Sodium and Cardiovascular Disease

Transcription

1 The new england journal of medicine correspondence 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 Nancy R. Cook, Sc.D. Brigham and Women s Hospital Boston, MA ncook@rics.bwh.harvard.edu 1. Institute of Medicine. Sodium intake in populations: assessment of evidence. Washington, DC: National Academies Press, O Donnell M, Mente A, Rangarajan S, et al. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med 2014;371: [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;1: Cogswell ME, Wang CY, Chen TC, et al. Validity of predictive equations for 24-h urinary sodium excretion in adults aged y. Am J Clin Nutr 2013;98: Cook NR, Appel LJ, Whelton PK. Lower levels of sodium intake and reduced cardiovascular risk. Circulation 2014;1: 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) n engl j med 371;22 nejm.org november 27, 2014

2 correspondence 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 Vecihi Batuman, M.D. Tulane University School of Medicine New Orleans, LA vbatuma@tulane.edu 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:f 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:f Kotchen TA, Cowley AW Jr, Frohlich ED. Salt in health and disease a delicate balance. N Engl J Med 2013;368: Batuman V. Salt and hypertension: why is there still a debate? Kidney Int Suppl (2011) 2013;3:6-20. Relative Risk of Cardiovascular Death Sodium Excretion (g/day) 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 level 2 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. 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 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 pierre-jean.saulnier@inserm.fr for the SURDIAGENE Group 1. The Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:8-41. [Erratum, N Engl J Med 2011;364:11.] 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 n engl j med 371;22 nejm.org november 27,

3 The new england journal of medicine 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;: To the Editor: The meta-analysis of randomized, controlled trials conducted by Mozaffarian and colleagues indicated that in a white, normotensive population at 50 years of age, each reduction of 2.30 g per day in sodium intake lowered systolic blood pressure by 3.74 mm Hg. 1 However, a subanalysis of our own meta-analysis, 2 from which the authors derived their references, shows that data from randomized trials involving normotensive middle-aged populations are biased by high baseline levels of systolic blood pressure 3 and a high body-mass index (Fig. 1). These biases inflate the effect of sodium reduction on systolic blood pressure. Still, in this group of studies, each reduction of 2 g per day in sodium intake lowered systolic blood pressure by only 1. mm Hg (Fig. 1), which is quite different from the effect postulated by Mozaffarian 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 genuine scientific data and shows that low sodium intake is concomitantly associated with lower blood pressure and an increased number of fatalities, confirming that low sodium intake is an independent risk factor for increased mortality. 4 Niels Graudal, M.D., D.M.Sc. Copenhagen University Hospital Copenhagen, Denmark graudal@dadlnet.dk 1. Mozaffarian D, Fahimi S, Singh GM, et al. Global sodium consumption and death from cardiovascular causes. N Engl J Med 2014;371: 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;11:CD Wright JD, Hughes, JP, Ostchega Y, Yoon SS, Nwankwo T. Mean systolic and diastolic blood pressure in adults aged 18 and over in the United States, Natl Health Stati Report 2008; 35:1-24. No. of Patients Baseline Systolic Blood Pressure mm Hg BMI Mean Difference, mm Hg (95% CI) Weight % Dickinson, 2009 DASH, 2001 Mascioli, 1991 TOHP (I), 1992 Puska, 1983 Nowson, 2009 TOHP (II), 1997 Jessani, 2008 Damgaard, 2006 Chiolero, 2000 HPT, 1990 Nowson, 2003 Overall Sodium Reduction mmol ( 7.86 to 2.14) 4.00 ( 6.35 to 1.65) 3.60 ( 5.36 to 1.84) 1.70 ( 2.86 to 0.54) 1.50 ( to 7.36) 1.10 ( 4.92 to 2.72) 1.00 ( 2.02 to 0.02) 1.00 ( 2.51 to 0.51) 0.00 ( 3.14 to 3.14) 0.00 ( 2.16 to 2.16) 0.10 ( 1.84 to 2.04) 0.40 ( 1.17 to 1.97) 1. ( 2.34 to 0.54) Heterogeneity: chi 2 =53.09, df=12 (P<0.001); I 2 =77% Test for overall effect: Z=7.07 (P<0.001) Sodium Reduction Usual Sodium Figure 1. The Effect of Sodium Reduction on Systolic Blood Pressure as Determined from Randomized Trials Involving Participants 40 to 59 Years of Age with Normal Blood Pressure. The lower 50% of normotensive persons between 40 and 59 years of age in the general population is represented in only 2 studies, accounting for 17% of the included study populations. These participants had a mean systolic blood pressure of 116 mm Hg, which was similar to the mean systolic blood pressure of the general population (117 mm Hg). 3 There were 3 studies (%) in which the mean systolic blood pressure was in the 50th to 75th percentile (117 to 124 mm Hg) 3 and 7 studies (58%) in which the mean systolic blood pressure was above the 75th percentile of the general population (>124 mm Hg). 3 Participants in 11 study populations (92%) were overweight. The duration of each study was at least 7 days. The abbreviation df denotes degrees of freedom, and I 2 the index of heterogeneity n engl j med 371;22 nejm.org november 27, 2014

