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HESI: Congestive Heart Failure Population (2014)

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

To determine the association between estimated urinary sodium and potassium excretion (as measures of intake) and cardiovascular (CV) events in patients with established CV disease or diabetes mellitus.

Inclusion Criteria:
  • Participants in ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and the TRANSCEND (Telmisartan Randomized Assessment study in ACE intolerant subjects with CV disease) trial who provided a baseline urinary sample
  • Patients at high risk of CV disease (aged at least 55 years, with established CV disease or high risk of diabetes mellitus).
Exclusion Criteria:
  • Heart failure
  • Low ejection fraction
  • Significant valvular disease
  • Serum creatinine greater than 3.0mg per dL
  • Renal artery stenosis
  • Nephrotic range proteinuria
  • Blood pressure higher than 160/100mmHg.
Description of Study Protocol:

Recruitment

  • Participants were recruited from 733 centers in 40 countries
  • Both studies recruited patients from the same sites and at the same time period.

Design
Prospective cohort.

Statistical Analysis

  • Baseline characteristics between different sodium and potassium excretion categories were compared using X2 test and analysis of variance (ANOVA)
  • A restricted cubic spline function with four knots (located at the fifth, 35th, 65th and 95th percentiles) was used to describe the association between sodium and potassium excretion and CV events and mortality and to identify reference categories for sodium and potassium
  • Group median was chosen to be the reference group for all spline plots (4.66g per day for sodium)
  • 4.0g to 5.99g per day of sodium excretion was selected as the reference category because this was the range associated with the lowest risk of all CV events
  • Risk of CV events associated with estimated 24-hour urinary sodium excretion was estimated using Cox proportional hazards models for each of these outcomes: Composite outcome (CV mortality, MI, stroke and hospitalization for CHF), CV mortality, non-CV mortality, MI, stroke and hospitalization for CHF
  • All models were adjusted for variables known to increase or reduce the risk of CV events: Age, sex, race or ethnicity, prior stroke or MI, creatinine, BMI, hypertension, diabetes mellitus, atrial fibrillation, smoking, LDL-cholesterol, HDL-cholesterol, treatment allocation and treatment with statins, beta-blockers, diuretics, calcium antagonist and antithrombotic therapy, fruit and vegetable consumption, level of exercise, urinary sodium and potassium excretion, baseline blood pressure and change in systolic blood pressure from baseline to last follow-up
  • To explore the potential for reverse causation, analysis that excluded all events during the first year of follow-up and analyses that excluded patients with previous history of cancer during follow-up were performed
  • To explore the effect of regression dilution bias, a secondary analysis using "usual" excretion of sodium was used. To calculate the "usual" excretion, the method described by Lewington et al, using regression dilution ratio was applied.
  • The assumptions of proportional hazard of sodium were assessed by fitting a model of primary outcome with interaction terms between the survival time and sodium (P=0.95)
  • A two-tailed P-value of less than 0.05 was considered statistically significant
  • All analyses used SAS version 8.2 for UNIX.
Data Collection Summary:

Timing of Measurements

  • Both trials had 56 months of follow-up from November 2001 to March 2008
  • Urine sample was obtained before the run-in period of the trial.

Dependent Variables

  • CV mortality
  • Myocardial infarction (MI)
  • Stroke
  • Hospitalization for CHF.

Independent Variables

Sodium and potassium excretion as measure of intake.

Control Variables

  • Age
  • Sex
  • Race or ethnicity
  • Prior stroke or MI
  • Creatinine
  • BMI
  • Hypertension
  • Diabetes mellitus
  • Atrial fibrillation
  • Smoking
  • LDL- and HDL-cholesterol
  • Treatment allocation and treatment with statins, beta-blockers, diuretics, calcium antagonist and anti-thrombotic therapy
  • Fruit and vegetable consumption
  • Level of exercise
  • Urinary sodium and potassium excretion
  • Baseline blood pressure
  • Change in systolic blood pressure from baseline to follow-up.
Description of Actual Data Sample:
  • Initial N: 31,546
  • Attrition (final N): 28,880 (20,276 male, 8,504 female). These were the only participants who provided a baseline morning fasting urine sample.
  • Age: 66.52±7.22 years
  • Ethnicity: 20,628 Europeans (71.4%).

Other Relevant Demographics

  • Most of the participants were white (71.4%)
  • Medications used by the participants were beta-blocker (approximately 56%), diuretic (26% to 43%), calcium antagonist (32% to 51%), ramipril (27%), telmisartan (37%) and ramipril plus telmisartan (27%)
  • Previous medical history of myocardial infarction (45% to 48%), stroke/TIA (around 23%), hypertension (68% to 82%), diabetes mellitus (32% to 52%).

Anthropometrics
BMI was at 30 for the participants in the sodium excretion range of more than eight grams per day. However, overall BMI was 28.

Location
40 different countries.

