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The effect of vitamin D supplementation on the progression of carotid intima-media thickness and arterial stiffness in elderly African American women: Results of a randomized placebo-controlled trial
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The effect of vitamin D supplementation on the progression of carotid intima-media thickness and arterial stiffness in elderly African American women: Results of a randomized placebo-controlled trial
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Content
The Effect of Vitamin D Supplementation on the Progression of Carotid Intima-Media
Thickness and Arterial Stiffness in Elderly African American Women: Results of a
Randomized Placebo-Controlled Trial
by
Melissa Koc
A thesis submitted in conformity with the requirements for the degree of
Master of Science in Biostatistics
in the Keck School of Medicine at the University of Southern California
December 2018
i
ACKNOWLEDGEMENTS
I would like to express my deepest gratitude to all who supported me in the completion of my
graduate degree and this thesis.
First, I am eternally grateful for the guidance, support, and infinite patience of my advisor
Professor Wendy Mack. I feel incredibly fortunate to have studied under her guidance and for all
the opportunities, both academic and professional, she has given me. My journey into biostatistics
would not have been possible without her.
I want to thank the other members of my thesis committee, Professor Howard Hodis and Professor
Roksana Karim, for sharing with me their time and knowledge and for providing me with valuable
feedback. Thank you to all members of my committee for allowing me to take a small part in the
breadth of research you do, all of which has been an invaluable learning experience.
I would like to convey my appreciation to Professor Roberta Mckean-Cowdin for her career
development seminar series on How to Write a Manuscript, which helped me restructure my
jumbled draft into an organized thesis.
I would also like to thank my family for their endless encouragement and support. To my best
friend and now husband, thank you for staying up with me until the early hours of the morning
pretending to work so I did not feel alone and for caring for my mental and physical wellbeing
when I neglected to do so.
Finally, thank you to USC for providing the foundation for my educational growth and for being
my forever Hogwarts.
ii
TABLE OF CONTENTS
ACKNOWLEDGEMENTS ............................................................................................................. i
1. INTRODUCTION ...................................................................................................................... 1
1.1 Motivation ............................................................................................................................. 1
1.2 Background ........................................................................................................................... 1
1.2.1 Atherosclerosis: Significance, Measurement, and Relation to Vitamin D ..................... 1
1.2.2 CVD Risk: Racial Disparities and the Potential Role of Vitamin D .............................. 3
1.3 Research Objectives .............................................................................................................. 4
2. METHODS ................................................................................................................................. 5
2.1 Study Design ......................................................................................................................... 5
2.1.1 The Parent Trial .............................................................................................................. 5
2.1.2 The Ancillary Study........................................................................................................ 6
2.2 Study Endpoints .................................................................................................................... 7
2.2.1 Primary endpoint and hypothesis ................................................................................... 7
2.2.2 Secondary endpoint and hypothesis ............................................................................... 7
2.3 Statistical Analyses ............................................................................................................... 8
3. RESULTS ................................................................................................................................. 12
3.1 Baseline Characteristics ...................................................................................................... 12
3.2 Progression of CIMT ........................................................................................................... 14
3.3 Progression of Arterial Stiffness ......................................................................................... 16
iii
3.4 Subgroup Analyses .............................................................................................................. 20
4. DISCUSSION ........................................................................................................................... 21
SUPPLEMENTARY MATERIAL ............................................................................................... 24
REFERENCES ............................................................................................................................. 26
1
1. INTRODUCTION
1.1 Motivation
Cardiovascular disease (CVD) remains the leading cause of death both globally and in the United
States (US), claiming more than 17.3 million lives per year globally, nearly 801,000 lives in the
US, and accounting for nearly one-third of all deaths both globally and nationally.
1
Although
people of all ages and backgrounds are affected by CVD, certain minority groups are faced with a
greater burden than others. African Americans have poorer cardiovascular health than whites in
the US, with notable differences in the prevalence of cardiovascular risk factors and subsequently
CVD-specific mortality. According to the National Health and Nutrition Examination Survey
(NHANES) data from 2011 to 2014, the prevalence of CVD in persons ≥20 years of age was
highest among non-Hispanic (NH) black females (47.7%) compared to any other reported
gender/race group (NH black males 46%; NH white males 37.7%; NH white females 35.1%;
Hispanic males 31.3%; Hispanic females 33.3%; NH Asian males 31.0%; and NH Asian females
27.0%). Despite advances in disease management and overall reductions in both the incidence of
and mortality from CVD over recent decades, the prevalence of cardiovascular risk factors
continues to be the highest among NH black females, highlighting the public health need to identify
factors contributing to the disparity and to further develop tailored management alternatives.
1,2
1.2 Background
1.2.1 Atherosclerosis: Significance, Measurement, and Relation to Vitamin D
Atherosclerosis is the underlying disease process for the majority of CVD events. It is a slowly
progressive, systemic process by which the inner layers of large and small artery walls thicken
due to the buildup of fatty deposits, inflammation, cells, and scar tissue.
This plaque buildup
2
can develop in arteries supplying a variety of organs including the heart.
2
Measurement of the
carotid artery intima-media thickness (CIMT) has become a widely used determinant of
subclinical atherosclerosis due to superficial access of the carotid artery and its relatively
stationary qualities.
3
Advances in noninvasive measures of atherosclerosis in recent decades have afforded
researchers low-risk and reliable tools for identifying and monitoring subclinical
atherosclerotic disease development and progression.
4
In particular, high-resolution B-mode
ultrasonography of CIMT has gained popularity as an efficient, low-risk, and low-cost method
of atherosclerosis detection and quantitation.
