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

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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

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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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