Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83 000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis

Mahmoud Barbarawi; Babikir Kheiri; Yazan Zayed; Owais Barbarawi; Harsukh Dhillon; Bakr Swaid; Anitha Yelangi; Saira Sundus; Ghassan Bachuwa; Mohammad Luay Alkotob; JoAnn E Manson

doi:10.1001/jamacardio.2019.1870

. 2019 Jun 19;4(8):765–775. doi: 10.1001/jamacardio.2019.1870

Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83 000 Individuals in 21 Randomized Clinical Trials

A Meta-analysis

Mahmoud Barbarawi ^1,^✉, Babikir Kheiri ¹, Yazan Zayed ¹, Owais Barbarawi ², Harsukh Dhillon ¹, Bakr Swaid ¹, Anitha Yelangi ¹, Saira Sundus ¹, Ghassan Bachuwa ¹, Mohammad Luay Alkotob ³, JoAnn E Manson ⁴

PMCID: PMC6584896 PMID: 31215980

Key Points

Question

Does vitamin D supplementation have any association with cardiovascular disease risk?

Findings

In this meta-analysis of randomized clinical trials that included more than 83 000 participants, vitamin D supplementation was not associated with reduced risks of major adverse cardiovascular events, myocardial infarction, stroke, cardiovascular disease mortality, or all-cause mortality compared with placebo.

Meaning

These results suggest that vitamin D supplementation may not confer cardiovascular protection and may not be indicated for this purpose.

This meta-analysis of 21 randomized clinical trials examines the role of vitamin D supplementation in reducing cardiovascular events and all-cause mortality.

Abstract

Importance

Observational studies have reported an association between low serum vitamin D levels and elevated risk of cardiovascular disease (CVD) events, but such studies cannot prove causation because of possible unmeasured confounding.

Objective

We conducted a meta-analysis of randomized clinical trials that tested the association of vitamin D supplementation with reduced CVD events and all-cause mortality.

Data Sources

Literature search through PubMed, the Cochrane Library, and Embase was completed by 2 reviewers from each database’s inception to December 15, 2018.

Study Selection

Inclusion criteria were randomized clinical trials that reported the effect of long-term (≥1 year) vitamin D supplementation on CVD events and all-cause mortality. Studies that did not include cardiovascular outcomes were excluded.

Data Extraction and Synthesis

Data were abstracted independently by 2 authors. Random-effects models were used to report the risk ratios (RRs) and 95% CIs.

Main Outcomes and Measures

Major adverse cardiovascular events was the primary outcome, and rates of myocardial infarction, stroke or cerebrovascular accident, CVD mortality, and all-cause mortality were the secondary end points.

Results

Twenty-one randomized clinical trials were included (including 83 291 patients, of whom 41 669 received vitamin D and 41 622 received placebos). The mean (SD) age of trial participants was 65.8 (8.4) years; 61 943 (74.4%) were female. Only 4 trials had prespecified CVD as a primary end point. Vitamin D supplementation compared with placebo was not associated with reduced major adverse cardiovascular events (RR, 1.00 [95% CI, 0.95-1.06]; P = .85) nor the secondary end points of myocardial infarction (RR, 1.00 [95% CI, 0.93-1.08]; P = .92), stroke (RR, 1.06 [95% CI, 0.98-1.15]; P = .16), CVD mortality (RR, 0.98 [95% CI, 0.90-1.07]; P = .68), or all-cause mortality (RR, 0.97 [95% CI, 0.93-1.02]; P = .23). Results were generally consistent by sex, baseline 25-hydroxyvitamin D level, vitamin D dosage, formulation (daily vs bolus dosing), and presence or absence of concurrent calcium administration.

Conclusions and Relevance

In this updated meta-analysis, vitamin D supplementation was not associated with reduced major adverse cardiovascular events, individual CVD end points (myocardial infarction, stroke, CVD mortality), or all-cause mortality. The findings suggest that vitamin D supplementation does not confer cardiovascular protection and is not indicated for this purpose.

