Muir, K.W.

English

Enlighten: Publications

 
 
 
 
 
 
 
Muir, K.W. (2008) The PREVAIL trial and low-molecular-weight 
heparin for prevention of venous thromboembolism. Stroke, 39 (7). pp. 
2174-2176. ISSN 0039-2499 
 
http://eprints.gla.ac.uk/17885/ 
 
Deposited on: 19 January 2012 
 
 
Enlighten – Research publications by members of the University of Glasgow 
http://eprints.gla.ac.uk 
Keith W. Muir
Venous Thromboembolism
The PREVAIL Trial and Low-Molecular-Weight Heparin for Prevention of
ISSN: 1524-4628 
Copyright © 2008 American Heart Association. All rights reserved. Print ISSN: 0039-2499. Online
Stroke is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514
doi: 10.1161/STROKEAHA.107.509588
2008, 39:2174-2176: originally published online April 24, 2008Stroke 
 http://stroke.ahajournals.org/content/39/7/2174
located on the World Wide Web at: 
The online version of this article, along with updated information and services, is
 http://www.lww.com/reprints
Reprints: Information about reprints can be found online at 
  
 journalpermissions@lww.com
410-528-8550. E-mail: 
Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. 
Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters
  
 http://stroke.ahajournals.org//subscriptions/
Subscriptions: Information about subscribing to Stroke is online at 
 at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from 
Section Editors: Marc Fisher, MD, and Kennedy Lees, MD
The PREVAIL Trial and Low-Molecular-Weight Heparin
for Prevention of Venous Thromboembolism
Keith W. Muir, MD, FRCP
Patients with stroke are at high risk for venous thrombo-embolism. Studies of the natural history in the era before
widespread use of antiplatelet agents or physical preventive
measures reported an incidence of deep vein thrombosis
(DVT) of over 50% within the first days.1 A lower incidence
might be expected with more aggressive routine acute treat-
ment, including early use of antiplatelet agents, early mobi-
lization, and graduated compression stockings, but the com-
bined control groups of randomized, controlled trials (RCTs)
predominantly undertaken in the 1990s still reported an
incidence of 37% when DVT was specifically sought.2 Older
studies found the incidence of pulmonary embolism (PE)
after stroke to be 10% to 20% and to account for up to 10%
of all fatalities (including cases in ambulant patients).3 In
contrast, symptomatic PE is consistently rarely reported in
RCTs in stroke, occurring in just 0.7% of randomized
subjects in the control group of trials comparing heparins
with antiplatelet therapy.4 However, clinical recognition of
PE remains poor. Half of all PEs in one series presented as
sudden death.5 Clinically unrecognized PE is also common,
with up to 50% of surgical patients with proximal DVT
having abnormal ventilation–perfusion lung scans.6 Even if
PE is rare, postthrombotic syndrome resulting from venous
valvular incompetence causes pain, swelling, and skin
changes, including varicose eczema, and may affect over
20% of those with symptomatic DVT within 2 years.
The effectiveness of low-dose unfractionated heparin for
prevention of VTE was established in the late 1970s, pre-
dominantly in surgical patients but also in stroke.7 The
superiority of low-molecular-weight (LMW) heparins over
unfractionated heparin in other clinical settings has also been
established with advantages including more predictable dose
effects, easier administration, and less risk of thrombocyto-
penia. Two previous RCTs comparing LMW heparin with
antiplatelet therapy reported reduction in symptomatic VTE
events,8,9 and in a systematic review of 6 previous RCTs,
LMW heparins or heparinoids were associated with greater
reduction in DVT or PE than unfractionated heparin (5000
U twice a day in 5 of the 6 RCTs, only one of which
