Nitric oxide for inhalation in ST-elevation myocardial infarction (NOMI): a multicentre, double-blind, randomized controlled trial

NOMI investigators

Research output: Contribution to journalArticle

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Abstract

Aims: Inhalation of nitric oxide (iNO) during myocardial ischaemia and after reperfusion confers cardioprotection in preclinical studies via enhanced cyclic guanosine monophosphate (cGMP) signalling. We tested whether iNO reduces reperfusion injury in patients with ST-elevation myocardial infarction (STEMI; NCT01398384).

Methods and results: We randomized in a double-blind, placebo-controlled study 250 STEMI patients to inhale oxygen with (iNO) or without (CON) 80 parts-per-million NO for 4 h following percutaneous revascularization. Primary efficacy endpoint was infarct size as a fraction of left ventricular (LV) size (IS/LVmass), assessed by delayed enhancement contrast magnetic resonance imaging (MRI). Pre-specified subgroup analysis included thrombolysis-in-myocardial-infarction flow in the infarct-related artery, troponin T levels on admission, duration of symptoms, location of culprit lesion, and intra-arterial nitroglycerine (NTG) use. Secondary efficacy endpoints included IS relative to risk area (IS/AAR), myocardial salvage index, LV functional recovery, and clinical events at 4 and 12 months. In the overall population, IS/LVmass at 48-72 h was 18.0 ± 13.4% in iNO (n = 109) and 19.4 ± 15.4% in CON [n = 116, effect size -1.524%, 95% confidence interval (95% CI) -5.28, 2.24; P = 0.427]. Subgroup analysis indicated consistency across clinical confounders of IS but significant treatment interaction with NTG (P = 0.0093) resulting in smaller IS/LVmass after iNO in NTG-naïve patients (n = 140, P < 0.05). The secondary endpoint IS/AAR was 53 ± 26% with iNO vs. 60 ± 26% in CON (effect size -6.8%, 95% CI -14.8, 1.3, P = 0.09) corresponding to a myocardial salvage index of 47 ± 26% vs. 40 ± 26%, respectively, P = 0.09. Cine-MRI showed similar LV volumes at 48-72 h, with a tendency towards smaller increases in end-systolic and end-diastolic volumes at 4 months in iNO (P = 0.048 and P = 0.06, respectively, n = 197). Inhalation of nitric oxide was safe and significantly increased cGMP plasma levels during 4 h reperfusion. The Kaplan-Meier analysis for the composite of death, recurrent ischaemia, stroke, or rehospitalizations showed a tendency toward lower event rates with iNO at 4 months and 1 year (log-rank test P = 0.10 and P = 0.06, respectively).

Conclusions: Inhalation of NO at 80 ppm for 4 h in STEMI was safe but did not reduce infarct size relative to absolute LVmass at 48-72h. The observed functional recovery and clinical event rates at follow-up and possible interaction with nitroglycerine warrant further studies of iNO in STEMI.

Original languageEnglish
Pages (from-to)2717-2725
Number of pages9
JournalEuropean Heart Journal
Volume39
Issue number29
DOIs
Publication statusPublished - Aug 1 2018

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Inhalation
Nitric Oxide
Randomized Controlled Trials
Nitroglycerin
Cyclic GMP
Reperfusion
ST Elevation Myocardial Infarction
Cine Magnetic Resonance Imaging
Confidence Intervals
Troponin T
Kaplan-Meier Estimate
Reperfusion Injury
Myocardial Ischemia
Ischemia
Arteries
Stroke
Myocardial Infarction
Placebos
Magnetic Resonance Imaging
Oxygen

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Nitric oxide for inhalation in ST-elevation myocardial infarction (NOMI) : a multicentre, double-blind, randomized controlled trial. / NOMI investigators .

In: European Heart Journal, Vol. 39, No. 29, 01.08.2018, p. 2717-2725.

