Low‐molecular‐weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke

Peter AG Sandercock; Tze Shin Leong

doi:10.1002/14651858.CD000119.pub4

急性虚血性脳卒中に対する低分子量ヘパリンまたはヘパリノイドと標準的な未分画ヘパリンの比較

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Referencias

References to studies included in this review

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References to ongoing studies

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References to other published versions of this review

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estudios incluidos
estudios excluidos
estudios en curso
otras referencias

Counsell C, Sandercock P. Low‐molecular‐weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2001, Issue 4. [DOI: 10.1002/14651858.CD000119]

Sandercock P, Counsell C, Stobbs SL. Low‐molecular‐weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2005, Issue 2. [DOI: 10.1002/14651858.CD000119.pub2]

Sandercock PAG, Counsell C, Tseng M‐C. Low‐molecular‐weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2008, Issue 3. [DOI: 10.1002/14651858.CD000119.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos
estudios en curso

Dumas 1994

Methods	R = sequentially numbered identical containers Double blind ITT Number lost to FU: not stated
Participants	Europe 76 men, 103 women, mean age 72 years 100% CT before entry Ischaemic stroke with leg paresis Less than 72 hours since stroke onset
Interventions	Rx: Org 10172 sc (1250 anti‐Xa units 24‐hourly) Control: heparin sc (5000 IU 12‐hourly) Duration: 9 to 13 days
Outcomes	Death + cause of death DVT (systematic I¹²⁵ scan with venography) PE (symptomatic) Intracranial haemorrhage (systematic CT) Extracranial haemorrhage
Notes	Ex: BP greater than 200/120, bleeding risk FU: 3 months
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation not stated
Allocation concealment (selection bias)	Unclear risk	Sealed envelope, but no details provided
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Treatment and control arms both involved 2 x daily injections. Manuscript states "patients, physicians and hospital staff were unaware of treatment allocation"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Treatment and control arms both involved 2 x daily injections. Manuscript states "patients, physicians and hospital staff were unaware of treatment allocation"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Number lost to follow‐up not stated
Selective reporting (reporting bias)	Unclear risk	Study protocol not available, study report does not give full details of data collected during follow‐up

Hageluken 1992

Methods	R = sequentially numbered containers Single blind (assessor) ITT Number lost to FU: not stated
Participants	Europe 79 men, 66 women, mean age 69 years 100% CT before entry Ischaemic stroke with leg paresis Less than 72 hours since stroke onset
Interventions	Rx: Org 10172 sc (375 anti‐Xa units 24‐hourly); Org 10172 sc (750 anti‐Xa units 24‐hourly); Org 10172 sc (1250 anti‐Xa units 24‐hourly) Control: heparin sc (5000 IU 12‐hourly) Duration: 9 to 11 days
Outcomes	Death + cause of death DVT (systematic I¹²⁵ scan with venography) PE (symptomatic) Intracranial haemorrhage (systematic CT) Extracranial haemorrhage
Notes	Ex: BP greater than 200/120, bleeding risk FU: 3 months
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No details provided
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No details provided
Selective reporting (reporting bias)	Unclear risk	Study protocol not available, study report does not give full details of data collected during follow‐up

Hillbom 1998

Methods	R = sequentially numbered containers Double blind ITT No loss to FU
Participants	Finland 127 men, 85 women, mean age 69 years 100% CT before entry Ischaemic stroke with leg paresis for more than 24 hours since stroke onset
Interventions	Rx: enoxaparin (40 mg once daily) Control: heparin sc (5000 IU 8‐hourly) Duration: 10 ± 2 days or discharge if sooner
Outcomes	Death DVT (systematic venography) PE (symptomatic) Extracranial haemorrhage Intracranial haemorrhage (systematic CT)
Notes	Ex: specified by protocol ‐ includes bleeding risk; GCS < 9; pre‐existing DVT FU: 3 months Sponsoring pharmaceutical company stopped before planned sample size of 400 people recruited, because of very slow recruitment rate
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation schedule had a block size of 4 and was generated by computer programme AC/BIOM/STAT
Allocation concealment (selection bias)	Unclear risk	Method for the participating doctor to obtain the treatment allocation not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Experimental and control treatments supplied in prefilled syringes of identical appearance
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Steps to blind assessors not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	Manuscript states no patients lost to follow‐up
Selective reporting (reporting bias)	Unclear risk	Study protocol not available, study report does not give full details of data collected during follow‐up

