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HESI: General Population (2014)

Pfister R, Michels G, Sharp SJ, Luben R, Wareham NJ, Khaw KT. Estimated urinary sodium excretion and risk of heart failure in men and women in the EPIC-Norfolk study. Eur J Heart Fail. 2014, Jan. 20 doi:10.1002/ejhf.56 (Epub ahead of published). PubMed ID: 24464931
Study Design:
Prospective Cohort Study
B - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
  • To investigate the prospective association of estimated 24-hour urinary sodium excretion as a surrogate of sodium intake with the risk of developing heart failure in a population of apparently healthy middle-aged men and women
  • They also examined the association with all-cause mortality since sodium intake might contrarily affect risk factors for heart failure and overall prognosis, respectively.
Inclusion Criteria:
  • This is a study from the European Prospective Investigation into Cancer and Nutrition (EPIC), Norfolk, UK
  • Details of the study design was published previously.
Exclusion Criteria:
Information previously published.
Description of Study Protocol:

Details of the recruitment process have been published previously: The EPIC-Norfolk population is broadly similar to the UK population in terms of the distribution of anthropometric, smoking and cardiovascular risk factors.

Prospective population study.

Statistical Analysis

  • Sensitivity analysis were performed inputting missing data on covariates using a chained equations approach. Risk factors were examined in five groups based on sex-specific quintiles of urinary sodium.
  • ANOVA was used for continuous variables and the X2 test for categorical variables to measure a potential association between urinary sodium quintiles and risk factors. Cox regression was used to estimate age-adjusted hazard rations (HRs) for combined fatal and non-fatal heart failure by quintiles of urinary sodium in men and women separately and combined, using the quintile with the lowest risk as reference.
  • Multivariable Cox regression was used to determine the independent contribution of urinary sodium for incident heart failure. Multi-variable analysis included established socio-demographic, cardiovascular and lifestyle risk factors of heart failure.
  • To assess the continuous association between estimated urinary sodium excretion and heart failure risk, restricted cubic splines with knots at the fifth, 25th, 75th and 95th percentiles, with the model centred at the median (3,634mg per day or 158mmol per day) and the plot truncated at the 2.5th and 97.5th percentiles were generated.
  • Secondary analysis excluded people with heart failure events occurring during the first two years of follow-up, people with a history of hypertension and people with baseline medication that may influence urinary sodium excretion. Analysis were stratified by age, BMI and systolic blood pressure. To assess whether the association of estimated urinary sodium excretion and heart failure was mediated by preceding coronary heart disease, hospitalization for ischemic heart disease as a time-dependent variable to the model was added.
  • To address the issue of unbalanced risk factors across quintiles of estimated urinary sodium excretion, two separate propensity scores were constructed using the same set of covariates included in the fully adjusted Cox model, one with and one without inclusion of systolic blood pressure and blood pressure medication
  • Logistic regression was used to calculate the probability of having low urinary sodium excretion (Quintile One) and, in a separating analysis, of having high urinary sodium excretion (Quintile Five), compared with the reference of Quintile Two
  • Cox regression, including the propensity score as a covariate, was also used to estimate HRs
  • Patients were dropped from the analysis without overlapping propensity scores between Quintile One or Quintile Five, respectively and Quintile Two and estimated HRs using Cox regression on the exposure of being in Quintile One or Quintile Five, respectively, compared with quintile compared with Quintile Two within the matched groups.
Data Collection Summary:

Timing of Measurements

  • Details of timing measurements have been published previously
  • The EPIC study in Norfolk had a mean follow-up of 12.9 years. The current study is based on follow-up to the end of June 2009.
  • Health and lifestyle questionnaire was completed by the participants at the baseline survey between 1993 and 1997
  • Height, weight, BMI, BP and blood samples were measured
  • A casual urine specimen was requested from each participant and frozen at this period. During 1998 and 2002, the urine samples were assayed for potassium, sodium and creatinine concentrations.
  • One year after the start of the study, plasma vitamin C was measured
  • Measurements of 24-hour urinary sodium excretion was obtained in a sub-sample of 163 subjects participating in continuing validation and calibration studies within the EPIC-Norfolk study with up to six 24-hour urine collections over one year. Estimates of 24-hour urinary sodium excretion from spot urine samples in a randomly selected sub-group of 1.551 post-menopausal women aged over 55 years and not taking hormone replacement therapy assessed at the second health examiation of the cohort was measured 3.5 years after the baseline survey.

Dependent Variables

  • Heart failure risk
  • All-cause mortality.

