The safety and efficacy of intracoronary nitrite infusion during acute myocardial infarction (NITRITE-AMI): a single centre, randomised, double-blind controlled trial.

DA Jones1,2, C Pellaton2, S Velmurugan1,2, M Andiapen2, S Antoniou2, S Van Eijl1, AJ Webb1, MA Westwood2, MK Parmar3, A Mathur1,2, A Ahluwalia1. 1Queen Mary University of London, London, UK, 2Barts Health NHS Trust, London, UK, 3MRC Clinical Trials Unit, London, UK

Background

Pre-clinical evidence demonstrates that inorganic nitrite, following its in situ conversion to nitric oxide, attenuates consequent myocardial reperfusion injury. In this study we sought to determine whether a significant improvement in infarct size can be achieved by the intra-coronary injection of nitrite during primary percutaneous coronary intervention (PCI) in acute myocardial infarction.

Methods

In this double-blind, placebo-controlled trial, we randomly assigned 80 patients presenting with acute ST-elevation myocardial infarction to receive either an intracoronary bolus (10 ml) of sodium nitrite (1.8 μmol in normal saline: nitrite group) or normal saline (placebo control group) during primary PCI. The primary endpoint was infarct size assessed in all patients by measuring the release of creatine kinase, secondary outcomes included infarct size assessed by measurement of troponin T release and in a subgroup of 68 patients by performing cardiac magnetic resonance imaging (CMR) on day 2. CMR was also used to calculate myocardial salvage index (MSI). Additional mechanistic endpoints measured were platelet aggregation and P-selectin expression at baseline, 30 minutes post delivery of nitrite/placebo, 4, 24 hours and 6 months after infarction

Results

The nitrite and control groups were similar with respect to baseline characteristics except for a longer ischaemia time in the nitrite group (p=0.031). There were no differences in release of serum creatine kinase (p=0.92) or troponin T (p=0.85) after reperfusion between the nitrite and control groups. No difference was seen in CMR assessed infarct size (p=0.254) but there was a trend to improved MSI in the nitrite group (mean 0.52 [95% confidence intervals [CI] of 0.46 to 0.58] vs. 0.44 [95% CI of 0.39 to 0.50], p=0.051). However, there was a difference in 1 year MACE with 2.6% in the nitrite group vs 15.8% in the control (p=0.04). In a subgroup of 66 patients with TIMI ≤1 flow at time of intervention there was a decrease in the release of serum creatine kinase in the nitrite group (p=0.030), with no difference in troponin T release (p=0.158). CMR analysis indicated a 19% reduction in infarct size (p=0.034), 35% reduction in microvascular obstruction and increased MSI (p=0.002) in the nitrite treated sub-group patients. No adverse effects of nitrite administration were detected. Platelet aggregation and P-selectin expression changed substantially over time in both placebo and nitrite treated groups. In all conditions, platelet reactivity was greatest at baseline with a decrease at 4 hours, followed by a slight elevation at 24 hours and a further decrease by 6 months. However, these changes were all suppressed in the nitrite group versus placebo in the whole cohort and in the TIMI ≤1 sub-group.

Conclusion

In this study population intra-coronary nitrite infusion is safe in all-comers presenting with STEMI but has no effect on infarct size although a trend to an improved myocardial salvage index and a significant reduction in MACE was evident. In a sub-group of patients with TIMI flow ≤1 nitrite reduced infarct size and MACE and improved MSI indicating that a large phase III trial assessing intra-coronary nitrite administration as an adjunct to PCI in STEMI patients is warranted.