Dal convegno "Novità diagnostico-terapeutiche in Allergologia e Immunologia Clinica" del 5 Novembre 2016, Torino

1. Quali prospettive di utilizzo degli
anticolinergici nell’asma
Paolo Solidoro
S.C.D.U. Pneumologia, Molinette Torino

2. • Speaker's hononaria from:
• Astra Zeneca, Boehringer Ingelheim,
Pfizer, GSK, Menarini, Novartis, Chiesi,
Almiral, Mundipharma, Dompè, Guidotti
and Malesci, Biotest, ABC farmaceutici.
• Consultant for training:
• Almiral, Novartis, ABC Farmaceutici,
Biotest.
Conflict of interest statement

4. • Diagnosi
• Recettori muscarinici
• Sinergie
• Asma non controllato
• Studi clinici: FEV1, PEF, QoL,
exacerbations
• Metanalisi
• Real Life
• Sottogruppi, indicazioni e rimborsabilità
LAMA IN ASMA

5. • Diagnosi
• Recettori muscarinici
• Sinergie
• Asma non controllato
• Studi clinici: FEV1, PEF, QoL,
exacerbations
• Metanalisi
• Real Life
• Sottogruppi, indicazioni e rimborsabilità
LAMA IN ASMA

8. • Diagnosi
• Recettori muscarinici
• Sinergie
• Asma non controllato
• Studi clinici: FEV1, PEF, QoL,
exacerbations
• Metanalisi
• Real Life
• Sottogruppi, indicazioni e rimborsabilità
LAMA IN ASMA

11. The parasympathetic network in the airway wall
regulates bronchoconstriction and mucus secretion.
Acetylcholine exerts an inflammatory effect by inducing
attraction and survival of inflammatory cells, with
subsequent cytokine release [21].
Racké K, Matthiesen S. The airway cholinergic system:
physiology and pharmacology. Pulm Pharmacol Ther.
2004;17:181-98.
Patients with asthma have increased bronchial
smooth muscle tone and mucus hypersecretion,
possibly as a result of elevated cholinergic activity

12. Muscarinic M1 receptors are expressed by
epithelial cells, where they play a modulatory
role in electrolyte and water secretion, and in the
ganglia, where they facilitate parasympathetic
neurotransmission.
Muscarinic M2 receptors are expressed by
neurons, where they function as autoreceptors,
inhibiting the release of acetylcholine from both
preganglionic nerves and from parasympathetic
nerve terminals.

13. Muscarinic M2 autoreceptors are dysfunctional in
allergic asthma owing to eosinophil-derived
release of major basic protein, which acts as an
allosteric antagonist of the M2 receptor, thus
augmenting acetylcholine release.
Furthermore, M2 receptors are widely expressed
by airway mesenchymal cells such as fibroblasts
and smooth muscle cells [24].

14. Muscarinic M3 receptors are probably the best-
characterized subtype and the dominant receptor
subtype in the regulation of mucus secretion from
submucosal glands and airway smooth muscle
contraction [24] (Figure 1).
As a result, muscarinic M3 receptors are the primary
target for LAMAs.
Aclidinium, glycopyrronium, umeclidinium and
tiotropium bind to human receptors M1 to M5 in a
concentration-dependent manner. They all have
higher selectivity for M3 receptors than for M2
receptors, and dissociate more slowly from M3
receptors than from M2 receptors [22,23].

15. The 3 LAMAs used for the treatment of
COPD, as well as tiotropium and umeclidium
(preliminary reports) for asthma, have
higher selectivity for M3 receptors than for
M2 receptors and dissociate more slowly
from the M3 receptors than from the M2
receptors

16. Furthermore, anticholinergic compounds may
also have anti-inflammatory properties.
Some LAMAs show anti-inflammatory effects,
inhibition of neutrophil chemotactic activity,
migration of alveolar neutrophils, decreased
levels of cytokines (IL-6, TNF-α) and leukotriene
B4 in bronchoalveolar lavage fluid, as well as
antiremodeling effects, such as inhibition of
mucus gland hypertrophy and decrease in
MUC5AC-positive goblet cell number

17. • Diagnosi
• Recettori muscarinici
• Sinergie
• Asma non controllato
• Studi clinici: FEV1, PEF, QoL,
exacerbations
• Metanalisi
• Real Life
• Sottogruppi, indicazioni e rimborsabilità
LAMA IN ASMA

19. constriction

22. • Diagnosi
• Recettori muscarinici
• Sinergie
• Asma non controllato
• Studi clinici: FEV1, PEF, QoL,
exacerbations
• Metanalisi
• Real Life
• Sottogruppi, indicazioni e rimborsabilità
LAMA IN ASMA

23. Uncontrolled Asthma1
• More than two daytime
symptoms or need for
rescue medication per
week
• Activity limitation
• Nocturnal awakening
• PEF or FEV1 <80%
predicted or personal best
Three or more features of
the following:
1 Global Initiative for Asthma [Global strategy for asthma management and prevention]. 2011.

