0811 Reduced dietary salt for the prevention of cardiovascular disease

Background An earlier Cochrane review of dietary advice identified insufficient evidence to assess effects of reduced salt intake on mortality or cardiovascular events. Objectives 1. To assess the long term effects of interventions aimed at reducing dietary salt on mortality and cardiovascular morbidity. 2. To investigate whether blood pressure reduction is an explanatory factor in any effect of such dietary interventions on mortality and cardiovascular outcomes. Search strategy The Cochrane Library (CENTRAL, Health Technology Assessment (HTA) and Database of Abstracts of Reviews of Effect (DARE)), MEDLINE, EMBASE, CINAHL and PsycInfo were searched through to October 2008. References of included studies and reviews were also checked. No language restrictions were applied. Selection criteria Trials fulfilled the following criteria: (1) randomised with follow up of at least six-months, (2) intervention was reduced dietary salt (restricted salt dietary intervention or advice to reduce salt intake), (3) adults, (4) mortality or cardiovascular morbidity 0811 Reduced dietary salt for the prevention of cardiovascular disease 2 / 49 data was available. Two reviewers independently assessed whether studies met these criteria. Data collection and analysis Data extraction and study validity were compiled by a single reviewer, and checked by a second. Authors were contacted where possible to obtain missing information. Events were extracted and relative risks (RRs) and 95% CIs calculated. Main results Seven studies (including 6,489 participants) met the inclusion criteria three in normotensives (n=3518), two in hypertensives (n=758), one in a mixed population of normoand hypertensives (n=1981) and one in heart failure (n=232) with end of trial follow-up of seven to 36 months and longest observational follow up (after trial end) to 12.7 yrs. Relative risks for all cause mortality in normotensives (end of trial RR 0.67, 95% CI: 0.40 to 1.12, 60 deaths; longest follow up RR 0.90, 95% CI: 0.58 to 1.40, 79 deaths) and hypertensives (end of trial RR 0.97, 95% CI: 0.83 to 1.13, 513 deaths; longest follow up RR 0.96, 95% CI; 0.83 to 1.11, 565 deaths) showed strong evidence of any effect of salt reduction. Cardiovascular morbidity in people with normal blood pressure (longest follow-up RR 0.71, 95% CI: 0.42 to 1.20, 200 events) or raised blood pressure at baseline (end of trial RR 0.84, 95% CI: 0.57 to 1.23, 93 events) also showed no strong evidence of benefit. Salt restriction increased the risk of all-cause death in those with congestive heart failure (end of trial relative risk: 2.59, 95% 1.04 to 6.44, 21 deaths). We found no information on participants health-related quality of life. Authors' conclusions Despite collating more event data than previous systematic reviews of randomised controlled trials (665 deaths in some 6,250 participants), there is still insufficient power to exclude clinically important effects of reduced dietary salt on mortality or cardiovascular morbidity in normotensive or hypertensive populations. Further RCT evidence is needed to confirm whether restriction of sodium is harmful for people with heart failure. Our estimates of benefits from dietary salt restriction are consistent with the predicted small effects on clinical events attributable to the small blood pressure reduction achieved. Plain language summary Cutting down on the amount of salt has no clear benefits in terms of likelihood of dying or experiencing cardiovascular disease Cardiovascular disease includes heart attacks, strokes, and the need for heart surgery and is a major cause of premature death and disability. This review set out to assess whether advice to cut down on salt in foods on altered our risk of death or cardiovascular disease. Intensive support and encouragement to reduce salt intake did lead to a reduction in salt eaten and a small reduction in blood pressure after more than six months. There was not enough information to understand the effect of these changes in salt intake on deaths or cardiovascular disease. Further research in needed to confirm our finding that dietary advice to reduce salt may increase deaths in people with heart failure. Background In 2002 it was estimated that nearly 17 million deaths globally per year result from cardiovascular disease (CVD) (Mackay 2004). Data on morbidity is more difficult to collect because there are so many different measures of cardiovascular morbidity. However, in 2002 it was estimated that over 34 million disability adjusted life years (DALYs) are lost each year to CVD in Europe (Allender 2008). The current public health recommendations in most developed countries are to reduce salt intake by about half, i.e. from approximately 10 to 5 g/day (He 2010; SACN 2003; Whelton 2002 ). Data from observational studies have indicated that a high dietary intake of salt is an important risk factor for cardiovascular disease (He 2002, He 2010). This was confirmed by a recently published systematic review and meta-analysis of 13 prospective studies including 177,000 participants. A high salt intake was associated with a greater risk of stroke (relative risk, 1.23, 95% CI: 1.06 to 1.43) (Starzzullo 2009). However, there was no association between salt intake and all cardiovascular events, and total mortality was not reported. Furthermore, the interpretation of this observational evidence base is complicated by the heterogeneity in estimating sodium intake (diet or urinary salt excretion), types