Electronic database search yielded 32 publications and 27 clinical trials of which 19 studies were finally included in the systematic literature review (Figure 2). Among the 31 publications identified on Pubmed search, nine articles were not related to stroke (29%), four articles applied chronic PostRIC (13%), three articles were reviews of literature, three articles described design of the studies or protocols (14-16), 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 perconditioning-RIPerC) and the studies that accept inclusion beyond 48 hours from the onset of symptoms were exclude; a total of 6 articles were included and analyzed in the systematic review (16-21), note that 4 out of the 6 papers were previously registered as clinical trials (18-21). Twenty-seven randomized clinical trials (RCTs) were identified on clinicaltrials.gov. Of these RCTs, 6 (22.2%) applied PostRIC and 4 (14.8%%) were not considered after inclusion/exclusion criteria were applied. 17 RCTs were further considered in the present systematic review (NCT0097596(21), RESCUE-BRAIN(15, 22), REVISE-1(18), rtPA-RIC1(19), ReCAST-2, rtPA-RIC, REMOTE-CAT, TRIPCAIS, REVISE-2, RICE PAC, SERIC-AIS, RICAMIS, RESIST(14), ICARUS, SERICT-AIS, RIC-SIID, PROTECT I). Table 1 provides a summary of study design characteristics of the 19 RTCs on RIPerC application on IS patients.
The first research paper was published by Hougard et al. in 2014 (21). Of 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 mRIC and control groups. The paper of Che et al. (19), included only 30 patients treated with rt-PA. Zhao et al. (18) demonstrated that RIC is safe in 20 patients who underwent mechanical thrombectomy. Moreover, England et al. (17) confirmed the applicability and feasibility of RIC on 13 IS patients within 24 hours after the onset of symptoms. Furthermore, RIC was associated with changes of plasma biomarkers related to ischemic tolerance (IT) phenomena, such as HSP27 and phosphorylated HSP27, whose expression was significantly different when both arms (control vs experimental) of the trial were compared (n=13) (17). These four publications included a limited and small number of recruited subjects (17-19, 21). In contrast with previous studies, the multicenter RESCUE-BRAIN trial (20) was not only focused on IS patients who received or were candidate for revascularization therapies. It included 188 patients with confirmed carotid IS who underwent magnetic resonance imaging within 6 hours after the onset of symptoms, and 171 (91%) patients received a recanalization therapy. In RESCUE_BRAIN trial, RIPerC was applied using an electronic device on the unaffected lower extremity (4 cycles of 5-minutes inflations and 5-minutes deflations). Brain infarction volume growth, which was the main outcome, was not significantly different between the intervention and control groups. In addition, no significant differences at 90-days mRS and mortality were observed between the two groups.
Up to now, there are 19 RCTs identified (where?) and 17 (89.5%) of them were registered in clinicaltrials.gov. Among them, 14 (73.4%) have been registered in the last 3 years, 9 (47.4%) have been developed in China, 9 (47.4%) in Europe and one (5.3%) in United States. Relating to the estimated number of enrolled patients on selected RTCs, special attention must be paid on RICAMIS (n=1800), RESIST (n=1500)(14), SERIC-AIS (n=912) and REMOTE-CAT (n=572).
There is a high variability in the inclusion and exclusion criteria among trials. Five RCTs require radiological confirmation of acute cerebral infarction despite of the subsequent treatment received (SERIC-AIS, RIC-SHD, RICAMIS, RECAST, RESCUE BRAIN). Finally, Danish RESIST RCTs, Spanish REMOTE-CAT and British RECAST-2 include patients that met stroke code criteria. Both REMOTE-CAT and RESIST consider the score of prehospital scales: RACE scale (23) and Prehospital Stroke Score (PreSS), respectively. Only 6 trials (31.6%) set up an upper age limit as an inclusion criterion. Like in previous RCTs of Hougard et al.(21) and Che et al. (19), 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(18) included patients who underwent thrombectomy.
Heterogeneity is also evidenced by the number of RIC cycles applied: 7 (36.8%) RCTs use 5 cycles, one (5.3%) RCT uses between 3 and 5 cycles, and the rest of the trials use 4 cycles. Thirteen (68.4%) RCTs perform a single application of RIC. Conversely, SERIC-AIS and RESIST(14) have planned up to two applications throughout seven days, like in the finished study of Che et al(19); only REPOST has planned to applied during four days(16). The application of RIC is located in the non-paretic lower limb only in one RCT (24), on both upper extremities in five (26.3%) RCTs, and on upper or lower non-paretic extremities in one (5.3%) RCT. In most cases, the application is restricted to the unaffected upper limb. The application of the RIC is manual in 5 (26.3%) RCTs: two completed RCT (17, 21), REPOST(16), RECAST 2 and RICE PAC. A simulated control group is only included in little over half of the considered RCTs.
Certain variability of timing of RIC application is observed within all selected studies. 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 of evolution of symptoms.
Only three RCTs, REMOTE-CAT, RESIST and the previous published by Hougard et al. (21), initiate the application of RIC in a prehospital setting, usually in the ambulance transportation of the patient to the hospital or stroke care center. Despite the low sample size (n=15), ICARUS trial aims to reveal the feasibility of RIC application on thrombectomy candidates who are transported to comprehensive stroke centers by aircraft.
C, outcome measurements, was there any information on the size of the final infarct volume, perfusion, recurrent stroke?
The high heterogeneity within RCTs is also observed on the main endpoints (Figure 3) and outcome measurements. The RCTs yielding the highest number of enrolled patients are still on-going (REMOTE-CAT, SERIC AIS, RESIT and RICAMIS) and all have considered the clinical endpoint as the main endpoint. In medium size studies 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(21). 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 (17-19) (Figure 3).