Review 821

Benet assessment of salt reduction in patients with hypertension: systematic overview

Eva Matyasa, Klaus Jeitlera,b, Karl Horvatha, Thomas Semlitscha, Lars G. Hemkensc, Nicole Pignittera and Andrea Siebenhoferd
Objective We assessed the benets and harm of reduced salt intake in patients with essential hypertension focusing on patient-relevant outcomes and blood pressure. Methods A systematic search of ve electronic databases was performed to identify high-quality secondary literature based on randomized controlled trials (RCTs). An update primary literature search (RCTs) was performed for the time period up to 2010 that was not covered by secondary literature. Major outcomes were death, cardiovascular morbidity/mortality, hospital stays, terminal renal failure, quality of life, and adverse events. Change in blood pressure was dened as surrogate parameter. Results Four different systematic reviews and two RCTs met the inclusion criteria. Only one review reported limited data on patient-relevant outcomes. Over an intervention period of up to 12 months, mean SBP was reduced by 3.68.0 mmHg in all reviews. For the same intervention period, a statistically signicant advantage with regard to mean DBP reduction ranging from 1.9 to 2.8 mmHg was found in three reviews. The fourth publication reported a nonsignicant reduction (DBP reduction of 4.7 mmHg). None of the RCTs identied in the primary literature search update reported data on patient-relevant outcomes. However, both RCTs found blood pressure improvements with salt reduction. Conclusion A benet from a salt-reduced diet in patients with high blood pressure is not proven with regard to patient-relevant outcomes based on systematic reviews and RCTs published up to 2010. The results indicate a blood pressure-lowering effect through reduced salt intake in hypertensive patients. J Hypertens 29:821828 Q 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Journal of Hypertension 2011, 29:821828 Keywords: diet, dietary, hypertension, sodium, sodium-restricted Abbreviations: HTA, health technology assessment; IQWiG, Institute for Quality and Efciency in Healthcare; RCTr, andomized controlled trial
a Department of Internal Medicine, EBM Review Center Medical University of Graz, bInstitute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria, cInstitute for Quality and Efciency in Healthcare (IQWiG), Cologne and dInstitute of General Practice, Goethe University Frankfurt, Frankfurt, Germany

Correspondence to Andrea Siebenhofer, MD, Institute of General Practice, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany Tel: +49 69 6301 7296; fax: +49 69 6301 6428; e-mail: siebenhofer@allgemeinmedizin.uni-frankfurt.de Received 23 June 2010 Revised 14 December 2010 Accepted 28 December 2010

See editorial comment on page 829

Introduction
Hypertension is a chronic condition associated with an increased risk of cardiovascular mortality and morbidity. High blood pressure is estimated to lead to over 7 million deaths each year, about 13% of the total deaths worldwide [1]. Lowering blood pressure levels in hypertensive patients has been shown to be a very effective means of reducing those patients cardiovascular risk, with a signicant reduction in cardiovascular morbidity and mortality [2,3]. The main treatments available for essential hypertension are blood pressure-lowering drugs and various nondrug treatment options. Consistently, epidemiological investigations have found an association between high blood pressure and different lifestyle factors, high sodium intake among them [47]. This assumption was also underlined by some recently published systematic reviews, including randomized controlled trials (RCTs) showing that salt reduction also lowered blood pressure [810]. In addition, higher salt intake was found to be
0263-6352 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

associated with increased cardiovascular events [11]. National and international professional associations recommend the consistent, long-term implementation of nondrug measures in the treatment of essential hypertension. Reduced salt intake is recommended in major guidelines as one of the rst-line interventions in the treatment of hypertensive patients [1216]. This investigation is based on a report of the Institute for Quality and Efciency in Healthcare in Germany (IQWiG), which aimed to assess the benets and harm of reduced salt intake. This report incorporated existing systematic reviews. According to the IQWiG methods [17], such an approach is deemed as resource-saving and reliable, provided that specic preconditions have been fullled (see below). Such overviews, sometimes called umbrella reviews or meta-reviews, which combine and compare different systematic reviews assessing interventions, have recently been adopted by the Cochrane Collaboration as well [18]. The present publication on reduced salt intake is part of a package of systematic
DOI:10.1097/HJH.0b013e3283442840

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benet assessments on different lifestyle interventions. Results based on previous reports on the effect of weight reduction have already been published [1921] and further reports, for example, on physical activity and alcohol reduction are in preparation. The present investigation aimed to review systematically the benets and harm of different interventions involving salt reduction in patients with essential hypertension according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [22].

the Cochrane Central Register of Controlled Trials (CENTRAL) was performed only for the time period that was not covered by secondary literature. As the last primary literature search in the systematic reviews was performed in 2005, we searched for RCTs published between 2005 and February 2010. The search strategy is published in detail in the IQWiG report [23]. Titles and abstracts were screened independently by multiple teams of two reviewers (K.H., K.J., T.W.G., E.M. and/or A.S.); potentially relevant secondary publications were assessed as full texts by the same reviewers. Differences between reviewers were resolved by discussion or a third reviewer was involved. The methodological quality assessment of the relevant reviews was done according to Oxman and Guyatts index [24,25]. Systematic reviews were included if they scored at least ve out of seven possible points. Identical inclusion criteria as for the systematic reviews were used to identify relevant RCTs. The quality assessment of the included RCTs was based on randomization, blinding, allocation concealment, intention-to-treat analysis, and further aspects of bias risk, and was conducted independently by K.H. and E.M., who graded the relevant RCTs as having no (A), moderate (B), or serious (C) methodological deciencies.