5,6
Higher CIMT measured at a single timepoint
and longitudinally-measured CIMT progression have been shown to be associated with both a
higher risk of CVD independent of cardiovascular risk factors,
7-14
and a higher prevalence of
CVD risk factors
15,16
in a number of previous studies.
Although the mechanisms contributing to atherogenesis are multifactorial and still somewhat
obscure, vitamin D insufficiency is a biologically plausible mechanism heavily supported by
literature in recent decades. In addition to the direct involvement of vitamin D with several
pathophysiologic processes related to atherosclerosis, such as the renin-angiotensin
system,
17,18
endothelial function,
17,19
parathyroid hormone (PTH) secretion,
17,20
augmenting
insulin secretion and sensitivity,
20
and inflammation,
17,21
an array of studies have linked
suboptimal levels of vitamin D with CVD events
22-25
and with multiple other established risk
factors, including age,
26,27
obesity,
28,29
and hypertension.
30,31
Many of these risk factors are also
of particular importance to the target population of the present analysis.
3
1.2.2 CVD Risk: Racial Disparities and the Potential Role of Vitamin D
Racial disparities in CVD rates observed in the US are likely a fusion of biological, genetic,
environmental, and socioeconomic factors. As mentioned above, a growing body of evidence
supports an association between insufficient levels of vitamin D and increased risk of
atherosclerotic CVD risk factors, events, and mortality. The strong inverse association between
vitamin D and risk of CVD and the higher rate of vitamin D insufficiency observed
predominantly in African Americans make vitamin D a likely biological contributor to the
observed race-related disparity observed in NH black women.
Insufficient levels of vitamin D are commonly defined as serum 25-hydroxyvitamin D
[25(OH)D] values below 75 nmol/L.
20
Previous studies have shown that African Americans
have a higher prevalence of vitamin D insufficiency and lower levels of 25(OH)D compared
to any other ethnic group, regardless of age or seasonal variations.
32,33
This is hypothesized to
be largely due to the dependence of vitamin D3 synthesis on the concentration of melanin in
the skin. Higher melanin concentrations in darker skin tones absorb more ultraviolet-B (UVB)
than lighter skin tones, thereby competing with 7-dehydrocholesterol for photons and thus
reducing the efficiency of conversion of previtamin D3 to vitamin D3 catalyzed from sun
exposure.
34
In addition to differences in the direct cutaneous photosynthesis of vitamin D3, African
Americans also suffer a greater burden of several cardiovascular risk factors. According to the
American Heart Association, the prevalence of hypertension in blacks in the US is among the
highest in the world, with the greatest burden estimated for NH black females (2010 to 2014
4
age-adjusted prevalence = 46.3%). Moreover, compared to males, the percentage of females
with hypertension is estimated to be higher for those ≥ 65 years of age regardless of
race/ethnicity. Among females, the prevalence of both obesity and class III obesity (BMI ≥40
kg/m
2
) is greatest among NH blacks and significantly greater than NH males when compared
by sex. The prevalence of CVD in adults increases with age and in particular, the prevalence
of total CVD events in women bypasses that of men among adults after 80 years of age.
2
Given
the association of vitamin D insufficiency with traditional CVD risk factors that
disproportionately burden African American women and the aging US population, an
investigation as to whether vitamin D supplementation influences progression of
atherosclerosis is strongly warranted in this high-risk population.
In the “Vitamin D and Osteoporosis Prevention in Elderly African American Women” trial,
the investigators proposed to investigate whether dietary supplementation with calcium and
vitamin D sufficient to maintain serum 25(OH)D at an optimum level above 75 nmol/L safely
reduced bone loss and bone turnover and improved physical performance in elderly African
American women under randomized, controlled, clinical trial conditions. With the support of
noninvasive vascular imaging techniques added to the study procedures, this thesis seeks to
investigate the effect of raising serum 25(OH)D on progression of CIMT as a clinical marker
of atherosclerosis in this particularly relevant and at-risk population.
1.3 Research Objectives
The objective of this ancillary study is to determine whether vitamin D3 supplementation reduces
subclinical atherosclerosis in this cohort of elderly African American women under randomized
5
clinical trial (RCT) conditions, with the ultimate goal of developing simple, cost-effective, and
safe strategies for atherosclerosis intervention and improving cardiovascular health in this unique
and understudied population of women.
2. METHODS
2.1 Study Design
2.1.1 The Parent Trial
The parent trial, titled “Vitamin D and Osteoporosis Prevention in Elderly African American
Women”, hereafter referred to as the Vitamin D Trial, was a randomized, double blinded,
placebo-controlled, single-center clinical trial of 4 years duration to investigate the effect of
vitamin D supplementation in elderly African American women who were vitamin D deficient.
Ambulatory women who were 65 years of age or older and self-declared as African American
were recruited for the trial. Key eligibility criteria included serum 25(OH)D levels between 20
and 65 nmol/L at both screening and baseline visits, last menstrual period occurring over 5
years prior to screening, and general overall good health, adequate cognitive function, and no
concurrent use of medications that would otherwise interfere with the validity of the study
outcomes. Consenting women meeting all eligibility criteria were randomized to receive
identical capsules of vitamin D3 or placebo in a 1:1 allocation ratio. Calcium supplementation
was also provided to both groups in order to allow for comparison of optimal vitamin D status
in calcium-sufficient patients. Randomized participants returned for follow-up visits every 3
months, which included dietary, medical, physical performance, and bone density assessments,
for a total of 4 years. The initial dose of study medication was based on serum 25(OH)D as
follows: 20-25 nmol/L 25(OH)D: 120 µg vitamin D3 daily; >25-50 nmol/L: 90 µg vitamin D3
6
daily; >50-65 nmol/L: 60 µg vitamin D3 daily. At every visit, the dose was adjusted to the
nearest 30 µg to maintain serum 25(OH)D between 75 and 172 nmol/L. Dose assignments
were made in real time by the unblinded research pharmacist and the blind was maintained by
randomly adjusting the placebo doses to match the distribution of changes in the active patients
who were at the same point in the study. All study pills were in the form of a capsule and
looked identical to maintain the study blind.