PREVAIL 2007

Methods	R = blocked and stratified randomisation, telephone to central randomisation system Study treatment was not blinded ITT Follow up: not available for 32 (15 Rx, 17 control) either by withdrawal of consent or loss to FU
Participants	International 994 men, 768 women, mean age 66 years 100% CT or MRI before entry Ischaemic stroke and unable to walk unassisted < 48 hours since stroke onset NIHSS score 2 or more
Interventions	Rx: enoxaparin 40 mg sc once daily Control: heparin sc (5000 IU 12‐hourly) Duration: 10 days (range 6 to 14)
Outcomes	Death DVT (systematic venography or ultrasound if venography not possible) PE (symptomatic) Extracranial haemorrhage Intracranial haemorrhage (systematic CT) Modified Rankin Scale
Notes	Ex: specified by protocol FU: 90 days Sponsored by Sanofi‐Aventis (Paris, France)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The sponsor generated the randomisation schedule in permuted blocks of 4, stratified by baseline stroke severity that was implemented centrally by an independent interactive voice‐response system
Allocation concealment (selection bias)	Low risk	The randomisation schedule was implemented centrally by an independent interactive voice‐response system
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not blinded, but all major outcome events were reviewed blind to treatment allocation by an adjudication committee
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Primary outcome data not available for 32 participants, number with missing modified Rankin Scale status not stated
Selective reporting (reporting bias)	Low risk	Trial registered NCT00077805, protocol‐specified outcomes all reported

PROTECT 2006

Methods	R = computer‐generated randomisation list Double‐blind ITT Losses to follow up: 67 (34 Rx, 33 control)
Participants	European Union 313 men, 232 women, 18 to 85 years, mean age 67 years 100% CT before entry Ischaemic stroke with leg paresis Less than 24 hours since stroke onset NIHSS score 4 to 30
Interventions	Rx: certoparin sc (3000 U once daily) plus 2 injections of placebo Control: heparin sc (5000 IU 8‐hourly) Duration: 12 to 16 days
Outcomes	Death related to DVT Proximal leg DVT (ultrasound) PE (symptomatic) Extracranial haemorrhage Intracranial haemorrhage (systematic CT)
Notes	Ex: specified by protocol ‐ includes bleeding risk, body weight < 55 kg FU: 3 months Sponsored by Novartis (Nürnberg, Germany)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random sequence generated by computer
Allocation concealment (selection bias)	Low risk	Manuscript states "Treatment allocation kept strictly confidential and available only to authorised persons"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Experimental and control treatments identical in appearance
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Experimental and control treatments identical in appearance
Incomplete outcome data (attrition bias) All outcomes	High risk	64 (10%) participants lost to follow‐up
Selective reporting (reporting bias)	Unclear risk	Study protocol not available, study report does not give full details of data collected during follow‐up

Stiekema 1988

Methods	R = sequentially numbered containers Single blind (assessor) Loss to follow‐up not stated
Participants	Europe 43 men, 39 women, 21 to 91 years 100% CT before entry Ischaemic stroke with leg paresis Less than 72 hours since stroke
Interventions	Rx: loading dose 1000 anti‐Xa units iv, then Org 10172 sc (1250 anti‐Xa units 12‐hourly) or Org 10172 sc (750 anti‐Xa units 12‐hourly) Control: heparin sc (5000 IU 12‐hourly) Duration: 10 days
Outcomes	Death + cause of death DVT (systematic I¹²⁵ scan with venography) PE (symptomatic) Intracranial haemorrhage (systematic CT) Extracranial haemorrhage
Notes	Ex: BP > 200/120, bleeding risk FU: 14 days
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Report to company describes this as an open trial, published abstract states double blind
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	Loss to follow‐up not stated
Selective reporting (reporting bias)	Unclear risk	Study protocol not available, study report does not give full details of data collected during follow‐up