Introduction

Observational studies have suggested an inverse association between serum 25-hydroxyvitamin D levels and risk of cardiovascular disease (CVD) events.^1,2,3 Specifically, low vitamin D levels have been linked to an increased risk of myocardial infarction (MI), stroke, CVD mortality, and heart failure in case-control and other prospective epidemiologic studies.^4,5 Additionally, vitamin D receptors are expressed in vascular tissues, including the myocardium and vascular smooth muscle,⁶ directly influencing calcium influx, muscle relaxation, and diastolic function.⁷ Vitamin D also has effects on the renin-angiotensin-aldosterone system and parathyroid hormone and may influence endothelial function and arterial thrombogenesis.^8,9,10

Vitamin D level supplementation has increased in primary care settings in the United States.^11,12 Assessment of vitamin D supplementation for cardiovascular disease prevention has been a subject of growing interest in recent randomized clinical trials (RCTs).^13,14,15,16 Owing to insufficient data regarding cardiovascular benefits of screening and treatment of asymptomatic low vitamin D in adults, the US Preventive Services Task Force has not recommended vitamin D supplementation to prevent cardiovascular disease (via I statement, which indicates insufficient evidence).¹¹ Although previous randomized clinical trials assessing vitamin D supplementation and cardiovascular disease have been limited and inconclusive, several recent large-scale trials have added substantial data to the evidence base.^13,14,15,16 Therefore, we conducted a meta-analysis of all RCTs to date that evaluate the efficacy of vitamin D supplementation in the prevention of cardiovascular disease.

Methods

Literature Search

For this meta-analysis, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines were followed.¹⁷ The meta-analysis was registered with the International Prospective Register of Systematic Reviews (PROSPERO identifier: CRD42019120689). Published trials from Embase, MEDLINE/PubMed, and the Cochrane Library for relevant trials were identified independently by 2 reviewers (A.Y. and S.S.) from inception to December 2018. The search terms vitamin D, cholecalciferol, ergocalciferol, cardiovascular, cardiac, myocardial, and heart were used. Any inconsistency between reviewers was resolved by a third independent reviewer (O.B.). There were no language restrictions. The references of included trials and published meta-analysis were screened for other potential trials.

Eligibility Criteria

In this analysis, only RCTs that evaluated long-term supplementation (≥1-year intervention) with vitamin D, with or without concurrent calcium and with cardiovascular outcomes, were included in this meta-analysis. Any vitamin D or its analogue supplementation was qualified. Studies that did not include cardiovascular outcomes were excluded after reviewing supplementary materials.

Data Extraction

Two reviewers (H.D. and Y.Z.) extracted relevant data independently by using a predetermined data collection table. Any discrepancies between reviewers were resolved by an independent reviewer (B.K.).

Quality Assessment

The Cochrane Collaboration’s tool was used to perform quality assessment and assess the risk of bias in the included RCTs for random sequence generation, allocation concealment, blinding of participants and health care personnel, blinded outcome assessment, completeness of outcome data, evidence of selective reporting, or other biases. Details are in eFigure 1 in the Supplement.

Outcomes of Interest

The primary end point was a composite of major adverse cardiovascular events (MACEs), as defined by each trial (eTable in the Supplement). Secondary end points were MI, stroke/cerebrovascular accident (CVA), CVD mortality, and all-cause mortality. The longest available follow-up time was used for each trial in the analysis.

Statistical Analysis

Results were presented as risk ratios (RRs) and 95% CIs on the basis of the Mantel-Haenszel random-effects model. Heterogeneity was evaluated by using the I² statistic. Publication bias of the primary end point was assessed by using the funnel plot. We conducted a sensitivity analysis of the primary end point by sequential removal of each trial. Sensitivity analyses of the primary MACE end point were conducted based on age, sex, inclusion of women who were postmenopausal only, use of pretreatment vitamin D level less than 25 ng/mL (to convert to nmol/L, multiply by 2.496), inclusion of patients with chronic kidney disease, exclusion of studies that used vitamin D analogues, and vitamin D dosage and formulation (daily vs bolus dosing). Meta-regression analyses based on study-level covariates (age, sex, follow-up duration, body mass index [BMI; calculated as weight in kilograms divided by height in meters squared], and pretreatment with statin) were conducted to explain any heterogeneity.

To avoid potential spurious inferences from repetitive significance testing and underpowered meta-analysis, we performed trial sequential analysis. By applying trial sequential monitoring boundaries, similar to those of interim analysis in RCTs, we would be able to obtain reliable results.¹⁸ We calculated the optimal information (sample) size to maintain a 2-sided type I error at .05 and a type II error at .20 (80% power), with a relative risk reduction of 25% and an incidence of 8.5% MACE in the placebo arm. Sensitivity analysis was performed using a MACE incidence of 7.86% from the included RCTs. We used Review Manager (RevMan) version 5.3 (Cochrane Community), Comprehensive Meta-analysis version 3 (Biostat), and Trial Sequential Analysis version 0.9.5.9 (Copenhagen Trial Unit) software to conduct all analyses. Data analysis was conducted from November 2018 to March 2019.

