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The safety and efficacy of intracoronary nitrite infusion during acute myocardial infarction (NITRITE-AMI): study protocol of a randomised controlled trial.

ABSTRACT: INTRODUCTION:Acute myocardial infarction (AMI) is a major cause of death and disability in the UK and worldwide. 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 clinical outcomes. However, the process of reperfusion can itself induce cardiomyocyte death, known as myocardial reperfusion injury, for which there is currently no effective therapy. Extensive preclinical evidence exists to suggest that sodium nitrite (as a source of endogenous nitric oxide) is an effective therapeutic strategy for preventing myocardial reperfusion injury. The purpose of NITRITE-AMI is to test whether sodium nitrite reduces reperfusion injury and subsequent infarct size in patients undergoing PPCI for MI. METHODS AND DESIGN:NITRITE-AMI is a double-blind, randomised, single-centre, placebo-controlled trial to determine whether intracoronary nitrite injection reduces infarct size in patients with myocardial infarction undergoing primary angioplasty. The study will enrol 80 patients presenting with ST-elevation myocardial infarction. Patients will be randomised to receive either a bolus of intracoronary sodium nitrite or placebo (sodium chloride) at the time of PPCI. The primary outcome is infarct size assessed by creatine kinase area under the curve (AUC) over 48 h. Secondary endpoints include troponin T AUC and infarct size, LV dimensions and myocardial salvage index assessed by cardiac MR (CMR), markers of platelet reactivity and inflammation, the safety and tolerability of intracoronary nitrite, and 1 year major adverse cardiac events. ETHICS AND DISSEMINATION:The study is approved by the local ethics committee (NRES Committee London West London: 11/LO/1500) and by the Medicines and Healthcare Products Regulatory Agency (MHRA) (EudraCT nr. 2010-022460-12). The results of the trial will be published according to the CONSORT statement and will be presented at conferences and reported in peer-reviewed journals. TRIAL REGISTRATION:United Kingdom Clinical Research Network (Study ID 12117), http://clinicaltrials.gov (NCT01584453) and Current Controlled Trials (ISRCTN:38736987).

SUBMITTER: Jones DA

PROVIDER: S-EPMC3641434 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The safety and efficacy of intracoronary nitrite infusion during acute myocardial infarction (NITRITE-AMI): study protocol of a randomised controlled trial.

Jones D A DA Andiapen M M Van-Eijl T J A TJ Webb A J AJ Antoniou S S Schilling R J RJ Ahluwalia A A Mathur A A

BMJ open 20130402 4

<h4>Introduction</h4>Acute myocardial infarction (AMI) is a major cause of death and disability in the UK and worldwide. 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 clinical outcomes. However, the process of reperfusion can itself induce cardiomyocyte death, known as myocardial reperfusion injury, for wh ...[more]

PMID: 23550096

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Project description:RationalePreclinical evidence demonstrates that inorganic nitrite, after its in situ conversion to nitric oxide, attenuates consequent myocardial reperfusion injury.ObjectiveWe investigated whether intracoronary injection of nitrite during primary percutaneous coronary intervention might improve infarct size in ST-elevated myocardial infarction.Methods and resultsPatients undergoing primary percutaneous coronary intervention (n=80) were randomized to receive intracoronary (10 mL) sodium nitrite (1.8 μmol) or NaCl (placebo) before balloon inflation. The primary end point was infarct size assessed by measuring creatine kinase release. Secondary outcomes included infarct size assessed by troponin T release and by cardiac MRI on day 2. Baseline characteristics were similar between the groups. No evidence of differences in creatine kinase release (P=0.92), troponin T (P=0.85), or cardiac MRI-assessed infarct size (P=0.254) were evident. In contrast, there was an improvement [corrected] in myocardial salvage index (P=0.05) and reduction in [corrected] major adverse cardiac event at 1 year (2.6% versus 15.8%; P=0.04) in the nitrite group. In a 66-patient subgroup with thrombolysis in myocardial infarction ≤1 flow, there was reduced serum creatine kinase (P=0.030) and a 19% reduction in cardiac MRI-determined infarct size (P=0.034) with nitrite. No adverse effects of nitrite were detected.ConclusionsIn this phase II study, intracoronary nitrite infusion did not alter infarct size, although a trend to improved myocardial salvage index and a significant reduction in major adverse cardiac event was evident. In a subgroup of patients with thrombolysis in myocardial infarction flow ≤1, nitrite reduced infarct size and major adverse cardiac event and improved myocardial salvage index, indicating that a phase III clinical trial assessing intracoronary nitrite administration as an adjunct to percutaneous coronary intervention in ST-elevated myocardial infarction patients is warranted.Clinical trial registration urlhttp://www.clinicaltrials.gov. Unique identifier: NCT01584453.