4 correspondence 4. Graudal N, Jürgens G, Baslund B, Alderman MH. Compared with usual sodium intake, low- and excessive-sodium diets are associated with increased mortality: a meta-analysis. Am J Hypertens 2014;27: To the Editor: The statistical modeling exercise performed by Mozaffarian and colleagues of the Global Burden of Diseases Nutrition and Chronic Diseases Expert (NUTRICODE) Group was introduced in This analysis does not directly associate sodium intake with cardiovascular disease. Instead, it involves three separate, sequential steps. First the effect of sodium intake (A) on blood pressure (B) is determined, then the effect of blood pressure (B) on cardiovascular disease (C), and finally the association between (A) and (C), in which the cardiovascular effect of sodium intake is predicted. The validity of this analysis requires a linear relation between A and B, B and C, and A and C. The analysis further assumes that there are no other pathophysiological consequences of sodium intake. Unfortunately, the relationships between sodium intake and blood pressure, blood pressure and cardiovascular disease, and sodium intake and cardiovascular disease are not linear. The effect of sodium on blood pressure is greater when intake is more than 5.0 g per day than when intake is less than 3.0 g per day (2.58 mm Hg per gram vs mm Hg per gram) 2 ; the risk of cardiovascular disease is increased at bloodpressure levels higher than 130/80 mm Hg but not at lower levels; and the association between sodium and cardiovascular disease is J-shaped. 3 Moreover, there are other pathophysiological effects of both high and low sodium intakes that are associated with an increased risk of cardiovascular disease. Advancing science renders obsolete what was, years ago, a reasonable hypothesis. The PURE study adds to 27 previous studies, 3 extending and validating the 2013 IOM report by identifying inadequate and excessive sodium intakes (<3.0 and >6.0 g per day, respectively) at which the risks of death from cardiovascular disease and all causes increase. Michael H. Alderman, M.D. Albert Einstein College of Medicine Bronx, NY michael.alderman@einstein.yu.edu 1. Law MR, Frost CD, Wald NJ. By how much does dietary salt reduction lower blood pressure? III Analysis of data from trials of salt reduction. BMJ 1991;302: Bibbins-Domingo K, Chertow GM, Coxson PG, et al. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med 2010;362: Graudal N, Jürgens G, Baslund B, Alderman MH. Compared with usual sodium intake, low- and excessive-sodium diets are associated with increased mortality: a meta-analysis. Am J Hypertens 2014;27: Dr. O Donnell and Colleagues Reply: The IOM panel review found insufficient evidence to support the contention that low sodium intake (<2.30 g per day) was associated with a risk of cardiovascular disease that was lower than that with moderate intake. The resultant confusion relates to making a recommendation for population-wide low sodium intake without clear evidence of benefit. The TOHP report cited by Cook has serious limitations, including a high rate (23%) of losses to follow-up for cardiovascular events and few events (193 of 2275 persons in the study had cardiovascular events, among which one third were revascularizations). In both their recent and previous analyses of these data, 1 the TOHP investigators did not report significantly lower cardiovascular risk in persons with low sodium intake than in persons with moderate intake. In contrast, the PURE study is the largest international study to examine the association between sodium intake and health. It included 101,945 people from the general population and reported more than 3000 outcome events and high rates of follow-up. Our estimates of 24- hour urinary sodium excretion were based on an approach that has been validated in an international cohort, 2 whereas the study by Cogswell and colleagues (cited by Cook) did not evaluate our approach to estimating 24-hour urinary sodium excretion, since they did not compare formula-derived estimates for a fasting morning urine sample with those from a preceding 24- hour urine collection. The PURE results are consistent with the collective body of evidence (including data on more than 270,000 persons) from which Graudal and colleagues 3 recently produced a meta-analysis, which indicated that the lowest risk of cardiovascular events and death occurred in persons whose sodium consumption was between 2.7 and 5.0 g per day. The results of the study by Saulnier and colleagues provide further evidence that the most healthful level of n engl j med 371;22 nejm.org november 27,

