- Email: [email protected]
Vitamin D supplementation in patients with COPD: Twitter discussions on behalf of the University of Toronto Respirology and Sleep Journal Club – Authors' Reply
Correspondence
Vitamin D supplementation in patients with COPD: Twitter discussions on behalf of the University of Toronto Respirology and Sleep Journal Club
For the Twitter-based journal club see https://twitter.com/ respandsleepjc
If you would like to respond to an article published in The Lancet Respiratory Medicine, please submit your correspondence online at: http:// ees.elsevier.com/thelancetrm
e24
We had the pleasure of discussing the ViDiCO trial1 with the lead author Adrian Martineau at our Twitter-based journal club on May 28, 2015. ViDiCO assessed whether vitamin D supplementation reduced the incidence of moderate or severe exacerbations and upper respiratory infections in patients with chronic obstructive pulmonary disease (COPD) versus placebo. Our discussion generated several questions. Vitamin D3 has potential antimicrobial and anti-inflammatory effects, which are the basis of its use in the treatment of COPD.2 However, in patients in ViDiCO with normal concentrations of vitamin D (≥50 nmol/L), the risk of moderate or severe exacerbations in patients treated with vitamin D3 was increased compared with placebo. We asked Martineau to suggest possible reasons for the discrepancy; in response, he explained that the finding from his study might be due to the suppression of protective adaptive immune responses by vitamin D3.3 We raised another discussion point regarding the effect of bolus versus daily vitamin D3 supplementation on the risk of exacerbation.4 Martineau clarified that daily supplementation might in fact work better than the bolus regimen used in the study because concentrations of the parent metabolite are increased, among other reasons.5 We noted that many participants did not complete followup in both the treatment group (24 [20%] of 122 patients) and the placebo group (29 [25%] of 118 patients),1 and believe that the investigators would have obtained a more accurate
analysis if they had used multiple imputations. 6 Finally, participants were stratified into groups on the basis of their FEV1 and participation in the sputum induction substudy.1 However, because one of the prespecified subgroup analyses was to examine whether the effect of the intervention on the coprimary outcomes of time to first moderate or severe exacerbation and first upper respiratory infection was modified by baseline vitamin D status, we believe that the stratified randomisation should ideally have been done on the basis of the patients’ baseline vitamin D status.7 Martineau responded that knowledge of patients’ baseline vitamin D status could have raised concerns regarding randomly assigning those with a known deficiency to placebo.8 Overall, our group felt that although the study showed a reduced risk of exacerbation with vitamin D3 in patients who were deficient in vitamin D, many of us would not initiate vitamin D3 supplementation in such patients for the purpose of reducing exacerbations. However, we agree with Martineau and colleagues that a randomised controlled trial of vitamin D supplementation in patients with COPD who are deficient in vitamin D would be important to confirm this study’s findings. We declare no competing interests.
*Anju Anand, Navjeet Uppal, Matthew Stanbrook [email protected] St Michael’s Hospital, Toronto, ON, Canada (AA); University of Toronto, Toronto, ON, Canada (NU, MS); Toronto Western Hospital, University Health Network, Toronto, ON, Canada (MS) 1
2
3
Martineau AR, James WY, Hooper RL, et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. Lancet Respir Med 2015; 3: 120–30. Stanbrook, Matthew (drstanbrook). Odd that looks like Vitamin D makes those with normal levels worse (even if not significant). May 28, 2015, 1637h GMT. Tweet. Martineau, Adrian (rsjcguest). If real worsening in normal vit D group may represent suppression of protective adaptive immune responses as we showed in TB PNAS 2012. May 28, 2015, 1655h GMT. Tweet.
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Anand, Anju (respandsleepjc). Thoughts why is daily vit D perhaps better than bolus for vit D? May 28, 2015, 1654h GMT. Tweet. Martineau, Adrian (rsjcguest). Daily may work better because it elevates parent metabolite, or because bolus causes unwanted upregulation of CYP2A4. May 28, 2015, 1659h GMT. Tweet. Anand, Anju (respandsleepjc). Dr. Martineau we r discussing differential dropout+lost to FU. Did you consider regression models to look @ this (multiple imputation)? May 28, 2015, 1701h GMT. Tweet. Stanbrook, Matthew (drstanbrook). Why did ViDiCO not stratify randomization for low vs normal Vitamin D levels, since a prespecified subgroup analysis? May 28, 2015, 1635h GMT. Tweet. Martineau, Adrian (rsjcguest). Knowledge of vitD status at baseline could have raised issues re randomising patients with known deficiency to placebo. May 28, 2015, 1642h GMT. Tweet.
