Protocol: does sodium nitrite administration reduce ischaemia-reperfusion injury in patients presenting with acute ST segment elevation myocardial infarction? Nitrites in acute myocardial infarction (NIAMI)

Abstract

BackgroundWhilst advances in reperfusion therapies have reduced early mortality from acute myocardial infarction, heart failure remains a common complication, and may develop very early or long after the acute event. Reperfusion itself leads to further tissue damage, a process described as ischaemia-reperfusion-injury (IRI), which contributes up to 50% of the final infarct size. In experimental models nitrite administration potently protects against IRI in several organs, including the heart. In the current study we investigate whether intravenous sodium nitrite administration immediately prior to percutaneous coronary intervention (PCI) in patients with acute ST segment elevation myocardial infarction will reduce myocardial infarct size. This is a phase II, randomised, placebo-controlled, double-blinded and multicentre trial.Methods and outcomesThe aim of this trial is to determine whether a 5 minute systemic injection of sodium nitrite, administered immediately before opening of the infarct related artery, results in significant reduction of IRI in patients with first acute ST elevation myocardial infarction (MI). The primary clinical end point is the difference in infarct size between sodium nitrite and placebo groups measured using cardiovascular magnetic resonance imaging (CMR) performed at 6–8 days following the AMI and corrected for area at risk (AAR) using the endocardial surface area technique. Secondary end points include (i) plasma creatine kinase and Troponin I measured in blood samples taken pre-injection of the study medication and over the following 72 hours; (ii) infarct size at six months; (iii) Infarct size corrected for AAR measured at 6–8 days using T2 weighted triple inversion recovery (T2-W SPAIR or STIR) CMR imaging; (iv) Left ventricular (LV) ejection fraction measured by CMR at 6–8 days and six months following injection of the study medication; and (v) LV end systolic volume index at 6–8 days and six months.Funding, ethics and regulatory approvalsThis study is funded by a grant from the UK Medical Research Council. This protocol is approved by the Scotland A Research Ethics Committee and has also received clinical trial authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) (EudraCT number: 2010-023571-26).Trial registrationClinicalTrials.gov: NCT01388504 and Current Controlled Trials: ISRCTN57596739

Extending the translational potential of targeting NO/cGMP‐regulated pathways in the CVS

“…In a randomized, placebo‐controlled, double‐blind phase II evaluation, a 5 min i.v. administration of sodium nitrite prior to angioplasty did not reduce infarct size (the primary end point), although a subgroup of patients with diabetes did show some improvement (Siddiqi et al ., ; NCT01388504 and ISRCTN57596739). This lack of efficacy is disappointing, given the preclinical observations, but may be dose related as the 70 μmol NaNO 2 administrated was insufficient to significantly increase circulating NO 2 − concentrations, at least to levels shown to be required for blood pressure effects in healthy volunteers and hypertensive patients.…”

Acute myocardial infarction: susceptibility-weighted cardiac MRI for the detection of reperfusion haemorrhage at 1.5 T

“…Further research will be required to determine the role of cardiac SWI in risk stratification post-STEMI and whether the detection of smaller micro-haemorrhages is predictive of a poorer outcome. While the presence of MVO or reperfusion haemorrhage does not presently influence patient management it may have a role in assessing cardio-protective strategies that aim to limit the consequences of ischaemia-reperfusion injury (33).…”

Inorganic Nitrate in Angina Study: A Randomized Double‐Blind Placebo‐Controlled Trial

“…A subgroup of 20 patients underwent blood tests for nitrate and nitrite levels and angiogenic markers (soluble fms‐like tyrosine kinase receptor‐1, placental growth ractor, and vascular endothelial growth factor) levels. Samples were collected and analyzed as previously reported . We modified the Seattle Questionnaire to reflect the short treatment period of 1 week when compared to the original assessment over 4 weeks.…”