|Year : 2015 | Volume
| Issue : 1 | Page : 65-68
Gajender Dubey1, Derek Cyr2, Ambuj Roy1
1 Department of Cardiology, Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi, India
2 Duke Clinical Research Institute, Durham, North Carolina, USA
|Date of Web Publication||22-May-2015|
Dr. Ambuj Roy
Department of Cardiology, Cardiothoracic Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Dubey G, Cyr D, Roy A. Journal review. J Pract Cardiovasc Sci 2015;1:65-8
| Article|| |
Martin O'Donnell, M.B., Ph.D., Andrew Mente, Ph.D., et al. for the PURE investigators. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med 2014;371:612-23.
- Sodium is the most important extracellular cation regulating extracellular fluid volume
- Sodium intake is known to be a modifiable determinant of hypertension
- Modest association between higher levels of sodium intake and higher blood pressure was seen in the INTERSALT study 
- Guidelines for prevention of cardiovascular disease recommend sodium intake of 1.5−2.4 g/day 
- There is a lack of definite evidence of benefit of this recommendation
- Several small prospective cohort studies have shown inconsistent association between sodium intake and cardiovascular events and death.
- The primary objective of this study is to determine the association between estimated daily sodium and potassium intake with a composite outcome of death from any cause and major cardiovascular events
- Major cardiovascular events included death from cardiovascular causes, stroke, myocardial infarction, or heart failure
- Large scale epidemiological prospective cohort study
- 156,424 persons, 35−70 years of age residing in 628 urban and rural communities in 17 low, middle and high-income countries were screened
- Final study sample consisted of 102,216 participants with a valid baseline fasting morning urine sample
- 42% participants were from China.
| Methods|| |
- Morning fasting midstream urine samples were collected from each participant and frozen at −20°C to −70°C
- Urine samples shipped in ambient packaging with STP-250 to regional research laboratories where the urinalysis was done to determine spot urinary sodium and potassium content
- Kawasaki formula was used to estimate 24-h urinary sodium and potassium excretion 
- The estimates were used as surrogates for daily sodium and potassium intake
- Data collection
- Questionnaire was used for Information on personal medical history and use of prescription medication
- Standardized case-report forms were used to capture data on major cardiovascular events and death during follow-up
- Follow-up was initiated in 2008 and completed by 2013
- At least one, and up to three visits were attempted at each site
- Prespecified definitions of end points were used for event monitoring.
- Chi-square test for categorical variables and analysis of variance for continuous variables
- Restricted cubic spline plots: To explore shape of the association between the estimated sodium and potassium excretion and the outcomes. The "spline" is a flexible strip of metal commonly used by drafters to draw curved lines. Cubic spline plots are useful tools to model nonlinear relationships
- Three models adjusted for various variables were used to determine associations
- Array approach sensitivity analysis and propensity score matched sensitivity analyses were also performed. Sensitivity analysis is the study of how the uncertainty in the output of a mathematical model can be attributed to different sources of uncertainty in its input variables. Taking an example from any budgeting process: There are always uncertain variables such as inflation rates, future taxes, interest rates, etc., Sensitivity analysis estimates what will be the effect on the budget and by how much by the change in each of these variables. In many studies, two study groups can be significantly different from each other, and their differences cannot be attributed to an intervention effect. Propensity score matched analysis methods offer a way to balance groups by matching treatment and control units based on a set of covariates
- Reference levels of usual intake were 4−5.99 g/day for sodium and <1.5 g/day for potassium.
| Results|| |
- Mean estimated 24-h sodium excretion was 4.93 g and mean estimated 24-h potassium excretion was 2.12 g
- Mean duration of follow-up was 3.7 years
- Follow-up was completed for 95% of the participants
- Primary composite outcome: 3317 participants (3.3%), 1976 deaths (650 cardiovascular causes), 857 myocardial infarction, 872 stroke, 261 heart failure
- Mean systolic and diastolic blood pressures were higher among participants with a higher estimated sodium excretion (P < 0.001)
- Participants may have had more than one cardiovascular event.
Sodium excretion and risk of primary outcome
- Excretion of 7.00 g/day compared with 4.00−5.99 g/day (reference range):
- Increased risks of the primary composite outcome (odds ratio, 1.15; 95% confidence interval [CI], 1.02−1.30).
- Increased risk of death from any cause (odds ratio, 1.25; 95% CI, 1.07−1.48)
- Increased risk of major cardiovascular event (odds ratio, 1.16; 95% CI, 1.01−1.34), death from cardiovascular causes (odds ratio, 1.54; 95% CI, 1.21−1.95), and stroke resulting in death or hospitalization (odds ratio, 1.29; 95% CI, 1.02−1.63) on multivariable analysis.
- The association was attenuated and became nonsignificant after adjustment for hypertension for all variables except death from any cause
- Estimated excretion of <3.00 g/day compared with excretion of 4.00−5.99 g/day:
- Increased risks of the primary composite outcome (odds ratio, 1.27; 95% CI, 1.12−1.44), death from any cause (odds ratio, 1.38; 95% CI, 1.15−1.66), a major cardiovascular event (odds ratio, 1.30; 95% CI, 1.13−1.50), death from cardiovascular causes (odds ratio, 1.77; 95% CI, 1.36−2.31), and stroke resulting in death or hospitalization (odds ratio, 1.37; 95% CI, 1.07−1.76)
- Associations remained significant after adjustment for blood pressure or prior diagnosis of hypertension.
Estimated potassium excretion and risk of outcomes
- Reduction in the risks of death and cardiovascular events with higher potassium excretion as compared to excretion of <1.50 g/day
- No evidence of an interaction between estimated potassium and sodium excretion with respect to the primary composite outcome (P = 0.55).
