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NA: Sodium or Sodium Chloride (2010)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To evaluate salt sensitivity in elderly subjects with different forms of hypertension and in control subjects and to investigate any modulation by genotype.

Inclusion Criteria:
  • Community-dwelling subjects, age 60 years and older
  • Untreated at least six weeks before study entry and throughout trial.
Exclusion Criteria:
  • Systolic blood pressure (SBP) 220mmHg or more
  • Diastolic blood pressure (DBP) 120mmHg or more
  • Secondary forms of hypertension
  • Significant medical disorders including
    • Dementia (score less than 25 on the Folstein mini-mental state examination)
    • History of stroke in the preceding one year
    • Substantial abnormalities on any of the screening tests, including renal disease beyond that expected for age
    • Requiring blood pressure-altering medication for cardiac disease or on echocardiography
    • Valvular abnormalities
    • Atrial or ventricular dysfunction.
Description of Study Protocol:

Recruitment

  • Subjects were recruited by advertisements in local and regional newspapers
  • Subjects were then screened for study inclusion and exclusion criteria.

Design

  • Screening procedures included:
    • Clinical assessment
    • Chest X-ray
    • 12-lead electrocardiograph
    • Transthoracic 2-D echocardiogram
    • Full blood count
    • Serum electrolytes
    • Urea
    • Creatinine
    • Blood glucose concentration
    • Liver function tests
    • Creatinine clearance
    • 24-hour urinary protein determination.
  • This study was designed as a randomized, double-blinded, placebo-controlled, Latin square clinical investigation
  • Based on mean initial BP measurement, subjects were stratified into three groups:
    • Those with isolated systolic hypertension (ISH) (SBP more than 160mmHg and DBP less than 90mmHg)
    • Those with diastolic+systolic hypertension (DBP more than 90mmHg irrespective of the SBP)
    • Those with normal BP (SBP less than 160mmHg and DBP less than 90mmHg).
  • All subjects were stabilized on a 140mmol per day sodium diet more than six weeks before the time of diagnosis with the assistance of intensive, individualized dietitian support and 24-hour urinary sodium monitoring
  • Following diagnostic classification, all subjects were started on a 40mmol per day sodium diet, derived from a standardized diet with the randomized sodium treatment in the form of slow-release sodium tablets (Novartis, Sydney, Australia)
  • This low-sodium diet was maintained throughout the study (including washout phases)
    • Compliance evaluated (subjectively) by interview
    • Compliance measured (objectively) by serial measurements of 24-hour urinary sodium and creatinine with appropriate dietitian review and advice where necessary
    • Numerous low-sodium food products provided.
  • After baseline measurements, subjects were administered, in random order, each of the  four treatments: 50mmol per day, 100mmol per day, 200mmol per day, 300mmol per day sodium chloride
  • Treatments were sequenced into four subject groups: ADBC, BACD, CBDA, DCAB
    • A=50mmol per day
    • B=100mmol per day
    • C=200mmol per day
    • D=300mmol per day.
  • Each treatment lasted for two weeks with two-week washout periods
  • Blood pressure medication was withdrawn in most (N=26) of the ISH and diastolic+systolic hypertension groups, but none of the normal BP group
  • All measurements were obtained at baseline and toward the completion of each treatment and washout out phase
    • Ambulatory BP (24-hour) and pulse rate were measured by Takeda TM-2420 ambulatory monitor (A&B Mercury, Adelaide, Australia)
    • Body weight was recorded at each visit and renal function (creatinine clearance), serum and 24-hour urinary sodium and potassium were determined by the Hitashi 747 auto-analyser (Roche Diagnostics, Sydney, Australia).
  • DNA was extracted from fresh blood (using standard techniques) to determine the M235T allelic variants of the angiotensinogen gene and the I/D allelic variants of the angiotensin converting enzyme (ACE) gene.

Blinding Used 

The same number of total tablets was administered to each individual, each day, comprising variable number of sodium chloride tablets and the remainder placebo tablets.

Intervention 

  • 14-day treatments
  • 50mmol per day, 100mmol per day, 200mmol per day and 300mmol per day of sodium chloride supplementation interspersed with 14-day washout periods on a salt-restricted diet.

Statistical Analysis

  • Standard deviations
  • Analysis of variance
  • Natural logarithmic scale
  • All analyses were based on intention-to-treat
  • Statistical significance was defined as P<0.05.
Data Collection Summary:

Timing of Measurements

  • All measurements were obtained at baseline and near the completion of each treatment and washout out phase
  • Body weight was recorded at each visit and renal function (creatinine clearance), serum and 24-hour urinary sodium and potassium were determined by the Hitashi 747 auto-analyser (Roche Diagnostics, Sydney, Australia).

