Safety and Effectiveness of Intra-coronary Nitrite in Acute Myocardial Infarction

Study Overview
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Brief Summary
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Despite advances in the treatment of heart attacks the complications and death rates from failure of the heart to pump properly after treatment remain high. A heart attack occurs when one or more of the arteries that supply blood to the heart become blocked, causing the heart to be starved of oxygen and nutrients. This results in damage to the heart and so the the heart pumps less well. The main treatment for a heart attack is balloon treatment to open the blocked artery (called primary angioplasty). Whilst re-opening the artery is essential and allows blood to flow to the area of the heart starved of oxygen, this process also causes damage itself (called reperfusion injury) and increases the size of the heart attack further. Currently there are no treatments available that reduce this reperfusion injury. The investigators and others have shown that a substance called sodium nitrite reduces reperfusion injury in experimental models of a heart attack. The aim of this research is to perform a trial to investigate whether during a heart attack, an infusion of sodium nitrite into the damaged artery protects against reperfusion injury and reduces heart attack size in patients.

Detailed Description
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Coronary heart disease is still the commonest cause of death in the UK (in the main as a consequence of acute myocardial infarction (AMI)). Presently, timely and effective reperfusion with primary percutaneous coronary intervention (PPCI) remains the most effective treatment strategy for limiting infarct size, preserving left ventricular ejection fraction (LVEF), and improving the clinical outcomes in such patients. However, substantial mortality and morbidity rates still persist with respect to longer term outcome. One of the main determinants of prognosis after AMI is the size of the infarct. Thus, identification of additional strategies that might decrease infarct size is desirable. Evidence from pre-clinical studies suggests that inorganic nitrite administration reduces infarct size in animal models of AMI. In this study we aim to translate these findings into man. We will test the hypothesis that in patients with STEMI undergoing PPCI, an intra-coronary injection of nitrite, initiated prior to establishment of full reperfusion reduces infarct size through prevention of ischemia-reperfusion injury.

Official Title
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A Randomised, Double-blind, Placebo-controlled Trial Assessing the Safety and Efficacy of Intracoronary Nitrite Infusion During Acute Myocardial Infarction

Conditions
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Myocardial Infarction, Reperfusion Injury, Myocardial Ischemia, Cardiovascular Diseases

Intervention / Treatment
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* Drug: Sodium Nitrite
* Drug: Sodium Chloride Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged at least 18 years Acute STEMI with ECG showing ST-segment elevation of 1mm or more in two adjacent limb leads or 2mm or more in at least two contiguous precordial leads or new left bundle branch block; Haemodynamically stable Estimated symptom to balloon or aspiration time < 6 hours Angiographically i) PPCI indicated for revascularisation ii) Single epicardial artery to be treated iii) Expected ability to use over the wire balloon Exclusion Criteria: Patients on organic nitrate treatment (Nicorandil, isosorbide mononitrate) Previous history of AMI, systolic dysfunction or CABG Subjects presenting with cardiogenic shock (systolic blood pressure <80 mmHg for > 30 minutes, or requiring inotropes/emergency intra aortic balloon pump or cardiopulmonary resuscitation Current diagnosis of or treatment for malignancy, other than non-melanoma skin cancer. Current life-threatening condition other than vascular disease that may prevent a subject completing the study. Use of an investigational device or investigational drug within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of study medication. Patients considered unsuitable to participate by the research team (e.g., due to medical reasons, laboratory abnormalities, or subject's unwillingness to comply with all study-related procedures). Severe acute infection, or significant trauma (burns, fractures). Pregnancy. Contra-indications to CMR scanning i) Pacemakers, intracranial clips or other metal implants ii) Claustrophobia iii) Renal failure (eGFR < 30mls/min) History of alcohol or drug abuse within the past 6 months. History of congenital methaemoglobinaemia. Angiographically severe vessel tortuosity, diffuse disease or severe calcification which may impede successful delivery of the the over the wire balloon.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sodium Nitrite<br> | Drug: Sodium Nitrite<br>* A bolus of sodium nitrite solution (1.8 micromol in 10 ml PRe-diluted in 0.9% sodium chloride in a syringe) will be delivered over 30-60 seconds via intracoronary injection initiated during the re-establishment of antegrade epicardial flow with PPCI.<br>|
| Placebo Comparator: Placebo<br> | Drug: Sodium Chloride Placebo<br>* The control intervention is a bolus of 0.9% sodium chloride solution (prepared with an identical appearance to the sodium nitrite).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infarct size measured by CK area under the curve | AUC measured over the 1st 48 hours after PPCI (0,4,8,12,18,24,36 and 48 hours) | 1st 48 hours after AMI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infarct size measured by Troponin T Area under the curve | AUC measured over the 1st 48 hours after PPCI (0,4,8,12,18,24,36 and 48 hours) | 1st 48 hours post AMI | 
| Infarct size, assessed by CMR at 6 months ± 2 weeks. | Infarct size, assessed by CMR at 6 months ± 2 weeks. | 6 months ± 2 weeks. | 
| Infarct size as a proportion of area at risk measured at 48 hours by CMR. | Infarct size as a proportion of area at risk measured at 48 hours by CMR. | 48 hours | 
| The acute safety and tolerability of intra-coronary nitrite in STEMI | Safety profile of IC nitrate (death, MI, CVA, arrhythmia, hypotension, methaemoglobinaemia) | 1st 48 hours | 
| Assessment of MACE endpoints at 6 and 12 months (death, heart failure, myocardial infarction, stroke, need for repeat revascularisation) |  | 12 months | 
| Markers of inflammation measured at baseline, 30 minutes, 4 and 24 hours post PCI | hs-CRP, MCP-1 | 24 hours | 
| Assessment of platelet reactivity at baseline, 30 minutes, 4 and 24 hours post PCI | ADP, collagen, PBS | 24 hours | 
| Plasma nitrite and cyclic guanosine monophosphatase (cGMP) concentrations measured at baseline, post procedure, at 4 hours and 24 hours post-PCI |  | 24 hours | 
| Cost-utility of Nitrite over at 3 years | ICER based on outcome and QoL (EQ5D) | 3 years |