Safety and Effectiveness of Intra-coronary Nitrite in Acute Myocardial Infarction (NITRITE-AMI)

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

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.

Study Overview

• Status: Completed
• Conditions: Myocardial Infarction; Myocardial Ischemia; Cardiovascular Diseases; Reperfusion Injury
• Intervention / Treatment: Drug: Sodium Nitrite; Drug: Sodium Chloride Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London
    • Bethnal Green, London, United Kingdom, E2 9JX
      • London Chest Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Sodium Chloride Placebo; The control intervention is a bolus of 0.9% sodium chloride solution (prepared with an identical appearance to the sodium nitrite).
EXPERIMENTAL: Sodium Nitrite	Drug: Sodium Nitrite; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Barts & The London NHS Trust
• Collaborators: Queen Mary University of London
• Investigators: Principal Investigator: Anthony Mathur, FRCP, PhD, Barts and the London NHS Trust/QMUL

Publications and helpful links

General Publications

• Jones DA, Khambata RS, Andiapen M, Rathod KS, Mathur A, Ahluwalia A. Intracoronary nitrite suppresses the inflammatory response following primary percutaneous coronary intervention. Heart. 2017 Apr;103(7):508-516. doi: 10.1136/heartjnl-2016-309748. Epub 2016 Sep 28.
• Jones DA, Pellaton C, Velmurugan S, Rathod KS, Andiapen M, Antoniou S, van Eijl S, Webb AJ, Westwood MA, Parmar MK, Mathur A, Ahluwalia A. Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction. Circ Res. 2015 Jan 30;116(3):437-47. doi: 10.1161/CIRCRESAHA.116.305082. Epub 2014 Dec 15. Erratum In: Circ Res. 2015 Mar 27;116(7):e55.
• Jones DA, Andiapen M, Van-Eijl TJ, Webb AJ, Antoniou S, Schilling RJ, Ahluwalia A, Mathur A. The safety and efficacy of intracoronary nitrite infusion during acute myocardial infarction (NITRITE-AMI): study protocol of a randomised controlled trial. BMJ Open. 2013 Apr 2;3(4):e002813. doi: 10.1136/bmjopen-2013-002813. Print 2013.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2012
• Primary Completion (ACTUAL): November 1, 2013
• Study Completion (ACTUAL): January 1, 2016

Study Registration Dates

• First Submitted: April 23, 2012
• First Submitted That Met QC Criteria: April 24, 2012
• First Posted (ESTIMATE): April 25, 2012

Study Record Updates

• Last Update Posted (ACTUAL): November 29, 2017
• Last Update Submitted That Met QC Criteria: November 28, 2017
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Heart Diseases; Vascular Diseases; Postoperative Complications; Myocardial Infarction; Infarction; Myocardial Ischemia; Cardiovascular Diseases; Ischemia; Reperfusion Injury
• Other Study ID Numbers: 11/LO/1500