Dependent Variables

  • SBP
  • DBP
  • 24-hour BP
  • Heart rate
  • Weight
  • Urinary sodium
  • Urinary potassium
  • Plasma potassium
  • Plasma sodium
  • Creatinine clearance 
  • Angiotensinogen (AGT)
  • ACE.

Independent Variables

Sodium chloride intake: 50mmol per day, 100mmol per day, 200mmol per day, 300mmol per day.

Description of Actual Data Sample:
  • Initial N: 46 (sex was not discussed in this study)
  • Attrition (final N): 40
    • Five withdrew from the study due to unforeseen social circumstances during the six-month commitment
    • One suffered an acute myocardial infarction (considered by the Research Ethics Committee to be unrelated to the study).
  • Age: 68.8±0.8 years (mean with standard error)
  • Ethnicity: Not specified
  • Location: Australia.
Summary of Results:

 Classification from baseline BP

  • ISH, N=15
    • Diastolic + systolic hypertension, N=8
    • Normotensive, N=17
    • Subjects with diastolic+systolic hypertension were significantly younger (P=0.004) than those with ISH and normal controls
    • There were no significant differences between groups in terms of heart rate, urinary potassium or plasma and urinary sodium.
  • By the mixed effect analysis of variance, there were no significant carryover effects detected for SBP or DBP
    • BP reverted to baseline levels during washout periods
    • A carryover effect was detected for heart rate (P=0.05), characterized by subjects in the sequence group. DCAB had the largest decrease in heart rate (-4.4±1.1 beats per minute) compared to patients in other sequences.
  • In the entire cohort, a significantly linear increase in SBP was associated with increased dose of sodium chloride
    • Change in DBP was also significantly associated with increasing dose of sodium chloride supplementation (although less than SBP)
    • Change in pulse increased with increasing sodium chloride.
  • Heart rate slowed significantly with increasing salt dose with 200mmol per day sodium chloride supplementation (P<0.01) and on 300mmol per day sodium chloride supplementation (P<0.01)
    • Varying the dose of salt did not significantly alter the following:
      • Body weight
      • Serum potassium
      • 24-hour urinary potassium
      • Creatinine clearance.
  • Analysis by patient group revealed that SBP increased significantly with increasing salt dose across all three groups. Most marked increment was in the ISH group, followed by diastolic + systolic hypertension group and then the normotensive group.
    • The increase in DBP among high salt dose was also higher in ISH patients compared with other groups
    • As expected urinary sodium increased proportionately with the salt dose in all three groups
    • There were no significant differences in other biochemical parameters between the groups.
  • After adjustment for potential cofounders, 24-hour urinary sodium was the major determinant of the observed increment in SBP with the increasing sodium dose accounting for 40% of the variability in the data 
    • Sodium-to-potassium ratio was not a significant predictor of change in BP
    • The rate of change in SBP/DBP (weighted by the inverse of the variance) was determined for the ISH group vs. the remaining two BP groups combined with the difference between the ISH group and the non-ISH group statistically significant for both SBP and DBP (P<0.05).
  • For the ACE gene, the relative frequency of allele D was 0.52±0.08. For the AGT gene, the relative frequency of eM was 0.61±0.08.
    • The distribution of ACE and AGT genotypes were consistent with the Hardy-Weinberg equilibrium law
    • There was no significant association between ACE genotype and the rate of salt related change in SBP or in DBP 
    • There was a significant association between AGT genotype and salt related change in DBP (P=0.006), but not SBP.
Author Conclusion:

In healthy older subjects, a linear increase in BP occurred with increasing salt dosage. It seemed most pronounced in subjects with ISH and could be modulated by AGT genotype.

Funding Source:
Government: The National Health and Medical Research Council of Australia
In-Kind support reported by Industry: Yes
Reviewer Comments:
  • Relatively small sample size (N=46)
  • Sex of subjects was not revealed or included in any way.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
  1. Was the research question clearly stated? Yes
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? No
  1.3. Were the target population and setting specified? No
  2. Was the selection of study subjects/patients free from bias? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
  3. Were study groups comparable? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? Yes
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? Yes
  4. Was method of handling withdrawals described? Yes
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
  5. Was blinding used to prevent introduction of bias? No
5. Was blinding used to prevent introduction of bias? No
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? ???
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? ???
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) ???
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) ???
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? Yes
  5.5. In diagnostic study, were test results blinded to patient history and other test results? Yes
  6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
  7. Were outcomes clearly defined and the measurements valid and reliable? Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? N/A
  7.6. Were other factors accounted for (measured) that could affect outcomes? N/A
  7.7. Were the measurements conducted consistently across groups? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
  8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
  9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  10. Is bias due to study's funding or sponsorship unlikely? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes
  10.2. Was the study free from apparent conflict of interest? Yes