Central Nervous System Diseases, Cerebrovascular Disorders, Hemorrhagic Stroke, Intracerebral Hemorrhage, Ischemic Stroke, Stroke, Acute
Conditions
Keywords
Remote Ischemic Conditioning, Neuroprotection
Brief summary
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.
Detailed description
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.
Interventions
DEVICERemote Ischemic Conditioning
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.
DEVICESham Remote Ischemic Conditioning
Sham Comparator (Sham-RIC)
Sponsors
Danish National Research Foundation
Central Denmark Region
Grethe Andersen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Participant. Outcome assessor.
Intervention model description
Prospective, randomized, patient-assessor blinded, sham-controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modified Rankin Scale at 3 Months in Acute Stroke (AIS and ICH) | 3 months | 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. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference Neurological Impairment During the First 24 Hours | 24 hours | Neurological deficits are documented using Prehospital Stroke Score (PreSS). Prehospital Stroke Score is assessed in the the ambulance and 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). The PreSS score range from 0-6, with 6 representing the most severe neurological deficits. |
| Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke | 3 months | Clinical outcome (modified Rankin Scale) at 3 months in acute stroke patients (target diagnosis) (generalized ordinal logistic regression). TThe assessment will performed by two independent telephone or face-to-face assessors. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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. |
| Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke Receiving Reperfusion Therapy | 3 months | Clinical outcome (modified Rankin Scale) at 3 months inacute ischemic stroke receiving reperfusion therapy (generalized ordinal logistic regression). The assessment will performed by two independent telephone or face-to-face assessors. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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. |
| Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Patients With Intracerebral Hemorrhage (ICH) | 3 months | Clinical outcome (modified Rankin Scale) at 3 months in patients with intracerebral hemorrhage (ICH) (generalized ordinal logistic regression). The assessment will performed by two independent telephone or face-to-face assessors. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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. |
| Difference in Proportion of Patients With Complete Remission of Symptoms Within 24 Hours (TIA; Both With and Without DWI) | 3 months | 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) | 3 months | 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. |
| Early Neurological Improvement in Acute Ischemic Stroke Patients (AIS) | 24 hours | Reduction in National Institute of Health Stroke Scale (NIHSS) ≥ 4 (baseline versus 24-Hour NIHSS). NIHSS range from 0 to 42, with higher scores representing worse neurological function. |
| Early Neurological Improvement in Patients With Intracerebral Hemorrhage (ICH) | 24 hours | Reduction in National Institute of Health Stroke Scale (NIHSS) ≥ 4 (baseline versus 24-Hour NIHSS). NIHSS range from 0 to 42, with higher scores representing worse neurological function. |
| Quality of Life Measures at 3 Months in AIS and ICH Patients | 3 months | Quality of life (WHO-5 Well-Being Index) measures in AIS and ICH patients at 3 months |
| Bed-day Use in AIS and ICH Patients | 3 months | Bed-day use, measured at 3 months, in AIS and ICH patients |
| Three-month and One-year Mortality | 3 and 12 months | All-cause mortality is assessed and subdivided into cardiovascular mortality versus non-cardiovascular mortality |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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) | 3 months | Clinical outcome (modified Rankin Scale (mRS) at 3 months in intracerebral hemorrhage patients and the extended remote ischemic postconditioning protocol The assessment will performed by two independent telephone or face-to-face assessors. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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. |
| Endovascular Treatment(EVT) -Eligibility (MRI Assessed) in RIC Treated AIS Patients With Large Vessel (Substudy at Aarhus University Hospital) | 6 hours | 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 |
| Infarct Growth in AIS Patients (Substudy at Aarhus University Hospital) | 24 hour | 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 | 24-hour hematoma growth (Difference in hematoma volume between acute and 24-hour CT/MRI) (Substudy at Aarhus University Hospital) |
| Difference in 7 Days Hematoma Volume in Patients With ICH (Substudy at Aarhus University Hospital) | 7 days | 7-day hematoma reduction (Difference in hematoma volume between acute and 7-day (day 5 to 9) CT ) (Substudy at Aarhus University Hospital) |
| Ektacytometry and Analytical Flow Cytometry for eryNOS3 Phosphorylation | 12 months | 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 | 12 months | MicroRNA and extracellular vesicle characterization of a possible RIC treatment profile (substudy at Aarhus University Hospital) |
| Prehospital microRNA and Extracellular Vesicles (Substudy at Aarhus University Hospital) | 12 months | 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 |
| Prehospital Glial Fibrillary Acidic Protein (Substudy at Aarhus University Hospital) | 12 months | 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 | 12 months | Functional and immunologic plasma assays will be employed to analyze proteins and pathways in coagulation and fibrinolysis (substudy at Aarhus University Hospital) |
| 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] | 3 months | Clinical outcome \[modified Rankin Scale (mRS) at 3 months in ischemic stroke patients and the extended remote ischemic postconditioning protocol Ordinal logistic regression analysis will be performed.The assessment will performed by two independent telephone or face-to-face assessors. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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. |
Countries
Denmark
Participant flow
Pre-assignment details
The RESIST trial is a prehospital stroke trial. Patients are randomzied to remote ischemic conditioning or sham in the ambualnce before their final diagnosis. Patients who have a stroke (ischemic stroke or intracerebral hemorrhage, n= 902) are the target population and treated further according to randomization and outcome assessed as 3 months modified Rankin Scale . Patients with a non stroke diagnosis (n=531) are not treated further and not followed beyond hospital discharge.