Results

After reviewing 7816 studies from the databases, 7796 studies were excluded. Twenty-one RCTs were included in the final analysis.^{13,14,15,16,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35} Eight trials included postmenopausal women,^{22,23,24,25,27,29,33,34} 9 trials included older patients,^{20,21,22,24,28,32,33,34,35} 2 trials included patients with chronic kidney disease,^14,26 2 trials included patients with heart failure,^15,30 and 1 trial included patients with chronic obstructive pulmonary disease.³¹ In total, 83 291 patients were included, 41 669 of whom received vitamin D supplementation and 41 622 of whom received placebo. The mean (SD) age was 65.8 (8.4) years, and 61 943 participants (74.4%) were female. Follow-up durations were variable between the included trials (range, 1-12 years). Fourteen trials used cholecalciferol,^{13,15,16,19,21,23,24,25,27,30,31,32,33,35} 2 trials used ergocalciferol,^20,22 and 3 trials used vitamin D analogues (alfacalcidol, paricalcitol, and calcitriol).^14,26,34 The search strategy is illustrated in Figure 1. All of the included trials reported the incidence of mortality except the study by Prince et al.²⁰ On the other hand, 3 trials did not report the incidence of MI.^15,30,33 For the Women’s Health Initiative trial, we included a follow-up and post hoc analysis that were done on the data.^36,37 The characteristics of the included trials with the patients’ demographic features are presented in Table 1 and Table 2.

Table 1. Characteristics of the Involved Trials.

