Remote ischaemic conditioning for preventing and treating ischaemic stroke

Wenbo Zhao; Jing Zhang; Mordechai G Sadowsky; Ran Meng; Yuchuan Ding; Xunming Ji

doi:10.1002/14651858.CD012503.pub2

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Figure 1

Study 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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Analysis 1.1

Comparison 1 RIC versus non‐RIC for preventing ischaemic stroke, Outcome 1 Ischaemic stroke or recurrent ischaemic stroke at completion of follow‐up.

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Analysis 1.2

Comparison 1 RIC versus non‐RIC for preventing ischaemic stroke, Outcome 2 Death or dependency at completion of follow‐up.

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Analysis 1.3

Comparison 1 RIC versus non‐RIC for preventing ischaemic stroke, Outcome 3 Stroke severity.

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Analysis 1.6

Comparison 1 RIC versus non‐RIC for preventing ischaemic stroke, Outcome 6 Cardiovascular events.

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Analysis 1.8

Comparison 1 RIC versus non‐RIC for preventing ischaemic stroke, Outcome 8 Adverse events associated with RIC treatment.

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Analysis 2.2

Comparison 2 RIC versus non‐RIC treating ischaemic stroke, Outcome 2 Death or dependency at the completion of follow up.

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Analysis 2.3

Comparison 2 RIC versus non‐RIC treating ischaemic stroke, Outcome 3 Stroke severity.

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Analysis 2.5

Comparison 2 RIC versus non‐RIC treating ischaemic stroke, Outcome 5 Improvement in psychological and cognitive impairment at completion of follow‐up.

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Summary of findings for the main comparison. RIC versus non‐RIC for preventing ischaemic stroke

RIC versus non‐RIC for preventing ischaemic stroke
Patient or population: people at risk for ischaemic stroke Setting: clinic and inpatient Intervention: RIC Comparison: non‐RIC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with non‐RIC for preventing ischaemic stroke	Risk with RIC
Ischaemic stroke or recurrent ischaemic stroke	Symptomatic intracerebral artery stenosis or carotid stenting		RR 0.31 (0.12 to 0.76)	371 (3 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}
	92 per 1000	29 per 1000 (11 to 70)
Death or dependency	Symptomatic intracerebral artery stenosis or carotid stenting		not estimable	292 (2 RCTs)	‐
	0 per 1000	0 per 1000 (0 to 0)
Improvement in neurological impairment ‐ not reported	‐	‐	‐	‐	‐
Improvement in psychological and cognitive impairment ‐ not measured	‐	‐	‐	‐	‐
Cardiovascular events ‐ not reported	‐	‐	‐	‐	‐
Adverse events associated with RIC treatment	Symptomatic intracerebral artery stenosis or carotid stenting		RR 10.91 (2.01 to 59.28)	371 (3 RCTs)	⊕⊕⊝⊝ LOW ^{1 3}
	0 per 1000	0 per 1000 (0 to 0)
Stroke severity	‐	MD 0.17 lower (0.23 lower to 0.11 lower)	‐	189 (1 study)	⊕⊕⊝⊝ LOW ^{4 5}
*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; RIC: remote ischaemic conditioning; RCT: randomised controlled trial;
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: 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 certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgrade by two levels because of very serious risk of bias and serious imprecision. Very serious risk of bias resulted from: participants were not blinded to the treatment protocol in Meng 2012 and Zhao 2017; Meng 2012 and Meng 2015 used per‐protocol analysis methods; the corresponding author was one of the inventor of the RIC devices used in the studies; and there was large number of participants lost to follow up during the study period. ² Serious imprecision. Incidence of ischaemic stroke was very lower in Zhao 2017, and the CI for ischaemic stroke was wide. ³ Serious imprecision. Incidence of RIC‐associated adverse events were very lower, and the CI for this outcome was very wide. ⁴ Downgrade by two levels because of serious risk of bias and serious indirectness. Very serious risk of bias results from: participants were not blinded to the treatment protocol; the corresponding author was one of the inventor of the RIC devices used; and there was large number of participants lost to follow up during the study period in Zhao 2017. ⁵ Serious indirectness. The infarct volume was used as a surrogate endpoint to assess stroke severity in Zhao 2017.

Summary of findings for the main comparison. RIC versus non‐RIC for preventing ischaemic stroke

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Summary of findings 2. RIC versus non‐RIC treating ischaemic stroke

