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Tuesday, November 5, 2013

Predictors of response to tiotropium versus salmeterol in asthmatic adults

The severity of asthma symptoms is well known to be attenuated by inhaled corticosteroid (ICS) due to their anti-inflammatory effect.  Long-acting β-agonists (LABA) and long acting muscarinic antagonists (LAMA) are current treatment options for patients that do not respond well to low dose ICSs.  Using data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network’s Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid, Peters et al sought to determine individual and differential responses of asthmatic patients to salmeterol (LABA) and tiotropium (LAMA) when added to an inhaled corticosteroid, as well as predictors of a positive clinical response to the end points FEV₁, morning peak expiratory flow (PEF), and asthma control days (ACDs) (J Allergy Clin Immunol 2013; 132(5):1068-1074).

In the attempt to personalize the best treatment options for patients, investigators have used a variety of strategies, including the use of biomarkers, patient-specific and physiologic “predictors” and genetic/genomic approaches.  Predictors of response that have been investigated by researchers include short-acting bronchodilators and leukotriene modifiers, but more recently, predicting the response to glucocorticoids, namely ICSs have contributed valuable insight into this framework.  The author’s interest in long-acting bronchodilators, such as LABAs and LAMAs stems from the lack of information that has been published concerning these predictors of response, including intra-subject response of asthmatic patients treated with both a LABA and a LAMA.

Utilizing information from 210 asthmatic adults, the authors discovered that the use of tiotropium with a low dose of ICS resulted in a superior primary outcome compared to doubling the ICS alone, as assessed by improvement of morning PEF, evening PEF, a decrease in ACDs, and an increase in FEV₁.  Salmeterol had a similar but less robust response, and subjects showed a differential response to tiotropium for FEV₁, but not for salmeterol.  Furthermore, younger patients responded better to tiotropium in terms of ACDs.  Peters also reports that large numbers of patients responded to either salmeterol or tiotropium, but not to both agents.  This suggests that at the time of administration, different mechanisms were operating to produce airway constriction and symptoms in these 2 groups of patients.  Finally, although the use of a short-acting bronchodilator did predict a positive response to a long-acting bronchodilator controller of the same class, albuterol response better predicted a response to tiotropium than did ipratropium. 


While these findings need to be replicated in an independent study, the data suggest that asthmatics that have suboptimal asthma control using ICSs alone, with airway obstruction as demonstrated by a reduced FEV₁/FVC ratio, a positive response to albuterol, or both, should be good candidates for treatment with tiotropium as an add-on therapy.  This could be used for patients where combination ICS-LABA therapy fails or when ICS monotherapy in inadequate for symptom control.  

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