TRACE 2004

Methods	R = not described Unblinded ITT Losses to follow up: not stated
Participants	Germany Caucasian, 57 men, 33 women, mean age 68 years 100% CT or MRI before entry Ischaemic stroke less than 24 hours since stroke onset
Interventions	Rx: enoxaparin 1 mg/kg sc twice daily (100 Anti‐Xa units 12‐hourly) Control: heparin iv (initial bolus of 80 IU/kg, followed by 18 IU/kg/h) Duration: 8 ± 2 days
Outcomes	Death Reduction in microembolic signals compared with baseline on day 2 and 5 (TCD verified) Cerebral ischaemic events, systemic embolic events, and bleeding complications Barthel Index
Notes	Ex: specified by protocol ‐ includes bleeding risk, severe organic cerebral disease FU: 3 months
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not stated
Selective reporting (reporting bias)	Unclear risk	Study protocol not available, study report does not give full details of data collected during follow‐up

Turpie 1992

Methods	R = sequentially numbered identical containers Double blind ITT No loss to FU
Participants	Canada 38 men, 49 women, mean age 72 years 100% CT before entry Non‐embolic ischaemic stroke with leg paresis Les than 7 days since stroke onset
Interventions	Rx: Org 10172 sc (750 anti‐Xa units 12‐hourly) Control: heparin sc (5000 IU 12‐hourly) Duration: 14 days
Outcomes	Death DVT (systematic I¹²⁵ scan + plethysmography with venography) PE (symptomatic) Intracranial haemorrhage (systematic CT)
Notes	Ex: bleeding risk; pre‐existing DVT FU: 3 months
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation not stated
Allocation concealment (selection bias)	Unclear risk	Method for concealment not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participamts, trial nurses, and physicians were all unaware of treatment allocation
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participamts, trial nurses, and physicians were all unaware of treatment allocation
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow‐up
Selective reporting (reporting bias)	Unclear risk	Study protocol not available, study report does not give full details of data collected during follow‐up

Wong 2000

Methods	R = not stated Single blind (CT scans only) Loss to follow‐up not stated
Participants	Taiwan 35 participants 2 groups had similar baseline characteristics 100% CT before entry Increase in severity or number of neurological symptoms less than 48 hours since stroke onset GCS decrease more than 2 points, limb weakness, onset of new neurological symptoms
Interventions	Rx: unspecified LMWH sc (0.4 mL 4100 anti‐Xa IU twice daily) Control: heparin (5000 IU bolus, then 15,000 IU/day for 24 hours, then dose adjusted to maintain APTT ratio at 1.5 to 2) Duration: 10 days
Outcomes	Haemorrhagic transformation (systematic CT on day 10 or symptomatic before day 10) Barthel Index
Notes	Ex: progression due to brain oedema or intracranial haemorrhage FU: 28 days
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	not stated
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not stated
Selective reporting (reporting bias)	Unclear risk	Study protocol not available, study report does not give full details of data collected during follow‐up

APTT: activated partial thromboplastin time
BP: blood pressure
CT: computerised tomography
DVT: deep venous thrombosis
Ex: exclusion criteria
FU: follow up
GCS: Glasgow coma scale
ITT: intention‐to‐treat
iv: intravenously
LMWH: low‐molecular‐weight heparin
MRI: magnetic resonance imaging
mRS: ???
NIHSS: National Institutes of Health stroke Scale
PE: pulmonary embolism
R: randomisation method
Rx: treatment
sc: subcutaneously
TCD: transcranial doppler