of participants (healthy, hypertensive, obese and non-obese), different end points, and definition of outcomes across studies (Alderman 2010). The relationship of salt intake to blood pressure is the basis for the belief that restriction in dietary sodium intake will prevent blood pressure related cardiovascular events (Elliot 1996). A number of meta-analyses of randomised controlled trials of salt reduction and blood pressure have been undertaken (He 2004; Jurgens 2004). Whilst these analyses consistently report a reduction in the level of blood pressure with reduced salt intake, the level of blood pressure reduction achieved is less impressive in the longer term. The 2004 Cochrane review of dietary salt restriction intervention studies of at least six months duration, found that intensive support and encouragement to reduce salt intake lowered blood pressure at 13 to 60 months but only by a small amount (systolic by 1.1 mm Hg, 95% CI: 1.8 to 0.4, diastolic by 0.6 mm Hg, 95% CI: 1.5 to -0.3) (Hooper 2004). The reduction in blood pressure appeared larger for people with higher blood pressure. A decrease in blood pressure is only important if it results in a decrease in cardiovascular events and deaths. Sustained reductions in mean blood pressure of 2-3 mmHg are necessary for important population reductions in cardiovascular events (Elliot 1991). Whilst the Cochrane review also sought to assess the impact of dietary salt restriction on mortality and cardiovascular events, across the included 11 RCTs there were only 17 deaths spread evenly across groups and 46 cardiovascular events in the controls compared with 36 in low sodium diet groups. This extremely low number of events substantially limited the ability of this review to detect small to moderate reductions in the risk of cardiovascular events. 0811 Reduced dietary salt for the prevention of cardiovascular disease 3 / 49 Given that the effect of interventions to reduce dietary salt on blood pressure is well established, the primary focus of this review is to confirm whether such changes in diet are associated with improvements in mortality and cardiovascular events. Objectives 1. To assess the long term effects of interventions aimed at reducing dietary salt on mortality and cardiovascular morbidity. 2. To investigate whether a reduction in blood pressure is an explanatory factor in the effect of such dietary interventions on mortality and cardiovascular outcomes. Interventions to reduce dietary salt were compared with usual, control or placebo diets, or no intervention. Methods Criteria for considering studies for this review Types of studies Randomised controlled trials (RCTs; individual or cluster level) with follow up of at least six months. Types of participants Studies of adults (18 years or older), irrespective of gender or ethnicity. Studies of children or pregnant women were excluded. Types of interventions The desired intervention was reduced dietary salt and could include studies that involved participants receiving a dietary intervention that restricted salt or studies where the intervention was advice to reduce salt intake. The comparison group could include usual, control or placebo diet, or no intervention. Types of outcome measures Primary outcomes Mortality (overall and cardiovascular), cardiovascular morbidity (including fatal and non-fatal myocardial infarction, stroke, angina, heart failure, peripheral vascular events, sudden death, revascularisation [coronary artery bypass surgery or angioplasty with or without stenting] and cardiovascular related hospital admissions). Primary outcomes were assessed at study end, and also at the latest trial follow up where participants had been followed observationally after the end of the original trial. Secondary outcomes In studies that reported primary outcomes we also sought the following secondary outcomes: systolic and diastolic blood pressure, and urinary salt excretion (or other method of estimation of salt intake) and health related quality of life using a validated outcome measure (e.g. Short Form 36, McHorney 1993). Search methods for identification of studies Electronic searches Randomised controlled trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 4, 2008), MEDLINE (Ovid, 1950 to 29 October 2008), EMBASE (Ovid, 1980 to 30 October 2008), CINAHL (Ovid, 2001 to 3 November 2008), and PsycINFO (Ovid, 1806 to October 2008), Health Technology Assessment (HTA) and Abstracts of Reviews of Effects (DARE) databases were searched via The Cochrane Library (Issue 4, 2008). Searches conducted in MEDLINE, EMBASE, CINAHL, and PsycINFO included a controlled trials filter. Additional filters were applied to restrict searches to non-animal studies in MEDLINE and EMBASE and to exclude certain publication types from the search results [Medline: case reports/letters, EMBASE: letters/editorials, and PsycInfo: editorials/letters]. No language or additional limits or filters were utilized. See Appendix 1 for details of the search strategies. Searching other resources Reference lists of all eligible trials and relevant systematic reviews were searched for additional studies. Data collection and analysis Selection of studies The titles and abstracts of studies identified by the search were independently screened by two reviewers (KA & RST) and clearly irrelevant studies discarded. In order to be selected, abstracts had to clearly identify the study design, an appropriate population and a relevant intervention/exposure, as described above. The full text reports of all potentially relevant