Remote Ischemic Conditioning in Patients With Acute Stroke (RESIST) (RESIST)

Remote Ischemic Conditioning in Patients With Acute Stroke: a Multicenter Randomized, Patient-assessor Blinded, Sham-controlled Study

Our primary aim is to investigate whether remote ischemic conditioning (RIC) as an adjunctive treatment can improve long-term recovery in acute stroke patients as an adjunct to standard treatment.

Stroke is the second-leading cause of death worldwide and a leading cause of serious, long-term disability. The most common type is acute ischemic stroke (AIS) which occurs in 85% of cases. Acute cerebral thromboembolism leads to an area of permanent damage (infarct core) in the most severely hypoperfused area and a surrounding area of impaired, yet salvageable tissue known as the "ischemic penumbra". Intravenous alteplase (IV tPA) and endovascular treatment (EVT) are approved acute reperfusion treatments of AIS to be started within the first 4½-6 hours (in some up to 24 hours) and as soon as possible after symptom onset to prevent the evolution of the infarct core. However, reperfusion itself may paradoxically result in tissue damage (reperfusion injury) and may contribute to infarct growth. Infarct progression can continue for days following a stroke, and failure of the collateral flow is a critical factor determining infarct growth. On the other hand, in intracerebral hemorrhage (ICH) the culprit is an eruption of blood into the brain parenchyma causing tissue destruction with a massive effect on adjacent brain tissues. Hematoma expansion as well as inflammatory pathways that are activated lead to further tissue damage, edema, and penumbral hypoperfusion. The prognosis after ICH is poor with a one-month mortality of 40%. Novel therapeutics and neuroprotective strategies that can be started ultra-early after symptom onset are urgently needed to reduce disability in both AIS and ICH. Ischemic conditioning is one of the most potent activators of endogenous protection against ischemia-reperfusion injury. Remote Ischemic Conditioning (RIC) can be applied as repeated short-lasting ischemia in a distant tissue that results in protection against subsequent long-lasting ischemic injury in the target organ. This protection can be applied prior to or during a prolonged ischemic event as remote ischemic pre-conditioning (RIPreC) and per-conditioning (RIPerC), respectively, or immediate after reperfusion as remote ischemic post-conditioning (RIPostC). RIC is commonly achieved by inflation of a blood pressure cuff to induce 5-minute cycles of limb ischemia alternating with 5 minutes of reperfusion. Preclinical studies show that RIC induces a promising infarct reduction in an experimental stroke model. Results from a recent proof-of-concept study at our institution indicate that RIPerC applied during ambulance transportation as an adjunctive to in-hospital IV tPA increases brain tissue survival after one month. Furthermore, RIPerC patients had less severe neurological symptoms at admission and tended to have decreased perfusion deficits. To-date, no serious adverse events have been documented in RIC. RIC is a non-pharmacologic and non-invasive treatment without noticeable discomfort that has first-aid potential worldwide. However, whether combined remote ischemic per- and postconditioning can improve long-term recovery in AIS and ICH has never been investigated in a randomized controlled trial.

Stroke, Acute, Ischemic Stroke, Hemorrhagic Stroke, Intracerebral Hemorrhage, Cerebrovascular Disorders, Central Nervous System Diseases

Remote ischemic conditioning (RIC) is applied in the hyperacute prehospital phase using an automated RIC device. Treatment characteristics: Five cycles (50 minutes), each consisting of five minutes of cuff inflation followed by five minutes with a deflated cuff. The cuff pressure will be 200 mmHg; but if initial systolic blood pressure is above 175 mmHg, the cuff is automatically inflated to 35 mmHg above the systolic blood pressure. Initial remote ischemic conditioning: prehospital phase, all included patients Remote ischemic conditioning at +6 hours: In-hospital, only patients with AIS and ICH, all centres Remote Ischemic Postconditioning (twice daily for 7 days): In-hospital/rehabilitation, Only patients with AIS and ICH and only at Aarhus University Hospital Usual care with or without acute reperfusion therapy

Sham remote ischemic conditioning (Sham-RIC) is applied in the hyperacute prehospital phase using an automated Sham-RIC device. Treatment characteristics: Five cycles (50 minutes), each consisting of five minutes of cuff inflation followed by five minutes with a deflated cuff. The cuff pressure will be always be 20 mmHg. Initial Sham remote ischemic conditioning: prehospital phase, all included patients Sham Remote ischemic conditioning at +6 hours: In-hospital, only patients with AIS and ICH, all centres Sham Remote Ischemic Postconditioning (twice daily for 7 days): In-hospital/rehabilitation, Only patients with AIS and ICH and only at Aarhus University Hospital Usual care with or without acute reperfusion therapy.

RIC is commonly achieved by inflation of a blood pressure cuff to induce 5-minute cycles of limb ischemia alternating with 5 minutes of reperfusion.

Clinical outcome (modified Rankin Scale) at 3 months in acute stroke patients (target diagnosis) (generalized ordinal logistic regression). The assessment will performed by two independent telephone or face-to-face assessors. If disagreement occurs the patient will be contacted by a third assessor (face-to-face or telephone) who is blinded to the intervention who will assess the level of dependency. If disagreement occurs between two telephone assessments - a third, and final, telephone or face-to-face assessment will be made. If disagreement occurs between one face-to-face assessment and one telephone assessment the face-to-face will be considered the final assessment If disagreement occurs between two face-to-face assessments - a third, and final, telephone or face-to-face assessment will be made.