Methods
Eligibility of publications

The investigation included systematic reviews of RCTs of at least 4 weeks duration involving nonpregnant patients aged 18 years or older with essential hypertension. The intervention to be tested in these trials was a reduction in salt intake compared to no such reduction in salt intake or a lower intended salt intake in the intervention group than in the control group. Any additional (antihypertensive) treatment had to be given equally in both groups. Excluded were systematic reviews and health technology assessment (HTA) reports in which the reduction in salt intake as a primary intervention was compared to another antihypertensive treatment as a primary intervention (e.g., reduced salt intake versus diet or versus blood pressure-lowering drugs).
Outcomes of interest

Results
Results from the secondary literature

The evaluation focused on patient-relevant therapy outcomes (mortality, cardiovascular morbidity and mortality, hospital stays, terminal renal failure, capacity for work, health-related quality of life, patient satisfaction, and adverse events) and blood pressure as a surrogate endpoint in hypertensive people. Patient-relevant therapy goals and surrogates were prospectively dened in a protocol and detailed criteria for assessment of the patient-relevant endpoints were determined in accordance with the IQWiG methods Version 3.0 [17].
Selection of publications and methods of assessment

As indicated in the Cochrane Handbook [18] and IQWiG methods Version 3.0 [17], the preparation of a review on the basis of secondary literature is feasible, if major key elements are considered as detailed in Table 1 in the Appendix, http://links.lww.com/HJH/A71. The bibliographic databases EMBASE and MEDLINE, and three databases of the Cochrane Library [HTA Database, The Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE)] were searched for related reviews published after the year 1997 up to February 2010. All systematic reviews published in English, German, French, or Spanish were included. In addition, a primary literature search update restricted to English and German publications in EMBASE, MEDLINE/PubMed and

We identied 1729 potentially relevant publications in the secondary literature and seven systematic reviews [810,2629] met the inclusion criteria. All of those were assessed with at least ve out of seven possible points by the Oxman and Guyatts score. These publications were allocated to four groups of authors and included 62 RCTs overall (Fig. 1 in the Appendix, http://links.lww.com/ HJH/A71). Table 1 [810,28] in the text gives an overview of the included systematic reviews. The search strategies, selection criteria used for inclusion of primary studies, number and duration of included RCTs, and the patient characteristics are shown (Table 1 in the text). In addition, Table 2 of the Appendix, http://links.lww.com/ HJH/A71 provides an outline of the database of relevant outcomes within the systematic reviews. Two systematic reviews (Hooper et al. [28] and Dickinson et al. [8]) aimed for patient-relevant outcomes, but only Hooper et al. [28] reported relevant patient-related outcomes such as mortality, cardiovascular events, quality of life, and adverse events. None of the reviews reported data on hospital stays, terminal renal failure, capacity for work, or patient satisfaction (Table 2 in the Appendix, http://links.lww.com/HJH/A71). Results of the review published by Hooper et al. [28] are described in the following: data on all-cause mortality were provided for three out of eight primary studies. One study reported four deaths in the intervention and ve deaths in the

Benefit assessment of salt reduction in hypertension Matyas et al. 823

Table 1

Characteristics of the systematic reviews/number and duration of the included relevant randomized controlled trials
Number/duration (median) of included RCTs 8 RCTs, 8 to 52 weeks (52 weeks) Patient characteristics Number of patients: 520; mean % female: 24; mean age: 52 years; mean BP: 151/95 mmHg

Systematic review Dickinson et al. [8]; Sponsoring: National Institute for Clinical Excellence (NICE)

Relevant selection criteria Inclusion criteria: RCTs; duration 8 weeks; adults; SBP 140 and/or DBP 85 mmHg; exclusion criteria: pregnancy; secondary hypertension; change in antihypertensive medication during follow-up Inclusion criteria: RCTs; duration: 4 weeks; age 18 years; net reduction in 24-h urinary sodium must be equal to or greater than 40 mmol; exclusion criteria: pregnancy Inclusion criteria: RCTs; duration 26 weeks; age 16 years; exclusion criteria: pregnancy, hospitalized patients

