Lay summary
Introduction
Methods
Studies of LABA as add-on to ICS
Studies of LTRA as add-on to ICS
Studies of LAMA as add-on to ICS
Results
Identification of relevant articles
Study | Reference | Included in previous systematic review | Design | Patient age | Primary outcome |
---|---|---|---|---|---|
LABA studies | |||||
Formoterol added to budesonide versus budesonide | |||||
SD-039-0719 NCT00646529 | Berger 2010 [32] | Yes (Chauhan) | 26-week, randomised, open-label, parallel-group, multicentre trial | 6–11 years | Safety |
SD-039-0725 NCT00646321 | Eid 2010 [33] | Yes (Chauhan) | 12-week, randomised, double-blind, parallel-group, multicentre trial | 6–15 years | PEF |
Study 0688 | Pohunek 2006 [34] | Yes (Chauhan) | 12-week, randomised, double-blind, parallel-group, multicentre trial | 4–11 years | Morning PEF |
SD-039-0714 ATTAIN | CSR 2003 [35] | Yes (Chauhan) | 12-week, randomised, double-blind, parallel-group, multicentre trial | 12–17 years | Morning PEF |
CHASE 3 NCT02091986 | Pearlman 2017 [29] | No | 12-week, randomised, double-blind, parallel-group, multicentre trial | 6–< 12 years | FEV1 |
Akpinarli 1999 [36] | Yes (Chauhan) | 6-week, randomised, double-blind, parallel-group, multicentre trial | 6–14 years | NR | |
SD-039-0718 NCT00651547 | Yes (Chauhan) | 12-week, randomised, double-blind, parallel-group, multicentre trial | 6–15 years | Morning PEF | |
SD-039-0682 | Morice 2008 [37] | Yes (Chauhan) | 12-week, randomised, double-blind, parallel-group, multicentre trial | 6–11 years | Morning PEF |
Salmeterol added to ICS versus ICS | |||||
SAS30031 | Malone 2005 [38] | Yes (Chauhan) | 12-week, randomised, double-blind, parallel-group, multicentre trial | 4–11 years | Safety |
Carroll 2010 [39] | Yes | 8-week, randomised, double-blind, parallel-group, single-centre study | 7–18 years | Salbutamol response following cold air challenge | |
MASCOT | Lenney 2013 [40] | Yes | 48-week, randomised, double-blind, parallel-group, multicentre trial | 6–14 years | Exacerbations |
Teper 2005 [41] | Yes (Chauhan) | 12-month, randomised, double-blind, parallel-group, single-centre trial | 6–14 years | NR | |
SFA100316 NCT00118690 | Murray 2011 [42] | Yes (Chauhan) | 4-week, randomised, double-blind, parallel-group, multicentre trial | 4–17 years | FEV1 following exercise |
SFA100314 | Pearlman 2009 [43] | Yes (Chauhan) | 4-week, randomised, double-blind, parallel-group, multicentre trial | 4–17 years | FEV1 following exercise |
Simons 1997 [44] | Yes (Chauhan) | 28-day, randomised, double-blind, crossover, single-centre trial | 12–18 years | NR | |
SAM40012a | Yes (Chauhan) | 6-month, randomised, double-blind, parallel-group, multicentre trial | 4–11 years | Symptom-free days/nights | |
SALMP/AH91/D89 | Russell 1995 [45] | Yes (Chauhan) | 12-week, randomised, double-blind, parallel-group, multicentre trial | 4–16 years | Morning PEF % predicted |
