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Sodium and Cardiovascular Disease To the Editor: In 2013, I served on an Institute of Medicine (IOM) panel whose members concluded that data published through 2012 relating cardiovascular outcomes to a sodium intake below 2300 mg per day were inconsistent and insufficient.1 The article by O’Donnell and colleagues (Aug. 14 issue),2 which presents data from the Prospective Urban Rural Epidemiology (PURE) study, only adds to the confusion. A single morning urine sample is an inaccurate measure of usual sodium intake, ignoring day-to-day variability in sodium intake, diurnal variation in sodium excretion, and the effects of medication.3 The Kawasaki formula also overestimates sodium exposure in the U.S. population.4 In contrast, in the Trials of Hypertension Prevention (TOHP),5 an average of three to seven 24-hour urine collections were performed over 1 to 4 years to derive a very accurate estimate of a person’s typical sodium intake. After the IOM report was released, the TOHP data showed a direct, progressive relationship between lower sodium intake (down to intake below 1500 mg per day) and lower cardiovascular risk and there was no indication of a J-shaped curve.5 The fact that the PURE study is the largest to date should not influence its interpretation. A large study size does not eliminate bias resulting from selection, reverse causation, or confounding but could lead to spurious results, with a very small confidence interval around a very biased estimate. this week’s letters 2134 Sodium and Cardiovascular Disease 2139 Pancreatic Adenocarcinoma 2141 Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban 2134

Nancy R. Cook, Sc.D. Brigham and Women’s Hospital Boston, MA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Institute of Medicine. Sodium intake in populations: assess-

ment of evidence. Washington, DC: National Academies Press, 2013. 2. O’Donnell M, Mente A, Rangarajan S, et al. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med 2014;371:612-23. [Erratum, N Engl J Med 2014;371: 1267.] 3. Cobb LK, Anderson CA, Elliott P, et al. Methodological issues in cohort studies that relate sodium intake to cardiovascular disease outcomes: a science advisory from the American Heart Association. Circulation 2014;129:1173-86. 4. Cogswell ME, Wang CY, Chen TC, et al. Validity of predictive equations for 24-h urinary sodium excretion in adults aged 1839 y. Am J Clin Nutr 2013;98:1502-13. 5. Cook NR, Appel LJ, Whelton PK. Lower levels of sodium intake and reduced cardiovascular risk. Circulation 2014;129:981-9. DOI: 10.1056/NEJMc1412113

To the Editor: The analysis by O’Donnell and colleagues, which states that persons with a daily sodium intake of less than 3.00 g had the highest mortality, has serious limitations. First, the use of a sodium level from urine samples obtained in the morning as a surrogate for habitual salt ­intake throughout the 3.7 years of the study is highly questionable. Second, the group in which urinary sodium levels were less than 3.00 g (making up 10.6% of the total study population) included persons with the highest rates of cardiovascular disease, diabetes mellitus, current alcohol use, and diuretic use. Third, in an environment in which it is nearly impossible to follow a low-salt diet, the relatively small subgroup assumed to follow a low-salt diet on the basis of the analysis of a single morning urine sample raises the question of what percentage of this subgroup had a salt-avid condition (e.g., heart failure, liver disease, nephrotic syndrome, or hypovolemia).

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correspondence

Vecihi Batuman, M.D. Tulane University School of Medicine New Orleans, LA [email protected] No potential conflict of interest relevant to this letter was reported. 1. He FJ, Li J, Macgregor GA. Effect of longer term modest salt

reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials. BMJ 2013;346:f1325. 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. Kotchen TA, Cowley AW Jr, Frohlich ED. Salt in health and disease — a delicate balance. N Engl J Med 2013;368:122937. 4. Batuman V. Salt and hypertension: why is there still a debate? Kidney Int Suppl (2011) 2013;3:316-20. DOI: 10.1056/NEJMc1412113

To the Editor: The large-scale study by O’Donnell and colleagues confirms the existence of a nonlinear relationship between estimated daily sodium excretion and cardiovascular mortality in the general population. In this study, only 9.1% of the overall population had diabetes, which is a major risk factor for cardiovascular complications.1 Glycosuria is a strong determinant of diuresis and urinary solute concentration in patients with diabetes. An estimation of sodium intake based on urinary sodium level2 might lead to a spurious relationship between sodium excretion and cardiovascular mortality. We have examined this question using data from the Survie, Diabete de type 2 et Genetique (SURDIAGENE) study, a prospective inception cohort of 1439 French patients with type 2 diabetes, in which the median duration of follow-up was 70 months.3 In our results, the relationship between sodium excretion and cardiovascular mortality was also nonlinear (Fig. 1). We found that glycosuria had no effect on the relationship between estimated sodium intake and cardiovascular mortality. Our data strongly support the findings reported by O’Donnell and colleagues in a specific population of patients with type 2 diabetes. n engl j med 371;22