Search MEDLINE (1998 to May 2003); EMBASE (1998 to May 2003); CENTRAL (1998 to May 2003); references of hypertension guidelines, systematic reviews and meta-analyses (before 1998)

He and MacGregor [9] (Update 2006); Sponsoring: no sponsor

MEDLINE (1966 to April 2005); EMBASE (1980 to April 2005); CINHAL (1982 to June 2001); Cochrane Library (up to April 2005); references of original articles and reviews MEDLINE (up to July 2000); EMBASE (up to July 2000); Cochrane Library (up to July 2000); CAB abstracts, CVRCT registry, SIGLE (up to May 1998); bibliographies of identied publications and reviews MEDLINE (1966 to December 2001); EMBASE, CCTR (no data of search time available)

20 RCTs, 4 to 52 weeks (5 weeks)

Hooper et al. [28]; Sponsoring: NW Research Development Training Fellowship

8 RCTs, 6 months to 7 years (12 months)

Number of patients: 802; Median % female: 47 (range: 1576); median age: 50 years; median BP: 149/94 mmHg Number of patients: 1188; median % female: 50 (range: 058); Mean age: n.a.; median BP: 145/86 mmHg

rgens and Graudal [10]; Ju Sponsoring: no sponsor

Inclusion criteria: RCTs, additional interventions had to be comparable in the intervention groups; at least 8 h urinary sodium excretion; age >15 years; exclusion criteria: pregnancy

54 RCTs, 4 to 365 days (28 days)

Number of patients: n.a.a; % female: n.a; mean age: 49 years; mean BP: n.a.

BP, blood pressure; n.a., no data available; RCT, randomized controlled trial. a In the meta-analyses, n 3391 (DBP) and n 3367 (SBP) were included. These numbers also include cross-over comparisons and several primary studies <4 weeks of duration.

control group (Morgan et al. [30]), whereas the other two studies counted no death (Alli et al. [31] and TONE [32,33]). Cardiovascular events were described in two (Alli et al. [31] and TONE [32,33]) out of eight studies and the presented meta-analysis showed no signicant difference between the salt-reduced and control groups (Hooper et al. [28]). In the review of Hooper et al. [28], health-related quality of life was described in only one trial (Thaler et al. [34]). Data were not scaled by a conventional measurement and it was not possible to compare the study groups. Adverse events were reported in two studies within the 2004 review by Hooper et al. In the study by Thaler et al. [34], muscle cramps were more frequent in the intervention group. As the difference between the groups with regard to frequency of muscle cramps was similar at study entry (29.5% in the intervention group versus 15.3% in the control group), there was no evidence of an increase in muscle cramps. A statistically signicant smaller number of participants in the salt-reducing group reported headache in the TONE trial [32,33], but further details necessary to interpret this nding were not reported. For investigations on blood pressure as a surrogate, most of the analyses showed a blood pressure-lowering effect in hypertensive patients through reduced salt intake when compared to a control treatment (Fig. 1 in the text;

Table 3 in the Appendix, http://links.lww.com/HJH/A71). Over an intervention period of up to 12 months, the analyses showed a statistically signicant difference with regard to mean SBP reduction ranging from 3.6 to 8.0 mmHg in favor of the intervention groups. For the same intervention period, a statistically signicant difference with regard to mean DBP reduction ranging from 1.9 to 2.8 mmHg was found in three reviews. In the fourth publication (Hooper et al. [28]), a more pronounced reduction was also observed for the intervention (difference of 4.7 mmHg compared to control treatment), but this was based on only four trials and without statistical signicance. All data primarily apply to analyses of patients without concomitant antihypertensive drug treatment. In the study by Dickinson et al. [8], results on blood pressure were based on a meta-analysis of six studies including 450 untreated patients and showed no heterogeneity. There was a statistically signicant weighted mean difference in studies lasting from 8 to 52 weeks in favor of the salt-reduced group. Including only studies with a duration of at least 6 months, there was no longer any statistically signicant weighted mean difference. Similar effects in untreated hypertensive patients favoring the intervention group were obtained in the metaanalysis lasting between 4 and 52 weeks of follow-up of

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Fig. 1

SBP
Systematic review
Dickinson 20068 He 2004
9

DBP
RCTs [n]
6 20 4 54

RCTs [n]
6 19 4 53

Weighted mean difference (95% CI) [mmHg]

3.6 (4.6; 2.5) 5.3 (6.7; 3.9) 8.0 (15.8; 0.2) 4.2 (5.1; 3.3) 15 0 15 Favours salt reduction Favours control

Weighted mean difference (95% CI) [mmHg]

2.5 (3.2; 1.7) 2.8 (3.6; 2.0) 4.7 (9.3; 0.04) 1.9 (2.5; 1.3) 15 0 15 Favours salt reduction Favours control

Hooper 200428 Jrgens 200410

Weighted mean differences for SBP and DBP: comparison of the results for the follow-up up to 12 months.

