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

Cochrane Database of Systematic Reviews

Condicionamiento isquémico remoto para la prevención y el tratamiento del accidente cerebrovascular isquémico

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DOI:

https://doi.org/10.1002/14651858.CD012503.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

05 julio 2018see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Accidentes cerebrovasculares

Copyright:

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Wenbo Zhao

Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
Jing Zhang

Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
Mordechai G Sadowsky

Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan, USA
Ran Meng

Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
Yuchuan Ding

Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan, USA
Xunming Ji

Correspondencia a: Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China

[email protected]

Contributions of authors

WBZ and JZ assessed all trials for eligibility, extracted data, and assessed the risk of bias. RM performed literature searches of the Chinese language studies. MGS helped with the related trials selection and looked for the full texts. YCD and XMJ drafted the review text with input from the other authors and revised the manuscript. All review authors contributed to writing and revising this review.

Sources of support

Internal sources

No sources of support supplied

External sources

National Key R&D Program of China (No. 2017YFC1308400), China.

Grant for the research of remote ischaemic conditioning for chronic cerebrovascular diseases
Beijing Municipal Administration of Hospitals Incubating Program (Code:PX2018033), China.

Grants for the research of remote ischaemic conditioning for intracranial atherosclerosis
Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding (ZYLX201706), China.

Grant for the research of ischaemic stroke

Declarations of interest

Wenbo Zhao: none known.
Jing Zhang: none known.
Mordechai G Sadowsky: none known.
Ran Meng: none known.
Yuchuan Ding: none known.
Xunming Ji: is one of the inventors of the electric auto‐control device that induces remote ischaemic conditioning. This device has been used in many studies, including the ones mentioned in this review. There is no conflict of interest in the conduct of this review. The ownership of the patent belongs to Xuanwu Hospital, Capital Medical University. Dr Ji does not participate in any commercial activities or profits related to the device.

Acknowledgements

We thank Hazel Fraser (Managing Editor, Cochrane Stroke Group) and Joshua Cheyne (Information Specialist, Cochrane Stroke Group) for their valuable help during the preparation and revision of this review. We thank Peter Langhorne, Paul Nederkoorn, Aryelly Rodriguez (the Cochrane Stroke Group editors), Jessica Sharp (the Copyeditor), and Dee Shneiderman (consumer reviewer for this review) for their expert advice, helpful comments and suggestions, and assistance with this review. We thank Jin Xu (Deparimen of Library, Xuanwu Hospital, Captial Medical University) for her valuable assistance when preparing and revising the review.

Version history

Published

Title

Stage

Authors

Version

2018 Jul 05

Remote ischaemic conditioning for preventing and treating ischaemic stroke

Review

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

https://doi.org/10.1002/14651858.CD012503.pub2

2017 Jan 11

Remote ischaemic conditioning for preventing and treating ischaemic stroke

Protocol

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

https://doi.org/10.1002/14651858.CD012503

Differences between protocol and review

We had planned to include participants undergoing cardiovascular intervention therapies, coronary artery bypass grafting, and any other type of cardiac surgery. However, we found that cardioembolism is the main cause of stroke in the above participants, which is closely related with operative procedures. In conventional studies focusing on ischaemic stroke, the above participants were excluded. In addition, all cardiac studies investigated the effects of RIC on cardiovascular events, plasma biomarkers or imaging outcomes; many of them did not report cerebrovascular events if they occurred. Some bias may be caused unintentionally if the above participants were included. Therefore, we did not include these participants this review.

We had intended to performed subgroup analyses to investigate heterogeneity by analysing differences in the number of RIC cycles and their length, and the position and length of RIC treatment. However, in this review only seven trials were eligible for analysis, including three studies for the analysis of RIC for preventing ischaemic stroke, and another four studies for the analysis of RIC for treating ischaemic stroke. Given the limited number of included studies, there were not enough data for subgroup analyses.

We had intended to perform sensitivity analyses if the results were substantially heterogeneous. However, we did not perform any sensitivity analyses because of the limited number of included studies, and we found no substantial heterogeneity in this review.

We had intended to include 'quality of life' as a outcome in the 'Summary of findings' table. However, no included measured this outcome. Instead, we included 'stroke severity', which has been assessed by NHISS scores or infarct volume in several studies, as a outcome in the 'Summary of findings' table.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

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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