Oxford Acute Myocardial Infarction - Pressure-controlled Intermittent Coronary Sinus Occlusion

The OxAMI-PICSO is a study about the use of pressure controlled intermittent coronary sinus occlusion (PICSO) to improve the treatment of patients presenting with heart attack. PICSO is a device consisting of a balloon which is deployed in the coronary sinus. When inflated the balloon can improve the blood flow to the region of heart affected by the heart attack. The study aims to analyse the potential benefit of PICSO in improving blood flow to heart muscle in a selected group of patients admitted with a large heart attack involving the anterior wall of the heart. The comparator group will be a well-matched group of participants of the ongoing OxAMI study.

In order to select patients with a large heart attack, we will measure the index of microcirculatory resistance (IMR), before completion of the heart attack treatment procedure. The IMR value provides measurement of the blood flow at the level of the tiny vessels branching from the large coronary arteries. Our preliminary data from the OxAMI study have shown that an IMR \> 40 suggests that the patient is having a large myocardial infarction (heart attack). Only patients with starting IMR \> 40 will be considered eligible for the PICSO treatment.

The benefit of PICSO will be assessed by measuring 1) indexes of coronary blood flow, 2) the extension of the infarcted area and 3) the levels of different molecules released in the blood.

The OxAMI-PICSO study is a prospective single centre observational cohort study of the use of pressure-control intermittent coronary sinus occlusion (PICSO) in patients presenting for primary percutaneous coronary intervention (PCI) for acute myocardial infarction.

Patients, age 30-90, presenting with ST elevation myocardial infarction will be considered for inclusion in the study. Measurement of index of microcirculatory resistance (IMR) before stenting is an essential prerequisite for the study: only patients with pre-stenting IMR \> 40 will be considered eligible for the PICSO treatment. Patients with IMR≤ 40 will remain in the study but will not undergo PICSO treatment.

The procedure for consent in patients undergoing emergency PCI will be as already established in the ongoing OxAMI study (Ethics Ref 11/SC/0397) Because of the urgency of the situation it is not feasible to obtain fully informed written consent. Fully informed consent requires that the potential participant have time to read and reflect on a patient information sheet which in this context is clinically inadvisable. We therefore propose to obtain verbal assent so as to optimize the amount of appropriate information conveyed to potential participants acutely and minimize the clinical risks involved with substantial delay. The research study will be discussed verbally with the patient and the risks and benefits explained. Only conscious patients, able to provide verbal assent will be enrolled in the study.

In detail the patient at the time of verbal assent process will be informed that as part of the research project he/she might undergo to measurement of the index of microcirculatory resistance (IMR) which allows to have an indirect assessment of the entity of the ongoing heart attack. The patient will be also informed that in case IMR value will be greater than 40, thus suggesting a possible significant damage to the heart muscle that may benefit from additional treatment, he/she might be asked to provide assent for PICSO treatment. Patients with pre-stenting IMR ≤ 40 or those with pre-stenting IMR \> 40 who elect not to receive PICSO treatment will be given the opportunity to continue to participate within the OxAMI-PICSO study, but without the use of the PICSO device.

Participants will be reminded that they have the right to withdraw from the study at any stage and that this will not affect their treatment or human rights. Once the emergency phase is over and treatment has been delivered, full written informed consent will be sought as soon as practical. For most patients this means within 12 hours of admission.

The PCI procedure will be undertaken in a standard fashion, and include the use of pressure wire measurements before and after stent deployment.

Only patients with pre-stenting IMR \> 40 and who assent to receive PICSO treatment will undergo 24 hours coronary angiogram with coronary physiology measurement, 24-48 hours CMR scan and 6 months CMR scan. Patients who assent to participate in the study but in whom the pre-stenting IMR ≤ 40, or those in whom the pre-stenting IMR \> 40 but the participant declines PICSO treatment will remain in the study for clinical data collection only at the same follow up time points (24 hours, 48 hours and 6 months).

The control group of the OxAMI-PICSO study will be represented by a matched cohort of patients with STEMI with pre-stenting IMR greater than 40 units already enrolled as part of the OxAMI study (Ethics Ref 11/SC/0397)

In details the OxAMI-PICSO study will consist of five stages:

Stage 1: Pre-Stenting

1. Diagnostic angiography will be performed in the standard manner using appropriate catheters.
2. Bivalirudin will be administered (0.75mg/kg bolus followed by an infusion of 1.75 mg/kg/min for up 4 hours after the procedure as clinically warranted), as routinely used for PCI. The lesion will be crossed with a coronary guide wire in the usual manner for PCI. Normal blood flow will be rapidly achieved by thrombus aspiration and/or predilation
3. Pre-stenting IMR will be measured, using a pressure wire, as used for routine clinical measurements in patients undergoing PCI.
4. If pre-stenting IMR is \> 40, patients will be invited to receive the PICSO device. If pre-stenting IMR is ≤ 40 PICSO device will not be proposed, but the patient will be invited to remain in the study for routine clinical data collection.

