A randomised, factorial trial to reduce arterial stiffness independently of blood pressure: Proof of concept? The 'VaSera' trial testing dietary nitrate and spironolactone

Charlotte E Mills, Virginia Govoni, Luca Faconti, Maria-Linda Casagrande, Steven V Morant, Hannah Crickmore, Fahad Iqbal, Perry Maskell, Alisha Masani, Elisa Nanino, Andrew J Webb, J Kennedy Cruickshank (Lead / Corresponding author)

Research output: Contribution to journalArticle

Abstract

AIM: To test if spironolactone or dietary nitrate from beetroot juice could reduce arterial stiffness as aortic pulse wave velocity (PWVart), a potential treatment target, independently of blood pressure METHODS: Daily spironolactone (≤50mg) versus doxazosin (control ≤16mg) and 70mL beetroot juice ('Beet-It' ≤11mmol nitrate) versus nitrate-depleted juice (placebo; 0mmol nitrate) were tested in people at risk or with type-2 diabetes using a double-blind, 6-month factorial trial. Vascular indices (baseline, 12, 24 weeks) were cardiac-ankle vascular index ('CAVI'), a nominally pressure-independent stiffness measure (primary outcome), pulse wave velocity (PWVart) secondary, central systolic pressure and augmentation. Analysis was intention-to-treat, adjusted for systolic pressure differences between trial arms.

RESULTS: Spironolactone did not reduce stiffness, with evidence for reduced CAVI on doxazosin rather than spironolactone (mean difference [95% confidence intervals]; 0.25[-0.3, 0.5] units, p=0.080), firmer for PWVart (0.37[0.01, 0.7] ms-1 , p=0.045). There was no difference in systolic pressure reduction between spironolactone and doxazosin (0.7[-4.8, 3.3]mmHg, p=0.7). Circulating nitrate and nitrite increased on active versus placebo juice, with central systolic pressure lowered -2.6[-4.5, - 0.8]mmHg, p=0.007 more on the active juice, but did not reduce CAVI, PWVart, nor peripheral pressure. Change in nitrate and nitrite concentrations were 1.5-fold [1.1-2.2] and 2.2-fold [1.3, 3.6] higher on spironolactone than on doxazosin respectively; both p<0.05.

CONCLUSION: Contrary to our hypothesis, in at-risk/type-2 diabetes patients, spironolactone did not reduce arterial stiffness, rather PWVart was lower on doxazosin. Dietary nitrate elevated plasma nitrite, selectively lowering central systolic pressure, observed previously for nitrite.

Original languageEnglish
Number of pages35
JournalBritish Journal of Clinical Pharmacology
Early online date13 Dec 2019
DOIs
Publication statusE-pub ahead of print - 13 Dec 2019

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Spironolactone
Vascular Stiffness
Doxazosin
Nitrates
Blood Pressure
Nitrites
Pulse Wave Analysis
Type 2 Diabetes Mellitus
Blood Vessels
Placebos
Pressure
Intention to Treat Analysis
Beta vulgaris
Ankle
Arm
Outcome Assessment (Health Care)
Confidence Intervals

