NITRATE-CIN Study: Protocol of a Randomized (1:1) Single-Center, UK, Double-Blind Placebo-Controlled Trial Testing the Effect of Inorganic Nitrate on Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography for Acute Coronary Syndromes.

BACKGROUND: Contrast-induced nephropathy (CIN), an acute kidney injury resulting from the administration of intravascular iodinated contrast media, is a significant cause of morbidity/mortality following coronary angiographic procedures in high-risk patients. Despite preventative measures intended to mitigate the risk of CIN, there remains a need for novel effective treatments. Evidence suggests that delivery of nitric oxide (NO) through chemical reduction of inorganic nitrate to NO may offer a novel therapeutic strategy to reduce CIN and thus preserve long term renal function. DESIGN: The NITRATE-CIN trial is a single-center, randomized, double-blind placebo-controlled trial, which plans to recruit 640 patients presenting with acute coronary syndromes (ACS) who are at risk of CIN. Patients will be randomized to either inorganic nitrate therapy (capsules containing 12 mmol KNO3) or placebo capsules containing potassium chloride (KCl) daily for 5 days. The primary endpoint is development of CIN using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. A key secondary endpoint is renal function over a 3-month follow-up period. Additional secondary endpoints include serum renal biomarkers (e.g. neutrophil gelatinase-associated lipocalin) at 6 h, 48 h and 3 months following administration of contrast. Cost-effectiveness of inorganic nitrate therapy will also be evaluated. SUMMARY: This study is designed to investigate the hypothesis that inorganic nitrate treatment decreases the rate of CIN as part of semi-emergent coronary angiography for ACS. Inorganic nitrate is a simple and easy to administer intervention that may prove useful in prevention of CIN in at-risk patients undergoing coronary angiographic procedures.

Sodium Nitrite-Mediated Cardioprotection in Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction: A Cost-Effectiveness Analysis.

OBJECTIVES: In the follow-up of patients in a trial of intracoronary sodium nitrite given during primary percutaneous coronary intervention (PCI) after acute myocardial infarction (AMI), we found a reduction in the incidence of major adverse cardiac events (MACEs). Specifically, MACE rates were 5.2% versus 25.0% with placebo at 3 years ( P = .013). Such MACE reductions should also be associated with economic benefit. Thus, we assessed the cost utility of sodium nitrite therapy versus standard primary PCI only. METHODS AND RESULTS: We developed a model to simulate costs and quality-adjusted life years (QALYs) over the first 36 months after ST-Segment Elevation Myocardial Infarction (STEMI). Decision tree analysis was used to assess different potential cardiovascular outcomes after STEMI for patients in both treatment groups. Model inputs were derived from the NITRITE-AMI study. Cost of comparative treatments and follow-up in relation to cardiovascular events was calculated from the United Kingdom National Health Service perspective. Higher procedural costs for nitrite treatment were offset by lower costs for repeat revascularization, myocardial infarction, and hospitalization for heart failure compared to primary PCI plus placebo. Nitrite treatment was associated with higher utility values (0.91 ± 0.19 vs 0.82 ± 0.30, P = .041). The calculated incremental cost-effectiveness ratio of £2177 per QALY indicates a cost-effective strategy. Furthermore, positive results were maintained when input parameters varied, indicating the robustness of our model. In fact, based on the difference in utility values, the cost of nitrite could increase by 4-fold (£2006 per vial) and remain cost-effective. CONCLUSION: This first analysis of sodium nitrite as a cardioprotective treatment demonstrates cost-effectiveness. Although more comparative analysis and assessment of longer follow-up times are required, our data indicate the considerable potential of nitrite-mediated cardioprotection.

Variation in anticoagulation for atrial fibrillation between English clinical commissioning groups: an observational study.

BACKGROUND: Despite improvement in anticoagulation for atrial fibrillation (AF), substantial variation in anticoagulation persists between clinical commissioning groups (CCGs) and regions in England. AIM: To identify reasons for variation between English CCGs in anticoagulation for AF. DESIGN AND SETTING: A 4-year observational study from 2012/2013 to 2015/2016, of the national Quality and Outcomes Framework. METHOD: Multiple regression and Pearson's correlation coefficients were used to analyse anticoagulation for AF in relation to older age, Index of Multiple Deprivation, prescription of non-vitamin K antagonist oral anticoagulants (NOACs), and exception reporting, as well as stroke hospital admission and mortality. RESULTS: The proportion of eligible patients in England prescribed anticoagulants for AF without exceptions for clinical complexity or patient dissent increased from 65.1% in 2012/2013 to 77.9% in 2015/2016. In 2015, 290 920 additional eligible people were anticoagulated in association with use of the CHA2DS2VASc rather than CHADS2 score. From 2012 to 2015, exception reporting almost halved from 20% to 10.2%. Variation in CCG anticoagulation was not associated with deprivation or NOAC use. There was a strong negative association between exception reporting representing patient complexity and anticoagulation performance, accounting for 57% of the variation in anticoagulation without exceptions (multiple regression coefficient = -0.81; 95% confidence intervals = -0.92 to -0.71; P<0.001). CONCLUSION: Anticoagulation for AF has improved substantially in England in association with considerable increases in the eligible population as a result of decreased exception reporting and the use of the CHA2DS2VASc score. There is still substantial room for improvement in most CCGs because, even allowing for exceptions, nine out of 10 CCGs failed to achieve 90% anticoagulation.

