estimation of the relative effects of montelukast and zafirlukast on asthma exacerbations and safety...

8/12/2019 Estimation of the relative effects of montelukast and zafirlukast on asthma exacerbations and safety outcomes: A meta-analysis of adjusted indirect comparisons

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

Estimation of the relative effects of montelukast andzafirlukast on asthma exacerbations and safet outcomes:

a meta-analysis of adjusted indirect comparisons

SORONCZ-SZAB T,1,*NAGY A, FAN, T

There are no comparative data available on the relative effects of the

leukotriene receptor antagonists (LTRAs) montelukast (MON) and

con .

Results of Cochrane Reviews8-10

4 indirectcomparisons

for each outcome

za r u as on e ma o r ea ou comes n c ron c ronc aasthma, particularly asthma attacks, or their safety/tolerability.

ZAF vs. plac.9MON vs. plac.9

ZAF vs. ICS8MON vs. ICS8

ZAF vs. plac.9MON vs. plac.9


MON vs. ZAF

MON vs. ZAF

MON vs. ZAF

MON vs. ZAF

. rec compar sonsThree comparative studies (total 10 patient-years) provide no data in

this regard.1-3 The current knowledge is summarized in one of these ZAF vs. LABA10MON vs. LABA10


ZAF vs. LABA10MON vs. LABA10


MON vs. ZAF

MON vs. ZAF

MON vs. ZAF

MON vs. ZAF

articles:2 Indirect comparison from literature confirms the equivalenceof the two drugs at the doses commonly recommended in the control of

asthma symptoms and in the improvement in pulmonary function. We

.. .. ..

Finally, a fixed-effect meta-analysis was Combined

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

STATA 8.2 (StataCorp LP, College Station,Texas, USA).11

RR (95% CI)

In fact, direct comparison of LTRAs in terms of their effect onexacerbations would require long-term follow-up to obtain sufficient

Doses were used as approved in adult asthmatic patients: MON 110

mg/day; ZAF 220 mg/day. For efficacy outcomes, ZAF 280 mg wasooled with ZAF 220 m where results were not hetero eneous. Fornum ers o even s ue o e a mos mo era e expec e erenceamong two active drugs of the same class.

safety outcomes, incl. overall withdrawals, always the lower dose wasused 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.

RESULTSZAFbetterMON better ASTHMA EXACERBATIONS

Indirect estimatesRR (95%CI)

XIX.B, the use of indirect comparison of results obtained fromrandomized placebo-controlled trials of two drugs as the next bestevidence to determine whether one drug is exerting (more than) a class

(vs. plac.)

(vs. ICS)

0.54 (0.04, 8.35)

0.60 (0.34, 1.04)

e ec . uc er s approac ave een emp r ca y proven across awide range of therapeutic interventions to give valid estimates ofcomparative efficacy and safety.6 Very recently the Canadian Agency

(vs.LABA)

.

1.04 (0.35, 3.09)

. . , .

or rugs an ec no og es n ea ave ssue atechnology report on indirect treatment comparisons,7 expanding onthe 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

om ne(fixed)

. (0.39, 0.98)

Test for heterogeneity p= 0.663

Using Buchers AIC, the main assumption for an indirect estimate tobe valid is that the relative efficacy (MON vs. ZAF) is consistent in (vs. plac.)(vs. ICS)

ZAFbetterMON better

(vs. plac.)

(vs. ICS)

ZAFbetterMON better WITHDRAWAL DUE TO POOR CONTROL

0.44 0.250.800.45 0.082.37*

pa en s across eren r a s mos mpor an y, n epen en obaseline risk of the outcome studied). There is less probability (vs. adirect comparison) to demonstrate significant difference because the

-

(vs.LABA)

(vs. 2xICS)(vs. ICS2)

(vs.LABA)

(vs. 2xICS)(vs. ICS2) 0.19 0.02 2.05*

0.49 0.151.63

var a y o e n rec y compare es ma es a up. -

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


0.44 (0.27,0.71)

* Pooled ZAF doses* Pooled ZAF doses(2(280 mg and 280 mg and 220 mg)20 mg)

Estimation of the relative effects of MON and ZAF on exacerbationsand safety/tolerability outcomes by pooling the results of several (vs. ICS)

ZAFbetterMON better

.

(vs. ICS)

ZAFbetterMON better

.

WITHDRAWAL DUE TO ADVERSE EVENT0.77 (0.41, 1.44)

.

(vs.LABA)

(vs. 2xICS)

(vs. plac.) (No data on withdrawals due to AEwith add-on ZAF 220 m

(vs. ICS2)

(vs.LABA)

(vs. 2xICS)

(vs. plac.) (No data on withdrawals due to AEwith add-on ZAF 220 m

(vs. ICS2) . . , .

0.88 (0.38, 2.07)

Individual LTRAs were compared to 4 different treatments eachin patients with chronic bronchial asthma: RR withdrawal due to AEs (MON vs

.05 .1 .2 .4 .6 .8 1 1.5 2 3

Combined

. . -compared to placebo.)

RR withdrawal due to AEs (MON vs.05 .1 .2 .4 .6 .8 1 1.5 2 3

Combined

. . -compared to placebo.)


0.75 (0.46,1.21)

8 comparisons of LTRAs vs. other treatments:(vs. ICS)

ZAFbetterMON better

(vs. ICS)

ZAFbetterMON better OVERALL ADVERSE EVENTS0.97 (0.83, 1.14)

(vs.LABA)

(vs. 2xICS)

(vs. ICS2)

(vs.LABA)

(vs. 2xICS)

(vs. ICS2) 0.87 (0.70, 1.09)

1.00 (0.78, 1.28)

RR overall AEs (MON vs. ZAF).7 .8 .9 1 1.1 1.2 1.3

Combined

(vs. plac.) ( o da a on ove ra ra ewith add-on ZAF 220 mgcompared to placebo.)

RR overall AEs (MON vs. ZAF).7 .8 .9 1 1.1 1.2 1.3

Combined

(vs. plac.) ( o da a on ove ra ra ewith add-on ZAF 220 mgcompared to placebo.)

0.95 (0.85,1.06)

Double-line arrows denote comparisons on top of ICS therapy(i.e., both the LTRA and the com arator were add-on to ICS; thus,


ABNORMAL LIVER FUNCTION TESTZAFbetterMON better ZAFbetterMON better

ICS2 represents double-dose ICS); LABA = long-acting -agonist

The results of each of the 8 comparisons of the outcomes studied are

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 thepresent analysis for adjusted indirect comparisons calculated withBuchers method.5 0.43 (0.11, 1.65)

. . .

Combined

(vs. plac.) (No data on abnormal LFTwith add-on ZAF 220 mgcompared to placebo or LABA.)(vs. LABA)

. . .

Combined

(vs. plac.) (No data on abnormal LFTwith add-on ZAF 220 mgcompared to placebo or LABA.)(vs. LABA)

CONCLUSIONSTest 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)

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

. , .

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. BMJ2003;326:472. 7. Wells GA, et al. Indirect Evidence: Indirect TreatmentComparisons 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: [email protected]

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