Source	Year	Patients, No.		Study Period	Vitamin D Type and Dosage	Study Follow-up, y	Country	Major Inclusion Criteria	Primary Outcome
Source	Year	Vitamin D	Placebo	Study Period	Vitamin D Type and Dosage	Study Follow-up, y	Country	Major Inclusion Criteria	Primary Outcome
Aloia et al²⁵	1988	12	15	NA	Vitamin D³, 400 IU/d	2	United States	Women who were postmenopausal and aged 50-80 y, with osteoporosis (diagnosed by the presence of ≥1 nontraumatic vertebral compression fracture)	Bone mineral measurements and fracture incidence
Ott et al²³	1989	43	43	NA	Vitamin D³, 1000 mg/d	2	United States	Women who were postmenopausal, aged 50-80 y, and ambulatory, with ≥2 compression fractures (>15% reduction in anterior height) and without history of serious trauma or current medications for osteoporosis (except calcium supplements in some cases)	Total body calcium, change in bone mineral density, and fracture rate
Komulainen et al²⁹	1999	112	115	1989-1991	Vitamin D³, 300 and 100 IU/d	5	Finland	Women in early postmenopause who were nonosteoporotic	Lumber and femoral neck bone mineral density
STOP IT/Gallagher et al³⁴	2001	245	244	NA	Calcitriol, 0.25 μg twice daily	3	United States	Women aged 65-77 y with femoral neck density in normal range (SD, ≤2) for their age	Change in bone mineral density of the femoral neck and spine
Trivedi et al³⁵	2003	1345	1341	1996-1997	Vitamin D³, 100 000 IU/4 mo	5	United Kingdom	Participants aged 65-85 y	Fracture incidence and total mortality by cause
RECORD/Grant et al³²	2005	2649	2643	1999-2002	Vitamin D³, 800 IU daily	Median (IQR), 3.8 (3.1-4.3)	United Kingdom	Participants aged ≥70 y who had had a low trauma, osteoporotic fracture in the previous 10 y	The incidence of new low-energy fractures
Brazier et al³³	2005	95	97	NA	Vitamin D³, 400 IU twice daily	1	France	Ambulatory women aged >65 y	Vitamin D treatment–associated adverse events
WHI/Jackson et al²⁷	2006	18 176	18 106	1995 and 2000	Vitamin D³, 400 IU/d	12	United States	Women aged 50-79 y with no evidence of a medical condition associated with anticipated survival <3 y and no safety, adherence, or retention risks	Total number of fractures
Schleithoff et al³⁰	2006	61	62	2002-2003	Vitamin D³, 2000 IU/d	1.3	Germany	Participants with New York Heart Association functional class ≥II	Survival rates and biochemical variables, such as natriuretic peptides and cytokines
Berggren et al²⁸	2007	102	97	2000-2002	Vitamin D³, 800 IU/d	1	Sweden	Participants aged ≥70 y who had femoral neck fractures	Total number of falls
Zhu et al²²	2008	39	81	1998	Vitamin D³, 1000 IU/d	5	Australia	Women aged 70-80 y who were ambulatory	Change in hip bone mineral density, plasma 25-hydroxyvitamin D, biomarkers of bone turnover, parathyroid hormone, and intestinal calcium absorption
Prince et al²⁰	2008	151	151	2003 - 2004	Vitamin D³, 1000 IU/d	1	Australia	Women aged 70-90 y who were ambulatory	Number of falls
Vital D/Sanders et al²⁴	2010	1131	1125	2003-2005	Vitamin D³, 500 000 IU/y	Median (IQR), 2.96 (2.92-3.00)	Australia	Community-dwelling women aged ≥70 y at high risk of fracture (defined by criteria such as maternal hip fracture, past fracture, or self-reported fall)	Number of falls and fractures
Lehouck et al³¹	2012	91	91	2008-2009	Vitamin D, 100 000 IU/mo	1	Belgium	Current or former smokers aged ≥50 y who had a chronic obstructive pulmonary disease per diagnosis Global Initiative for Chronic Obstructive Lung Disease definition (postbronchodilator ratio of first second of forced expiration to the forced vital capacity _0.7) and a first second of forced expiration <80% anticipated	Incidence of chronic obstructive pulmonary disease exacerbations
VITDISH/Witham et al²¹	2013	80	79	2009-2001	Vitamin D³, 100 000 IU/3 mo	1	United Kingdom	Participants aged ≥70 y with isolated systolic hypertension (supine systolic blood pressure, >140 mm Hg; supine diastolic blood pressure, <90 mm Hg) and baseline 25-hydroxyvitamin D levels <30 ng/mL	Difference in in-office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and B-type natriuretic peptide level
OPERA/Wang et al²⁶	2014	30	30	2008-2010	Paricalcitol, 1 μg/d	1	Hong Kong	Participants with stages 3-5 chronic kidney disease and left ventricle hypertrophy	The change in left ventricle mass index measured by cardiac magnetic resonance imaging
Baron et al¹⁹	2015	1130	1129	2004-2008	Vitamin D³, 1000 IU\day	3	United States	Participants aged 45-75 y who had ≥1 colorectal adenoma removed within 120 d before enrollment and no remaining polyps after a complete colonoscopy	Incidence of colonic adenoma
EVITA/Zitterman et al¹⁵	2017	199	201	2010-2013	Vitamin D³, 4000 IU/d	3	Germany	Participants aged 18-79 y who were classified as having New York Heart Association functional class ≥II	All-cause mortality
VIDA/Scragg et al¹⁶	2017	2558	2550	2011-2015	Vitamin D³, Initial 200 000 IU, then 100 000 IU/mo	Median (IQR), 3.3 (2.5-4.2)	New Zealand	Participants aged 50-84 y	Incident cardiovascular disease and death
J-DAVID/Shoji et al¹⁴	2018	488	476	2011-2015	Alfacalcidol, 0.5 μg/d	Median (IQR), Vitamin D: 4.0 (2.6-4.0)^a; Placebo: 4.0 (3.5-4.0)	Japan	Participants aged 20-80 y who were receiving maintenance hemodialysis; had calcium ≤10.0 mg/dL, phosphate ≤6.0 mg/dL, and intact parathyroid hormone ≤180 pg/mL, and were not taking any vitamin D receptor activations at randomization	Composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb owing to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization
VITAL/Manson et al¹³	2018	12 927	12 944	2011-2014	Vitamin D³, 2000 IU/d	Median (IQR), 5.3 (3.8 to 6.1)^a	United States	Participants had no history of cancer (except nonmelanoma skin cancer) or cardiovascular disease at trial entry	Incidence of invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes)

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Abbreviations: EVITA, Effect of Vitamin D on All-Cause Mortality in Heart Failure patients; IQR, interquartile range; J-DAVID, Japan Dialysis Active Vitamin D; OPERA, Oral Paricalcitol in Retarding Cardiac Hypertrophy, Reducing Inflammation and Atherosclerosis in Stage 3-5 Chronic Kidney Disease; RECORD, Randomized Evaluation of Calcium or Vitamin D; STOP IT, Estrogen and Calcitriol in the Prevention of Age-Related Bone Loss; VIDA, Vitamin D Assessment; VITAL, Vitamin D and Omega-3 Trial; VITDISH, Vitamin D in Isolated Systolic Hypertension; WHI, Women’s Health Initiative.

