Reduced dietary salt for the prevention of cardiovascular disease

ABSTRACT BACKGROUND: This is an update of a Cochrane review that was first published in 2011 of the effects of reducing dietary salt intake, through advice to reduce salt intake or low-sodium salt substitution, on mortality and cardiovascular events. OBJECTIVES: 1. To assess the long-term effects of advice and salt substitution, 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. METHODS: Search methods: We updated the searches of CENTRAL (2013, Issue 4), MEDLINE (OVID, 1946 to April week 3 2013), EMBASE (OVID, 1947 to 30 April 2013) and CINAHL (EBSCO, inception to 1 April 2013) and last ran these on 1 May 2013. We also checked the references of included studies and reviews. We applied no language restrictions. Selection criteria: Trials fulfilled the following criteria: (1) randomised, with follow-up of at least six months, (2) the intervention was reduced dietary salt (through advice to reduce salt intake or low-sodium salt substitution), (3) participants were adults and (4) mortality or cardiovascular morbidity data were available. Two review authors independently assessed whether studies met these criteria. Data collection and analysis: A single author extracted data and assessed study validity, and a second author checked this. We contacted trial authors where possible to obtain missing information. We extracted events and calculated risk ratios (RRs) and 95% confidence intervals (CIs). MAIN RESULTS: Eight studies met the inclusion criteria: three in normotensives (n = 3518) and five in hypertensives or mixed populations of normo- and hypertensives (n = 3766). End of trial follow-up ranged from six to 36 months and the longest observational follow-up (after trial end) was 12.7 years. The risk ratios (RR) for all-cause mortality in normotensives were imprecise and showed no evidence of reduction (end of trial RR 0.67, 95% confidence interval (CI) 0.40 to 1.12, 60 deaths; longest follow-up RR 0.90, 95% CI 0.58 to 1.40, 79 deaths n = 3518) or in hypertensives (end of trial RR 1.00, 95% CI 0.86 to 1.15, 565 deaths; longest follow-up RR 0.99, 95% CI 0.87 to 1.14, 674 deaths n = 3085). There was weak evidence of benefit for cardiovascular mortality (hypertensives: end of trial RR 0.67, 95% CI 0.45 to 1.01, 106 events n = 2656) and for cardiovascular events (hypertensives: end of trial RR 0.76, 95% CI 0.57 to 1.01, 194 events, four studies, n = 3397; normotensives: at longest follow-up RR 0.71, 95% CI 0.42 to 1.20, 200 events; hypertensives: RR 0.77, 95% CI 0.57 to 1.02, 192 events; pooled analysis of six trials RR 0.77, 95% CI 0.63 to 0.95, n = 5912). These findings were driven by one trial among retirement home residents that reduced salt intake in the kitchens of the homes, thereby not requiring individual behaviour change. Advice to reduce salt showed small reductions in systolic blood pressure (mean difference (MD) -1.15 mmHg, 95% CI -2.32 to 0.02 n = 2079) and diastolic blood pressure (MD -0.80 mmHg, 95% CI -1.37 to -0.23 n = 2079) in normotensives and greater reductions in systolic blood pressure in hypertensives (MD -4.14 mmHg, 95% CI -5.84 to -2.43 n = 675), but no difference in diastolic blood pressure (MD -3.74 mmHg, 95% CI -8.41 to 0.93 n = 675). Overall many of the trials failed to report sufficient detail to assess their potential risk of bias. Health-related quality of life was assessed in one trial in normotensives, which reported significant improvements in well-being but no data were presented. AUTHORS’ CONCLUSIONS: Despite collating more event data than previous systematic reviews of randomised controlled trials, there is insufficient power to confirm clinically important effects of dietary advice and salt substitution on cardiovascular mortality in normotensive or hypertensive populations. Our estimates of the clinical benefits from advice to reduce dietary salt are imprecise, but are larger than would be predicted from the small blood pressure reductions achieved. Further well-powered studies would be needed to obtain more precise estimates. Our findings do not support individual dietary advice as a means of restricting salt intake. It is possible that alternative strategies that do not require individual behaviour change may be effective and merit further trials.

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.
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.

O B J E C T I V E S
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.

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 EM-BASE 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.