The primary aims of this trial were to determine whether vitamin D3 supplementation sufficient
to raise serum 25(OH)D levels above 75 nmol/L for 4 years: 1) reduces bone density loss,
markers of bone turnover, and serum PTH in elderly black women; and, 2) inhibits the decline
in physical performance with aging. The secondary aim of this trial was to evaluate the harms
of vitamin D3 supplementation that raises 25(OH)D levels above 75 nmol/L for 4 years in a
calcium-sufficient population. The study was conducted at New York University (NYU)
Winthrop Hospital and completed in 2016. The target sample size for this study was 250
women; a total of 260 patients were randomized (130 per treatment group). Randomization
was stratified to assure an equal distribution by age (above and below 75 years) in each
treatment group.
2.1.2 The Ancillary Study
To investigate whether vitamin D3 supplementation influences the progression of
atherosclerosis in this cohort of elderly African American women, carotid artery ultrasound
measurements were added to the study procedures at the start of the parent trial. Carotid
ultrasound examinations were performed at baseline and every 6 months on-trial for a total of
7
4 years, each of which were accompanied by a total of 5 standardized blood pressure
measurements. The study investigators utilized high-resolution B-mode ultrasound to directly
visualize superficial vessels and to measure CIMT. All investigators and participants were
blinded to randomization group throughout the study, with the exception of the pharmacist and
the statistician. Both the parent trial and the ancillary study were approved by the University
of Southern California institutional review board and consent for conducting the carotid artery
ultrasound examinations was incorporated into the written informed consent.
2.2 Study Endpoints
2.2.1 Primary endpoint and hypothesis
The primary subclinical atherosclerosis endpoint for this study was the rate of change in the
right distal common carotid artery (CCA) far wall intima-media thickness. The investigators
hypothesized that vitamin D3 supplementation will reduce the rate of progression of subclinical
atherosclerosis as measured by CIMT in this population of elderly African American women.
2.2.2 Secondary endpoint and hypothesis
The secondary subclinical atherosclerosis endpoint for this study was the rate of change in
carotid artery stiffness determined from serial common carotid artery (CCA) lumen measures.
Arterial stiffness was determined from 3 indices: distensibility, Peterson’s elastic modulus, and
compliance, where lower distensibility, higher elastic modulus, and lower compliance indicate
greater arterial stiffness. The investigators hypothesized that vitamin D3 supplementation will
8
reduce the rate of progression of subclinical atherosclerosis as measured by these 3 measures
of stiffness in this population of elderly African American women.
2.3 Statistical Analyses
To assess baseline comparability of treatment groups, demographics, risk factors (blood pressure),
and relevant laboratory values were compared between treatment groups for all participants in our
analytical sample. Continuous variables were compared by an independent Student’s t-test and
expressed as mean ± standard deviation (SD), while categorical variables were compared by the
chi-square test and expressed as the proportion within each treatment group. The normal
distribution of each continuous variable was assessed both graphically and by the Shapiro-Wilk
test. Non-normal variables were normalized by log-transformation.
For the primary outcome, average values for each duplicate CIMT measurement were calculated
at each timepoint. Intrareader reliability was assessed by calculating the intraclass correlation
coefficient (ICC) via covariance parameters from mixed effects models. For the secondary
outcome, the three indices of arterial stiffness were calculated as follows:
1) Arterial distensibility =
s d/ d
x [10
6
/133.3] (10
-5
x N x m
-2
)
2) Peterson’s elastic modulus = Ep =
s d/ d
kilopascals (kPA)
3) Arterial compliance =
s
d
arbitrary compliance units (ACU)
Where Ds is the measurement of the right CCA lumen diameter at systole; Dd is the measurement
of the right CCA lumen diameter at diastole; and pulse pressure (PP) is determined by subtracting
9
systole (Ps) – diastole (Pd) pressures as determined by automated oscillometric methods at the end
of each ultrasound examination.
5
For consistency, Ds and Dd used to calculate the 3 separate
measures of arterial stiffness were determined at the same site as CIMT measurements using B-
mode ultrasound.
Baseline levels of CIMT and the 3 arterial stiffness outcomes were first compared between
treatment groups by the methods described above. All post-randomization atherosclerotic
outcomes were analyzed by linear mixed effects models for longitudinal data. Key assumptions of
the model, including (1) normality of the outcome, (2) homogeneity of the variances between
treatment groups, (3) linearity of the outcomes against time on-trial, and (4) normality and
independence of the model residuals were verified. Treatment group (indicator variable), years
since baseline ultrasound examination (continuous variable), and their interaction were included
as fixed effects. To allow for individual women to deviate from their treatment group means for
both baseline and rate of change of the outcome measures, a random intercept-slope model was
specified. Several covariance structures were tested; an unstructured covariance structure was
selected based on the Akaike Information Criterion (AIC), where a smaller AIC was considered to
be indicative of a better model with more predictive value. The overall equation describing the
crude linear mixed model can be represented as:
Yij = β0 + β1 yearsij + β2 groupi + β3 yearsij x groupi + b0i + b1i yearsij + eij
Fixed Random
where Y represents CIMT for the primary outcome or any of the 3 indices of stiffness for the
secondary outcome. We assume that the covariance between individual intercepts and slopes and
10
the variance of the residual errors do not differ by treatment group. In order to address the primary
and secondary hypotheses, the rate of change of each measure was compared between treatment
groups specifically by determining the significance of the regression coefficient β3 associated with
the two-way interaction term of treatment group by years on-study. Both crude and adjusted model
estimates were reported. For the adjusted model, covariates included the randomization
stratification factor (age < or ≥ 75; indicator variable) and any baseline variables found to be
significantly different between treatment groups. Log-transformed values of elasticity and
compliance were calculated due to skewed distributions. However, because the log-transformed
outcome models were not statistically different from the untransformed models, effect estimates
were reported using the untransformed arterial elasticity and compliance for ease of interpretation
and to preserve clinical meaningfulness. All analyses were performed on the intent-to-treat
population, defined as all randomized participants who had a baseline and at least 1 follow-up
ultrasound examination. Any missing observations were considered to be missing at random.
