Electronic database search yielded 25 publications and 27 clinical trials of which 18 studies (5 research articles and 13 clinical trials) were finally included in the systematic literature review (Fig. 1). Among the 25 publications identified on Pubmed search, nine articles were not related to stroke (36%), four articles applied chronic PostRIC (16%), three articles were reviews of literature, two articles were the description of studies, two articles were on subarachnoid hemorrhage patients, one article was a sub-study and four articles were not eligible. After applying the inclusion criteria (acute ischemic stroke-AIS patients and application of remote ischemic per-conditioning-RIPerC) and exclude the studies that accept inclusion beyond 48 hours from the onset of symptoms, a total of 5 articles, which were previously registered clinical trials, were finally included and analyzed (14–18). Twenty-seven randomized clinical trials (RCT) were identified on clinicaltrials.gov. Of these RCT, 6 (22%) applied PostRIC and 17 (62%) were not considered once inclusion/exclusion criteria were applied. 13 RCT were further considered in the present systematic review (SERIC-AIS, SERICT-AIS, RIC-SIID, REVISE-2, PROTECT I, RICE PAC, RICAMIS, rtPA-RIC, REMOTE-CAT, RESIST, TRIPCAIS, ReCAST-2, ICARUS).
Table 1 provides a summary of study design characteristics of the 5 research papers and 13 clinical trials of remote ischemic per-conditioning (RIPerC) application on IS patients. All included research papers were related to completed clinical trials and only one described the trial protocol (18)[Che, 2019, rt-PA with remote ischemic postconditioning for acute ischemic stroke][Che, 2019, rt-PA with remote ischemic postconditioning for acute ischemic stroke].
The first research paper was published by Hougard et al. in 2014 (14). Of the 443 randomized patients, 247 received manual remote ischemic conditioning (mRIC) during transportation in the ambulance to the hospital. After adjustment for baseline multimodal magnetic resonance imaging (MRI) findings, voxel-wise logistical analysis showed better radiological evolution of mRIC treated patients than non-treated patients. However, there were no significant differences in clinical neurological outcome between the mRIC and control groups. It was focused on rt-PA subjects, as Che et al. (17), which only included 30 patients. Zhao et al. (16) demonstrated that RIC is safe in 20 patients who were treated by thrombectomy. Moreover, England et al. (15) confirmed the applicability and feasibility of RIC in 13 patients with ischemic stroke within 24 hours of evolution. Furthermore, RIC was associated with changes in the concentration of plasma biomarkers related to the phenomenon of ischemic tolerance (IT), such as HSP27 and phosphorylated HSP27, when both arms (control vs experimental) of the trial were compared (n = 13) (15). These four publications had a limited and small number of recruited subjects (14–17). Finally, in contrast to the previous studies, RESCUE-BRAIN trial (18) was not only focused on IS patients who received or were candidate for revascularization therapies. It included 200 patients with IS with less than 6 hours evolution of symptoms and it demonstrated ischemic damage on MRI. RESCUE-BRAIN’s results were presented at the last European Stroke Organization Conference’19 (19) and showed that RIC applied on affected lower extremity had a futile effect on functional evolution and infarct volume.
Up to now, there are 18 RCT identified and 17 (94.4%) of them registered in clinicaltrials.gov. Among them, 13 (72.2%) have been registered in the last 3 years, 9 (50%) have been developed in China, 8 (44.4%) in Europe and one (5.6%) in United States. Regarding the estimated number of enrolled patients, we highlight RICAMIS (n = 1800), RESIST (n = 1500), SERIC-AIS (n = 912) and REMOTE-CAT (n = 572). There is a high variability in the inclusion and exclusion criteria among trials. Only 6 trials (33.3%) set up an upper age limit as an inclusion criterion. As in the previous RCT of Hougard et al. (14) and Che et al. (17), three on-going RCTs (SERICT-AIS, rtPA-RIC, TRIPCAIS) are focused on the RIC’s role as an adjuvant treatment of thrombolytic therapy. In contrast, REVISE-2, PROTECT I and REVISE-1 (16) included patients who went under thrombectomy. Despite the low estimated sample size (n = 15), ICARUS trial wants to reveal the feasibility of RIC application on thrombectomy candidates who are transported to comprehensive stroke centers by aircraft. Five studies require radiological confirmation of acute cerebral infarction regardless of the subsequent treatment received (SERIC-AIS, RIC-SHD, RICAMIS, RECAST, RESCUE BRAIN). Finally, Danish RESIST study, Spanish REMOTE-CAT and British RECAST-2 include patients with stroke code criteria. Both REMOTE-CAT and RESIST consider the score of prehospital scales: RACE scale (20) and Prehospital Stroke Score (PreSS), respectively. In both trials as in the previous published by Hougard et al. (14), the application of RIC begins already in the ambulance transportation of the patient to the hospital.
Certain variability of inclusion time window is observed within the 18 RCTs. Concretely, in the RESIST trial, temporal inclusion criterion is set at < 4 hours while in RIC-SIID and RICAMIS is extended to 48 hours. RCTs focused on patients treated with intravenous fibrinolysis set the maximum time for the evolution of symptoms to 4.5 hours. Instead, among RCTs assessing the effect of RIC on thrombectomy, the time is set up at 6 hours. The Spanish REMOTE-CAT trial includes patients with less than 8 hours evolution of symptoms. Heterogeneity is also evidenced by the number of cycles of RIC application: 7 (38.9%) RCTs use 5 cycles, one (5.6%) RCTs uses between 3 and 5 cycles, and the rest of the trials use 4 cycles. Thirteen (72.2%) trials perform a single application of RIC. Conversely, SERIC-AIS and RESIST plan up to two applications throughout seven days. The application of RIC is located in the non-paretic lower limb only in one RCT (18), on both upper extremities in five (27.8%) RCTs, and on upper or lower non-paretic extremities in one (5.6%) RCT. In most cases, the application is restricted to the unaffected upper limb. The application of the RIC is manual in 4 (22.2%) RCTs: two research articles (14, 15) and RECAST 2 and RICE PAC. A simulated control group is only included on half of the considered RCTs.
The high heterogeneity within RCTs is also observed on the main endpoints (Fig. 2). The RCTs yielding the highest number of enrolled patients are still on-going as REMOTE-CAT, SERIC AIS, RESIT and RICAMIS, that consider the clinical endpoint as main endpoint. In medium-size studies (18) and endovascular therapy related studies, the main endpoints are infarct volume and/or neuroimaging outputs. On the first research published paper on the application of RIC on IS patients, the main endpoint considered was the neuroimaging outcome (14). Ischemic tolerance-related biomarkers are included in TRIPCAIS and RIC-SIID trials. However, other RCTs would also study biomarkers to detect differential expression changes. Small-size recruited patients studies demonstrate whether RIC application is feasible in AIS patients and AIS patients treated with rt-PA and/or endovascular therapy (15–17) (Fig. 2).