studies were obtained and assessed independently for eligibility, based on the defined inclusion criteria, by two reviewers (KA & RST). Any disagreement was resolved by discussion or where agreement could not be reached, by consultation with an independent third person (LH). Data extraction and management Standardised data extraction forms were used. Relevant data regarding inclusion criteria (study design, participants, intervention/exposure, and outcomes), risk of bias (see below) and outcome data were extracted. Data extraction was carried out by a single reviewer (KA or RST) and checked by a second reviewer (RST or KA). Disagreements were resolved by 0811 Reduced dietary salt for the prevention of cardiovascular disease 4 / 49 discussion or if necessary by a third reviewer (LH). We extracted outcomes at the latest follow up point within the trial, and also at the latest follow up after the trial where this was available, as we reasoned this would maximise the number of events reported. All included authors were contacted to clarify any missing outcome data or issues of risk of bias assessment. Assessment of risk of bias in included studies Factors considered included random sequence generation and allocation concealment, description of drop-outs and withdrawals, blinding (participants, personnel and outcome assessment) and selective outcome reporting. In addition evidence was sought that the groups were balanced at baseline, that intention to treat analysis was undertaken and whether the period over which the salt intervention lasted and follow up of outcome were equivalent. The risk of bias of included studies was assessed by a single reviewer (KA) and checked by a second reviewer (RST). Disagreements were resolved by discussion or if necessary by a third reviewer (LH). Data synthesis Data were processed as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). For mortality and cardiovascular events, risk ratio and 95% confidence intervals were calculated for each trial. For blood pressure and urinary sodium excretion, mean group differences and 95% confidence intervals were calculated using weighted mean difference. Heterogeneity amongst included studies was explored qualitatively (by comparing the characteristics of included studies), and quantitatively (using the Chi2 statistic of heterogeneity and I2 statistic). Results from included studies were combined for each outcome to give an overall estimate of treatment effect at the latest point available within the randomised trial, and, as a secondary analysis, at the latest point available (including where participants were followed after the end of the randomisation period). A fixed-effect meta-analysis was used except where statistical heterogeneity (Chi2 P ≤ 0.05 and I2 value ≥ 50%) was identified, in which case methodological and clinical reasons for heterogeneity were considered and a random-effects model was used. Subgroup analysis and investigation of heterogeneity It was planned to use stratified meta-analysis to explore the differential effects that occur as a result of: individual advice vs. population level interventions, baseline risk of cardiovascualr disease (CVD), and salt reduction only interventions vs. multicomponent dietary interventions that include salt restriction; and meta-regression to assess the effects of level of salt reduction achieved, baseline blood pressure (BP) and change in BP on mortality and CV event outcomes. Results Description of studies Our electronic and reference list searches identified a total of 2,649 titles of which 2,605 were excluded on title and abstract. After examining the full texts of the remaining 44 papers, seven trials were included (38 reports) (Chang 2006 [31 mo]; HPT 1989 [36 mo]; Morgan 1978 [7-71 mo]; Paterna 2008 [6.4 mo]; TOHP I 1992 [18 mo]; TOHP II 1997 [36 mo]; TONE 1998 [30 mo]). The study selection process is summarised in the flow diagram shown in Figure 1. Five studies from an earlier Cochrane review (Hooper 2004) met the inclusion criteria (TOHP I 1992 [18 mo]; TOHP II 1997 [36 mo]; TONE 1998 [30 mo]; HPT 1989 [36 mo]; Morgan 1978 [7-71 mo]). The other six included studies from Hooper 2004 were excluded as they did not report mortality or cardiovascular events (Alli 1992; Arroll 1995; Costa 1981; Morgan 1987; Silman 1983; Thaler 1982). Studies that were assessed in full text, but excluded, are listed in Characteristics of excluded studies section. Responses to our request for additional details were obtained from three of the included trial authors i.e. TOHP I and II and TONE. Included studies The seven included studies are described in Characteristics of included studies section. Three trials in people with normotension (n=3518, HPT 1989 [36 mo]; TOHP I 1992 [18 mo]; TOHP II 1997 [36 mo]), two in people with hypertension (n=758, Morgan 1978 [7-71 mo]; TONE 1998 [30 mo]), one in a mixed population of people with normoand hypertension (n=1981, Chang 2006 [31 mo]) and one in people with heart failure (n=232, Paterna 2008 [6.4 mo]) were included. Postrandomisation follow up varied from up to six to nine months (Morgan 1978 [7-71 mo]; Paterna 2008 [6.4 mo]), to ~threeyears (Chang 2006 [31 mo]; HPT 1989 [36 mo]) and 10-15 years (TOHP I 1992 [18 mo]; TOHP II 1997 [36 mo]; TONE 1998 [30 mo]). The three normotensive trials were in healthy people (predominantly [>75%] white, male [75%], median age 40) conducted in the USA. Entry criteria varied between trials, but included those with diastolic blood pressure from 78 to 89 mmHg, with a narrow range of means from 83 to 