Participants by arm
| Arm | Count |
|---|---|
| Remote Ischemic Conditioning Remote Ischemic Conditioning (Active) | 436 |
| Sham Remote Ischemic Conditioning (Sham) | 466 |
| Total | 902 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Non stroke = non target population | 277 | 254 |
| Overall Study | Withdrawal by Subject | 36 | 31 |
Baseline characteristics
| Characteristic | Sham | Total | Remote Ischemic Conditioning |
|---|---|---|---|
| Age, Continuous | 73 years | 73 years | 72 years |
| Diagnosis Acute ischemic stroke | 388 Participants | 737 Participants | 349 Participants |
| Diagnosis Intracerebral hemorrhage | 78 Participants | 165 Participants | 87 Participants |
| National Institutes of Health Stroke Scale (NIHSS) | 5 points on NIHSS | 5 points on NIHSS | 5 points on NIHSS |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Denmark | 466 participants | 902 participants | 436 participants |
| Sex: Female, Male Female | 170 Participants | 335 Participants | 165 Participants |
| Sex: Female, Male Male | 296 Participants | 567 Participants | 271 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 713 | 47 / 720 |
| other Total, other adverse events | 54 / 713 | 11 / 720 |
| serious Total, serious adverse events | 335 / 713 | 325 / 720 |
Outcome results
Primary
Modified Rankin Scale at 3 Months in Acute Stroke (AIS and ICH)
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. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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.
Time frame: 3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Remote Ischemic Conditioning (RIC) | Modified Rankin Scale at 3 Months in Acute Stroke (AIS and ICH) | 2 units on a scale |
| Sham | Modified Rankin Scale at 3 Months in Acute Stroke (AIS and ICH) | 1 units on a scale |
Secondary
Bed-day Use in AIS and ICH Patients
Bed-day use, measured at 3 months, in AIS and ICH patients
Time frame: 3 months
Secondary
Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke
Clinical outcome (modified Rankin Scale) at 3 months in acute stroke patients (target diagnosis) (generalized ordinal logistic regression). TThe assessment will performed by two independent telephone or face-to-face assessors. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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.
Time frame: 3 months
Population: Acute ischemic stroke patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Remote Ischemic Conditioning (RIC) | Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke | 1 units on a scale |
| Sham | Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke | 1 units on a scale |
Secondary
Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke Receiving Reperfusion Therapy
Clinical outcome (modified Rankin Scale) at 3 months inacute ischemic stroke receiving reperfusion therapy (generalized ordinal logistic regression). The assessment will performed by two independent telephone or face-to-face assessors. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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.
Time frame: 3 months
Population: Patients with acute ischemic stroke who were treated with reperfusion therapies (intravenous thrombolysis and/or trombectomy)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Remote Ischemic Conditioning (RIC) | Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke Receiving Reperfusion Therapy | 1 units on a scale |
| Sham | Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke Receiving Reperfusion Therapy | 1 units on a scale |
Secondary
Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Patients With Intracerebral Hemorrhage (ICH)
Clinical outcome (modified Rankin Scale) at 3 months in patients with intracerebral hemorrhage (ICH) (generalized ordinal logistic regression). The assessment will performed by two independent telephone or face-to-face assessors. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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.
Time frame: 3 months
Population: Patients diagnosed with intracerebral hemorrhage
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Remote Ischemic Conditioning (RIC) | Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Patients With Intracerebral Hemorrhage (ICH) | 3 units on a scale |
| Sham | Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Patients With Intracerebral Hemorrhage (ICH) | 3 units on a scale |
Secondary
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
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Remote Ischemic Conditioning (RIC) | Difference in Proportion of Patients With Complete Remission of Symptoms Within 24 Hours (TIA; Both With and Without DWI) | 96 Participants |
| Sham | Difference in Proportion of Patients With Complete Remission of Symptoms Within 24 Hours (TIA; Both With and Without DWI) | 90 Participants |
Secondary
Difference Neurological Impairment During the First 24 Hours
Neurological deficits are documented using Prehospital Stroke Score (PreSS). Prehospital Stroke Score is assessed in the the ambulance and 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). The PreSS score range from 0-6, with 6 representing the most severe neurological deficits.
