Randomised, double-blind, placebo-controlled study investigating the effects of inorganic nitrate on vascular function, platelet reactivity and restenosis in stable angina: protocol of the NITRATE-OCT study

Krishnaraj S Rathod, Daniel A Jones, T J A Van-Eijl, Hilda Tsang, Helen Warren, Stephen M Hamshere, Vikas Kapil, Ajay K Jain, Andrew Deaner, Neil Poulter, Mark J Caulfield, Anthony Mathur, Amrita Ahluwalia, Krishnaraj S Rathod, Daniel A Jones, T J A Van-Eijl, Hilda Tsang, Helen Warren, Stephen M Hamshere, Vikas Kapil, Ajay K Jain, Andrew Deaner, Neil Poulter, Mark J Caulfield, Anthony Mathur, Amrita Ahluwalia

Abstract

Introduction: The mainstay treatment for reducing the symptoms of angina and long-term risk of heart attacks in patients with heart disease is stent implantation in the diseased coronary artery. While this procedure has revolutionised treatment, the incidence of secondary events remains a concern. These repeat events are thought to be due, in part, to continued enhanced platelet reactivity, endothelial dysfunction and ultimately restenosis of the stented artery. In this study, we will investigate whether a once a day inorganic nitrate administration might favourably modulate platelet reactivity and endothelial function leading to a decrease in restenosis.

Methods and design: NITRATE-OCT is a double-blind, randomised, single-centre, placebo-controlled phase II trial that will enrol 246 patients with stable angina due to have elective percutaneous coronary intervention procedure with stent implantation. Patients will be randomised to receive 6 months of a once a day dose of either nitrate-rich beetroot juice or nitrate-deplete beetroot juice (placebo) starting up to 1 week before their procedure. The primary outcome is reduction of in-stent late loss assessed by quantitative coronary angiography and optical coherence tomography at 6 months. The study is powered to detect a 0.22±0.55 mm reduction in late loss in the treatment group compared with the placebo group. Secondary end points include change from baseline assessment of endothelial function measured using flow-mediated dilation at 6 months, target vessel revascularisation (TVR), restenosis rate (diameter>50%) and in-segment late loss at 6 months, markers of inflammation and platelet reactivity and major adverse cardiac events (ie, myocardial infarction, death, cerebrovascular accident, TVR) at 12 and 24 months.

Ethics and dissemination: The study was approved by the Local Ethics Committee (15/LO/0555). Trial results will be published according to the CONSORT statement and will be presented at conferences and reported in peer-reviewed journals.

Trial registration numbers: NCT02529189 and ISRCTN17373946, Pre-results.

Conflict of interest statement

AA is a co-director of Heartbeet which is a company that seeks to identify commercial potential of dietary nitrate.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Figures

Figure 1
Figure 1
hsCRP, high-sensitivity C reactive protein; IL-6, interlukin 6; MACE, major adverse cardiac events; NHS, National Health Service; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; QCA, quantitative coronary angiography; TVR, target vessel revascularisation; XOR, xanthine oxidoreductase.