For participants who did not contribute longitudinally to comparisons on atherosclerosis endpoints,
baseline characteristics were compared with the analytical sample by the methods detailed above
in order to evaluate possible biases resulting from selective dropout. Due to a large number of
participants who did not contribute to the intent-to-treat analysis (n=62), a post hoc sensitivity
analysis was performed on all of the available data, relying on the robustness of mixed models to
missing data and the assumption of linear change of CIMT over time. In another sensitivity
analysis, the methods above were repeated for participants who were at least 80% compliant with
the study regimen. Compliance was determined based on total capsule-return counts and the
participants’ total days on-study. A prespecified subgroup analysis for mixed models was
11
performed according to the median baseline CIMT (indicator variable). Subgroup-treatment
interaction effects were assessed by testing the significance of a three-way interaction of treatment
x years on-study x dichotomized median baseline CIMT for a mixed model on change from
baseline CIMT. Baseline values of CIMT were not included in the outcome vector in order to avoid
the inclusion of baseline CIMT as both dependent and independent variables in the model. A post
hoc subgroup analysis was additionally performed according to median baseline BMI (indicator
variable); the significance of a three-way interaction of treatment x years on-study x dichotomized
median baseline BMI for the mixed model on all CIMT measurements was tested. In the advent
that a significant three-way interaction was observed for either of the aforementioned subgroup
analyses, results were reported stratified by the appropriate subgroups. Statistical tests were
considered statistically significant at p<0.05 and all tests were two-sided. All statistical analyses
were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC)
Sample size estimates calculated for the parent trial were confirmed to be sufficient for detecting
treatment groups differences for this ancillary study by the study biostatistician at the time of the
proposal. In summary, preliminary data from the investigators’ most recent randomized clinical
trials measuring CIMT in postmenopausal women were used to estimate a treatment effect (mean
group difference/ SD) of 0.42 based on a mean CIMT difference of 46 μm (or 11.5 μm/year in 4-
year CIMT progression)
37,38
and a SD of 110 μm (or 10 μm/year) in women using vitamin D
supplements.
38-41
Testing at a 2-sided alpha level of 0.05 at 80% power and allowing for up to a
20% loss of CIMT follow-up, the trial sample size of 250 participants was confirmed to be
adequately powered to allow for the detection of even smaller treatment group differences on
12
longitudinal CIMT progression of at least 3.56 μm/year, or 86% of that suggested by the
investigators’ preliminary data.
3. RESULTS
3.1 Baseline Characteristics
A total of 260 women (130 in each treatment group) were randomized to the parent trial. Of these
women, 18 did not have CIMT data, 25 lacked a baseline carotid artery ultrasound, and 62 did not
have at least 1 follow-up ultrasound, leaving 155 (70 vitamin D and 85 placebo) participants in the
intent-to-treat sample. All participants in the analytical sample were compared on baseline
characteristics by treatment group (Table 1). Participants in the active treatment group did not
significantly differ from the placebo group in regards to mean ± standard deviation age (67.4±4.1
vs. 68.9±5.7 years in active treatment vs. placebo group, respectively; p=0.07), BMI (31.0±5.8 vs.
31.1±6.7 kg/m
2
in active treatment vs. placebo group, respectively; p=0.89), or baseline laboratory
values including glucose, triglycerides, total/HDL/LDL cholesterol, PTH, and 25(OH)D. Mean
diastolic blood pressure (DBP) was also similar in both treatment groups (75.9±8.4 vs. 75.5±7.0
mm Hg in the active treatment and placebo groups, respectively; p=0.75). However, mean PP was
significantly higher in participants randomized to the placebo group (51.9±10.8 mm Hg) compared
to women in the vitamin D group (47.8±11.0 mm Hg; p=0.02). Well balanced between groups,
mean CIMT was 0.82±0.10 mm in the active treatment group and 0.84±0.13 mm in the placebo
group (p=0.36); all 3 measures of stiffness were similarly comparable between treatment groups
at baseline. Baseline characteristics by treatment group were additionally summarized for the total
sample of 260 women in the trial (Supplementary Table 1). Results were comparable with the
analytical sample with the exception of treatment group differences in mean SBP, which crept up
13
from a marginal (p=0.07) to a significant difference of p=0.007, likely a result of increased power
in this larger sample of women.