Project description:BackgroundThe use of adult stem cells is limited by the quality and quantity of host stem cells. It has been demonstrated that Wharton's jelly-derived mesenchymal stem cells (WJMSCs), a primitive stromal population, could integrate into ischemic cardiac tissues and significantly improve heart function. In this randomized, controlled trial, our aim was to assess the safety and efficacy of intracoronary WJMSCs in patients with ST-elevation acute myocardial infarction (AMI).MethodsIn a multicenter trial, 116 patients with acute ST-elevation MI were randomly assigned to receive an intracoronary infusion of WJMSCs or placebo into the infarct artery at five to seven days after successful reperfusion therapy. The primary endpoint of safety: the incidence of adverse events (AEs) within 18 months, was monitored and quantified. The endpoint of efficacy: the absolute changes in myocardial viability and perfusion of the infarcted region from baseline to four months, global left ventricular ejection fraction (LVEF) from baseline to 18 months were measured using F-18-fluorodeoxyglucose positron emission computed tomography (F-18-FDG-PET) and 99mTc-sestamibi single-photon emission computed tomography (99mTc-SPECT), and two-dimensional echocardiography, respectively.ResultsDuring 18 months follow-up, AEs rates and laboratory tests including tumor, immune, and hematologic indexes were not different between the two groups. The absolute increase in the myocardial viability (PET) and perfusion within the infarcted territory (SPECT) was significantly greater in the WJMSC group [6.9 ± 0.6 % (95 %CI, 5.7 to 8.2)] and [7.1 ± 0.8 % (95 %CI, 5.4 to 8.8) than in the placebo group [3.3 ± 0.7 % (95 %CI, 1.8 to 4.7), P <0.0001] and 3.9 ± 0.6(95 %CI, 2.8 to 5.0), P = 0.002] at four months. The absolute increase in the LVEF at 18 months in the WJMSC group was significantly greater than that in the placebo group [7.8 ± 0.9 (6.0 to approximately 9.7) vs. 2.8 ± 1.2 (0.4 to approximately 5.1), P = 0.001]. Concomitantly, the absolute decreases in LV end-systolic volumes and end-diastolic volumes at 18 months in the WJMSC group were significantly greater than those in the placebo group (P = 0.0004, P = 0.004, respectively).ConclusionsIntracoronary infusion of WJMSCs is safe and effective in patients with AMI, providing clinically relevant therapy within a favorable time window. This study encourages additional clinical trials to determine whether WJMSCs may serve as a novel alternative to BMSCs for cardiac stem cell-based therapy.Trial registrationClinical Trials NCT01291329 (02/05/2011).

Project description:BackgroundCardiosphere-derived cells (CDCs) reduce scarring after myocardial infarction, increase viable myocardium, and boost cardiac function in preclinical models. We aimed to assess safety of such an approach in patients with left ventricular dysfunction after myocardial infarction.MethodsIn the prospective, randomised CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial, we enrolled patients 2-4 weeks after myocardial infarction (with left ventricular ejection fraction of 25-45%) at two medical centres in the USA. An independent data coordinating centre randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1·5-3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumour formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). We also assessed preliminary efficacy endpoints on MRI by 6 months. Data analysers were masked to group assignment. This study is registered with ClinicalTrials.gov, NCT00893360.FindingsBetween May 5, 2009, and Dec 16, 2010, we randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumours, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1·00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0·001), increases in viable heart mass (p=0·01) and regional contractility (p=0·02), and regional systolic wall thickening (p=0·015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months.InterpretationWe show intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes.FundingUS National Heart, Lung and Blood Institute and Cedars-Sinai Board of Governors Heart Stem Cell Center.

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The safety and efficacy of intracoronary nitrite infusion during acute myocardial infarction (NITRITE-AMI): study protocol of a randomised controlled trial.

Publications

The safety and efficacy of intracoronary nitrite infusion during acute myocardial infarction (NITRITE-AMI): study protocol of a randomised controlled trial.

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