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos
estudios en curso

Study	Reason for exclusion
Assadian 2008	Target participants were not people with acute ischaemic stroke
Dunatov 2008	Intervention did not include unfractionated heparin
EMSG 1996	Enoxaparin 20 mg subcutaneously once daily versus standard unfractionated heparin 5000 IU subcutaneously twice daily for 10 days in immobile people (38 strokes) Data on subset of participants with stroke are still awaited from sponsor
EUROTOAST 1996	Comparison of different doses of heparinoid, no UFH group
EXCLAIM 2010	Target participants were not people with acute ischaemic stroke
Feiz 2016	2 treatment groups confounded by co‐administration of different warfarin regimens
Geng 2004	Intervention did not include UFH
Harenberg 1999	Enoxaparin versus heparin for prophylaxis of thromboembolic events in people with medical conditions Data have not been reported separately for people with stroke alone
Heparinas 2013	Ongoing trial of heparin versus nadroparin versus placebo. Complex confounded regimens
HESIM 1990	About 150 (19%) participants had neurological disease Data have not been reported separately for people with stroke alone Some data may be the same as those reported in Harenberg 1999
IRCT201109067495N1	Comparison of LMWH with aspirin instead of UFH
MAGELLAN 2013	Intervention did not include UFH
McCarthy 1993	Data have not been reported
Mikulik 2006	Intervention did not include UFH
Moulin 1994	Enoxaparin/CY216 versus standard UFH The trial was closed prematurely due to funding constraints Data have not been reported
NCT01763606	Target participants were not people with acute ischaemic stroke
Necioglu Orken 2009	Intervention did not include UFH
Nikc Evic 2006	Not acute stroke, method of treatment allocation not random
Szirmai 1986	Uncontrolled study
Tan 2002	Published in China and only available as an abstract. Attempted to contact authors as well as seek help from colleagues from China to obtain the full text article but to no avail
Trencev 2008	Intervention did not include UFH
Trouillas 2008	Intervention did not include LMWH
Wang 2012	Published in China and only available as an abstract. Attempted to contact authors as well as seek help from colleagues from China to obtain the full text article but to no avail
Xing 2006	Intervention did not include UFH

LMWH: low‐molecular‐weight heparin
UFH: unfractionated heparin

Characteristics of ongoing studies [ordered by study ID]

Ir a:

estudios incluidos
estudios excluidos

Aventis 2002

Trial name or title	An open‐label, randomised, parallel group, multicentre study to evaluate the efficacy and safety of enoxaparin versus unfractionated heparin in the prevention of venous thromboembolism in people following acute ischaemic stroke
Methods
Participants
Interventions
Outcomes
Starting date
Contact information	Ms S Wellington, Senior Clinical Project Leader, Aventis Pharma, Aventis House, 50 Kings Hill Avenue, Kings Hill, West Malling, Kent, UK
Notes

Young 2001

Trial name or title	Low‐molecular‐weight heparin (enoxaparin) in anticoagulation transition to oral warfarin in ischaemic cerebral vascular accident or transient ischaemic attack
Methods
Participants	Acute ischaemic stroke
Interventions	Enoxaparin sc + oral warfarin versus UFH sc + oral warfarin
Outcomes
Starting date
Contact information	Dr WD Young, North Mississippi Medical Centre, 830 S Gloster Street, Tupelo MS 38801, USA
Notes

