ONLINE SUPPLEMENT
THE RISK OF MORTALITY ASSOCIATED WITH FORMOTEROL
TREATMENT: A SYSTEMATIC REVIEW AND META-ANALYSIS
1
1
M Wijesinghe, 2M Weatherall, 1K Perrin, 1,3R Beasley
Medical Research Institute of New Zealand, Wellington, New Zealand
2
3
University of Otago Wellington, Wellington, New Zealand
University of Southampton, Southampton, United Kingdom
1
Reference List:
The 62 studies identified in the systematic review which were
included in the meta-analysis
Study No.
1
Reference/Trial
Akpinarli A, Tuncer A, Saraçlar Y, Sekerel BE, Kalayci O.
Effect of
formoterol on clinical parameters and lung functions in patients with
bronchial asthma: a randomised controlled trial. Arch Dis Child 1999;81:458.
2
AstraZeneca.
Efficacy and safety of budesonide/formoterol turbuhaler
(160/4.5µg BID delivered dose) compared to budesonide turbuhaler (200µg
BID metered dose) in steroid-using asthmatic adolescent patients: a doubleblind, double-dummy, randomised, parallel group, phase III multicentre
study. (ATTAIN Study)
3
Bateman ED, Bantje TA, João Gomes M, Toumbis MG, Huber RM, Naya I,
et al. Combination therapy with single inhaler budesonide/formoterol
compared with high dose of fluticasone propionate alone in patients with
moderate persistent asthma. Am J Respir Med 2003; 2: 275-281.
4
Bensch G, Lapidus RJ, Levine BE, Lumry W, Yegen U, Kiselev P et al. A
randomized, 12-week, double-blind, placebo-controlled study comparing
formoterol dry powder inhaler with albuterol metered-dose inhaler. Ann
Allergy Asthma Immunol 2001; 86: 19-27.
2
5
Bensch G, Berger WE, Blokhin BM, Socolovsky AL, Thomson MH, Till
MD et al. One-year efficacy and safety of inhaled formoterol dry powder in
children with persistent asthma. Ann Allergy Asthma Immunol 2002; 89:
180-190.
6&7
Bijl-Hofland ID, Cloosterman SGM, Folgering HTM, van den Elshout FJJ,
van Weel C, van Schayck CP. Inhaled corticosteroids, combined with longacting 2-agonists improve the perception of bronchoconstriction in asthma.
Am J Respir Crit Care Med 2001; 164: 764-769.
8
Bouros D, Bachlitzanakis N, Kottakis J, Pfister P, Polychronopoulos V,
Papadakis E et al.
Formoterol and beclomethasone versus higher dose
beclomethasone as maintenance therapy in adult asthma. Eur Respir J 1999;
14: 627-632.
9
Brambilla C, Le Gros V, Bourdeix I. Formoterol 12µg BID administered via
single-dose dry powder inhaler in adults with asthma suboptimally controlled
with salmeterol or on-demand salbutamol: a multicenter, randomized, openlabel parallel-group study. Clin Ther 2003; 25: 2022-2036.
10
Buhl R, Creemers JPHM, Vondra V, Martelli NA, Naya IP, Ekström T.
Once-daily budesonide/formoterol in a single inhaler in adults with moderate
persistent asthma. Respir Med 2003; 97: 323-330.
3
11
Busse W, Levine B, Andriano K, Lavecchia C, Yegen U.
Efficacy,
tolerability, and effect on asthma-related quality of life of formoterol bid via
multidose dry powder inhaler and albuterol QID via metered dose inhaler in
patients with persistent asthma: a multicenter, randomized, double-blind,
double-dummy, placebo-controlled, parallel-group study. Clin Ther 2004;
26: 1587-1598.
12
Ceylan E, Gencer M, Aksoy S. Addition of formoterol or montelukast to
low-dose budesonide: an efficacy comparison in short- and long-term asthma
control. Respiration 2004; 71: 594-601.
13&14
Chuchalin A, Kasl M, Bengtsson T, Nihlen U, Rosenborg J. Formoterol
used as needed in patients with intermittent or mild persistent asthma. Respir
Med 2005; 99: 461-470.