Summary of Results:

Key Findings

  • Compared with baseline sodium excretion of 4.0g to 5.99g per day, higher and lower baselines of sodium excretion were associated with an increased risk of hospitalization for CHF [6.5% for over eight grams per day (HR, 1.51; 95% CI, 1.12 to 2.05); 5.2% for two grams to 2.99g/day (HR, 1.23; 95% CI, 1.01 to 1.49)]
  • Compared with baseline excretion of 4.0g to 5.99g per day, higher sodium excretion was also associated with an increased risk of CV death [9.7% for 7.0g to 8.0g per day (HR, 1.53; 95% CI,1.26 to 1.86); 11.2% for over eight grams per day (HR,1.66; 95% CI, 1.31 to 2.10)], MI [6.8% for over eight grams per day (HR, 1.48; 95% CI, 1.11 to 1.98)] and stroke [6.6% for over eight grams per day (HR, 1.48; 95% CI, 1.09, 2.01)]
  • Compared with baseline excretion of 4.0g to 5.99g per day, lower sodium excretion was also associated with an increased risk of CV death [8.6% for 2.0g to 2.99g per day (HR, 1.19; 95% CI, 1.02 to 1.39); 10.6% for less than two grams per day (HR, 1.37; 95% CI, 1.09 to 1.73)].

Other Findings

The composite outcome occurred in 16.4% (4,729) of the participants, including 2,057 CV deaths, 1,412 with MI, 1,282 with stroke and 1,213 with hospitalization for CHF.
Author Conclusion:
  • The association between estimated sodium excretion and CV events was J-shaped
  • Compared with baseline sodium excretion of 4.0g to 5.99g per day, sodium excretion of greater than seven grams per day was associated with an increased risk of all CV events and a sodium excretion of less than three grams per day was associated with increased risk of CV mortality and hospitalization for CHF
  • Higher estimated potassium excretion was associated with a reduced risk of stroke.
Funding Source:
Industry:
Boehringe-Ingelheim
Pharmaceutical/Dietary Supplement Company:
Reviewer Comments:

Some of the limitations and strengths reported by the authors:

  • Estimation of sodium and potassium excretion may be considered both a limitation and strength due to the single urine measurement. However, this method provides a more accurate measure of sodium intake at a population level.
  • This cohort included participants with established CV disease recruited into an RCT. For the most part, patients who participated in an RCT may have different lifestyle behaviors from those who declined participation. In addition, the population studied is at higher risk of CV events than the primary prevention cohort and may be more vulnerable to the extremes of sodium intake. Therefore, these results may not apply to a lower-risk population.
  • The main strengths included the very large number of patients and outcomes, the international representation of the cohort, high completeness of data, use of a central laboratory for urinary electrolyte measurement and the availability of detailed covariates to adjust for a broad range of potential confounders.

Some points to make:

  • None of the observational studies were designed to address the relationship between daily sodium intake and CVD risk and few had 24-hour urine collection
  • Estimation of 24-hour urinary sodium excretion using a single urine sample may be very risky
  • The majority of participants included in the two cohorts was white European, which might not represent other populations
  • Interpretation of the results should be viewed carefully due to the health benefits from a low sodium-diet consumption supported by evidence-based science.
What was the baseline nutrient status (i.e., sodium)? For example the baseline sodium status can be used as an inclusion criterion for entry into study, and recorded in the report of the trial. CV patients: 4.77g
What was the target of sodium intake in the intervention and comparison groups? N/A
Was the difference in sodium status (i.e., change in urinary sodium excretion) measured between groups? If so, please specify. N/A
Was the status of other nutrient (e.g., potassium and calcium) measured in order to ensure that the test nutrient (i.e., sodium) is the only nutrition-related, limiting factor in the response? If yes, please specify. CV patients (baseline): 2.19g
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
  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
  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
  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
  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. 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
  1.1. 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
  1.2. 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? Yes
  1.3. Were the target population and setting specified? Yes
  1.3. Were the target population and setting specified? Yes
  1.3. Were the target population and setting specified? Yes
  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. 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
  2.1. 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
  2.2. 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
  2.3. 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? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  3. Were study groups comparable? Yes
  3. Were study groups comparable? Yes
  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) N/A
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  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
  3.4. 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
  3.5. 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")? N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
  4. Was method of handling withdrawals described? Yes
  4. Was method of handling withdrawals described? 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
  4.1. 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%.) No
  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%.) No
  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%.) No
  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%.) No
  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
  4.3. 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
  4.4. 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? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
  5. Was blinding used to prevent introduction of bias? ???
  5. Was blinding used to prevent introduction of bias? ???
  5. Was blinding used to prevent introduction of bias? ???
5. Was blinding used to prevent introduction of bias? ???
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  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.) N/A
  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.) N/A
  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.) N/A
  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.) N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? ???
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? ???
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? ???
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? ???
  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
  5.4. 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? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
  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. 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? N/A
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  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
  6.3. 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
  6.4. 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
  6.5. 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? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  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
  6.7. 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
  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. 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
  7.1. 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
  7.2. 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
  7.3. 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? ???
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? ???
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? ???
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? ???
  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
  7.5. 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? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? N/A
  7.7. Were the measurements conducted consistently across groups? N/A
  7.7. Were the measurements conducted consistently across groups? N/A
  7.7. Were the measurements conducted consistently across groups? N/A
  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. 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
  8.1. 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
  8.2. 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
  8.3. 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
  8.4. 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
  8.5. 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
  8.6. 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
  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. 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
  9.1. 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
  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. 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
  10.1. 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
  10.2. Was the study free from apparent conflict of interest? Yes
  10.2. Was the study free from apparent conflict of interest? Yes