Authors’ Reply We thank Anju Anand and colleagues for their comments and Twitter discussion about our Article on vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (COPD; ViDiCO).1 The trend towards increased exacerbation risk among patients with higher baseline concentrations of 25-hydroxyvitamin D (25[OH]D) who were randomly assigned to receive vitamin D has been reported in findings from another trial.2 This effect is not necessarily inconsistent with the antiinflammatory effects of vitamin D; suppression of responses to type 1 interferon3 might compromise the response to respiratory viruses, and could lead to an increased risk of upper respiratory infection that might precipitate exacerbations. Irrespective of potential adverse effects in patients with higher serum concentrations of 25(OH)D, the findings from two trials1,4 suggest that the benefits of vitamin D supplementation for prevention of exacerbations are restricted to participants who are deficient in vitamin D at baseline. Clinicians who wish to offer vitamin D supplementation to patients with COPD should therefore check the patients’ serum 25(OH)D concentrations and offer targeted supplementation to deficient individuals, rather www.thelancet.com/respiratory Vol 3 August 2015
Correspondence
than offering indiscriminate supplementation to all without testing. With respect to potential differences in biological responses to bolusdose versus daily supplementation with vitamin D, the findings from the ViDiFlu trial5 showed that the addition of intermittent bolus-dose supplementation of vitamin D to a daily, low-dose regimen was associated with increased risk of upper respiratory infections in older adults. This study adds to the scientific literature suggesting that daily dosing with vitamin D might be more beneficial than intermittent bolus dosing for the prevention of adverse health outcomes. With respect to missing data, we emphasise that our coprimary outcomes were time to first moderate or severe exacerbation and time to first upper respiratory infection, and although several participants did not complete the 1-year followup, 225 (94%) of 240 participants had at least one follow-up visit and contributed data to the analysis of the coprimary outcomes.1 However, we agree that a randomised controlled trial of vitamin D supplementation in patients with COPD who are deficient in vitamin D will be important to confirm or refute the findings of existing trials in this field; one such study—PRECOVID—is in progress. We declare no competing interests.
*Adrian R Martineau, Richard L Hooper [email protected] Centre for Primary Care and Public Health and Asthma UK Centre for Applied Research (ARM), Blizard Institute, Barts and The London School of Medicine and Dentistry (ARM, RLH), Queen Mary University of London, London E1 2AB, UK 1
2
3
Martineau AR, James WY, Hooper RL, et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. Lancet Respir Med 2015; 3: 120–30. Janssens W, Decramer M, Mathieu C, Korf H. Vitamin D and chronic obstructive pulmonary disease: hype or reality? Lancet Respir Med 2013; 1: 804–12. Greiller CL, Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients 2015; 7: 4240–70.
www.thelancet.com/respiratory Vol 3 August 2015
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5
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: 105–14. Martineau AR, Hanifa Y, Witt KD, et al. Doubleblind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu). Thorax 2015; published online June 10. DOI:10.1136/ thoraxjnl-2015-206996.
Bronchodilator reversibility and cardiac considerations with use of tiotropium In his Comment,1 Kian Fan Chung provides an overview of our Article2 on the findings from our two 24-week, replicate, randomised active-comparator trials of tiotropium add-on therapy in adult patients with symptomatic asthma despite treatment with medium-dose inhaled corticosteroids. We would like to clarify two points made in Chung’s Comment. First, he notes that we recorded a numerically, albeit not significantly, greater increase in FEV 1 with tiotropium 2·5 μg than with 5 μg— ie, an inverse dose-response—and that we attribute this finding partly to the “imbalance and variability in bronchodilator reversibility between the treatment groups”. Chung writes that “no such difference was reported in the present study; therefore, this observation remains unexplained.” However, we do report a difference in bronchodilator reversibility in table 1 of our Article:2 the mean reversibility was 456 mL in the tiotropium 5 μg group, but was higher in the tiotropium 2·5 μg and salmeterol groups (501 mL and 494 mL, respectively). As we stated in our Article, this finding might partly account for the greater FEV 1 responses in the tiotropium 2·5 μg group compared with the 5 μg group.
Second, in the conclusion of his Comment, Chung refers to the ongoing debate regarding “the risk of mortality with treatment with tiotropium Respimat inhaler in patients with COPD, in particular in those with cardiovascular disease and cardiac arrhythmias”, and writes “a note of caution should be taken regarding chronic use of this treatment in patients with asthma with such a cardiac background.” However, results from the TIOSPIR trial,3 a long-term study (mean followup 2·3 years) of 17 135 patients with COPD, do not support a conclusion of increased risk of mortality with tiotropium Respimat: there was no increase in risk of death with tiotropium Respimat 5 μg versus tiotropium HandiHaler 18 μg in 1221 patients with a history of cardiac arrhythmia (614 patients received tiotropium Respimat 5 μg, 607 patients received tiotropium HandiHaler 18 μg; hazard ratio 0·81, 95% CI 0·58–1·12). No deaths have occurred in the phase 3 clinical trials of tiotropium Respimat add-on therapy in asthma that have been published up to now.2,4,5 In our studies of tiotropium Respimat add-on therapy to inhaled corticosteroids over 24 weeks2 and add-on to inhaled corticosteroids plus longacting β-agonists given over 48 weeks, 4 in 3012 patients with symptomatic asthma, the incidence of cardiac adverse events was less than 2%, with no difference in occurrence between the active or placebo treatment groups. 2,4 Therefore, we conclude from the data that tiotropium Respimat addon therapy safely improves asthma control in patients with symptomatic asthma despite treatment with medium-dose inhaled corticosteroids.
For the PRECOVID study see https://clinicaltrials.gov/ct2/ show/NCT02122627
The authors’ competing interests remain the same as those declared in the original article.
*Huib AM Kerstjens, Petra Moroni-Zentgraf [email protected]
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Vitamin D supplementation in patients with COPD: Twitter discussions on behalf of the University of Toronto Respirology and Sleep Journal Club
For the Twitter-based journal club see https://twitter.com/ respandsleepjc
If you would like to respond to an article published in The Lancet Respiratory Medicine, please submit your correspondence online at: http:// ees.elsevier.com/thelancetrm
e24
We had the pleasure of discussing the ViDiCO trial1 with the lead author Adrian Martineau at our Twitter-based journal club on May 28, 2015. ViDiCO assessed whether vitamin D supplementation reduced the incidence of moderate or severe exacerbations and upper respiratory infections in patients with chronic obstructive pulmonary disease (COPD) versus placebo. Our discussion generated several questions. Vitamin D3 has potential antimicrobial and anti-inflammatory effects, which are the basis of its use in the treatment of COPD.2 However, in patients in ViDiCO with normal concentrations of vitamin D (≥50 nmol/L), the risk of moderate or severe exacerbations in patients treated with vitamin D3 was increased compared with placebo. We asked Martineau to suggest possible reasons for the discrepancy; in response, he explained that the finding from his study might be due to the suppression of protective adaptive immune responses by vitamin D3.3 We raised another discussion point regarding the effect of bolus versus daily vitamin D3 supplementation on the risk of exacerbation.4 Martineau clarified that daily supplementation might in fact work better than the bolus regimen used in the study because concentrations of the parent metabolite are increased, among other reasons.5 We noted that many participants did not complete followup in both the treatment group (24 [20%] of 122 patients) and the placebo group (29 [25%] of 118 patients),1 and believe that the investigators would have obtained a more accurate
analysis if they had used multiple imputations. 6 Finally, participants were stratified into groups on the basis of their FEV1 and participation in the sputum induction substudy.1 However, because one of the prespecified subgroup analyses was to examine whether the effect of the intervention on the coprimary outcomes of time to first moderate or severe exacerbation and first upper respiratory infection was modified by baseline vitamin D status, we believe that the stratified randomisation should ideally have been done on the basis of the patients’ baseline vitamin D status.7 Martineau responded that knowledge of patients’ baseline vitamin D status could have raised concerns regarding randomly assigning those with a known deficiency to placebo.8 Overall, our group felt that although the study showed a reduced risk of exacerbation with vitamin D3 in patients who were deficient in vitamin D, many of us would not initiate vitamin D3 supplementation in such patients for the purpose of reducing exacerbations. However, we agree with Martineau and colleagues that a randomised controlled trial of vitamin D supplementation in patients with COPD who are deficient in vitamin D would be important to confirm this study’s findings. We declare no competing interests.