Independent Variables

  • Urinary sodium excretion: A casual urine specimen was collected from each participant. Measurements of 24-hour urinary sodium excretion was obtained in a sub-sample of the population.
  • Another selected sub-group of post-menopausal women aged over 55 years and not under hormone replacement therapy had a 24-hour urinary sodium excretion measured from a spot of urine samples.

Control Variables

  • Age
  • Sex
  • BMI
  • Cholesterol
  • Diabetes
  • Social class
  • Educational level
  • Smoking
  • Phisical activity
  • Alcohol consumption
  • cardiovascular and lifestyle risk
  • Systolic blood pressure
  • Blood pressure medication.
Description of Actual Data Sample:

Initial N

Attrition (Final N)

  • 19,857: 9,017 male, 10,840 female
  • Exclusion reasons
    • History of heart attack, stroke or any cancer at the baseline clinic visit: 2,423
    • Baseline medical heart failure treatment: 114 
    • Without available data on estimated 24-hour urinary sodium excretion: 461 
    • Missing data on covariates included in multi-variable anlayses: 2,784.

Mean age: 58±9.2 years
Range: 39 to 79 years.

Not available.

Other Relevant Demographics

  • Estimated urinary excretion was 3,772mg per day (164±38mmol per day) in men and 3,565mg per day (155±42mmol per day) in women
  • There was a statistically signficant difference across quintiles of estimated urinary sodium excretion for age, BMI, blood pressure, C-reactive protein (CRP), history of hypertension, rate of blood pressure medication use and occupational social class in men and women, for physical acitivity in men only and for rate of alcohol consumption in women only. 

BMI was not different between men and women or across quintiles for same sex.

United Kingdom.

Summary of Results:

Key Findings

  • When compared with the reference category of the 24-hour urinary sodium excretion (UNAE), between 2,944mg (128mmol) per day and 3,404mg (148mmol) per day, UNAE of between 4,393mg (191mmol) per day was associated with a significantly increased hazard (HR) of heart failure in multi-variable analysis (1.32,1.07 to 1.62), adjusting for age, sex, BMI, diabetes, cholesterol, social class, educational level, smoking, physical activity and alcohol consumption, with a marked attenuation (1.21, 0.98 to 1.49) when further adjusting for blood pressure (BP)
  • UNAE of no more than 2,921mg (127mmol) per day was also associated with an increased hazard of heart failure (1.29, 1.04 to 1.60) in multi-variable analysis without relevant attenuation by BP adjustment (1.26, 1.02 to 1.56), but with a greater attenuation when adjusting for interim ischemic heart disease and baseline C-reactive protein levels and exclusion of events (1.18, 0.96 to 1.47) during the first two years
  • A total of 1,210 incident cases of heart failure were identified (137 fatal and 1,073 non-fatal) in 702 men and 508 women during a mean follow-up of 12.9 years.

Other Findings

  • There was a U-shaped association between quintiles of estimated urinary sodium excretion and hazard of all-cause death in age- and sex-adjusted analyses, with the highest risk associated with the lowest quintile (127mmol or less per day) of estimated UNAE
  • For total mortality, the association for the highest quintile (191mmol or more per day) or of estimated UNAE was attenuated after adjustment for blood pressure, whereas for the lowest quintile it was also attenuated after adjustment for interim ischemic heart disease, CRP levels and exclusion events during the first two years
  • There was a stronger association between estimated UNAE and heart failure in older and obese participants and participants with higher systolic blood pressure, although the interactions by age, BMI and systolic blood pressure were not statistically significant.
Author Conclusion:
  • The authors demonstrated a U-shaped association between estimated urinary sodium excretion and heart failure risk in an apparently healthy middle-aged population
  • The risk associated with the high range of estimated urinary sodium excretion was mediated through blood pressure, whereas the risk associated with the low range of estimated urinary sodium excretion seemed to be at least partly explained by pre-existing disease processes.
Funding Source:
Reviewer Comments:
Limitations mentioned by the authors included:
  • Sodium excretion was measured from a single casual urinary sample, which can lead to a measurement error due to day to day variations in sodium intake and does not account for changes of habitual sodium intake occurring during the follow-up
  • Definition of heart failure cases is not in accordance with current guidelines, however in a recent validation study, the heart failure cases in this study showed a high positive predictive value for the definition recommended by the European Society of Cardiology
  • No information on the etiology of incident heart failure cases.
Other comments
  • The study is well designed and included a large population from the UK
  • The incidence of heart failure risks decreased with a sodium intake range of approximately 2,900mg to 3,400mg per day.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? ???
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? ???
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? ???
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? N/A
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes