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All Studies   Meta Analysis    Recent:   

Vitamin D, acute respiratory infections, and Covid-19: the curse of small-size randomised trials. A critical review with meta-analysis of randomised trials

Autier et al., medRxiv, doi:10.1101/2024.04.26.24306354
Apr 2024  
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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.
4,800+ studies for 98 treatments. c19early.org
Unregistered meta analysis cherry-picking the ICU outcome and including 9 late treatment RCTs with ICU outcomes for vitamin D. It's unclear why ICU risk would be used when there are more studies reporting mortality which is also less subject to bias.
8 of the 9 report lower risk with treatment and one reports higher risk. The one study with a higher risk is also the study with the largest number of patients1. Authors suggest this trial is more trustworthy than the many more positive studies, however Cannata-Andía et al. has very high negative bias, containing a trifecta of poor design, which is a more logical reason for the observed results.
Studies show that earlier treatment is more effective than later treatment2, ongoing treatment with multiple doses is more effective than single bolus doses3, and late stage treatment with calcitriol/calcifediol and analogs is more effective than cholecalciferol4. Cannata-Andía et al. uses very late stage treatment (>80% pulmonary involvement at baseline), uses a single bolus dose, and uses cholecalciferol rather than calcitriol/calcifediol and analogs.
Note that all of the authors' exclusions and trim and fill in Table 2 still result in a lower risk with treatment, just no longer reaching statistical significance. Also note that the funnel plot conclusions are not valid5 - asymmetry may result from many factors, including poor design in a subset of trials, as seen in Cannata-Andía et al.
19 meta analyses show significant improvements with vitamin D treatment for mortality6-19, mechanical ventilation6,11,12,17,20,21, ICU admission6,8,11,12,15,17,19-23, hospitalization10,17, severity7,9,11,16,24, and cases13,23,24.
Currently there are 122 vitamin D treatment for COVID-19 studies, showing 36% lower mortality [28‑43%], 19% lower ventilation [-3‑36%], 45% lower ICU admission [28‑58%], 19% lower hospitalization [9‑29%], and 17% fewer cases [9‑24%].
Autier et al., 27 Apr 2024, preprint, 6 authors. Contact: philippe.autier@i-pri.org.
This PaperVitamin DAll
Vitamin D, acute respiratory infections, and Covid-19: the curse of small-size randomised trials. A critical review with meta-analysis of randomised trials
Philippe Autier, Giulia Doi, Patrick Mullie, Patrick Vankrunkelsven, Oriana D’ecclesiis, Sara Gandini
doi:10.1101/2024.04.26.24306354
Background: Randomised trials conducted before 2021 indicated that vitamin D supplementation (VDS) was able to prevent severe COVID-19 and acute respiratory infections (ARI). However, these health benefits were not confirmed by larger randomised trials published after 2021. Objective: To examine the characteristics of randomised trials on VDS to COVID-19 patients and admission to intensive care unit (ICU), and on VDS for the prevention of ARI. Method: A systematic search retrieved randomised trials on VDS to COVID-19 patients and admission to ICU. Data on VDS and ARI were extracted from the meta-analysis of Jolliffe et al., 2021. The associations between VDS vs no VDS, and admission to ICU were evaluated using random effect models. Meta-analyses were done for all trials and by groups trial size. Publication bias was assessed using the LFK index (no bias if index between -1 and +1) and the Trim and Fill method. Results: Nine trials on VDS for preventing admission to ICU were identified. The summary odds ratio (SOR) was 0.61 (95%CI: 0.39-0.95) for all trials, 0.34 (0.13-0.93) for trials including 50 to <106 patients and 0.88 (0.62-1.24) for trials including 106 to 548 patients (effect modification: p=0.04). The LFK index was -3.79, and after Trim and Fill, the SOR was 0.80 (0.40-1.61). The SOR for the 37 trials on VDS for ARI prevention was 0.92 (0.86-0.99) for all trials, 0.69 (0.57-0.83) for trials including 25 to <248 patients and 0.98 (0.94-1.03) for trials including 248 to 16,000 patients (effect modification p=0.0001). The LFK index was -3.11, and after Trim and Fill, the SOR was 0.96 (0.88-1.05). Conclusion: Strong publication bias affected randomised trials on VDS for the prevention of severe COVID-19 and of ARI. Systematic reviews should beware of smallsize randomised trials that generally exaggerate health benefits.
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However, these health ' 'benefits were not confirmed by larger randomised trials published after ' '2021.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To examine the ' 'characteristics of randomised trials on VDS to COVID-19 patients and admission to intensive ' 'care unit (ICU), and on VDS for the prevention of ' 'ARI.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>A systematic search ' 'retrieved randomised trials on VDS to COVID-19 patients and admission to ICU. Data on VDS and ' 'ARI were extracted from the meta-analysis of Jolliffe et al., 2021. The associations between ' 'VDS vs no VDS, and admission to ICU were evaluated using random effect models. Meta-analyses ' 'were done for all trials and by groups trial size. Publication bias was assessed using the ' 'LFK index (no bias if index between -1 and +1) and the Trim and Fill ' 'method.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Nine trials on ' 'VDS for preventing admission to ICU were identified. The summary odds ratio (SOR) was 0.61 ' '(95%CI: 0.39-0.95) for all trials, 0.34 (0.13-0.93) for trials including 50 to &lt;106 ' 'patients and 0.88 (0.62-1.24) for trials including 106 to 548 patients (effect modification: ' 'p=0.04). The LFK index was -3.79, and after Trim and Fill, the SOR was 0.80 (0.40-1.61). The ' 'SOR for the 37 trials on VDS for ARI prevention was 0.92 (0.86-0.99) for all trials, 0.69 ' '(0.57-0.83) for trials including 25 to &lt;248 patients and 0.98 (0.94-1.03) for trials ' 'including 248 to 16,000 patients (effect modification p=0.0001). The LFK index was -3.11, and ' 'after Trim and Fill, the SOR was 0.96 ' '(0.88-1.05).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Strong ' 'publication bias affected randomised trials on VDS for the prevention of severe COVID-19 and ' 'of ARI. Systematic reviews should beware of small-size randomised trials that generally ' 'exaggerate health benefits.</jats:p></jats:sec>', 'DOI': '10.1101/2024.04.26.24306354', 'type': 'posted-content', 'created': {'date-parts': [[2024, 4, 27]], 'date-time': '2024-04-27T22:15:16Z', 'timestamp': 1714256116000}, 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Vitamin D, acute respiratory infections, and Covid-19: the curse of small-size randomised ' 'trials. 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