RIC versus non‐RIC for treating ischaemic stroke
Patient or population: people with ischaemic stroke Setting: emergency, clinic and inpatient Intervention: RIC Comparison: non‐RIC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with non‐RIC treating ischaemic stroke	Risk with RIC	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Ischaemic stroke or recurrent ischaemic stroke at completion of follow‐up ‐ not measured	‐	‐	‐	‐	‐
Death or dependency	Acute ischaemic stroke treated with intravenous thrombolysis		RR 2.34 (1.19 to 4.61)	285 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}
Death or dependency	80 per 1000	187 per 1000 (95 to 369)	RR 2.34 (1.19 to 4.61)	285 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}
Improvement in neurological impairment ‐ not measured	‐	‐	‐	‐	‐
Improvement in psychological and cognitive impairment at completion of follow‐up	The mean psychological function was 55.4 points and the mean cognitive function was 27.08 points.	SMD 0.29 lower (0.68 lower to 0.11 higher)	‐	105 (3 RCTs)	⊕⊕⊝⊝ LOW ^{3 4}
Cardiovascular events ‐ not reported	‐	‐	‐	‐	‐
Adverse events associated with RIC treatment ‐ not reported	‐	‐	‐	‐	‐
Stroke severity	‐	SMD 0.24 lower (1.02 lower to 0.54 higher)	‐	175 (2 study)	⊕⊝⊝⊝ VERY LOW ^{4 5 6}
*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; RIC: remote ischaemic conditioning; SMD: standardised mean difference; RCT: randomised controlled trial;
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: 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 certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgrade two levels by very serious risk of bias and serious imprecision. High risk of bias resulted from the unclear of allocation concealment, the unblinded treatment protocol to the participants, and large number of participants lost to follow up during the study period in Hougaard 2014. ² Serious imprecision. There was a large number of participants excluded from the study after randomising in Hougaard 2014. ³ Downgrade two levels by very serious risk of bias and serious inconsistency. Very serious risk of bias resulted from the unclear of allocation concealment and high risk of other bias in Mi 2016 and Wang 2017, only a small number of participant were included for this outcome, and the corresponding author was one of the inventors of the RIC devices used in Mi 2016 and Wang 2017. ⁴ Serious inconsistency. We detected high level of the heterogeneity for the cognitive impairment. ⁵ Downgrade two levels by very serious risk of bias, serious inconsistency and serious indirectness. High risk of bias resulted from the unclear of allocation concealment, the unblinded treatment protocol to the participants, and large number of participants lost to follow up during the study period in Hougaard 2014; and the small number of participants in England 2016. ⁶ Serious indirectness. The infarct volume was used as a surrogate endpoint to assess stroke severity in Hougaard 2014.

Summary of findings 2. RIC versus non‐RIC treating ischaemic stroke

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Comparison 1. RIC versus non‐RIC for preventing ischaemic stroke

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Ischaemic stroke or recurrent ischaemic stroke at completion of follow‐up Show forest plot	3	371	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.12, 0.76]

1.1 Ischaemic stroke	1	189	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.01, 4.03]
1.2 Recurrent ischaemic stroke	2	182	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.12, 0.83]
2 Death or dependency at completion of follow‐up Show forest plot	2	292	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

2.1 Death	2	292	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Dependency	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Stroke severity Show forest plot	1	189	Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.23, ‐0.11]

3.1 RIC vs sham control	1	94	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.22, ‐0.08]
3.2 RIC vs blank control	1	95	Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.30, ‐0.12]
4 Improvement in neurological impairment	0		Mean Difference (IV, Random, 95% CI)	Totals not selected
5 Improvement in psychological and cognitive impairment at completion of follow‐up	0		Mean Difference (IV, Random, 95% CI)	Totals not selected
6 Cardiovascular events Show forest plot	2	292	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

6.1 RIC vs sham control	1	94	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.2 RIC vs blank control	2	198	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Haemorrhagic stroke	0		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8 Adverse events associated with RIC treatment Show forest plot	3	371	Risk Ratio (M‐H, Random, 95% CI)	10.91 [2.01, 59.28]

8.1 RIC vs sham control	2	173	Risk Ratio (M‐H, Random, 95% CI)	9.78 [1.23, 77.71]
8.2 RIC vs blank control	2	198	Risk Ratio (M‐H, Random, 95% CI)	13.58 [0.72, 255.07]

Comparison 1. RIC versus non‐RIC for preventing ischaemic stroke

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Comparison 2. RIC versus non‐RIC treating ischaemic stroke

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Ischaemic stroke or recurrent ischaemic stroke at completion of follow‐up	0		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Death or dependency at the completion of follow up Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3 Stroke severity Show forest plot	2	175	Std. Mean Difference (IV, Random, 95% CI)	‐0.24 [‐1.02, 0.54]

3.1 NIHSS scores	1	26	Std. Mean Difference (IV, Random, 95% CI)	‐0.73 [‐1.53, 0.07]
3.2 Infarct volume	1	149	Std. Mean Difference (IV, Random, 95% CI)	0.08 [‐0.24, 0.41]
4 Improvement in neurological impairment	0		Mean Difference (IV, Random, 95% CI)	Totals not selected
5 Improvement in psychological and cognitive impairment at completion of follow‐up Show forest plot	3	105	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.29 [‐0.68, 0.11]

5.1 Psychological impairment	1	26	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.37 [‐1.15, 0.41]
5.2 Cognitive impairment	3	79	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.26 [‐0.72, 0.21]
6 Cardiovascular events	0		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
7 Hemorrhagic stroke	0		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8 Adverse events associated with RIC treatment	0		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 2. RIC versus non‐RIC treating ischaemic stroke

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