Table 3.
Meta-Regression Analyses of Study Design-, Intervention- and Patient-Related Characteristics Associated with Discontinuation, Efficacy, and Safety Outcomes
| All-cause discontinuation | Discontinuation due to Aes | Discontinuation due to LoE | Cognitive function | Global change | Neuropsychiatric symptoms | Functional capacity | Mortality | Proportion patients AEs | Proportion patients SAEs | |
|---|---|---|---|---|---|---|---|---|---|---|
| Constant (95%CI) | Constant (95%CI) | Constant (95%CI) | Constant (95%CI) | Constant (95%CI) | Constant (95%CI) | Constant (95%CI) | Constant (95%CI) | Constant (95%CI) | Constant (95%CI) | |
| ROR (95%CI) | ROR (95%CI) | ROR (95%CI) | Diff SMD (95%CI) | Diff SMD (95%CI) | Diff SMD (95%CI) | Diff SMD (95%CI) | ROR (95%CI) | ROR (95%CI) | ROR (95%CI) | |
| Study site | ||||||||||
| Single site (ref.) | 2.550 (1.251, 3.846) |
3.096 (1.104, 5.081) |
0.001 (-0.822, 0.824) |
0.087 (-0.268, 0.441) |
(NA) | -0.170 (-0.443, 0.103) |
(NA) | (NA) | (NA) | (NA) |
| Multi-site | -0.965 (-2.315, 0.385) |
-1.381 (-3.390, 0.630) |
0.600 (-0.253, 1.451) |
0.313 (-0.056, 0.681) |
(NA) | 0.207 (-0.073, 0.488) |
(NA) | (NA) | (NA) | (NA) |
| Lead-in period | ||||||||||
| No (ref.) | 1.785 (1.346, 2.223) |
1.885 (1.536, 2.233) |
0.675 (0.437, 0.913) |
0.387 (0.267, 0.507) |
0.314 (0.247, 0.381) |
-0.019 (-0.111, 0.073) |
0.159 (0.086, 0.232) |
0.564 (0.341, 0.787) |
1.846 (1.558, 2.133) |
1.190 (0.896, 1.484) |
| Yes | -0.407 (-1.200, 0.382) |
-0.491 (-1.147, 0.164) |
-0.428 (-0.889, 0.032) |
-0.032 (-0.246, 0.181) |
-0.114 (-0.234, 0.006) |
0.086 (-0.041, 0.213) |
-0.003 (-0.101, 0.095) |
0.248 (-0.131, 0.626) |
-0.400 (-0.865, 0.065) |
-0.344 (-0.907, 0.218) |
| Placebo lead-in period | ||||||||||
| No (ref.) | 1.755 (1.321, 2.189) |
1.885 (1.536, 2.233) |
0.675 (0.437, 0.913) |
0.388 (0.269, 0.505) |
0.314 (0.247, 0.381) |
-0.016 (-0.103, 0.071) |
0.159 (0.086, 0.232) |
0.576 (0.359, 0.793) |
1.846 (1.558, 2.133) |
1.190 (0.896, 1.484) |
| Yes | -0.330 (-1.138, 0.478) |
-0.491 (-1.147, 0.164) |
-0.428 (-0.889, 0.032) |
-0.038 (-0.256, 0.180) |
-0.114 (-0.234, 0.006) |
0.089 (-0.037, 0.215) |
-0.003 (-0.101, 0.095) |
0.242 (-0.151, 0.635) |
-0.400 (-0.865, 0.065) |
-0.344 (-0.907, 0.218) |
| Intervention | ||||||||||
| Donepezil (ref.) | 1.071 (0.610, 1.531)* † |
1.549 (1.096, 2.001) |
0.333 (-0.292, 0.959) |
0.383 (0.230, 0.536) |
0.410 (0.326, 0.494)* |
-0.076† (-0.157, 0.004) |
0.177 (0.073, 0.282) |
0.626 (0.372, 0.881) |
1.662 (1.294, 2.030) |
1.189 (0.844, 1.534) |
| Galantamine | 0.650 (-0.119, 1.418) † |
0.181 (-0.525, 0.887) |
0.171 (-0.596, 0.937) |
-0.087 (-0.319, 0.146) |
-0.247 (-0.363, -0.131)* |
0.181 (0.063, 0.298)* † |