Group and sensitivity analyses
- Hypertension at baseline significantly modified the association between a high estimated sodium excretion and the composite outcome (P = 0.02 for interaction)
- No other significant subgroup interactions were there
- Findings from the sodium and potassium analyses were not affected by exclusion of participants with cardiovascular disease (at baseline) or cancer (at baseline or follow-up) or those who had events in the 1 st year of follow-up did not materially affect the
- Propensity-score - matched analysis
- 21,220 participants
- Low estimated sodium excretion (<3.00 g/day), as compared with a moderate level (3.00−5.99 g/day), was associated with an increased risk of the composite outcome (odds ratio, 1.26; 95% CI, 1.09−1.46)
- Similar results were seen in analysis of 40,618 participants, with high estimated sodium excretion (>6.00 g/day), associated with an increased risk of the composite outcome (odds ratio, 1.19; 95% CI, 1.06−1.34).
| Discussion|| |
- Large international prospective cohort study reflecting patterns of sodium and potassium intake in a diverse population groups
- Investigated association between estimated sodium and potassium excretion and composite of death and cardiovascular outcomes
- Shows that the global salt consumptions are significantly higher than the currently recommended intake of 1.5−2.4 g/day, with only small percentage (4%) consuming the recommended amount
- Findings suggest lowest risk of death and cardiovascular events with moderate salt intake
- Both higher and lower intake were associated with increased risk of adverse outcomes
- Association between high estimated sodium excretion and increased risk was amplified by the presence of hypertension
- This risk attenuated after adjustment for blood pressure, suggesting effects of sodium intake on blood pressure
- Association between a low estimated sodium excretion and increased risk were unaffected by adjustment for blood pressure
- Guideline recommendations of low salt intake are based on short-term clinical studies showing reduction in blood pressure with low sodium and assuming a linear relationship between blood pressure and adverse outcomes
- Assumed no unsafe lower limit of sodium intake
- Low sodium intake may be harmful as low sodium levels may lead to inappropriate activation of renin-angiotensin-aldosterone system leading to deleterious effects
- Few prior studies showed increased risk with low sodium intake, however, these included high-risk patients raising possibility of reverse causation 
- Majority of patients included in this study were free of major cardiovascular disease
- Exclusion of cancer, cardiovascular disease, diabetes, those with events in 2 years didn't cause alteration in results
- Although reverse causation cannot totally be ruled out but results do suggest that low sodium intake may not be completely innocuous
- Higher potassium excretion proved to be a negative risk factor
- May act by reducing blood pressure
- Furthermore, there was interaction between sodium and potassium excretion with accentuated rise in blood pressure with increased sodium excretion in the presence of low potassium excretion
- Effects of potassium were attenuated after adjustment of fruit and vegetable intake.
| Limitations|| |
- Most important limitation of this study is an estimation of daily sodium and potassium excretion from single morning urinary sample instead of using the more reliable method of multiple 24-h urine sample analysis
- Furthermore, the Kawasaki formula for estimation of 24-h potassium excretion is not well validated
- Sampling was not random and may not be representative of the general population
- Possibility of unmeasured confounding variables remains high
- Inability to completely rule out reverses causation
- Provides an epidemiological comparison of groups consuming different amounts of salt, not the effect of reducing salt intake
- High-risk patients with established cardiovascular disease were not included, so the findings are not applicable to such patients.
| Comments|| |
- Another study (SALT)  from same sample population studied the association between sodium and potassium excretion and blood pressure levels, showing nonlinear relationship with most pronounced effects in persons consuming high-sodium diets, persons with hypertension, and older persons
- The results of PURE study should not be considered as the final verdict regarding the optimal amount of salt consumption as there is an ample amount of conflicting evidence also
- The NUTRICODE  study published simultaneously, although based on statistical modeling, showed that sodium consumption higher than 2 g/day contributes to 1.65 million cardiovascular deaths annually worldwide
- The debate regarding optimal salt intake continues as American Heart Association has released a statement mentioning this study as an observational study attempting to link dietary sodium intake with subsequent cardiovascular events
- The editorial  on this study draws attention to the biggest drawback of the study, that is, the method of estimation of 24-h sodium and potassium excretion and on lack of interventional component to assess the direct effects of altering sodium and potassium intake on blood pressure and cardiovascular disease outcomes, hence making it impossible to establish causality
- The editorial also stresses on the need of a large randomized controlled trial to address these issues.
| Conclusions|| |
- Estimated sodium intake of 3-6 g/day is associated with lower risk of death and cardiovascular outcomes compared to higher or lower intake
- Potassium intake higher than 1.5 g/day is associated with lower risk of adverse cardiovascular outcomes
- Blanket recommendation of low sodium intake may not be beneficial for the general population
- Recommendations in high-risk groups need to be individualized.
- Results from this study can only be considered as hypothesis generating, and a randomized controlled trial is required to prove or disprove the utility of low salt intake
- Furthermore, there is a need for standardized and well-validated technique for measurement of daily sodium and potassium intake as estimation of these variables from a single urinary sample is unlikely to be accurate.
| References|| |
Intersalt: An international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group. BMJ 1988;297:319-28.
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Kawamura M, Kusano Y, Takahashi T, Owada M, Sugawara T. Effectiveness of a spot urine method in evaluating daily salt intake in hypertensive patients taking oral antihypertensive drugs. Hypertens Res 2006;29:397-402.
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Global sodium consumption and death from cardiovascular causes. N Engl J Med 2014;371:624-34.
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