N/A | Langton Hewer 1995 [46] | Yes (Chauhan) | 8-week, randomised, double-blind, parallel-group, single-centre trial | 12–17 years | Not identified |
Verberne 1998 [47] | Yes (Chauhan) | 54-week, randomised, double-blind, parallel-group, multicentre trial | 6–16 years | FEV1 and response to methacholine | |
Meijer 1995 [48] | Yes (Chauhan) | 16-week, randomised, double-blind, parallel-group, single-centre trial | 7–15 years | NR | |
Vilanterol added to fluticasone propionate versus fluticasone propionate | |||||
NCT01573767 | Oliver 2016 [28] | No | 4-week, randomised, double-blind, parallel-group, multicentre trial | 5–11 years | Evening PEF |
Tiotropium studies | |||||
Tiotropium added to ICS versus ICS | |||||
RubaTinA-asthma® NCT01257230 2010–021093-11 | Hamelmann 2016 [11] | No | 48-week, randomised, double-blind, parallel-group, multicentre trial | 12–17 years | Peak FEV1 response |
CanoTinA-asthma® NCT01634139 2011–001758-26 | Vogelberg 2018 [31] | No | 48-week, randomised, double-blind, parallel-group, multicentre trial | 6–11 years | Peak FEV1 response |
PensieTinA-asthma® NCT01277523 2010–021778-13 | Hamelmann 2017 [14] | No | 12-week, randomised, double-blind, parallel-group, multicentre trial | 12–17 years | Peak FEV1 response |
VivaTinA-asthma® NCT01634152 2011–001777-43 | Szefler 2017 [13] | No | 12-week, randomised, double-blind, parallel-group, multicentre trial | 6–11 years | Peak FEV1 response |
Montelukast studies | |||||
Simons 2001 [49] | Yes (Castro-Rodriguez) | 12-week, randomised, double-blind, crossover, multicentre trial | 6–14 years | % change in FEV1 from baseline | |
Miraglia del Giudice 2007 [50] | Yes (Castro-Rodriguez) | 1-month, randomised, double-blind, crossover, single-centre study | 7–11 years | NR | |
Stelmach 2007 [51] | Yes (Zhao) | 4-week, randomised, double-blind, parallel-group, single-centre study | 6–18 years | 4 lung function parameters | |
NCT01266772 | Stelmach 2015 [30] | No | 7-month, randomised, double-blind, parallel-group, single-centre study | 6–14 years | NR |
Random sequence generation (selection bias) | Allocation concealment (selection bias) | Blinding (performance bias and detection bias) | Incomplete outcome data (attrition bias) | Selective reporting (reporting bias) | Other bias | |
---|---|---|---|---|---|---|
LABA added to ICS versus ICS | ||||||
Akpinarli 1999 | ? | ? | + | ? | + | ? |
Berger 2010 | + | + | – | + | ? | ? |
Carroll 2010 | ? | + | + | + | + | + |
Eid 2010aa | ? | ? | + | ? | – | + |
Eid 2010ba | ? | ? | + | ? | – | + |
Langton Hewer 1995 | ? | ? | + | ? | + | ? |
Lenney 2013 | + | + | + | + | + | + |
Malone 2005 | + | + | + | – | + | + |
Meijer 1995 | ? | ? | + | ? | ? | ? |
Morice 2008aa | + | ? | + | ? | – | + |
Morice 2008ba | + | ? | + | ? | – | + |