adjusted dose by coagulation parameters), with an OR of
0.52 (95% CI: 0.56 to 0.79).10 Too few symptomatic PEs
occurred in any of the RCTs to be significant as an end
point in itself, but odds were reduced with heparin com-
pared with control. The PREVAIL trial,11 recently pub-
lished by David Sherman and colleagues, adds consider-
able further data to this question, randomizing 1762
nonambulant patients with stroke.
The PREVAIL investigators chose its primary end point to
be the incidence of VTE at day 14. Patients with ischemic
stroke with leg weakness of at least 2 on the National
Institutes of Health Stroke Scale (NIHSS) were randomized
to receive either 5000 U unfractionated heparin twice a day or
the 40 mg of the LMW heparin enoxaparin daily starting
within 48 hours of the event and continued for 10 days.
Treatment allocation was not blinded, but the end points were
objectively defined by routine venography (in 82% of sub-
jects) and/or compression ultrasound in all subjects, and
results were independently reviewed blind to treatment
allocation.
Not surprisingly, enoxaparin was associated with a
significant relative risk reduction in VTE events compared
with unfractionated heparin of 43%, representing approx-
imately 8 fewer events per 100 patients treated (number
needed to treat for benefit: 13). Those with more severe
strokes, defined in the trial as NIHSS score 14, were
twice as likely to have VTE but were also at higher risk of
bleeding complications, and the absolute risk among less
severe strokes (NIHSS 14) in the enoxaparin group
remained high at 8.3%.
The PREVAIL trial addressed a specific (and logical)
end point of VTE, but has to be viewed on the background
of the failure of either unfractionated or LMW heparins in
a number of RCTs to reduce the end points of death or
dependence, or stroke recurrence, and the main trial
publication does not fully detail the results with respect to
these. The failure to find a benefit for these end points has
Received on July 24, 2007; and accepted November 8, 2007.
From the Division of Clinical Neurosciences, University of Glasgow, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK.
Correspondence to Keith W. Muir, MD, FRCP, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, UK. E-mail
k.muir@clinmed.gla.ac.uk
(Stroke. 2008;39:2174-2176.)
© 2008 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.107.509588
2174
Emerging Therapies
 at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from 
led many clinicians to avoid heparin in acute stroke in
favor of antiplatelet therapy alone. Whether the findings of
PREVAIL should influence clinical practice depends on a
judgment regarding the clinical importance of VTE pre-
vention in itself and an assessment of the safety of the
interventions.
First, were the events prevented by enoxaparin treatment
in PREVAIL of clinical importance? The statistical differ-
ence in VTE events in PREVAIL resulted from prevention
of asymptomatic DVTs. Both PE (7 of 1335 in total
[0.5%]) and symptomatic DVT (5 of 1335 [3.7%]) were
rare, although there were fewer of both of these events in
the enoxaparin group (one PE and one symptomatic DVT
versus 6 and 4, respectively, for unfractionated heparin).
However, location of the clot rather than whether it causes
symptoms is of greater importance, and enoxaparin was
associated with significantly fewer proximal as well as
distal DVTs (relative risk: 0.47, 95% CI: 0.31 to 0.72).
Assumptions about the small risk of isolated distal DVT
are based on the natural history after hip or knee replace-
ment surgery, where DVTs generally start in calf veins and
only approximately one in 6 progresses to involve proxi-
mal veins.6 It is unknown whether the risk of extension of
