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M.J. O'Donnell, A. Mente, A. Smyth, S. Yusuf, Salt intake and cardiovascular disease: why are the data inconsistent?, European Heart Journal, Volume 34, Issue 14, 7 April 2013, Pages 1034–1040, https://doi.org/10.1093/eurheartj/ehs409
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Abstract
Effective population-based interventions are required to reduce the global burden of cardiovascular disease (CVD). Reducing salt intake has emerged as a leading target, with many guidelines recommending sodium intakes of 2.3 g/day or lower. These guideline thresholds are based largely on clinical trials reporting a reduction in blood pressure with low, compared with moderate, intake. However, no large-scale randomized trials have been conducted to determine the effect of low sodium intake on CV events. Prospective cohort studies evaluating the association between sodium intake and CV outcomes have been inconsistent and a number of recent studies have reported an association between low sodium intake (in the range recommended by current guidelines) and an increased risk of CV death. In the largest of these studies, a J-shaped association between sodium intake and CV death and heart failure was found. Despite a large body of research in this area, there are divergent interpretations of these data, with some advocating a re-evaluation of the current guideline recommendations. In this article, we explore potential reasons for the differing interpretations of existing evidence on the association between sodium intake and CVD. Similar to other areas in prevention, the controversy is likely to remain unresolved until large-scale definitive randomized controlled trials are conducted to determine the effect of low sodium intake (compared to moderate intake) on CVD incidence.
Comments
We thank Prof Cappuccio and colleagues for their letter. In our article (1), we state that reductions in sodium intake reduce blood pressure, an association that is clearer in those with hypertension. Moreover, the epidemiologic data support that high sodium intake is associated with increased risk of cardiovascular (CV) disease, and sodium intake should be reduced in those who consume high sodium diets.(1) The area of disagreement rests in whether there is a sufficient evidence-base to recommend reducing sodium intake in those with average (moderate) intake (3-5g/day), especially to very low levels (<1.5g/day). Therefore, our position is not whether sodium should be reduced, but in whom, and to what range sodium intake should be reduced. The reason this area is the 'object of chronic criticism' is that the evidence-base supporting that a reduction from moderate (average) intake to low intake reduces CV events is weak, and some studies even suggest harm at low sodium intakes.(2-4) In a recent meta-analysis of prospective cohort studies, co-authored by Prof Cappuccio (5), there was no significant association between sodium intake and all CV disease (RR 1.12; 0.93-1.34; n=46,483), or mortality, in a comparison between highest and lowest sodium intake groups, which is certainly not compelling evidence. They do report a significant (RR: 1.24; 1.08 to 1.43) increase in stroke with the highest sodium intake. In one cohort study of over 28,000 people at high CV risk(3), we reported a J- shaped association between sodium intake and all CV events, while an increased risk of stroke was only seen in those with high sodium intake (versus moderate), which may explain why an analysis (5) comparing lowest sodium intake to highest may not detect a significant association for all CV events, but significant for stroke. A meta-analysis (5) of the randomized controlled trials (n=720; 2 trials) also failed to show a significant benefit of reducing sodium intake on CV events, demonstrating that the available trial data are far too limited to provide any reliable conclusions. We encourage Cappuccio and colleagues to present the 'compelling' data that demonstrate 'substantial' reductions in CV disease when populations reduce sodium intake from moderate to low levels. We are unable to identify these data.
The case to support recommending low sodium intake (versus moderate) is based on the results of short-term clinical trials reported a modest reduction in blood pressure with lowering sodium intake from moderate to lower intake ranges.(5) The contention that any reductions in blood pressure, irrespective of mechanism, will translate into reductions in CV events in all populations is questionable. Prospective cohort studies reporting an inverse association between low sodium intake and CV events, have also reported a positive association with blood pressure.(2,3) Other studies have reported adverse effects of low sodium intake on surrogates of CV risk.(6) In addition, blood pressure lowering (by any means) has not always translated into reductions in CV events.(7) These considerations have prompted many independent scientists and some organizations to re- appraise the evidence-base for current recommendations on low sodium intake, which reflects that questions are being asked by 'many' rather than a 'few'.(8)
The analogy with smoking is incorrect. Unlike sodium intake, tobacco smoke is not a physiological requirement, and the evidence that smoking increases CV risk, and that cessation reduces that risk, is overwhelming. Humans live healthier lives without tobacco smoke, but cannot survive without sodium.
In their letter, Cappuccio et al criticize the use of single urine measures as opposed to 24-hour collections. Single measurement (e.g. blood pressure, cholesterol) can be used to estimate epidemiologic associations reliably. Further, estimates of sodium intake from single urine measures correlate with blood pressure levels to the same extent as 24- hour urine collection (3), emphasizing the validity of this simple approach. This approach provides the tools to conduct much larger studies involving large numbers of individuals (e.g. PURE study)(9) with large numbers of events. Studies of such size are required to reliably describe the nature (direction, magnitude and shape) of the association of CV disease, and each of its components, to sodium intake.