15
Chuchalin AG, Ovcharenko SI, Goriachkina LA, Sidorenko IV, Tsoi AN.
The safety and efficacy of formoterol (OXIS®) turbuhaler® plus budesonide
(Pulmicort®) turbuhaler in mild to moderate asthma: a comparison with
budesonide turbuhaler alone and current non-corticosteroid therapy in
Russia. Int J Clin Pract 2002; 56: 15-20.
16
Cloosterman SGM, Bijl-Hofland ID, van Herwaarden CLA, Akkermans RP,
van den Elshout FJJ, Folgering HTM et al. A placebo-controlled clinical
trial of regular monotherapy with short-acting and long-acting 2-agonists in
allergic asthmatic patients. Chest 2001; 119: 1306-1315.
4
17
Corren J, Korenblat PE, Miller CJ, O’Brien CD, Mezzanotte WS. Twelveweek randomized placebo-controlled multicenter study of the efficacy and
tolerability of budesonide and formoterol in one metered-dose inhaler
compared with budesonide alone and formoterol alone in adolescents and
adults with asthma. Clint her 2007; 29: 823-843.
18
Ekström T, Ringdal N, Sobradillo V, Runnerström E, Soliman S. Low-dose
formoterol Turbuhaler® (Oxis®) bid, a 3-month placebo-controlled
comparison with terbutaline (qid). Respir Med 1998; 92: 1040-1045.
19
Ekström T, Ringdal N, Tukiainen P, , Runnerström E, Soliman S. A 3month comparison of formoterol with terbutaline via turbuhaler: a placebocontrolled study. Ann Allergy Asthma Immunol 1998; 81: 225-230.
20
FitzGerald JM, Chapman KR, Della Cioppa G, Stubbing D, Fairbarn MS,
Till MD et al. Sustained bronchoprotection, bronchodilatation, and symptom
control during regular formoterol use in asthma of moderate or greater
severity. J Allergy Clin Immunol 1999; 103: 427-435.
21
Jenkins C, Kolarikova R, Kuna P, Caillaud D, Sanchis J, Popp W et al.
Efficacy and safety of high-dose budesonide/formoterol (Symbicort®)
compared with budesonide administered either concomitantly with
formoterol or alone in patients with persistent symptomatic asthma. Respirol
2006; 11: 276-286.
5
22
Kesten S, Chapman KR, Broder I, Cartier A, Hyland RH, Knight A et al. A
three-month comparison of twice daily inhaled formoterol versus four times
daily inhaled albuterol in the management of stable asthma. Am Rev Respir
Dis 1991; 144: 622-625.
23
Kips JC, O’Connor BJ, Inman MD, Svensson K, Pauwels RA, O’Byrne PM.
A long-term study of the anti-inflammatory effect of low-dose budesonide
plus formoterol versus high-dose budesonide in asthma. Am J Respir Crit
Care Med 2000; 161: 996-1001.
24
Kozlik-Feldmann R, von Berg A, Berdel D, Reinhardt D. Long-term effects
of formoterol and salbutamol on bronchial hyperreactivity and adrenoceptor density on lympocytes in children with bronchial asthma. Eur J
Med Res 1996; 1: 465-470.
25
Kuna P, Creemers JPHM, Vondra V, Black PN, Lindqvist A, Nihlen U et al.
Once-daily dosing with budesonide/formoterol compared with twice-daily
budesonide/formoterol and once-daily budesonide in adults with mild to
moderate asthma. Respir Med 2006; 100: 2151-2159.
26
LaForce C, Prenner BM, Andriano K, Lavecchia C, Yegen U. Efficacy and
safety of formoterol delivered via a new multidose dry powder inhaler
(Certihaler™) in adolescents and adults with persistent asthma. J Asthma
2005; 42: 101-106.
6
27
Levy R, Pinnas J, Milgrom H, Smith J, Yegen U. Safety and efficacy in
children with persistent asthma treated with formoterol 10µg BID delivered
via Certihaler™: a novel multidose dry-powder inhaler. Pediatr Asthma
Allergy Immunol 2005; 18: 25-35.