Table 1
Baseline characteristics of intent-to-treat sample (n=155)
Characteristic Vitamin D Placebo P-value
Total randomized 70 85 -
Age, yr
Continuous
Stratification factor
<75
≥75
67.4±4.1
67 (95.7%)
3 (4.3%)
68.9±5.7
72 (84.7%)
13 (15.3%)
0.07
0.02
BMI, kg/m
2
31.0±5.8 31.1±6.7 0.89
Blood pressure, mm Hg
Systolic
Diastolic
Pulse Pressure
123.8±12.7
75.9±8.4
47.8±11.0
127.4±11.8
75.5±7.0
51.9±10.8
0.07
0.75
0.02
Glucose, mg/dL
a
93.6±14.1 95.6±15.1 0.41
Triglycerides, mg/dL
a
83.5±36.9 90.6±40.1 0.26
Cholesterol, mg/dL
a
Total
HDL
LDL
212.8±35.3
68.0±15.7
127.4±33.0
213.3±41.7
68.9±18.5
125.8±37.4
0.94
0.76
0.78
Parathyroid hormone, pg/mL 55.5±24.7 56.8±25.7 0.74
25(OH)D, ng/ml
25(OH)D2
b
25(OH)D3
1.3±3.3
21.2±5.8
0.8±2.2
22.8±6.5
0.60
0.11
Outcome Variables
CIMT, mm
Distensibility
a
Elasticity
a,b
Compliance
a,b
0.82±0.10
15.4±4.9
1077±342
0.11±0.04
0.84±0.13
14.5±5.0
1165±421
0.10±0.04
0.36
0.31
0.24
0.46
P-values comparing the two treatment groups were obtained using Student’s t-test for continuous variables and chi-square test for categorical
variables (dichotomized age); data represent mean±SD or N(%), respectively.
a
N missing: Glucose has 3 missing (2 vitamin D, 1 placebo); triglyceride has 2 missing (1 vitamin D, 1 placebo); total cholesterol has 2 missing
(1 vitamin D, 1 placebo); HDL and LDL have 4 missing (2 vitamin D, 2 placebo); distensibility, elasticity, and compliance have 9 missing (4
vitamin D, 5 placebo).
b
Natural log-transformed values used for t-test due to non-normality. Untransformed values reported for ease of interpretation.
14
3.2 Progression of CIMT
The median follow-up time was 3.9 (range 0.5 – 4.3) years for both active treatment and placebo
groups. Each participant contributed a median of 4 (range 2-9) ultrasound measurements. Intra-
reader reliability among the duplicate CIMT measurements was strong (ICC=0.92). The primary
outcome, mean CIMT progression, was 0.022 (95% CI: 0.017-0.026) mm/year in the vitamin D
arm and 0.017 (95% CI: 0.013-0.021) mm/year in the placebo arm, after adjusting for age and
differences in baseline PP (Table 2; Figure 1). Vitamin D supplementation did not reduce the rate
of CIMT progression in this population of calcium sufficient elderly African American women
(interaction p=0.14). Similarly, no effect of vitamin D supplementation was found when the
analysis was repeated for all available data. In order to assess any biases related to selective
dropout, baseline characteristics were compared between women in the intent-to-treat sample and
those who did not contribute longitudinally (Supplementary Table 2). Baseline characteristics
appear comparable with the exception of age, SBP, and PTH. Compared to the women in the
analytical sample, women who discontinued follow-up were slightly older (69.9±5.4 vs. 68.2±5.1
years; p=0.04), had a slightly lower SBP (122.1±10.4 vs 125.8±12.3 mm Hg; p=0.04), and had
higher levels of PTH (64.3±28.4 vs 56.2±25.1 pg/mL; p=0.04).
Approximately 79% of the intent-to-treat sample (77% of vitamin D group and 81% of placebo
group) were at least 80% compliant to the study regimen. In order to remove any dilution in the
effect estimates from non-compliant participants, a sensitivity analysis limiting the mixed model
analyses to only compliant women was conducted but failed to detect any differences in CIMT
progression rates by treatment group (interaction p=0.27; Table 2).
15
Table 2
Carotid artery intima-media thickness baseline measures and progression by treatment group in the intent-to-treat sample (n=155)
Unadjusted Model Adjusted Model
Outcome Vitamin D N Placebo N P-value
a
Vitamin D N Placebo N P-value
a
Baseline CIMT, mm
Intent-to-treat 0.82
(0.80,0.85)
70 0.84
(0.81,0.86)
85 0.42 0.85
(0.81,0.89)
70 0.85
(0.82,0.88)
85 0.96
Total sample 0.83
(0.81,0.86)
85 0.85
(0.83,0.87)
95 0.37 0.86
(0.83,0.89)
85 0.86
(0.83,0.87)
95 0.89
Compliant 0.82
(0.79,0.85)
54 0.84
(0.82,0.87)
69 0.23 0.85
(0.80,0.89)
54 0.85
(0.82,0.89)
69 0.77
Mean CIMT progression, mm/year
Intent-to-treat 0.022
(0.017,0.026)
70 0.017
(0.013,0.021)
85 0.14 0.022
(0.017,0.026)
70 0.017
(0.013,0.021)
85 0.14
Total sample 0.020
(0.016,0.023)
120 0.018
(0.014,0.022)
122 0.48 0.020
(0.016,0.023)
120 0.018
(0.014,0.022)
122 0.48
Compliant 0.022
(0.017,0.027)
54 0.018
(0.013,0.022)
69 0.27 0.022
(0.017,0.027)
54 0.018
(0.013,0.022)
69 0.27
Data represent the regression coefficients (95% CI) associated with the mean slope by treatment group for CIMT progression and the LS-means (95% CI) by treatment group at 0 years for baseline
CIMT. The median follow-up time for both treatment groups was 3.9 years. Adjusted models included differences in baseline PP and stratification factor baseline age (< or ≥ 75 years). The intent-to-
treat sample includes all participants with a baseline and at least 1 follow-up CIMT measurement. The total sample includes all available CIMT measurements. The compliant sample includes only
participants who were at least 80% compliant to the study regimen.
a
P-value for difference in LS-means for baseline or the treatment group by years on-study interaction term for progression.