24. Uncontrolled Asthma
Challenge to MDs
Optimal doses of
recommended meds
inadequate for control
Additional controllers
needed

25. • Diagnosi
• Recettori muscarinici
• Sinergie
• Asma non controllato
• Studi clinici: FEV1, PEF, QoL,
exacerbations
• Metanalisi
• Real Life
• Sottogruppi, indicazioni e rimborsabilità
LAMA IN ASMA

26. FEV1 response 0–3 hours at Week 24: Trial
1
Add-on to ICS+LABA
Kerstjens et al. N Engl J Med. 2012;367:1198-
1207.
Time post-dosing (h)
*P<0.05; **P<0.01
Error bars represent standard errors
Placebo Respimat®
(n=211)Tiotropium Respimat®
(n=217)
450
400
0
50
100
150
200
250
300
350
500
**
**
*
*
**
0 0.5 1.0 2.0 3.0
FEV1(mL)–changefrombaseline

27. FEV1 response 0–3 hours at Week 24: Trial
2
Kerstjens et al. N Engl J Med. 2012;367:1198-1207.
FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA,
long-acting β2-agonist
Time post-dosing (h)
*P<0.0001
Error bars represent standard errors.
*
FEV1(mL)–changefrombaseline
*
0
50
100
150
200
250
300
350
400
450
500
0 0.5 1.0 2.0 3.0
* *
*
Add-on to ICS+LABA
Placebo Respimat®
(n=218)Tiotropium Respimat®
(n=204)

28. Tiotropium Respimat®
: 282 days; Placebo Respimat®
: 226 days (25th percentile)
20
0
10
30
40
50
250 50 75 100 125 150 175 200 225 250 275 300 325
Placebo
Respimat®
Tiotropium
Respimat®
Patientswithatleastone
severe
asthmaexacerbation(%)
Time
(days)
Add-on to ICS+LABA
Number needed to treat: 15
Patients at risk
Placebo
Respimat®
Tiotropium
Respimat®
454 435 412 388 379 367 356 339 332 319 303
290 282 272
453 430 409 401 389 378 363 353 348 339 331 319 308 298
Tiotropium Respimat®
n=122 (26.9%), Placebo Respimat®
n=149 (32.8%)
HR=0.79; Risk reduction of 21% (P=0.03)
Kerstjens et al. N Engl J Med. 2012;367:1198-1207.
HR, hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist
Co-primary endpoint: Time to first severe
asthma exacerbation – pooled

29. Asthma Control Questionnaire (ACQ)

30. Kerstjens et al. N Engl J Med. 2012;367:1198-1207.
ACQ, Asthma Control Questionnaire; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist
†Adjusted for treatment, centre, visit, baseline, treatment x visit and baseline x visit.
Error bars represent standard errors. *P<0.05; **P<0.01; ***P<0.0001
Trial
2
Add-on to ICS+LABA
ACQ: Mean score over 48 weeks
Placebo Respimat®
Tiotropium Respimat®
Trial
1
ACQmeanscore†
Week
2.5
2.4
2.3
2.2
2.1
2.0
1.9
4 8 12 16 20 24 28 32 36 40 44 480
2.6
2.7
2.6
Week
2.5
2.4
2.3
2.2
2.1
2.0
1.9
4 8 12 16 20 24 28 32 36 40 44 48
*
***
** ***
0