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 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 Chi 2 statistic of heterogeneity and I 2 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 (Chi 2 P ≤ 0.05 and I 2 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. multi-component dietary interventions that include salt restriction; and metaregression to assess the effects of level of salt reduction achieved, baseline blood pressure (BP) and change in BP on mortality and CV event outcomes. The study selection process is summarised in the flow diagram shown in Figure 1.  , 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 semi-monthly 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 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  • 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).

Description of studies
• 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. . 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

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.

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.

Summary of main results
This Cochrane review identified seven randomised controlled trials that assessed the long-term (> six-months) effects of interventions aimed at reducing dietary salt on mortality and cardiovascular morbidity. 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.

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 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 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.

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 demonstrat-ing 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.

A C K N O W L E D G E M E N T S
This review was supported by a UK NIHR Cochrane Collaboration Programme grant 'Cochrane Heart Public Health and Prevention Reviews' CPGS10.  Blinding (performance bias and detection bias) All outcomes

Characteristics of included studies [ordered by study ID]
Low risk "The veterans were told about the trial, but were not told to which salt they were assigned." Yes -participants. Unclear -study personnel and outcome assessors.
Incomplete outcome data (attrition bias) All outcomes High risk It appears that all subjects were followed-up for the deaths outcome. A consort diagram and reasons for losses to followup for other outcomes are given. No sensitivity analysis or imputation was carried out to assess the impact of missing data.
Selective reporting (reporting bias) Low risk All outcomes described in the methods are reported in the results. IV that was unresponsive to treatment with high doses of oral furosemide up to 250-500mg/day and/or combinations of diuretics, ACE-inhibitors, digitalis, beta-blockers and nitrates, and to be under this therapy at least 2 weeks prior to hospitalisation. Patients also had to have left ventricular ejection fraction (LVEF) <35%, serum creatinine <2mg/dl, blood urea nitrogen <=60mg/dl, a decreased urinary volume (<500ml/24h) and low natriuresis (<60mmol/24h), despite receiving established treatments. None of the patients had to take non-steroidal anti-inflammatory drugs (NSAIDS). All patients received high-dose furosemide (250-1000mg, twice a day), Hypertonic Saline Solution (HSS), a normal sodium diet (120mmol) and a decreased fluid intake (1000ml/day) during hospitalisation. When compensated state was achieved (NYHA class II), patients received oral furosemide (250-500mg, twice a day), a normal sodium diet (120mmol sodium) and a fluid intake of 1000ml/day. This continued after discharge, and patients were considered clinically compensated when they reached a change in NYHA functional class to at least class II and the accomplishment of an ideal body weight. Patients received tailored therapy after discharge. Only patients in NYHA class II at 30 days after discharge were included in the study and randomised. Exclusion: Cerebral vascular disease, dementia, cancer, uncompensated diabetes, and severe hepatic disease. Patients requiring pacemaker implantation and those with an alcoholic habit. Patients who declined to take part in the study protocol (but continued the prescribed treatment), were unable to follow the assigned treatment, did not follow the treatment protocol or attend the scheduled clinic visits, did not adhere to the fluid intake of 1000ml/day, or had a reduction or discontinuation of prescribed treatments. Also, patients experiencing side effects of ACE-inhibitor treatment, even if these patients were given angiotensin II receptor blockers.

TOHP I 1992 [18 mo] (Continued)
Exclusion: Long list of exclusion criteria, generally designed to eliminate patients with: evidence of medically diagnosed hypertension (DBP >= 90mmHg or use of BP medications within 2mths of first evaluation), cardiovascular or other life-threatening or disabling diseases, gross obesity (BMI>36.14), a contraindication to any of the phase I interventions, or might have difficulty complying with the treatment or follow-up requirements of the trial.

Intervention Total duration: 18mths
Salt reduction/advice component: Dietary and behavioural counselling on how to identify sodium in the diet, self-monitor intake, and select or prepare low sodium foods and condiments suited to personal preferences. Individual and weekly group counselling sessions were provided during the first 3mths, with additional less frequent counselling and support for the remainder of follow-up. Sessions were provided by nutritionists, psychologists, or other experienced counsellors. The objective was to reduce urinary sodium excretion in the intervention group to 80mmol/24h. Comparator Dietary: Usual diet. General guidelines for healthy eating were given.