Murray 2011 | ? | ? | + | + | + | + |
Oliver 2016 | + | ? | + | + | ? | + |
Pearlman 2009 | + | ? | + | + | + | + |
Pohunek 2006aa | + | + | + | ? | ? | + |
Pohunek 2006ba | + | + | + | ? | ? | + |
Russell 1995 | + | + | + | – | + | ? |
SAM40012 | + | + | + | ? | ? | ? |
SD 0390714 | ? | ? | + | ? | ? | + |
SD 0390718 | ? | ? | + | ? | ? | + |
Simons 1997 | + | ? | + | + | + | ? |
Teper 2005 | ? | ? | + | ? | ? | ? |
Verberne 1998aa | + | + | + | ? | + | ? |
Verberne 1998ba | + | + | + | ? | + | ? |
Tio added to ICS versus ICS | ||||||
Hamelmann 2016 | + | + | + | + | + | + |
Vogelberg 2018 | + | + | + | + | + | + |
Tio added to ICS with other controllers versus ICS with other controllers | ||||||
Hamelmann 2017 | + | + | + | + | + | + |
Szefler 2017 | + | + | + | + | + | + |
LTRA added to ICS versus ICS | ||||||
Simons 2001 | ? | + | + | + | ? | + |
Miraglia del Giudice 2007 | + | + | + | + | ? | + |
Stelmach 2007 | + | ? | + | + | ? | + |
Stelmach 2015 | + | + | + | + | ? | + |
FEV1 results
FEV1: absolute difference in litres
FEV1 response: percent predicted
Drug | Age, years | na | Mean difference FEV1, % predicted (95% CI) active drug vs placebo |
---|---|---|---|
LABA added to ICS versus ICS, FEV1 response (Cochrane analysis: Chauhan 2015) | 534 | 2.99 (0.86, 5.11)b | |
Formoterol added to ICS versus ICS | |||
Akpinarli 1999 Formoterol 12 μg BID add-on to ICS 400–800 μg/day | 6–14 | 32 | 2.00 (−24.10, 28.10)b |
Salmeterol added to beclomethasone dipropionate versus beclomethasone dipropionate | |||
Verberne 1998 Salmeterol/beclomethasone dipropionate 50/200 μg BID vs beclomethasone dipropionate 200 μg BID | 6–16 | 117 | 3.08 (−0.49, 6.65)b |
Meijer 1995 Salmeterol 50 μg BID + beclomethasone dipropionate 250 μg BID | 7–15 | 39 | 3.60 (−2.94, 10.14)b |
Salmeterol added to fluticasone propionate versus fluticasone propionate | |||
Carroll 2010 Fluticasone/salmeterol 100/50 BID vs fluticasone 100 μg BID | 7–18 | 37 | 5.20 (−1.04, 11.44)b |
Lenney 2013 Fluticasone propionate/salmeterol 100/50 μg BID vs fluticasone propionate 100 μg BID | 6–14 | 21 | 15.42 (1.51, 29.33)b |
Teper 2005 Fluticasone/salmeterol 125/25 μg BID vs fluticasone 125 μg BID | 6–14 | 82 | −0.40 (−5.03, 4.23)b |
Salmeterol added to ICS versus ICS | |||
Russell 1995 Salmeterol 50 μg BID add-on to ICS 400–2400 μg/day | 4–16 | 206 | 3.40 (−1.54, 8.34)b |
Tiotropium in moderate asthma | |||
Tiotropium 5 μg Add-on to 400–800 μg/day budesonide (200–800 μg/day for patients aged 12–14 years) | 12–17 | 268 268 | Trough: 3.205 (0.209, 6.201) Peak: 4.492 (1.700, 7.285) |
Tiotropium 2.5 μg Add-on to 400–800 μg/day budesonide (200–800 μg/day for patients aged 12–14 years) | 12–17 | 256 257 | Trough: 2.850 (−0.229, 5.929) Peak: 4.066 (1.208, 6.924) |
Tiotropium 5 μg Add-on to 200–400 μg budesonide | 6–11 | 260 260 | Trough: 4.439 (1.207, 7.671) Peak: 6.521 (3.717, 9.325) |