31. Asthma Quality of Life Questionnaire (AQLQ)

32. Kerstjens et al. N Engl J Med. 2012;367:1198-1207.
AQLQ, Asthma Quality of Life Questionnaire; ICS, inhaled corticosteroid; LABA,
long-acting β2-agonist
†Adjusted for treatment, centre, visit, baseline, treatment x visit and baseline x visit.
Error bars represent standard errors; *P<0.05; **P<0.01
Add-on to ICS+LABA
AQLQ: Mean score over 48 weeks
Placebo Respimat®
Tiotropium Respimat®
Week
Trial 1
MeanAQLQScore†
5.2
5.0
4.9
4.8
4.7
4.6
4.5
4 8 12 16 20 24 28 32 36 40 44 48
5.1
0
Trial
2
**
5.2
5.0
4.9
4.8
4.7
4.6
4.5
4 8 12 16 20 24 28 32 36 40 44 48
5.1 ** *
*
*
Week
0

33. Kerstjens et al. N Engl J Med. 2012;367:1198-1207.
CRF, case report form; PEF, peak expiratory flow
Exacerbations: Episodes of asthma
worsening
• Symptoms
▪One or more asthma symptoms, as documented by the
investigator in the CRF, outside of the patient’s usual range of
day-to-day asthma that lasted for at least two consecutive days;
and/or
▪Decrease of patient’s best morning PEF of ≥30% from patient’s
mean screening morning PEF for at least two consecutive days
▪As documented by the investigator in the CRF
• Asthma worsening refers to all types of exacerbations
▪including severe exacerbations leading to loss of control
• Time to first episode of asthma worsening
• Pooled analysis over 48 weeks

34. Tiotropium Respimat®
, n=226 (49.9%); Placebo Respimat®
, n=287 (63.2%)
HR=0.69; Risk reduction of 31% (P<0.0001)
Tiotropium Respimat®
315 days; Placebo Respimat®
181 days (median)
250 50 75 100 125 150 175 200 225 250 275 300 325
20
0
10
30
40
50
60
70
80
90
100
Patientswithatleastone
episodeofasthmaworsening(%)
Days
Add-on to ICS+LABA
Placebo
Respimat®
Tiotropium
Respimat®
Patients at risk
Placebo
Respimat®
Tiotropium
Respimat®
454 393 345 302 280 250 236 219 207 190 180 163 154 146
453 396 357 339 323 306 290 272 263 251 241 227 212 203
Kerstjens et al. N Engl J Med. 2012;367:1198-1207.
HR, hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist
Episodes of asthma worsening

35. Kaplan-Meier Plot of the Cumulative
Percentage of Patients With at Least One Severe
Asthma Exacerbation in PrimoTinA-asthma®
Kerstjens et al. NEJM 2012;367:1198-1207
21%

36. Cumulative Percentage of Patients With at
Least 1 Asthma Exacerbation in PrimoTinA-asthma®
Kerstjens et al. NEJM 2012;367:1198-1207
31%

37. • Diagnosi
• Recettori muscarinici
• Sinergie
• Asma non controllato
• Studi clinici: FEV1, PEF, QoL,
exacerbations
• Metanalisi
• Real Life
• Sottogruppi, indicazioni e rimborsabilità
LAMA IN ASMA

39. PEF Mattutino

40. PEF Pomeridiano

41. PEF Mattutino

42. PEF Pomeridiano

43. PEF Mattutino

44. PEF Pomeridiano

45. TIME TO FIRST SEVERE ASTHMA
EXACERBATION
BY BASELINE CHARACTERISTICS
Pooled subgroup analysis
Kerstjens et al. NEJM 2012;367:1198-1207

46. Tiotropium MSIis effective independent
of baseline demographics
Age class, years (P=0.841)
<40 (n=136) 23/16 0.67 (0.35, 1.27)
40–60 (n=494) 78/71 0.81 (0.58, 1.11)
>60 (n=277) 48/35 0.82 (0.53, 1.27)
Smoking status (P=0.423)
Ex-smoker
>2–10 pack-years (n=179)
32/26 0.65 (0.39, 1.09)
Never smoked and
ex-smoker ≤2 pack-years (n=728)
117/96 0.83 (0.63, 1.08)
Baseline
characteristics
Eventsa
: placebo
Respimat®
/
Tiotropium
Respimat®
Hazard ratiob
(95% CI)
Sex (P=0.493)
Female (n=549) 93/78 0.85 (0.63, 1.14)
Male (n=358) 56/44 0.71 (0.48, 1.05)
Kerstjens et al. AJRCCM 2013; 187:A4217
a
Only the first occurrence of an event; b
Tiotropium Respimat®
versus
placebo Respimat®
. Cox regression adjusted for treatment, (pooled)
centre, visit, baseline, treatment visit and baseline visit
CI, confidence interval
Kerstjens et al. NEJM 2012;367:1198-1207