Time frame: 24 hours
Population: 24-hour difference in prehospital stroke score
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Remote Ischemic Conditioning (RIC) | Difference Neurological Impairment During the First 24 Hours | -1 units on a scale |
| Sham | Difference Neurological Impairment During the First 24 Hours | -2 units on a scale |
Secondary
Early Neurological Improvement in Acute Ischemic Stroke Patients (AIS)
Reduction in National Institute of Health Stroke Scale (NIHSS) ≥ 4 (baseline versus 24-Hour NIHSS). NIHSS range from 0 to 42, with higher scores representing worse neurological function.
Time frame: 24 hours
Population: Target population with acute stroke
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Remote Ischemic Conditioning (RIC) | Early Neurological Improvement in Acute Ischemic Stroke Patients (AIS) | 108 Participants |
| Sham | Early Neurological Improvement in Acute Ischemic Stroke Patients (AIS) | 131 Participants |
Secondary
Early Neurological Improvement in Patients With Intracerebral Hemorrhage (ICH)
Reduction in National Institute of Health Stroke Scale (NIHSS) ≥ 4 (baseline versus 24-Hour NIHSS). NIHSS range from 0 to 42, with higher scores representing worse neurological function.
Time frame: 24 hours
Secondary
Major Adverse Cardiac and Cerebral Events (MACCE)
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.
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Remote Ischemic Conditioning (RIC) | Major Adverse Cardiac and Cerebral Events (MACCE) | 57 Participants |
| Sham | Major Adverse Cardiac and Cerebral Events (MACCE) | 62 Participants |
Secondary
Quality of Life Measures at 3 Months in AIS and ICH Patients
Quality of life (WHO-5 Well-Being Index) measures in AIS and ICH patients at 3 months
Time frame: 3 months
Secondary
Three-month and One-year Mortality
All-cause mortality is assessed and subdivided into cardiovascular mortality versus non-cardiovascular mortality
Time frame: 3 and 12 months
Other Pre-specified
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)
Clinical outcome (modified Rankin Scale (mRS) at 3 months in intracerebral hemorrhage patients and the extended remote ischemic postconditioning protocol The assessment will performed by two independent telephone or face-to-face assessors. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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.
Time frame: 3 months
Other Pre-specified
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]
Clinical outcome \[modified Rankin Scale (mRS) at 3 months in ischemic stroke patients and the extended remote ischemic postconditioning protocol Ordinal logistic regression analysis will be performed.The assessment will performed by two independent telephone or face-to-face assessors. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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.
Time frame: 3 months
Other Pre-specified
Coagulation Profile of Putative Stroke Patients in Prehospital Obtained Blood Samples
Functional and immunologic plasma assays will be employed to analyze proteins and pathways in coagulation and fibrinolysis (substudy at Aarhus University Hospital)
Time frame: 12 months
Other Pre-specified
Difference in 7 Days Hematoma Volume in Patients With ICH (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)
Time frame: 7 days
Other Pre-specified
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)
Time frame: 24 hour
Other Pre-specified
Ektacytometry and Analytical Flow Cytometry for eryNOS3 Phosphorylation
Ektacytometry for Erythrocytic Deformability and Analytical Flow Cytometry (FC) for eryNOS3 phosphorylation (pNOS3Ser1177) and s-nitrosylation (-SNO) in RBC
Time frame: 12 months
Other Pre-specified
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
Time frame: 6 hours
Other Pre-specified
Infarct Growth in AIS Patients (Substudy at Aarhus University Hospital)
24-hour infarct growth on DWI-MRI (Difference in lesion volume between acute and 24-hour DWI-MRI) (Substudy at Aarhus University Hospital)
Time frame: 24 hour
Other Pre-specified
MicroRNA and Extracellular Vesicle Profile of RIC-induced Neuroprotection
MicroRNA and extracellular vesicle characterization of a possible RIC treatment profile (substudy at Aarhus University Hospital)
Time frame: 12 months
Other Pre-specified
Prehospital Glial Fibrillary Acidic Protein (Substudy at Aarhus University Hospital)
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
Time frame: 12 months
Other Pre-specified
Prehospital microRNA and Extracellular Vesicles (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
Time frame: 12 months