Remote Ischaemic Conditioning in STEMI Patients in Sub-Saharan AFRICA

Study Overview
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Brief Summary
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The RIC-AFRICA trial is a multi-centre, sham-controlled, double-blinded, randomised controlled trial (RCT) involving 1200 ST-segment elevation myocardial infarction (STEMI) patients presenting within ≤ 24 hours of myocardial infarction (MI) onset, across approximately 20 sites in four sub-Saharan African countries (South Africa, Kenya, Sudan and Uganda). Patients presenting with STEMI and deemed ineligible for the RIC AFRICA RCT because they present >24 hours from MI onset but less than 72 hours, will be recruited into the observational arm of the study with the same endpoints as the trial. The purpose of the RCT is to determine whether Remote Ischaemic Conditioning (RIC) can reduce the rates of all-cause death and early post-myocardial heart failure at 30-days in STEMI patients treated predominantly with thrombolytic therapy.

Detailed Description
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Background: Remote ischaemic conditioning (RIC) using transient limb ischaemia and reperfusion has been shown to reduce myocardial infarct size in animal studies and small proof-of-concept clinical studies in ST-segment elevation myocardial infarction (STEMI) patients. However, RIC failed to improve clinical outcomes in the large European CONDI-2/ERIC-PPCI multi-centre randomised clinical trial. Potential reasons for this failure include the low-risk patients recruited into the study and the fact that patients received timely and optimal reperfusion therapy by primary percutaneous coronary intervention. The RIC-AFRICA trial will investigate whether RIC can improve clinical outcomes in higher-risk STEMI patients treated by thrombolysis in sub-Saharan Africa. Study design: The RIC-AFRICA trial is a multi-centre, sham-controlled, double-blinded, randomised controlled trial (RCT) involving 1200 ST-segment elevation myocardial infarction (STEMI) patients presenting within ≤ 24 hours of myocardial infarction (MI) onset, across approximately 20 sites in four sub-Saharan African countries (South Africa, Kenya, Sudan and Uganda). Patients will be randomised to receive either RIC or sham control initiated prior to thrombolysis and applied daily for the next 2 days. The RIC protocol will comprise four 5-minute cycles of inflation (to 20mmHg above systolic blood pressure) and deflation of an automated pneumatic cuff placed on the upper arm. The sham control protocol will comprise four 5-minute cycles of low-pressure inflation (to 20mmHg) and deflation by a visually identical pneumatic cuff. The primary composite endpoint will be all-cause death and new-onset heart failure at 30-days post STEMI. Patients presenting with STEMI and deemed ineligible for the RIC AFRICA RCT because they present >24 hours from MI onset but less than 72 hours, will be recruited into the observational arm of the study with the same endpoints as the trial. Implications: The RIC-AFRICA trial will determine whether RIC can reduce rates of death and prevent heart failure in higher-risk STEMI patients treated by thrombolytic therapy in sub-Saharan Africa, thereby potentially providing a low-cost, non-invasive therapy for improving health outcomes.

Official Title
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Remote Ischaemic Conditioning in STEMI Patients in Sub-Saharan AFRICA: The RIC-AFRICA Trial

Conditions
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STEMI, Remote Ischaemic Conditioning, Myocardial Reperfusion Injury

Intervention / Treatment
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* Device: Remote Ischaemic Conditioning (RIC)
* Device: Sham-control