86 mmHg diastolic and 124 to 127 mmHg systolic and the number of participants included ranged from 392 to 2382. All three studies (as well as TONE, below) in normotensives aimed to reduce salt by a comprehensive dietary and behaviour change programmes led by experienced personnel, including group counselling sessions, regularly over several months, with newsletters between sessions, self assessment, goal setting, food tasting and recipes. For example, the HPT study ran ten weekly group counselling sessions on food selection, food preparation and behaviour management skills, followed by semimonthly and then bi-monthly meetings throughout the trial (with newsletters in the months where no meetings occurred). Sessions were run by nutritionists and behavioural scientists and individual counselling was provided where participants missed sessions or had special needs. Techniques used in the sessions included group discussions, instructions for dietary record keeping, goal setting, individual diet analysis for each participant, cooking demonstrations, provision of recipe books 0811 Reduced dietary salt for the prevention of cardiovascular disease 5 / 49 and tasting of new foods. The intervention duration ranged from seven months in the TONE study to some 36 months in TOHP II study. Control groups received no active intervention. Sodium excretion goals were set at less than 70 to 80mmol/24 hours. The three trials that included hypertensives included one trial in treated hypertensive participants (TONE 1998 [30 mo]) and two for participants with untreated hypertension (Chang 2006 [31 mo]; Morgan 1978 [7-71 mo]). Some 40 percent of participants in the Chang study were defined as hypertensive. Studies were carried out in Australia, Taiwan and USA and ranged in size from 77 to 1,981 participants. 58 to 100% of participants were male with median age of 66 yrs and 76% were white in the TONE study and 100% were Asian in the Chang study (ethnicity was not reported in Morgan study). At study entry mean diastolic blood pressure ranged from 71 mmHg (Chang 2006 [31 mo]; TONE 1998 [30 mo] on treatment) to 97 mmHg (Morgan 1978 [7-71 mo], untreated) and systolic blood pressure ranged from approximately 131mmHg (Chang 2006 [31 mo] untreated; TONE 1998 [30 mo] on treatment) to 162 mmHg (Morgan 1978 [7-71 mo], untreated). Interventions in the three studies included: a dietary programme by the cook of the kitchen to which they were assigned (clustered random allocation), to 'high potassium salt' containing 49% sodium chloride, 49% potassium chloride, and 2% other additives or control prepared diet using 'usual salt' containing 99.6% sodium chloride and 0.4% other additives (Chang 2006 [31 mo]). advice to reduce dietary sodium chloride intake, with advice repeated at 6 months compared with no dietary intervention in the control group (Morgan 1978 [7-71 mo]). Anti-hypertensive medication was stopped two months after randomisation to intervention or control, but restarted if diastolic blood pressure rose. After 6 months, four out of 10 men on low sodium diet were taking anti-hypertensive medication, compared to nine of the ten controls (relative risk: 0.44, 95% CI: 0.20 to 0.98). a four-month ‘intensive’ plus three-month ‘extended’ individual nutrition and behavioural counselling programme (as above) or no such programme but with invitations to meetings on unrelated topics in the control group (TONE 1998 [30 mo]). In the TONE study hypertensive medication withdrawal could be attempted began at three-months post randomisation. The primary composite outcome (high blood pressure at any visit, restarting anti-hypertensive medication or a cardiovascular event) was less common in the sodium reduction group than control (relative risk 0.83, 95% CI: 0.75 to 0.92). The proportions of individuals restarting medication was not separately reported. Sodium goals varied from <80 mmol/day (TONE 1998 [30 mo]) to 70-100 mmol/day and unspecified (Chang 2006 [31 mo]) sodium intake. The final study was undertaken in Italy and included a population of participants diagnosed with uncompensated heart failure (NYHA class III or IV) (Paterna 2008 [6.4 mo]). The majority of participants were male with a mean age of 73, mean diastolic blood pressure of 82.5 mmHg and mean systolic blood pressure of 125.5 mmHg. The intervention group received written standard diet sheets containing 80mmol of sodium daily prepared by dietitians and the control group received the same dietary advice but with the addition of 40mmol of sodium per day. In addition to either low-sodium or control diet, both groups received a high dose diuretic (furosemide, 250-500 mg bid). Risk of bias in included studies A number of studies failed to give sufficient detail to assess their potential risk of bias. Details of generation and concealment of random allocation sequence were particularly poorly reported (Figure 2; Figure 3). However, in all cases there was objective evidence of balance in baseline characteristics of intervention and control participants. While studies reported loss to follow up and reasons for loss for follow, only a few undertook a sensitivity or imputation analysis to assess the impact of these losses, followed up participants for event outcomes and described reasons for loss to follow up for other outcomes. In the TONE trial, the authors stated that data were collected via psychological questionnaires at randomisation and a number of the follow-up visits. However, none of these data were found in trial reports. Although often not stated, all studies appeared