sc: subcutaneously
UFH: unfractionated heparin

Data and analyses

Open in table viewer

Comparison 1. LMWH/heparinoid versus standard UFH in acute ischaemic stroke

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Dead or dependent at the end of follow‐up	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Death from all causes during treatment period Show forest plot	8	3102	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.06 [0.78, 1.46]
Open in figure viewer Analysis 1.2 Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 2 Death from all causes during treatment period.
2.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.19 [0.62, 2.26]
2.2 LMWH versus standard UFH	4	2609	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.03 [0.72, 1.47]
3 Death from all causes during follow‐up Show forest plot	8	3102	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.98 [0.79, 1.23]
Open in figure viewer Analysis 1.3 Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 3 Death from all causes during follow‐up.
3.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.16 [0.69, 1.94]
3.2 LMWH versus standard UFH	4	2609	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.95 [0.74, 1.21]
4 Vascular death during follow‐up Show forest plot	5	1038	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.15 [0.72, 1.85]
Open in figure viewer Analysis 1.4 Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 4 Vascular death during follow‐up.
4.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.15 [0.68, 1.94]
4.2 LMWH versus standard UFH	1	545	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.17 [0.39, 3.53]
5 Deep venous thrombosis during treatment period Show forest plot	7	2585	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.55 [0.44, 0.70]
Open in figure viewer Analysis 1.5 Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 5 Deep venous thrombosis during treatment period.
5.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.52 [0.31, 0.86]
5.2 LMWH versus standard UFH	3	2092	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.56 [0.44, 0.73]
6 Pulmonary embolism during follow‐up Show forest plot	6	1250	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.57 [0.23, 1.41]
Open in figure viewer Analysis 1.6 Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 6 Pulmonary embolism during follow‐up.
6.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.64 [0.18, 2.21]
6.2 LMWH versus standard UFH	2	757	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.51 [0.13, 1.90]
7 Any intracranial haemorrhage/haemorrhagic transformation of the cerebral infarct during treatment period Show forest plot	9	3137	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.75 [0.46, 1.23]
Open in figure viewer Analysis 1.7 Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 7 Any intracranial haemorrhage/haemorrhagic transformation of the cerebral infarct during treatment period.
7.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.12 [0.43, 2.94]
7.2 LMWH versus standard UFH	5	2644	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.66 [0.37, 1.15]
8 Symptomatic intracranial haemorrhage/haemorrhagic transformation of the infarct during treatment period Show forest plot	8	3102	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.73 [0.35, 1.54]
Open in figure viewer Analysis 1.8 Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 8 Symptomatic intracranial haemorrhage/haemorrhagic transformation of the infarct during treatment period.
8.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.90 [0.19, 4.40]
8.2 LMWH versus standard UFH	4	2609	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.69 [0.30, 1.60]
9 Extracranial haemorrhage during treatment period Show forest plot	7		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.9 Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 9 Extracranial haemorrhage during treatment period.
9.1 Major extracranial haemorrhage	7	3012	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.79 [1.30, 11.06]
9.2 Minor extracranial haemorrhage	7	3012	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.91 [0.67, 1.24]
10 Effect of recurrent ischaemic stroke or recurrent stroke of unknown pathological type during treatment period Show forest plot	2	1839	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.94 [0.61, 6.11]
Open in figure viewer Analysis 1.10 Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 10 Effect of recurrent ischaemic stroke or recurrent stroke of unknown pathological type during treatment period.
10.1 LMWH versus UFH	2	1839	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.94 [0.61, 6.11]
11 Deep venous thrombosis according to heparinoid dosage regimen Show forest plot	4		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.11 Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 11 Deep venous thrombosis according to heparinoid dosage regimen.
11.1 350 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	1	60	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.11 [0.67, 6.59]
11.2 750 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	1	72	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.54 [0.14, 2.14]
11.3 1250 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	2	246	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.63 [0.32, 1.26]
11.4 750 anti‐Xa units 12‐hourly versus 5000 IU UFH 12‐hourly	2	140	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.30 [0.13, 0.71]
11.5 1250 anti‐Xa units 12‐hourly versus 5000 IU UFH 12‐hourly	1	55	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.06, 1.23]
12 Intracranial and extracranial haemorrhage during treatment according to dosage regimen Show forest plot	4		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.12 Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 12 Intracranial and extracranial haemorrhage during treatment according to dosage regimen.
12.1 350 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	1	60	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.29 [0.45, 3.68]
12.2 750 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	1	72	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.90 [0.33, 2.50]
12.3 1250 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	2	246	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.69 [0.38, 1.25]
12.4 750 anti‐Xa units 12‐hourly versus 5000 IU UFH 12‐hourly	2	138	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.73 [1.03, 7.24]
12.5 1250 anti‐Xa units 12‐hourly versus 5000 IU UFH 12‐hourly	1	53	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.71 [0.31, 9.25]

