Comparison 2. Leukotriene Receptor Antagonists (LTRA) + ICS vs. DOUBLE dose of ICS in SYMPTOMATIC PATIENTS.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Patients with 1 or more exacerbations requiring systemic steroids at LICENSED DOSES	2	1179	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.56, 1.51]
1.1 Montelukast 10 mg die	1	885	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.45, 1.33]
1.2 Zafirlukast 20 mg bid	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	2.30 [0.61, 8.73]
2 Patients with 1 or more exacerbations requiring systemic steroids at HIGHER THAN LICENSED DOSES	2	816	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.55, 2.00]
2.1 Zafirlukast 40 mg bid	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.36, 2.77]
2.2 Zafirlukast 80 mg bid	2	556	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.47, 2.50]
3 Patients with 1 or more exacerbations requiring hospital admission at LICENSED DOSES	2	1179	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.1 Montelukast 10 mg die	1	885	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Zafirlukast 20 mg bid	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Change from baseline FEV1(L) at LICENSED DOSES at 12 weeks	2	225	Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.12, 0.06]
4.1 Montelukast 10 mg die	1	2	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Zafirlukast 20 mg bid	1	223	Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.12, 0.06]
5 Change from baseline FEV1 (L) at HIGHER THAN LICENSED doses at 12 +/‐ 4 weeks	2	638	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.05, 0.07]
5.1 Zafirlukast 40 mg bid	1	206	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.12, 0.10]
5.2 Zafirlukast 80 mg bid	2	432	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.05, 0.09]
6 Change from baseline Am PEFR (L/min) at LICENSED DOSES at 12 weeks weeks	2	1130	Mean Difference (IV, Random, 95% CI)	1.56 [‐5.77, 8.89]
6.1 Montelukast 10 mg die	1	889	Mean Difference (IV, Random, 95% CI)	3.40 [‐5.19, 11.99]
6.2 Zafirlukast 20 mg bid	1	241	Mean Difference (IV, Random, 95% CI)	‐3.40 [‐17.49, 10.69]
7 Change from baseline Am PEFR (L/min) at HIGHER THAN LICENSED DOSES at 12 +/‐ 4 weeks	2	663	Mean Difference (IV, Fixed, 95% CI)	6.05 [‐1.26, 13.36]
7.1 Zafirlukast 40 mg bid	1	208	Mean Difference (IV, Fixed, 95% CI)	7.60 [‐4.70, 19.90]
7.2 Zafirlukast 80 mg bid	2	455	Mean Difference (IV, Fixed, 95% CI)	5.21 [‐3.89, 14.30]
8 % Change from baseline mean diurnal variation in PEF at LICENSED DOSES at 12 +/‐ 4 weeks	1	241	Mean Difference (IV, Random, 95% CI)	‐6.40 [‐15.63, 2.83]
8.1 Zafirlukast 20 mg bid	1	241	Mean Difference (IV, Random, 95% CI)	‐6.40 [‐15.63, 2.83]
9 Change (% or L/min) from baseline mean diurnal variation in PEF at HIGHER THAN LICENSED DOSES at 12 +/‐ 4 wee	2	746	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.11 [‐0.25, 0.03]
9.1 Zafirlukast 40 mg bid	1	251	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.37, 0.13]
9.2 Zafirlukast 80 mg bid	2	495	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.11 [‐0.28, 0.07]
10 Change from baseline mean symptom scores at LICENSED DOSES at 12 +/‐ 4 weeks	2	1101	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.09, 0.10]
10.1 Montelukast 10 mg die	1	860	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.10, 0.12]
10.2 Zafirlukast 20 mg bid	1	241	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.18, 0.18]
11 Change from baseline mean symptom scores at HIGHER THAN LICENSED DOSES at 12 +/‐ 4 weeks	2	664	Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.16, 0.03]
11.1 Zafirlukast 40 mg bid	1	208	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.17, 0.15]
11.2 Zafirlukast 80 mg bid	2	456	Mean Difference (IV, Fixed, 95% CI)	‐0.09 [‐0.21, 0.03]
12 Change from baseline mean daily use of B2‐agonists at LICENSED DOSES at 12 +/‐ 4 weeks	2	1015	Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.24, 0.18]
12.1 Montelukast 10 mg die	1	774	Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.25, 0.19]
12.2 Zafirlukast 20 mg bid	1	241	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.74, 0.74]
13 Change from baseline mean daily use of B2‐agonists at HIGHER THAN LICENSED DOSES at 12 +/‐ 4 weeks	2	663	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.37, 0.37]
13.1 Zafirlukast 40 mg bid	1	208	Mean Difference (IV, Fixed, 95% CI)	0.29 [‐0.34, 0.92]
13.2 Zafirlukast 80 mg bid	2	455	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐0.62, 0.31]
14 Change in night‐time awakenings per week at LICENSED DOSES at 12 +‐4 weeks	1	241	Mean Difference (IV, Fixed, 95% CI)	0.4 [‐0.60, 1.40]
14.1 Zafirlukast 20 mg bid	1	241	Mean Difference (IV, Fixed, 95% CI)	0.4 [‐0.60, 1.40]
15 Change in night‐time awakenings per week at HIGHER THAN LICENSED DOSES at 12 +‐4 weeks	1	236	Mean Difference (IV, Fixed, 95% CI)	0.20 [‐0.73, 1.13]
15.1 Zafirlukast 80 mg bid	1	236	Mean Difference (IV, Fixed, 95% CI)	0.20 [‐0.73, 1.13]
16 Overall withdrawals at LICENSED DOSES	2	1183	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.63, 1.55]
16.1 Montelukast 10 mg die	1	889	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.43, 1.34]
16.2 Zafirlukast 20 mg bid	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [0.74, 3.64]
17 Withdrawals due to adverse effects at LICENSED DOSES	2	1183	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.55, 2.37]