He et al. [9], including 20 comparisons with about 800 patients. There was marked heterogeneity in the blood pressure results and possible reasons given by the authors were differences between studies in age, ethnic group, baseline blood pressure levels, the amount and the duration of salt intake reduction, and the study quality. They did not perform further sensitivity analyses due to the small number of trials and the very limited information reported in the studies. A meta-analysis by Hooper et al. [28] containing four studies lasting between 6 and 12 months of follow-up covering 179 hypertensive patients without antihypertensive drug treatment showed a statistically signicant advantage in favor of the intervention group for the SBP only. There was moderate heterogeneity (P 0.15; I2 43%). For DBP, there were two studies with the same follow-up period with 87 untreated hypertensive
Table 2 RCT He and MacGregor [38]; Sponsoring: UK Food Standards Agency

patients that only showed a trend in favor of the intervention group. Hooper et al. identied only one small trial (Morgan et al. [30,35]) with 62 patients lasting more than a year in which only the DBP was signicantly reduced due to salt reduction. In addition, Hooper et al. [28] included three studies with treated hypertensive patients as well, but the authors did not explain why a meta-analysis was not performed. One of these trials (TONE [32,33]) did not report any blood pressure results. In a study by Morgan and Anderson [36], in which antihypertensive drug treatment was withdrawn after 3 months in both groups, after 9 months of follow-up, blood pressure increased less under salt reduction. In the study by Arroll and Beaglehole [37], there was a greater mean decrease after 6 months of intervention for SBP in the salt-reduced group than in the control group [9.1 (standard deviation 21.7); 6.2 (standard deviation 21.0) mmHg]. For DBP, the mean decrease was smaller in the salt-reduced group

Characteristics of the randomized controlled trials from primary literature search update
Relevant selection criteria Inclusion criteria: age: 3075 years; SBP 140170 or DBP 90105 mmHg; exclusion criteria: pregnancy, previous treatment for raised BP; secondary hypertension, previous stroke, ischemic heart disease, heart failure, diabetes mellitus, malignancy or liver disease; women on oral contraceptives Inclusion criteria: age: 2075 years, patients on antihypertensive drugs; SBP 160210 and/or DBP 90115 mmHg; exclusion criteria: drug-induced hypertension; use of antihypertensives due to other cardiovascular illnesses Study design/ duration of study RCT; double-blind; cross-over/ 6 weeks Intervention 2 weeks run-in phase on a reduced-salt diet; IG: 9 slow sodium tablets (10 mmol per tablet) daily; CG: 9 placebo tablets daily Patient characteristics No separate analyses for IG and CG available; number of patients: 169; % female: n.a.; mean age: 50 years; mean BP: 147/91 mmHg Outcomes Patient-relevant endpoints: n.a.; surrogate endpoints: duration and extent of blood pressure changes; BP at study end [mean difference (mmHg]: SBP: 4.8 (95%CI: 6.4 to 3.2); P < 0.001; DBP: 2.2 (95%CI: 3.1 to 1.4); P < 0.001]

Meland and Aamland [39]; Sponsoring: Norske Hoechst AS, University of Bergen student grant, Solstrandsfondet

RCT; double-blind; parallel/8 weeks

Salt-reduced diet in both groups; IG: 5 capsules of 10 mmol sodium/day; CG: 5 placebo capsules /day (identical capsules to IG)

Number of patients IG/CG: 57/55; % female: n.a; mean age: IG/CG: 57/55 years; mean BP: IG/CG; SBP: 157/155 mmHg; DBP 93/92 mmHg

Patient-relevant endpoints: n.a.; surrogate endpoints: duration and extent of blood pressure changes; BP at study end [mean difference (mmHg): SBP: 5 (95%CI: 11 to 0); P < 0.07; DBP: 5 (95% CI: 7 to 1); P < 0.02

CG, control group; CI, condence interval; IG, intervention group; n.a., no data available; RCT, randomized controlled trial.

Benefit assessment of salt reduction in hypertension Matyas et al. 825

than in the control group [1.7 (standard deviation 34.9); 4.8 (standard deviation 36.1) mmHg]. In the fourth systematic review including 54 studies rgens and Graudal [10]), no separate analyses for (Ju treated and untreated hypertensive people were performed. For both SBP including 3391 participants in the analysis and for the DBP including 3367 participants, there was a signicant weighted mean difference in favor of the intervention group. There was no signicant heterogeneity found for either of the blood pressure analyses.
Results from randomized controlled trials published between 2005 and 2010