5 The new england journal of medicine sodium consumption resides in the moderate range. We fully agree with the statement in the editorial by Oparil 4 that until randomized, controlled trials demonstrate that low levels of sodium intake are safe and beneficial, the current evidence argues against reduction of dietary sodium as an isolated public health recommendation. In response to Batuman: we adjusted our analysis for regression dilution bias on the basis of a repeat measurement in a subgroup and found the same pattern of association. Batuman notes the higher prevalence of diabetes, cardiovascular disease, and diuretic use in persons with lower sodium intake. Our analyses adjusted for these variables, and the exclusion of participants with these risk factors did not alter the findings. Batuman s claim that the the preponderance of published data indicate that a low-sodium diet is safe and saves lives, is incorrect and not supported by the totality of the data on more than 370,000 people. 3 Martin O Donnell, M.B., Ph.D. Andrew Mente, Ph.D. Salim Yusuf, M.D. McMaster University Hamilton, ON, Canada odonnm@mcmaster.ca Since publication of their article, the authors report no further potential conflict of interest. 1. Cook NR, Obarzanek E, Cutler JA, et al. Joint effects of sodium and potassium intake on subsequent cardiovascular disease: the Trials of Hypertension Prevention follow-up study. Arch Intern Med 2009;169: Mente A, O Donnell MJ, Dagenais G, et al. Validation and comparison of three formulae to estimate sodium and potassium excretion from a single morning fasting urine compared to 24-h measures in 11 countries. J Hypertens 2014;32: Graudal N, Jürgens G, Baslund B, Alderman MH. Compared with usual sodium intake, low- and excessive-sodium diets are associated with increased mortality: a meta-analysis. Am J Hypertens 2014;27: Oparil S. Low sodium intake cardiovascular health benefit or risk? N Engl J Med 2014;371: Dr. Mozaffarian and Colleagues Reply: Graudal s meta-analysis contains key limitations. Standardizing reductions in sodium intake (which varied enormously across these trials), distinguishing mean blood pressure from systolic blood pressure, and using available 24-hour ambulatory blood pressure, the pooled reduction in blood pressure in these few studies is 2.81 mm Hg (95% confidence interval, 4.14 to 1.48) per each reduction in sodium of 2.30 g per day (Fig. 1). More to the point, our investigation pooled not a few handpicked studies but 103 trials including 107 group comparisons, with joint incorporation of heterogeneity according to age, hypertensive status, and race. Identified effects were similar No. of Patients Baseline Systolic Blood Pressure mm Hg BMI Mean Difference, mm Hg (95% CI) Weight % Dickinson, 2009 DASH, Mascioli, TOHP (I), Puska, Nowson, TOHP (II), Jessani, Damgaard, HPT, Nowson, Overall (I 2 =45.8%, P=0.048) Sodium Reduction mmol Note: Weights are from random-effects analysis ( 8.55 to 2.) 5.19 ( 8. to 2.13) 5.07 ( 7.54 to 2.60) 3.86 ( 6.51 to 1.21) 1.67 ( to 8.17) 2.50 ( to 6.18) 2.38 ( 4.81 to 0.05) 1.23 ( 3.09 to 0.63) 0.00 ( 2.43 to 2.43) 0.43 ( 8.00 to 8.86) 0.80 ( 4.70 to 3.10) 2.81 ( 4.14 to 1.48) Sodium Reduction Usual Sodium Figure 1. Meta-Analysis of the Trials of Normotensive Participants Selected by Graudal, with Standardization of Differences in Mean Blood Pressure to a Reduction in Sodium of 2.30 g per Day. Mean differences in systolic blood pressure and corresponding variances were standardized to a reduction in sodium intake of 2.30 g per day. One study (Chiolero) was excluded because mean blood pressure rather than systolic blood pressure was reported, which would have invalidated comparisons of central effects and variance. When available (Nowson), 24-hour ambulatory blood pressure was used. The Nowson study used a specific high-potassium diet that would blunt the effects of sodium reduction, but this study was retained. Overall, systolic blood pressure was reduced by 2.81 mm Hg for each reduction of 2.30 g of sodium per day n engl j med 371;22 nejm.org november 27, 2014

