HTN: Vitamins (2015)


Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA. Vitamin D deficiency and supplementation and relation to cardovascular health. Am J Cardiol. 2012; 109: 359-363.

PubMed ID: 22071212
Study Design:
Retrospective Cohort Study
B - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:
To investigate the association of vitamin D deficiency and cardiovascular morbidity and mortality, as well as the effect of supplementation on survival.
Inclusion Criteria:
  • Patients followed in cardiovascular practice between January 1, 2004 and October 8, 2009
  • Serum vitamin D measurement
Exclusion Criteria:
Less than 18 years of age.
Description of Study Protocol:


Patients seen between January 1, 2004 and October 8, 2009 were identified from patient records of a cardiovascular practice.


Retrospective cohort study.

Blinding used:

Implied with measurements.

Statistical Analysis

  • Vitamin D analyzed as both a continuous variable and a dichotomous variable (30ng or more per ml or less than 30ng per ml)
  • Descriptive statistics
  • Univariate analysis (unpaired T-tests for continuous variables)
  • Chi-square analysis
  • Multivariate logistic regression analysis for odds ratios
  • Survival analysis and Cox proportional hazard modeling
  • Interaction between vitamin D deficiency and supplementation studied by development of an interaction variable for retesting the outcomes models, with confirmation using the Wald statistic and likelihood ratio and proportionality testing.
Data Collection Summary:

Timing of Measurements 

Not specified, varied for each patient

Dependent Variables

  • Survival: Interval between the date of sample collection and the date of death or the end of study period
  • Death: All-cause data obtained from the Social Security Death Index
  • Cardiovascular events:
    • Coronary artery disease
    • Atrial fibrillation
    • Diabetes mellitus
    • Cardiomyopathy
    • Hypertension.

Independent Variables

  • Vitamin D level (normal vs. deficient): 30ng or more per ml vs. less than 30ng per ml
  • Vitamin D supplementation: Active prescription for vitamin D or its analogs or patient-reported use of vitamin D supplements (not all doses reported; usual reported doses ranged from 1,000 IU per day to 50,000 IU weekly; sample mean was 2,254±316 IU; use of multivitamins not included).
Description of Actual Data Sample:
  • Initial N: 10,899 patients
  • Attrition (final N): 10,899 (71% female)
  • Age: 58.3±14.9 years.

BMI of total sample: 29.9±7.7kg/m2.
Variable Vitamin D (Normal Range) Vitamin D (Deficient) P Value
Age (years) 60±15 58±15 <0.0001
Women (%) 77 69 <0.0001
BMI (kg/m2) 28±7 31±8 <0.0001
Vitamin D (ng per ml) 40±11 17±7 <0.0001
Vitamin D supplement use (%) 34 39 <0.0001

Other significant differences between groups:

  • Coronary artery disease (11% vs. 9%)
  • Hypertension (defined as higher than 140/90mm Hg) (29% vs. 36%)
  • Diabetes mellitus (9% vs. 19%).




Summary of Results:

Key Findings

  • Risk of cardiovascular conditions:
    • Vitamin D deficiency as a dichotomous variable in univariate analysis was significantly associated with an increased risk of:
      • Coronary artery disease (OR 1.16; 95% CI: 1.012 to 1.334)
      • Diabetes (OR 2.31; 95% CI: 2.018 to 2.644
      • Hypertension (OR 1.4; 95% CI: 1.285 to 1.536)
      • All cause death (OR 2.95; 95% CI: 2.135 to 4.073).
    • Vitamin D was negatively associated with risk of atrial fibrillation (OR 0.83; 95% CI: 0.693 to 0,984).
  • All-cause death:
    • In stepwise multivariate logistic regression analysis, vitamin D deficiency was a strong independent predictor of all-cause death (OR 2.64; 95% CI: 1.901 to 3.662, P<0.0001)
    • Hazard ratio for reduced survival with vitamin D deficiency (dichotomous) (l=2.48) (P<0.0001).
  • Effect of supplementation (risk for death):
    • Vitamin D supplementation improved survival overall, but to significant degree only in deficient patients
    • Univariate analysis (risk all cause death for subjects taking vitamin D supplements): OR 0.62 (95% CI: 0.469 to 0.806, P=0.0004)
    • Stepwise regression analysis for death (OR for vitamin D supplementation): OR 0.44, P<0.0001
    • Hazard ratio for death for those taking supplements: 0.40 (95% CI: 0.335 to 0.576), P<0.0001
    • OR for death in vitamin D-deficient subjects with supplementation: 1.47; 95% CI: 0.760 to 2.799, NS
    • OR for death in vitamin D-deficient subjects without supplementation: 3.07, 95% CI: 2.222 to 4.228, P<0.0001.
Author Conclusion:
Vitamin D deficiency was associated with a significant risk of cardiovascular disease and reduced survival. Vitamin D supplementation was significantly associated with better survival, specifically in patients with documented deficiency.
Funding Source:
University/Hospital: University of Kansas Medical Center and Hospital
Reviewer Comments:
Significant differences between groups in terms of age, sex, BMI and presence of coronary artery disease, hypertension and diabetes mellitus. Possible selection bias. Isolated vitamin D measurement might not reflect long-term levels. Dose and duration of vitamin D supplementation are not known for all subjects. Inclusion of vitamin D in multivitamins was not considered.
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
  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
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? No
  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? ???
  2.2. Were criteria applied equally to all study groups? 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? ???
3. Were study groups comparable? No
  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? No
  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? No
  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
4. Was method of handling withdrawals described? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  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%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? N/A
  4.4. Were reasons for withdrawals similar across groups? 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? Yes
  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.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? Yes
  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
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? ???
  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
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? ???
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? No
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) 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
  6.8. 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
  7.1. 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
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? ???
  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
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  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
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? ???
  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)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  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
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes