Abstract：
To examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer\'s dementia (AD).
Systematic review and individual patient data (IPD) network meta-analysis (NMA) based on our previously published systematic review and aggregate data NMA.
MEDLINE, Embase, Cochrane Methodology Register, CINAHL, AgeLine and Cochrane Central Register of Controlled Trials up to March 2016.
80 randomised controlled trials (RCTs) including 21 138 adults with AD, and 12 RCTs with IPD including 6906 patients.
Cognitive enhancers (donepezil, rivastigmine, galantamine and memantine) alone or in any combination against other cognitive enhancers or placebo.
We requested IPD from authors, sponsors and data sharing platforms. When IPD were not available, we used aggregate data. We appraised study quality with the Cochrane risk-of-bias. We conducted a two-stage random-effects IPD-NMA, and assessed their findings using CINeMA (Confidence in Network Meta-Analysis).
We included trials assessing cognition with the Mini-Mental State Examination (MMSE), and adverse events.
Our IPD-NMA compared nine treatments (including placebo). Donepezil (mean difference (MD)=1.41, 95% CI: 0.51 to 2.32) and donepezil +memantine (MD=2.57, 95% CI: 0.07 to 5.07) improved MMSE score (56 RCTs, 11 619 participants; CINeMA score: moderate) compared with placebo. According to P-score, oral rivastigmine (OR=1.26, 95% CI: 0.82 to 1.94, P-score=16%) and donepezil (OR=1.08, 95% CI: 0.87 to 1.35, P-score=30%) had the least favourable safety profile, but none of the estimated treatment effects were sufficiently precise when compared with placebo (45 RCTs, 15 649 patients; CINeMA score: moderate to high). For moderate-to-severe impairment, donepezil, memantine and their combination performed best, but for mild-to-moderate impairment donepezil and transdermal rivastigmine ranked best. Adjusting for MMSE baseline differences, oral rivastigmine and galantamine improved MMSE score, whereas when adjusting for comorbidities only oral rivastigmine was effective.
The choice among the different cognitive enhancers may depend on patient\'s characteristics. The MDs of all cognitive enhancer regimens except for single-agent oral rivastigmine, galantamine and memantine, against placebo were clinically important for cognition (MD larger than 1.40 MMSE points), but results were quite imprecise. However, two-thirds of the published RCTs were associated with high risk of bias for incomplete outcome data, and IPD were only available for 15% of the included RCTs.
CRD42015023507.
Systematic review and individual patient data (IPD) network meta-analysis (NMA) based on our previously published systematic review and aggregate data NMA.
MEDLINE, Embase, Cochrane Methodology Register, CINAHL, AgeLine and Cochrane Central Register of Controlled Trials up to March 2016.
80 randomised controlled trials (RCTs) including 21 138 adults with AD, and 12 RCTs with IPD including 6906 patients.
Cognitive enhancers (donepezil, rivastigmine, galantamine and memantine) alone or in any combination against other cognitive enhancers or placebo.
We requested IPD from authors, sponsors and data sharing platforms. When IPD were not available, we used aggregate data. We appraised study quality with the Cochrane risk-of-bias. We conducted a two-stage random-effects IPD-NMA, and assessed their findings using CINeMA (Confidence in Network Meta-Analysis).
We included trials assessing cognition with the Mini-Mental State Examination (MMSE), and adverse events.
Our IPD-NMA compared nine treatments (including placebo). Donepezil (mean difference (MD)=1.41, 95% CI: 0.51 to 2.32) and donepezil +memantine (MD=2.57, 95% CI: 0.07 to 5.07) improved MMSE score (56 RCTs, 11 619 participants; CINeMA score: moderate) compared with placebo. According to P-score, oral rivastigmine (OR=1.26, 95% CI: 0.82 to 1.94, P-score=16%) and donepezil (OR=1.08, 95% CI: 0.87 to 1.35, P-score=30%) had the least favourable safety profile, but none of the estimated treatment effects were sufficiently precise when compared with placebo (45 RCTs, 15 649 patients; CINeMA score: moderate to high). For moderate-to-severe impairment, donepezil, memantine and their combination performed best, but for mild-to-moderate impairment donepezil and transdermal rivastigmine ranked best. Adjusting for MMSE baseline differences, oral rivastigmine and galantamine improved MMSE score, whereas when adjusting for comorbidities only oral rivastigmine was effective.
The choice among the different cognitive enhancers may depend on patient\'s characteristics. The MDs of all cognitive enhancer regimens except for single-agent oral rivastigmine, galantamine and memantine, against placebo were clinically important for cognition (MD larger than 1.40 MMSE points), but results were quite imprecise. However, two-thirds of the published RCTs were associated with high risk of bias for incomplete outcome data, and IPD were only available for 15% of the included RCTs.
CRD42015023507.
