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Vitamina D para el tratamiento del asma

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Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database

Frequency of search

CENTRAL (the Cochrane Library)

Monthly

MEDLINE (Ovid)

Weekly

EMBASE (Ovid)

Weekly

PsycINFO (Ovid)

Monthly

CINAHL (EBSCO)

Monthly

AMED (EBSCO)

Monthly

Handsearches: core respiratory conference abstracts

Conference

Years searched

American Academy of Allergy, Asthma and Immunology (AAAAI)

2001 onwards

American Thoracic Society (ATS)

2001 onwards

Asia Pacific Society of Respirology (APSR)

2004 onwards

British Thoracic Society Winter Meeting (BTS)

2000 onwards

Chest Meeting

2003 onwards

European Respiratory Society (ERS)

1992, 1994, 2000 onwards

International Primary Care Respiratory Group Congress (IPCRG)

2002 onwards

Thoracic Society of Australia and New Zealand (TSANZ)

1999 onwards

MEDLINE search strategy used to identify trials for the CAGR

Asthma search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti‐asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1‐15

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1‐7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases.

Appendix 2. Search strategy to retrieve trials from the CAGR

#1 AST:MISC1

#2 MeSH DESCRIPTOR Asthma Explode All

#3 asthma*:ti,ab

#4 #1 or #2 or #3

#5 MeSH DESCRIPTOR Vitamin D Explode All

#6 MeSH DESCRIPTOR Vitamin D Deficiency Explode All

#7 "vitamin d"

#8 #5 or #6 or #7

#9 #4 and #8

(in search line #1, MISC1 refers to the field in the record where the reference has been coded for condition, in this case, asthma)

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: 1 Vitamin D versus placebo (all studies), outcome: 1.1 Rate ratio, exacerbations requiring systemic corticosteroids.
Figures and Tables -
Figure 3

Forest plot of comparison: 1 Vitamin D versus placebo (all studies), outcome: 1.1 Rate ratio, exacerbations requiring systemic corticosteroids.

Forest plot of comparison: 1 Vitamin D versus placebo (all studies), outcome: 1.5 People with one or more exacerbations requiring ED visit or hospitalisation or both.
Figures and Tables -
Figure 4

Forest plot of comparison: 1 Vitamin D versus placebo (all studies), outcome: 1.5 People with one or more exacerbations requiring ED visit or hospitalisation or both.

In the control group 6 out of 100 people had a visit to ED or hospitalisation over 8 months, compared to 3 (95% CI 1 to 5) out of 100 on vitamin D.
Figures and Tables -
Figure 5

In the control group 6 out of 100 people had a visit to ED or hospitalisation over 8 months, compared to 3 (95% CI 1 to 5) out of 100 on vitamin D.

Forest plot of comparison: 1 Vitamin D versus placebo (low risk of bias), outcome: 1.10 People with one or more study‐defined exacerbations.
Figures and Tables -
Figure 6

Forest plot of comparison: 1 Vitamin D versus placebo (low risk of bias), outcome: 1.10 People with one or more study‐defined exacerbations.

In the control group 29 out of 100 people had a study‐defined exacerbation over 7 months, compared to 18 (95% CI 10 to 29) out of 100 on Vitamin D.
Figures and Tables -
Figure 7

In the control group 29 out of 100 people had a study‐defined exacerbation over 7 months, compared to 18 (95% CI 10 to 29) out of 100 on Vitamin D.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 1 Rate ratio, exacerbations requiring systemic corticosteroids.
Figures and Tables -
Analysis 1.1

Comparison 1 Vitamin D versus placebo (all studies), Outcome 1 Rate ratio, exacerbations requiring systemic corticosteroids.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 2 Time to first exacerbation requiring systemic corticosteroids.
Figures and Tables -
Analysis 1.2

Comparison 1 Vitamin D versus placebo (all studies), Outcome 2 Time to first exacerbation requiring systemic corticosteroids.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 3 People with one or more exacerbations requiring systemic corticosteroids.
Figures and Tables -
Analysis 1.3

Comparison 1 Vitamin D versus placebo (all studies), Outcome 3 People with one or more exacerbations requiring systemic corticosteroids.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 4 People with one or more exacerbations requiring systemic corticosteroids (risk difference).
Figures and Tables -
Analysis 1.4

Comparison 1 Vitamin D versus placebo (all studies), Outcome 4 People with one or more exacerbations requiring systemic corticosteroids (risk difference).