Table 2. Patients’ Demographic and Clinical Characteristics.

Source	Year	Patients, No.	Subgroup	Age, Mean (SD), y	Male, No. (%)	Current Smoker, No. (%)	BMI, Mean (SD)	Total Cholesterol, Mean (SD), mg/dL	Baseline 25-Hydroxyvitamin D Level, Mean (SD), ng/mL	Statin User, No. (%)	Systolic Blood Pressure, mm Hg, Mean (SD)	Hypertension, No. (%)	Diabetes, No. (%)
Aloia et al²⁵	1988	17	Vitamin D	64.1 (1.5)	0	NA	NA	NA	21.9 (7)	NA	NA	NA	NA
Aloia et al²⁵	1988	17	Placebo	64.9 (1.7)	0	NA	NA	NA	26.6 (12)	NA	NA	NA	NA
Ott et al²³	1989	43	Vitamin D	67.9 (1.0)	0	NA	NA	NA	26.7 (1.9)	NA	NA	NA	NA
Ott et al²³	1989	43	Placebo	67.1 (1.2)	0	NA	NA	NA	26.3 (2.4)	NA	NA	NA	NA
Komulainen et al²⁹	1999	112	Vitamin D	53 (0.3)	0	NA	27.2 (0.3)	NA	NA	NA	NA	NA	4 (3.6)
Komulainen et al²⁹	1999	115	Placebo	53 (0.3)	0	NA	26.6 (0.4)	NA	NA	NA	NA	NA	3 (3)
STOP IT/Gallagher et al³⁴	2001	245	Vitamin D or vitamin D plus HRT	71 (3.5)	0	NA	27.3 (5)	NA	31.2 (11)	NA	NA	NA	NA
STOP IT/Gallagher et al³⁴	2001	244	Placebo or placebo plus HRT	71.4 (4)	0	NA	27.4 (6)	NA	32 (10)	NA	NA	NA	NA
Trivedi et al³⁵	2003	1345	Vitamin D	74.8 (4.6)	1019 (75.8)	59 (4.4)	24.3 (3.4)	NA	NA	NA	NA	NA	NA
Trivedi et al³⁵	2003	1341	Placebo	74.7 (4.6)	1018 (75.9)	53 (4.0)	24.4 (3.0)	NA	NA	NA	NA	NA	NA
RECORD/Grant et al³²	2005	2649	Vitamin D or vitamin D plus calcium	77 (6)	409 (15.4)	298 (11.2)	NA	NA	NA	NA	NA	NA	NA
RECORD/Grant et al³²	2005	2643	Placebo and calcium	77 (6)	402 (15.2)	320 (12.1)	NA	NA	NA	NA	NA	NA	NA
Brazier et al³³	2005	95	Vitamin D plus calcium	74.2 (6.4)	0	NA	27.0 (4.4)	NA	7.3	NA	138 (11)	NA	NA
Brazier et al³³	2005	97	Placebo	75.0 (7.3)	0	NA	26.4 (4.3)	NA	7.0	NA	138 (14)	NA	NA
WHI/Jackson et al²⁷	2006	18 176	Vitamin D plus calcium	62.4 (7.0)	0	1405 (7.7)	29.1 (5.9)	208.1	NA	1178 (6.5)	127 (17)	5447 (30.0)	1055 (5.8)
WHI/Jackson et al²⁷	2006	18 106	Placebo	62.4 (6.9)	0	1356 (7.5)	29.0 (5.9)	208.1	NA	1149 (6.3)	128 (17)	5476 (30.2)	1036 (5.7)
Schleithoff et al³⁰	2006	61	Vitamin D	57.6 (7.5)	52 (85.2)	9 (14.8)	26.3 (3.8)	NA	Median (IQR), 15.2 (12.0-22.1)	53 (86.9)	120 (6)	38 (62.3)	20 (32.8)
Schleithoff et al³⁰	2006	62	Placebo	55.3 (9)	50 (80.6)	7 (11.3)	26 (3.1)	NA	Median (IQR), 15.2 (12.0-22.1)	42 (67.7)	125 (8)	32 (51.6)	23 (37.1)
Berggren et al²⁸	2007	102	Vitamin D	82.3 (6.6)	28 (27.5)	NA	NA	NA	NA	NA	NA	NA	23 (22.5)
Berggren et al²⁸	2007	97	Placebo	82.0 (5.9)	23 (23.7)	NA	NA	NA	NA	NA	NA	NA	17 (17.5)
Zhu et al²²	2008	39	Vitamin D plus calcium	75.4 (2.7)	0	NA	27.6 (4)	NA	26.8 (10.4)	NA	NA	NA	NA