Tiotropium 2.5 μg Add-on to 200–400 μg budesonide | 6–11 | 257 257 | Trough: 5.048 (1.811, 8.285) Peak: 7.698 (4.892, 10.505) |
Tiotropium in severe asthma | |||
Tiotropium 5 μg Add-on to high-dose ICSc + ≥1 controller or medium-dose ICSd + ≥2 controllers | 12–17 | 262 262 | Trough: 0.827 (−2.354, 4.008) Peak: 1.643 (−1.252, 4.539) |
Tiotropium 2.5 μg Add-on to high-dose ICSc + ≥1 controller or medium-dose ICSd + ≥2 controllers | 12–17 | 258 258 | Trough: 3.283 (0.075, 6.491) Peak: 3.106 (0.188, 6.024) |
Tiotropium 5 μg Add-on to > 400 μg budesonide + ≥1 controller or 200–400 μg budesonide + ≥2 controllers | 6–11 | 258 258 | Trough: 3.848 (0.576, 7.120) Peak: 6.325 (3.264, 9.385) |
Tiotropium 2.5 μg Add-on to > 400 μg budesonide + ≥1 controller or 200–400 μg budesonide + ≥2 controllers | 6–11 | 265 265 | Trough: 2.350 (−0.909, 5.609) Peak: 3.587 (0.540, 6.634) |
Montelukast | |||
Castro-Rodriguez 2010 Meta-analysis: Montelukast 5 mg QD Add-on to 200–800 μg/day budesonide | 5–18 | 188a | 0.09 (−0.07, 0.25)b |
Simons 2001 Montelukast 5 mg QD + budesonide 200 μg BID vs budesonide 200 μg BID | 6–14 | 279 | 1.3 (− 0.1, 2.7)b |
Miraglia del Giudice 2007 Montelukast 5 μg QD + budesonide 200 μg BID vs budesonide 200 μg BID | 7–11 | 48 | 10.8 (NR)b |
Zhao 2015 Network meta-analysis: Montelukast 4–10 mg QD add-on to 100–200 μg/day budesonide | ≤18 | NR | |
Stelmach 2007 Montelukast 5–10 μg QD + 200 μg budesonide BID vs 200 μg budesonide BID | 6–18 | 76 | 2.6 (NR)b |
Stelmach 2015 Montelukast 5 mg QD add-on to 200–600 μg budesonidee | 6–14 | 76 | 2.5 (NR)b,f |
Exacerbations requiring OCS
Drug | Time period | na | Number of patients with exacerbations requiring OCS, n/N (%) | Exacerbations requiring OCSb | |
---|---|---|---|---|---|
Active treatment | Comparator | Risk ratio (95% CI) | |||
Cochrane analysis of LABA studies (Chauhan 2015) | 1669 | 0.95 (0.70, 1.28) | |||
Formoterol added to ICS versus ICS | |||||
Eid 2010 Budesonide/formoterol 160/18 μg daily vs budesonide 160 μg QD | 12 weeks | 267 | 15/183 (8.2) | 13/84 (15.5) | 0.53 (0.26, 1.06) |
Eid 2010 Budesonide/formoterol 160/9 μg daily vs budesonide 160 μg daily | 12 weeks | 252 | 33/168 (19.6) | 13/84 (15.5) | 1.27 (0.71, 2.28) |
Salmeterol added to ICS versus ICS | |||||
Langton Hewer 1995 Salmeterol 100 μg BID add-on to usual ICS (baseline mean 400 μg) | 8 weeks | 23 | 3/11 (27.2) | 3/12 (25.0) | 1.09 (0.28, 4.32) |
Lenney 2013 Fluticasone propionate/salmeterol 100/50 μg BID vs fluticasone propionate 100 μg BID | 48 weeks | 26 | 5/15 (33.3) | 1/11 (9.1) | 3.67 (0.50, 27.12) |
Malone 2005 Salmeterol/fluticasone 50/100 μg BID vs fluticasone 100 μg BID | 3 months | 203 | 2/101 (2.0) | 3/102 (2.9) | 0.67 (0.11, 3.94) |
Murray 2011 Salmeterol/fluticasone 50/100 μg BID vs fluticasone 100 μg BID | 4 weeks | 231 | 2/113 (1.8) | 1/118 (0.8) | 2.09 (0.19, 22.71) |