Comparison 1 Vitamin D versus placebo (all studies), Outcome 5 People with one or more exacerbations requiring ED visit or hospitalisation or both.
Figures and Tables -
Analysis 1.5

Comparison 1 Vitamin D versus placebo (all studies), Outcome 5 People with one or more exacerbations requiring ED visit or hospitalisation or both.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 6 ACT/C‐ACT score.
Figures and Tables -
Analysis 1.6

Comparison 1 Vitamin D versus placebo (all studies), Outcome 6 ACT/C‐ACT score.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 7 People with fatal asthma exacerbation.
Figures and Tables -
Analysis 1.7

Comparison 1 Vitamin D versus placebo (all studies), Outcome 7 People with fatal asthma exacerbation.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 8 FEV1, % predicted.
Figures and Tables -
Analysis 1.8

Comparison 1 Vitamin D versus placebo (all studies), Outcome 8 FEV1, % predicted.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 9 People with one or more serious adverse event due to any cause.
Figures and Tables -
Analysis 1.9

Comparison 1 Vitamin D versus placebo (all studies), Outcome 9 People with one or more serious adverse event due to any cause.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 10 People with one or more exacerbation as defined in primary trials.
Figures and Tables -
Analysis 1.10

Comparison 1 Vitamin D versus placebo (all studies), Outcome 10 People with one or more exacerbation as defined in primary trials.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 11 % eosinophils, lower airway.
Figures and Tables -
Analysis 1.11

Comparison 1 Vitamin D versus placebo (all studies), Outcome 11 % eosinophils, lower airway.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 12 Peak expiratory flow rate.
Figures and Tables -
Analysis 1.12

Comparison 1 Vitamin D versus placebo (all studies), Outcome 12 Peak expiratory flow rate.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 13 People with one or more adverse reactions attributed to vitamin D.
Figures and Tables -
Analysis 1.13

Comparison 1 Vitamin D versus placebo (all studies), Outcome 13 People with one or more adverse reactions attributed to vitamin D.

Comparison 1 Vitamin D versus placebo (all studies), Outcome 14 People withdrawing from trial.
Figures and Tables -
Analysis 1.14

Comparison 1 Vitamin D versus placebo (all studies), Outcome 14 People withdrawing from trial.

Comparison 2 Vitamin D versus placebo (sensitivity analysis excluding studies at high risk of bias), Outcome 1 People with one or more study‐defined exacerbation.
Figures and Tables -
Analysis 2.1

Comparison 2 Vitamin D versus placebo (sensitivity analysis excluding studies at high risk of bias), Outcome 1 People with one or more study‐defined exacerbation.

Comparison 2 Vitamin D versus placebo (sensitivity analysis excluding studies at high risk of bias), Outcome 2 People withdrawing from trial.
Figures and Tables -
Analysis 2.2

Comparison 2 Vitamin D versus placebo (sensitivity analysis excluding studies at high risk of bias), Outcome 2 People withdrawing from trial.

Summary of findings for the main comparison. Vitamin D versus placebo for the management of asthma (all studies)

Vitamin D versus placebo for the management of asthma (all studies)

Patient or population: children and adults with predominantly mild to moderate asthma

Setting: primary and secondary care
Intervention: vitamin D3 administered orally over study duration of 4 to 12 months
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo

Risk with vitamin D

Rate ratio, exacerbations requiring systemic corticosteroids
assessed with: number of events per participant per year. Follow‐up: 6 to 12 months

Study population

RR 0.64
(0.46 to 0.90)

680
(3 RCTs)

⊕⊕⊕⊕
HIGH

Evidence based primarily on adults with mild to moderate asthma

0.44 events per person per year1

0.28 events per person per year (0.20 to 0.40)

People with 1 or more exacerbations requiring ED visit or hospitalisation or both. Follow‐up: 6 to 12 months

Study population

OR 0.39
(0.19 to 0.78)

963
(7 RCTs)

⊕⊕⊕⊕
HIGH

Evidence based primarily on children and adults with mild to moderate asthma

63 per 1000

25 per 1000
(13 to 50)