distal DVTs after stroke is the same, obvious differences
being rapid mobilization after orthopedic procedures with
accordingly reduced risk of incident DVT,6 in contrast to
more prolonged immobility in many patients with stroke.
Measuring the final outcome at day 14 ensures better
completeness of follow-up, but this early time point will
not capture the full risk of VTE.
Second, was treatment safe? Major bleeding complications
were rare in PREVAIL with an incidence of just over 1%.
Symptomatic intracerebral hemorrhage was documented in
1% (4 of 877) of subjects in the enoxaparin group. A slight
excess of major extracranial bleeds with enoxaparin was seen
(7 events compared with none in the unfractionated heparin
group), but there was no significant difference in events
considered to represent “clinically important hemorrhage” (a
post hoc definition including a composite of bleeding events).
No differences in all-cause mortality were evident, and the
total mortality rates (12% at day 90) were somewhat lower
than previous studies would suggest should be expected given
the trial population. These event rates were also on a
background of more than 90% of patients receiving antiplate-
let therapies.
The PREVAIL results indicate that LMW heparin in
doses appropriate for VTE prophylaxis is reasonably safe
even when used acutely after moderately severe ischemic
stroke and on a background of modern antiplatelet therapy.
Any additional hazard over unfractionated heparin is
greatly outweighed by superior efficacy. Enoxaparin (or
equivalent LMW heparin) should therefore replace unfrac-
tionated heparin for VTE prevention after stroke.
The more difficult issues are whether all patients require
VTE prophylaxis, when it should start, and for how long
treatment is necessary; PREVAIL does not answer these
issues completely.
As noted, VTE is an important cause of morbidity and
mortality after stroke and clinical recognition remains poor.
The high incidence of VTE in PREVAIL (11% proximal
DVT or PE within 14 days in the control arm) indicates that
modern stroke unit care (presumably, but not explicitly,
including early mobilization and mechanical VTE preventive
treatment in the trial) and antiplatelet therapy by themselves
are insufficient. It is also very difficult to identify a low-risk
group within the PREVAIL population. Leg weakness pre-
dominantly defines VTE risk after stroke,1,12 and subgroup
analyses identified no difference in benefit irrespective of
age, sex, stroke severity, or obesity. It seems unlikely
therefore that it will be possible to easily define a risk score
that could target treatment any better than the trial entry
criteria achieved. So long as there is no significant increase in
hazard, prevention of VTE is a worthwhile goal and preven-
tive treatment for all who fulfill PREVAIL entry criteria
should be considered. The failure of heparins in general to
reduce death or dependence, or stroke recurrence, is insuffi-
cient reason not to consider treatment; many other interven-
tions in stroke do not affect these end points and given its low
incidence, a very large trial indeed would be required for
prevention of PE to be reflected in a significant reduction in
all-cause mortality.
Could the bleeding risks of heparin be reduced by later
introduction of preventive treatment? PREVAIL began
treatment within 48 hours and on average just over 1 day
after a stroke. Symptomatic intracerebral hemorrhage rates
are lower when heparin is started more than 24 hours after
onset compared with under 24 hours,2,8 and there was no
difference in observed benefit when the subgroups starting
treatment within, or after, 24 hours were compared. How-
ever, most bleeding events were related to extracranial
hemorrhage and whether this is also reduced by deferred