28
Lalloo UG, Malolepszy J, Kozma D, Krofta K, Ankerst J, Johansen B et al.
Budesonide and formoterol in a single inhaler improves asthma control
compared with increasing the dose of corticosteroid in adults with mild-tomoderate asthma. Chest 2003; 123: 1480-1487.
29
Midgren B, Melander B, Persson G. Formoterol a new long-acting 2agonist inhaled twice daily in stable asthmatic subjects. Chest 21992; 101:
1019-1022.
30
Mitchell C, Jenkins C, Scicchitano R, Rubinfeld A, Kottakis J. Formoterol
(Foradil®) and medium-high doses of inhaled corticosteroids are more
effective than high doses of corticosteroids in moderate-to-severe asthma.
Pulmon Pharmacol Ther 2003; 16: 299-306.
31
Molimard M, Bourcereau J, Le Gros V, Bourdeix I, Leynadier F, Duroux P.
Comparison between formoterol 12µg bid and on-demand salbutamol in
moderate persistent asthma. Respir Med 2001; 95: 64-70.
32
Morice AH, Osmanliev D, Arheden L, Beckman O. Therapeutic equivalence
of a novel budesonide/formoterol pMDI versus budesonide/formoterol
Turbuhaler® in adolescents and adults with asthma. J Allergy Clin Immunol
2005; 115(Suppl 2): S2 Abstract 8.
7
33
Morice AH, Kukova Z, Arheden L, Beckman O.
budesonide/formoterol
pMDI
is
therapeutically
The novel
equivalent
to
budesonide/formoterol Turbuhaler® in children with asthma. J Allergy Clin
Immunol 2005; 115(Suppl 2): S209 Abstract 833.
34
Noonan M, Rosenwasser LJ, Martin P, O’Brien CD, Dowd L. Efficacy and
safety of budesonide and formoterol in one pressurised metered-dose inhaler
in adults and adolescents with moderate to severe asthma: a randomised
clinical trial. Drugs 2006; 66: 2235-2254.
35
O’Byrne PM, Bisgaard H, Godard PP, Massimo P, Palmqvist M, Zhu Y et al.
Budesonide/formoterol combination therapy as both maintenance and
reliever medication in asthma. Am J Respir Crit Care Med 2005; 171: 129136.
36
O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T,
Svensson K et al. Low dose inhaled budesonide and formoterol in mild
persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care
Med 2001; 164: 1392-1397.
37
Overbeek SE, Mulder PG, Baelemans SM, Hoogsteden HC, Prins J-B.
Formoterol added to low-dose budesonide has no additional antiinflammatory effect in asthmatic patients. Chest 2005; 128: 1121-1127.
38
Pauwels RA, Löfdahl C-G, Postma DS, Tattersfield AE, O’Byrne P, Barnes
PJ et al. Effect of inhaled formoterol and budesonide on exacerbations of
asthma. N Engl J Med 1997; 337: 1405-1411.
8
39
Pauwels RA, Sears MR, Campbell M, Villasante C, Huang S, Lindh A, et al.
Formoterol as relief medication in asthma: a worldwide safety and
effectiveness trial. Eur Respir J 2003; 22: 787-794.
40
Pleskow W, LaForce CF, Yegen U, Matos D, Della Cioppa G. Formoterol
delivered via the dry powder aerolizer inhaler versus albuterol MDI and
placebo in mild-to-moderate asthma: a randomized, double-blind, doubledummy trial. J Asthma 2003; 40: 505-514.
41
Pohl WR, Vetter N, Zwick H, Hrubos W. Adjustable maintenance dosing
with budesonide/formoterol or budesonide: double-blind study. Respir Med
2006; 100: 551-560.
42
Pohunek P, Kuna P, Jorup C, De Boeck K. Budesonide/formoterol improves
lung function compared with budesonide alone in children with asthma.
Pediatr Allergy Immunol 2006; 17: 458-465.
43&44
Price D, Dutchman D, Mawson A, Bodalia B, Duggan S, Todd P. Early
asthma control and maintenance with eformoterol following reduction of
inhaled corticosteroid dose. Thorax 2002; 57: 791-798.