Zhu et al²²	2008	81	Placebo or calcium	74.4 (2.4)	0	NA	28.2 (4.1)	NA	28 (10.4)	NA	NA	NA	NA
Prince et al²⁰	2008	151	Vitamin D plus calcium	77.0 (4.2)	0	NA	29.6 (3.5)	NA	18.1 (5.0)	NA	NA	NA	NA
Prince et al²⁰	2008	151	Placebo plus calcium	77.4 (5.0)	0	NA	28.2 (3.2)	NA	17.7 (5.1)	NA	NA	NA	NA
Vital D/Sanders et al²⁴	2010	1131	Vitamin D	76.4 (5.7)	0	NA	NA	NA	53 (7)	NA	NA	NA	NA
Vital D/Sanders et al²⁴	2010	1125	Placebo	76.5 (5)	0	NA	NA	NA	47 (5)	NA	NA	NA	NA
Lehouck et al³¹	2012	91	Vitamin D	68 (9)	72 (79.1)	13 (14.3)	25 (5)	NA	20 (12)	NA	NA	NA	NA
Lehouck et al³¹	2012	91	Placebo	68 (8)	73 (80.2)	19 (20.9)	24 (5)	NA	20 (11)	NA	NA	NA	NA
VitDISH/Witham et al²¹	2013	80	Vitamin D	76.9 (4.8)	40 (50.0)	NA	28.5 (5.0)	189 (46)	18 (6)	41 (51.3)	136 (11)	80 (100.0)	11 (13.9)
VitDISH/Witham et al²¹	2013	79	Placebo	76.7 (4.5)	42 (53.2)	NA	27.9 (4.5)	193 (42)	18 (6)	46 (58.2)	133 (11)	79 (100.0)	11 (13.9)
OPERA/Wang et al²⁶	2014	30	Vitamin D	60.8 (10.2)	18 (60.0)	3 (10.0)	26.6 (4.4)	167 (39)	NA	18 (60.0)	131 (19)	30 (100.0)	8 (26.7)
OPERA/Wang et al²⁶	2014	30	Placebo	62.2 (10.7)	14 (46.7)	3 (10.0)	26.2 (4.5)	185 (41)	NA	20 (66.7)	135 (15)	30 (100.0)	13 (43.3)
Baron et al¹⁹	2015	1130	Vitamin D plus calcium	58.1 (7)	712 (63.0)	119 (10.5)	28.9 (5.0)	NA	24.7 (8)	NA	NA	NA	NA
Baron et al¹⁹	2015	1129	Placebo plus calcium	58.0 (7)	711 (63.0)	96 (8.5)	29.2 (5.1)	NA	24.4 (8)	NA	NA	NA	NA
EVITA/Zitterman et al¹⁵	2017	199	Vitamin D	55 (10)	166 (83.4)	NA	27.8 (1.7)	NA	13 (3)	113 (56.8)	115 (19)	57 (28.6)	51 (26.7)
EVITA/Zitterman et al¹⁵	2017	201	Placebo	54 (8)	166 (82.6)	NA	27.9 (2.1)	NA	14 (3)	105 (52.2)	117 (18)	63 (31.3)	46 (22.9)
VIDA/Scragg et al¹⁶	2017	2558	Vitamin D	65.9 (8.3)	1512 (59.1)	164 (6.4)	27.9 (4.2)	185 (42)	25.5 (9.5)	NA	139 (19)	955 (37.3)	265 (10.4)
VIDA/Scragg et al¹⁶	2017	2550	Placebo	65.9 (8.3)	1457 (57.1)	156 (6.1)	27.9 (5.7)	189 (42)	25.2 (9.4)	NA	139 (19)	930 (36.5)	239 (9.4)
J-DAVID/Shoji et al¹⁴	2018	488	Vitamin D	65 (10.4)	301 (61.7)	NA	21.1 (3)	153 (32)	NA	77 (15.8)	145 (22)	NA	NA
J-DAVID/Shoji et al¹⁴	2018	476	Placebo	65 (9.67)	277 (58.2)	NA	21.1 (3)	150 (29)	NA	81 (17.0)	147 (19)	NA	NA
VITAL/Manson et al¹³	2018	12 927	Vitamin D	67.1 (7.0)	6380 (49.4)	921 (7.1)	28.1 (5.7)	NA	30.9 (10)	4822 (37.3)	NA	6352 (49.1)	1812 (14.0)
VITAL/Manson et al¹³	2018	12 944	Placebo	67.1 (7.1)	6406 (49.5)	915 (7.1)	28.1 (5.8)	NA	30.8 (10)	4702 (36.3)	NA	6439 (49.7)	1737 (13.4)

