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Figure 1.
The Study Selection Strategy
The Study Selection Strategy
Figure 2.
Forest Plot Illustrating the Results of the Primary and Secondary End Points, Part 1
Forest Plot Illustrating the Results of the Primary and Secondary End Points, Part 1
Figure 3.
Forest Plot Illustrating the Results of the Primary and Secondary End Points, Part 2
Forest Plot Illustrating the Results of the Primary and Secondary End Points, Part 2
Table 1.  
Characteristics of the Involved Trials
Characteristics of the Involved Trials
Table 2.  
Patients’ Demographic and Clinical Characteristics
Patients’ Demographic and Clinical Characteristics
1.
Giovannucci  E, Liu  Y, Hollis  BW, Rimm  EB.  25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study.  Arch Intern Med. 2008;168(11):1174-1180. doi:10.1001/archinte.168.11.1174PubMedGoogle ScholarCrossref
2.
Pekkanen  MP, Ukkola  O, Hedberg  P,  et al.  Serum 25-hydroxyvitamin D is associated with major cardiovascular risk factors and cardiac structure and function in patients with coronary artery disease.  Nutr Metab Cardiovasc Dis. 2015;25(5):471-478. doi:10.1016/j.numecd.2015.02.005PubMedGoogle ScholarCrossref
3.
Gandini  S, Boniol  M, Haukka  J,  et al.  Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma.  Int J Cancer. 2011;128(6):1414-1424. doi:10.1002/ijc.25439PubMedGoogle ScholarCrossref
4.
Kheiri  B, Abdalla  A, Osman  M, Ahmed  S, Hassan  M, Bachuwa  G.  Vitamin D deficiency and risk of cardiovascular diseases: a narrative review.  Clin Hypertens. 2018;24:9. doi:10.1186/s40885-018-0094-4PubMedGoogle ScholarCrossref
5.
Kim  DH, Sabour  S, Sagar  UN, Adams  S, Whellan  DJ.  Prevalence of hypovitaminosis D in cardiovascular diseases (from the National Health and Nutrition Examination Survey 2001 to 2004).  Am J Cardiol. 2008;102(11):1540-1544. doi:10.1016/j.amjcard.2008.06.067PubMedGoogle ScholarCrossref
6.
Norman  AW.  From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health.  Am J Clin Nutr. 2008;88(2):491S-499S. doi:10.1093/ajcn/88.2.491SPubMedGoogle ScholarCrossref
7.
Simpson  RU, Hershey  SH, Nibbelink  KA.  Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse.  J Steroid Biochem Mol Biol. 2007;103(3-5):521-524. doi:10.1016/j.jsbmb.2006.12.098PubMedGoogle ScholarCrossref
8.
Beveridge  LA, Witham  MD.  Vitamin D and the cardiovascular system.  Osteoporos Int. 2013;24(8):2167-2180. doi:10.1007/s00198-013-2281-1PubMedGoogle ScholarCrossref
9.
Al Mheid  I, Patel  RS, Tangpricha  V, Quyyumi  AA.  Vitamin D and cardiovascular disease: is the evidence solid?  Eur Heart J. 2013;34(48):3691-3698. doi:10.1093/eurheartj/eht166PubMedGoogle ScholarCrossref
10.
Al Mheid  I, Quyyumi  AA.  Vitamin D and cardiovascular disease: controversy unresolved.  J Am Coll Cardiol. 2017;70(1):89-100. doi:10.1016/j.jacc.2017.05.031PubMedGoogle ScholarCrossref
11.
LeFevre  ML; U.S. Preventive Services Task Force.  Screening for vitamin D deficiency in adults: U.S. Preventive Services Task Force recommendation statement.  Ann Intern Med. 2015;162(2):133-140. doi:10.7326/M14-2450PubMedGoogle ScholarCrossref
12.
Kantor  ED, Rehm  CD, Du  M, White  E, Giovannucci  EL.  Trends in dietary supplement use among US adults from 1999-2012.  JAMA. 2016;316(14):1464-1474. doi:10.1001/jama.2016.14403PubMedGoogle ScholarCrossref
13.
Manson  JE, Cook  NR, Lee  I-M,  et al; VITAL Research Group.  Vitamin D supplements and prevention of cancer and cardiovascular disease.  N Engl J Med. 2019;380(1):33-44. doi:10.1056/NEJMoa1809944PubMedGoogle ScholarCrossref
14.
Shoji  T, Inaba  M, Fukagawa  M,  et al; J-DAVID Investigators.  Effect of oral alfacalcidol on clinical outcomes in patients without secondary hyperparathyroidism receiving maintenance hemodialysis: the J-DAVID randomized clinical trial.  JAMA. 2018;320(22):2325-2334. doi:10.1001/jama.2018.17749PubMedGoogle ScholarCrossref
15.
Zittermann  A, Ernst  JB, Prokop  S,  et al.  Effect of vitamin D on all-cause mortality in heart failure (EVITA): a 3-year randomized clinical trial with 4000 IU vitamin D daily.  Eur Heart J. 2017;38(29):2279-2286. doi:10.1093/eurheartj/ehx235PubMedGoogle ScholarCrossref
16.