47. Tiotropium MSI is effective independent
of BMI
Baseline characteristics
Eventsa
: placebo
Respimat®
/
tiotropium Respimat®
Hazard ratiob
(95%
CI)
BMI class (P=0.942)
<20 (n=35) 6/4 0.90 (0.25, 3.21)
20-<25 (n=260) 39/33 0.88 (0.55, 1.40)
25-<30 (n=332) 53/42 0.76 (0.51, 1.15)
≥30 (n=280) 51/43 0.73 (0.48, 1.09)
Kerstjens et al. AJRCCM 2013; 187:A4217
a
Only the first occurrence of an event; b
Tiotropium Respimat®
versus
placebo Respimat®
; Cox regression adjusted for treatment, (pooled)
centre, visit, baseline, treatment visit and baseline visit
BMI, body mass index; CI, confidence interval
Kerstjens et al. NEJM 2012;367:1198-1207

48. Tiotropium MSIis effective independent
of disease characteristics
Baseline
characteristics
Eventsa
: placebo
Respimat®
/ Tiotropium
Respimat®
Hazard ratiob
(95% CI)
Number of hospital admissions in past year (P=0.375)
≥1 (n=162) 23/27 1.00 (0.58, 1.75)
0 (n=745) 126/95 0.75 (0.57, 0.98)
FEV1 (% predicted) post-bronchodilation at screening (P=0.988)
<60% (n=360) 68/55 0.79 (0.55, 1.12)
≥60% (n=547) 81/67 0.79 (0.57, 1.09)
FEV1 reversibility (≥12% and 200 mL) at screening (P=0.656)
No (n=473) 75/70 0.83 (0.60, 1.15)
Yes (n=434) 74/52 0.75 (0.52, 1.06)
ACQ at randomisation relative to mean (P=0.853)
<mean (n=477) 74/63 0.81 (0.58, 1.13)
≥mean (n=430) 75/59 0.77 (0.55, 1.09)
Overall population
Overall(N=907) 149/122 0.79 (0.62, 1.00)
Disease duration, years (P=0.733)
5-20 (n=214) 23/22 0.87 (0.48, 1.56)
≥20 (n=693) 126/100 0.78 (0.60, 1.02)
Kerstjens et al. AJRCCM 2013; 187:A4217
a
Only the first occurrence of an event; b
Tiotropium Respimat®
versus placebo Respimat®
. Cox regression adjusted for
treatment, (pooled) centre, visit, baseline, treatment visit and
baseline visit
ACQ, Asthma Control Questionnaire; CI, confidence interval;
FEV1, forced expiratory volume in 1 secondKerstjens et al. NEJM 2012;367:1198-1207

49. Tiotropium MSIis effective independent
of omalizumab and steroid medication
Omalizumab at baseline (P=0.032)
No (n=870) 133/119 0.86 (0.67, 1.10)
Yes (n=37) 16/3 0.23 (0.07, 0.80)
Number of systemic steroid courses in past year (P=0.720)
<3 (n=734) 97/84 0.80 (0.60, 1.07)
3-5 (n=128) 36/27 0.86 (0.52, 1.41)
>5 (n=45) 16/11 1.15 (0.53, 2.49)
Oral steroid at baseline (P=0.262)
No (n=862) 136/115 0.82 (0.64, 1.05)
Yes (n=45) 13/7 0.50 (0.20, 1.25)
Baseline
characteristics
Eventsa
: placebo
Respimat®
/ tiotropium
Respimat®
Hazard ratiob
(95% CI)
Kerstjens et al. AJRCCM 2013; 187:A4217
a
Only the first occurrence of an event; b
Tiotropium Respimat®
versus placebo Respimat®
. Cox regression adjusted for
treatment, (pooled) centre, visit, baseline, treatment visit and
baseline visit
CI, confidence interval Kerstjens et al. NEJM 2012;367:1198-1207