Figure 1

PRISMA flow diagram

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Funnel plot of comparison: 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, outcome: death from all causes during treatment period

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Figure 5

Funnel plot of comparison: 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, outcome: death from all causes during follow‐up

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Analysis 1.2

Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 2 Death from all causes during treatment period.

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Analysis 1.3

Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 3 Death from all causes during follow‐up.

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Analysis 1.4

Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 4 Vascular death during follow‐up.

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Analysis 1.5

Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 5 Deep venous thrombosis during treatment period.

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Analysis 1.6

Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 6 Pulmonary embolism during follow‐up.

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Analysis 1.7

Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 7 Any intracranial haemorrhage/haemorrhagic transformation of the cerebral infarct during treatment period.

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Analysis 1.8

Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 8 Symptomatic intracranial haemorrhage/haemorrhagic transformation of the infarct during treatment period.

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Analysis 1.9

Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 9 Extracranial haemorrhage during treatment period.

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Analysis 1.10

Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 10 Effect of recurrent ischaemic stroke or recurrent stroke of unknown pathological type during treatment period.

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Analysis 1.11

Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 11 Deep venous thrombosis according to heparinoid dosage regimen.

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Analysis 1.12

Comparison 1 LMWH/heparinoid versus standard UFH in acute ischaemic stroke, Outcome 12 Intracranial and extracranial haemorrhage during treatment according to dosage regimen.

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Summary of findings for the main comparison. Low‐molecular‐weight heparins or heparinoids compared with unfractionated heparin for acute ischaemic stroke

Low‐molecular‐weight heparins (LMWH) or heparinoids compared with unfractionated heparin (UFH) for acute ischaemic stroke
Patient or population: acute ischaemic stroke Setting: patients admitted to hospital with stroke of sufficient severity to cause immobility Intervention: LMWH/heparinoids Comparison: UFH
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with UFH	Risk with LMWH/heparinoids
Death from all causes during treatment (range 6 days to 16 days)	Moderate risk population		OR 1.06 (0.78 to 1.46)	3102 (8 RCTs)	⊕⊕⊝⊝ LOW¹ ²
	90 per 1000³	95 per 1000 (72 to 126)
	High risk population
	131 per 1000⁴	138 per 1000 (105 to 180)
Death from all causes during follow up (range 2 weeks to 12 weeks)	Moderate risk population		OR 0.98 (0.79 to 1.23)	3102 (8 RCTs)	⊕⊕⊝⊝ LOW¹ ²
	225 per 1000³	221 per 1000 (187 to 263)
	High risk population
	251 per 1000⁴	247 per 1000 (209 to 292)
Deep vein thrombosis during treatment period (range 6 days to 16 days)	Moderate risk population		OR 0.55 (0.44 to 0.70)	2585 (7 RCTs)	⊕⊕⊝⊝ LOW¹ ⁵
	189 per 1000⁶	114 per 1000 (93 to 140)
	High risk population
	211 per 1000⁴	128 per 1000 (105 to 158)
Pulmonary embolism during treatment period (range 6 days to 16 days)	Moderate		OR 0.57 (0.23 to 1.41)	1250 (6 RCTs)	⊕⊕⊝⊝ LOW¹ ⁷
	5 per 1000³	3 per 1000 (1 to 7)
	High risk population
	24 per 1000⁴	14 per 1000 (6 to 34)
Symptomatic intracranial haemorrhage/haemorrhagic transformation of the cerebral infarct during treatment period (range 6 days to 16 days)⁹	Moderate risk population		OR 0.73 (0.35 to 1.54)	3102 (8 RCTs)	⊕⊕⊝⊝ LOW¹ ⁸
	12 per 1000³	9 per 1000 (4 to 18)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; RCT: randomised controlled trial; LWMH: low‐molecular‐weight heparin; UFH: unfractionated heparin
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ There were unclear risk of selection bias in Hageluken 1992, Dumas 1994, Stiekema 1988, TRACE 2004, Turpie 1992 and Wong 2000. Hageluken 1992 and Stiekema 1988 were single blinded studies; PREVAIL 2007 was an open label study. Hence, making all these study high risk of performance and detection bias (downgraded 1 level). ² Small number of deaths were recorded throughout studies (downgraded 1 level). ³ Calculated based on control event rate from IST 1997 where based on the inclusion criteria, it was interpreted that people are of average risk (hence, they are classified as 'moderate risk population') of developing complications such as deep vein thrombosis (DVT), pulmonary embolism (PE), cranial haemorrhages etc. that resulted in death or disability. ⁴ Calculated based on control event rate from CLOTS3 2015 trial where based on the inclusion criteria, people are of high risk (hence they are classified as 'high risk population') of developing complications such as DVT, PE, cranial haemorrhages that resulted in death or disability. ⁵ Methods of detection of detection of DVT were variable across the studies (downgraded 1 level). ⁶ Calculated based on mean baseline risk from the studies of this Cochrane Review because IST 1997 did not include this outcome data. ⁷ Small number of PEs across the studies. ⁸ Small number of symptomatic intracranial haemorrhage across studies. ⁹ High risk population not available as CLOTS3 2015 trial did not include this outcome data.