References

    1. Berger PB, Ellis SG, Holmes DR Jr et al. . Relationship between delay in performing direct coronary angioplasty and early clinical outcome in patients with acute myocardial infarction: results from the global use of strategies to open occluded arteries in Acute Coronary Syndromes (GUSTO-IIb) trial. Circulation 1999;100:14–20. 10.1161/01.CIR.100.1.14
    1. McNamara RL, Wang Y, Herrin J et al. . Effect of door-to-balloon time on mortality in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2006;47:2180–6. 10.1016/j.jacc.2005.12.072
    1. Montalescot G, Sechtem U, Achenbach S et al. . 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003. 10.1093/eurheartj/eht296
    1. Smith EJ, Mathur A, Rothman MT. Recent advances in primary percutaneous intervention for acute myocardial infarction. Heart 2005;91:1533–6. 10.1136/hrt.2005.064493
    1. O'Gara PT, Kushner FG, Ascheim DD et al. . 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127:e362–425. 10.1161/CIR.0b013e3182742cf6
    1. Keeley EC, Boura JA, Grines CL. Comparison of primary and facilitated percutaneous coronary interventions for ST-elevation myocardial infarction: quantitative review of randomised trials. Lancet 2006;367:579–88. 10.1016/S0140-6736(06)68148-8
    1. Weisz G, Leon MB, Holmes DR Jr et al. . Five-year follow-up after sirolimus-eluting stent implantation results of the SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) Trial. J Am Coll Cardiol 2009;53:1488–97. 10.1016/j.jacc.2009.01.050
    1. Steinberg DH, Gaglia MA Jr, Pinto Slottow TL et al. . Outcome differences with the use of drug-eluting stents for the treatment of in-stent restenosis of bare-metal stents versus drug-eluting stents. Am J Cardiol 2009;103:491–5. 10.1016/j.amjcard.2008.09.107
    1. Kastrati A, Mehilli J, von Beckerath N et al. . Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial. JAMA 2005;293:165–71. 10.1001/jama.293.2.165
    1. Stone GW, Witzenbichler B, Weisz G et al. . Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013;382:614–23. 10.1016/S0140-6736(13)61170-8
    1. Bredt DS. Nitric oxide signaling specificity--the heart of the problem. J Cell Sci 2003;116(Pt 1):9–15. 10.1242/jcs.00183
    1. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002–12. 10.1056/NEJM199312303292706
    1. Neunteufl T, Katzenschlager R, Hassan A et al. . Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 1997;129:111–18. 10.1016/S0021-9150(96)06018-2
    1. Moncada S, Higgs EA. Nitric oxide and the vascular endothelium. Handb Exp Pharmacol 2006;176:213–54. 10.1007/3-540-32967-6_7
    1. Fukuto J, Cho J, Switzer C. The chemical properties of nitric oxide and related nitrogen oxides. In: Ignarro L, ed.. Nitric oxide: biology and pathobiology. San Diego: Academic Press, 2000,23–40.
    1. Moro MA, Russel RJ, Cellek S et al. . cGMP mediates the vascular and platelet actions of nitric oxide: confirmation using an inhibitor of the soluble guanylyl cyclase. Proc Natl Acad Sci USA 1996;93:1480–5. 10.1073/pnas.93.4.1480
    1. Radomski MW, Palmer RM, Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 1990;87:5193–7. 10.1073/pnas.87.13.5193
    1. Sarkar R, Gordon D, Stanley JC et al. . Cell cycle effects of nitric oxide on vascular smooth muscle cells. Am J Physiol 1997;272(Pt 2):H1810–18.
    1. Duranski MR, Greer JJ, Dejam A et al. . Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J Clin Invest 2005;115:1232–40. 10.1172/JCI22493
    1. Webb A, Bond R, McLean P et al. . Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci USA 2004;101:13683–8. 10.1073/pnas.0402927101
    1. Alef MJ, Vallabhaneni R, Carchman E et al. . Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats. J Clin Invest 2011;121:1646–56. 10.1172/JCI44079
    1. Kapil V, Milsom AB, Okorie M et al. . Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension 2010;56:274–81. 10.1161/HYPERTENSIONAHA.110.153536