compared to a control treatment. The reported extent of the effect size varied among the reviews. Our ndings are not unexpected against the background of the epidemiological data suggesting that salt intake is positively associated with blood pressure levels [11,4144]. None of the RCTs included in the identied systematic reviews was powered to detect a potential benet indicating that salt-reduced diet decreases unfavorable patient-relevant outcomes. Consequently, evidence for the assumption that salt restriction is associated with a tremendous reduction in cardiovascular outcomes as well, is only based on epidemiological observations [11,41,45]. In the recently published systematic review and meta-analysis of prospective studies published by Strazzullo et al. in 2009 [11], including 19 independent cohort samples with more than 170 000 participants and a follow-up between 3.5 and 19 years, higher salt intake was associated with a signicantly greater risk of stroke (pooled relative risk 1.23; 95% condence interval 1.06 1.43; P 0.007) and a tendentially higher, though nonsignicant, risk of cardiovascular disease was observed (pooled relative risk 1.14, 95% condence interval 0.99 1.32; P 0.07). In a recently published narrative review, multiple studies have shown that the adjusted relative risk reduction in controlled observational studies aiming for reduced sodium intake ranged from 25% over 15 years to 41% over 3 years [45]. The effect of a direct application of a salt reduction in daily life has been demonstrated in an RCT, which investigated the Dietary Approaches for Stop Hypertension (DASH) diet, rich in fruits and vegetables and low-fat diary products in combination with reduced dietary sodium uptake. In patients having such a diet, it has been shown that the SBP was 11.5 mmHg lower compared to patients with control diet with high sodium intake [46]. It has been reported that this blood pressure reduction has been further improved when patients on the DASH diet additionally exercise and follow a weight management program [47]. This evidence is further underlined in a long-term observational follow-up study of two hypertension prevention trials (TOHP I and II) with prehypertensive patients. This study does not meet the inclusion criteria of our review; however, as long-term results are of major relevance in this context, we would like to discuss them in further detail. A total of 3126 patients randomly assigned to salt restriction in TOPH I and TOPH II were observed for a further 1015 years after the end of the original RCTs lasting for 1848 months. Follow-up information on cardiovascular outcomes was 77% and for death 100%, and blinded endpoint evaluation by medical records was performed. In this long-term observation, the risk of a cardiovascular event was about 2530% lower among those in the salt-reduced group and there was a trend to a lower mortality rate, which was, however, not statistically signicant [48]. On the basis of those studies, reduced salt intake is recommended by many leading

The primary literature search update revealed 573 additional references. Two RCTs [38,39] were included in this systematic overview. The trial ow is given in Fig. 2 in the Appendix, http://links.lww.com/HJH/A71. Table 2 [38,39] in the text provides information on relevant characteristics of the included RCTs. The quality assessment of these two studies is presented in Table 4 in the Appendix, http://links.lww.com/HJH/ A71; one was judged to have moderate and the other one serious risk of bias. Both trials lasted only a few weeks and no data on patientrelevant outcomes were reported. However, blood pressure changes were shown in both studies and indicated a benet in the salt-reduced patient groups. The results in the study by He et al. [38] showed a statistically signicant difference in SBP and DBP between the intervention and the control groups [SBP: 4.8 mmHg (95% condence interval 6.4 to 3.2); P < 0.001; DBP: 2.2 mmHg (95% condence interval 3.1 to 1.4); P < 0.001]. In the study by Meland and Aamland [39], there was a statistically signicant difference between the groups in favor of the intervention group only in the DBP [5 mmHg (95% condence interval 7 to 1); P < 0.02]. For the SBP, the difference was not statistically signicant [5 mmHg; (95% condence interval 11 to 0); P < 0.07; see Table 2 in the text].

Discussion
Based on high quality secondary literature and an extensive update search for RCTs, we conducted a systematic overview examining the question of whether salt reduction in patients with essential hypertension is benecial or harmful. The robustness of the results appears plausible as this overview covers the high quality evidence available to date, and a primary literature search update was performed. Within the systematic reviews included, no primary study was identied in which the primary objective was to investigate the reduction in salt intake as an intervention in order to prevent patientrelevant complications. In relation to blood pressure, all analyses showed a blood pressure-lowering effect in hypertensive patients through reduced salt intake when