*Anju Anand, Navjeet Uppal, Matthew Stanbrook [email protected] St Michael’s Hospital, Toronto, ON, Canada (AA); University of Toronto, Toronto, ON, Canada (NU, MS); Toronto Western Hospital, University Health Network, Toronto, ON, Canada (MS) 1
2
3
Martineau AR, James WY, Hooper RL, et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. Lancet Respir Med 2015; 3: 120–30. Stanbrook, Matthew (drstanbrook). Odd that looks like Vitamin D makes those with normal levels worse (even if not significant). May 28, 2015, 1637h GMT. Tweet. Martineau, Adrian (rsjcguest). If real worsening in normal vit D group may represent suppression of protective adaptive immune responses as we showed in TB PNAS 2012. May 28, 2015, 1655h GMT. Tweet.
4
5
6
7
8
Anand, Anju (respandsleepjc). Thoughts why is daily vit D perhaps better than bolus for vit D? May 28, 2015, 1654h GMT. Tweet. Martineau, Adrian (rsjcguest). Daily may work better because it elevates parent metabolite, or because bolus causes unwanted upregulation of CYP2A4. May 28, 2015, 1659h GMT. Tweet. Anand, Anju (respandsleepjc). Dr. Martineau we r discussing differential dropout+lost to FU. Did you consider regression models to look @ this (multiple imputation)? May 28, 2015, 1701h GMT. Tweet. Stanbrook, Matthew (drstanbrook). Why did ViDiCO not stratify randomization for low vs normal Vitamin D levels, since a prespecified subgroup analysis? May 28, 2015, 1635h GMT. Tweet. Martineau, Adrian (rsjcguest). Knowledge of vitD status at baseline could have raised issues re randomising patients with known deficiency to placebo. May 28, 2015, 1642h GMT. Tweet.
Authors’ Reply We thank Anju Anand and colleagues for their comments and Twitter discussion about our Article on vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (COPD; ViDiCO).1 The trend towards increased exacerbation risk among patients with higher baseline concentrations of 25-hydroxyvitamin D (25[OH]D) who were randomly assigned to receive vitamin D has been reported in findings from another trial.2 This effect is not necessarily inconsistent with the antiinflammatory effects of vitamin D; suppression of responses to type 1 interferon3 might compromise the response to respiratory viruses, and could lead to an increased risk of upper respiratory infection that might precipitate exacerbations. Irrespective of potential adverse effects in patients with higher serum concentrations of 25(OH)D, the findings from two trials1,4 suggest that the benefits of vitamin D supplementation for prevention of exacerbations are restricted to participants who are deficient in vitamin D at baseline. Clinicians who wish to offer vitamin D supplementation to patients with COPD should therefore check the patients’ serum 25(OH)D concentrations and offer targeted supplementation to deficient individuals, rather www.thelancet.com/respiratory Vol 3 August 2015
Correspondence
than offering indiscriminate supplementation to all without testing. With respect to potential differences in biological responses to bolusdose versus daily supplementation with vitamin D, the findings from the ViDiFlu trial5 showed that the addition of intermittent bolus-dose supplementation of vitamin D to a daily, low-dose regimen was associated with increased risk of upper respiratory infections in older adults. This study adds to the scientific literature suggesting that daily dosing with vitamin D might be more beneficial than intermittent bolus dosing for the prevention of adverse health outcomes. With respect to missing data, we emphasise that our coprimary outcomes were time to first moderate or severe exacerbation and time to first upper respiratory infection, and although several participants did not complete the 1-year followup, 225 (94%) of 240 participants had at least one follow-up visit and contributed data to the analysis of the coprimary outcomes.1 However, we agree that a randomised controlled trial of vitamin D supplementation in patients with COPD who are deficient in vitamin D will be important to confirm or refute the findings of existing trials in this field; one such study—PRECOVID—is in progress. We declare no competing interests.