treatment is not known.
PREVAIL trial treatment was mandated for only 10 days
and there are no data reported on interventions thereafter.
The initial difference in VTE risk appears to have been
maintained up to day 90, although beyond day 14, end
point events were not routinely sought by investigation. Is
10 days of treatment sufficient? Even if the majority of
DVTs start in the days immediately after the stroke,13 10%
of patients develop a new DVT during rehabilitation.14
Incident PE continues throughout the poststroke period, at
least up to 120 days.5 Continued prophylaxis so long as
immobility persists seems clinically logical, albeit not
supported by specific evidence. Studies on the long-term
safety and efficacy of LMW heparins would therefore be
welcome.
The PREVAIL findings significantly advance the case for
routine use of prophylactic-dose LMW heparin in immobile
patients for VTE prevention after stroke. As is ever the case
with heparin, further questions remain to be addressed and
there is scope for further trials.
Disclosures
None.
References
1. Warlow C, Ogston D, Douglas AS. Deep venous thrombosis of the legs
after strokes. Part I—incidence and predisposing factors. BMJ. 1976;1:
1178–1181.
Muir PREVAIL Trial and LMWH to Prevent VTE 2175
 at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from 
2. Bath PM, Iddenden R, Bath FJ. Low-molecular-weight heparins and
heparinoids in acute ischemic stroke: a meta-analysis of randomized
controlled trials. Stroke. 2000;31:1770–1778.
3. Viitanen M, Winblad B, Asplund K. Autopsy-verified causes of death
after stroke. Acta Med Scand. 1987;222:401–408.
4. Berge E, Sandercock P. Anticoagulants versus antiplatelet agents for
acute ischaemic stroke. Cochrane Database Syst Rev. 2002;4:CD003242.
5. Wijdicks EF, Scott JP. Pulmonary embolism associated with acute stroke.
Mayo Clin Proc. 1997;72:297–300.
6. Kearon C. Natural history of venous thromboembolism. Circulation.
2003;107:I22–I30.
7. McCarthy ST, Turner JJ, Robertson D, Hawkey CJ, Macey DJ. Low-dose
heparin as a prophylaxis against deep-vein thrombosis after acute stroke.
Lancet. 1977;2:800–801.
8. Bath PM, Lindenstrom E, Boysen G, De Deyn P, Friis P, Leys D, Marttila
R, Olsson J, O’Neill D, Orgogozo J, Ringelstein B, van der SJ, Turpie
AG. Tinzaparin in Acute Ischaemic Stroke (TAIST): a randomised
aspirin-controlled trial. Lancet. 2001;358:702–710.
9. Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight
heparin versus aspirin in patients with acute ischaemic stroke and atrial
fibrillation: a double-blind randomised study. HAEST Study Group.
Heparin in Acute Embolic Stroke Trial. Lancet. 2000;355:1205–1210.
10. Sandercock P, Counsell C, Stobbs SL. Low-molecular-weight heparins or
heparinoids versus standard unfractionated heparin for acute ischaemic
stroke. Cochrane Database Syst Rev. 2005;2:CD000119.
11. Sherman DG, Albers GW, Bladin C, Fieschi C, Gabbai AA, Kase CS,
O’Riordan W, Pineo GF. The efficacy and safety of enoxaparin versus
unfractionated heparin for the prevention of venous thromboembolism
after acute ischaemic stroke (PREVAIL study): an open-label randomised
comparison. Lancet. 2007;369:1347–1355.
12. Kamran SI, Downey D, Ruff RL. Pneumatic sequential compression
reduces the risk of deep vein thrombosis in stroke patients. Neurology.
1998;50:1683–1688.
13. Warlow C, Ogston D, Douglas AS. Deep venous thrombosis of the legs
after strokes: part 2—natural history. BMJ. 1976;1:1181–1183.
14. Desmukh M, Bisignani M, Landau P, Orchard TJ. Deep vein thrombosis
in rehabilitating stroke patients. Incidence, risk factors and prophylaxis.
Am J Phys Med Rehabil. 1991;70:313–316.
KEY WORDS: antiplatelet agents  venous thromboembolism
2176 Stroke July 2008
 at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from 