45
Rabe KF, Pizzichini E, Ställberg B, Romero S, Balanzat M, Atienza T et al.
Budesonide/formoterol in a single inhaler for maintenance and relief in mildto-moderate asthma: a randomized double-blind trial. Chest 2006; 129: 246256.
46
Schreurs AJM, Sinninghe Damsté HEJ, de Graaff CS, Greefhorst APM. A
dose-response study with formoterol Turbuhaler® as maintenance therapy in
asthmatic patients. Eur Respir J 1996; 9: 1678-1683.
9
47
Scicchitano R, Aalbers R, Ukena D, Manjra A, Fouquert L, Centanni S.
Efficacy and safety of budesonide/formoterol single inhaler therapy versus a
higher dose of budesonide in moderate to severe asthma. Curr Med Res
Opin 2004; 20: 1403-1418.
48
Stålenheim G, Wegener T, Grettve L, Lundäck B, Melander B, Osterman K
et al. Efficacy and tolerance of a 12-week treatment with inhaled formoterol
in patients with reversible obstructive lung disease. Respiratoin 1994; 61:
305-309.
49
Steffensen I, Faurschou P, Riska H, Rostrup J, Wegener T.
Inhaled
formoterol dry powder in the treatment of patients with reversible obstructive
airway disease: a 3-month, placebo-controlled comparison of the efficacy
and safety of formoterol and salbutamol, followed by a 12-month trial with
formoterol. Allergy 1995; 50: 657-663.
50
Stelmach I, Jerzynska J, Kuna P. A randomized, double-blind trial of the
effect of glucocorticoid, antileukotriene and -agonist treatment on IL-10
serum levels in children with asthma. Clin Exp Allergy 2002; 32: 264-269.
51
Stelman I, Gorski P, Jerzynska J, Stelmach W, Majak P, Kuna P.
A
randomized, double-blind trial of the effect of treatment with formoterol on
clinical and inflammatory parameters of asthma in children. Ann Allergy
Asthma Immunol 2002; 89: 67-73.
52
Tal A, Simon G, Vermeulen JH, Petru V, Cobos N, Everard ML et al.
Budesonide/formoterol in a single inhaler versus inhaled corticosteroids
alone in the treatment of asthma. Pediatr Pulmonol 2002; 34: 342-350.
10
53
Tattersfield AE, Löfdahl C-G, Postma DS, Elvindson A, Schreurs AGM,
Rasidakis A.
Comparison of formoterol and terbutaline for as-needed
treatment of asthma: a randomised trial. Lancet 2001; 357: 257-261.
54
van der Molen T, Postma DS, Turner MO, Meyboom-de Jong B, Malo JL,
Chapman K et al. Effects of the long acting -agonist formoterol on asthma
control in asthmatic patients using inhaled corticosteroids. Thorax 1996; 52:
535-539.
55
van Schayck CP, Cloosterman SGM, Bijl-Hofland ID, van den Hoogen H,
Folgering HTM, Van Weel C. Is the increase in bronchial responsiveness or
FEV1 shortly after cessation of 2-agonists reflecting a real deterioration of
the disease in allergic asthmatic patients? A comparison between shortacting and long-acting 2-agonists. Respir Med 2002; 96: 155-162.
56
van Schayck CP, Bijl-Hofland ID, Cloosterman SGM, Folgering HTM, van
der Elshout FJJ, Van Weel C.
Potential masking effect on dyspnoea
perception by short- and long-acting 2-agonists in asthma. Eur Respir J
2002; 19: 240-245.
57
Villa J, Kuna P, Egner J, Brander R. Safety of formoterol reliever therapy
compared with terbutaline in asthmatic children taking anti-inflammatory
therapy. Eur Respir J 2002; 20(Suppl 38): 431.
58
Von Berg A, Papageorgiu Saxon F, Wille S, Carrillo T, Kattamis C, Helms
P-J. Efficacy and tolerability of formoterol Turbuhaler® in children. Int J
Clin Pract 2003; 57: 852-856.