-0.039 (-0.163, 0.084) |
0.054 (-0.376, 0.484) |
-0.035 (-0.556, 0.484) |
-0.219 (-0.779, 0.341) |
| Rivastigmine | 1.658 (0.871, 2.445)* † |
0.544 (-0.196, 1.283) |
0.303 (-0.389, 0.994) |
0.079 (-0.166, 0.323) |
-0.135 (-0.251, -0.020)* |
0.171 (0.032, 0.310)* † |
0.008 (-0.140, 0.155) |
0.056 (-0.532, 0.643) |
0.257 (-0.414, 0.928) |
-0.162 (-0.971, 0.645) |
| Dose | ||||||||||
| Low (ref.) | 1.225 (0.577, 1.873) |
1.483 (0.962, 2.004) |
0.507 (0.105, 0.907) |
0.385 (0.207, 0.563) |
0.302 (0.196, 0.408) |
0.066 (-0.065, 0.197) |
0.175 (0.089, 0.260) |
0.630 (0.263, 0.996) |
1.446 (1.064, 1.828) |
0.853 (0.425, 1.280) |
| High | 0.628 (-0.151, 1.406) |
0.390 (-0.245, 1.024) |
0.081 (-0.410, 0.572) |
-0.013 (-0.228, 0.202) |
-0.034 (-0.162, 0.094) |
-0.054 (-0.206, 0.099) |
-0.027 (-0.131, 0.078) |
0.028 (-0.398, 0.453) |
0.382 (-0.094, 0.857) |
0.365 (-0.158, 0.888) |
| Dosage | ||||||||||
| Fixed (ref.) | 1.378 (0.918, 1.837) |
1.701 (1.307, 2.095) |
0.553 (0.113, 0.992) |
0.330 (0.210, 0.449) |
0.269 (0.193, 0.345) |
0.015 (-0.068, 0.099) |
0.152 (0.092, 0.211) |
0.555 (0.314, 0.796) |
1.682 (1.396, 1.968) |
1.110 (0.813, 1.407) |
| Flexible | 0.699 (-0.024, 1.422) |
0.108 (-0.505, 0.720) |
0.011 (-0.503, 0.524) |
0.138 (-0.068, 0.342) |
0.022 (-0.098, 0.142) |
0.03 (-0.107, 0.168) |
0.017 (-0.086, 0.120) |
0.219 (-0.147, 0.585) |
0.035 (-0.468, 0.538) |
-0.051 (-0.620, 0.517) |
| Length (weeks) | ||||||||||
| Intercept | 2.320 (1.242, 3.395) |
2.589 (1.709, 3.468) |
0.689 (-0.164, 1.540) |
0.188 (-0.086, 0.462) |
0.191 (-0.026, 0.408) |
-0.025 (-0.565, 0.515) |
0.190 (-0.009, 0.389) |
0.265 (-0.186, 0.715) |
1.810 (1.367, 2.252) |
0.817 (0.111, 1.523) |
| -0.026 (-0.067, 0.014) |
-0.033 (-0.065, 0.000) |
-0.005 (-0.036, 0.026) |
0.008 (-0.003, 0.018) |
0.004 (-0.005, 0.012) |
0.002 (-0.021, 0.025) |
-0.001 (-0.009, 0.006) |
0.014 (-0.001, 0.029) |
-0.008 (-0.035, 0.020) |
0.011 (-0.015, 0.037) |
|
| Age (years) | ||||||||||
| Intercept | 0.453 (-1.919, 2.821) |
6.701 (0.804, 12.536) |
-1.986 (-8.233, 4.321) |
0.070 (-0.536, 0.676) |
1.172 (-0.393, 2.734) |
-0.640 (-1.364, 0.085) |
-0.197 (-1.520, 1.124) |
1.638 (-1.702, 4.961) |
1.982 (0.691, 3.269) |
7.648 (4.794, 10.474) |
| 0.017 (-0.016, 0.049) |
-0.066 (-0.144, 0.012) |
0.035 (-0.051, 0.119) |
0.004 (-0.004, 0.012) |
-0.012 (-0.033, 0.009) |
0.009 (-0.001, 0.018) |
0.005 (-0.013, 0.022) |
-0.013 (-0.056, 0.031) |
-0.004 (-0.022, 0.014) |
-0.088 (-0.125, -0.050)* |
|
| Women (%) | ||||||||||
| Intercept | 2.7779 (1.701, 3.855) |
2.845 (1.902, 3.786) |
0.605 (0.035, 1.174) |
0.217 (-0.136, 0.570) |
0.310 (0.113, 0.505) |
0.021 (-0.553, 0.595) |
0.077 (-0.515, 0.668) |
0.505 (-0.993, 2.001) |