Participation Criteria
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Eligibility Criteria
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We will be recruiting 3 different strata of STEMI patients. Adult patients (≥18 years old) presenting with STEMI receiving thrombolytic therapy within guideline-recommended time (i.e., within <12 hours of most severe chest pain onset). Adult patients (≥18 years old) presenting with STEMI who are ineligible for thrombolysis because they present outside of guideline-recommended time (<12 hours) but within 24 hours of most severe chest pain onset. Adult patients (≥18 years old) presenting with evidence of STEMI who do not receive thrombolysis and who present ≥24 hours and within 72 hours of most severe chest pain onset. Interventional arm of the Study: Randomized Control Trial Patients who are deemed eligible for randomization into the trial on account of presentation with STEMI within 24 hours, will be eligible for the interventional arm of the study if the following inclusion/exclusion criteria are met. Inclusion Criteria I. Adult patients (≥18 years old) presenting with suspected STEMI (ST-elevation at the J-point in two contiguous leads ( ≥ 0.2mV in men or ≥ 0.15mV in women in leads V2-V3 and/or ≥ 0.1mV in other lead); and II. Within 24 hours of onset of myocardial infarction as deemed by the attending clinician; and III. Signed informed consent. Exclusion criteria I. STEMI patients due to undergo primary percutaneous coronary intervention; II. STEMI patients presenting with cardiogenic shock or haemodynamic instability as defined by: systolic blood pressure (SBP) measurement of <90 mm Hg for ≥30 minutes; or use of pharmacological and/or mechanical support to maintain SBP ≥ 90 mm Hg; and evidence of end-organ damage defined by: urine output of <30 mL/h; altered mental status; and/or serum lactate >2.0 mmol/L; III. Contraindications for the use of RIC or sham-control on either arm such as: severe active skin disease/burns on both arms; or bilateral upper limb amputations; or evidence of acute limb ischaemia on either arm; or active upper limb gangrene of any digits; breast cancer with lymph-node involvement on the ipsilateral side of RIC; or bilateral arteriovenous fistulae needed for haemodialysis. IV. Inter-current disease with an expected life expectancy of less than 24 hours; V. Contra-indication to thrombolytic therapy in patients presenting within guideline-recommended time (<12 hours). Observational arm of the study Patients who are deemed ineligible for randomization into the trial on account of presentation beyond 24 hours, will be eligible for the observational arm of the study if the following inclusion/exclusion criteria are met. Inclusion Criteria I. Signed informed consent; and II. Clinical evidence of STEMI older than 24 hours and less than 72 hours as defined by: Compatible history with maximal chest pain between 24 -72 hours prior to presentation; and Compatible biomarkers (elevated cardiac troponin); and ECG compatible with recent STEMI; and/or Compatible echocardiography. Exclusion criteria I. Refusal or inability to sign informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Consented participants presenting with STEMI within 24 hours and who fulfil the study's eligibility criteria will be assigned a participant identification number and randomised to receive either RIC or sham control in a 1:1 ratio to ensure equal distribution amongst experimental arm. Randomisation will be conducted via a secure website and will be stratified by recruiting centre and patient stratum to ensure that a minimum of 2 participants in stratum 1 (eligible for thrombolysis and within <12 hours of MI onset) are recruited for every participant in stratum 2 (ineligible for thrombolysis because they present outside of guideline-recommended time (<12 hours) but presenting within 24 hours of most severe chest pain onset). The patient, treating clinician, study investigator and research team analysing the data will be blinded to the treatment allocation. Study intervention will be applied by the research nurse who will not have any further contact with the participant or trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Remote Ischaemic Conditioning (RIC)<br>Consented STEMI participants presenting < 24 hours who are randomised to the RIC protocol, will receive blood pressure cuff inflation by the automated RIC blood pressure device to 20 mmHg above systolic blood pressure for 5 minutes and deflation for a further 5 minutes, a cycle which will be completed four times in total. The RIC protocol will be repeated daily for the next 2 days. | Device: Remote Ischaemic Conditioning (RIC)<br>* The RIC protocol will comprise inflation of the automated RIC device to 20 mmHg above systolic blood pressure for 5 minutes and deflation for a further 5 minutes, a cycle which will be completed four times in total. The RIC protocol will be repeated daily for the next 2 days.<br>|
| Sham Comparator: Sham-control<br>Consented STEMI participants presenting < 24 hours who are randomised to the sham protocol will receive low-pressure cuff inflation to 20 mmHg for 5 minutes and deflation for a further 5 minutes, a cycle which will be completed four times in total by a visually identical pneumatic cuff. The sham control protocol will be repeated daily for the next 2 days. | Device: Sham-control<br>* The sham protocol will comprise low-pressure inflation to 20 mmHg for 5 minutes and deflation for a further 5 minutes, a cycle which will be completed four times in total by a visually identical pneumatic cuff used in the active arm. The sham control protocol will be repeated daily for the next 2 days.<br>|
| No Intervention: Observational<br>Consented STEMI participants presenting > 24 hours but within 72 hours of MI onset will be recruited into the observational arm of the study which will have the same study endpoints as the RCT. These participants will not be randomised or receive any trial intervention. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause death and early post-MI heart failure | The primary endpoint of the study will be a composite of all-cause death and early post-MI heart failure. The latter describes both a] pre-discharge (in-hospital) heart failure; or b] post discharge heart failure hospitalisation within 30 days for patients discharged free of heart failure after the index MI admission. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite clinical endpoint for MACCE | Secondary outcome measures will include a composite clinical endpoint of MACCE at 30 days follow-up, defined as rates of (i) all-cause mortality; (ii) non-fatal myocardial infarction; (iii) transient ischaemic attack or stroke; and (iv) heart failure with or without hospitalisation. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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STEMI, Cardioprotection, Ischaemia/reperfusion injury, ST-Elevation myocardial infarction, Hospitalisation for post-myocardial infarction heart failure, Remote Ischaemic Conditioning, Cardiovascular mortality