).
Although no studies prospectively examined the incidence of PE,
all 10 trials recorded the incidence of events diagnosed clinically
and confirmed by pulmonary angiography or ventilation-perfusion
scanning. Although the risk of PE was low (Figure 3), the odds of PE
were significantly reduced by two thirds in those subjects receiving
LMWH (Table 3), a finding that was present irrespective of
trial design: phase II studies, OR 0.72 (95% CI 0.04 to 12.19, 2
trials, 177 subjects); DVT prophylaxis studies, OR 0.39 (95% CI 0.07
to 2.06, 5 trials, 318 subjects); and phase III studies, OR 0.30 (95%
CI 0.13 to 0.68, 3 trials, 2341 subjects).
Other Events
LMWH nonsignificantly reduced the rate of recurrent
ischemic stroke (Table 3). Conversely, rates of fatal
myocardial infarction tended to be higher in those patients receiving
LMWH, although the total number of events was very small.
Trial Protocol and Event Rates
There were no significant differences in the ORs for death when
assessed by the type of trial (phase II or III or DVT prophylaxis),
time to treatment (within 24 hours, or longer), route of drug
administration (intravenous, intramuscular, or
subcutaneous), inclusion or exclusion of subjects with presumed
cardioembolic stroke, and the drug class used (heparin or
heparinoid) (Table 4).
Similarly, ORs were not dissimilar for combined death and disability,
apart from the analysis for time to treatment, for which LMWH
appeared to be effective when given in trials with a wider recruitment
window than 24 hours. To further explore this finding, the effects of
LMWH on SICH and disability by time of administration were assessed;
LMWH significantly increased SICH in trials that provided treatment
within 24 hours (3 trials, 2082 subjects; OR 2.06, 95% CI 1.01 to
4.22) but not in those studies that provided treatment later than 24
hours (5 trials, 601 subjects; OR 1.69, 95% CI 0.43 to 6.67).
Similarly, LMWH significantly reduced disability in trials that
recruited patients beyond 24 hours (3 trials, 483 subjects; OR 0.62,
95% CI 0.42 to 0.91) but not in those that recruited only within 24
hours (2 trials, 2037 subjects; OR 0.92, 95% CI 0.75 to 1.14).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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LMWHs are used routinely by many physicians in patients with acute ischemic stroke, and it is pertinent to question this practice in light of all the available data from RCTs. Evidence from completed trials of LMWHs suggest they may reduce death and disability by a small (OR 0.87) degree compared with control treatment. However, the body of data is relatively small, and the CIs are wide, such that LMWH could reduce this composite end point by 28% or increase it by 6%. When death alone was assessed, LMWH had no obvious effect (OR 1.05). Although not a usual outcome in trials in acute stroke, analysis of data for disability suggested it was reduced (OR 0.84).
The use of heparin has been promulgated in some types of ischemic stroke, notably secondary to presumed cardioembolism (usually due to atrial fibrillation), such that some LMWH trials excluded such patients on the grounds that it would be unethical to include them. Additionally, the TOAST trial (Trial of ORG 10172 in Acute Stroke Treatment) found, in a post hoc analysis, that patients with stroke of presumed large artery disease appeared to benefit from LMWH administration.16 However, our review does not support the view that LMWHs are effective in particular subgroups of ischemic stroke, a conclusion that was also reached for UFH in the International Stroke Trial.1
Many physicians use LMWH for the prophylaxis of venous thromboembolic events (DVT and PE) during the acute phase of stroke. Our review confirms that LMWHs do reduce the risk of DVT and PE, but only at the expense of an increased risk of major extracranial hemorrhage and probably SICH. Dose-dependent effects of LMWHs on DVT and bleeding were observed, with weight-adjusted daily doses of >100 IU of anti-Xa per kilogram preventing most venous thromboembolic events but causing more intracranial and extracranial hemorrhages than lower doses. There did not appear to be any dose effect on end-of-trial case fatality or combined death and disability.
The findings of our review appear to be robust and are in line with the results of individual medium-sized trials, eg, TOAST and FISS bis,16 17 which found that LMWH has no significant effect on functional outcome after acute ischemic stroke. The trials did not show significant heterogeneity for outcomes other than DVT, and a funnel plot analysis did not suggest that trials had not been identified (although data on 1 small trial of danaparoid involving 180 subjects were unavailable for analysis). Statistical heterogeneity was present for DVT and was largely due to the FISS bis trial, which found, surprisingly, that nadroparin had no effect in preventing DVT, although it did reduce PE events; this contradictory observation is inconsistent with other LMWH trials both within and without stroke and is probably due to chance.
In spite of the absence of statistical heterogeneity in most of the results, considerable differences existed in the trial aims and protocols, and our "mixing" of apparently very different studies can be questioned. Nevertheless, analyses did not suggest that these differences altered the overall message of the findings. (However, such comparisons of trials are nonrandomized and are therefore subject to confounding as well as being underpowered.) In particular, the inclusion or exclusion of patients with presumed cardioembolic stroke, use of heparin or heparinoids, route of drug administration, and study aim did not alter the results. However, differences were present when outcome was assessed by the time at which treatment was started; LMWH appeared to reduce the rate of disability and combined death and disability in those trials in which treatment was initiated beyond 24 hours, whereas SICH rates were higher when LMWH was started early. Although the former findings are counterintuitive because it is expected that early drug treatment is necessary to improve outcome after stroke, the data are compatible with the notion that LMWHs are safer if started after 24 hours, when their effect on SICH is less, thereby allowing their beneficial effect on death and disability to be observed. (Conversely, early treatment with LMWH causes SICH and ultimately disability, therefore masking beneficial effects on functional outcome). If true, this efficacy-timing relationship may explain why results from FISS, which recruited patients up to 48 hours after stroke, were positive while results from FISS bis, which limited recruitment to 24 hours, were neutral.17 34 Nevertheless, these observations could be due to chance, because few subjects were recruited in trials with delayed treatment, and this hypothesis needs to be tested prospectively in an analysis of individual patient data from the existing LMWH trials and in any ongoing or future studies.