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national and international professional associations [1216]. There is solid evidence for a health benet when blood pressure is reduced to recommended levels, and in certain patients, lifestyle changes may enable them to reduce or stop drug therapy as well [32]. In terms of salt intake, experts in this eld advise patients to rst decrease their consumption of processed food, refrain from adding salt, and eat more fruits and vegetables [49]. Limitations of our overview are that most of the RCTs included in the systematic reviews provided only a small number of patients and short follow-up. As a consequence, none had the power to evaluate patient-relevant outcomes and no answer can be provided on these aspects. In addition, the included systematic reviews differ in their chosen outcomes, inclusion criteria, and search strategies, which also might cause the differences in the numbers of studies included in the systematic reviews. Although we included only high quality systematic reviews, another limitation is that the reviews might have some aws that are passed over to our review as well. Nonetheless, the results obtained in terms of blood pressure point in the same direction, which once again further conrms the assumptions known for a long time that dietary salt restriction appears to be effective with regard to this surrogate. However, an important limitation is that almost none of the analyses presented results on patients who were simultaneously taking antihypertensive drugs, and an additional blood pressure-lowering capacity in those patients taking such medication remains unclear. This needs to be emphasized as this raises the question whether the results are generalizable to patients being treated with antihypertensive drugs. In addition, only one (Hooper et al. [28]) of the four included systematic reviews presented some limited information on how salt intake was reduced with the different interventions. This in turn means that no recommendations can be given on the basis of these results as to how salt intake should best be reduced. Moreover, valid long-term data are not available and well founded information on patient-relevant outcomes does not exist. The importance of this uncertainty is emphasized by an example from a study with successful weight reduction. The Swedish Obese Subject Study (SOS) in which more than 1700 patients successfully reduced their body weight by means of bariatric surgery has shown that the initial postsurgical blood pressure reduction was still present after 2 years, but was almost gone 10 years later [50]. In terms of adverse events, Klaus et al. [45] gave an overview on possible risks in terms of a dietary salt reduction, suggesting that with a modest dietary salt restriction to 56 g/day, short episodes of severe diarrhea or longer episodes of vomiting are not likely to cause sodium deciency. Even in geriatric patients and pregnant women, Klaus et al. [45] deem the benet as exceeding potential harm. Drastic salt restrictions to 1 g/day are not recommended due to pathophysiological considerations [45].

Since the 1980s, the salt industry has tried to promote the view that salt reduction provides only a negligible benet [41,51], but now, concerted efforts of relevant working groups and advisory panels throughout the world and the WHO are exerting pressure on them to change their strategy [49,52]. These organizations publish action plans for the implementation of salt-reducing strategies and give recommendations for a populationwide salt intake reduction. For example, the WHO has set out a worldwide target of less than 5 g/day for adults [49], or a reduction of salt intake by approximately one half per day assuming that western people consume about 10 g sodium daily. Though these measures are all voluntary and not regulated by law, reduction of sodium in the diet is increasingly becoming a public health issue. A coronary heart disease model including the entire US population has recently indicated that lowering salt intake in the population would in all likelihood reduce cardiovascular disease and deaths, and lower medical costs [53]. Most of the strategies are based on the United Kingdom Food Standards Agencys program on salt reduction, the Consensus Action on Salt and Health (CASH) [52]. CASH involves government, business, and consumer and health groups, based on the premise that action must address people, environment, and products. Since CASH was set up in 1996, with the stepwise and slow reduction of salt content in primary processed foods bought in supermarkets, public health campaigns, and a clear labeling, salt intake has already fallen as documented by a random sample of the population [40]. Preexisting strategies can now act as a model for other initiatives in different countries such as the less salt for all task force [54], which is currently being planned in Germany. After the critical assessment of risks and benets of a general restriction of dietary salt intake, they want to implement short-term, mediumterm and long-term goals. Short and medium goals are to concentrate on the improvement of the health status of the population aiming for sodium labeling of food products and the stepwise reduction of salt in processed food, in fast food chains and restaurants. For long-term goals, individual patients should be addressed via sustainable health promotion (e.g. advice for nutritional behavior changes with the focus of promotion in media, schools, and other education sites). For hypertensive patients, structured training courses could be a key, because such training programs with appropriate information on nutrition have been successfully implemented to improve patients understanding of hypertension and associated complications, thus increasing adherence with nondrug and drug-based treatments and improving patient-relevant outcomes [5559]. Our overview based on secondary and primary literature published to date proves a blood pressure-lowering effect when hypertensive patients reduce their salt intake. However, no valid information was available to show

Benefit assessment of salt reduction in hypertension Matyas et al. 827

conclusively that salt reduction is benecial or harmful in terms of patient-relevant outcomes.