The PREVAIL trial and low-molecular-weight heparin for prevention of venous thromboembolism

Crossref

The PREVAIL Trial and Low-Molecular-Weight Heparin for Prevention of Venous Thromboembolism

Enlighten

       Muir, K.W. (2008) The PREVAIL trial and low-molecular-weight heparin for prevention of venous thromboembolism. Stroke, 39 (7). pp. 2174-2176. ISSN 0039-2499  http://eprints.gla.ac.uk/17885/  Deposited on: 19 January 2012   Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Keith W. MuirVenous ThromboembolismThe PREVAIL Trial and Low-Molecular-Weight Heparin for Prevention ofISSN: 1524-4628 Copyright © 2008 American Heart Association. All rights reserved. Print ISSN: 0039-2499. OnlineStroke is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514doi: 10.1161/STROKEAHA.107.5095882008, 39:2174-2176: originally published online April 24, 2008Stroke  http://stroke.ahajournals.org/content/39/7/2174located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/reprintsReprints: Information about reprints can be found online at    journalpermissions@lww.com410-528-8550. E-mail: Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters   http://stroke.ahajournals.org//subscriptions/Subscriptions: Information about subscribing to Stroke is online at  at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from Section Editors: Marc Fisher, MD, and Kennedy Lees, MDThe PREVAIL Trial and Low-Molecular-Weight Heparinfor Prevention of Venous ThromboembolismKeith W. Muir, MD, FRCPPatients with stroke are at high risk for venous thrombo-embolism. Studies of the natural history in the era beforewidespread use of antiplatelet agents or physical preventivemeasures reported an incidence of deep vein thrombosis(DVT) of over 50% within the first days.1 A lower incidencemight be expected with more aggressive routine acute treat-ment, including early use of antiplatelet agents, early mobi-lization, and graduated compression stockings, but the com-bined control groups of randomized, controlled trials (RCTs)predominantly undertaken in the 1990s still reported anincidence of 37% when DVT was specifically sought.2 Olderstudies found the incidence of pulmonary embolism (PE)after stroke to be 10% to 20% and to account for up to 10%of all fatalities (including cases in ambulant patients).3 Incontrast, symptomatic PE is consistently rarely reported inRCTs in stroke, occurring in just 0.7% of randomizedsubjects in the control group of trials comparing heparinswith antiplatelet therapy.4 However, clinical recognition ofPE remains poor. Half of all PEs in one series presented assudden death.5 Clinically unrecognized PE is also common,with up to 50% of surgical patients with proximal DVThaving abnormal ventilation–perfusion lung scans.6 Even ifPE is rare, postthrombotic syndrome resulting from venousvalvular incompetence causes pain, swelling, and skinchanges, including varicose eczema, and may affect over20% of those with symptomatic DVT within 2 years.The effectiveness of low-dose unfractionated heparin forprevention of VTE was established in the late 1970s, pre-dominantly in surgical patients but also in stroke.7 Thesuperiority of low-molecular-weight (LMW) heparins overunfractionated heparin in other clinical settings has also beenestablished with advantages including more predictable doseeffects, easier administration, and less risk of thrombocyto-penia. Two previous RCTs comparing LMW heparin withantiplatelet therapy reported reduction in symptomatic VTEevents,8,9 and in a systematic review of 6 previous RCTs,LMW heparins or heparinoids were associated with greaterreduction in DVT or PE than unfractionated heparin (5000U twice a day in 5 of the 6 RCTs, only one of whichadjusted dose by coagulation parameters), with an OR of0.52 (95% CI: 0.56 to 0.79).10 Too few symptomatic PEsoccurred in any of the RCTs to be significant as an endpoint in itself, but odds were reduced with heparin com-pared with control. The PREVAIL trial,11 recently pub-lished by David Sherman and colleagues, adds consider-able further data to this question, randomizing 1762nonambulant patients with stroke.The PREVAIL investigators chose its primary end point tobe the incidence of VTE at day 14. Patients with ischemicstroke with leg weakness of at least 2 on the NationalInstitutes of Health Stroke Scale (NIHSS) were randomizedto receive either 5000 U unfractionated heparin twice a day orthe 40 mg of the LMW heparin enoxaparin daily startingwithin 48 hours of the event and continued for 10 days.Treatment allocation was not blinded, but the end points wereobjectively defined by routine venography (in 82% of sub-jects) and/or compression ultrasound in all subjects, andresults were independently reviewed blind to treatmentallocation.Not surprisingly, enoxaparin was associated with asignificant relative risk reduction in VTE events comparedwith unfractionated heparin of 43%, representing approx-imately 8 fewer events per 100 patients treated (numberneeded to treat for benefit: 13). Those with more severestrokes, defined in the trial as NIHSS score 14, weretwice as likely to have VTE but were