to undertake an intention to treat analysis in that groups were analysed according to initial random allocation. All studies assessed compliance to salt reduction intervention using diet diaries or monitoring USE. However, in the longer term follow up of the TOHP I (11.5 yrs), TOHP II (8 yrs) and TONE (12.7 yrs) trials such compliance data was not reported beyond the official end of the study. Therefore it was unclear whether intervention groups encouraged to continue their low salt diets, or return to their pre-trial diet. Similarly, control groups may have been left to continue with their usual diet or advised to reduce their salt at the end of the trial. Effects of interventions Given the heterogeneity in populations, results are presented and pooled separately for studies of people with normotension, hypertension and heart failure. Outcomes were pooled at end of trial and at longest follow up point unless otherwise indicated. Mortality All cause mortality was reported at the end of the trial in five of the included studies (HPT 1989; TOHP I 1992; TOHP II 1997; Chang 2008; Morgan 1978). Trials were homogeneous and therefore pooled using a fixed effect model. There was weak evidence of a reduction in the number of deaths in the reduced salt group relative to controls for normotensives (fixed effects RR 0.67, 95% CI: 0.40 to 1.12, 60 deaths in total, Chi2 p-value=0.96,I2 = 0%) and hypertensive populations (fixed effects RR 0.97, 95% CI: 0.83 to 1.13, 513 deaths, Chi2 p-value = 0.98, I2 = 0%). Compared to control there was an increase in deaths with dietary salt reduction in the single heart failure study (relative risk: 2.59, 95% CI: 1.04 to 6.44, 21 deaths). See Analysis 1.1 A longer observational follow up following the end of the randomised trial period was reported for the TOHP I (11.5 yrs) and 0811 Reduced dietary salt for the prevention of cardiovascular disease 6 / 49 TOHP II (8 yrs) trials (Cook 2007) and we were able to obtain longer observational unpublished data from the authors from the TONE study (12.7 yrs). Trials remained homogeneous. At longest follow up, there was still no strong evidence of a reduction in the number of deaths in the reduced salt group relative to controls, for the normotensives (fixed effects RR 0.90, 95% CI: 0.58 to 1.40, 79 deaths in total, Chi2 p-value=1.00,I2 = 0%) or hypertensive populations (fixed effects RR 0.96, 95% CI: 0.83 to 1.11, 565 deaths, Chi2 p-value = 0.92); I2 = 0%). See Analysis 1.2 Cardiovascular mortality was only reported in two studies of hypertensive patients. Both studies only reported trial end data. Chang reported a lower proportion of cardiovascular deaths in reduced salt group (27 died; 1310.0 per 100,000 person years) than in the control group (66 died; 2,140 per 100,000 person years). Morgan reported only five cardiovascular deaths, three in the intervention and two in control group. The pooled relative risk was consistent with a halving of the relative risk of cardiovascular deaths or a small increase (fixed effects RR 0.69, 95% CI: 0.45 to 1.05, 98 cardiovascular deaths, Chi2 pvalue = 0.26, I2 = 0%). See Analysis 1.3 Cardiovascular morbidity Overall cardiovascular morbidity was available for four trials. There was some evidence of statistical heterogeneity which may reflect that the definition of CV morbidity varied from trial to trial, although it broadly consisted of a composite of myocardial infarction, stroke, coronary artery bypass, PTCA, or death from a cardiovascular cause. At longer term observational follow up, TOHP I reported a relative risk reduction of cardiovascular events of 49% (95% CI: 9% to 71%) with reduced salt although when pooled with long term observational follow up of TOHP II there was no strong evidence of benefit in normotensive participants (random effects relative risk: 0.71, 95% CI: 0.42 to 1.20, 200 events, Chi2 p-value = 0.10; I2 = 63%). There were no reports of cardiovascular morbidity during or at the end of the randomised period for TOHP I or II trials. We found no strong evidence of benefits of salt reduction in hypertensive individuals (fixed effects relative risk: 0.84, 95% CI: 0.57 to 1.24, 93 events, Chi2 p-value = 0.53; I2 = 0%) at end of trial. See Analysis 1.4 Individual cardiovascular morbidity outcomes were infrequently reported and at trial end only. Paterna et al reported 39 cardiovascular-related hospital admissions (30 intervention, nine control) in their study of congestive heart failure patients ( Paterna 2008 [6.4 mo]). In TONE, three patients experienced strokes (one intervention, two control); six experienced a myocardial infarction (two intervention, four control); three developed heart failure (two intervention, one control) and 26 suffered from angina (nine intervention, 17 control) (TONE 1998 [30 mo]). Blood pressure End of trial blood pressure was reported by all studies. There was evidence of substantial statistical heterogeneity. Systolic blood pressure was reduced in all intervention arms normotensives (random effects mean difference 1.1 mmHg, 95% CI 0.1 to 2.3, Chi2 p-value = 0.05, I2 = 67%), hypertensives (fixed effect mean difference 4.1 mmHg, 95% CI 2.4 to 5.8, Chi2 pvalue = 0.64; I2 = 0%) and those with heart failure (by 4.0 mmHg, 95% CI 0.7 to 7.3). Diastolic blood pressure was also reduced in normotensives (fixed effect mean difference 0.8 mmHg, 95% CI 0.2 to 1.4, Chi2 p-value = 0.39); I2 = 0%) but not in hypertensives (random effect mean difference -3.7 mmHg, 95% CI: 0.9 to -8.4, Chi2 p-value = 0.08; I2 = 67%) or those with heart failure (mean