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Acknowledgements
The authors thank Siw Waffenschmidt (IQWiG) for assistance with the literature search strategies, Thomas ringer for support in data Werner Gratzer and Ursula Pu editing, and Eugenia Lamont for nal editing of the article. E.M., K.J., K.H., T.S., N.P., and A.S. are involved as external experts in the preparation of rapid reports on the benet assessment of nondrug treatment strategies in patients with essential hypertension for IQWiG, the German Institute for Quality and Efciency in Healthcare. L.G.H. is an employee of IQWiG.
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References
1 World Health Organization (WHO). The World Health Report 2002: reducing risks, promoting healthy life; 2002. http://www.who.int/entity/ whr/2002/en/whr02_en.pdf. [Accessed 16 February 2010]. Staessen JA, Li Y, Thijs L, Wang JG. Blood pressure reduction and cardiovascular prevention: an update including the 20032004 secondary prevention trials. Hypertens Res 2005; 28:385407. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003; 362:15271535. Frost CD, Law MR, Wald NJ. By how much does dietary salt reduction lower blood pressure? II: analysis of observational data within populations. BMJ 1991; 302:815818. 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; 302:819824. Wannamethee SG, Shaper AG. Patterns of alcohol intake and risk of stroke in middle-aged British men. Stroke 1996; 27:10331039. Wilson PW, DAgostino RB, Sullivan L, Parise H, Kannel WB. Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med 2002; 162:18671872. Dickinson HO, Mason JM, Nicolson DJ, Campbell F, Beyer FR, Cook JV, et al. Lifestyle interventions to reduce raised blood pressure: a systematic review of randomized controlled trials. J Hypertens 2006; 24:215233. He FJ, MacGregor GA. Effect of longer-term modest salt reduction on blood pressure. Cochrane Database Syst Rev 2004:CD004937. rgens G, Graudal NA. Effects of low sodium diet versus high sodium diet Ju on blood pressure, renin, aldosterone, catecholamines, cholesterols, and triglyceride. Cochrane Database Syst Rev 2004:CD004022. Strazzullo P, DElia L, Kandala NB, Cappuccio FP. Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies. BMJ 2009; 339:b4567. European Society of Hypertension, European Society of Cardiology. 2007 guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25:11051187. National Institute for Health and Clinical Excellence (NICE). Essential hypertension: managing adult patients in primary care. 2004. http:// www.nice.org.uk/nicemedia/pdf/CG18background.pdf. [Accessed 16 February 2010]. World Health Organization (WHO). Clinical guidelines for the management of hypertension; 2005. http://www.emro.who.int/dsaf/ dsa234.pdf. [Accessed 16 February 2010]. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:25602572. Canadian Hypertension Education Program (CHEP). Recommendations for the Management of Hypertension. http://hypertension.ca/downloads/ chep/ids/docs/PDF/Complete_Recommendations_2009.pdf. [Accessed 16 February 2010]. Institute for Quality and Efciency in Healthcare. General Methods: Version 3.0. http://www.iqwig.de/download/IQWiG_General_methods_V-3-0.pdf. [Accessed 16 February 2010]. 24 25

26

27 28

6 7

29

30

31

9 10

32

11

33

12

34

13

35

36

14

37 38

15

16

39

17

40

Becker LA, Oxman AD. Chapter 22. Overviews of reviews; 2008. http:// www.cochrane-handbook.org/. [Accessed 16 February 2010]. Horvath K, Jeitler K, Siering U, Stich AK, Skipka G, Gratzer TW, Siebenhofer A. Long-term effects of weight-reducing interventions in hypertensive patients: systematic review and meta-analysis. Arch Intern Med 2008; 168:571580. t und Wirtschaftlichkeit im Gesundheitswesen. r Qualita Institut fu ser Behandlungsstrategien bei Nutzenbewertung nichtmedikamento Patienten mit Bluthochdruck: Gewichtsreduktion; Abschlussbericht. Version 1.0; A05-21A. https://www.iqwig.de/download/A0521A_Abschlussbericht_Gewichtsreduktion_bei_Bluthochdruck_neu.pdf. [Accessed 9 October 2009]. Siebenhofer A, Horvath K, Jeitler K, Berghold A, Stich AK, Matyas E, et al. Long-term effects of weight-reducing drugs in hypertensive patients. Cochrane Database Syst Rev 2009:CD007654. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339:b2700. t und Wirtschaftlichkeit im Gesundheitswesen. r Qualita Institut fu ser Behandlungsstrategien bei Nutzenbewertung nichtmedikamento Patienten mit essenzieller Hypertonie: Kochsalzreduktion; Rapid Report. Version 1.0; A05-21B. http://www.iqwig.de/download/ A05-21B_Rapid_Report_Nichtmedikamentoese_Behandlungsstrategien_ bei_Hypertonie_Kochsalzreduktion.pdf. [Accessed 16 February 2010]. Oxman AD, Guyatt GH. Validation of an index of the quality of review articles. J Clin Epidemiol 1991; 44:12711278. Oxman AD, Guyatt GH, Singer J, Goldsmith CH, Hutchison BG, Milner RA, Streiner DL. Agreement among reviewers of review articles. J Clin Epidemiol 1991; 44:9198. He FJ, MacGregor GA. Effect of modest salt reduction on blood pressure: a meta-analysis of randomized trials. Implications for public health [see comment]. J Hum Hypertens 2002; 16:761770. He FJ, MacGregor GA. How far should salt intake be reduced? Hypertension 2003; 42:10931099. Hooper L, Bartlett C, Davey SG, Ebrahim S. Advice to reduce dietary salt for prevention of cardiovascular disease [update of Cochrane Database Syst Rev 2003:CD003656; PMID: 12917977]. Cochrane Database Syst Rev 2004:CD003656. Hooper L, Bartlett C, Davey Smith G, Ebrahim S. Systematic review of long term effects of advice to reduce dietary salt in adults [see comment]. BMJ 2002; 325:628. Morgan T, Adam W, Gillies A, Wilson M, Morgan G, Carney S. Hypertension treated by salt restriction. Lancet 1978; 1:227 230. Alli C, Avanzini F, Bettelli G, Bonati M, Colombo F, Corso R, et al. Feasibility of a long-term low-sodium diet in mild hypertension. J Hum Hypertens 1992; 6:281286. Whelton PK, Appel LJ, Espeland MA, Applegate WB, Ettinger WH Jr, Kostis JB, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of Nonpharmacologic Interventions in the Elderly (TONE). TONE Collaborative Research Group. JAMA 1998; 279:839846. Appel LJ, Espeland MA, Easter L, Wilson AC, Folmar S, Lacy CR. Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE). Arch Intern Med 2001; 161:685693. Thaler BI, Paulin JM, Phelan EL, Simpson FO. A pilot study to test the feasibility of salt restriction in a community. N Z Med J 1982; 95:839 842. Morgan TO, Adams WR, Hodgson M, Gibberd RW. Failure of therapy to improve prognosis in elderly males with hypertension. Med J Aust 1980; 2:2731. Morgan T, Anderson A. Sodium restriction can delay the return of hypertension in patients previously well controlled on drug therapy. Can J Physiol Pharmacol 1987; 65:17521755. Arroll B, Beaglehole R. Salt restriction and physical activity in treated hypertensives. N Z Med J 1995; 108:266268. He FJ, Marciniak M, Visagie E, Markandu ND, Anand V, Dalton RN, MacGregor GA. Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives. Hypertension 2009; 54:482488. Meland E, Aamland A. Salt restriction among hypertensive patients: modest blood pressure effect and no adverse effects. Scand J Prim Healthcare 2009; 27:97103. He FJ, MacGregor GA. A comprehensive review on salt and health and current experience of worldwide salt reduction programmes. J Hum Hypertens 2009; 23:363384.

