Clinical trial NCT04813159: Remote Ischaemic Conditioning in STEMI Patients in AFRICA
Official title: Remote Ischaemic Conditioning in STEMI Patients in AFRICA: The RIC-AFRICA Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: STEMI
Remote Ischaemic Conditioning
Myocardial Reperfusion Injury
Keywords: Cardioprotection
Ischaemia/reperfusion injury
ST-Elevation myocardial infarction
Hospitalisation for post-myocardial infarction heart failure
Remote Ischaemic Conditioning
Cardiovascular mortality
STEMI
Lead sponsor: University of Cape Town
Sponsor class: OTHER
Collaborators: name: Groote Schuur Hospital, South Africa
name: Uganda Heart Institute
name: Mombasa Hospital, Kenya
name: Coast General Teaching Hospital, Kenya
name: Kenyatta National Hospital
name: Al Shaab Teaching Hospital, Sudan
name: Sudan Heart Centre, Sudan
name: Aliaa Specialist Hospital, Sudan
name: Medani Heart Centre, Sudan
name: Al Saha Specialised Hospital, Sudan
name: Omdurman Hospital, Sudan
name: Victoria Hospital, South Africa
name: George Hospital, South Africa
name: Charlotte Maxeke Hospital, South Africa
name: Tshepong Hospital, South Africa
name: Wentworth Hospital, South Africa
name: Grey's Hospital
name: Universitas Academic Hospital, South Africa
name: University College, London
name: Royal Care international Hospital, Sudan
name: Nairobi West Hospital, Kenya
First posted: 2021-03-24
Enrollment: 1400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: The RIC-AFRICA trial is a multi-centre, sham-controlled, randomised controlled trial (RCT) involving 1400 ST-segment elevation myocardial infarction (STEMI) patients presenting within ≤ 24 hours of myocardial infarction (MI) onset, across approximately 25 sites in 7 African countries (South Africa, Kenya, Sudan, Uganda, Mozambique, Senegal and Mauritius). 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: 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 Africa.

Study design:

The RIC-AFRICA trial is a multi-centre, sham-controlled, randomised controlled trial (RCT) involving 1400 ST-segment elevation myocardial infarction (STEMI) patients presenting within ≤ 24 hours of myocardial infarction (MI) onset, across approximately 20 sites in 7 African countries (South Africa, Kenya, Sudan, Uganda, Mozambique, Senegal and Mauritius). 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 Africa, thereby potentially providing a low-cost, non-invasive therapy for improving health outcomes.

Eligibility criteria: We will be recruiting 3 different strata of STEMI patients.

1. 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).
2. 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.
3. 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:

1. severe active skin disease/burns on both arms; or
2. bilateral upper limb amputations; or
3. evidence of acute limb ischaemia on either arm; or
4. active upper limb gangrene of any digits;
5. breast cancer with lymph-node involvement on the ipsilateral side of RIC; or
6. 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:

1. Compatible history with maximal chest pain between 24 -72 hours prior to presentation; and
2. Compatible biomarkers (elevated cardiac troponin); and
3. ECG compatible with recent STEMI; and/or
4. Compatible echocardiography.

Exclusion criteria

I. Refusal or inability to sign informed consent.

Primary outcomes:
measure: All-cause death and early post-MI heart failure
timeFrame: 30 days
Secondary outcomes:
measure: Composite clinical endpoint for MACCE
timeFrame: 30 days
Other outcomes:
Locations:
city: Mombasa
country: Kenya
facility: Coast General Teaching Hospital
city: Mombasa
country: Kenya
facility: Mombasa Hospital
city: Nairobi
country: Kenya
facility: Kenyatta National Hospital
city: Nairobi
country: Kenya
facility: Nairobi West hospital
city: Maputo
country: Mozambique
facility: Hospital Central de Mpauto
city: Dakar
country: Senegal
facility: Hopital Principal de Dakar
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Hospital
state: Gauteng
city: Durban
country: South Africa
facility: Wentworth Hospital
state: KwaZulu Natal
city: Klerksdorp
country: South Africa
facility: Tshepong Hospital
state: North West
city: Cape Town
country: South Africa
facility: Mitchell's Plain District Hospital
state: Western Cape
city: Cape Town
country: South Africa
facility: Groote Schuur Hospital
state: Western Cape
city: Cape Town
country: South Africa
facility: Victoria Hospital
state: Western Cape
city: George
country: South Africa
facility: George Hospital
state: Western Cape
city: Khartoum
country: Sudan
facility: Al Saha Specialised Hospital
state: Khartoum State
city: Khartoum
country: Sudan
facility: Al Shaab Teaching Hospital
state: Khartoum State
city: Khartoum
country: Sudan
facility: Sudan Heart Centre
state: Khartoum State
city: Khartoum
country: Sudan
facility: The Royal Care International Hospital
city: Omdurman
country: Sudan
facility: Aliaa Specialist Hospital
city: Wad Medani
country: Sudan
facility: Medani Heart Centre
city: Kampala
country: Uganda
facility: Uganda Heart Institute
Study officials:
affiliation: University of Cape Town
name: Mpiko Ntsekhe, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hatter Cardiovascular Institute
name: Derek Hausenloy, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hatter Cardiovascular Institute
name: Derek Yellon, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hatter Cardiovascular Institute
name: Malcolm Walker, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lukhna K, Hausenloy DJ, Ali AS, Bajaber A, Calver A, Mutyaba A, Mohamed AA, Kiggundu B, Chishala C, Variava E, Elmakki EA, Ogola E, Hamid E, Okello E, Gaafar I, Mwazo K, Makotoko M, Naidoo M, Abdelhameed ME, Badri M, van der Schyff N, Abozaid O, Xafis P, Giesz S, Gould T, Welgemoed W, Walker M, Ntsekhe M, Yellon DM. Remote Ischaemic Conditioning in STEMI Patients in Sub-Saharan AFRICA: Rationale and Study Design for the RIC-AFRICA Trial. Cardiovasc Drugs Ther. 2023 Apr;37(2):299-305. doi: 10.1007/s10557-021-07283-y. Epub 2021 Nov 5.