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

Abstract

BackgroundIn 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 ResultsSeventy 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.ConclusionsSodium 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.

Acute Dietary Nitrate Supplementation Improves Flow Mediated Dilatation of the Superficial Femoral Artery in Healthy Older Males

“…Our interest in the impact of NO 3 − supplementation on vascular function in the leg began with the observation that NO 3 − supplementation was associated with a decrease in blood pressure [62] and an improvement in exercise tolerance in older adults [22], and in patients with peripheral arterial disease [23,24], heart failure with preserved ejection fraction [47], and stable angina [63]. It was proposed that dietary NO 3 − may enhance plasma NO 2 − , which may increase NO bioavailability [31].…”

Safety of low-dose dobutamine stress test in coronary slow flow phenomenon

“…Echocardiography monitoring revealed that ST-segment depression in the precordial leads and a heart ultrasound had uncoordinated ventricular wall motion. These symptoms were relieved when the dobutamine infusion was interrupted or when inorganic nitrates were used [18]. However, ST-segment depression was not observed in other patients with LAD or LCX disease who also had chest tightness.…”

Does dietary nitrate say NO to cardiovascular ageing? Current evidence and implications for research

“…Dietary nitrate was associate with small but significant improvements in FMD, PWV and platelet aggregation CHD Schwarz (111) Seventy patients with stable angina (108) Twenty coronary artery disease patients on clopidogrel therapy (122) Nine patients with heart failure R, CO, P, DB BJ (2 h) Nitrate-free BJ Physical performance, clinic resting and exercise BP Inorganic nitrate increased peak knee extensor power but did not modify BP Eggebeen (123) Twenty patients with heart failure with preserved ejection fraction (124) Seventeen patients with heart failure with preserved ejection fraction (113) Eight patients with heart failure with reduced ejection fraction R, CO, P, DB BJ (2 h) Nitrate-free BJ Physical performance, clinic resting and exercise BP Dietary nitrate improved muscle performance but did not have an effect on resting and exercise BP Shaltout (121) Nineteen patients with heart failure with preserved ejection fraction in both human subjects and experimental animals (106,107) . Two studies have found a positive effect of dietary NO − 3 supplementation on platelet aggregation in hypercholesterolaemic patients (94) and platelet-derived extracellular vesicles in coronary artery disease patients on clopidogrel therapy (108) .…”

“…Moreover, low-dose sodium attenuated myocardial ischaemia and vascular reperfusion injury in a human experimental study ( 110 ) . However, Schwarz et al ( 111 ) showed that supplementation with sodium marginally improved exercise performance in patients with chronic angina on prescribed medications. Conversely, positive effects of dietary supplementation were found on exercise tolerance and onset of claudication intermittens in eight patients with peripheral arterial disease ( 112 ) .…”

“…Several studies have been conducted in patients with hypertension and chronic heart failure, but the results have been contrasting, whereas for other cardiovascular disorders such as diabetes, CHD or chronic kidney failure, there is simply a paucity of studies. In addition, the evidence is further weakened by the pilot nature of these studies both in terms of short duration (longest trial is 8 weeks) ( 83 ) of the interventions and small sample size (largest population is seventy patients) ( 111 ) . Future research efforts should be therefore directed at the conduction of more robust, confirmatory trials to provide strong and unbiased evidence on the effects of dietary on cardiovascular outcomes.…”