There are no head-to-head comparisons of different LMWHs in stroke, so it was not possible to make judgments on the relative merits of each drug. However, comparisons of LMWHs in other situations have not suggested that major differences in efficacy or safety exist.35 Five small RCTs directly compared LMWH with UFH.24 36 37 38 Because only 705 patients were studied, definitive statements are not possible, but heparinoids appeared to be superior in preventing DVT (OR 0.52, 95% CI 0.56 to 0.79). No differences in case fatality, PE, or SICH were observed, although the event rates were very low for the latter 2 outcomes.24 Larger studies would be required to assess whether LMWHs are superior to UFH, although LMWHs appear to have a better risk:benefit ratio in other vascular conditions, including prevention and treatment of DVT.13 14 Furthermore, uncomplicated DVT and PE can be treated with LMWH given on an outpatient basis.39 40 41 A recent study15 showed that LMWH was superior to UFH in reducing death or myocardial infarction in patients with unstable coronary artery disease (unstable angina or non–Q-wave myocardial infarction).
It can be argued, on the basis of this meta-analysis, that LMWHs should be used routinely in acute ischemic stroke even though they do not significantly reduce the rate of combined death and disability. After all, LMWHs do appear to reduce disability, especially if started later than 24 hours after stroke onset, and they do reduce PE, an often fatal condition. These advantages could be construed to outweigh the hazards of a definite increase in extracranial bleeding, a situation that can normally be treated with a blood transfusion, and probably SICH. Nevertheless, a meta-analysis should rarely change clinical practice but rather should be used as a basis to justify or stop further trials. This is particularly pertinent for 3 reasons: first, our analyses are based on small numbers of subjects (only 2855 patients), with resulting wide CIs; second, it is not clear which LMWH regimen (drug, dosing, or timing) should be recommended; and third, the risk of DVT and PE can already be reduced adequately in most stroke patients through the routine use of rehydration, early mobilization, aspirin,1 and probably venous compression stockings. Hence, we recommend that LMWHs should not be used routinely in acute ischemic stroke until additional trial data become available and substantiate or refute our findings. Nevertheless, LMWHs may still be useful in patients at particularly high risk of venous thromboembolic events, eg, those with a prior history of DVT, PE, or inherited thrombophilic tendency, or who are morbidly obese, or who go on to develop a venous event. Patients with progressing stroke secondary to presumed thromboembolism or those with venous stroke42 may also benefit, although all of these situations are sufficiently rare that reliable RCT evidence is unlikely to become available.
Sufficient questions remain about the use of LMWH in acute
ischemic stroke that we suggest that additional, larger trials
be performed. On the basis of the frequency of combined death and
disability in control subjects and the relative risk reduction seen
with LMWH, a trial of 10 000 subjects would be required (assuming
=0.05, power=0.90). However, such a trial should probably include
aspirin, because it is now the de facto treatment for patients with
ischemic stroke according to the results of the International
Stroke Trial1 and Chinese Aspirin Stroke
Trial.2 Hence, any future trial would need to include
aspirin in both treatment arms or compare LMWH with aspirin, as some
recent studies have done.43 44 Further systematic
analysis of individual patient data from the existing LMWH
trials is also warranted to facilitate more detailed investigation of
some questions that the current report cannot adequately address,
especially the effects of LMWH by timing of administration, stroke
subtype (cardioembolic or large-vessel stroke), and stroke severity. We
are initiating a collaboration of the trialists with these aims in
mind.
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Acknowledgments |
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P.M.W.B. is Stroke Association Professor of Stroke Medicine. F.J.B. was supported by National Health Service Executive (Trent) grant No. SPGS 236. The study received no funding from the pharmaceutical industry. We thank the Cochrane Stroke Group (Prof P. Sandercock, Mrs H. Fraser) for helping with this review, in particular by providing a list of completed stroke trials. We also thank Dr J. Brom (Novartis, Switzerland), Dr A. Chamorro (Spain), Dr A. Elias (France), Prof R. Kay (Hong Kong), Dr P. Kon (Rhone-Poulenc Rorer, UK), Prof H. Kwiecinski (Poland), Dr E. Lindenstrom (Leo Pharmaceuticals, Denmark), and Dr H. Magnani (Organon, the Netherlands), who were involved with some of the included trials and who each kindly commented on an early version of this paper; the views given here are ours and do not necessarily reflect their opinions.
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Footnotes |
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P.M.W.B. was a local investigator in the International Stroke Trial and is principal investigator of the Tinzaparin in Acute Ischaemic Stroke Trial, funded by Leo Pharmaceuticals.
Received March 7, 2000; revision received April 21, 2000; accepted April 28, 2000.
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