Summary of findings for the main comparison. Low‐molecular‐weight heparins or heparinoids compared with unfractionated heparin for acute ischaemic stroke

Ir a la tabla de la revisión

Comparison 1. LMWH/heparinoid versus standard UFH in acute ischaemic stroke

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Dead or dependent at the end of follow‐up	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Death from all causes during treatment period Show forest plot	8	3102	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.06 [0.78, 1.46]

2.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.19 [0.62, 2.26]
2.2 LMWH versus standard UFH	4	2609	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.03 [0.72, 1.47]
3 Death from all causes during follow‐up Show forest plot	8	3102	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.98 [0.79, 1.23]

3.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.16 [0.69, 1.94]
3.2 LMWH versus standard UFH	4	2609	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.95 [0.74, 1.21]
4 Vascular death during follow‐up Show forest plot	5	1038	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.15 [0.72, 1.85]

4.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.15 [0.68, 1.94]
4.2 LMWH versus standard UFH	1	545	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.17 [0.39, 3.53]
5 Deep venous thrombosis during treatment period Show forest plot	7	2585	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.55 [0.44, 0.70]

5.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.52 [0.31, 0.86]
5.2 LMWH versus standard UFH	3	2092	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.56 [0.44, 0.73]
6 Pulmonary embolism during follow‐up Show forest plot	6	1250	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.57 [0.23, 1.41]

6.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.64 [0.18, 2.21]
6.2 LMWH versus standard UFH	2	757	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.51 [0.13, 1.90]
7 Any intracranial haemorrhage/haemorrhagic transformation of the cerebral infarct during treatment period Show forest plot	9	3137	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.75 [0.46, 1.23]

7.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.12 [0.43, 2.94]
7.2 LMWH versus standard UFH	5	2644	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.66 [0.37, 1.15]
8 Symptomatic intracranial haemorrhage/haemorrhagic transformation of the infarct during treatment period Show forest plot	8	3102	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.73 [0.35, 1.54]

8.1 Heparinoid versus standard UFH	4	493	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.90 [0.19, 4.40]
8.2 LMWH versus standard UFH	4	2609	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.69 [0.30, 1.60]
9 Extracranial haemorrhage during treatment period Show forest plot	7		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