Neurological deficits are documented using PreSS (Prehospital Stroke score both prehospital and in-hospital). Prehospital Stroke Score is assessed at 24-hour or at discharge (if discharge occurs before 24 hours). The PreSS score consists of the Cincinnati Prehospital Stroke Scale (CPSS) with an additional opportunity to report other neurological symptoms (e.g. ataxia, sensory disturbances and visual field loss), and PASS (Prehospital Acute Stroke Severity Scale) Ordinal logistic regression

The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.

Clinical outcome (modified Rankin Scale (mRS) at 3 months in acute ischemic stroke receiving reperfusion therapy

The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.

Clinical outcome (modified Rankin Scale (mRS) at 3 months in patients with intracerebral hemorrhage (ICH)

The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.

Difference in proportion of patients with complete remission of symptoms within 24 hours (TIA; both with and without DWI)

Difference in proportion of patients with complete remission of symptoms within 24 hours (TIA; both with and without DWI) Diagnosis of TIA is documented in the electronic case report form

Major Adverse Cardiac and Cerebral Events (MACCE) and recurrent ischemic events based on registry data at 3 and 12 months in ICH, AIS patients, TIA and non-vascular diagnosis

MACCE is defined as: Cardiovascular events (cardiovascular death, myocardial infarction, acute ischemic or hemorrhagic stroke) Cardiovascular death: Death from known cardiovascular cause or sudden death from unknown cause (no identified cause of death in medical history and/or autopsy) Acute myocardial infarction: Admission with a discharge diagnosis of ST-elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UAP) Stroke: Admission with a discharge diagnosis of acute ischemic or hemorrhagic stroke. Evaluation is performed using the Danish National Patient Register (LPR) and the DSR at two time points (6 and 15 months after the inclusion of the last patient). Diagnosis of AIS/TIA, ICH and MI (STEMI, NSTEMI, and UAP) are made according to national clinical practice guidelines.

All-cause mortality is assessed and subdivided into cardiovascular mortality versus non-cardiovascular mortality

Clinical outcome (modified Rankin Scale (mRS) at 3 months in ischemic stroke patients and the extended remote ischemic postconditioning protocol (substudy at Aarhus University Hospital)

The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.

Clinical outcome (modified Rankin Scale (mRS) at 3 months in intracerebral hemorrhage patients and the extended remote ischemic postconditioning protocol (substudy at Aarhus University Hospital)

The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.

Endovascular treatment(EVT) -eligibility (MRI assessed) in RIC treated AIS patients with large vessel (substudy at Aarhus University Hospital)

Proportion of RIC treated AIS patients with large vessel occlusion (LVO) eligible to EVT treatment compared to standard treatment, adjusted for prehospital stroke severity (PreSS) and symptom duration Severe Stroke (NIHSS ≥ 10) Groin puncture feasible within 6 hours from stroke onset MRI-time-of-flight (TOF) documented internal carotid artery (ICA), Intracranial ICA (ICA-T) and first and second stem of the middle cerebral artery (M1 and M2, respectively) No contraindications to MRI (pacemaker, vomiting, respiratory insufficiency, obesity) MRI-Diffusion weighted imaging (DWI) lesion volume ≤ 70 mL

24-hour infarct growth on DWI-MRI (Difference in lesion volume between acute and 24-hour DWI-MRI) (Substudy at Aarhus University Hospital)

Difference in acute (24-hour) hematoma expansion in patients with ICH (substudy at Aarhus University Hospital)

24-hour hematoma growth (Difference in hematoma volume between acute and 24-hour CT/MRI) (Substudy at Aarhus University Hospital)

7-day hematoma reduction (Difference in hematoma volume between acute and 7-day (day 5 to 9) CT ) (Substudy at Aarhus University Hospital)

Ektacytometry for Erythrocytic Deformability and Analytical Flow Cytometry (FC) for eryNOS3 phosphorylation (pNOS3Ser1177) and s-nitrosylation (-SNO) in RBC

MicroRNA and extracellular vesicle profile of RIC-induced neuroprotection (substudy at Aarhus University Hospital)

Diagnostic abilities of a prehospital microRNA and extracellular vesicles blood samples profile combined with prehospital stroke severity on the differentiation of hemorrhagic from ischemic stroke and to grade ischemic stroke severity

Predictive abilities of Glial Fibrillary Acidic Protein (GFAP) in prehospital obtained blood samples combined with prehospital stroke severity to differentiate hemorrhagic from ischemic stroke and to grade ischemic stroke severity

Coagulation profile of putative stroke patients in prehospital obtained blood samples (substudy at Aarhus University Hospital)

Functional and immunologic plasma assays will be employed to analyze proteins and pathways in coagulation and fibrinolysis.

Inclusion Criteria: Male and female patients (≥ 18 years) Prehospital putative stroke (Prehospital Stroke Score, PreSS >= 1) Onset of stroke symptoms < 4 hours before RIC/Sham-RIC Independent in daily living before symptom onset (mRS ≤ 2) Exclusion Criteria: Intracranial aneurisms, intracranial arteriovenous malformation, cerebral neoplasm or abscess Pregnancy Severe peripheral arterial disease in the upper extremities Concomitant acute life-threatening medical or surgical condition Arteriovenous fistula in the arm selected for RIC

Individual participant data that underlie the results reported in this article after deidentification

Proprosals should be directed to rolfblau@rm.dk. To gain access data requestors will need to sign a data processing agreement.

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Blauenfeldt RA, Hjort N, Gude MF, Behrndtz AB, Fisher M, Valentin JB, Kirkegaard H, Johnsen SP, Hess DC, Andersen G. A multicentre, randomised, sham-controlled trial on REmote iSchemic conditioning In patients with acute STroke (RESIST) - Rationale and study design. Eur Stroke J. 2020 Mar;5(1):94-101. doi: 10.1177/2396987319884408. Epub 2019 Oct 25.