Abstract
Background: While low sodium intake (<2.3g/day) is recommended for all, there is uncertainty about feasibility and net cardiovascular effects. In COSTICK, we evaluated the effects of a dietary counselling intervention (reduced sodium intake) on intermediate cardiorenal outcomes in patients with(STICK) and without (COSIP) mild/moderate kidney disease. Methods: This is a protocol for two phase IIb randomised, two-group, parallel, open-label, controlled, single centre trials. Participants were aged >40 years with stable blood pressure, unchanged anti-hypertensive medications, willing to modify diet and provided written informed consent. Participants were excluded for abnormal sodium handling, heart failure, high dose diuretics, immunosuppression, pregnancy/lactation, postural hypotension, cognitive impairment, high or low body mass index (BMI) or inclusion in another trial. STICK participants had estimated glomerular filtration rate (eGFR) 30-60ml/min/1.73m 2 and were excluded for acute kidney Injury, rapidly declining eGFR; known glomerular disease or current use of non-steroidal anti-inflammatory drugs. For COSIP, participants were excluded for known kidney or cardiovascular disease. Participants were randomized to usual care only (healthy eating) or an additional sodium lowering intervention (target <100mmol/day) through specific counseling (sodium use in foods, fresh over processed foods, sodium content of foods and eating outside of home). In STICK the primary outcome is change in 24-hour urinary creatinine clearance. In COSIP, the primary outcome is change in five biomarkers (renin, aldosterone, high sensitivity troponin T, pro-B-type natriuretic peptide and C-reactive protein). Our primary report (COSTICK), reports six biomarker outcome measures in the entire population at 2 years follow-up. Discussion: These Phase II trials will explore uncertainty about low sodium intake and cardiovascular and kidney biomarkers, and help determine the feasibility of low sodium intake. Trial results will also provide preliminary information to guide a future definitive clinical trial, if indicated. Trial registration: STICK: ClinicalTrials.gov NCT02738736 (04/04/2016); COSIP: ClinicalTrials.gov NCT02458248 (15/05/2016).
Highlights
In this study protocol of two randomized controlled trials, which intend to investigate the optimal sodium intake in cardiovascular and kidney diseases, the authors correctly state that the evidence supporting low sodium intake is based on Phase II trials reporting a reduction in blood pressure (BP)
There is major uncertainty about whether low sodium intake is associated with more benefit than harm, which needs to be interrogated with clinical trials
The authors state that “These trials will help determine the feasibility of sodium restriction to current guideline levels and determine if this reduction in intake is sustainable.”. This is an important point, supported by the fact that the duration of sodium reduction in RCTs sponsored by the National Heart, Lung and Blood Institute decreased from 36 months (The Hypertension Prevention Trial: Arch Intern Med 1990; 150: 153–162) to 6 months (The Trials of Hypertension Prevention, JAMA 1992; 267: 1213–1220 and Arch Intern Med 1997; 157: 657–667) to 1-month (the Dietary Approaches to Stop Hypertension (DASH) diet N Engl J Med 2001; 344: 3–10)
Summary
BP=Blood Pressure; FFQ=Food Frequency Questionnaire; ABPM=Ambulatory Blood Pressure Monitor; eGFR=estimated Glomerular Filtration Rate). Withdrawal of intervention The study intervention was withdrawn if: (i) symptomatic orthostatic hypotension with systolic BP ≤100mmHg; (ii) diagnosis of glomerular disease (as listed in exclusion criteria); (iii) diagnosis of ESRD, initiation of dialysis or renal transplantation; (iv) prescription of sodium bicarbonate therapy or treating physician recommended against sodium restriction; (v) pregnancy; or (vi) acquired new dietary requirement that precluded the intervention These participants were encouraged to complete all remaining follow-up visits. To ensure estimates are more robust to potential effects of missing data at 24-month follow-up, an inverse probability weighting will be applied in all regression analyses to account for the differing propensity of patients with certain baseline characteristics to be included in the final analysis. Ahead of database lock, statistical analyses and trial reporting
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