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Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients

Loucera et al., Scientific Reports, doi:10.1038/s41598-021-02701-5 (date from preprint)
Apr 2021  
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Mortality 33% Improvement Relative Risk Mortality (b) 27% Mortality (c) 25% Mortality (d) 12% Vitamin D for COVID-19  Loucera et al.  Prophylaxis Is prophylaxis with vitamin D beneficial for COVID-19? PSM retrospective 1,604 patients in Spain Lower mortality with vitamin D (p=0.0088) c19early.org Loucera et al., Scientific Reports, Apr 2021 Favorsvitamin D Favorscontrol 0 0.5 1 1.5 2+
Vitamin D for COVID-19
8th treatment shown to reduce risk in October 2020
 
*, now with p < 0.00000000001 from 122 studies, recognized in 9 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,400+ studies for 79 treatments. c19early.org
Retrospective 15,968 hospitalized patients in Spain showing a significant reduction in mortality associated with the prescription of vitamin D, especially calcifediol, within 15-30 days prior to hospitalization.
This is the 31st of 122 COVID-19 controlled studies for vitamin D, which collectively show efficacy with p<0.0000000001 (1 in 587 sextillion).
30 studies are RCTs, which show efficacy with p=0.0000032.
risk of death, 33.0% lower, HR 0.67, p = 0.009, treatment 374, control 374, calcifediol, <15 days before hospitalization, Cox model with inverse propensity weighting.
risk of death, 27.0% lower, HR 0.73, p = 0.02, treatment 439, control 439, calcifediol, <30 days before hospitalization, Cox model with inverse propensity weighting.
risk of death, 25.0% lower, HR 0.75, p = 0.005, treatment 570, control 570, cholecalciferol, <15 days before hospitalization, Cox model with inverse propensity weighting.
risk of death, 12.0% lower, HR 0.88, p = 0.11, treatment 802, control 802, cholecalciferol, <30 days before hospitalization, Cox model with inverse propensity weighting.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Loucera et al., 29 Apr 2021, retrospective, propensity score matching, Spain, peer-reviewed, 11 authors, dosage varies (calcifediol).
This PaperVitamin DAll
Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients
Carlos Loucera, María Peña-Chilet, Marina Esteban-Medina, Dolores Muñoyerro-Muñiz, Román Villegas, Jose Lopez-Miranda, Jesus Rodriguez-Baño, Isaac Túnez, Roger Bouillon, Joaquin Dopazo, Jose Manuel Quesada Gomez
Scientific Reports, doi:10.1038/s41598-021-02701-5
COVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15-30 days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan-Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95% confidence interval, CI, of [0.50-0.91]) than for cholecalciferol (HR = 0.75, with 95% CI of [0.61-0.91]), when prescribed 15 days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30 days prior hospitalization is considered (calcifediol HR = 0.73, with 95% CI [0.57-0.95] and cholecalciferol HR = 0.88, with 95% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization.
