XXVIII EAACI Congress, Warsaw, Poland, 6-10 June 2009

Estimation of the relative effects of montelukast and Estimation of the relative effects of montelukast and
zafirlukast on asthma exacerbations and safety outcomes: zafirlukast on asthma exacerbations and safety outcomes:
a meta-analysis of adjusted indirect comparisons
SORONCZ-SZAB T,
1,*
NAGY A, FAN, T
432
BACKGROUND
432
METHODS (contd.) BACKGROUND
There are no comparative data available on the relative effects of the
leukotriene receptor antagonists (LTRAs) montelukast (MON) and
zafirlukast (ZAF) on the major health outcomes in chronic bronchial
METHODS (contd.)
Results of Cochrane Reviews
8-10
4 indirect
comparisons
for each outcome
zafirlukast (ZAF) on the major health outcomes in chronic bronchial
asthma, particularly asthma attacks, or their safety/tolerability.
1. Direct comparisons
ZAF vs. plac.
9
MON vs. plac.
9
ZAF vs. ICS
8
MON vs. ICS
8
ZAF vs. plac.
9
MON vs. plac.
9
ZAF vs. ICS
8
MON vs. ICS
8
MON vs. ZAF
MON vs. ZAF
MON vs. ZAF
MON vs. ZAF
1. Direct comparisons
Three comparative studies (total 10 patient-years) provide no data in
this regard.
1-3
The current knowledge is summarized in one of these
articles:
2
Indirect comparison from literature confirms the equivalence
ZAF vs. LABA
10
MON vs. LABA
10
ZAF vs. ICS2
9
MON vs. ICS2
9
ZAF vs. LABA
10
MON vs. LABA
10
ZAF vs. ICS2
9
MON vs. ICS2
9
MON vs. ZAF
MON vs. ZAF
MON vs. ZAF
MON vs. ZAF
articles:
2
Indirect comparison from literature confirms the equivalence
of the two drugs at the doses commonly recommended in the control of
asthma symptoms and in the improvement in pulmonary function. We
did not find any difference between subjects treated with one or
ZAF vs. LABA MON vs. LABA ZAF vs. LABA MON vs. LABA MON vs. ZAF MON vs. ZAF
Finally, a fixed-effect meta-analysis was
used to pool the 4 indirect estimates using
Combined
estimate
did not find any difference between subjects treated with one or
another drug, although the study was not adequately powered to
assess for such difference.
2
used to pool the 4 indirect estimates using
STATA 8.2 (StataCorp LP, College Station,
Texas, USA).
11
estimate
RR (95% CI)
In fact, direct comparison of LTRAs in terms of their effect on
exacerbations would require long-term follow-up to obtain sufficient
numbers of events due to the (at most) moderate expected difference
Doses were used as approved in adult asthmatic patients: MON 110
mg/day; ZAF 220 mg/day. For efficacy outcomes, ZAF 280 mg was
pooled with ZAF 220 mg where results were not heterogeneous. For
numbers of events due to the (at most) moderate expected difference
among two active drugs of the same class.
2. Adjusted indirect comparison (AIC)
pooled with ZAF 220 mg where results were not heterogeneous. For
safety outcomes, incl. overall withdrawals, always the lower dose was
used only.
2. Adjusted indirect comparison (AIC)
In the lack of randomized head-to-head trials, the Evidence-Based
Medicine Working Group proposed, in their Users Guides series no.
XIX.B, the use of indirect comparison of results obtained from
RESULTS
ZAF better MON better
ASTHMA EXACERBATIONS
Indirect estimates
RR (95%CI)
XIX.B, the use of indirect comparison of results obtained from
randomized placebo-controlled trials of two drugs as the next best
evidence to determine whether one drug is exerting (more than) a class
effect.
4
Buchers AIC approach
5
have been empirically proven across a
(vs. ICS2)
(vs. plac.)
(vs. ICS)
ASTHMA EXACERBATIONS
0.33 (0.08, 1.41)
0.54 (0.04, 8.35)
0.60 (0.34, 1.04)
effect.
4
Buchers AIC approach
5
have been empirically proven across a
wide range of therapeutic interventions to give valid estimates of
comparative efficacy and safety.