*Adrian R Martineau, Richard L Hooper [email protected] Centre for Primary Care and Public Health and Asthma UK Centre for Applied Research (ARM), Blizard Institute, Barts and The London School of Medicine and Dentistry (ARM, RLH), Queen Mary University of London, London E1 2AB, UK 1
2
3
Martineau AR, James WY, Hooper RL, et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. Lancet Respir Med 2015; 3: 120–30. Janssens W, Decramer M, Mathieu C, Korf H. Vitamin D and chronic obstructive pulmonary disease: hype or reality? Lancet Respir Med 2013; 1: 804–12. Greiller CL, Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients 2015; 7: 4240–70.
www.thelancet.com/respiratory Vol 3 August 2015
4
5
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: 105–14. Martineau AR, Hanifa Y, Witt KD, et al. Doubleblind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu). Thorax 2015; published online June 10. DOI:10.1136/ thoraxjnl-2015-206996.
Bronchodilator reversibility and cardiac considerations with use of tiotropium In his Comment,1 Kian Fan Chung provides an overview of our Article2 on the findings from our two 24-week, replicate, randomised active-comparator trials of tiotropium add-on therapy in adult patients with symptomatic asthma despite treatment with medium-dose inhaled corticosteroids. We would like to clarify two points made in Chung’s Comment. First, he notes that we recorded a numerically, albeit not significantly, greater increase in FEV 1 with tiotropium 2·5 μg than with 5 μg— ie, an inverse dose-response—and that we attribute this finding partly to the “imbalance and variability in bronchodilator reversibility between the treatment groups”. Chung writes that “no such difference was reported in the present study; therefore, this observation remains unexplained.” However, we do report a difference in bronchodilator reversibility in table 1 of our Article:2 the mean reversibility was 456 mL in the tiotropium 5 μg group, but was higher in the tiotropium 2·5 μg and salmeterol groups (501 mL and 494 mL, respectively). As we stated in our Article, this finding might partly account for the greater FEV 1 responses in the tiotropium 2·5 μg group compared with the 5 μg group.
Second, in the conclusion of his Comment, Chung refers to the ongoing debate regarding “the risk of mortality with treatment with tiotropium Respimat inhaler in patients with COPD, in particular in those with cardiovascular disease and cardiac arrhythmias”, and writes “a note of caution should be taken regarding chronic use of this treatment in patients with asthma with such a cardiac background.” However, results from the TIOSPIR trial,3 a long-term study (mean followup 2·3 years) of 17 135 patients with COPD, do not support a conclusion of increased risk of mortality with tiotropium Respimat: there was no increase in risk of death with tiotropium Respimat 5 μg versus tiotropium HandiHaler 18 μg in 1221 patients with a history of cardiac arrhythmia (614 patients received tiotropium Respimat 5 μg, 607 patients received tiotropium HandiHaler 18 μg; hazard ratio 0·81, 95% CI 0·58–1·12). No deaths have occurred in the phase 3 clinical trials of tiotropium Respimat add-on therapy in asthma that have been published up to now.2,4,5 In our studies of tiotropium Respimat add-on therapy to inhaled corticosteroids over 24 weeks2 and add-on to inhaled corticosteroids plus longacting β-agonists given over 48 weeks, 4 in 3012 patients with symptomatic asthma, the incidence of cardiac adverse events was less than 2%, with no difference in occurrence between the active or placebo treatment groups. 2,4 Therefore, we conclude from the data that tiotropium Respimat addon therapy safely improves asthma control in patients with symptomatic asthma despite treatment with medium-dose inhaled corticosteroids.
For the PRECOVID study see https://clinicaltrials.gov/ct2/ show/NCT02122627
The authors’ competing interests remain the same as those declared in the original article.
*Huib AM Kerstjens, Petra Moroni-Zentgraf [email protected]
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