Scragg  R, Stewart  AW, Waayer  D,  et al.  Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study : a randomized clinical trial.  JAMA Cardiol. 2017;2(6):608-616. doi:10.1001/jamacardio.2017.0175PubMedGoogle ScholarCrossref
17.
Liberati  A, Altman  DG, Tetzlaff  J,  et al.  The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.  J Clin Epidemiol. 2009;62(10):e1-e34. doi:10.1016/j.jclinepi.2009.06.006PubMedGoogle ScholarCrossref
18.
Thorlund  K, Devereaux  PJ, Wetterslev  J,  et al.  Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses?  Int J Epidemiol. 2009;38(1):276-286. doi:10.1093/ije/dyn179PubMedGoogle ScholarCrossref
19.
Baron  JA, Barry  EL, Mott  LA,  et al.  A trial of calcium and vitamin D for the prevention of colorectal adenomas.  N Engl J Med. 2015;373(16):1519-1530. doi:10.1056/NEJMoa1500409PubMedGoogle ScholarCrossref
20.
Prince  RL, Austin  N, Devine  A, Dick  IM, Bruce  D, Zhu  K.  Effects of ergocalciferol added to calcium on the risk of falls in elderly high-risk women.  Arch Intern Med. 2008;168(1):103-108. doi:10.1001/archinternmed.2007.31PubMedGoogle ScholarCrossref
21.
Witham  MD, Price  RJG, Struthers  AD,  et al.  Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.  JAMA Intern Med. 2013;173(18):1672-1679. doi:10.1001/jamainternmed.2013.9043PubMedGoogle Scholar
22.
Zhu  K, Devine  A, Dick  IM, Wilson  SG, Prince  RL.  Effects of calcium and vitamin D supplementation on hip bone mineral density and calcium-related analytes in elderly ambulatory Australian women: a five-year randomized controlled trial.  J Clin Endocrinol Metab. 2008;93(3):743-749. doi:10.1210/jc.2007-1466PubMedGoogle ScholarCrossref
23.
Ott  SM, Chesnut  CH  III.  Calcitriol treatment is not effective in postmenopausal osteoporosis.  Ann Intern Med. 1989;110(4):267-274. doi:10.7326/0003-4819-110-4-267PubMedGoogle ScholarCrossref
24.
Sanders  KM, Stuart  AL, Williamson  EJ,  et al.  Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.  JAMA. 2010;303(18):1815-1822. doi:10.1001/jama.2010.594PubMedGoogle ScholarCrossref
25.
Aloia  JF, Vaswani  A, Yeh  JK, Ellis  K, Yasumura  S, Cohn  SH.  Calcitriol in the treatment of postmenopausal osteoporosis.  Am J Med. 1988;84(3 pt 1):401-408. doi:10.1016/0002-9343(88)90259-8PubMedGoogle ScholarCrossref
26.
Wang  AY-M, Fang  F, Chan  J,  et al.  Effect of paricalcitol on left ventricular mass and function in CKD—the OPERA trial.  J Am Soc Nephrol. 2014;25(1):175-186. doi:10.1681/ASN.2013010103PubMedGoogle ScholarCrossref
27.
Jackson  RD, LaCroix  AZ, Gass  M,  et al; Women’s Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of fractures.  N Engl J Med. 2006;354(7):669-683. doi:10.1056/NEJMoa055218PubMedGoogle ScholarCrossref
28.
Berggren  M, Stenvall  M, Olofsson  B, Gustafson  Y.  Evaluation of a fall-prevention program in older people after femoral neck fracture: a one-year follow-up.  Osteoporos Int. 2008;19(6):801-809. doi:10.1007/s00198-007-0507-9PubMedGoogle ScholarCrossref
29.
Komulainen  M, Kröger  H, Tuppurainen  MT,  et al.  Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women: a population-based 5-year randomized trial.  J Clin Endocrinol Metab. 1999;84(2):546-552. doi:10.1210/jcem.84.2.5496PubMedGoogle Scholar
30.
Schleithoff  SS, Zittermann  A, Tenderich  G, Berthold  HK, Stehle  P, Koerfer  R.  Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.  Am J Clin Nutr. 2006;83(4):754-759. doi:10.1093/ajcn/83.4.754PubMedGoogle ScholarCrossref
31.
Lehouck  A, Mathieu  C, Carremans  C,  et al.  High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial.  Ann Intern Med. 2012;156(2):105-114. doi:10.7326/0003-4819-156-2-201201170-00004PubMedGoogle ScholarCrossref
32.
Grant  AM, Avenell  A, Campbell  MK,  et al; RECORD Trial Group.  Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or Vitamin D, RECORD): a randomised placebo-controlled trial.  Lancet. 2005;365(9471):1621-1628. doi:10.1016/S0140-6736(05)63013-9PubMedGoogle ScholarCrossref
33.
Brazier  M, Grados  F, Kamel  S,  et al.  Clinical and laboratory safety of one year’s use of a combination calcium + vitamin D tablet in ambulatory elderly women with vitamin D insufficiency: results of a multicenter, randomized, double-blind, placebo-controlled study.  Clin Ther. 2005;27(12):1885-1893. doi:10.1016/j.clinthera.2005.12.010PubMedGoogle ScholarCrossref
