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

Konstantin Schwarz; Satnam Singh; Satish K Parasuraman; Amelia Rudd; Lee Shepstone; Martin Feelisch; Magdalena Minnion; Shakil Ahmad; Melanie Madhani; John Horowitz; Dana K Dawson; Michael P Frenneaux

doi:10.1161/JAHA.117.006478

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

Konstantin Schwarz, Satnam Singh, Satish K Parasuraman, Amelia Rudd, Lee Shepstone, Martin Feelisch, Magdalena Minnion, Shakil Ahmad, Melanie Madhani, John Horowitz, Dana K Dawson, Michael P Frenneaux

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Abstract

BACKGROUND: In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina.

METHODS AND RESULTS: Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, P=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, P=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] μmol/L, P<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, P=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation.

CONCLUSIONS: Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication.

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02078921. EudraCT number: 2012-000196-17.

Original language	English
Article number	e006478
Pages (from-to)	1-17
Number of pages	17
Journal	Journal of the American Heart Association
Volume	6
Issue number	9
Early online date	8 Sept 2017
DOIs	https://doi.org/10.1161/JAHA.117.006478
Publication status	Published - Sept 2017

Bibliographical note

Acknowledgments
We are very grateful to Amanda Cardy (Scottish Primary Research Network) for her help with recruitment from primary care centers. Further thanks are to Maggie Bruce, Val Harries, and Frances Adamson for their assistance with study recruitment. The last and foremost thanks are to all participating patients. The Trial Steering Committee consisted of Awsan Noman, Michael Frenneaux,
Konstantin Schwarz, Zaid Mahmood, Frank Thies. The Data Monitoring Committee included Mathew Yuyun, Markus Zeitlinger, and Roger Beadle.

Sources of Funding
The study was funded by the Medical Research Council, (UK) grant number G1001536.

Keywords

angina
exercise
inorganic nitrate
ischemia
nitrite
randomized trial

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10.1161/JAHA.117.006478Licence: CC BY

Inorganic Nitrate in Angina Study: A Randomized Double-Blind Placebo-Controlled Trial
© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Final published version, 1.35 MBLicence: CC BY

Dana Dawson
Person: Clinical Academic

Cite this

Schwarz, K., Singh, S., Parasuraman, S. K., Rudd, A., Shepstone, L., Feelisch, M., Minnion, M., Ahmad, S., Madhani, M., Horowitz, J., Dawson, D. K., & Frenneaux, M. P. (2017). Inorganic Nitrate in Angina Study: A Randomized Double-Blind Placebo-Controlled Trial. Journal of the American Heart Association, 6(9), 1-17. Article e006478. https://doi.org/10.1161/JAHA.117.006478

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title = "Inorganic Nitrate in Angina Study: A Randomized Double-Blind Placebo-Controlled Trial",

abstract = "BACKGROUND: In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina.METHODS AND RESULTS: Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, P=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, P=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] μmol/L, P<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, P=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation.CONCLUSIONS: Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02078921. EudraCT number: 2012-000196-17.",

keywords = "angina, exercise, inorganic nitrate, ischemia, nitrite, randomized trial",

author = "Konstantin Schwarz and Satnam Singh and Parasuraman, {Satish K} and Amelia Rudd and Lee Shepstone and Martin Feelisch and Magdalena Minnion and Shakil Ahmad and Melanie Madhani and John Horowitz and Dawson, {Dana K} and Frenneaux, {Michael P}",

note = "Acknowledgments We are very grateful to Amanda Cardy (Scottish Primary Research Network) for her help with recruitment from primary care centers. Further thanks are to Maggie Bruce, Val Harries, and Frances Adamson for their assistance with study recruitment. The last and foremost thanks are to all participating patients. The Trial Steering Committee consisted of Awsan Noman, Michael Frenneaux, Konstantin Schwarz, Zaid Mahmood, Frank Thies. The Data Monitoring Committee included Mathew Yuyun, Markus Zeitlinger, and Roger Beadle. Sources of Funding The study was funded by the Medical Research Council, (UK) grant number G1001536.",

year = "2017",

month = sep,

doi = "10.1161/JAHA.117.006478",

language = "English",

volume = "6",

pages = "1--17",

journal = "Journal of the American Heart Association",

issn = "2047-9980",

publisher = "Wiley-Blackwell",

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TY - JOUR

T1 - Inorganic Nitrate in Angina Study

T2 - A Randomized Double-Blind Placebo-Controlled Trial

AU - Schwarz, Konstantin

AU - Singh, Satnam

AU - Parasuraman, Satish K

AU - Rudd, Amelia

AU - Shepstone, Lee

AU - Feelisch, Martin

AU - Minnion, Magdalena

AU - Ahmad, Shakil

AU - Madhani, Melanie

AU - Horowitz, John

AU - Dawson, Dana K

AU - Frenneaux, Michael P

N1 - Acknowledgments We are very grateful to Amanda Cardy (Scottish Primary Research Network) for her help with recruitment from primary care centers. Further thanks are to Maggie Bruce, Val Harries, and Frances Adamson for their assistance with study recruitment. The last and foremost thanks are to all participating patients. The Trial Steering Committee consisted of Awsan Noman, Michael Frenneaux, Konstantin Schwarz, Zaid Mahmood, Frank Thies. The Data Monitoring Committee included Mathew Yuyun, Markus Zeitlinger, and Roger Beadle. Sources of Funding The study was funded by the Medical Research Council, (UK) grant number G1001536.

PY - 2017/9

Y1 - 2017/9

N2 - BACKGROUND: In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina.METHODS AND RESULTS: Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, P=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, P=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] μmol/L, P<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, P=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation.CONCLUSIONS: Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02078921. EudraCT number: 2012-000196-17.

AB - BACKGROUND: In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina.METHODS AND RESULTS: Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, P=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, P=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] μmol/L, P<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, P=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation.CONCLUSIONS: Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02078921. EudraCT number: 2012-000196-17.

KW - angina

KW - exercise

KW - inorganic nitrate

KW - ischemia

KW - nitrite

KW - randomized trial

U2 - 10.1161/JAHA.117.006478

DO - 10.1161/JAHA.117.006478

M3 - Article

C2 - 28887315

SN - 2047-9980

VL - 6

SP - 1

EP - 17

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

IS - 9

M1 - e006478

ER -

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

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