16
FIGURE 1.
Predictions from mixed model incorporating the random effect.
3.3 Progression of Arterial Stiffness
Of the total 260 women randomized to the trial, 170 had diameter and pulse pressure data; 24 of
these women did not have at least 1 follow-up measurement of stiffness, leaving 146 (66 vitamin
D and 80 placebo) participants in the intent-to-treat sample for the secondary outcome measures.
Results for both crude and adjusted models are presented in Table 3. Although differences in PP
were observed between treatment groups at baseline, mixed models for secondary outcomes were
not adjusted for PP since it was used in the calculation for all measures of stiffness. Adjustment
for baseline age strata had minimal effect on any of the stiffness indices. Comparison of the slopes
of each measure of arterial stiffening between vitamin D and placebo showed similar rates of
progression in each treatment group (Figure 2). After adjusting for baseline age, carotid artery
17
distensibility decreased with time in both treatment groups at an average of 0.95 (95% CI: 1.34-
0.51) 10
-5
x N x m
-2
/ year for women taking vitamin D and 0.53 (95% CI: 0.92-0.13) 10
-5
x N x
m
-2
/ year for women taking placebo (interaction p=0.18). Compared to placebo, the mean rate of
progression of elastic modulus was slightly higher in the vitamin D group (76.3 [95% CI: 38.6-
114.1] kPa/year vs. 52.0 [95% CI: 16.0-88.1] kPa/year in vitamin D vs. placebo group,
respectively) although the difference did not reach significance (log-transformed model interaction
p=0.23). The mean yearly decline of arterial compliance was 0.005 (95% CI: 0.008-0.002)
ACU/year for the vitamin D group and 0.003 (95% CI: 0.006-0.001) ACU/year for the placebo
group after adjustment for age; again, the difference between the 2 treatment arms was not
statistically significant (log-transformed model interaction p=0.26).
18
Table 3
Baseline and progression of measures of carotid arterial stiffness by treatment group in the intent-to-treat sample (n=146)
Unadjusted Model Adjusted Model
Outcome Vitamin D Placebo P-value
a
Vitamin D Placebo P-value
a
Total N 66 80 - 66 80 -
Distensibility Baseline 15.30
(14.30,16.31)
14.59
(13.68,15.51)
0.31 14.85
(13.56,16.14)
14.26
(13.17,15.36)
0.40
Progression -0.92
(-1.34,-0.50)
-0.52
(-0.92,-0.13)
0.17 -0.92
(-1.34,-0.51)
-0.53
(-0.92,-0.13)
0.18
Elasticity
b
Baseline 1088
(1001,1175)
1170
(1090,1249)
0.22 1117
(1000,1234)
1191
(1093,1289)
0.28
Progression 76.4
(38.6,114.2)
51.9
(15.7,87.9)
0.22 76.3
(38.6,114.1)
52.0
(16.0,88.1)
0.23
Compliance
b
Baseline 0.11
(0.10,0.11)
0.10
(0.09,0.11)
0.41 0.11
(0.10,0.12)
0.10
(0.09,0.11)
0.36
Progression -0.005
(-0.008,-0.002)
-0.003
(-0.006,-0.001)
0.27 -0.005
(-0.008,-0.002)
-0.003
(-0.006,-0.001)
0.26
Data represent the regression coefficients (95% CI) associated with the mean slope by treatment group for stiffness progression and the LS-means (95% CI) by treatment group at 0 years for baseline
stiffness. Units for distensibility 10
-5
x N x m
-2
, for elasticity kPa, for compliance ACU. Progression rates are reported per year. Adjusted models included the stratification factor baseline age (< or ≥
75 years).
a
P-value for difference in LS-means for baseline or the treatment group by years on-study interaction term for progression.
b
Natural log-transformed due to non-normality. Effect estimates are from the untransformed models; p-values are from the log-transformed models.
19
FIGURE 2.
Predictions from mixed model incorporating the random effect.
20
3.4 Subgroup Analyses
In the first subgroup analysis, no differences in treatment effects on the mean progression of CIMT
were observed by median baseline CIMT (0.829 mm). The three-way interaction between
treatment x years on-study x median baseline CIMT was highly non-significant at p=0.99 (results
not shown).
Table 4 shows the treatment effects on the mean progression of CIMT stratified by median
baseline BMI (30 kg/m
2
). High vs. low baseline BMI did not modify the effect of treatment on
CIMT progression rates, even after adjustment for baseline age (interaction p=0.30). The three-
way interaction model was not adjusted for PP due to the significant association between BMI
subgroup and baseline PP; women in the high BMI group were more likely to have a higher PP
compared to women in the low BMI group (Student’s t-test p<0.001). Although the three-way
interaction p-value for treatment x years on-study x median baseline BMI did not reach statistical
significance, results are presented in each BMI subgroup due to a trend for significance observed
between the treatment groups in the higher BMI group (years x treatment interaction p=0.09).
Stratified models were adjusted for differences in baseline PP and stratification factor baseline age.
In women who were ≥ 30 kg/m
2
at baseline, the rate of CIMT progression in the placebo group
curiously drops to 0.014 (95% CI: 0.008-0.020) mm/year compared to the 0.022 (95% CI: 0.015-
0.028) mm/year maintained in the Vitamin D group, after adjusting for differences in PP and age.
21
4. DISCUSSION
In this ancillary analysis to a randomized, placebo controlled trial, supplementation with vitamin
D sufficient to maintain serum 25(OH)D at an optimum level above 75 nmol/L did not reduce
atherosclerotic progression as measured by CIMT or arterial stiffening in elderly African
American women over a 4-year period. Possible explanations for these null findings are multitude.