Research output: Contribution to journalArticle

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title = "Nitric oxide for inhalation in ST-elevation myocardial infarction (NOMI): a multicentre, double-blind, randomized controlled trial",
abstract = "Aims: Inhalation of nitric oxide (iNO) during myocardial ischaemia and after reperfusion confers cardioprotection in preclinical studies via enhanced cyclic guanosine monophosphate (cGMP) signalling. We tested whether iNO reduces reperfusion injury in patients with ST-elevation myocardial infarction (STEMI; NCT01398384).Methods and results: We randomized in a double-blind, placebo-controlled study 250 STEMI patients to inhale oxygen with (iNO) or without (CON) 80 parts-per-million NO for 4 h following percutaneous revascularization. Primary efficacy endpoint was infarct size as a fraction of left ventricular (LV) size (IS/LVmass), assessed by delayed enhancement contrast magnetic resonance imaging (MRI). Pre-specified subgroup analysis included thrombolysis-in-myocardial-infarction flow in the infarct-related artery, troponin T levels on admission, duration of symptoms, location of culprit lesion, and intra-arterial nitroglycerine (NTG) use. Secondary efficacy endpoints included IS relative to risk area (IS/AAR), myocardial salvage index, LV functional recovery, and clinical events at 4 and 12 months. In the overall population, IS/LVmass at 48-72 h was 18.0 ± 13.4{\%} in iNO (n = 109) and 19.4 ± 15.4{\%} in CON [n = 116, effect size -1.524{\%}, 95{\%} confidence interval (95{\%} CI) -5.28, 2.24; P = 0.427]. Subgroup analysis indicated consistency across clinical confounders of IS but significant treatment interaction with NTG (P = 0.0093) resulting in smaller IS/LVmass after iNO in NTG-na{\"i}ve patients (n = 140, P < 0.05). The secondary endpoint IS/AAR was 53 ± 26{\%} with iNO vs. 60 ± 26{\%} in CON (effect size -6.8{\%}, 95{\%} CI -14.8, 1.3, P = 0.09) corresponding to a myocardial salvage index of 47 ± 26{\%} vs. 40 ± 26{\%}, respectively, P = 0.09. Cine-MRI showed similar LV volumes at 48-72 h, with a tendency towards smaller increases in end-systolic and end-diastolic volumes at 4 months in iNO (P = 0.048 and P = 0.06, respectively, n = 197). Inhalation of nitric oxide was safe and significantly increased cGMP plasma levels during 4 h reperfusion. The Kaplan-Meier analysis for the composite of death, recurrent ischaemia, stroke, or rehospitalizations showed a tendency toward lower event rates with iNO at 4 months and 1 year (log-rank test P = 0.10 and P = 0.06, respectively).Conclusions: Inhalation of NO at 80 ppm for 4 h in STEMI was safe but did not reduce infarct size relative to absolute LVmass at 48-72h. The observed functional recovery and clinical event rates at follow-up and possible interaction with nitroglycerine warrant further studies of iNO in STEMI.",
author = "{NOMI investigators} and Janssens, {Stefan P.} and Jan Bogaert and Jaroslaw Zalewski and Attila Toth and Tom Adriaenssens and Ann Belmans and Johan Bennett and Piet Claus and Walter Desmet and Christophe Dubois and Kaatje Goetschalckx and Peter Sinnaeve and Katleen Vandenberghe and Pieter Vermeersch and Arpad Lux and Zsolt Szelid and Monika Durak and Piotr Lech and Krzysztof Zmudka and Peter Pokreisz and Pascal Vranckx and B. Merkely and Bloch, {Kenneth D.} and {Van de Werf}, Frans",
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doi = "10.1093/eurheartj/ehy232",
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pages = "2717--2725",
journal = "European Heart Journal",
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TY - JOUR

T1 - Nitric oxide for inhalation in ST-elevation myocardial infarction (NOMI)

T2 - a multicentre, double-blind, randomized controlled trial

AU - NOMI investigators

AU - Janssens, Stefan P.

AU - Bogaert, Jan

AU - Zalewski, Jaroslaw

AU - Toth, Attila

AU - Adriaenssens, Tom

AU - Belmans, Ann

AU - Bennett, Johan

AU - Claus, Piet

AU - Desmet, Walter

AU - Dubois, Christophe

AU - Goetschalckx, Kaatje

AU - Sinnaeve, Peter

AU - Vandenberghe, Katleen

AU - Vermeersch, Pieter

AU - Lux, Arpad

AU - Szelid, Zsolt

AU - Durak, Monika

AU - Lech, Piotr

AU - Zmudka, Krzysztof

AU - Pokreisz, Peter

AU - Vranckx, Pascal

AU - Merkely, B.

AU - Bloch, Kenneth D.