6
Very recently the Canadian Agency
for Drugs and Technologies in Health (CADTH) have issued a
Combined
(vs.LABA)
(vs. ICS2)
0.62
1.04 (0.35, 3.09)
0.33 (0.08, 1.41)
for Drugs and Technologies in Health (CADTH) have issued a
technology report on indirect treatment comparisons,
7
expanding on
the methodology of indirect comparisons from more complex data sets.
RR exacerbations (MON vs. ZAF)
.03 .05 .1 .2 .4 .6 .8 1 1.5 2 3 5 8
Combined
(fixed)
0.62 (0.39, 0.98)
Test for heterogeneity p= 0.663
ZAF better MON better ZAF better MON better
WITHDRAWAL
Using Buchers AIC, the main assumption for an indirect estimate to
be valid is that the relative efficacy (MON vs. ZAF) is consistent in
patients across different trials (most importantly, independent of
(vs. plac.)
(vs. ICS)
ZAF better MON better
(vs. plac.)
(vs. ICS)
ZAF better MON better
WITHDRAWAL DUE TO POOR CONTROL
0.44 0.25 0.80
0.45 0.08 2.37*
patients across different trials (most importantly, independent of
baseline risk of the outcome studied). There is less probability (vs. a
direct comparison) to demonstrate significant difference because the
variability of the indirectly compared estimates add up.
5-7
(vs.LABA)
(vs. 2xICS) (vs. ICS2)
(vs.LABA)
(vs. 2xICS) (vs. ICS2)
0.44
0.19 0.02 2.05*
0.49 0.15 1.63
variability of the indirectly compared estimates add up.
5-7
OBJECTIVE
RR withdrawal due to poor contro
.01 .05 .1 .2 .4 .6 .8 1 1.5 2 3
Combined
RR withdrawal due to poor contro
.01 .05 .1 .2 .4 .6 .8 1 1.5 2 3
Combined
Test for heterogeneity p= 0.919
0.44 (0.27, 0.71)
* Pooled ZAF doses * Pooled ZAF doses
(2 (280 mg and 2 80 mg and 220 mg) 20 mg)
OBJECTIVE
Estimation of the relative effects of MON and ZAF on exacerbations
and safety/tolerability outcomes by pooling the results of several
adjusted indirects comparisons in adult patients with chronic asthma.
(vs. ICS)
ZAF better MON better
(vs. ICS2)
(vs. ICS)
ZAF better MON better
(vs. ICS2)
WITHDRAWAL DUE TO ADVERSE EVENT
0.77 (0.41, 1.44)
0.34 (0.07, 1.74)
adjusted indirects comparisons in adult patients with chronic asthma.
METHODS
(vs.LABA)
(vs. 2xICS)
(vs. plac.)
(No data on withdrawals due to AE
with add-on ZAF 220 mg
(vs. ICS2)
(vs.LABA)
(vs. 2xICS)
(vs. plac.)
(No data on withdrawals due to AE
with add-on ZAF 220 mg
(vs. ICS2) 0.34 (0.07, 1.74)
0.88 (0.38, 2.07)
METHODS
Individual LTRAs were compared to 4 different treatments each
in patients with chronic bronchial asthma:
RR withdrawal due to AEs (MON vs
.05 .1 .2 .4 .6 .8 1 1.5 2 3
Combined
(vs. plac.) with add-on ZAF 220 mg
compared to placebo.)
RR withdrawal due to AEs (MON vs
.05 .1 .2 .4 .6 .8 1 1.5 2 3
Combined
(vs. plac.) with add-on ZAF 220 mg
compared to placebo.)
Test for heterogeneity p= 0.593
0.75 (0.46, 1.21)
MON MON ZAF ZAF
8 comparisons of LTRAs vs. other treatments:
(vs. ICS)
ZAF better MON better
(vs. ICS)
ZAF better MON better OVERALL ADVERSE EVENTS
0.97 (0.83, 1.14)
MON MON ZAF ZAF
(vs.LABA)
(vs. 2xICS)
(No data on overall AE rate
(vs. ICS2)
(vs.LABA)
(vs. 2xICS)
(No data on overall AE rate
(vs. ICS2) 0.87 (0.70, 1.09)
1.00 (0.78, 1.28)
ICS Placebo ICS2 LABA
RR overall AEs (MON vs. ZAF)
.7 .8 .9 1 1.1 1.2 1.3
Combined
(vs. plac.)
(No data on overall AE rate
with add-on ZAF 220 mg
compared to placebo.)