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41

42

43

44

45 46

47

48

49

He FJ, MacGregor GA. A comprehensive review on salt and health and current experience of worldwide salt reduction programmes. J Hum Hypertens 2009; 23:363384. Khaw KT, Bingham S, Welch A, Luben R, OBrien E, Wareham N, Day N. Blood pressure and urinary sodium in men and women: the Norfolk Cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk). Am J Clin Nutr 2004; 80:13971403. Intersalt Cooperative Research Group. Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 h urinary sodium and potassium excretion. Intersalt Cooperative Research Group. BMJ 1988; 297:319328. Elliott P, Stamler J, Nichols R, Dyer AR, Stamler R, Kesteloot H, Marmot M. Intersalt revisited: further analyses of 24 h sodium excretion and blood pressure within and across populations. Intersalt Cooperative Research Group. BMJ 1996; 312:12491253. Klaus D, Hoyer J, Middeke M. Salt restriction for the prevention of cardiovascular disease. Dtsch Arztebl Int 2010; 107:457462. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001; 344:310. Blumenthal JA, Babyak MA, Hinderliter A, Watkins LL, Craighead L, Lin PH, et al. Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study. Arch Intern Med 2010; 170:126135. Cook NR, Cutler JA, Obarzanek E, Buring JE, Rexrode KM, Kumanyika SK, et al. Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP). BMJ 2007; 334:885888. World Health Organization (WHO). Reducing salt intake in populations; 2007. http://www.who.int/dietphysicalactivity/reducingsaltintake_EN.pdf. [Accessed 16 February 2010].

50

51 52 53

54

55

56

57

58

59

Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004; 351:26832693. Godlee F. The food industry ghts for salt. BMJ 1996; 312:12391240. Consensus Action on Salt and Health (CASH). http:// www.actiononsalt.org.uk/. [Accessed 10 November 2010]. Bibbins-Domingo K, Chertow GM, Coxson PG, Moran A, Lightwood JM, Pletcher MJ, Goldman L. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med 2010; 362:590599. Klaus S, Middeke L, Hoyer H. An appeal to start a Task Force Lower salt intake for everybody [in German]. Dtsch Med Wochenschr 2008; 133:13171319. The ALLHAT Ofcers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:29812997. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42:12061252. Psaty BM, Manolio TA, Smith NL, Heckbert SR, Gottdiener JS, Burke GL, et al. Time trends in high blood pressure control and the use of antihypertensive medications in older adults: the Cardiovascular Health study. Arch Intern Med 2002; 162:23252332. Fahey T, Schroeder K, Ebrahim S. Educational and organisational interventions used to improve the management of hypertension in primary care: a systematic review. Br J Gen Pract 2005; 55:875882. Trocha AK, Schmidtke C, Didjurgeit U, Muhlhauser I, Bender R, Berger M, Sawicki PT. Effects of intensied antihypertensive treatment in diabetic nephropathy: mortality and morbidity results of a prospective controlled 10-year study. J Hypertens 1999; 17:14971503.