also at higher risk ofbleeding complications, and the absolute risk among lesssevere strokes (NIHSS 14) in the enoxaparin groupremained high at 8.3%.The PREVAIL trial addressed a specific (and logical)end point of VTE, but has to be viewed on the backgroundof the failure of either unfractionated or LMW heparins ina number of RCTs to reduce the end points of death ordependence, or stroke recurrence, and the main trialpublication does not fully detail the results with respect tothese. The failure to find a benefit for these end points hasReceived on July 24, 2007; and accepted November 8, 2007.From the Division of Clinical Neurosciences, University of Glasgow, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK.Correspondence to Keith W. Muir, MD, FRCP, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, UK. E-mailk.muir@clinmed.gla.ac.uk(Stroke. 2008;39:2174-2176.)© 2008 American Heart Association, Inc.Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.107.5095882174Emerging Therapies at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from led many clinicians to avoid heparin in acute stroke infavor of antiplatelet therapy alone. Whether the findings ofPREVAIL should influence clinical practice depends on ajudgment regarding the clinical importance of VTE pre-vention in itself and an assessment of the safety of theinterventions.First, were the events prevented by enoxaparin treatmentin PREVAIL of clinical importance? The statistical differ-ence in VTE events in PREVAIL resulted from preventionof asymptomatic DVTs. Both PE (7 of 1335 in total[0.5%]) and symptomatic DVT (5 of 1335 [3.7%]) wererare, although there were fewer of both of these events inthe enoxaparin group (one PE and one symptomatic DVTversus 6 and 4, respectively, for unfractionated heparin).However, location of the clot rather than whether it causessymptoms is of greater importance, and enoxaparin wasassociated with significantly fewer proximal as well asdistal DVTs (relative risk: 0.47, 95% CI: 0.31 to 0.72).Assumptions about the small risk of isolated distal DVTare based on the natural history after hip or knee replace-ment surgery, where DVTs generally start in calf veins andonly approximately one in 6 progresses to involve proxi-mal veins.6 It is unknown whether the risk of extension ofdistal DVTs after stroke is the same, obvious differencesbeing rapid mobilization after orthopedic procedures withaccordingly reduced risk of incident DVT,6 in contrast tomore prolonged immobility in many patients with stroke.Measuring the final outcome at day 14 ensures bettercompleteness of follow-up, but this early time point willnot capture the full risk of VTE.Second, was treatment safe? Major bleeding complicationswere rare in PREVAIL with an incidence of just over 1%.Symptomatic intracerebral hemorrhage was documented in1% (4 of 877) of subjects in the enoxaparin group. A slightexcess of major extracranial bleeds with enoxaparin was seen(7 events compared with none in the unfractionated heparingroup), but there was no significant difference in eventsconsidered to represent “clinically important hemorrhage” (apost hoc definition including a composite of bleeding events).No differences in all-cause mortality were evident, and thetotal mortality rates (12% at day 90) were somewhat lowerthan previous studies would suggest should be expected giventhe trial population. These event rates were also on abackground of more than 90% of patients receiving antiplate-let therapies.The PREVAIL results indicate that LMW heparin indoses appropriate for VTE prophylaxis is reasonably safeeven when used acutely after moderately severe ischemicstroke and on a background of modern antiplatelet therapy.Any additional hazard over unfractionated heparin isgreatly outweighed by superior efficacy. Enoxaparin (orequivalent LMW heparin) should therefore replace unfrac-tionated heparin for VTE prevention after stroke.The more difficult issues are whether all patients requireVTE prophylaxis, when it should start, and for how longtreatment is necessary; PREVAIL does not answer theseissues completely.As noted, VTE is an important cause of morbidity andmortality after stroke and clinical recognition remains poor.The high incidence of VTE in PREVAIL (11% proximalDVT or PE within 14 days in the control arm) indicates thatmodern stroke unit care (presumably, but not explicitly,including early mobilization and mechanical VTE preventivetreatment in the trial) and antiplatelet therapy by themselvesare insufficient. It is also very difficult to identify a low-riskgroup within the PREVAIL population. Leg weakness pre-dominantly defines VTE risk after stroke,1,12 and subgroupanalyses identified no difference in benefit irrespective ofage, sex, stroke severity, or obesity. It seems unlikelytherefore that it will be possible to easily define a risk scorethat could target treatment any better than the trial entrycriteria achieved. So long as there is no significant increase inhazard, prevention of VTE is a worthwhile goal and preven-tive treatment for all who fulfill PREVAIL entry criteriashould be considered. The