difference -2.0 mmHg, 0.70 to -4.80). See Analysis 1.5 and Analysis 1.6. Urinary sodium excretion Changes in urinary sodium excretion (USE) at the end of trial were reported by all studies. There was some evidence of statistical heterogeneity which may reflect different approaches to the assessment of 24-hr urinary sodium excretion. In the study by Morgan (Morgan 1978 [7-71 mo]), results were only reported as samples and therefore contained repeated observations for a number of patients. As for BP, in a number of studies, the last USE available was at a time point much preceding the timing of the reported mortality or CV events (BP follow up time: Morgan six mo; TONE 30 mo, TOHP I 18 mo, TOHP II 36 mo). Urinary 24-hour USE was reduced by a similar amount across the three study subgroups – normotensives (by random effects 34.2 mmol/24 hrs, 95% CI: 18.8 to 49.6, Chi2 p-value = 0.03, I2 = 76%), hypertensive (by fixed effects 39.1 mmol/24 hrs, 95% CI: 31.1 to 47.1, Chi2 p-value = 0.35; I2 = 0%) and heart failure (by 27.0 mmol/24hrs, 95% CI: 24.5 to 29.5). See Analysis 1.7 Health-related quality of life No studies reported outcomes using a validated health-related quality of life instrument. Subgroup analyses and investigation of heterogeneity In order to take to take account of the heterogeneity in populations and CV baseline risk, we stratified meta-analyses according to whether studies were undertaken in normotensive, hypertensive or heart failure populations. However, there was insufficient variability and number of studies to formally investigate heterogeneity. For example, as all studies applied participant level salt reduction interventions, we were unable to compare the effect of individual vs. population level interventions. Small study bias Given the small number of included studies it was not possible to assess small study bias using either funnel plot or statistically. Discussion Summary of main results This Cochrane review identified seven randomised controlled trials that assessed the long-term (> six-months) effects of 0811 Reduced dietary salt for the prevention of cardiovascular disease 7 / 49 interventions aimed at reducing dietary salt on mortality and cardiovascular morbidity. Three trials were in normotensives (HPT 1989 [36 mo], TOHP I 1992 [18 mo]; TOHP II 1997 [36 mo], n=3518 participants), two in hypertensives (Morgan 1978 [7-71 mo]; TONE 1998 [30 mo], n=758 participants), one in a mixed population of normoand hypertensives (Chang 2006 [31 mo], n=1981 participants) and one in heart failure (Paterna 2008 [6.4 mo], n=232 participants). We found no strong evidence that salt reduction reduced all-cause mortality in normotensives (end of trial RR 0.67, 95% CI 0.40 to 1.12, 60 deaths, 3518 participants; longest follow up relative risk: 0.90, 95% CI: 0.58 to 1.40, 79 deaths, 3518 participants) or hypertensives (end of trial relative risk: 0.97, 95% CI 0.83 to 1.13, 513 deaths, 2058 participants; longest follow up relative risk: 0.96, 95% CI; 0.83 to 1.11, 565 deaths, 2349 participants). A single RCT showed increase the risk of all-cause death in one study (relative risk: 2.59, 95% 1.04 to 6.44, 21 deaths, 232 participants) in those with congestive heart failure receiving a low salt diet. Few cardiovascular events were reported, and the lack of a statistically significant effect of reduced salt on cardiovascular morbidity in people with normal blood pressure (end of trial relative risk: 0.71, 95% CI: 0.42 to 1.20, 200 events, 2502 participants) and high blood pressure (end of trial relative risk: 0.84, 95% CI: 0.57 to 1.23, 93 events, 720 participants). We found no information on participant’s health-related quality of life assessed using either validated generic or disease-specific instruments. The interventions were capable of reducing urinary sodium excretion and indicated that participants continued to comply with sodium restriction in the long-term, at least to some degree, although, as noted in a previous Cochrane review, the degree of sodium restriction is likely to attenuate over time (Hooper 2004). End of trial systolic and diastolic blood pressure were reduced by an average of some 1 mmHg in normotensives and by an average of 2 to 4 mmHg in hypertensives and those with heart failure. Sustained long-term reductions of blood pressure of 1 and 4 mmHg would be predicted to reduce CVD mortality by 5% and 20% respectively (MacMahon 1990). Our point estimates are consistent with effects of this size but have wide confidence intervals owing to the relatively small number of events. Overall completeness and applicability of evidence A previous Cochrane review was limited by the lack of reported events (17 deaths, 93 cardiovascular events) (Hooper 2004). In this review, because of longer observational follow up (up to 10 to 15-years) of three of the trials included in the previous Cochrane review (TOHP I 1992 [11.5 yrs]; TOHP II 1997 [8 yrs]; TONE 1998 [12.7 yrs]) and inclusion of two more recent RCTs (Chang 2006 [31 mo]; Chang 2006 [31 mo] ; Paterna 2008 [6.4 mo]) we have gathered more evidence on mortality and cardiovascular outcomes (~6,500 participants, 665 deaths, 293 cardiovascular events). Nevertheless the total amount of evidence on events remains limited. Assuming a control risk of 14% (hypertension trial control event risk in present review) we would require some 2500 cardiovascular events in over 18,000 trial participants to detect a small reduction in relative risk (0.90) with dietary salt advice (at 80% power and 5% alpha). Although a relatively small evidence base, the