Pearlman 2009 Salmeterol/fluticasone 50/100 μg BID vs fluticasone 100 μg BID | 4 weeks | 248 | 1/124 (0.8) | 1/124 (0.8) | 1.00 (0.06, 15.81) |
Simons 1997 Salmeterol 50 μg QD add-on to BDP 200–400 μg/day | 4 weeks | 32 | 0/16 (0.0) | 1/16 (6.3) | 0.33 (0.01, 7.62) |
Verberne 1998 Salmeterol/BDP 50/200 μg BID vs BDP 200 μg BID | 54 weeks | 117 | 10/60 (16.7) | 10/57 (17.5) | 0.95 (0.43, 2.11) |
Russell 1995 Salmeterol 50 μg BID add-on to ICS 400–2400 μg/day | 12 weeks | 198 | 16/99 (16.2) | 18/99 (18.2) | 0.89 (0.48, 1.64) |
Tiotropium added to ICS versus ICS | Hazard ratio (95% CI) | ||||
Hamelmann 2016 Tiotropium 5 μg add-on to 400–800 μg/day budesonide (200–800 μg/day for patients aged 12–14 years) | 48 weeks | 272 | 2/134 (1.5) | 9/138 (6.5) | 0.23 (0.05, 1.08)c |
Hamelmann 2016 Tiotropium 2.5 μg add-on to 400–800 μg/day budesonide (200–800 μg/day for patients aged 12–14 years) | 48 weeks | 263 | 5/125 (4.0) | 9/138 (6.5) | 0.63 (0.21, 1.87)c |
Vogelberg 2018 Tiotropium 5 μg add-on to 200–400 μg budesonide | 48 weeks | 266 | 7/135 (5.2) | 6/131 (4.6) | 1.14 (0.38, 3.39)c |
Vogelberg 2018 Tiotropium 2.5 μg add-on to 200–400 μg budesonide | 48 weeks | 266 | 7/135 (5.2) | 6/131 (4.6) | 1.14 (0.38, 3.38)c |
Tiotropium added to ICS plus other controller(s) versus ICS plus other controller(s) | |||||
Hamelmann 2017 Tiotropium 5 μg add-on to high-dose ICSd + ≥1 controller or medium-dose ICSe + ≥2 controllers | 12 weeks | 265 | 2/130 (1.5) | 1/135 (0.7) | 2.06 (0.19, 22.70)c |
Hamelmann 2017 Tiotropium 2.5 μg add-on to high-dose ICSd + ≥1 controller or medium-dose ICSe + ≥2 controllers | 12 weeks | 262 | 1/127 (0.8) | 1/135 (0.7) | 1.06 (0.07, 16.95)c |
Szefler 2017 Tiotropium 5 μg add-on to > 400 μg budesonide + ≥1 controller or 200–400 μg budesonide + ≥2 controllers | 12 weeks | 264 | 7/130 (5.4) | 8/134 (6.0) | 1.01 (0.35, 2.88)c |
Szefler 2017 Tiotropium 2.5 μg add-on to > 400 μg budesonide + ≥1 controller or 200–400 μg budesonide + ≥2 controllers | 12 weeks | 270 | 3/136 (2.2) | 8/134 (6.0) | 0.40 (0.10, 1.55)c |
Montelukast added to ICS versus ICS | |||||
Castro-Rodriguez 2010 systematic review Montelukast 5 mg add-on to 200–800 μg/day budesonide | NR | NR | NR | NR | Risk ratio (95% CI) 0.53 (0.10, 2.74)f |
Zhao 2015 network meta-analysis Montelukast 4–10 mg add-on to 100–200 μg/day budesonide | 4–16 weeks | NR | NR | NR | Odds ratio (95% CI) 0.94 (0.58, 1.45) |
Stelmach 2015 Montelukast 5 mg add-on to 200–600 μg budesonideg | 7 months | 76 | NR | NR | Odds ratio (95% CI) 0.26 (0.09, 0.76) |
Adverse events and serious adverse events
Drug | Duration | na | Number of patients with AE, n (%) | Number of patients with SAE, n (%) | ||
---|---|---|---|---|---|---|
Active | Comparator | Active | Comparator | |||
LABAs added to ICS versus ICS | ||||||
