Canadian Thoracic Society Asthma Committee Commentary on Long-Acting Beta-2 Agonist Use for Asthma in Canada

Background: A step-up approach (increasing inhaled corticosteroid [ICS] dose and/or add-on treatment) is recommended for asthma that is uncontrolled despite ICS plus long-acting beta-2‐agonist (LABA) combination treatment. Understanding the impact of different treatment options on health outcomes can help guide treatment decision-making. Objective: To compare the effectiveness of add-on tiotropium 1.25 µg (two puffs once daily) versus an increased ICS plus LABA dose in a real-world cohort of patients with asthma initiated on ICS plus LABA. Methods: De-identified data from patients ages ≥12 years and with asthma who were initiated on ICS plus LABA, and then had tiotropium added (Tio group; index date) or an ICS plus LABA dose increased (inc-ICS group; index date) were collected from two medical and pharmacy claims data bases (2014‐2018). To account for population/group differences, propensity score matching was performed. The primary end point was the exacerbation risk after the index date. Secondary end points included exacerbation rates 6 and 12 months postindex, health-care resource utilization, costs, and short-acting beta-2‐agonist (SABA) refills 12 months postindex. Results: Overall, 7857 patients (Tio group, 2619; inc-ICS group, 5238) were included. The exacerbation risk was 35% lower in the Tio group than in the inc-ICS group (hazard ratio 0.65 [95% confidence interval, 0.43‐0.99]; p = 0.044). Exacerbation rates in the Tio group also were significantly lower within 6 and 12 months postindex (64% and 73%, respectively). All-cause and asthma-related emergency department (ED) visits were 47% and 74% lower, respectively (p < 0.0001 for both), and all-cause and asthma-related hospitalizations were 48% (p < 0.01) and 76% (p < 0.001) lower, respectively, in the Tio group. Also, significantly fewer patients in the Tio group versus the inc-ICS group required SABA refills (56% versus 67%, p < 0.0001). Conclusion: Add-on tiotropium significantly decreased the risk and rate of exacerbations, decreased all-cause and asthma-related ED visits and hospitalizations, and reduced SABA refills compared with increasing the ICS plus LABA dose. The findings supported the use of add-on tiotropium for patients with uncontrolled asthma taking ICS plus LABA.

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The Scientific Rationale of Combining Inhaled Glucocorticoids and Long Acting Beta 2 Adrenoceptor Agonists

Current Pharmaceutical Design ◽

10.2174/1381612023393774 ◽

2002 ◽

Vol 8 (20) ◽

pp. 1863-1869 ◽

Cited By ~ 5

Author(s):

Alan Knox

Keyword(s):

Adrenoceptor Agonists ◽

Beta 2 ◽

Long Acting ◽

Inhaled Glucocorticoids ◽

Scientific Rationale

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Anabolic effects of the beta 2-adrenoceptor agonist salmeterol are dependent on route of administration

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.267.3.e475 ◽

1994 ◽

Vol 267 (3) ◽

pp. E475-E484 ◽

Cited By ~ 7

Author(s):

N. G. Moore ◽

G. G. Pegg ◽

M. N. Sillence

Keyword(s):

Soleus Muscle ◽

Body Weight Gain ◽

Route Of Administration ◽

Duration Of Action ◽

Routes Of Administration ◽

Adrenoceptor Agonists ◽

Slow Twitch ◽

Beta 2 ◽

Long Acting

It is reported that a long duration of action is required for beta 2-adrenoceptor agonists to evoke an anabolic response. In the present study, we compare the potency of clenbuterol with that of the new long-acting compound salmeterol, when given at equimolar doses to female Wistar rats by different routes of administration. Given orally for 10 days, salmeterol had no effect on growth at a dose of 120 micrograms/day, whereas at 2.4 mg/day the drug caused significant increases in body and carcass weight and in the mass of the mixed-fiber gastrocnemius/plantaris and tibialis anterior muscles, but there were no increases in the slow-twitch soleus muscles. A similar growth response was seen when clenbuterol was given orally at a dose of only 97 micrograms/day, with an additional response seen in soleus muscle at 1.9 mg/day. Thus clenbuterol was more potent than salmeterol when given by this route of administration. When the drugs were infused by osmotic minipump, both salmeterol (130 micrograms/day) and clenbuterol (100 micrograms/day) caused increases in body weight gain and in the weights of the mixed-fiber muscles, with the most dramatic effect of infusion being to greatly increase the anabolic effect of salmeterol in soleus muscle. A single intraperitoneal injection of salmeterol (53 micrograms) or clenbuterol (40 micrograms) caused a similar rapid increase in the concentration of adenosine 3',5'-cyclic monophosphate in gastrocnemius muscle. These results indicate that the potency of salmeterol in vivo is dependent on its route of administration and that slow-twitch muscles are less sensitive than mixed-fiber muscles to the anabolic effects of beta 2-adrenoceptor agonists.

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The Beta-2-Adrenoreceptor Agonists, Formoterol and Indacaterol, but Not Salbutamol, Effectively Suppress the Reactivity of Human NeutrophilsIn Vitro

Mediators of Inflammation ◽

10.1155/2014/105420 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 14

Author(s):

Ronald Anderson ◽

Annette J. Theron ◽

Helen C. Steel ◽

Chrisna Durandt ◽

Gregory R. Tintinger ◽

...

Keyword(s):

Platelet Activating Factor ◽

Leukotriene B4 ◽

Molecular Structures ◽

Intracellular Camp ◽

Flow Cytometric ◽

Activated Neutrophils ◽

Blood Neutrophils ◽

Beta 2 ◽

Long Acting

The clinical relevance of the anti-inflammatory properties of beta-2 agonists remains contentious possibly due to differences in their molecular structures and agonist activities. The current study has compared the effects of 3 different categories ofβ2-agonists, namely, salbutamol (short-acting), formoterol (long-acting) and indacaterol (ultra-long-acting), at concentrations of 1–1000 nM, with human blood neutrophilsin vitro. Neutrophils were activated with either N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP, 1 µM) or platelet-activating factor (PAF, 200 nM) in the absence and presence of theβ2-agonists followed by measurement of the generation of reactive oxygen species and leukotriene B4, release of elastase, and expression of theβ2-integrin, CR3, using a combination of chemiluminescence, ELISA, colorimetric, and flow cytometric procedures respectively. These were correlated with alterations in the concentrations of intracellular cyclic-AMP and cytosolic Ca2+. At the concentrations tested, formoterol and indacaterol caused equivalent, significant (P<0.05at 1–10 nM) dose-related inhibition of all of the pro-inflammatory activities tested, while salbutamol was much less effective (P<0.05at 100 nM and higher). Suppression of neutrophil reactivity was accompanied by elevations in intracellular cAMP and accelerated clearance of Ca2+from the cytosol of activated neutrophils. These findings demonstrate thatβ2-agonists vary with respect to their suppressive effects on activated neutrophils.

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