Cite this

Mills, Charlotte E ; Govoni, Virginia ; Faconti, Luca ; Casagrande, Maria-Linda ; Morant, Steven V ; Crickmore, Hannah ; Iqbal, Fahad ; Maskell, Perry ; Masani, Alisha ; Nanino, Elisa ; Webb, Andrew J ; Cruickshank, J Kennedy. / A randomised, factorial trial to reduce arterial stiffness independently of blood pressure : Proof of concept? The 'VaSera' trial testing dietary nitrate and spironolactone. In: British Journal of Clinical Pharmacology. 2019.
@article{e2c33648445f4c70a7a50abcbe471453,
title = "A randomised, factorial trial to reduce arterial stiffness independently of blood pressure: Proof of concept? The 'VaSera' trial testing dietary nitrate and spironolactone",
abstract = "AIM: To test if spironolactone or dietary nitrate from beetroot juice could reduce arterial stiffness as aortic pulse wave velocity (PWVart), a potential treatment target, independently of blood pressure METHODS: Daily spironolactone (≤50mg) versus doxazosin (control ≤16mg) and 70mL beetroot juice ('Beet-It' ≤11mmol nitrate) versus nitrate-depleted juice (placebo; 0mmol nitrate) were tested in people at risk or with type-2 diabetes using a double-blind, 6-month factorial trial. Vascular indices (baseline, 12, 24 weeks) were cardiac-ankle vascular index ('CAVI'), a nominally pressure-independent stiffness measure (primary outcome), pulse wave velocity (PWVart) secondary, central systolic pressure and augmentation. Analysis was intention-to-treat, adjusted for systolic pressure differences between trial arms.RESULTS: Spironolactone did not reduce stiffness, with evidence for reduced CAVI on doxazosin rather than spironolactone (mean difference [95{\%} confidence intervals]; 0.25[-0.3, 0.5] units, p=0.080), firmer for PWVart (0.37[0.01, 0.7] ms-1 , p=0.045). There was no difference in systolic pressure reduction between spironolactone and doxazosin (0.7[-4.8, 3.3]mmHg, p=0.7). Circulating nitrate and nitrite increased on active versus placebo juice, with central systolic pressure lowered -2.6[-4.5, - 0.8]mmHg, p=0.007 more on the active juice, but did not reduce CAVI, PWVart, nor peripheral pressure. Change in nitrate and nitrite concentrations were 1.5-fold [1.1-2.2] and 2.2-fold [1.3, 3.6] higher on spironolactone than on doxazosin respectively; both p<0.05.CONCLUSION: Contrary to our hypothesis, in at-risk/type-2 diabetes patients, spironolactone did not reduce arterial stiffness, rather PWVart was lower on doxazosin. Dietary nitrate elevated plasma nitrite, selectively lowering central systolic pressure, observed previously for nitrite.",
author = "Mills, {Charlotte E} and Virginia Govoni and Luca Faconti and Maria-Linda Casagrande and Morant, {Steven V} and Hannah Crickmore and Fahad Iqbal and Perry Maskell and Alisha Masani and Elisa Nanino and Webb, {Andrew J} and Cruickshank, {J Kennedy}",
note = "This article is protected by copyright. All rights reserved.",
year = "2019",
month = "12",
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doi = "10.1111/bcp.14194",
language = "English",
journal = "British Journal of Clinical Pharmacology",
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A randomised, factorial trial to reduce arterial stiffness independently of blood pressure : Proof of concept? The 'VaSera' trial testing dietary nitrate and spironolactone. / Mills, Charlotte E; Govoni, Virginia; Faconti, Luca; Casagrande, Maria-Linda; Morant, Steven V; Crickmore, Hannah; Iqbal, Fahad; Maskell, Perry; Masani, Alisha; Nanino, Elisa; Webb, Andrew J; Cruickshank, J Kennedy (Lead / Corresponding author).

In: British Journal of Clinical Pharmacology, 13.12.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A randomised, factorial trial to reduce arterial stiffness independently of blood pressure

T2 - Proof of concept? The 'VaSera' trial testing dietary nitrate and spironolactone

AU - Mills, Charlotte E

AU - Govoni, Virginia

AU - Faconti, Luca

AU - Casagrande, Maria-Linda

AU - Morant, Steven V

AU - Crickmore, Hannah

AU - Iqbal, Fahad

AU - Maskell, Perry

AU - Masani, Alisha

AU - Nanino, Elisa

AU - Webb, Andrew J

AU - Cruickshank, J Kennedy

N1 - This article is protected by copyright. All rights reserved.