9.1 Major extracranial haemorrhage	7	3012	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.79 [1.30, 11.06]
9.2 Minor extracranial haemorrhage	7	3012	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.91 [0.67, 1.24]
10 Effect of recurrent ischaemic stroke or recurrent stroke of unknown pathological type during treatment period Show forest plot	2	1839	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.94 [0.61, 6.11]

10.1 LMWH versus UFH	2	1839	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.94 [0.61, 6.11]
11 Deep venous thrombosis according to heparinoid dosage regimen Show forest plot	4		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

11.1 350 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	1	60	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.11 [0.67, 6.59]
11.2 750 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	1	72	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.54 [0.14, 2.14]
11.3 1250 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	2	246	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.63 [0.32, 1.26]
11.4 750 anti‐Xa units 12‐hourly versus 5000 IU UFH 12‐hourly	2	140	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.30 [0.13, 0.71]
11.5 1250 anti‐Xa units 12‐hourly versus 5000 IU UFH 12‐hourly	1	55	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.06, 1.23]
12 Intracranial and extracranial haemorrhage during treatment according to dosage regimen Show forest plot	4		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

12.1 350 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	1	60	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.29 [0.45, 3.68]
12.2 750 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	1	72	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.90 [0.33, 2.50]
12.3 1250 anti‐Xa units 24‐hourly versus 5000 IU UFH 12‐hourly	2	246	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.69 [0.38, 1.25]
12.4 750 anti‐Xa units 12‐hourly versus 5000 IU UFH 12‐hourly	2	138	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.73 [1.03, 7.24]
12.5 1250 anti‐Xa units 12‐hourly versus 5000 IU UFH 12‐hourly	1	53	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.71 [0.31, 9.25]

Comparison 1. LMWH/heparinoid versus standard UFH in acute ischaemic stroke

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Referencias

References to studies included in this review

Dumas 1994 {published and unpublished data}

Hageluken 1992 {unpublished data only}

Hillbom 1998 {published and unpublished data}

PREVAIL 2007 {published data only}

PROTECT 2006 {published data only}

Stiekema 1988 {published and unpublished data}

TRACE 2004 {published data only}

Turpie 1992 {published and unpublished data}

Wong 2000 {published and unpublished data}

References to studies excluded from this review

Assadian 2008 {published data only}

Dunatov 2008 {published and unpublished data}

EMSG 1996 {published data only}

EUROTOAST 1996 {published data only (unpublished sought but not used)}

EXCLAIM 2010 {published data only}

Feiz 2016 {published data only}

Geng 2004 {published data only}

Harenberg 1999 {published data only}

Heparinas 2013 {published data only}

HESIM 1990 {published data only}

IRCT201109067495N1 {published and unpublished data}

MAGELLAN 2013 {published data only}

McCarthy 1993 {unpublished data only}

Mikulik 2006 {published data only}

Moulin 1994 {unpublished data only}

NCT01763606 {published and unpublished data}

Necioglu Orken 2009 {published data only}

Nikc Evic 2006 {published data only}

Szirmai 1986 {unpublished data only}

Tan 2002 {published data only}

Trencev 2008 {published data only}

Trouillas 2008 {published data only}

Wang 2012 {published data only}

Xing 2006 {published data only}

References to ongoing studies

Aventis 2002 {unpublished data only}

Young 2001 {unpublished data only}

Additional references

Amin 2013

Bath 2000

Caplan 2009

Cella 1986

Choay 1989

Chung 2016

CLOTS3 2015

Cruickshank 1991

Garcia 2012

Gordon 1990

Gubitz 2004

Higgins 2011

Holbrook 2012

IST 1997

Lederle 2011

Lozano 2012

Meuleman 1992

Odgaard‐Jensen 2011

RevMan 2014 [Computer program]

Sandercock 1993

Sandercock 2014

Sandercock 2015

Shorr 2008

TOAST 1998

Warlow 2008

Weitz 1997

References to other published versions of this review

Counsell 2001

Sandercock 2005

Sandercock 2008

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Data and analyses

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