17.1 Montelukast 10 mg die	1	889	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.31, 1.98]
17.2 Zafirlukast 20mg bid	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	2.30 [0.61, 8.73]
18 Withdrawals due to poor asthma control/exacerbations at LICENSED DOSES	2	1183	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.15, 1.63]
18.1 Montelukast 10 mg die	1	889	Risk Ratio (M‐H, Fixed, 95% CI)	0.28 [0.06, 1.35]
18.2 Zafirlukast 20 mg bid	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [0.18, 21.52]
19 Overall adverse effects at LICENSED DOSES	2	1183	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.84, 1.06]
19.1 Montelukast 10 mg die	1	889	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.76, 1.06]
19.2 Zafirlukast 20 mg bid	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.90, 1.19]
20 Elevated liver enzymes at LICENSED DOSES	2	1147	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.34, 1.92]
20.1 Montelukast 10 mg die	1	853	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.18, 1.61]
20.2 Zafirlukast 20 mg bid	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [0.37, 10.61]
21 Headache at LICENSED DOSES	2	1183	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.76, 1.52]
21.1 Montelukast 10 mg die	1	889	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.72, 1.86]
21.2 Zafirlukast 20 mg bid	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.60, 1.62]
22 Nausea at LICENSED DOSES	2	1183	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.25, 1.60]
22.1 Montelukast 10 mg die	1	889	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.19, 2.31]
22.2 Zafirlukast 20 mg bid	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.14, 2.43]
23 Oral Moniliasis at LICENSED DOSES	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.08, 2.00]
23.1 Zafirlukast 20 mg bid	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.08, 2.00]
24 Death at LICENSED DOSES	2	1183	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
24.1 Montelukast 10 mg die	1	889	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
24.2 Zafirlukast 20 mg bid	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
25 Patients with 1 or more exacerbations requiring hospital admission at HIGHER THAN LICENSED DOSES	2	699	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.12, 73.04]
25.1 Zafirlukast 40 mg bid	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
25.2 Zafirlukast 80 mg bid	2	439	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.12, 73.04]
26 Nightime awakenings/week at USUAL LICENSED DOSES at 12 weeks	1	820	Mean Difference (IV, Fixed, 95% CI)	1.0 [‐2.69, 4.69]
26.1 Montelukast 10 mg die	1	820	Mean Difference (IV, Fixed, 95% CI)	1.0 [‐2.69, 4.69]
27 Overall withdrawals at HIGHER THAN LICENSED DOSES	2	816	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.73, 1.50]
27.1 Zafirlukast 40 mg bid	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.57, 1.74]
27.2 Zafirlukast 80 mg bid	2	556	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.68, 1.72]
28 Withdrawals due to adverse effects at HIGHER THAN LICENSED DOSES	2	816	Risk Ratio (M‐H, Fixed, 95% CI)	2.27 [0.95, 5.45]
28.1 Zafirlukast 40 mg bid	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.14, 6.99]
28.2 Zafirlukast 80 mg bid	2	556	Risk Ratio (M‐H, Fixed, 95% CI)	2.77 [1.02, 7.58]
29 Withdrawals due to poor asthma control/exacerbations at HIGHER THAN LICENSED DOSES	2	816	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.29, 1.76]
29.1 Zafirlukast 40 mg bid	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	0.6 [0.15, 2.46]
29.2 Zafirlukast 80 mg bid	2	556	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.25, 2.62]
30 Overall adverse effects at HIGHER THAN LICENSED DOSES	2	816	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.89, 1.07]
30.1 Zafirlukast 40 mg bid	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.77, 1.08]
30.2 Zafirlukast 80 mg bid	2	556	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.90, 1.12]
31 Elevated liver enzymes at HIGHER THAN LICENSED DOSES	2	816	Risk Ratio (M‐H, Fixed, 95% CI)	4.97 [1.45, 17.00]
31.1 Zafirlukast 40 mg bid	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.12, 72.97]
31.2 Zafirlukast 80 mg bid	2	556	Risk Ratio (M‐H, Fixed, 95% CI)	5.36 [1.40, 20.44]
32 Headache at HIGHER THAN LICENSED DOSES	2	816	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.79, 1.63]
32.1 Zafirlukast 40 mg bid	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [0.65, 2.86]
32.2 Zafirlukast 80 mg bid	2	556	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.71, 1.62]
33 Nausea at HIGHER THAN LICENSED DOSES	2	816	Risk Ratio (M‐H, Fixed, 95% CI)	1.77 [0.79, 3.95]
33.1 Zafirlukast 40 mg bid	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.62, 14.59]
33.2 Zafirlukast 80 mg bid	2	556	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.55, 3.66]
34 Oral moniliasis at HIGHER THAN LICENSED DOSES	2	816	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.10, 0.81]
34.1 Zafirlukast 40 mg bid	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	0.6 [0.15, 2.46]
34.2 Zafirlukast 80 mg bid	2	556	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.03, 0.77]
35 Death at HIGHER THAN LICENSED DOSES	2	820	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
35.1 Zafirlukast 40 mg bid	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
35.2 Zafirlukast 80 mg bid	2	560	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]