Compared to the healthy post-menopausal women in the ELITE trial,
35
the women in this study
had much thicker baseline CIMT. While the mean baseline CIMT for women in the ELITE study
was approximately 0.77 mm, women in this trial were on average 0.6 mm higher at a mean of 0.83
mm for both treatment groups combined. Given that atherosclerosis is a slowly-progressing
lifetime process, the already high levels of CIMT at baseline may be a reflection of the possible
inalterability of CIMT progression and arterial stiffening after a certain threshold. Another possible
explanation is that the 4-year follow-up period was too short to capture the slow progression of
CIMT and any non-linearities that may exist with the effect of vitamin D, making any possible
Table 4
Carotid artery intima-media thickness progression by treatment group stratified by median
baseline BMI
Mean CIMT
progression,
mm/year
Vitamin D N Placebo N P-value
a
P-value
b
< 30 kg/m
2
0.022
(0.016-0.028)
37 0.020
(0.015-0.026)
42 0.74
0.30
≥ 30 kg/m
2
0.022
(0.015-0.028)
33 0.014
(0.008-0.020)
43 0.09
Data represent the regression coefficients (95% CI) associated with the mean slope by treatment group for CIMT progression.
a
P-value for difference in treatment group by years on-study interaction term for progression based on the models stratified by median
baseline BMI. Stratified models were adjusted for baseline differences in PP and stratification factor baseline age (< or ≥ 75 years).
b
P-value for three-way interaction term for treatment x years on-study x BMI subgroup. Model adjusted for stratification factor baseline age
(< or ≥ 75 years).
22
differences in rates difficult to detect. The lack of benefit detected for vitamin D3 supplementation
may also be attributed to the inadequate power stemming from the reduced sample size of women
with available ultrasound data for this ancillary study. As with any randomized, controlled trial,
non-compliance may have diluted the results, increasing type II error. Although we conducted
sensitivity analyses to address any biases resulting from missing data and non-compliance, results
did not differ from our intent-to-treat sample. However, our sample size was likely not large
enough to overcome this dilution, if existent. In an analysis of selective dropout, differences in
age and SBP between the intent-to-treat sample and those who did not contribute a follow-up were
small although statistically significant and PTH was approximately 8 pg/mL higher in the sample
of participants who did not contribute longitudinally (Supplementary Table 2). In addition to
those described above, this ancillary study has several other limitations. Data on smoking status
and the use of lipid-lowering and blood pressure medication were not available at the time of the
analysis. The validity and reproducibility of the indices of arterial stiffness are also limited by their
dependence on blood pressure.
Neither baseline CIMT nor BMI were statistically significant modifiers of the effect of vitamin D
compared with that of placebo on mean CIMT progression. These results may be explained by
other underlying biological mechanisms at play or may simply be limited by a lack of power given
the fair amount of missing ultrasound data observed, particularly for the latter. A trend for
significance was observed in an obese subgroup; however, given that this analysis was done post
hoc, one must be cautious of its validity. The median baseline BMI of 30 kg/m
2
of the cohort is
also the cutoff for obesity as defined by the CDC.
36
Given that vitamin D deficiency has been
associated with obesity
28,29
and African American obese women have a higher risk of
23
cardiovascular disease
1
and odds of CIMT progression,
37
further research in this particular
subgroup of women is merited.
Despite a strong backing of non-trial literature suggesting an association between vitamin D
deficiency and CVD, this RCT concluded that vitamin D supplementation did not influence the
progression of subclinical atherosclerosis as measured by CIMT and arterial stiffening in an at-
risk cohort of elderly African American women. Although atherosclerosis is reversible in nature,
38
it is possible that earlier detection is required in effectively reducing its progression with vitamin
D. Future research plans for this data should include an investigation on the potential confounding
or modifying effect of smoking status on the progression of CIMT in the sample, a sensitivity
analysis limited to participants who did not use lipid-lowering medication during the trial, and
imputation of missing data to increase power. The null findings of this trial should not discourage
future research on a greater scale than this data alone. Future trials with a larger number of
participants, of a longer duration, and/or constrained to a more refined cohort of African American
women with lower baseline CIMT levels is nevertheless warranted to assess the effect of vitamin
D supplementation on subclinical atherosclerosis progression.
24
SUPPLEMENTARY MATERIAL
Supplementary Table 1
Baseline characteristics of total sample (n=260)
Characteristic Vitamin D Placebo P-value
Total randomized 130 130 -
Age, yr
Continuous
Stratification factor
<75
≥75
68.5±5.0
117 (90.0%)
13 (10.0%)
69.4±5.6
106 (81.5%)
24 (18.5%)
0.19
0.05
BMI, kg/m
2
31.1±6.3 31.0±6.2 0.86
Blood pressure, mm Hg
Systolic
Diastolic
Pulse Pressure
122.5±12.0
74.7±8.2
47.8±9.7
126.5±11.8
75.3±7.3
51.1±10.5
0.007
0.51
0.008
Glucose, mg/dL
a
93.7±13.4 94.4±16.8 0.73
Triglycerides, mg/dL
a
90.5±46.0 89.8±39.3 0.90
Cholesterol, mg/dL
a
Total
HDL
LDL
211.2±36.4
67.3±15.7
125.1±34.7
210.0±39.7
67.8±17.8
124.2±35.8
0.81
0.83
0.85
Parathyroid hormone, pg/mL
a
60.2±28.3 59.3±26.3 0.79
25(OH)D, ng/ml
a
25(OH)D2
b
25(OH)D3
1.3±2.8
21.5±6.5
1.0±2.4
22.2±6.9
0.81
0.35
CIMT, mm
a
Distensibility
a
Elasticity
a,b
Compliance
a,b
0.82±0.12
15.37±5.49
1090±358
0.11±0.04
0.85±0.13
14.45±4.79
1158±401
0.10±0.04
0.18
0.25
0.25
0.48
P-values comparing the two cohorts were obtained using Student’s t-test for continuous variables and chi-square test for categorical variables
(dichotomized age); data represent mean±SD or N(%), accordingly.
