Remote Ischaemic Conditioning in STEMI Patients in AFRICA

Official title

Remote Ischaemic Conditioning in STEMI Patients in AFRICA: The RIC-AFRICA Trial

Overview

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.

Interventions

• Device Remote Ischaemic Conditioning (RIC)
  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.
• Device Sham-control
  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.

Primary outcome measures

• All-cause death and early post-MI heart failure [Time frame: 30 days]

Secondary outcome measures (1)

• Composite clinical endpoint for MACCE [Time frame: 30 days]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

South Africa · 7 centers

• Charlotte Maxeke Hospital — Johannesburg
• Wentworth Hospital — Durban
• Tshepong Hospital — Klerksdorp
• Mitchell's Plain District Hospital — Cape Town
• Groote Schuur Hospital — Cape Town
• Victoria Hospital — Cape Town
• George Hospital — George

Sudan · 6 centers

• Al Saha Specialised Hospital — Khartoum
• Al Shaab Teaching Hospital — Khartoum
• Sudan Heart Centre — Khartoum
• The Royal Care International Hospital — Khartoum
• Aliaa Specialist Hospital — Omdurman
• Medani Heart Centre — Wad Medani

Kenya · 4 centers

• Coast General Teaching Hospital — Mombasa
• Mombasa Hospital — Mombasa
• Kenyatta National Hospital — Nairobi
• Nairobi West hospital — Nairobi

Mozambique · 1 center

• Hospital Central de Mpauto — Maputo

Senegal · 1 center

• Hopital Principal de Dakar — Dakar

Uganda · 1 center

• Uganda Heart Institute — Kampala

Publications

• 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 a PMID 34739648

Identifiers

NCT: NCT04813159 · RIC AFRICA

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