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Relative Risk of Cardiovascular Death

The conclusion that low salt intake is risky is not justifiable given the design and the unreliability of the basic assumptions used in this study. A sound understanding of cardiovascular physiology and the preponderance of published data indicate that a low-sodium diet is safe and saves lives.1-4

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Sodium Excretion (g/day)

Figure 1. Association of Estimated 24-hour Urinary Sodium Excretion with the Risk of Death from Cardiovascular Disease. In this spline plot based on Cox models, adjustments were made for age, sex, history of cardiovascular disease, systolic blood pressure, estimated glomerular filtration rate, diabetes duration, the rate of urinary albumin excretion, and presence of glycosuria. Dashed lines indicate 95% confidence intervals. Sodium excretion associated with a lower level of risk is the reference standard (approximately 5.3 g per day). The spline curve is truncated at 12.0 g per day (among participants with sodium excretion of >12.0 g per day: 5 deaths were reported for 131 participants).

Pierre-Jean Saulnier, M.D., Ph.D. Elise Gand, M.Sc. Samy Hadjadj, M.D., Ph.D. Centre Hospitalier Universitaire de Poitiers Poitiers, France [email protected]

for the SURDIAGENE Study Group No potential conflict of interest relevant to this letter was reported. 1. The Emerging Risk Factors Collaboration. Diabetes melli-

tus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:829-41. [Erratum, N Engl J Med 2011;364:1281.] 2. 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;20:7-14. [Erratum, Clin Exp Pharmacol Physiol 1993;20:199.] 3. Hadjadj S, Fumeron F, Roussel R, et al. Prognostic value of the insertion/deletion polymorphism of the ACE gene in type 2

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diabetic subjects: results from the Non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE), and Survie, Diabete de type 2 et Genetique (SURDIAGENE) studies. Diabetes Care 2008;31:1847-52.

and colleagues. It is therefore essential that the authors publish the individual study data. In Mozaffarian’s modeling study,1 the direct link between sodium reduction and mortality is missing. The unreliability of the conclusion is emphasized by the PURE study, which is based on DOI: 10.1056/NEJMc1412113 genuine scientific data and shows that low sodium intake is concomitantly associated with lower To the Editor: The meta-analysis of random- blood pressure and an increased number of faized, controlled trials conducted by Mozaffarian talities, confirming that low sodium intake is an and colleagues indicated that in a white, normo- independent risk factor for increased mortality.4 tensive population at 50 years of age, each reduc- Niels Graudal, M.D., D.M.Sc. tion of 2.30 g per day in sodium intake lowered Copenhagen University Hospital systolic blood pressure by 3.74 mm Hg.1 How- Copenhagen, Denmark 2 ever, a subanalysis of our own meta-analysis, [email protected] from which the authors derived their references, No potential conflict of interest relevant to this letter was reshows that data from randomized trials involving ported. normotensive middle-aged populations are bi1. Mozaffarian D, Fahimi S, Singh GM, et al. Global sodium ased by high baseline levels of systolic blood consumption and death from cardiovascular causes. N Engl J 3 pressure and a high body-mass index (Fig. 1). Med 2014;371:624-34. These ­biases inflate the effect of sodium reduc- 2. Graudal NA, Hubeck-Graudal T, Jurgens G. Effects of low sodium diet versus high sodium diet on blood pressure, renin, tion on systolic blood pressure. Still, in this aldosterone, catecholamines, cholesterol, and triglyceride. group of studies, each reduction of 2 g per day in ­Cochrane Database Syst Rev 2011;11:CD004022. sodium intake lowered systolic blood pressure by 3. Wright JD, Hughes, JP, Ostchega Y, Yoon SS, Nwankwo T. Mean systolic and diastolic blood pressure in adults aged 18 and only 1.44 mm Hg (Fig. 1), which is quite differ- over in the United States, 2001. Natl Health Stati Report 2008; ent from the effect postulated by Mozaffarian 35:1-24.

Study

Sodium No. of Baseline Systolic Patients Blood Pressure BMI Reduction mm Hg

Dickinson, 2009 29 116 DASH, 2001 54 129 Mascioli, 1991 48 131 TOHP (I), 1992 744 125 Puska, 1983 38 131 Nowson, 2009 59 131 TOHP (II), 1997 1190 128 Jessani, 2008 184 122 Damgaard, 2006 12 120 Chiolero, 2000 12 116 HPT, 1990 351 124 Nowson, 2003 91 131 Overall 2812 125 Heterogeneity: chi2 =53.09, df=12 (P

Sodium and cardiovascular disease.

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