Outcomes
All cause mortality, CV morbidity, BP and 24hr urinary sodium excretion Notes TOHP I design included allocation to other interventions (weight loss, stress management & supplements e.g.. fish oil)

Bias Authors' judgement Support for judgement
Random sequence generation (selection bias)

Unclear risk Not reported
Allocation concealment (selection bias) Low risk "the clinic notified the coordinating center [of participant eligibility] by telephone and obtained a randomisation assignment. Clinics were also provided with sealed envelopes containing randomization assignments for use when telephone contact with the coordinating center was not possible." "adherence to the appropriate assignment sequence was monitored by the coordinating center." Blinding (performance bias and detection bias) All outcomes Low risk "To minimize bias, [BP] observers were blinded to treatment allocation. Persons certified to measure BP were not involved with intervention aspects of the trial, nor were they allowed access to data that would reveal group assignment. When possible, separate facilities or entrances were used for data collection visits as compared to intervention visits." "In order to reduce observer bias, data collectors were blinded to the treatment assignment of the participants." No -participants; Yes -data collectors; Unclear -data analysts.

TOHP I 1992 [18 mo] (Continued)
Incomplete outcome data (attrition bias) All outcomes Low risk "In the analyses shown, participants with no follow-up visits [...] were assigned a zero value for BP change ("intention-to-treat" analysis). These results did not differ appreciably from those in which missing BP values were treated as missing at random and excluded from the analysis." "The effect of missing urinary sodium excretion data at followup on estimates of the absolute change from baseline was assessed by assuming no change (the baseline sodium excretion value was imputed). To reduce the likelihood that estimates of treatment group differences were influenced by the inclusion of incomplete samples, mean differences in urinary sodium excretion at 6, 12, and 18 months were recalculated excluding urine values associated with a volume less than 500g or, in separate analyses , associated with creatinine or creatinine per kilogram of body weight less than 85% of the within-person average. Mean treatment group differences with these exclusions were very similar to each other and to those calculated when all samples were included." Selective reporting (reporting bias) Low risk All outcomes described in methods are reported in results. Groups balanced at baseline? Low risk "Baseline characteristics were evenly distributed, except for age, which was higher in the sodium reduction intervention group" Intention to treat analysis? Low risk "In a sensitivity analysis using logistic regression we performed an intention to treat analysis treating non-responders as non-events Because mortality follow-up was virtually complete, we included all randomised participants in analyses of mortality alone in a full intention to treat analysis." Free from follow up bias? High risk Longest event follow up for mortality and CV morbidity was 11.5 years but last stated diet advice stated as 18 months. No urinary sodium excretion data available at longest follow up
Exclusion: Evidence of current hypertension. History of CVD, diabetes mellitus, malignancy other than nonmelanoma skin cancer during the past 5yrs, or any other serious life-threatening illness that requires regular medical treatment. Current use of prescription medications that affect BP, as well as non-prescription diuretics. Serum creatinine level >= 1.7mg/dL for men or 1.5mg/dL for women, or casual serum glucose >=200mg/ dL. Current alcohol intake >21 drinks/wk. Pregnancy, or intent to become pregnant during the study. Plans to move or inability to cooperate.

Intervention
Total duration: 36 mths Salt reduction/advice component: Individual and weekly group counselling sessions were provided initially followed by additional less intensive counselling and support for the remainder of follow-up. Mini-modules to reinforce the content of the counselling session were offered in the later years of the intervention. The content of sessions included sodium information, self-management and social support components. Sessions were provided by registered dieticians mainly, plus a few psychologists, or other experienced counsellors. The objective was to reduce urinary sodium excretion in the intervention group to 80mmol/24h. Other: The salt reduction intervention was combined with a weight loss intervention or alone.

Comparator Dietary: No advice
Other: Usual care or weight loss intervention alone.