AU - Van de Werf, Frans

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Aims: Inhalation of nitric oxide (iNO) during myocardial ischaemia and after reperfusion confers cardioprotection in preclinical studies via enhanced cyclic guanosine monophosphate (cGMP) signalling. We tested whether iNO reduces reperfusion injury in patients with ST-elevation myocardial infarction (STEMI; NCT01398384).Methods and results: We randomized in a double-blind, placebo-controlled study 250 STEMI patients to inhale oxygen with (iNO) or without (CON) 80 parts-per-million NO for 4 h following percutaneous revascularization. Primary efficacy endpoint was infarct size as a fraction of left ventricular (LV) size (IS/LVmass), assessed by delayed enhancement contrast magnetic resonance imaging (MRI). Pre-specified subgroup analysis included thrombolysis-in-myocardial-infarction flow in the infarct-related artery, troponin T levels on admission, duration of symptoms, location of culprit lesion, and intra-arterial nitroglycerine (NTG) use. Secondary efficacy endpoints included IS relative to risk area (IS/AAR), myocardial salvage index, LV functional recovery, and clinical events at 4 and 12 months. In the overall population, IS/LVmass at 48-72 h was 18.0 ± 13.4% in iNO (n = 109) and 19.4 ± 15.4% in CON [n = 116, effect size -1.524%, 95% confidence interval (95% CI) -5.28, 2.24; P = 0.427]. Subgroup analysis indicated consistency across clinical confounders of IS but significant treatment interaction with NTG (P = 0.0093) resulting in smaller IS/LVmass after iNO in NTG-naïve patients (n = 140, P < 0.05). The secondary endpoint IS/AAR was 53 ± 26% with iNO vs. 60 ± 26% in CON (effect size -6.8%, 95% CI -14.8, 1.3, P = 0.09) corresponding to a myocardial salvage index of 47 ± 26% vs. 40 ± 26%, respectively, P = 0.09. Cine-MRI showed similar LV volumes at 48-72 h, with a tendency towards smaller increases in end-systolic and end-diastolic volumes at 4 months in iNO (P = 0.048 and P = 0.06, respectively, n = 197). Inhalation of nitric oxide was safe and significantly increased cGMP plasma levels during 4 h reperfusion. The Kaplan-Meier analysis for the composite of death, recurrent ischaemia, stroke, or rehospitalizations showed a tendency toward lower event rates with iNO at 4 months and 1 year (log-rank test P = 0.10 and P = 0.06, respectively).Conclusions: Inhalation of NO at 80 ppm for 4 h in STEMI was safe but did not reduce infarct size relative to absolute LVmass at 48-72h. The observed functional recovery and clinical event rates at follow-up and possible interaction with nitroglycerine warrant further studies of iNO in STEMI.

AB - Aims: Inhalation of nitric oxide (iNO) during myocardial ischaemia and after reperfusion confers cardioprotection in preclinical studies via enhanced cyclic guanosine monophosphate (cGMP) signalling. We tested whether iNO reduces reperfusion injury in patients with ST-elevation myocardial infarction (STEMI; NCT01398384).Methods and results: We randomized in a double-blind, placebo-controlled study 250 STEMI patients to inhale oxygen with (iNO) or without (CON) 80 parts-per-million NO for 4 h following percutaneous revascularization. Primary efficacy endpoint was infarct size as a fraction of left ventricular (LV) size (IS/LVmass), assessed by delayed enhancement contrast magnetic resonance imaging (MRI). Pre-specified subgroup analysis included thrombolysis-in-myocardial-infarction flow in the infarct-related artery, troponin T levels on admission, duration of symptoms, location of culprit lesion, and intra-arterial nitroglycerine (NTG) use. Secondary efficacy endpoints included IS relative to risk area (IS/AAR), myocardial salvage index, LV functional recovery, and clinical events at 4 and 12 months. In the overall population, IS/LVmass at 48-72 h was 18.0 ± 13.4% in iNO (n = 109) and 19.4 ± 15.4% in CON [n = 116, effect size -1.524%, 95% confidence interval (95% CI) -5.28, 2.24; P = 0.427]. Subgroup analysis indicated consistency across clinical confounders of IS but significant treatment interaction with NTG (P = 0.0093) resulting in smaller IS/LVmass after iNO in NTG-naïve patients (n = 140, P < 0.05). The secondary endpoint IS/AAR was 53 ± 26% with iNO vs. 60 ± 26% in CON (effect size -6.8%, 95% CI -14.8, 1.3, P = 0.09) corresponding to a myocardial salvage index of 47 ± 26% vs. 40 ± 26%, respectively, P = 0.09. Cine-MRI showed similar LV volumes at 48-72 h, with a tendency towards smaller increases in end-systolic and end-diastolic volumes at 4 months in iNO (P = 0.048 and P = 0.06, respectively, n = 197). Inhalation of nitric oxide was safe and significantly increased cGMP plasma levels during 4 h reperfusion. The Kaplan-Meier analysis for the composite of death, recurrent ischaemia, stroke, or rehospitalizations showed a tendency toward lower event rates with iNO at 4 months and 1 year (log-rank test P = 0.10 and P = 0.06, respectively).Conclusions: Inhalation of NO at 80 ppm for 4 h in STEMI was safe but did not reduce infarct size relative to absolute LVmass at 48-72h. The observed functional recovery and clinical event rates at follow-up and possible interaction with nitroglycerine warrant further studies of iNO in STEMI.

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JO - European Heart Journal

JF - European Heart Journal

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