补充维生素D预防哮喘恶化：个体参与者数据的系统回顾和荟萃分析
2017/10/23
摘要
背景：既往的随机对照试验的汇总数据荟萃分析显示，补充维生素D可降低需要全身糖皮质激素治疗的哮喘患者的哮喘恶化程度。这种影响是否局限于低水平维生素D状态的患者尚不清楚。
方法：为对个人参与者数据进行系统回顾和一步法与两步法meta分析，我们检索了MEDLINE，EMBASE和Cochrane临床对照试验资料库以及科学网，检索自数据库成立至2016年10月26日之间发表的有关哮喘急性发作率与补充维生素D3或维生素D2的随机双盲安慰剂对照试验。我们分析个人参与者数据符合主要调查员要求的标准，调整年龄和性别，并通过研究进行聚类。主要结果是需要全身糖皮质激素治疗的哮喘患者哮喘恶化发生率，采用混合效应回归模型，得到95% CI的混合干预效果。亚组分析来确定，维生素D对哮喘恶化风险的影响是否基于不同基线的25羟维生素D（25 [OH] D）浓度、年龄、民族、种族、身体质量指数、维生素D的剂量方案，使用吸入糖皮质激素，或结束研究时25（OH）D水平；根据性别和研究时间进行后亚组分析。这项研究是在普罗斯佩罗登记，编号crd42014013953。
发现：我们的研究检索了483项独立研究，其中八项是符合条件的随机对照试验（共1078人）。我们在七项研究（955人）寻找到了每个参与者的个人数据。补充维生素D降低参与研究的需要全身糖皮质激素治疗的哮喘患者急性发作率（调整后的发病率[aIRR（调整后的内部返回率）] 0·74, 95 CI为0·56-0·97；P = 0·03；7项研究的955人；高质量证据）。维生素D和安慰剂在至少一次急性发作或首次发作时的比例上没有显著性差异。对于应用全身性糖皮质激素治疗的哮喘患者急性发作频率进行亚组分析发现，25(OH)D基线浓度小于25 nmol/L对患者有保护作用（aIRR 0·33, 0·11-0·98；P = 0·046；3项研究中92人；中等质量的证据），而不是参与者有高25（OH）D基线水平（aIRR 0·77, 0·58-1·03；P = 0·08；6项研究的764人；中等质量的证据；Pinteraction = 25）。所有其他亚组分析的相互作用p值也高于0·05，因此，我们没有表明任何一个亚组的干预效果比另一个亚组强。六项研究被评定为低偏倚风险，一项研究被评定为不明确的偏倚风险。两阶段的meta分析没有发现效果的异质性（I2＝0·0，p＝0·56）。
说明：补充维生素D可降低需要全身糖皮质激素治疗哮喘的恶化程度。我们没有发现确切证据表明，这种干预的效果在不同的亚组患者之间不同。
资助：国家卫生研究所卫生技术评估计划（参考编号13／03／25）。
Vitamin D supplementation to prevent asthma exacerbations a systematic review and meta-analysis of individual participant data
Jolliffe DA, Greenberg L, Hooper RL, Griffiths CJ, Camargo CA Jr, Kerley CP, Jensen ME, Mauger D, Stelmach I, Urashima M, Martineau AR.
Abstract
BACKGROUND: A previous aggregate data meta-analysis of randomised controlled trials showed that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with systemic corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D status is unknown. METHODS: For this systematic review and one-step and two-step meta-analysis of individual participant data, we searched
MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of vitamin D3 or vitamin D2 supplementation in people with asthma that reported incidence of asthma exacerbation, published between database inception and Oct 26, 2016. We analysed individual participant data requested from the principal investigator for each eligible trial, adjusting for age and sex, and clustering by study. The primary outcome was the incidence of asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were done to determine whether effects of vitamin D on risk of asthma exacerbation varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, age, ethnic or racial origin, body-mass index, vitamin D dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels; post-hoc subgroup analyses were done according to sex and study duration. This study was registered with PROSPERO, number CRD42014013953.
FINDINGS: Our search identified 483 unique studies, eight of which were eligible randomised controlled trials (total 1078 participants). We sought individual participant data for each and obtained it for seven studies (955 participants). Vitamin D supplementation reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56-0·97; p=0·03; 955 participants in seven studies; high-quality evidence). There were no significant differences between vitamin D and placebo in the proportion of participants with at least one exacerbation or time to first exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11-0·98; p=0·046; 92 participants in three studies; moderate-quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58-1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; pinteraction=0·25). p values for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not show that the effects of this intervention are stronger in any one subgroup than in another. Six studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect (I2=0·0, p=0·56).
INTERPRETATION: Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of this intervention differed across subgroups of patients.
FUNDING: Health Technology Assessment Program, National Institute for Health Research (reference number 13/03/25).