Outcomes
All cause mortality CV morbidity (a composite of myocardial infarction, stroke, coronary revascularisation or CV death), BP, urinary excretion Notes This study had a 2x2 factorial design in which the groups were: weight loss alone, sodium reduction alone, a combination of weight loss and sodium reduction, and a usual care group. The long term effects of the sodium reduction intervention were analysed by grouping data for the two sodium reduction interventions (alone or with weight loss) and for the two non-sodium reduction groups (usual care and weight loss alone) This study had a 2x2 factorial design in which the groups were: weight loss alone, sodium reduction alone, a combination of weight loss and sodium reduction, and a usual care group. The long term effects of the sodium reduction intervention were analysed by grouping data for the two sodium reduction interventions (alone or with weight loss) and for the two non-sodium reduction groups (usual care and weight loss alone) Exclusion: Diagnosis or treatment of cancer within the last 5yrs; treatment with diuretics, ACE-inhibitors, or digitalis for CHF or unknown reason; drug therapy with nitrates, beta blockers, or calcium channel blockers for CHD or reason other than hypertension; MI or stroke within 6mths; "active" CHD (e.g. angina pectoris); CHF; atrial fibrillation; second-or third-degree heart block without permanent pacemaker; drug therapy for ventricular arrhythmias; self-report of heart valve replacement; clinically important valvular heart disease; insulin dependent diabetes mellitus; severe hypertension; current or recent (within 6mths) drug therapy for asthma or chronic obstructive lung disease; use of corticosteroid therapy for >1mth; serious mental or physical illness; unexplained or involuntary weight loss (>=4.5kg) during the previous year; BMI<21 in men or women, or >33 in men or >37 in women; serum creatinine >2mg/dL; non-fasting blood glucose level of >260mg/dL; hyperkalemia (>5.5mmol/L); anaemia (Hb level <110g/L); >14 alcoholic drinks per week (assessed by self-report); severe visual or hearing impairment; other reason making it difficult for the participant to comply fully with any part of the study protocol.

Risk of bias
Interventions Intervention Total duration: 4mth "intensive" phase, plus 3mth "extended" phase, and then a maintenance phase (duration of this phase is unclear) Salt reduction/advice component: Individual & group sessions with an interventionist (typically a registered dietician) who provided information using both centrally and locally prepared materials, motivated participants to make and sustain long-term lifestyle changes, and frequently monitored progress of groups and individuals. Individualised feedback was provided. Participants learned about sources of sodium, in particular those foods with a high salt content, and they learned about possible alternatives. They also learned how to adapt the recommendations for a low salt diet to their own lifestyle. The goal of this intervention for the group was to achieve and maintain a 24hr dietary sodium intake of 80mmol (1800mg) or less (as measured by 24hr urine collection).
Other: Attempt to withdraw hypertensive therapy began 3 months post randomisation MI or stroke within 6mths; "active" CHD (e.g. angina pectoris); CHF; atrial fibrillation; second-or third-degree heart block without permanent pacemaker; drug therapy for ventricular arrhythmias; self-report of heart valve replacement; clinically important valvular heart disease; insulin dependent diabetes mellitus; severe hypertension; current or recent (within 6mths) drug therapy for asthma or chronic obstructive lung disease; use of corticosteroid therapy for >1mth; serious mental or physical illness; unexplained or involuntary weight loss (>=4.5kg) during the previous year; BMI<21 in men or women, or >33 in men or >37 in women; serum creatinine >2mg/dL; non-fasting blood glucose level of >260mg/dL; hyperkalemia (>5.5mmol/L); anaemia (Hb level <110g/L); >14 alcoholic drinks per week (assessed by self-report); severe visual or hearing impairment; other reason making it difficult for the participant to comply fully with any part of the study protocol.
Interventions Intervention Total duration: 4mth "intensive" phase, plus 3mth "extended" phase, and then a maintenance phase (duration of this phase is unclear) Salt reduction/advice component: Individual & group sessions with an interventionist (typically a registered dietician) who provided information using both centrally and locally prepared materials, motivated participants to make and sustain long-term lifestyle changes, and frequently monitored progress of groups and individuals. Individualised feedback was provided. Participants learned about sources of sodium, in particular those foods with a high salt content, and they learned about possible alternatives. They also learned how to adapt the recommendations for a low salt diet to their own lifestyle. The goal of this intervention for the group was to achieve and maintain a 24hr dietary sodium intake of 80mmol (1800mg) or less (as measured by 24hr urine collection Incomplete outcome data (attrition bias) All outcomes

High risk
The only reason given for losses to follow-up was non-attendance at follow-up visits. No sensitivity analysis or imputation undertaken to assess impact of loss to follow-up.

Selective reporting (reporting bias) Unclear risk
The authors report that data was collected via psychological questionnaires at randomisation and a number of the follow-up visits, but none of the data from these appear to be reported, unless they

C O N T R I B U T I O N S O F A U T H O R S
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.

Internal sources
• No sources of support supplied

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
-Given the small number of trials included in this review it was not possible to undertake exploration of heterogeneity using stratified meta-analysis or meta-regression -Studies reporting death or cardiovascular outcomes were included regardless of the number of events in intervention and controls.