Author contributions C.L.: Data curation, Formal Analysis, Investigation, Visualization; M.P.C.: Formal Analysis; M.E.M.: Formal Analysis; D.M.M.: Resources; R.V.: Resources; J.L.M.: Writing-review and editing; J.R.B.: Writing-review and editing; I.T.: Writing-review and editing; R.B.: Writing-review and editing; J.D.: Supervision, Project administration, Writing-original draft; J.M.Q.G.: Supervision, Writing-original draft. All authors reviewed the manuscript. Competing interests RB declares payment of honoraria for lectures by FAES (Spain), Abiogen (Italy) and Fresenius (Germany). JMQ declares small consulting fees and small lecture fees from Amgen and FESE Farma (Spain). The rest of authors declare no competing interests. Additional information Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1038/ s41598-021-02701-5. Correspondence and requests for materials should be addressed to J.D. or J.M.Q.G. Reprints and permissions information is available at www.nature.com/reprints. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Interv.'}, { 'key': '2701_CR24', 'doi-asserted-by': 'crossref', 'first-page': '1', 'DOI': '10.1007/s00392-016-1025-6', 'volume': '106', 'author': 'MR Cowie', 'year': '2017', 'unstructured': 'Cowie, M. R. et al. Electronic health records to facilitate clinical ' 'research. Clin. Res. Cardiol. 106, 1–9 (2017).', 'journal-title': 'Clin. Res. Cardiol.'}, { 'key': '2701_CR25', 'doi-asserted-by': 'crossref', 'first-page': '105', 'DOI': '10.1016/j.gaceta.2019.03.003', 'volume': '34', 'author': 'D Muñoyerro-Muñiz', 'year': '2019', 'unstructured': 'Muñoyerro-Muñiz, D. et al. Health record linkage: Andalusian health ' 'population database. Gac. Sanit. 34, 105–113 (2019).', 'journal-title': 'Gac. Sanit.'}, { 'key': '2701_CR26', 'doi-asserted-by': 'crossref', 'first-page': '369', 'DOI': '10.1002/cpt.1586', 'volume': '107', 'author': 'G Carrigan', 'year': '2020', 'unstructured': 'Carrigan, G. et al. 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Ther.'}, { 'key': '2701_CR31', 'doi-asserted-by': 'crossref', 'first-page': '1195', 'DOI': '10.1007/s40520-020-01570-8', 'volume': '32', 'author': 'PC Ilie', 'year': '2020', 'unstructured': 'Ilie, P. C., Stefanescu, S. & Smith, L. The role of vitamin D in the ' 'prevention of coronavirus disease 2019 infection and mortality. Aging ' 'Clin. Exp. Res. 32, 1195–1198 (2020).', 'journal-title': 'Aging Clin. Exp. Res.'}, { 'key': '2701_CR32', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.medidd.2020.100041', 'volume': '6', 'author': 'PE Marik', 'year': '2020', 'unstructured': 'Marik, P. E., Kory, P. & Varon, J. Does vitamin D status impact ' 'mortality from SARS-CoV-2 infection?. Med. Drug Discov. 6, 100041 ' '(2020).', 'journal-title': 'Med. Drug Discov.'}, { 'key': '2701_CR33', 'doi-asserted-by': 'crossref', 'first-page': '1967', 'DOI': '10.1002/jbmr.4387', 'volume': '36', 'author': 'JL Pérez-Castrillón', 'year': '2021', 'unstructured': 'Pérez-Castrillón, J. L. et al. 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' 'Vitamin D deficiency is associated with higher hospitalization risk from ' 'COVID-19: A retrospective case-control study. J. Clin. Endocrinol. ' 'Metab. 106, e4708–e4715. https://doi.org/10.1210/clinem/dgab439 (2021).', 'journal-title': 'J. Clin. Endocrinol. Metab.'}, { 'key': '2701_CR41', 'doi-asserted-by': 'crossref', 'first-page': 'R133', 'DOI': '10.1530/EJE-20-0665', 'volume': '183', 'author': 'JP Bilezikian', 'year': '2020', 'unstructured': 'Bilezikian, J. P. et al. Mechanisms in endocrinology: Vitamin D and ' 'COVID-19. Eur. J. Endocrinol. 183, R133–R147 (2020).', 'journal-title': 'Eur. J. Endocrinol.'