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.
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Barbarawi M, Kheiri B, Zayed Y, et al. Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83 000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis. JAMA Cardiol. 2019;4(8):765–776. doi:10.1001/jamacardio.2019.1870
Does vitamin D supplementation have any association with cardiovascular disease risk?
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.
These results suggest that vitamin D supplementation may not confer cardiovascular protection and may not be indicated for this purpose.
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.
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.
Literature search through PubMed, the Cochrane Library, and Embase was completed by 2 reviewers from each database’s inception to December 15, 2018.
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.
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.
Observational studies have suggested an inverse association between serum 25-hydroxyvitamin D levels and risk of cardiovascular disease (CVD) events.1-3 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.8-10
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).13-16 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.13-16 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.
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.
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.
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.).
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.
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.
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.
After reviewing 7816 studies from the databases, 7796 studies were excluded. Twenty-one RCTs were included in the final analysis.13-16,19-35 Eight trials included postmenopausal women,22-25,27,29,33,34 9 trials included older patients,20-22,24,28,32-35 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,13,15,16,19,21,23-25,27,30-33,35 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.
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.
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.
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.20-22,24,28,32-35 Only 4 trials focused on cardiovascular events as a primary prespecified end point; however, these trials also did not show cardiovascular or mortality benefits.13-16
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 disease14,26 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.
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.
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.
Accepted for Publication: April 10, 2019.
Published Online: June 19, 2019. doi:10.1001/jamacardio.2019.1870
Correction: This article was corrected on November 6, 2019, to fix multiple errors in Table 1 and Figures 2 and 3. In Table 1, the study period of the Vitamin D in Isolated Systolic Hypertension (VITDISH) study by Witham et al was stated as 2009 to 2001 but should have been 2009 to 2011. The study period of Vitamin D and Omega-3 Trial (VITAL) study by Manson et al was reported as 2011 to 2014, but this should have been 2011 to 2017. There are also several errors in Figure 2. With respect to the major adverse cardiovascular events (MACE) outcome, the total number of populations in the study by Jackson et al are given as 18 106 in the vitamin D group and 18 176 in the placebo group; these values should be 18 176 and 18 106, respectively. Per resulting recalculations, the upper bound of the 95% CI of the Jackson et al study decreased by 0.01 (from 0.96-1.11 to 0.96-1.10). In addition, in the same section, the total population for the MACE outcome was reported incorrectly as 39 528 and 39 583 in the vitamin D and placebo groups, respectively; the numbers should instead be 39 598 and 39 513, respectively. In addition, in the MACE portion of Figure 2, several statistical phrases were incorrect, including a 95% CI reported as 0.95 to 1.06 (corrected to 0.95-1.05), a P value stated as .85 (corrected to .93), and an I2 statistic stated as 11% (corrected to 8%). In the all-cause mortality section of Figure 2, event numbers for the Lehouck et al study are listed as 8 events in the group receiving vitamin D and 0 in those receiving placebo; there should have been reported as 9 and 6 events, respectively. With regard to the all-cause mortality values for the study by Jackson et al, the total population numbers were listed as 18 178 and 18 176 for the vitamin D and placebo groups, respectively, but these should have been 18 176 and 18 106, respectively. This change means that the associated 95% CI has been corrected from 0.92 to 1.04 to 0.91 to 1.03. Finally, in Figure 2, the hazard ratio (95% CI) for the cardiovascular (CVD) mortality subtotal was given as 0.98 (0.00-1.07); this should instead have been 0.98 (0.90-1.07). In Figure 3, there are 2 further errors. With respect to the myocardial infarction outcome, the relative ratio (95% CI) for the Prince et al study is listed as 0.87 (0.11-3.83); it should instead have been stated as 0.67 (0.11-3.93). Finally, the 95% CI of the subtotal in the myocardial infarction section of Figure 3 was stated as 0.03 to 1.08; it should have been 0.93 to 1.08. These errors have been corrected.
Corresponding Author: Mahmoud Barbarawi, MD, Department of Internal Medicine, Hurley Medical Center, Michigan State University, Two Hurley Plaza, Ste 212, Flint, MI 48503 (email@example.com; firstname.lastname@example.org).
Author Contributions: Dr Barbarawi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: M. Barbarawi, Kheiri, Zayed, Dhillon, Swaid, Bachuwa, Manson.
Acquisition, analysis, or interpretation of data: M. Barbarawi, Kheiri, Zayed, O. Barbarawi, Yelangi, Sundus, Alkotob, Manson.
Drafting of the manuscript: M. Barbarawi, Kheiri, Zayed, Dhillon, Sundus.
Critical revision of the manuscript for important intellectual content: M. Barbarawi, Kheiri, O. Barbarawi, Swaid, Yelangi, Sundus, Bachuwa, Alkotob, Manson.
Statistical analysis: M. Barbarawi, Kheiri, Zayed.
Administrative, technical, or material support: O. Barbarawi, Dhillon, Yelangi, Sundus, Manson.
Supervision: M. Barbarawi, Swaid, Bachuwa, Alkotob, Manson.
Conflict of Interest Disclosures: Dr Manson received funding from the US National Institutes of Health to conduct the Vitamin D and ω-3 Trial (VITAL). Vitamin D study pills were donated by Pharmavite LLC and Omega-3 supplements were donated by Pronova BioPharma and BASF. No other disclosures were reported.
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