59
Wolfe J, LaForce C, Friedman B, Sokol W, Till D, Della Cioppa G et al.
Formoterol, 24µg bid, and serious asthma exacerbations. Chest 2006; 129:
27-38.
11
60
Yurdakul AS, Calisir HC, Tunctan B, Ogretsoy M. Comparison of second
controller medications in addition to inhaled corticosteroid patients with
moderate asthma. Respir Med 2002; 96: 322-329.
61
Zetterström O, Buhl R, Mellem H, Perpina M, Hedman J, O’Neill S et al.
Improved asthma control with budesonide/formoterol in a single inhaler,
compared with budesonide alone. Eur Respir J 2001; 18: 262-268.
62
Zimmerman B, D’Urzo A, Bérubé D. Efficacy and safety of formoterol
Turbuhaler® when added to inhaled corticosteroid treatment in children with
asthma. Pediatr Pulmonol 2004; 37: 122-127.
12
Table E1: The number of subjects in formoterol and comparator arms, trial length and
observation times in the 62 studies included in the meta-analysis
Study
Formoterol
arm (n)
Comparator
arm (n)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
16
136
168
271
342
22
22
69
4,141
352
80
20
228
333
111
50
253
135
114
89
341
73
29
11
409
86
127
230
19
102
130
462
415
362
1,828
869
20
426
8,924
275
65
417
333
16
134
176
270
176
42
42
65
674
171
159
20
227
341
114
95
258
261
229
182
115
72
31
11
207
179
122
237
18
101
129
217
207
234
925
1,101
20
427
8,938
279
68
213
330
Trial length
(weeks)
6
12
12
12
52
12
12
12
4
12
12
8
52
52
12
12
12
12
12
24
24
12
52
13
12
12
12
12
4
12
12
12
12
12
52
52
16
52
24
12
20
12
20
Total participant observation time
(weeks)
(years)
192
3,240
4,128
6,492
26,936
768
768
1,608
19,260
6,276
2,868
320
23,660
35,048
2,700
1,740
6,132
4,752
4,116
6,504
10,944
1,740
3,120
286
7,392
3,180
2,988
5,604
148
2,436
3,108
8,148
7,464
7,152
143,156
102,440
640
44,356
428,688
6,648
2,660
7,560
13,260
3.7
62.3
79.4
124.8
518.0
14.8
14.8
30.9
370.4
120.7
55.2
6.2
455.0
674.0
51.9
33.5
117.9
91.4
79.2
125.1
210.5
33.5
60.0
5.5
142.2
61.2
57.5
107.8
2.8
46.8
59.8
156.7
143.5
137.5
2,753.0
1,970.0
12.3
853.0
8,244.0
127.8
51.2
145.4
255.0
13
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
Totals
250
354
165
947
42
103
18
15
148
182
125
46
46
277
164
1,571
25
238
200
27,821
255
342
56
943
47
201
73
17
138
180
114
88
82
275
84
514
39
124
101
21,506
4
24
4
52
12
12
8
4
12
12
24
12
12
24
12
16
12
12
12
2,020
16,704
884
98,280
1,068
3,648
728
128
3,432
4,344
5,736
1,608
1,536
13,248
2,976
33,360
768
4,344
3,612
1,169,050
38.8
321.2
17.0
1,890.0
20.5
70.2
14.0
2.5
66.0
83.5
110.3
30.9
29.5
254.8
57.2
641.5
14.8
83.5
69.5
22,481.7
14
Figure E1:
Calculation of number of subjects exposed to formoterol and salbutamol, but not
salmeterol in the RELIEF study [E39].
Subjects
randomized to
formoterol
n=8,924
Subjects
receiving
maintenance
salmeterol
excluded
n=1,429
Subjects
randomized to
salbutamol
n=8,938
Subjects receiving
maintenance formoterol
n=969
and subjects
inadvertently receiving
formoterol
n=2
Subjects exposed
to formoterol, but
not salmeterol
n=8,466
Subjects
receiving
maintenance
salmeterol
excluded
n=1,490
Subjects exposed
to salbutamol, but
not formoterol or
salmeterol
n=6,477
15