The effect of intracoronary sodium nitrite on the burden of ventricular arrhythmias following primary percutaneous coronary intervention for acute myocardial infarction.

OBJECTIVE: Pre-clinical evidence suggests delivery of nitric oxide (NO) through administration of inorganic nitrite suppresses arrhythmias resulting from acute ischaemia and reperfusion (I/R). To date no assessment of whether inorganic nitrite might limit reperfusion arrhythmia has occurred in man, therefore we explored the effects on I/R-induced ventricular arrhythmias in the NITRITE-AMI cohort. METHODS: In the NITRITE-AMI cohort, Holter analysis was performed prior to and for 24 h after primary PCI in 80 patients who received either intra-coronary sodium nitrite (N = 40) or placebo (N = 40) during primary PCI for AMI. RESULTS: Ventricular rhythm disturbance was experienced by 100% patients; however, there was no difference in the number between the groups, p = .2196. Non-sustained ventricular tachycardia (NSVT) occurred in 67.5% (27/40) of nitrite-treated patients compared to 89% (35/39) of those treated with placebo (p = .027). There was a significant reduction in both the number of runs (63%, p ≤.0001) and total beats of NSVT (64%, p = .0019) in the nitrite-treated patients compared to placebo. Post-hoc analyses demonstrate a direct correlation of occurrence of NSVT with infarct size, with the correlation stronger in the placebo versus the nitrite group initiating an independent nitrite effect (Nitrite: r = 0.110, p = .499, placebo: r = 0.527, p = .001, p for comparison: 0.004). CONCLUSION: Overall no difference in ventricular rhythm disturbance was seen with intra-coronary nitrite treatment during primary PCI in STEMI patients, however nitrite treatment was associated with an important reduction in the incidence and severity of NSVT. In view of the sustained reduction of MACE seen, this effect warrants further study in a large-scale trial.

Management of Hypertensive Patients With Multiple Drug Intolerances: A Single-Center Experience of a Novel Treatment Algorithm.

Multiple drug intolerance to antihypertensive medications (MDI-HTN) is an overlooked cause of nonadherence. In this study, 55 patients with MDI-HTN were managed with a novel treatment algorithm utilizing sequentially initiated monotherapies or combinations of maximally tolerated doses of fractional tablet doses, liquid formulations, transdermal preparations, and off-label tablet medications. A total of 10% of referred patients had MDI-HTN, resulting in insufficient pharmacotherapy and baseline office blood pressure (OBP) of 178±24/94±15 mm Hg. At baseline, patients were intolerant to 7.6±3.6 antihypertensives; they were receiving 1.4±1.1 medications. After 6 months on the novel MDI-HTN treatment algorithm, both OBP and home blood pressure (HBP) were significantly reduced, with patients receiving 2.0±1.2 medications. At 12 months, OBP was reduced from baseline by 17±5/9±3 mm Hg (P<.01, P<.05) and HBP was reduced by 11±5/12±3 mm Hg (P<.01 for both) while patients were receiving 1.9±1.1 medications. Application of a stratified medicine approach allowed patients to tolerate increased numbers of medications and achieved significant long-term lowering of blood pressure.

Sharps legislation and assessment of needle protection systems.

Needlestick injuries (NSIs) carry the potential for transmission of serious blood-borne infections and pose a significant risk to patients and healthcare staff. These infections come with an estimated cost of £300 million per year in the UK (Saia et al, 2010). An EU directive mandated in May of 2013 has sought to minimise the risk of NSI though the introduction of needle-protection systems. The authors of this article set out to assess nursing knowledge of this legislation and ascertain which needle-protection systems for low-molecular weight heparin/anti Xa (for subcutaneous administration) were preferred in a large teaching trust. Approximately half of the nurses questioned had some knowledge of the legislation and almost all agreed that there is a need for needle protection systems. All four devices tested meet requirements for the legislation but the preferred devices were the needle protection system for enoxaparin and fondaparinux with a self-sheathing style device after activation.