Stage 2: PICSO treatment

1. In patients with IMR \>40 who assent to PICSO treatment, the PICSO device will be deployed and PICSO treatment delivered until a PICSO dose of 800 mmHg is achieved

Stage 3: Stenting

1. Stenting is performed as usual clinical practice.
2. Post-dilation is left to operator's discretion, as in clinical routine.
3. At the end of the procedure a final reassessment of IMR is performed again as previously described.

Stage 4: 24-48 hours post PCI

Full written consent to take part to the OxAMI-PICSO study is obtained as soon as practicable. The following study assessments may be carried out:

1. Repeat coronary angiogram for assessment of coronary physiology parameters assessment - for participants who receive the PICSO device only
2. Cardiac magnetic resonance - for participants who receive the PICSO device only
3. Data Collection, Patient Reported Outcomes and Cardiovascular Outcomes

Stage 5: 6 months post PCI Participants will be invited to attend the hospital as an outpatient at approximately 6 months post-PPCI for the following research assessments

1. Cardiovascular MRI - for participants who receive the PICSO device only
2. Data Collection, Patient Reported Outcomes and Cardiovascular Outcomes

Recruitment to the study will cease as soon as 25 participants have undergone PICSO treatment and have completed follow-up at 6 months. The study will end on the date of the last CMR at 6 months follow up of the last participant recruited.

Sample Size

The OxAMI-PICSO study aims to investigate the potential benefit of PICSO in a highly selected population of STEMI patients. In line with the data reported by Sayeed et al in a previous metanalysis on 7 studies about PICSO application in animal models, the recently published Prepare-RAMSES study also observed a 30% reduction in IS in the treatment arm, however such reduction was not statistically significant in comparison to the control arm. The study, however could still show a benefit of PICSO in terms of IS reduction at six months follow up in the subgroup of patients receiving high PICSO quantity. The study, however, was significantly hampered by the inclusion of relative low risk patients and by a small sample size. The author managed indeed to deliver full PICSO treatment only in 63% of the initial planned cohort (12 patients, of the 30 planned, received a prolonged treatment with PICSO).

In order to address the first limitation of the Prepare-RAMSES study, OxAMI-PICSO study will select patients with a pre-stenting higher IMR. In this way PICSO is meant to be applied only in a population at higher risk and highly likely to get benefit from its application.

In this regard assuming that the stricter inclusion criteria may allow to detect a substantial benefit from PICSO compared to the control group and expecting that this will allow to achieve a significant 29% reduction in IS as shown in Sayeed's metanalysis, we initially calculated a final sample size of 12 patients with complete final data per each group with an interval of confidence at 95% and a 80% power. However, considering that this was the final same sample size enrolled in the Prepare-RAMSES study, initially meant to recruit 30 patients per arm, we propose to double the actual sample size from 12 to 25 per arm.

Allowing for participants who do not wish to undergo repeat cardiac catheterisation, or cardiac MRI, we anticipate that approximately 75 patients may be recruited to the study in order to achieve full participation and complete follow up in 25 subjects.

Eligibility Criteria:
Inclusion Criteria:

* Male or Female, aged 30 to 90 years,
* Clinical presentation with STEMI
* Referred for coronary angiography with view to proceed to PCI with stenting.

Exclusion Criteria:

* Patients in whom safety or clinical concerns preclude participation.
* Known anaemia (Hb \<9).
* Pregnant or breast feeding females.
* Revascularization by mean of balloon angioplasty without stenting
* History of stroke, TIA or reversible ischemic neurological disease within last 6 months
* Known severe renal failure (eGFR \< 30 ml/min/1.73m2) or history of dialysis or renal transplant
* Previous coronary bypass artery grafting
* Known severe valvular abnormalities
* Previous STEMI presentation
* Presentation with cardiogenic shock
* Severe bradycardia (Heart rate \< 50 beats per minutes)
* STEMI due to stent thrombosis
* Unconscious on presentation
* Non-cardiac comorbidities and life expectancy \< 1 year
* Use of warfarin
* Presence of pacemaker or other electrodes in the coronary sinus
* Contraindications to adenosine
* Additional exclusion criteria for participants undergoing CMR

  * claustrophobia which limits / prevents participants from remaining in CMR scanner.
  * patients who cannot lie flat on the scan table.
  * patients with metallic implants, pacemakers, implantable defibrillators etc, unless known to be CMR compatible.
  * patients with known allergy to medium of contrast (gadolinium)