背景：既往的随机对照试验的汇总数据荟萃分析显示，补充维生素D可降低需要全身糖皮质激素治疗的哮喘患者的哮喘恶化程度。这种影响是否局限于低水平维生素D状态的患者尚不清楚。
方法：为对个人参与者数据进行系统回顾和一步法与两步法meta分析，我们检索了MEDLINE，EMBASE和Cochrane临床对照试验资料库以及科学网，检索自数据库成立至2016年10月26日之间发表的有关哮喘急性发作率与补充维生素D3或维生素D2的随机双盲安慰剂对照试验。我们分析个人参与者数据符合主要调查员要求的标准，调整年龄和性别，并通过研究进行聚类。主要结果是需要全身糖皮质激素治疗的哮喘患者哮喘恶化发生率，采用混合效应回归模型，得到95% CI的混合干预效果。亚组分析来确定，维生素D对哮喘恶化风险的影响是否基于不同基线的25羟维生素D（25 [OH] D）浓度、年龄、民族、种族、身体质量指数、维生素D的剂量方案，使用吸入糖皮质激素，或结束研究时25（OH）D水平；根据性别和研究时间进行后亚组分析。这项研究是在普罗斯佩罗登记，编号crd42014013953。
发现：我们的研究检索了483项独立研究，其中八项是符合条件的随机对照试验（共1078人）。我们在七项研究（955人）寻找到了每个参与者的个人数据。补充维生素D降低参与研究的需要全身糖皮质激素治疗的哮喘患者急性发作率（调整后的发病率[aIRR（调整后的内部返回率）] 0·74, 95 CI为0·56-0·97；P = 0·03；7项研究的955人；高质量证据）。维生素D和安慰剂在至少一次急性发作或首次发作时的比例上没有显著性差异。对于应用全身性糖皮质激素治疗的哮喘患者急性发作频率进行亚组分析发现，25(OH)D基线浓度小于25 nmol/L对患者有保护作用（aIRR 0·33, 0·11-0·98；P = 0·046；3项研究中92人；中等质量的证据），而不是参与者有高25（OH）D基线水平（aIRR 0·77, 0·58-1·03；P = 0·08；6项研究的764人；中等质量的证据；Pinteraction = 25）。所有其他亚组分析的相互作用p值也高于0·05，因此，我们没有表明任何一个亚组的干预效果比另一个亚组强。六项研究被评定为低偏倚风险，一项研究被评定为不明确的偏倚风险。两阶段的meta分析没有发现效果的异质性（I2＝0·0，p＝0·56）。
说明：补充维生素D可降低需要全身糖皮质激素治疗哮喘的恶化程度。我们没有发现确切证据表明，这种干预的效果在不同的亚组患者之间不同。
资助：国家卫生研究所卫生技术评估计划（参考编号13／03／25）。
（中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校）
（Lancet Respir Med. 2017 Oct 3. pii: S2213-2600(17)30306-5.doi: 10.1016/S2213-2600(17)30306-5.）
Vitamin D supplementation to prevent asthma exacerbations a systematic review and meta-analysis of individual participant data
Jolliffe DA, Greenberg L, Hooper RL, Griffiths CJ, Camargo CA Jr, Kerley CP, Jensen ME, Mauger D, Stelmach I, Urashima M, Martineau AR.
Abstract
BACKGROUND: A previous aggregate data meta-analysis of randomised controlled trials showed that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with systemic corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D status is unknown. METHODS: For this systematic review and one-step and two-step meta-analysis of individual participant data, we searched
MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of vitamin D3 or vitamin D2 supplementation in people with asthma that reported incidence of asthma exacerbation, published between database inception and Oct 26, 2016. We analysed individual participant data requested from the principal investigator for each eligible trial, adjusting for age and sex, and clustering by study. The primary outcome was the incidence of asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were done to determine whether effects of vitamin D on risk of asthma exacerbation varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, age, ethnic or racial origin, body-mass index, vitamin D dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels; post-hoc subgroup analyses were done according to sex and study duration. This study was registered with PROSPERO, number CRD42014013953.
FINDINGS: Our search identified 483 unique studies, eight of which were eligible randomised controlled trials (total 1078 participants). We sought individual participant data for each and obtained it for seven studies (955 participants). Vitamin D supplementation reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56-0·97; p=0·03; 955 participants in seven studies; high-quality evidence). There were no significant differences between vitamin D and placebo in the proportion of participants with at least one exacerbation or time to first exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11-0·98; p=0·046; 92 participants in three studies; moderate-quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58-1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; pinteraction=0·25). p values for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not show that the effects of this intervention are stronger in any one subgroup than in another. Six studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect (I2=0·0, p=0·56).
INTERPRETATION: Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of this intervention differed across subgroups of patients.
FUNDING: Health Technology Assessment Program, National Institute for Health Research (reference number 13/03/25).
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