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Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); EVITA, Effect of Vitamin D on All-Cause Mortality in Heart Failure Patients; HRT, hormone therapy; IQR, interquartile range; J-DAVID, Japan Dialysis Active Vitamin D; NA, not available; OPERA, Oral Paricalcitol in Retarding Cardiac Hypertrophy, Reducing Inflammation and Atherosclerosis in Stage 3-5 Chronic Kidney Disease; RECORD, Randomized Evaluation of Calcium or Vitamin D; STOP IT, Estrogen and Calcitriol in the Prevention of Age-Related Bone Loss; VIDA, Vitamin D Assessment; VITAL, Vitamin D and Omega-3 Trial; VITDISH, Vitamin D in Isolated Systolic Hypertension; WHI, Women’s Health Initiative.

Primary End Point

There was no significant difference of vitamin D supplementation between groups with regard to MACE incidence (6243 cases; RR, 1.0 [95% CI, 0.95-1.06]; P = .85; I² = 11%; Figure 2 and Figure 3). A funnel plot examination for publication bias is provided in eFigure 2 in the Supplement. Sensitivity analyses through removal of each study sequentially and through stratifications by age, sex, inclusion of only postmenopausal women, pretreatment vitamin D levels of less than 25 ng/mL, inclusion of patients with chronic kidney disease, exclusion of studies that used vitamin D analogues, and vitamin D dosage and formulation (daily vs bolus dosing) showed nonsignificant results (eFigures 3-12 in the Supplement). Meta-regression analysis based on sex, BMI, follow-up duration, and age showed a significant association of reduced MACE incidence with advanced age (R² = 100%; b, −0.01; SE = .004; P = .04), but the P value was not adjusted for multiple comparisons (eFigure 13 in the Supplement).

In trial sequential analysis, the optimal information size was obtained (diversity adjusted), indicating firm evidence for the lack of an association of MACE reductions with vitamin D supplementation. Details are presented in eFigure 14 in the Supplement.

Secondary End Points

Vitamin D supplementation, compared with placebo, was not associated with a reduced risk of MI (2550 cases; RR, 1.00 [95% CI, 0.93-1.08]; P = .92; I² = 0%), stroke/CVA (2354 cases; RR, 1.06 [95% CI, 0.98-1.15]; P = .16; I² = 0%), cardiovascular mortality (2202 cases; RR, 0.98 [95% CI, 0.90-1.07]; P = .68; I² = 2%), or all-cause mortality (6502 cases; RR, 0.97 [95% CI, 0.93-1.02]; P = .23; I² = 0%). Figure 2 and Figure 3 present these data.

Discussion

In this comprehensive meta-analysis of randomized clinical trials (n = 83 291 participants) evaluating the cardiovascular effect of vitamin D, we found that vitamin D supplementation was not associated with reduced risk of incident MACE, MI, stroke/CVA, CVD mortality, or all-cause mortality. Observational studies have shown significant associations between low vitamin D level, CVD events, and all-cause mortality.³⁸ However, observational studies are susceptible to uncontrolled confounding by outdoor physical activity, nutritional status, and prevalent chronic disease, which may influence serum 25 hydroxyvitamin D levels.³⁹ Supplementation with vitamin D has not been associated with reduced rates of CVD in previous meta-analyses of RCTs.^40,41 In this updated meta-analysis, which extended the earlier findings and included several recent RCTs, we did not find any association between vitamin D supplementation and cardiovascular events. Interestingly, a stratified analysis according to age showed a significantly reduced MACE rate with advanced age, and this was suggested by the Manson et al¹³ and Trivedi et al³⁵ studies, because vitamin D supplementation in elderly people showed a trend toward lower CVD events. On the other hand, a stratified analysis did not show significant differences by sex, concurrent calcium administration, pretreatment 25-hydroxyvitamin D level (<25 ng/mL vs higher), BMI, vitamin D dosage, formulation (daily vs bolus dosing), or other factors. The regression analysis findings for age should be interpreted cautiously owing to lack of adjustment for multiple comparisons.

