Editorial <\/p>\n\n\n\n
August 16, 2022<\/p>\n\n\n\n
Stroke is the second leading cause of death and disability in the world.1<\/a><\/sup> In 1996, tissue plasminogen activator (tPA) was approved by the US Food and Drug Administration and remains the only approved pharmacologic agent for treatment of ischemic stroke in the US.2<\/a><\/sup>,3<\/a><\/sup> In 2015, mechanical thrombectomy was shown to be beneficial for large vessel occlusion ischemic stroke, although 50% of patients treated with mechanical thrombectomy remain disabled at 3 months.4<\/a><\/sup> Due to short time windows for thrombolytic therapy administration and the stroke system infrastructure needed for mechanical thrombectomy, these reperfusion therapies are available to only a small proportion of patients who experience stroke. Worldwide, these treatments are used in less than 5% of patients with stroke, and in many low-income nations they are rarely used.5<\/a><\/sup><\/a><\/p>\n\n\n\n To complement these therapies aimed at ending the ischemic insult by reperfusion, neurovascular investigators have long sought to develop neuroprotective agents that could allow brain parenchyma to better tolerate ischemia prior to reperfusion or reduce reperfusion injury after ischemia ends. However, promising results in preclinical animal models have repeatedly ended in translational failure when randomized clinical trials (RCTs) did not meet their primary end points. This led to reluctance by some pharmaceutical companies to invest in developing new medications for stroke treatment and pivoting by the National Institutes of Health to invest in a multicenter preclinical stroke network to more rigorously select interventions to advance into clinical trial.6<\/a><\/sup> To redefine the neuroprotection model, the Stroke Treatment Academic Industry Roundtable (STAIR) XI introduced the term cerebroprotection<\/em> to highlight the importance of protecting the neurovascular unit and whole brain, not solely neurons.7<\/a><\/sup> The STAIR consensus group also highlighted the desirability of interventions with multiple, pleiotropic mechanisms of action, instead of approaches that target a single injury pathway.7<\/a><\/sup><\/a><\/p>\n\n\n\n Remote ischemic conditioning (RIC), which involves brief, reversible episodes of ischemia and reperfusion in one vascular bed to activate ischemia tolerance in remote tissues and organs, represents a new potential approach for cerebroprotection.8<\/a><\/sup> Remote conditioning induces multiple protective pathways that elicit a protective and resilient phenotype. In 1986, Murry et al9<\/a><\/sup> reported that the phenomenon of direct ischemic conditioning in the canine heart by repeatedly clamping\/declamping the circumflex artery for 5 minutes for 4 cycles reduced later ischemic damage from occlusion of the circumflex. The first key translational break to take this approach from the bench to the bedside occurred when it was shown that ischemia could be applied to the limb with a blood pressure cuff repeatedly inflated and deflated. The second key was that the remote stimulus was effective if applied not just before ischemia (preconditioning), but also during ischemia (per-conditioning) and after reperfusion (postconditioning). RIC has multiple possible targets and multiple potential mechanisms of action including humoral effects (nitric oxide synthase 3, nitrite, SDF-1, microRNAs) and immunologic changes in the ratio of proinflammatory\/anti-inflammatory macrophages and other immune cells and neurogenic mechanisms. Importantly, RIC is a collateral enhancer, increasing cerebral flood flow in areas of ischemia.10<\/a><\/sup> RIC shares some mechanisms of action with physical exercise and is a proposed exercise mimetic.8<\/a><\/sup><\/a><\/p>\n\n\n\n In this issue of JAMA<\/em>, Chen and colleagues11<\/a><\/sup> report the results of the Remote Ischemic Conditioning For Acute Moderate Ischemic Stroke (RICAMIS) trial, the largest randomized clinical trial to date of RIC in patients with stroke. The authors report that compared with usual care, RIC was beneficial in patients with moderate ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score, 6-16; median, 7) who did not receive tPA or mechanical thrombectomy and were treated within 48 hours of stroke (mean, 25 hours). RIC was applied with an automated device applied to both arms twice per day and inflated to 200 mm Hg then deflated for 5 minutes and for 5 cycles for 14 days.