6 correspondence when trials with weaker designs were included, in which case the total number of trials included was 160, with 169 group comparisons. Our metaanalysis provides robust, reliable evidence of the effects of sodium on blood pressure. Graudal and Alderman highlight J-shaped relationship between urinary sodium and the risk of cardiovascular disease reported in the PURE study, in which approximately 4.5 g of sodium per day was associated with the lowest level of risk. Although the PURE study is a large, multinational study, it represents a single observational study. The particular biases involved in the assessment of daily sodium intake in observational studies, in which urine collection or questionnaires on diet are used, are well-established. 1 Most important are incomplete 24-hour urine collections (which do not apply to the PURE study), reverse causation (with at-risk participants actively lowering sodium intake), and confounding by physical activity (given the strong correlation between sodium intake and total energy intake). These limitations together could explain the J-shaped curves seen in certain observational studies. In the PURE study, participants with lowest sodium levels had many more risks of cardiovascular disease at baseline. Appropriately, the authors acknowledged that reverse causation cannot be completely ruled out and may account in part for the increased risk observed in the group of participants with a low estimated sodium excretion. Furthermore, physical activity was self-reported, greatly increasing the potential for residual confounding (i.e., with participants with the lowest sodium intake being the most sedentary). During extended surveillance in a large, randomized trial focused on sodium reduction, which overcomes such limitations, participants with sodium intakes of less than 2300 mg per day had a risk of adverse events related to cardiovascular disease that was 32% lower than the risk among those who consumed 3600 to 4800 mg per day, with indications of a linear relationship between the extent of sodium reduction and the reduction in cardiovascular risk. 2 In addition, our investigation relied on multiple lines of evidence, not blood pressure alone, to establish causality: blood-pressure reductions in trials, strength of blood pressure as a surrogate outcome, the relationship of sodium intake with cardiovascular disease events in meta-analyses of observational studies and extended trial followups, and ecologic and experimental studies. Indeed, the latter suggest that long-term high intake of sodium induces blood-pressure independent toxicity, including myocardial, vascular, renal fibrosis harms not incorporated into our risk estimates. No substantial mechanistic harms have been identified that could nullify, let alone reverse, the benefits of sodium reduction and explain the J-shaped relationships at 4.5 g per day, although straightforward sources of bias could explain such observations. We recognize that the adverse effects of extreme, rapid reductions in sodium intake could have some adverse effects and that optimal lower limits remain uncertain (especially with regard to intakes of <2.0 g of sodium per day). Yet considering all the evidence, we conclude as have many national and international organizations that sodium intakes that exceed an approximate range of 1.5 to 2.0 g per day are harmful. Dariush Mozaffarian, M.D., Dr.P.H. Gitanjali M. Singh, Ph.D. Friedman School of Nutrition Science and Policy Boston, MA dariush.mozaffarian@tufts.edu John Powles, M.B., B.S. Cambridge Institute of Public Health Cambridge, United Kingdom Since publication of their article, the authors report no further potential conflict of interest. 1. 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;1: Cook NR, Appel LJ, Whelton PK. Lower levels of sodium intake and reduced cardiovascular risk. Circulation 2014;1: To the Editor: In their review of pancreatic adenocarcinoma, Ryan and colleagues (Sept. 11 issue) 1 only briefly mention the issue of symptom control. However, severe abdominal pain (due to celiac plexus involvement), nausea, dyspnea, fatigue, Pancreatic Adenocarcinoma anorexia or cachexia, and anxiety are frequent and substantially impair patients health, whereas communication needs may fluctuate. 2 Moreover, according to the landmark study comparing gemcitabine with fluorouracil, a clinical benefit n engl j med 371;22 nejm.org november 27,