    1. Webb AJ, Patel N, Loukogeorgakis S et al. . Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension 2008;51:784–90. 10.1161/HYPERTENSIONAHA.107.103523
    1. Velmurugan S, Kapil V, Ghosh SM et al. . Antiplatelet effects of dietary nitrate in healthy volunteers: involvement of cGMP and influence of sex. Free Radic Biol Med 2013;65:1521–32. 10.1016/j.freeradbiomed.2013.06.031
    1. Velmurugan S, Gan JM, Rathod KS et al. . Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr 2016;103:25–38. 10.3945/ajcn.115.116244
    1. Mayer B, Beretta M. The enigma of nitroglycerin bioactivation and nitrate tolerance: news, views and troubles. Br J Pharmacol 2008;155:170–84. 10.1038/bjp.2008.263
    1. Kapil V, Khambata RS, Robertson A et al. . Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study. Hypertension 2015;65:320–7. 10.1161/HYPERTENSIONAHA.114.04675
    1. Eggebeen J, Kim-Shapiro DB, Haykowsky M et al. . One week of daily dosing with beetroot juice improves submaximal endurance and blood pressure in older patients with heart failure and preserved ejection fraction. JACC Heart Fail 2016;4:428–37. 10.1016/j.jchf.2015.12.013
    1. Rammos C, Hendgen-Cotta UB, Totzeck M et al. . Impact of dietary nitrate on age-related diastolic dysfunction. Eur J Heart Fail 2016;18:599–610. 10.1002/ejhf.535
    1. Ignarro LJ, Fukuto JM, Griscavage JM et al. . Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: comparison with enzymatically formed nitric oxide from L-arginine. Proc Natl Acad Sci USA 1993;90:8103–7. 10.1073/pnas.90.17.8103
    1. Hickson SS, Butlin M, Broad J et al. . Validity and repeatability of the Vicorder apparatus: a comparison with the SphygmoCor device. Hypertens Res 2009;32:1079–85. 10.1038/hr.2009.154
    1. Celermajer DS, Sorensen KE, Gooch VM et al. . Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–15. 10.1016/0140-6736(92)93147-F
    1. Corretti MC, Anderson TJ, Benjamin EJ et al. . Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257–65. 10.1016/S0735-1097(01)01746-6
    1. Gemignani V, Faita F, Ghiadoni L et al. . A system for real-time measurement of the brachial artery diameter in B-mode ultrasound images. IEEE Trans Med Imaging 2007;26:393–404. 10.1109/TMI.2006.891477
    1. Mauri L, Orav EJ, Kuntz RE. Late loss in lumen diameter and binary restenosis for drug-eluting stent comparison. Circulation 2005;111:3435–42. 10.1161/CIRCULATIONAHA.104.513952
    1. Davies WR, Brown AJ, Watson W et al. . Remote ischemic preconditioning improves outcome at 6 years after elective percutaneous coronary intervention: the CRISP stent trial long-term follow-up. Circ Cardiovasc Interv 2013;6:246–51. 10.1161/CIRCINTERVENTIONS.112.000184
    1. Lupattelli G, Marchesi S, Lombardini R et al. . Artichoke juice improves endothelial function in hyperlipemia. Life Sci 2004;76:775–82. 10.1016/j.lfs.2004.07.018
    1. Katz DL, Davidhi A, Ma Y et al. . Effects of walnuts on endothelial function in overweight adults with visceral obesity: a randomized, controlled, crossover trial. J Am Coll Nutr 2012;31:415–23.
    1. Kay CD, Hooper L, Kroon PA et al. . Relative impact of flavonoid composition, dose and structure on vascular function: a systematic review of randomised controlled trials of flavonoid-rich food products. Mol Nutr Food Res 2012;56:1605–16. 10.1002/mnfr.201200363
    1. Gilchrist M, Winyard PG, Aizawa K et al. . Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes. Free Radic Biol Med 2013;60:89–97. 10.1016/j.freeradbiomed.2013.01.024
    1. Gilchrist M, Winyard PG, Fulford J et al. . Dietary nitrate supplementation improves reaction time in type 2 diabetes: development and application of a novel nitrate-depleted beetroot juice placebo. Nitric Oxide 2014;40:67–74. 10.1016/j.niox.2014.05.003
    1. Lansley KE, Winyard PG, Bailey SJ et al. . Acute dietary nitrate supplementation improves cycling time trial performance. Med Sci Sports Exerc 2011;43:1125–31. 10.1249/MSS.0b013e31821597b4

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다