a
N missing: Glucose has 7 missing (3 vitamin D, 4 placebo); triglyceride has 8 missing (3 vitamin D, 5 placebo); total cholesterol has 7 missing
(3 vitamin D, 4 placebo); HDL and LDL have 10 missing (4 vitamin D, 6 placebo); PTH, 25(OH)D
2
, and 25(OH)D
3
have 2 missing in the
placebo group; CIMT has 75 missing (45 vitamin D; 35 placebo); distensibility, elasticity, and compliance have 90 missing (50 vitamin D, 40
placebo).
b
Natural log-transformed values used for t-test due to non-normality. Untransformed values reported for ease of interpretation.
25
Supplementary Table 2
Evaluation of selective dropout
Characteristic Intent-to-treat No FU P-value
Total N 155 62 -
Allocated to Vitamin D Group 70 (45.2%) 35 (56.5%) 0.15
Age, yr
Continuous
Stratification factor
<75
≥75
68.2±5.1
139 (90.0%)
16 (10.0%)
69.9±5.4
50 (80.7%)
12 (19.3%)
0.04
0.11
BMI, kg/m
2
31.0±6.3 31.2±6.7 0.89
Blood pressure, mm Hg
Systolic
Diastolic
Pulse Pressure
125.8±12.3
75.7±7.6
50.0±11.0
122.1±10.4
74.3±7.7
47.9±7.4
0.04
0.21
0.09
Glucose, mg/dL
a
94.7±14.7 94.0±18.5 0.80
Triglycerides, mg/dL
a
87.4±38.7 89.2±39.7 0.76
Cholesterol, mg/dL
a
Total
HDL
LDL
213.1±38.8
68.5±17.2
126.5±35.4
207.8±37.7
66.5±16.8
122.9±36.3
0.37
0.45
0.51
Parathyroid hormone, pg/mL
a
56.2±25.1 64.3±28.4 0.04
25(OH)D, ng/ml
a
25(OH)D2
b
25(OH)D3
1.1±2.7
22.1±6.3
0.8±1.6
22.0±6.7
0.74
0.95
P-values comparing the two treatment groups were obtained using Student’s t-test for continuous variables and Fisher’s exact test for categorical
variables (dichotomized age); data represent mean±SD or N(%), accordingly. FU = follow-up.
a
N missing: Glucose has 6 missing (3 ITT, 3 no FU); triglycerides and total cholesterol have 5 missing (2 ITT, 3 no FU); HDL and LDL have
7 missing (4 ITT, 3 no FU); PTH, 25(OH)D
2
, and 25(OH)D
3
have 1 missing in the no FU group.
b
Natural log-transformed values used for t-test due to non-normality. Untransformed values reported for ease of interpretation.
26
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Abstract (if available)
Abstract
BACKGROUND: African American women are disproportionately burdened by cardiovascular disease (CVD) risk factors and mortality and have generally demonstrated the least benefit from traditional CVD interventions. The higher rate of vitamin D insufficiency observed predominantly in African Americans makes vitamin D a possible biological contributor to the observed race-related disparity. Given the aging US population, an investigation as to whether vitamin D supplementation influences atherosclerotic progression is strongly warranted in order to develop simple, cost-effective, and safe strategies for improving cardiovascular health in this at-risk and understudied population of women. ❧ OBJECTIVE: As an ancillary study to “Vitamin D and Osteoporosis Prevention in Elderly African Americans,” the aim of this study was to investigate whether dietary supplementation with calcium and vitamin D sufficient to maintain serum 25(OH)D at an optimum level above 75 nmol/L reduces subclinical atherosclerosis in a cohort of elderly African American women under randomized, controlled, clinical trial conditions. ❧ METHODS: The “Vitamin D and Osteoporosis Prevention in Elderly African Americans” trial was a randomized, double-blind, placebo-controlled, single-institution clinical trial to investigate the effect of vitamin D supplementation in elderly African American women who were vitamin D deficient. Participants were randomized to receive vitamin D3 or placebo in a 1:1 allocation ratio. Subclinical atherosclerosis was measured by high-resolution B-mode ultrasounds of the carotid artery and defined as (1) the rate of change of the common carotid artery intima-media thickness (CIMT) and (2) the rate of change of arterial stiffness, as determined from 3 indices: distensibility, Peterson’s elastic modulus, and compliance. Carotid ultrasound examinations were performed at baseline and every 6 months on-trial for a total of 4 years. All atherosclerotic outcomes were analyzed by linear mixed effects models
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Koc, Melissa
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The effect of vitamin D supplementation on the progression of carotid intima-media thickness and arterial stiffness in elderly African American women: Results of a randomized placebo-controlled trial
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Keck School of Medicine
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Master of Science
Degree Program
Biostatistics
Publication Date
11/13/2018
Defense Date
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Thesis
Format
application/pdf (imt)
Rights
Koc, Melissa
Type
texts
Source
University of Southern California
(contributing entity),
University of Southern California Dissertations and Theses
(collection)
Access Conditions
The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...
Repository Name
University of Southern California Digital Library
Repository Location
USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA
Tags
arterial stiffness
atherosclerosis
carotid intima-media thickness
clinical trial
vitamin D