external validity of the review was potentially high. Most studies included men and women at varying levels of risk of cardiovascular risk, primarily free-living in a community setting in industrialised countries. One study was undertaken in veterans in a residential setting in Taiwan, a recently graduated developing economy (Chang 2006 [31 mo]). Quality of the evidence Although all included studies were randomised controlled trials, only one of the seven included studies provided sufficient detail to be judged as having adequate random sequence generation, allocation concealment and outcome blinding. Nevertheless, all trials provided evidence of baseline balance. Although lack of blinding is unlikely to alter outcome assessment when outcomes include mortality and cardiovascular events, failure to blind participants may have lead to a positive change the lifestyle and dietary behaviours of control participants, leading to a reduction in the difference between groups. Most trials appeared to be free from dietary changes in the intervention and control group apart from dietary sodium. The one major exception was the trial by Chang where sodium was replaced by a high potassium substitute (Chang 2006 [31 mo]). Potassium has effects on blood pressure and may have deleterious effects in individuals with renal disease (Cappuccio 2000 ). Two studies in hypertensives allowed changes in anti-hypertensive medication during the period of the trial (Morgan 1978 [7-71 mo]; TONE 1998 [30 mo]). In both trials, lower levels of hypertensive medication in the intervention group compared to control may have reduced the blood pressure lowering effect of reduced dietary sodium and therefore offset mortality and cardiovascular morbidity benefits. By incorporating data from the longest follow up point, we sought to maximise the opportunity to capture all deaths and cardiovascular events that were affected by alterations in dietary salt, not just those within the RCT period. However, in doing so we may have introduced a major source of bias. For three large studies (TOHP I 1992 [11.5 yrs], TOHP II 1997 [8 yrs], TONE 1998 [12.7 yrs]) the longest follow up was considerably beyond the official end of the trial and therefore observational. It was unclear if the intervention groups continued their low salt diets and whether control groups were left to continue with dietary advice or advised to reduce their salt. For this reason we included the primary analysis in each case as the latest data trial end, more robust but with slightly fewer deaths and cardiovascular events. In summary, the overall internal validity of the evidence base in this review was limited and therefore our conclusions regarding the effect of a reduction in dietary salt may not be robust. Potential biases in the review process We searched comprehensively for randomised controlled trials of dietary sodium reduction, with a duration of 6-months or more and that reported mortality or cardiovascular events. We attempted to contact all authors of included studies to verify 0811 Reduced dietary salt for the prevention of cardiovascular disease 8 / 49 events. Nevertheless, we were unable to report all relevant outcomes for all trials. The small number of included studies prevented us from being able to assess the presence of small study or publication bias. In common with previous systematic reviews of dietary interventions, we observed marked heterogeneity across studies in terms of their population, sample size and follow up. Whilst we stratified meta-analysis by differing sub-populations (normotensives, hypertensives and congestive heart failure) and pooled studies using weighting based on sample size we did not account for the duration of follow up. A previous Cochrane review (Hooper 2004) suggests that over time the sodium reduction achieved is greatly reduced, as is the effect on blood pressure and therefore the effect on events potentially diminished. Agreements and disagreements with other studies or reviews Our finding of a lack of strong evidence of an effect of dietary sodium reduction on mortality and cardiovascular events is in contrast to Starzzullo 2009 who systematically reviewed prospective observational studies that examined the relationship between dietary sodium and cardiovascular events. They included 13 cohort studies (177,025 participants) over follow up three-17 years and found higher salt intake to be associated with greater risk of stroke (pooled relative risk: 1.23, 95% CI: 1.06 to 1.43, 5161 events) and cardiovascular events (pooled relative risk: 1.14, 95% CI: 0.99 to 1.32, 5346 events). Total and cardiovascular mortality were not reported. The inherent limitation of the Starzzullo review is the observational nature of the evidence i.e. studies describe the life course of persons who follow a chosen diet but provide no information about what might happen if that diet were experimentally allocated. People who choose a lower salt diet are likely to also eat a diet of fresh foods, lower in fats and refined carbohydrate, take more exercise and be less likely to smoke, so that their lower levels of deaths and disease may not relate to salt intake at all. Authors' conclusions Implications for practice Our findings are consistent with the belief that salt reduction is beneficial in normotensive and hypertensive people. However, the methods of achieving salt reduction in the trials included in our review, and other systematic reviews, were relatively modest in their impact on sodium excretion and on blood pressure levels, generally