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*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere006478
JournalJournal of the American Heart Association
Volume6
Issue number9
DOIs
Publication statusPublished - 8 Sep 2017

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Nitrates
Placebos
Exercise Test
Electrocardiography
Exercise
Therapeutics
Antacids
Dobutamine
Stable Angina
Hematologic Tests
Nitrites
Cross-Over Studies
Myocardial Ischemia
Ischemia
Confidence Intervals
sodium nitrate

Bibliographical note

Copyright: 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.

Funding: Medical Research Council, (UK) grant number G1001536.

Keywords

  • Angina
  • Exercise
  • Inorganic nitrate
  • Ischemia
  • Nitrite
  • Randomized trial

Cite this

Schwarz, K., Singh, S., Parasuraman, S. K., Rudd, A., Shepstone, L., Feelisch, M., ... Frenneaux, M. P. (2017). Inorganic nitrate in angina study: A randomized double-blind placebo-controlled trial. Journal of the American Heart Association, 6(9), [e006478]. https://doi.org/10.1161/JAHA.117.006478
Schwarz, Konstantin ; Singh, Satnam ; Parasuraman, Satish K. ; Rudd, Amelia ; Shepstone, Lee ; Feelisch, Martin ; Minnion, Magdalena ; Ahmad, Shakil ; Madhani, Melanie ; Horowitz, John ; Dawson, Dana K. ; Frenneaux, Michael P. / Inorganic nitrate in angina study : A randomized double-blind placebo-controlled trial. In: Journal of the American Heart Association. 2017 ; Vol. 6, No. 9.
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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.",
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note = "Copyright: 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. Funding: Medical Research Council, (UK) grant number G1001536.",
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Schwarz, K, Singh, S, Parasuraman, SK, Rudd, A, Shepstone, L, Feelisch, M, Minnion, M, Ahmad, S, Madhani, M, Horowitz, J, Dawson, DK & Frenneaux, MP 2017, 'Inorganic nitrate in angina study: A randomized double-blind placebo-controlled trial', Journal of the American Heart Association, vol. 6, no. 9, e006478. https://doi.org/10.1161/JAHA.117.006478

Inorganic nitrate in angina study : A randomized double-blind placebo-controlled trial. / Schwarz, Konstantin; Singh, Satnam; Parasuraman, Satish K.; Rudd, Amelia; Shepstone, Lee; Feelisch, Martin; Minnion, Magdalena; Ahmad, Shakil; Madhani, Melanie; Horowitz, John; Dawson, Dana K.; Frenneaux, Michael P.

In: Journal of the American Heart Association, Vol. 6, No. 9, e006478, 08.09.2017.

Research output: Contribution to journalArticle

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 - Copyright: 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. Funding: Medical Research Council, (UK) grant number G1001536.

PY - 2017/9/8

Y1 - 2017/9/8

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.

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.

KW - Angina

KW - Exercise

KW - Inorganic nitrate

KW - Ischemia

KW - Nitrite

KW - Randomized trial

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DO - 10.1161/JAHA.117.006478

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Schwarz K, Singh S, Parasuraman SK, Rudd A, Shepstone L, Feelisch M et al. Inorganic nitrate in angina study: A randomized double-blind placebo-controlled trial. Journal of the American Heart Association. 2017 Sep 8;6(9). e006478. https://doi.org/10.1161/JAHA.117.006478