Guideline topic: Pharmacological management of asthma
Evidence table 4.4d: Leukotriene receptor antagonists with short-acting beta-agonists

Author

Year

Study type

Quality rating

Population

Outomes measured

Effect size

Confidence intervals / p values

Comments

Adults

Altman¹

1998

Randomised placebo controlled, double-blind comparing placebo with 10, 100, 200 mg once daily in evening, or 10 or 50 mg bd (6gps)

++

Similar to Noonan

Similar to Noonan

Results similar as above in terms of changes in FEV1, PEFR, global assessment and beta-agonist usage, with no dose response observed.

Activity domain is significantly improved, but not on environment for QoL (for pooled data)
Note 10 mg/day no sign increase in am PEFR.

CI provided in Tables

Similar to Noonan

Fish²

1997

13 week randomised, double-blin, placebo-controlled, parallel gtroup comparing zafirlukast 20mg bd vs placebo

+

N=762 (12-76 years) 514 ZAF; 248: PLAC
As needed beta-agonist Asthma score >8 over 7 consec days

Symptom score beta-agonist use AM/PM usage FEV1 daily PEFR adverse events

Total symptom score reduction: 27 vs 13

(Z vs P) p<0.05

beta-agonist use; 3.1 vs 3.9 puffs/day p<0.01

FEV1; 3.0 vs 2.95 p<0.05

AM PEFR; 418 vs 405 p<0.05

Mean + - SEM shown; No. 95% CI shown

Study has power to detect diff of 10% in FEV1.

Changes achieved are small

Placebo effect

Kemp³

1999

13 wk randomised placebo controlled parallel multicenter; 4 separate randomised trials

+

N=261

As needed beta-agonist

Steroid naïve FEV1 <60%

Trials analysed separately and together also!!

FEV1; am PEFR; Asthma symptoms

64% increase in >10% FEV1 vs 50% for placebo

FEV1 diff (95%CI) 0.01, 0.27 p=0.039

AM PEF 0.1, 7.0 p<0.001

Daytime symptom score –2.7, -0.7p=0.001

beta-agonist use-1.8, -0.6p<0.001

Mean SEM and 95% CI shown

Small changes

Placebo effect

Nathan⁴

1998

13 wk double-blind multicenter placebo controlled parallel group. ZAF 20 mg bd vs placebo

++

N=454 (Z231; P223)

374 completed; >12 years; FEV1 45-80% pred; reversibility of 15% with beta-agonist; symptomatic.

No oral/inhaled steroidsAsthma symptoms B2-agonist use Nasal congestion score

PEFR am/pm

FEV1

AQLQ

Daytime symptoms; -23% vs-16%

Night time: -18.7% vs 8.7%

beta-agonist: -23.7% vs –0.6%

AM PEFR:24.1 vs 13.1 p<0.01 FEV1 change; 0.05 NS

QoL: overall p=0.004 (0.26 unit change)

Blood eos: sign greater fall with ZAF

Mean +- shown; No 95% CI shown.

Study has power to detect 0.2 unit diff in asthma symptom, score

Small changes observed; no sign changes in FEV1

Placebo effect

Noonan⁵

1998

Randomised parallel group, double blind, comparing 2, 10 or 50 mg/daily pm dose

++

Chronic asthma (28-65 yrs); 40-80% pred FEV1; <15% increase in FEV1 with beta agonist; weekly daytime symptom score of >32; >1 puff of Ventolin/day; in 20% inhaled steroid permitted.

1] Morning and evening FEV1

2] Asthma symptoms and beta agonist use

3] PEFR

4] Global evaluation

5] Asthma specific QoL

Changes in AM FEV1 not different across doses but sign diff from placebo (MEAN% CHANGE: 6.2, 14.7, 13.5, 13.1)
But no sign change in afternoon FEV1.

Improved, no dose response, except 2mg showed no effect

Both am and pm PEFR sign increased equally amongst the doses.

Physician ge sign with 10 & 50 mg doses of placebo
Improved in symptom, environment and emotion, not activity.

CI provided in Tables

P<0.05 of placebo.

p<0.05

p<0.05

p<0.05

Nearly all patients completed. Main emphasis on dose response; prob on basis of this study the 10 mg dose was used. Interest in evening FEV1 not improved: the 24 hour effect worn off then?

A power of 80% for 11% change in FEV1 requred 50 in each group (70 actual in each group).

Good evidence that there is a bronchodilator effect of montelukast, with improved asthma control in patients with asthma not on IS (only 20% were on IS)

Reiss⁶

1998

Randomised, double blind, placebo, parallel group. Comparing placebo to Montelukast 10 mg/pm dose)

++

>15 years; 15% increase in FEV1 after beta agonist; moderate symptom score; at least 1 puff ventolin per day. 23% on inhaled steroids

FEV1 and saytime symptom scores were 1 ary end-points

13.1% increase vs placebo of 4.2% FEV1

Improvements in a, {EFR; reduction in beta-agonist use; daytime symptom score; improved QoL across all measures.

Mean diff of 8.9% (CI 6.8 to 11%)

p<0.001

Note 14.3% discontinuation in MON and 8.6% in placebo. Results applicable to Step 2 or 3.

Spector⁷

1994

6 wk randomised double-blind, placebo controlled, parallel group comparing 10, 20 or 40 mg ZAF per day with placebo

+

N=276 (10 mg:68; 20 mg:68; 40 mg:70; placebo: 70). FEV1 40- 75%; FEV1 increased by 15% with beta-agonist; 18-65 years; asthma score of >10

Asthma symptom acore PEF am/pm Inhaler use FEV1

Symptoms: -28% - 8%, 09%, 010%

Inhaler use: -31%, -18%, -20%, -15%

AM PEF: 6%, 6%, 7%, 2%

FEV1: 11%, 6%, 7%, 1%

Mean +-

SEM shown

Well –balanced group

Changes biggest with 40 mg dose

Dose response with serum levels of ZAF

Effectsd fairly modest, again a placebo response