PY - 2019/12/13

Y1 - 2019/12/13

N2 - AIM: To test if spironolactone or dietary nitrate from beetroot juice could reduce arterial stiffness as aortic pulse wave velocity (PWVart), a potential treatment target, independently of blood pressure METHODS: Daily spironolactone (≤50mg) versus doxazosin (control ≤16mg) and 70mL beetroot juice ('Beet-It' ≤11mmol nitrate) versus nitrate-depleted juice (placebo; 0mmol nitrate) were tested in people at risk or with type-2 diabetes using a double-blind, 6-month factorial trial. Vascular indices (baseline, 12, 24 weeks) were cardiac-ankle vascular index ('CAVI'), a nominally pressure-independent stiffness measure (primary outcome), pulse wave velocity (PWVart) secondary, central systolic pressure and augmentation. Analysis was intention-to-treat, adjusted for systolic pressure differences between trial arms.RESULTS: Spironolactone did not reduce stiffness, with evidence for reduced CAVI on doxazosin rather than spironolactone (mean difference [95% confidence intervals]; 0.25[-0.3, 0.5] units, p=0.080), firmer for PWVart (0.37[0.01, 0.7] ms-1 , p=0.045). There was no difference in systolic pressure reduction between spironolactone and doxazosin (0.7[-4.8, 3.3]mmHg, p=0.7). Circulating nitrate and nitrite increased on active versus placebo juice, with central systolic pressure lowered -2.6[-4.5, - 0.8]mmHg, p=0.007 more on the active juice, but did not reduce CAVI, PWVart, nor peripheral pressure. Change in nitrate and nitrite concentrations were 1.5-fold [1.1-2.2] and 2.2-fold [1.3, 3.6] higher on spironolactone than on doxazosin respectively; both p<0.05.CONCLUSION: Contrary to our hypothesis, in at-risk/type-2 diabetes patients, spironolactone did not reduce arterial stiffness, rather PWVart was lower on doxazosin. Dietary nitrate elevated plasma nitrite, selectively lowering central systolic pressure, observed previously for nitrite.

AB - AIM: To test if spironolactone or dietary nitrate from beetroot juice could reduce arterial stiffness as aortic pulse wave velocity (PWVart), a potential treatment target, independently of blood pressure METHODS: Daily spironolactone (≤50mg) versus doxazosin (control ≤16mg) and 70mL beetroot juice ('Beet-It' ≤11mmol nitrate) versus nitrate-depleted juice (placebo; 0mmol nitrate) were tested in people at risk or with type-2 diabetes using a double-blind, 6-month factorial trial. Vascular indices (baseline, 12, 24 weeks) were cardiac-ankle vascular index ('CAVI'), a nominally pressure-independent stiffness measure (primary outcome), pulse wave velocity (PWVart) secondary, central systolic pressure and augmentation. Analysis was intention-to-treat, adjusted for systolic pressure differences between trial arms.RESULTS: Spironolactone did not reduce stiffness, with evidence for reduced CAVI on doxazosin rather than spironolactone (mean difference [95% confidence intervals]; 0.25[-0.3, 0.5] units, p=0.080), firmer for PWVart (0.37[0.01, 0.7] ms-1 , p=0.045). There was no difference in systolic pressure reduction between spironolactone and doxazosin (0.7[-4.8, 3.3]mmHg, p=0.7). Circulating nitrate and nitrite increased on active versus placebo juice, with central systolic pressure lowered -2.6[-4.5, - 0.8]mmHg, p=0.007 more on the active juice, but did not reduce CAVI, PWVart, nor peripheral pressure. Change in nitrate and nitrite concentrations were 1.5-fold [1.1-2.2] and 2.2-fold [1.3, 3.6] higher on spironolactone than on doxazosin respectively; both p<0.05.CONCLUSION: Contrary to our hypothesis, in at-risk/type-2 diabetes patients, spironolactone did not reduce arterial stiffness, rather PWVart was lower on doxazosin. Dietary nitrate elevated plasma nitrite, selectively lowering central systolic pressure, observed previously for nitrite.

U2 - 10.1111/bcp.14194

DO - 10.1111/bcp.14194

M3 - Article

C2 - 31833569

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

ER -