failure of heparins in general toreduce death or dependence, or stroke recurrence, is insuffi-cient reason not to consider treatment; many other interven-tions in stroke do not affect these end points and given its lowincidence, a very large trial indeed would be required forprevention of PE to be reflected in a significant reduction inall-cause mortality.Could the bleeding risks of heparin be reduced by laterintroduction of preventive treatment? PREVAIL begantreatment within 48 hours and on average just over 1 dayafter a stroke. Symptomatic intracerebral hemorrhage ratesare lower when heparin is started more than 24 hours afteronset compared with under 24 hours,2,8 and there was nodifference in observed benefit when the subgroups startingtreatment within, or after, 24 hours were compared. How-ever, most bleeding events were related to extracranialhemorrhage and whether this is also reduced by deferredtreatment is not known.PREVAIL trial treatment was mandated for only 10 daysand there are no data reported on interventions thereafter.The initial difference in VTE risk appears to have beenmaintained up to day 90, although beyond day 14, endpoint events were not routinely sought by investigation. Is10 days of treatment sufficient? Even if the majority ofDVTs start in the days immediately after the stroke,13 10%of patients develop a new DVT during rehabilitation.14Incident PE continues throughout the poststroke period, atleast up to 120 days.5 Continued prophylaxis so long asimmobility persists seems clinically logical, albeit notsupported by specific evidence. Studies on the long-termsafety and efficacy of LMW heparins would therefore bewelcome.The PREVAIL findings significantly advance the case forroutine use of prophylactic-dose LMW heparin in immobilepatients for VTE prevention after stroke. As is ever the casewith heparin, further questions remain to be addressed andthere is scope for further trials.DisclosuresNone.References1. Warlow C, Ogston D, Douglas AS. Deep venous thrombosis of the legsafter strokes. Part I—incidence and predisposing factors. BMJ. 1976;1:1178–1181.Muir PREVAIL Trial and LMWH to Prevent VTE 2175 at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from 2. Bath PM, Iddenden R, Bath FJ. Low-molecular-weight heparins andheparinoids in acute ischemic stroke: a meta-analysis of randomizedcontrolled trials. Stroke. 2000;31:1770–1778.3. Viitanen M, Winblad B, Asplund K. Autopsy-verified causes of deathafter stroke. Acta Med Scand. 1987;222:401–408.4. Berge E, Sandercock P. Anticoagulants versus antiplatelet agents foracute ischaemic stroke. Cochrane Database Syst Rev. 2002;4:CD003242.5. Wijdicks EF, Scott JP. Pulmonary embolism associated with acute stroke.Mayo Clin Proc. 1997;72:297–300.6. Kearon C. Natural history of venous thromboembolism. Circulation.2003;107:I22–I30.7. McCarthy ST, Turner JJ, Robertson D, Hawkey CJ, Macey DJ. Low-doseheparin as a prophylaxis against deep-vein thrombosis after acute stroke.Lancet. 1977;2:800–801.8. Bath PM, Lindenstrom E, Boysen G, De Deyn P, Friis P, Leys D, MarttilaR, Olsson J, O’Neill D, Orgogozo J, Ringelstein B, van der SJ, TurpieAG. Tinzaparin in Acute Ischaemic Stroke (TAIST): a randomisedaspirin-controlled trial. Lancet. 2001;358:702–710.9. Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weightheparin versus aspirin in patients with acute ischaemic stroke and atrialfibrillation: a double-blind randomised study. HAEST Study Group.Heparin in Acute Embolic Stroke Trial. Lancet. 2000;355:1205–1210.10. Sandercock P, Counsell C, Stobbs SL. Low-molecular-weight heparins orheparinoids versus standard unfractionated heparin for acute ischaemicstroke. Cochrane Database Syst Rev. 2005;2:CD000119.11. Sherman DG, Albers GW, Bladin C, Fieschi C, Gabbai AA, Kase CS,O’Riordan W, Pineo GF. The efficacy and safety of enoxaparin versusunfractionated heparin for the prevention of venous thromboembolismafter acute ischaemic stroke (PREVAIL study): an open-label randomisedcomparison. Lancet. 2007;369:1347–1355.12. Kamran SI, Downey D, Ruff RL. Pneumatic sequential compressionreduces the risk of deep vein thrombosis in stroke patients. Neurology.1998;50:1683–1688.13. Warlow C, Ogston D, Douglas AS. Deep venous thrombosis of the legsafter strokes: part 2—natural history. BMJ. 1976;1:1181–1183.14. Desmukh M, Bisignani M, Landau P, Orchard TJ. Deep vein thrombosisin rehabilitating stroke patients. Incidence, risk factors and prophylaxis.Am J Phys Med Rehabil. 1991;70:313–316.KEY WORDS: antiplatelet agents  venous thromboembolism2176 Stroke July 2008 at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from 

Anticoagulants versus antiplatelet agents for acute ischaemic stroke. Cochrane Database Syst Rev.

Autopsy-verified causes of death after stroke. Acta Med Scand.

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Deep venous thrombosis of the legs after strokes: part 2—natural history.

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The PREVAIL trial and low-molecular-weight heparin for prevention of venous thromboembolism

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