What is needed are large international prospective cohort studies which assess the effects of sodium intake on CV events, as well as large randomized trials that assess whether low sodium intake (versus moderate) will indeed reduce CV disease. While these are all major efforts, it is important that public health policy is based on robust data and not mere extrapolations from observations on surrogate outcomes. The costs of an erroneous public health policy could be very large, both in terms of economics and lives (as it may divert resources and attention from more clearly proven strategies to reduce CV disease).
Martin O'Donnell, MB PhD MRCPI, NUI Galway, Ireland and Population Health Research Institute, McMaster University, Canada. Correspondence: [email protected]
Andrew Mente, PhD, Population Health Research Institute, McMaster University, Canada
Andrew Smyth, MB MRCPI, Population Health Research Institute, McMaster University, Canada
Salim Yusuf, DPhil FRCPC FRSC, Population Health Research Institute, McMaster University, Canada
Reference List
(1) O'Donnell MJ, Mente A, Smyth A, Yusuf S. Salt intake and cardiovascular disease: why are the data inconsistent? Eur Heart J 2013;34:1034-1040.
(2) Stolarz-Skrzypek K, Kuznetsova T, Thijs L et al. Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion. JAMA 2011;305:1777-1785.
(3) O'Donnell MJ, Yusuf S, Mente A et al. Urinary sodium and potassium excretion and risk of cardiovascular events. JAMA 2011;306:2229- 2238.
(4) Thomas MC, Moran J, Forsblom C et al. The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes. Diabetes Care 2011;34:861-866.
(5) Aburto NJ, Ziolkovska A, Hooper L, Elliott P, Cappuccio FP, Meerpohl JJ. Effect of lower sodium intake on health: systematic review and meta-analyses. BMJ 2013;346:f1326.
(6) Graudal NA, Hubeck-Graudal T, Jurgens G. Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride. Cochrane Database Syst Rev 2011;CD004022.
(7) Cushman WC, Evans GW, Byington RP et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-1585.
(8) Kotchen TA, Cowley AW, Jr., Frohlich ED. Salt in health and disease--a delicate balance. N Engl J Med 2013;368:1229-1237.
(9) Yusuf S, Islam S, Chow CK et al. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle- income, and low-income countries (the PURE Study): a prospective epidemiological survey. Lancet 2011;378:1231-1243.
Conflict of Interest:
A.M. received a $500 honorarium from the American Society of Nutrition in June 2012
There is now a large body of evidence on the causal relationship between a moderate reduction in population salt intake and the substantial and cost-effective reduction in avoidable cardiovascular events through blood pressure lowering. This extensive evidence has informed consistent national and global public health policies (1 - 5). Yet this concept is still apparently the object of chronic criticism by a few respondents, mostly selecting confounded study results, underpowered statistical analyses or problematic subgroup analyses. Thus O'Donnell and coll. in the Eur Heart J (6) again contend that dietary salt of less than 5g per day might be harmful. These arguments are not new and have been discussed at length and demolished in past years (7-10). Again, no new data is provided here (apart from a dubious re-analysis of one meta-analysis by 'continents', which itself is open to a high risk of bias from post-hoc reiterations). Several opinions are then used to try and bolster their shaky argument. For instance, asserting that there is "underestimation of sodium intake in populations with increased sodium excreted in sweat" lacks a referenced proof. Likewise, it is incorrect to assume that "estimated urinary sodium excretion from early fasting morning urine [...] has been shown to be a valid group estimate compared with 24h urine". The studies by Kawasaki et al. (11) and, subsequently, by Tanaka et al. (12) have been thoroughly reviewed and subjected to major criticisms (13) (14). The over-dependence on a single morning spot urine is one of several flaws identified in the secondary analysis of ONTARGET and TRANSEND (15). Others include systematic error in the assessment of sodium intake, inappropriate methods to assess agreement with 24h urines, residual confounding, the likelihood of reverse causality and, crucially, the selection of high risk and sick older patients on multiple drug therapy. The remaining three studies supporting their contention include a secondary analysis of only 84 events (16) and two diabetic cohorts (17,18) with a high baseline incidence of macrovascular disease and a very high mortality rate, making reverse causality distinctly possible once again. These important limitations seriously undermine any generalisability of their findings (5).
According to O'Donnell and coll., the research gaps which still exist for several regions of the world, e.g. Africa, South America, India and Russia, represent another reason to defer policy action. This confuses absence of evidence with evidence of absent effects. Accepting similarly muddled reasoning in earlier decades would have prevented the development of valuable policies on tobacco control, smoke free legislation, clean water and seatbelts. Furthermore, the huge trial proposed by O'Donnell and coll. has very little chance of ever being funded or completed for many reasons. These obstacles include the huge size of the study populations required to demonstrate significant effects on hard outcomes, methodological difficulties in assessing long term compliance to dietary salt reduction, the need for a very long observation period, substantial ethical problems, and the difficulty in ensuring financial support (10). A prolonged wait for this 'mother of all trials' would be unreasonable and irresponsible, potentially delaying a major global public health benefit. In conclusion, successfully implementing population-based salt reduction strategies, as recommended by the WHO (1) and many other agencies, could save tens of thousands of lives every year. Further obstruction would thus be irresponsible and harmful.