34.
Gallagher  JC, Fowler  SE, Detter  JR, Sherman  SS.  Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss.  J Clin Endocrinol Metab. 2001;86(8):3618-3628. doi:10.1210/jcem.86.8.7703PubMedGoogle ScholarCrossref
35.
Trivedi  DP, Doll  R, Khaw  KT.  Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.  BMJ. 2003;326(7387):469. doi:10.1136/bmj.326.7387.469PubMedGoogle ScholarCrossref
36.
Cauley  JA, Chlebowski  RT, Wactawski-Wende  J,  et al.  Calcium plus vitamin D supplementation and health outcomes five years after active intervention ended: the Women’s Health Initiative.  J Womens Health (Larchmt). 2013;22(11):915-929. doi:10.1089/jwh.2013.4270PubMedGoogle ScholarCrossref
37.
Hsia  J, Heiss  G, Ren  H,  et al; Women’s Health Initiative Investigators.  Calcium/vitamin D supplementation and cardiovascular events.  Circulation. 2007;115(7):846-854. doi:10.1161/CIRCULATIONAHA.106.673491PubMedGoogle ScholarCrossref
38.
Grandi  NC, Breitling  LP, Brenner  H.  Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies.  Prev Med. 2010;51(3-4):228-233. doi:10.1016/j.ypmed.2010.06.013PubMedGoogle ScholarCrossref
39.
Ross  AC, Taylor  CL, Yaktine  AL, Del Valle  HB, eds.  Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press;2011. doi:10.17226/13050.
40.
Elamin  MB, Abu Elnour  NO, Elamin  KB,  et al.  Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis.  J Clin Endocrinol Metab. 2011;96(7):1931-1942. doi:10.1210/jc.2011-0398PubMedGoogle ScholarCrossref
41.
Ford  JA, MacLennan  GS, Avenell  A, Bolland  M, Grey  A, Witham  M; RECORD Trial Group.  Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis.  Am J Clin Nutr. 2014;100(3):746-755. doi:10.3945/ajcn.113.082602PubMedGoogle ScholarCrossref
42.
Sarnak  MJ, Levey  AS, Schoolwerth  AC,  et al; American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.  Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.  Circulation. 2003;108(17):2154-2169. doi:10.1161/01.CIR.0000095676.90936.80PubMedGoogle ScholarCrossref
43.
Harris  SS.  Vitamin D and African Americans.  J Nutr. 2006;136(4):1126-1129. doi:10.1093/jn/136.4.1126PubMedGoogle ScholarCrossref
44.
Zhang  X, Tu  W, Manson  JE,  et al.  Racial/ethnic differences in 25-hydroxy Vitamin D and parathyroid hormone levels and cardiovascular disease risk among postmenopausal women.  J Am Heart Assoc. 2019;8(4):e011021. doi:10.1161/JAHA.118.011021PubMedGoogle ScholarCrossref
45.
Wang  Y, Ji  H, Tong  Y, Zhang  ZB.  Prognostic value of serum 25-hydroxyvitamin D in patients with stroke.  Neurochem Res. 2014;39(7):1332-1337. doi:10.1007/s11064-014-1316-0PubMedGoogle ScholarCrossref
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Original Investigation
June 19, 2019

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

Author Affiliations
  • 1Department of Internal Medicine, Hurley Medical Center, Michigan State University, Flint
  • 2Department of Internal Medicine, Mutah University, Al-Karak, Jordan
  • 3Division of Cardiology, Hurley Medical Center, Michigan State University, Flint
  • 4Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
JAMA Cardiol. 2019;4(8):765-775. doi:10.1001/jamacardio.2019.1870
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.

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.1-3 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.

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.13-16,19-35 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.

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.20-22,24,28,32-35 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.

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.

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Article Information

Accepted for Publication: April 10, 2019.

Corresponding Author: Mahmoud Barbarawi, MD, Department of Internal Medicine, Hurley Medical Center, Michigan State University, Two Hurley Plaza, Ste 212, Flint, MI 48503 (mahmoud.albarbarawi@gmail.com; mbarbar1@hurleymc.com).

Published Online: June 19, 2019. doi:10.1001/jamacardio.2019.1870

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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