50. Clinician judgement of allergic status (P=0.745c
)
No (n=352) 40/33 0.75 (0.47, 1.19)
Yes (n=555) 109/89 0.82 (0.62, 1.08)
IgE class (Harrison reference) (P=0.21c
)
Missing (n=161) 37/12 0.38 (0.20, 0.74)
≤430 μg/L (n=352) 52/41 0.75 (0.50, 1.12)
>430 μg/L (n=394) 60/69 1.05 (0.75, 1.49)
Blood eosinophilia (Harrison reference) (P=0.748c
)
Missing (n=25) 6/2 0.36 (0.07, 1.76)
≤0.6 × 109
/L (n=696) 104/85 0.81 (0.61, 1.09)
>0.6 × 109
/L (n=186) 39/35 0.75 (0.48, 1.19)
Baseline
characteristics
Eventsa
: placebo
Respimat®
/ tiotropium
Respimat®
Hazard ratiob
(95% CI)
Kerstjens et al. AJRCCM 2013; 187:A4217
a
Only the first occurrence of an event; b
Tiotropium
Respimat®
versus placebo Respimat®
; c
Interaction P values
only calculated between nonmissing categories
CI, confidence interval; IgE, immunoglobulin E
Tiotropium MSI is effective independent
of allergic status
Favours tiotropium
Respimat®
Favours placebo
Respimat®
Kerstjens et al. NEJM 2012;367:1198-1207

51. TIOTROPIUM FOR
UNCONTROLLED ASTHMA:
a meta analysis
ERS 2013
Ralph Elvi M. Villalobos, MD1
Charles Vincent O. Uy, MD1
Marc Gregory Y. Yu, MD1
Manuel C. Jorge, MD2
Philippine General Hospital
Manila, Philippines

52. RESULTS: STUDIES INCLUDED
Author
Year
Title Design Duration/
N/
Run-in
Outcomes Comparison
Peters
et al
2010
Tiotropium bromide step-up
therapy for adults with
uncontrolled asthma
RCT
Crossover
design
52 wk
N=210
Run-in=4 wk
PEF, FEV1,
Rescue
medication use,
AQLQ scores
Doubling ICS
dose (with a
Placebo arm)
Kerstjens et
al
2011
Tiotropium improves lung
function in patients with severe
uncontrolled asthma: a
randomized controlled trial
RCT
Separate
experimental
and control
24 wk
N=107
Run-in=2wk
PEF, FEV1 Placebo
Bateman et
al
2011
Tiotropium is noninferior to
salmeterol in maintaining
improved lung function in B16-
Arg/Arg patients with asthma
RCT
Crossover
design
16 wk
N=388
Run-in=4 wk
PEF, FEV1,
Rescue
medication use,
asthma
symptoms, AQLQ
scores
Placebo,
Salmeterol
Kerstjens
et al
2012
(A,B)
Tiotropium in asthma poorly
controlled with standard
combination therapy
RCT
Separate
experimental
and control
(2 arms)
48 wk
N=912
Run-in=4 wk
PEF, FEV1,
Rescue
medication use,
asthma
symptoms,
exacerbations,
AQLQ scores
Placebo

53. RESULTS: CLINICAL ENDPOINT-
REDUCTION IN THE USE OF RESCUE
MEDICATION (PUFFS/24H)

54. RESULTS: CLINICAL ENDPOINT-
IMPROVEMENT IN QOL (AQLQ SCORE)

55. RESULTS: ADVERSE EVENTS
Adverse Event No. of
Studies
Tiotropium Control P value
Asthma
Exacerbation
5 216 276 P <0.0001
Nasopharyngitis 4 65 76 P=0.37
Bronchitis 4 21 29 P=0.25
Headache 4 32 35 P=0.74
URTI 4 25 21 P=0.55

56. Summary: Primary analysis
• Tiotropium Respimat®
added on to at least ICS+LABA
resulted in:
– Up to154 mL improvement in lung function,
– 68% more likely to improve asthma control,
– 21% risk reduction for severe asthma exacerbation,
– 31% risk reduction for asthma worsening,
– Safety profile comparable to placebo
Kerstjens et al. NEJM 2012;367:1198-1207 and data on file
ACQ, Asthma Control Questionnaire; AQLQ, Asthma Qualify of Life Questionnaire; ICS,
inhaled corticosteroid; LABA, long-acting β2-agonist

57. • Diagnosi
• Recettori muscarinici
• Sinergie
• Asma non controllato
• Studi clinici: FEV1, PEF, QoL,
exacerbations
• Metanalisi
• Real Life
• Sottogruppi, indicazioni e rimborsabilità
LABA IN ASMA

60. • Diagnosi
• Recettori muscarinici
• Sinergie
• Asma non controllato
• Studi clinici: FEV1, PEF, QoL,
exacerbations
• Metanalisi
• Real Life
• Sottogruppi, indicazioni e rimborsabilità
LABA IN ASMA

61. Attempts to identify subgroups that respond better
to anticholinergics have not been very successful.
several years ago it was reported that
anticholinergics may be better in the following
groups:
older patients [14],
Patients intolerant to ß2-agonists,
patients with nocturnal asthma,
patients with chronic asthma and concurrent fixed
airway obstruction,
patients with intrinsic asthma, and
patients with a longer duration of asthma
Cazzola M, Centanni S, Donner CF. Anticholinergic agents.
Pul Pharmacol Ther. 1998;11:381-92.