*Francesco P Cappuccio MD DSc FRCP FFPH FAHA Professor of Cardiovascular Medicine & Epidemiology, University of Warwick, WHO Collaborating Centre, Coventry, UK *Correspondence to: [email protected]
Simon Capewell MD DSc FFPH FAHA Professor of Clinical Epidemiology, University of Liverpool, UK
Pasquale Strazzullo MD FAHA Professor of Medicine, Federico II University of Naples, Italy
Wayne Sunman MD FRCP Consultant Stroke Physician, Nottingham University Hospitals NHS Trust, UK
References
1. World Health Organization. Guideline: Sodium intake for adults and children. Geneva, World Health Organization (WHO), 2012, pp.1-56
2. Aburto NJ, Ziolkovska A, Hooper L, Elliott P, Cappuccio FP, Meerpohl JJ. Effect of lower sodium intake on health: systematic review and meta-analyses. BMJ 2013; 346: f1326
3. He FJ, Li J, MacGregor GA. Effect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomized trials. BMJ 2013; 346: f1325
4. Kotchen TA, Cowley AW jr, Frohlich ED. Salt in health and disease. A delicate balance. NEJM 2013; 368: 1229-37
5. Whelton PK, Appel LJ, Sacco RL, Anderson CAM, Antman EM, Campbell N, et al. Sodium, Blood Pressure, and Cardiovascular Disease: Further Evidence Supporting the American Heart Association Sodium Reduction Recommendations. Circulation 2012; 126: 2880-89
6. O'Donnell MJ, Mente A, Smyth A, Yusuf S. Salt intake and cardiovascular disease: why are the data inconsistent? Eur Heart J 2013; 34: 1034-40
7. Campbell N, Cappuccio FP, Tobe SW. Unnecessary controversy regarding dietary sodium. A lot about a little. Can J Cardiol 2011; 27: 404-6
8. Campbell N, Correa-Rotter R, Neal B & Cappuccio FP. New evidence relating to the health impact of reducing salt intake. Nutr Metab Cardiovasc Dis 2011; 21(9): 617-9
9. He FJ, Appel LJ, Cappuccio FP, de Wardener HE, MacGregor GA. Does reducing salt intake increase cardiovascular mortality? Kidney Int 2011; 80: 696-8
10. Strazzullo P. Benefit assessment of dietary salt reduction: while the doctors study, should more people die? J Hypertens 2011; 29: 829-31
11. Kawasaki T, Itoh K, Uezono K, Sasaki H. A simple method for estimating 24 h urinary sodium and potassium excretion from second morning voiding urine specimen in adults. Clin Exp Pharmacol Physiol 1993; 20(1): 7-14.
12. Tanaka T, Okamura T, Miura K, Kadowaki T, Ueshima H, Nakagawa H, et al. A simple method to estimate populational 24-h urinary sodium and potassium excretion using a casual urine specimen. J Hum Hypertens 2002; 16(2):97-103.
13. Ji C, Sykes L, Paul C, Dary O, Legetic B, Campbell NRC, Cappuccio FP on behalf of the Sub-Group for Research & Surveillance of the PAHO/WHO Regional Expert Group for Cardiovascular Disease Prevention through population-wide Dietary Salt Reduction. Systematic review of studies comparing 24-h vs spot urine collections for estimating population salt intake. Rev Panam Salud Publica 2012; 32(4): 307-15
14. Ji C, Miller MA, Cappuccio FP. Comparisons of spot vs 24-h urine samples for estimating salt intake. J Hum Hypertens 2011; 25: 628
15. O'Donnell MJ, Yusuf S, Mente A, Gao P, Mann JF, Teo K, et al. Urinary sodium and potassium excretion and risk of cardiovascular events. JAMA. 2011;306: 2229-38
16. Stolarz-Skrzypek K, Kuznetsova T, Thijs L, Tikhonoff V, Seidlerova J, Richart T et al. European Project on Genes in Hypertension (EPOGH) Investigators. Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion. JAMA. 2011; 305: 1777-85
17. Thomas MC, Moran J, Forsblom C, Harjutsalo V, Thorn L, Ahola A et al. The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes. Diabetes Care. 2011; 34: 861- 6
18. Ekinci EI, Clarke S, Thomas MC, Moran JL, Cheong K, MacIsaac RJ, Jerums G. Dietary salt intake and mortality in patients with type 2 diabetes. Diabetes Care. 2011; 34: 703-9
Conflict of Interest:
All authors are unpaid members of Consensus Action on Salt & Health.