FEV1, % predicted. Follow‐up: 6 to 12 months

The mean FEV1, % predicted was 85.62%

The mean FEV1, % predicted in the intervention group was 0.48% more (0.93 fewer to 1.89 more)

387
(4 RCTs)

⊕⊕⊕⊕2
HIGH

Evidence based primarily on children and adults with mild to moderate asthma

ACT/C‐ACT score. Follow‐up: 6 to 12 months

The mean ACT/C‐ACT score was 20 points

The mean ACT/C‐ACT score in the intervention group was 0.08 points fewer (0.7 fewer to 0.54 more)

713
(3 RCTs)

⊕⊕⊕⊕2
HIGH

Evidence based primarily on adults with mild to moderate asthma

People with fatal asthma exacerbation. Follow‐up: 6 to 12 months

Study population

Not estimable

963
(7 RCTs)

⊕⊕◯◯3

LOW

No fatal asthma exacerbations occurred in included studies

0 per 1000

0 per 1000
(0 to 0)

People with 1 or more serious adverse event due to any cause. Follow‐up: 6 to 12 months

Study population

OR 1.01
(0.54 to 1.89)

879
(5 RCTs)

⊕⊕⊕◯4

MODERATE

Evidence based primarily on children and adults with mild to moderate asthma

48 per 1000

49 per 1000
(27 to 87)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
ACT, Asthma Control Test; C‐ACT, Childhood Asthma Control Test; CI, confidence interval; ED, emergency department; FEV1, forced expiratory volume in one second; OR, odds ratio; RCT, randomised controlled trial; RR, rate ratio.

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect

1The event rate in participants randomised to placebo was estimated by calculating the weighted mean of event rates reported in placebo arms of included studies.
2Despite null effects of the intervention on these outcomes, we are confident that the true effect lies close to the estimates, as 95% confidence intervals for these estimates are very narrow.
3Downgraded two levels due to imprecision (no events occurred in included studies).
4Downgraded one level due to imprecision (wide confidence intervals).

Figures and Tables -
Summary of findings for the main comparison. Vitamin D versus placebo for the management of asthma (all studies)
Table 1. Sensitivity analysis: random‐effects versus fixed‐effect models

Analysis

Random‐effects model

Fixed‐effect model

People with 1 or more exacerbations requiring systemic corticosteroids (risk difference)

(RD ‐0.01, 95% CI ‐0.04 to 0.02)

(RD ‐0.03, 95% CI ‐0.07 to 0.01)

ACT/C‐ACT score

(MD ‐0.08, 95% CI ‐0.70 to 0.54)

(MD ‐0.09, 95% CI ‐0.64 to 0.46)

People with 1 or more serious adverse event due to any cause

(OR 1.01, 95% CI 0.54 to 1.89)

(OR 1.00, 95% CI 0.54 to 1.85)

People with 1 or more study‐defined exacerbation

(OR 0.53, 95% CI 0.28 to 0.99)

(OR 0.66, 95% CI 0.48 to 0.91)

% eosinophils, lower airway

(MD ‐0.38, 95% CI ‐1.92 to 1.15)

(MD ‐0.26, 95% CI ‐1.35 to 0.83)

Peak expiratory flow rate

(MD 3.16, 95% CI ‐13.40 to 19.72)

(MD 4.09, 95% CI ‐1.34 to 9.52)

People withdrawing from the trial

(OR 1.07, 95% CI 0.73 to 1.58)

(OR 1.09, 95% CI 0.74 to 1.59)

Sensitivity analyses are presented only for those outcomes where results of analyses using random‐effects versus fixed‐effect models are non‐identical.

Abbreviations: CI, confidence interval; MD, mean difference; OR, odds ratio; RD, risk difference.

Figures and Tables -
Table 1. Sensitivity analysis: random‐effects versus fixed‐effect models
Table 2. Definitions of asthma exacerbation used in primary trials

Study

Definition

Castro 2014

Meeting criteria for treatment failure and 1 or more of the following:

  • failure to respond to rescue algorithm within 48 hours;

  • FEV1 of less than 50% of baseline measurement on 2 consecutive measurements;

  • FEV1 of less than 40% of predicted level on 2 consecutive measurements;

  • use of 16 puffs/day or more of as‐needed levalbuterol for 48 hours;

  • experiencing an exacerbation of asthma according to physician opinion;

  • use of oral or parenteral corticosteroids due to asthma.

