Remote ischaemic conditioning for preventing and treating ischaemic stroke

Abstract

Rationale: Remote ischaemic conditioning (RIC) has been innovatively utilised as a neuroprotective method in the prevention and treatment of stroke. RIC typically involves transiently restricting then restoring blood flow to limbs. The current evidence, as derived from various studies, indicates some beneficial effects of RIC, but also highlights the need for further investigation due to the presence of uncertainties and variations in study designs and outcomes.

Objectives: To evaluate the benefits and harms of remote ischaemic conditioning in preventing and treating ischaemic stroke compared to sham or standard treatments.

Search methods: We searched CENTRAL, MEDLINE, Embase, Web of Science, three Chinese databases, five trials registers, and conference proceedings, together with reference checking and citation searching. The latest search date was 11 March 2025.

Eligibility criteria: We included randomised controlled trials (RCTs) comparing RIC with sham RIC or standard medical management, over any length of follow-up, in people with ischaemic stroke.

Outcomes: Our critical outcomes were mortality, recurrence of ischaemic stroke, and excellent functional outcome (Modified Rankin Scale (mRS) score 0-1). Our important outcomes were treatment-related adverse events, functional independence (mRS score 0-2), haemorrhagic stroke, stroke severity, improvement in neurological impairment, and cardiovascular events.

Risk of bias: We assessed risk of bias using the original Cochrane risk of bias tool (RoB 1).

Synthesis methods: We used standard Cochrane methodology. We synthesised results for each outcome through meta-analysis where possible, using either the inverse variance or Mantel-Haenszel method with a random-effects model. We used the GRADE approach to assess the certainty of the evidence.

Included studies: This review included 20 RCTs with 7687 participants, though we analysed two publications from a single RCT as two separate studies. Sixteen RCTs with 7166 participants were new to this update. The studies were conducted in China, Denmark, the UK, the Netherlands, France, and Romania, and were published between 2012 and 2025. Fourteen studies investigated short-duration RIC, four evaluated medium-duration RIC, and three investigated long-duration RIC. Because studies reported the timing of RIC application after stroke onset in various ways, we made assumptions to combine data, which may have introduced extra heterogeneity or bias and affected the certainty of our conclusions regarding the optimal RIC application timing. We also identified 21 ongoing trials.

Synthesis of results: The evidence suggests that RIC compared to non-RIC probably results in a slight reduction in the risk of ischaemic stroke recurrence (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.73 to 0.98; 16 RCTs, 6828 participants; moderate-certainty evidence) and probably has no little to no effect on mortality risk (RR 0.91, 95% CI 0.74 to 1.12; 15 RCTs, 7203 participants; moderate-certainty evidence). RIC may result in a slight increase in excellent functional outcome (mRS 0-1) at 90 days (RR 1.14, 95% CI 1.01 to 1.28; 10 RCTs, 3091 participants; low-certainty evidence), but probably has little to no effect on functional independence (mRS 0-2) at 90 days (RR 1.03, 95% CI 0.97 to 1.09; 11 RCTs, 3979 participants; moderate-certainty evidence). Studies measured improvement in neurological impairment on the National Institutes of Health Stroke Scale (NIHSS), and the pooled evidence suggests a slight improvement with RIC, but the evidence is very uncertain (mean difference (MD) -0.97, 95% CI -1.74 to -0.21; 12 RCTs, 1341 participants; very low-certainty evidence). RIC compared to non-RIC may result in little to no difference in the risk of intracerebral haemorrhagic events (RR 0.96, 95% CI 0.59 to 1.57; 12 RCTs, 5908 participants; low-certainty evidence) and cardiovascular events (RR 0.85, 95% CI 0.68 to 1.08; 8 RCTs, 4357 participants; low-certainty evidence), but may result in a large increase in treatment-related adverse events (RR 6.13, 95% CI 2.85 to 13.18; 17 RCTs, 7274 participants; low-certainty evidence).

Authors' conclusions: There is moderate-certainty evidence that RIC compared to non-RIC probably reduces recurrence of ischaemic stroke slightly, and low-certainty evidence that RIC may result in a slight increase in excellent functional outcome (mRS 0-1). Evidence for improvement in NIHSS scores is very uncertain due to risk of bias and imprecision. RIC demonstrated an acceptable harm profile with no increase in intracerebral haemorrhage or mortality; however, treatment-related adverse events were more common. The certainty of evidence was limited by high risk of bias for blinding in most studies, incomplete outcome data in some studies, and imprecision in several outcomes. However, the generalisability of these findings may be limited because 79.3% of participants were from China, highlighting the need for further studies in diverse populations to confirm the results. The optimal timing, duration, and method of RIC administration require further investigation through large, high-quality randomised trials with standardised protocols to establish definitive evidence for clinical practice. This updated analysis includes 16 new RCTs, and these findings highlight the need for ongoing research and careful consideration of study design and methodology in future investigations.

Funding: This Cochrane review was supported by the National Natural Science Foundation of China (82422024) and the Beijing Natural Science Foundation (JQ22020).

Registration: Protocol: Cochrane Library via DOI 10.1002/14651858.CD012503. Original review, Cochrane Library via 10.1002/14651858.CD012503.pub2.