摘要：
通过患者特征检查认知增强剂治疗阿尔茨海默氏痴呆(AD)的比较疗效和安全性。
基于我们先前发表的系统评价和汇总数据NMA的系统评价和个体患者数据（IPD）网络荟萃分析（NMA）。
MEDLINE,Embase,Cochrane方法论登记册，CINAHL,截至2016年3月，AgeLine和Cochrane中央受控试验登记册。
80项随机对照试验（RCT），包括21138名患有AD的成年人，12个RCT与IPD，包括6906例患者。
认知增强剂(多奈哌齐，利伐斯的明,加兰他敏和美金刚）单独或以任何组合对抗其他认知增强剂或安慰剂。
我们要求作者提供IPD，赞助商和数据共享平台。当IPD不可用时，我们使用聚合数据。我们用Cochrane偏倚风险评估了研究质量。我们进行了两阶段随机效应IPD-NMA，并使用CINeMA(网络Meta分析信心)评估他们的发现。
我们纳入了用迷你精神状态检查(MMSE)评估认知的试验，和不良事件。
我们的IPD-NMA比较了9种治疗方法（包括安慰剂）。多奈哌齐（均差（MD）=1.41，95％CI：0.51至2.32）和多奈哌齐+美金刚（MD=2.57，95％CI：0.07至5.07）改善了MMSE评分（56个RCT，11619名参与者；CINeMA评分：中等）与安慰剂相比。根据P分数，口服利伐斯的明（OR=1.26，95％CI：0.82至1.94，P评分=16％）和多奈哌齐（OR=1.08，95％CI：0.87至1.35，P评分=30％）的安全性最差，但与安慰剂相比，估计的治疗效果都不够精确(45项随机对照试验，15649例患者；CINeMA评分：中到高）。对于中度至重度损伤，多奈哌齐,美金刚和他们的组合表现最好，但对于轻度至中度损伤，多奈哌齐和经皮卡巴拉汀排名最好。调整MMSE基线差异，口服卡巴拉汀和加兰他敏可改善MMSE评分，而当调整合并症时，仅口服卡巴拉汀有效。
不同认知增强剂之间的选择可能取决于患者的特征。除单药口服利伐斯的明外，所有认知增强剂方案的MD，加兰他敏和美金刚,与安慰剂相比，对认知具有临床重要意义(MD大于1.40MMSE点)，但结果并不精确.然而,2/3发表的RCT与不完整结局数据的高偏倚风险相关,IPD仅适用于15%的纳入随机对照试验。
CRD42015023507。
基于我们先前发表的系统评价和汇总数据NMA的系统评价和个体患者数据（IPD）网络荟萃分析（NMA）。
MEDLINE,Embase,Cochrane方法论登记册，CINAHL,截至2016年3月，AgeLine和Cochrane中央受控试验登记册。
80项随机对照试验（RCT），包括21138名患有AD的成年人，12个RCT与IPD，包括6906例患者。
认知增强剂(多奈哌齐，利伐斯的明,加兰他敏和美金刚）单独或以任何组合对抗其他认知增强剂或安慰剂。
我们要求作者提供IPD，赞助商和数据共享平台。当IPD不可用时，我们使用聚合数据。我们用Cochrane偏倚风险评估了研究质量。我们进行了两阶段随机效应IPD-NMA，并使用CINeMA(网络Meta分析信心)评估他们的发现。
我们纳入了用迷你精神状态检查(MMSE)评估认知的试验，和不良事件。
我们的IPD-NMA比较了9种治疗方法（包括安慰剂）。多奈哌齐（均差（MD）=1.41，95％CI：0.51至2.32）和多奈哌齐+美金刚（MD=2.57，95％CI：0.07至5.07）改善了MMSE评分（56个RCT，11619名参与者；CINeMA评分：中等）与安慰剂相比。根据P分数，口服利伐斯的明（OR=1.26，95％CI：0.82至1.94，P评分=16％）和多奈哌齐（OR=1.08，95％CI：0.87至1.35，P评分=30％）的安全性最差，但与安慰剂相比，估计的治疗效果都不够精确(45项随机对照试验，15649例患者；CINeMA评分：中到高）。对于中度至重度损伤，多奈哌齐,美金刚和他们的组合表现最好，但对于轻度至中度损伤，多奈哌齐和经皮卡巴拉汀排名最好。调整MMSE基线差异，口服卡巴拉汀和加兰他敏可改善MMSE评分，而当调整合并症时，仅口服卡巴拉汀有效。
不同认知增强剂之间的选择可能取决于患者的特征。除单药口服利伐斯的明外，所有认知增强剂方案的MD，加兰他敏和美金刚,与安慰剂相比，对认知具有临床重要意义(MD大于1.40MMSE点)，但结果并不精确.然而,2/3发表的RCT与不完整结局数据的高偏倚风险相关,IPD仅适用于15%的纳入随机对照试验。
CRD42015023507。