2.454 (1.625, 3.281) |
2.270 (1.011, 3.527) |
| -0.019 (-0.036, -0.002)* † |
-0.018 (-0.033, -0.003)* † |
-0.001 (-0.01, 0.009) |
0.003 (-0.003, 0.008) |
-0.001 (-0.004, 0.003) |
0 (-0.001, 0.018) |
0.001 (-0.007, 0.010) |
-0.002 (-0.020, 0.024) |
-0.013 (-0.026, 0.001) |
-0.019 (-0.038, 0.001) |
|
| Cognitive function (mean) | ||||||||||
| Intercept | 2.348 (1.396, 3.300) |
0.693 (-0.158, 1.542) |
3.643 (-1.472, 8.669) |
0.377 (0.077, 0.677) |
0.154 (-0.029, 0.338) |
-0.048 (-0.175, 0.079) |
0.159 (0.047, 0.271) |
0.572 (-0.109, 1.251) |
1.696 (1.108, 2.283) |
1.294 (0.648, 1.939) |
| -0.013 (-0.030, 0.004) |
0.019 (0.004, 0.034)* † |
-0.048 (-0.128, 0.318) |
0.000 (-0.005, 0.005) |
0.002 (-0.001, 0.005) |
0.002 (-0.001, 0.004) |
0 (-0.002, 0.002) |
0.001 (-0.011, 0.014) |
0 (-0.011, 0.011) |
-0.004 (-0.016, 0.008) |
|
| Neuropsychiatric symptoms severity (mean) | ||||||||||
| Intercept | 1.823 (1.405, 2.241) |
1.846 (1.060, 2.186) |
0.426 (0.177, 0.675) |
0.399 (0.286, 0.512) |
0.290 (0.222, 0.358) |
-0.027 (-0.143, 0.090) |
0.138 (0.066, 0.210) |
0.759 (0.459, 1.058) |
1.669 (1.427, 1.969) |
1.194 (0.890, 1.498) |
| -0.034 (-0.083, 0.015) |
-0.022 (-0.061, 0.017) |
0.019 (-0.001, 0.039) |
-0.005 (-0.018, 0.008) |
-0.002 (-0.009, 0.005) |
0.004 (-0.004, 0.013) |
0.002 (-0.003, 0.007) |
-0.06 (-0.035, 0.022) |
-0.003 (-0.031, 0.026) |
-0.011 (-0.040, 0.020) |
|
| Functionality (mean) | ||||||||||
| Intercept | 1.767 (1.330, 2.204) |
1.761 (1.390, 2.186) |
0.381 (0.075, 0.686) |
0.375 (0.251, 0.498) |
0.300 (0.221, 0.379) |
-0.073 (-0.169, 0.023) |
0.162 (0.033, 0.292) |
0.722 (0.424, 1.019) |
1.677 (1.363, 1.991) |
1.280 (1.012, 1.548) |
| -0.005 (-0.017, 0.007) |
-0.001 (-0.01, 0.009) |
0.005 (-0.001, 0.011) |
0 (-0.003, 0.003) |
-0.001 (-0.003, 0.001) |
0.002 (0.001, 0.004)* † |
0 (-0.002, 0.002) |
0 (-0.007, 0.007) |
0 (-0.007, 0.007) |
-0.006 (-0.014, 0.001) |
|
| Type of scalea | ||||||||||
| Intercept (ref.) | (NA) | (NA) | (NA) | 0.420 (0.311, 0.528) |
0.275 (0.211, 0.339) |
-0.058 (-0.253, 0.138) |
-0.054 (-0.150, 0.042) |
(NA) | (NA) | (NA) |
| (NA) | (NA) | (NA) | -0.198 (-0.430, 0.034) |
0.023 (-0.139, 0.185) |
0.064 (-0.076, 0.204) |
0.232 (0.091, 0.373) |
(NA) | (NA) | (NA) | |
Abbreviations: AEs, adverse events; LoE, lack of efficacy; ROR, risk of odd ratios; Diff SMD, difference of standardized mean differences; NA, not applicable; SAEs, serious adverse events.
aType of scale used to evaluate the efficacy. Cognitive function MMSE or ADAS-Cog, global change CIBIC-Plus or CGI, neuropsychiatric symptoms NPI or BEHAVE-AD, functional capacity ADCS-ADL or DAD.
*Statistically significant effect (P < .05).
†Covariates included in multivariate analysis.