required considerable efforts to implement and would not be expected to have major impacts on the burden of CVD. The challenge for clinical and public health practice is to find more effective interventions for reducing salt intake that are both practicable and inexpensive. Many countries have national authoritative recommendations, often sanctioned by government, that call for reduced dietary sodium. In UK, the National Institute of Health and Clinical Guidance (NICE) has recently called for an acceleration of the reduction in salt in the general population from a maximum intake of 6 g per day per adult by 2015 and 3 g by 2025 (NICE 2010). Despite collating more events than previous systematic reviews of randomised controlled trials (565 deaths in almost 7,000 participants) we were unable to demonstrate a robustly estimated effect of reduced dietary salt on mortality or cardiovascular morbidity in normotensive or hypertensive populations. Including a further 79 deaths from long-term observational follow up of three trials did not improve the statistical power of the meta-analysis which is underpowered to assess the likely small relative risk reductions on all-cause mortality or cardiovascular events of dietary salt restriction. Implications for research In accord with the research recommendation of a previous Cochrane review, three of the large trials (TOHP I, TOHP II, TONE) have assessed the long-term effects of reduced dietary salt advice on mortality and cardiovascular morbidity. Our findings support the recent call for further rigorous large long-term randomised controlled trials, capable of definitively demonstrating the cardiovascular benefit of dietary salt reduction (Alderman 2010). Such trials need to assess population level interventions that are likely to lead to sustained reductions in salt intake and are commensurate with current public health guidelines. Further RCT evidence is needed to assess whether dietary restriction of sodium is harmful for people with heart failure. It will be important to evaluate the effects of voluntary salt reductions by food industries as these may hold greater opportunities for practicable and inexpensive means of reducing salt intake in the population at large than focusing on dietary advice for individuals. Acknowledgements This review was supported by a UK NIHR Cochrane Collaboration Programme grant 'Cochrane Heart Public Health and Prevention Reviews' CPGS10. Contributions of authors All the authors were involved in the design of the review. Tiffany Moxham developed the search strategy. Kate Ashton and Rod Taylor will independently select studies for inclusion. Data extraction was carried out by Kate Ashton and Rod Taylor. Synthesis/analysis was carried out by Rod Taylor and Kate Ashton. Rod Taylor and Kate Ashton wrote the first draft of the review, with contributions and comments from all other co-authors. Declarations of interest None known Differences between protocol and review Given the small number of trials included in this review it was not possible to undertake exploration of heterogeneity using 0811 Reduced dietary salt for the prevention of cardiovascular disease 9 / 49 stratified meta-analysis or meta-regression Studies reporting death or cardiovascular outcomes were included regardless of the number of events in intervention and controls. Published notes Characteristics of studies Characteristics of included studies Chang 2006 [31 mo] Methods Cluster RCT [5 kitchens] Participants N Randomised: 1991 (N=768, intervention, 2 kitchens; N=1213 control, 3 kitchens) Baseline Blood Pressure: Int.: SBP mean 131.3 (SD 19.7), DBP mean 71.2 (SD 10.8); Ctrl: SBP mean 130.7 (SD 20.4), DBP mean 71.4 (SD 10.8) Case mix: Int.: 40.2% hypertension; Ctrl.: 40.4% hypertension Age: mean 75.6 (SD 7.7), 74.8 (7.0), 74.8 (7.3), 74.6 (6.7), 74.6 (6.1) in kitchens 2 and 3 (int. group), and 1, 4, and 5 (ctrl group) respectively. CV diagnoses: None reported Percentage male: 100% Percentage white: Not reported. Inclusion/exclusion criteria: Inclusion: Veterans registered into a retired home in Northern Taiwan. Exclusion: Bed-ridden veterans, high serum creatinine (i.e. >=3.5mg/dL) Interventions Intervention Total duration: Average of 31 months. Salt reduction/advice component: Ate food prepared by the cook of the kitchen to which they were assigned, using salt containing 49% sodium chloride, 49% potassium chloride, and 2% other additives. The 'potassium enriched salt' replaced the regular salt in the selected kitchens in a gradual manner. It was mixed with regular salt in a 1:3 ratio for the first week, it was then increased to 1:1 for the second week, and 3:1 for the third week. By the fourth week cooks used solely the potassium enriched salt. Other dietary component: Other condiments and spices such as soy sauce and monosodium glutamate were not limited because reasonably priced low-sodium soy sauce and monosodium glutamate were not available at the time of the trial. Comparator Dietary: Ate food prepared by the cook of the kitchen to which they were assigned using 'regular salt' containing 99.6% sodium chloride and 0.4% other additives at all times. Other condiments and spices such as soy sauce and monosodium glutamate were not limited because reasonably priced low-sodium soy sauce and monosodium glutamate were not available at the time of the trial. Outcomes Deaths (all cause & CVD) Follow up Average 31 months Country & setting Taiwan Veteran’s retirement home Notes Outcomes are not reported by kitchen so not able to quantify effect of clustering