}, { 'key': '2701_CR42', 'volume': '202', 'author': 'JM Quesada-Gomez', 'year': '2020', 'unstructured': 'Quesada-Gomez, J. M., Entrenas-Castillo, M. & Bouillon, R. Vitamin D ' 'receptor stimulation to reduce acute respiratory distress syndrome ' '(ARDS) in patients with coronavirus SARS-CoV-2 infections: Revised Ms ' 'SBMB 2020_166. J. Steroid Biochem. Mol. 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' 'Steroids 76, 1305–1309 (2011).', 'journal-title': 'Steroids'}, { 'key': '2701_CR45', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.bcp.2020.113955', 'volume': '177', 'author': 'S Zheng', 'year': '2020', 'unstructured': 'Zheng, S. et al. Vitamin D attenuates lung injury via stimulating ' 'epithelial repair, reducing epithelial cell apoptosis and inhibits TGF-β ' 'induced epithelial to mesenchymal transition. Biochem. Pharmacol. 177, ' '113955 (2020).', 'journal-title': 'Biochem. Pharmacol.'}, { 'key': '2701_CR46', 'doi-asserted-by': 'crossref', 'first-page': '2116', 'DOI': '10.1210/me.2013-1146', 'volume': '27', 'author': 'J Kong', 'year': '2013', 'unstructured': 'Kong, J. et al. VDR attenuates acute lung injury by blocking Ang-2-Tie-2 ' 'pathway and renin-angiotensin system. Mol. Endocrinol. 27, 2116–2125 ' '(2013).', 'journal-title': 'Mol. Endocrinol.'}, { 'key': '2701_CR47', 'doi-asserted-by': 'crossref', 'first-page': '1186', 'DOI': '10.3892/mmr.2015.4685', 'volume': '13', 'author': 'YY Shi', 'year': '2016', 'unstructured': 'Shi, Y. Y. et al. Vitamin D/VDR signaling attenuates ' 'lipopolysaccharide-induced acute lung injury by maintaining the ' 'integrity of the pulmonary epithelial barrier. Mol. Med. Rep. 13, ' '1186–1194 (2016).', 'journal-title': 'Mol. Med. Rep.'}, { 'key': '2701_CR48', 'doi-asserted-by': 'crossref', 'first-page': '1367', 'DOI': '10.1096/fj.15-272872', 'volume': '30', 'author': 'JM Martinez-Moreno', 'year': '2016', 'unstructured': 'Martinez-Moreno, J. M. et al. Vitamin D modulates tissue factor and ' 'protease-activated receptor 2 expression in vascular smooth muscle ' 'cells. FASEB J. 30, 1367–1376 (2016).', 'journal-title': 'FASEB J.'}, { 'key': '2701_CR49', 'doi-asserted-by': 'crossref', 'first-page': '1447', 'DOI': '10.1530/EC-19-0429', 'volume': '8', 'author': 'M Blondon', 'year': '2019', 'unstructured': 'Blondon, M. et al. Thrombin generation and fibrin clot structure after ' 'vitamin D supplementation. Endocr. Connect. 8, 1447–1454 (2019).', 'journal-title': 'Endocr. Connect.'}, { 'key': '2701_CR50', 'doi-asserted-by': 'crossref', 'first-page': '7432', 'DOI': '10.3892/mmr.2017.7546', 'volume': '16', 'author': 'J Xu', 'year': '2017', 'unstructured': 'Xu, J. et al. Vitamin D alleviates lipopolysaccharide-induced acute lung ' 'injury via regulation of the renin-angiotensin system. Mol. Med. Rep. ' '16, 7432–7438 (2017).', 'journal-title': 'Mol. Med. Rep.'}, { 'key': '2701_CR51', 'doi-asserted-by': 'crossref', 'first-page': '1189', 'DOI': '10.1093/ajcn/nqab123', 'volume': '114', 'author': 'N Charoenngam', 'year': '2021', 'unstructured': 'Charoenngam, N. et al. A pilot-randomized, double-blind crossover trial ' 'to evaluate the pharmacokinetics of orally administered ' '25-hydroxyvitamin D3 and vitamin D3 in healthy adults with differing BMI ' 'and in adults with intestinal malabsorption. Am. J. Clin. Nutr. 114, ' '1189–1199 (2021).', 'journal-title': 'Am. J. Clin. Nutr.'}, { 'key': '2701_CR52', 'doi-asserted-by': 'crossref', 'first-page': '1697', 'DOI': '10.1007/s00198-018-4520-y', 'volume': '29', 'author': 'J Quesada-Gomez', 'year': '2018', 'unstructured': 'Quesada-Gomez, J. & Bouillon, R. Is calcifediol better than ' 'cholecalciferol for vitamin D supplementation?. Osteoporos. Int. 29, ' '1697–1711 (2018).', 'journal-title': 'Osteoporos. 