63. While approximately equal numbers of patients showed a differential
response to salmeterol and tiotropium in terms of AM PEF (90 and 78,
respectively), and Asthma Control Days (49 and 53, respectively),
more showed a differential response to tiotropium for FEV1 (104) than
salmeterol (62).
An acute response to a short-acting bronchodilator, especially albuterol,
predicted a positive clinical response to tiotropium for FEV1 (OR 4.08 [CI
2.00–8.31], P < 0.001) and AM PEF (OR 2.12 [CI 1.12–4.01], P = 0.021), as
did a decreased FEV1/FVC ratio (FEV1 response increased 0.39% of
baseline for every 1% decrease in the FEV1/FVC ratio).
Higher cholinergic tone was also a predictor,
while ethnicity, gender, atopy, IgE Level, sputum eosinophils, FENO,
asthma duration, and BMI were not.

64. The possible differences in responsiveness
to anticholinergics between different
patient groups illustrate the
heterogeneous nature of asthma, which is
further compounded by the overlap
between asthma and COPD

65. INDICAZIONE
TIOTROPIO Respimat è indicato come trattamento broncodilatatore aggiuntivo
di mantenimento in pazienti adulti con asma, che sono al momento trattati con
la combinazione di mantenimento a base di corticosteroidi per via inalatoria
(budesonide ≥800 µg/giorno o equivalente) e beta-2-agonisti a lunga durata
d’azione, che hanno manifestato una o più riacutizzazioni gravi nel corso
dell’ultimo anno.
La dose raccomandata per gli adulti è di 5 microgrammi di tiotropio,
somministrati tramite due erogazioni per mezzo dell’inalatore
Respimat una volta al giorno, alla stessa ora
Attualmente Tiotropio indicato nell’asma è in attesa di rimborsabilità

66. RELIEVER
STEP 1
As-needed short-acting beta2-agonist (SABA)
PREFERRED
CONTROLLER
CHOICE
As-needed SABA or low dose ICS/formoterol #
GINA 2016
GINA 2016, Box 3-5, Step 5; © Global Initiative for Asthma

STEP 2
Low dose ICS
STEP 3
Low dose
ICS/LABA**
STEP 4
Med/high
ICS/LABA
STEP 5
Refer for
add-on
treatment
e.g.
tiotropium*
omalizumab
mepolizumab*
Other
controller
options
Consider low
dose ICS
Leukotriene receptor antagonists (LTRA)
Low dose theophylline*
Med/high dose ICS
Low dose ICS+LTRA
(or + theoph*)
Add tiotropium*
High dose ICS
+ LTRA
(or + theoph*)
Add low
dose OCS
e.g.
tiotropium*
omalizumab
mepolizumab*
e.g.
tiotropium*
omalizumab
mepolizumab*
Add tiotropium*
High dose ICS
+ LTRA
(or + theoph*)
Add tiotropium*
High dose ICS
+ LTRA
(or + theoph*)
*Not for children <12 years. **For children 6–11 years, the preferred Step 3 treatment is medium dose
ICS; # Low dose ICS/formoterol is the reliever medication for patients prescribed low dose budesonide/
formoterol or low dose beclometasone/formoterol for maintenance and reliever therapy.
 
Tiotropium by mist inhaler is an add-on treatment for patients
with a history of exacerbations (not for children <12 years)

Tiotropium by mist inhaler is an add-on treatment for patients
with a history of exacerbations (not for children <12 years)
Attualmente Tiotropio indicato nell’asma è in attesa di rimborsabilità

67. LAMA

68. LAMA
Studi

69. L’A MAS

70. Quali prospettive di utilizzo degli
anticolinergici nell’asma
Paolo Solidoro
S.C.D.U. Pneumologia, Molinette Torino