Remote Ischemic Perconditioning as an Adjunct Therapy to Thrombolysis in Patients With Acute Ischemic Stroke A Randomized Trial

Stroke is a leading cause of death and disability worldwide. Intravenous administration of alteplase (rtPA) within 4.5 hours of symptom onset is currently the only approved drug treatment of acute ischemic stroke (AIS). Various forms of neuroprotection have proven effective in animal models of acute ischemia, but their translation into successful therapies in human stroke has so far been unsuccessful. Remote ischemic preconditioning, by which ischemia induced in 1 organ leads to ischemic tolerance in other organs, is a potent endogenous protective mechanism. Preconditioning is not practical in a clinical setting because it must be initiated before the ischemic event. Remote ischemic perconditioning (rPerC) by which the sublethal ischemic stimulus is administered during the ischemic event may, however, be beneficial after an acute stroke. Both remote ischemic preand perconditioning have now been proven effective in animal models, and remote Background and Purpose—Remote ischemic preconditioning is neuroprotective in models of acute cerebral ischemia. We tested the effect of prehospital rPerC as an adjunct to treatment with intravenous alteplase in patients with acute ischemic stroke. Methods—Open-label blinded outcome proof-of-concept study of prehospital, paramedic-administered rPerC at a 1:1 ratio in consecutive patients with suspected acute stroke. After neurological examination and MRI, patients with verified stroke receiving alteplase treatment were included and received MRI at 24 hours and 1 month and clinical re-examination after 3 months. The primary end point was penumbral salvage, defined as the volume of the perfusion–diffusion mismatch not progressing to infarction after 1 month. Results—Four hundred forty-three patients were randomized after provisional consent, 247 received rPerC and 196 received standard treatment. Patients with a nonstroke diagnosis (n=105) were excluded from further examinations. The remaining patients had transient ischemic attack (n=58), acute ischemic stroke (n=240), or hemorrhagic stroke (n=37). Transient ischemic attack was more frequent (P=0.006), and National Institutes of Health Stroke Scale score on admission was lower (P=0.016) in the intervention group compared with controls. Penumbral salvage, final infarct size at 1 month, infarct growth between baseline and 1 month, and clinical outcome after 3 months did not differ among groups. After adjustment for baseline perfusion and diffusion lesion severity, voxelwise analysis showed that rPerC reduced tissue risk of infarction (P=0.0003). Conclusions—Although the overall results were neutral, a tissue survival analysis suggests that prehospital rPerC may have immediate neuroprotective effects. Future clinical trials should take such immediate effects, and their duration, into account. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00975962. (Stroke. 2014;45:00-00.)