In a previous meta-analysis of RCTs,⁴¹ vitamin D supplementation showed no benefit in reducing MI, but a potential benefit for heart failure was observed. This meta-analysis confirms an absence of benefit for MI, as well as no reduction in stroke, CVD mortality, or a composite MACE end point. Despite the fact that we aimed in this analysis to study cardiovascular outcomes, most of the trials were not designed to assess CVD events as primary prespecified outcomes; rather, they were designed to assess effects of vitamin D on fracture or osteoporosis and tended to include primarily older patients and women who were postmenopausal.^{20,21,22,24,28,32,33,34,35} Only 4 trials focused on cardiovascular events as a primary prespecified end point; however, these trials also did not show cardiovascular or mortality benefits.^13,14,15,16

Although observational studies have suggested that low serum levels of 25-hydroxyvitamin D are associated with an increased risk of CVD events, the effects of vitamin D supplementation did not appear to vary according to baseline 25-hydroxyvitamin D levels in either the Vitamin D and Omega-3 Trial (VITAL)¹³or Vitamin D Assessment (VIDA) trials.¹⁶ Furthermore, in the sensitivity analysis for trials that had a mean 25-hydroxyvitamin D of 25 ng/mL or less, we did not find an association of vitamin D supplementation with significantly reduced CVD events or all-cause mortality in these participants. Moreover, although several studies focused on patients with chronic kidney disease^14,26 because they have low 25-hydroxyvitamin D levels and are at high risk of cardiovascular disease,⁴² the sensitivity analysis of these trials did not show cardiovascular benefit of vitamin D supplementation in these patients.

Higher prevalence of lower 25-hydroxyvitamin D levels among racial/ethnic groups who are darker skinned than white people are, likely in association with lower vitamin D synthesis in the skin and differences in vitamin D metabolism, has been reported previously.⁴³ However, previous studies have shown no associations of such low levels with CVD events,⁴⁴ even with vitamin D supplementation.¹³ Similarly, although low vitamin D levels have been associated with both the risk of CVA and the functional outcome after CVA in observational studies,⁴⁵ this meta-analysis did not demonstrate a protective effect of vitamin D supplementation with regard to stroke/CVA.^40,41 In summary, the included trials, although different in their inclusion criteria, showed consistent findings of no significant benefit of vitamin D supplementation in reducing CVD events and all-cause mortality.

Limitation

This study has limitations that warrant consideration. Most of the included trials had not prespecified CVD as the primary end point and were underpowered for CVD events. Also, the definition of MACE was variable in the included trials, and few trials included data on heart failure. In addition, the results of the subgroup analyses should be interpreted cautiously owing to low data counts, and additional large trials are needed for definitive conclusions. Finally, we lacked patient-level data and could not examine some of the subgroups of interest.

Conclusions

Vitamin D supplementation was not associated with reduced risks of MACE, MI, stroke, cardiovascular mortality, or all-cause mortality. Additional trials of higher-dose vitamin D supplementation, perhaps targeting members of older age groups and with attention to other CVD end points such as heart failure, are of interest.

Supplement.

eTable. Major adverse cardiovascular event definition per each study.

eFigure 1. Risk of bias summary: review authors’ judgments about each risk of bias item for each included study.

eFigure 2. Funnel plot of primary endpoints (Major adverse cardiovascular events).

eFigure 3. Forest plot of the sensitivity analysis for elderly patients.

eFigure 4. Forest plot of the sensitivity analysis for female and male patients.

eFigure 5. Forest plot of the sensitivity analysis for postmenopausal women.

eFigure 6. Forest plot of the sensitivity analysis for studies with pretreatment 25-hydroxyvitamin D level less than 25 ng/ml.

eFigure 7. Forest plot of the sensitivity analysis for chronic kidney disease.

eFigure 8. Forest plot of the sensitivity analysis by excluding studies that used vitamin D analogues.

eFigure 9. Forest plot of the sensitivity analysis by including only the studies that used daily vitamin D supplementation.

eFigure 10. Forest plot of the sensitivity analysis by including only the studies that used bolus vitamin D supplementation.

eFigure 11. Forest plot of the sensitivity analysis by including studies that used vitamin D supplementation with calcium.

eFigure 12. Forest plot of the sensitivity analysis by including studies that used vitamin D supplementation without calcium.

eFigure 13. Meta-regression analysis on major adverse cardiovascular events according to age.

eFigure 14. Trial sequential analysis for major adverse cardiovascular events.

Click here for additional data file.^{(511KB, pdf)}

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