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Matching as nonparametric ' 'preprocessing for reducing model dependence in parametric causal ' 'inference. Polit. Anal. 15, 199–236 (2007).', 'journal-title': 'Polit. Anal.'}, { 'key': '2701_CR58', 'doi-asserted-by': 'crossref', 'first-page': '1151', 'DOI': '10.1002/bimj.201700330', 'volume': '60', 'author': 'D Hajage', 'year': '2018', 'unstructured': 'Hajage, D. et al. Closed-form variance estimator for weighted propensity ' 'score estimators with survival outcome. Biom. J. 60, 1151–1163 (2018).', 'journal-title': 'Biom. J.'}, { 'key': '2701_CR59', 'doi-asserted-by': 'crossref', 'first-page': '4', 'DOI': '10.1162/003465304323023651', 'volume': '86', 'author': 'GW Imbens', 'year': '2004', 'unstructured': 'Imbens, G. W. Nonparametric estimation of average treatment effects ' 'under exogeneity: A review. Rev. Econ. Stat. 86, 4–29 (2004).', 'journal-title': 'Rev. Econ. 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Res. Methodol. 20, 1–10 (2020).', 'journal-title': 'BMC Med. Res. Methodol.'}, { 'key': '2701_CR63', 'first-page': '8', 'volume': '42', 'author': 'EA Stuart', 'year': '2011', 'unstructured': 'Stuart, E. A., King, G., Imai, K. & Ho, D. MatchIt: Nonparametric ' 'preprocessing for parametric causal inference. J. Stat. Softw. 42, 8 ' '(2011).', 'journal-title': 'J. Stat. Softw.'}, { 'key': '2701_CR64', 'unstructured': 'Hajage, D. hrIPW: Hazard ratio estimation using Cox model weighted by ' 'the estimated propensity score. https://CRAN.R-project.org/package=hrIPW ' '(2020).'}, { 'key': '2701_CR65', 'unstructured': 'Uno, H. et al. survRM2: Comparing restricted mean survival time. ' 'https://CRAN.R-project.org/package=survRM2 (2020).'}, { 'key': '2701_CR66', 'unstructured': 'Therneau, T. A package for survival analysis in R. ' 'https://CRAN.R-project.org/package=survival (2020).'}, { 'key': '2701_CR67', 'unstructured': 'Kassambara, A., Kosinski, M., Biecek, P. & Fabian, S. Package ' '‘survminer’. https://rpkgs.datanovia.com/survminer/ (2017).'}], 'container-title': ['Scientific Reports'], 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://www.nature.com/articles/s41598-021-02701-5.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41598-021-02701-5', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41598-021-02701-5.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2021, 12, 3]], 'date-time': '2021-12-03T11:11:41Z', 'timestamp': 1638529901000}, 'score': 1, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2021, 12]]}, 'references-count': 67, 'journal-issue': {'issue': '1', 'published-print': {'date-parts': [[2021, 12]]}}, 'alternative-id': ['2701'], 'URL': 'http://dx.doi.org/10.1038/s41598-021-02701-5', 'relation': {}, 'ISSN': ['2045-2322'], 'issn-type': [{'value': '2045-2322', 'type': 'electronic'}], 'subject': ['Multidisciplinary'], 'published': {'date-parts': [[2021, 12]]}, 'assertion': [ { 'value': '3 September 2021', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '19 November 2021', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '3 December 2021', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': 'RB declares payment of honoraria for lectures by FAES (Spain), Abiogen (Italy) ' 'and Fresenius (Germany). JMQ declares small consulting fees and small lecture ' 'fees from Amgen and FESE Farma (Spain). The rest of authors declare no ' 'competing interests.', 'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '23380'}
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