Jensen 2016

Exacerbation requiring rescue oral corticosteroids, documented in medical or pharmacy records or both

Lewis 2012

Exacerbation not defined or reported in study manuscript

Majak 2009

Exacerbation not defined or reported in study manuscript; authors confirmed that no exacerbations requiring systemic corticosteroid treatment occurred in the study

Majak 2011

Reported but not defined in study manuscript; authors confirmed that no exacerbations requiring systemic corticosteroid treatment occurred in the study

Martineau 2015

Deterioration in asthma resulting in (A) treatment with oral corticosteroids, or (B) hospital admission or emergency department treatment, or (C) decrease in the morning PEFR to more than 25% below the mean run‐in value on 2 or more consecutive days

Tachimoto 2016

Worsening of asthma symptoms prompting a need for a change in asthma treatment (from authors)

Urashima 2010

Asthma attack that included wheezing, improved by inhalation of a beta‐stimulant in participants who already had a diagnosis of asthma; authors confirmed that no exacerbations requiring systemic corticosteroid treatment occurred in the study

Yadav 2014

Reported but not defined in study manuscript

FEV1, forced expiratory volume in one second; PEFR, peak expiratory flow rate.

Figures and Tables -
Table 2. Definitions of asthma exacerbation used in primary trials
Comparison 1. Vitamin D versus placebo (all studies)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Rate ratio, exacerbations requiring systemic corticosteroids Show forest plot

3

680

Rate Ratio (Random, 95% CI)

0.64 [0.46, 0.90]

2 Time to first exacerbation requiring systemic corticosteroids Show forest plot

2

658

Hazard Ratio (Random, 95% CI)

0.69 [0.48, 1.00]

3 People with one or more exacerbations requiring systemic corticosteroids Show forest plot

7

933

Odds Ratio (Random, 95% CI)

0.74 [0.49, 1.10]

4 People with one or more exacerbations requiring systemic corticosteroids (risk difference) Show forest plot

7

933

Risk Difference (M‐H, Random, 95% CI)

‐0.01 [‐0.04, 0.02]

5 People with one or more exacerbations requiring ED visit or hospitalisation or both Show forest plot

7

963

Odds Ratio (Random, 95% CI)

0.39 [0.19, 0.78]

6 ACT/C‐ACT score Show forest plot

3

713

Mean Difference (Random, 95% CI)

‐0.08 [‐0.70, 0.54]

7 People with fatal asthma exacerbation Show forest plot

7

963

Risk Difference (M‐H, Random, 95% CI)

0.0 [‐0.01, 0.01]

8 FEV1, % predicted Show forest plot

4

387

Mean Difference (Random, 95% CI)

0.48 [‐0.93, 1.89]

9 People with one or more serious adverse event due to any cause Show forest plot

5

879

Odds Ratio (M‐H, Random, 95% CI)

1.01 [0.54, 1.89]

10 People with one or more exacerbation as defined in primary trials Show forest plot

7

999

Odds Ratio (Random, 95% CI)

0.53 [0.28, 0.99]

11 % eosinophils, lower airway Show forest plot

3

525

Mean Difference (Random, 95% CI)

‐0.38 [‐1.92, 1.15]

12 Peak expiratory flow rate Show forest plot

2

302

Mean Difference (Random, 95% CI)

3.16 [‐13.40, 19.72]

13 People with one or more adverse reactions attributed to vitamin D Show forest plot

5

879

Risk Difference (M‐H, Random, 95% CI)

0.0 [‐0.01, 0.01]

14 People withdrawing from trial Show forest plot

9

1093

Odds Ratio (M‐H, Random, 95% CI)

1.07 [0.73, 1.58]

Figures and Tables -
Comparison 1. Vitamin D versus placebo (all studies)
Comparison 2. Vitamin D versus placebo (sensitivity analysis excluding studies at high risk of bias)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 People with one or more study‐defined exacerbation Show forest plot

6

899

Odds Ratio (Random, 95% CI)

0.64 [0.34, 1.21]

2 People withdrawing from trial Show forest plot

7

963

Odds Ratio (M‐H, Random, 95% CI)

1.17 [0.73, 1.88]

Figures and Tables -
Comparison 2. Vitamin D versus placebo (sensitivity analysis excluding studies at high risk of bias)