<\/a><\/p>\n\n\n\n In the full analysis set of 1776 patients, the primary outcome of nondisabled neurologic outcome (modified Rankin Scale [mRS] score of 0 or 1 at 90 days), the secondary outcomes of functional independence (mRS score of 0 to 2) at 90 days, and reduced disability (favorable shift across the full range of mRS scores) at 90 days all favored RIC and were statistically significant. This effect magnitude of about 5 more of every 100 treated patients achieving nondisabled outcome is moderate compared with that of reperfusion therapies, including intravenous tPA administered in the less than 3-hour window (13 more nondisabled outcomes per 100 patients treated)2<\/a><\/sup> and intravenous tPA in the 3 to 4.5-hour window (7.4 more nondisabled outcomes per 100 patients treated).2<\/a><\/sup>,12<\/a><\/sup> Nonetheless, the RIC intervention appears clinically worthwhile.12<\/a><\/sup> There was no difference in the remaining secondary outcomes of change in NIHSS score between baseline and day 12, neurologic deterioration as measured by NIHSS, stroke-associated pneumonia, recurrent stroke and vascular events at 90 days, and mortality. RIC was well tolerated and the only RIC-related adverse events were swelling or redness (0.3%) or petechiae (0.2%) in the arms.<\/a><\/p>\n\n\n\n This trial by Chen et al also has some limitations. First, the trial used an open-label design, such that a sham device and arm cuff were not used (such as inflating to 20-60 mm Hg), and patients and physicians were not blinded to the intervention. However, the final disability assessment at 90 days was performed by 2 trained and certified observers who were blinded to patient treatment assignment. Second, the investigators did not collect data about rehabilitation treatments to see whether these concomitant therapies were equivalent in the groups.<\/a><\/p>\n\n\n\n Third, the optimal dose of RIC is not known. Most dosing regimens use variations on the 5 minutes of occlusion followed with 4 to 5 cycles first reported by Murry et al.9<\/a><\/sup> The RICAMIS trial administered RIC using both arms twice per day for 14 days. Other trials in acute stroke and myocardial infarction have used 1 arm. The CONDI-2\/ERIC-PPCI (Effect of Remote Ischaemic Conditioning on Clinical Outcomes in ST-segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention) study, a large RCT of RIC in ST-segment elevation myocardial infarction only applied 4 cycles of 5-minute occlusions in 1 arm and RIC did not improve outcome at 1 year.13<\/a><\/sup> Longer dosing and using 2 arms may be of benefit. Most animal models of RIC in stroke have used bilateral lower limb RIC.14<\/a><\/sup><\/a><\/p>\n\n\n\n Fourth, the timing of therapy start in the trial is notable. In the RICAMIS trial, the RIC intervention was not started until a mean of more than 25 hours after last known well and likely after the end of the ischemic period in most patients. Accordingly, this was a trial of mostly postconditioning. While cerebroprotection may still be occurring, enhancement of recovery via immune cells or yet undiscovered mechanisms may be more plausible. The favorable results observed in the RICAMIS trial contrast with the neutral results of 2 prior small RCTs in patients with ischemic stroke that explored remote ischemic per-conditioning, with treatments started within 4.5 to 6 hours of last known well before stroke.15<\/a><\/sup>,16<\/a><\/sup><\/a><\/p>\n\n\n\n RIC has advantages over thrombolytics. It appears to be safe and also may be effective in intracerebral hemorrhage. In a mouse model, RIC reduced intracerebral hemorrhage hematoma volume and improved functional outcome with the mechanism involving anti-inflammatory macrophages expressing CD36.17<\/a><\/sup> Therefore, this approach could potentially be attractive as an out-of-hospital intervention or in settings where early brain imaging cannot be performed.<\/a><\/p>\n\n\n\n These promising results for RIC in patients with ischemic stroke reported by Chen et al in this issue of JAMA<\/em>should be confirmed in another large RCT. Several trials are under way. The Danish RESIST trial (NCT03481777<\/a>) is a multicenter, randomized, sham-controlled out-of-hospital trial of RIC that involves pre- and postconditioning on 1 arm with the first treatment started within 4 hours and continued in-hospital as postconditioning.18<\/a><\/sup> Enrollment (target sample size of 1500) is expected to be completed in December 2022 and results are anticipated in summer of 2023.<\/a><\/p>\n\n\n\n If the results of the RICAMIS study reported by Chen et al are confirmed in other RCTs and in different populations, RIC may be the first cerebroprotective therapy to prove translatable to humans. In that case, RIC could represent a feasible, safe treatment that would not require a large infrastructure and the intervention could be applied in a variety of settings without specialized personnel.<\/p>\n","protected":false},"excerpt":{"rendered":" Editorial August 16, 2022 Remote Ischem […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[24,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/22471"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=22471"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/22471\/revisions"}],"predecessor-version":[{"id":22472,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/22471\/revisions\/22472"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=22471"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=22471"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=22471"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}