Berger 2010 Budesonide/formoterol pMDI 320/9 μg BID | 26 weeks | 186 | 104 (84.6) | 54 (85.7) | 2 (1.6) | 1 (1.6) |
Eid 2010 Budesonide/formoterol 160/18 μg daily | 12 weeks | 184 | 120 (65.2) | 100 (59.2) | 2 (1.1) | 1 (0.6) |
Eid 2010 Budesonide/formoterol 160/9 μg daily | 12 weeks | 168 | 104 (61.9) | 100 (59.2) | 3 (1.8) | 1 (0.6) |
Langton Hewer 1995 Salmeterol 100 μg BID | 8 weeks | 24 | 10 (91) | 9 (75) | NR | NR |
Malone 2005 Salmeterol/fluticasone 50/100 μg BID | 3 months | 203 | 101 (59) | 102 (57) | NR | NR |
Morice 2008a Budesonide/formoterol 160/9 μg DPI BID | 12 weeks | 419 | 100 (47) | 81 (39) | 2 (0.9) | 0 |
Morice 2008b Budesonide/formoterol 160/9 μg MDI BID | 12 weeks | 410 | 92 (45) | 81 (39) | 3 (1.5) | 0 |
Murray 2011 Salmeterol/fluticasone 50/100 μg BID | 4 weeks | 231 | 20 (18) | 25 (21) | 0 | 0 |
Pearlman 2009 Salmeterol/fluticasone 50/100 μg BID | 4 weeks | 248 | 37 (30) | 35 (28) | 0 | 0 |
SD 0390718 Formoterol/budesonide 9/80 μg BID | 12 weeks | 273 | 90 (70.3) | 92 (63.4) | 0 | 0 |
Verberne 1998a Salmeterol/beclomethasone dipropionate 50/200 μg BID | 54 weeks | 117 | 59 (98) | 52 (93) | NR | NR |
Russell 1995 Salmeterol 50 μg BID | 12 weeks | 206 | 74 (75) | 81 (76) | 10 (10) | 13 (12) |
SD 0390714 Formoterol/budesonide 4.5/160 μg BID | 12 weeks | 270 | 66 (49) | 65 (49) | 1 (0.7) | 1 (0.7) |
SAM40012 Salmeterol/fluticasone propionate 50/100 μg BID | 6 months | 362 | 99 (55) | 111 (61) | 2 (1) | 1 (< 1) |
Pearlman 2017 | 12 weeks | |||||
Budesonide/formoterol 160/9 μg BID | 18 | 42 (46.7) | 40 (44.4) | 0 | 2 (2.2) | |
Budesonide/formoterol 160/4.5 μg BID | 183 | 41 (44.1) | 40 (44.4) | 0 | 2 (2.2) | |
Oliver 2016 | 4 weeks | |||||
Vilanterol 6.25 μg QD | 229 | 33 (29) | 25 (22) | NR | NR | |
Vilanterol 12.5 μg QD | 228 | 37 (33) | 25 (22) | |||
Vilanterol 25 μg QD | 229 | 32 (28) | 25 (22) | |||
Tiotropium added to ICS vs ICS | ||||||
Hamelmann 2016 | 48 weeks | |||||
Tiotropium 5 μg QD | 272 | 84 (62.7) | 82 (59.4) | 3 (2.2) | 2 (1.4) | |
Tiotropium 2.5 μg QD | 263 | 79 (63.2) | 82 (59.4) | 2 (1.6) | 2 (1.4) | |
Vogelberg 2018 | 48 weeks | |||||
Tiotropium 5 μg QD | 266 | 82 (60.7) | 89 (67.9) | 1 (0.7) | 6 (4.6) | |
Tiotropium 2.5 μg QD | 266 | 86 (63.7) | 89 (67.9) | 3 (2.2) | 6 (4.6) | |
Tiotropium added to ICS with other controllers vs ICS with other controllers | ||||||
Hamelmann 2017 | 12 weeks | |||||
Tiotropium 5 μg QD | 265 | 43 (33.1) | 48 (35.6) | 2 (1.5) | 0 | |
Tiotropium 2.5 μg QD | 262 | 42 (33.1) | 48 (35.6) | 1 (0.8) | 0 | |
Szefler 2017 | 12 weeks | |||||
Tiotropium 5 μg QD | 264 | 56 (43.1) | 66 (49.3) | 4 (3.1) | 2 (1.5) | |
Tiotropium 2.5 μg QD | 270 | 59 (43.4) | 66 (49.3) | 2 (1.5) | 2 (1.5) | |
LTRAs added to ICS vs ICS | ||||||
Simons 2001 Montelukast 5 mg | 4 weeks (crossover trial) | 279 | 277 (42) | 270 (45) | NR | NR |