RR overall AEs (MON vs. ZAF)
.7 .8 .9 1 1.1 1.2 1.3
Combined
(vs. plac.)
(No data on overall AE rate
with add-on ZAF 220 mg
compared to placebo.)
0.95 (0.85, 1.06)
ICS Placebo ICS2 LABA
Double-line arrows denote comparisons on top of ICS therapy
(i.e., both the LTRA and the comparator were add-on to ICS; thus,
Test for heterogeneity p= 0.668
ABNORMAL LIVER FUNCTION TEST ZAF better MON better ZAF better MON better
(i.e., both the LTRA and the comparator were add-on to ICS; thus,
ICS2 represents double-dose ICS); LABA = long-acting -agonist
The results of each of the 8 comparisons of the outcomes studied are
taken from published Cochrane Reviews,
8-10
which were used in the
0.62 (0.10, 3.82)
0.27 (0.04, 2.03)
(vs. 2xICS)
(vs. ICS)
(vs. ICS2) (vs. 2xICS)
(vs. ICS)
(vs. ICS2)
taken from published Cochrane Reviews,
8-10
which were used in the
present analysis for adjusted indirect comparisons calculated with
Buchers method.
5 0.43 (0.11, 1.65)
.05 .5 1 1.5 5
Combined
(vs. plac.)
(No data on abnormal LFT
with add-on ZAF 220 mg
compared to placebo or LABA.) (vs. LABA)
.05 .5 1 1.5 5
Combined
(vs. plac.)
(No data on abnormal LFT
with add-on ZAF 220 mg
compared to placebo or LABA.) (vs. LABA)
CONCLUSIONS
Test for heterogeneity p= 0.555
RR elevated liver enzymes (MON v
.05 .5 1 1.5 5
vs. ZAF) RR elevated liver enzymes (MON v
.05 .5 1 1.5 5
vs. ZAF)
CONCLUSIONS
Based on a meta-analysis of adjusted indirect comparisons derived from the Cochrane Reviews, the risk of asthma exacerbations is 38% (95%CI: 2%
to 61%) less with MON compared to ZAF, and the other economically relevant efficacy and safety outcomes consistently suggest an advantage of
MON. Thus, MON may prevent more asthma exacerbations with 39% (95%CI: 22% to 52%) fewer withdrawals compared to ZAF. MON. Thus, MON may prevent more asthma exacerbations with 39% (95%CI: 22% to 52%) fewer withdrawals compared to ZAF.
References 1. Coreno A, et al. J Allergy Clin Immunol. 2000 Sep;106(3):500-6. 2. Tonelli M, et al. Pulm Pharmacol Ther. 2003;16(4):237-40. 3. Riccioni G, et al. Allergy Asthma Proc. 2004 Nov-Dec;25(6):445-8. 4. McAlister FA, et al. for the Evidence-
CONFLICTS OF INTEREST Authors are (A.N., T.F.) or were (T.S-S) employees of Merck & Co., Inc. (or its fully owned subsidiary), manufacturer of MON.
Based Medicine Working Group. JAMA 1999;282(14):1371-1377. 5. Bucher HC, et al. J Clin Epidemiol 1997;50(6):683-91. 6. Song F, et al. BMJ 2003;326:472. 7. Wells GA, et al. Indirect Evidence: Indirect Treatment Comparisons in Meta-Analysis.
Ottawa: Canadian Agency for Drugs and Technologies in Health (CADTH); March 2009. 8. Ducharme FM, Di Salvio F. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD002314. DOI: 10.1002/14651858.CD002314.pub2.
9. Ducharme F, et al. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003133. DOI: 10.1002/14651858.CD003133.pub2. 10. Ducharme FM, et al. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD003137.
DOI: 10.1002/14651858.CD003137.pub3. 11. Sterne JC, et al. Meta-analysis in Stata in: Systematic Reviews in Health Care: Meta-Analysis in Context, 2nd Edition (Eds. Egger M, Davey Smith G, Altman DG.) BMJ Publishing Group, 2001:347-369.
1 2
1
MSD Hungary Ltd. (* currently: Schering-Plough Hungary Ltd.), Budapest, Hungary;
2
Outcomes Research and Pricing Support, Merck & Co., Inc., Whitehouse Station, NJ, USA
e-mail: soroncz@t-online.hu