See below the proposal from Guy Brussele from the Department of Respiratory Medicine, Ghent University Hospital Belgium and Katia Verhamme from the Department of Medical Informatics of the Erasmus MC:
Does use of inhaled long-acting muscarinic antagonists (LAMA) without concomitant use of inhaled corticosteroids in patients with asthma increase mortality risk?
Asthma is a chronic disease of the airways, associated with chronic airway inflammation, variable airflow limitation and variable symptoms of cough, shortness of breath and chest tightness. Viral respiratory tract infections, and exposure to allergens and pollutants can induce asthma attacks (i.e. asthma exacerbations), which can be life-threatening. In 2015, world-wide 400.000 patients with asthma died due to asthma (Global Burden of Disease Study, Lancet RM 2017). The mainstay of treatment of asthma are inhaled corticosteroids (ICS). In patients with moderate to severe asthma (Global Initiative for Asthma [GINA] steps 3-5), long-acting bronchodilators are added to the maintenance treatment with ICS: either long-acting beta2-agonists (LABA) and/or long-acting muscarinic antagonists (LAMA). In asthma, most clinical evidence of add-on therapy with LAMA to ICS (with or without LABA) is available for tiotropium (Spiriva [Handihaler or Respimat]), but other LAMAs encompass glycopyrronium, umeclidinium and aclidinium.
For LABA, it is well established that LABA monotherapy (without concomitant therapy with ICS) in patients with asthma is associated with an increased risk of asthma attacks and mortality. Therefore, a LABA should always be added to an ICS when treating patients with moderate-to-severe persistent asthma; ideally in one single fixed dose combination inhaler (ICS + LABA). For LAMA, it is not yet known whether LAMA monotherapy (without concomitant therapy with ICS) in patients with asthma is associated with an increased risk of asthma attacks and/or mortality. However, since both LABA and LAMA do not reduce the chronic airway inflammation in asthma, we put forward the hypothesis that in patients with asthma LAMA monotherapy – similar to LABA monotherapy – increases the risk of mortality. Moreover, since there are no fixed dose combination inhalers of LAMA and ICS, the risk of asthma patients using a LAMA without an ICS is substantial.
Clinical research question
Is use of inhaled long-acting muscarinic antagonists (LAMA) without concomitant use of inhaled corticosteroids (ICS) in patients with asthma associated with an increased mortality risk?
In patients with asthma,
A) is use of monotherapy of inhaled LAMA without concomitant use of ICS associated with an increased risk of mortality compared with use of LAMA and ICS?
B) Is use of inhaled LAMA (with or without LABA; with or without Leukotriene Receptor Antagonist [LTRA]) without concomitant use of ICS associated with an increased risk of mortality compared with use of LAMA and ICS (with or without LABA; with or without Leukotriene Receptor Antagonist [LTRA])?
5- core elements of the comparative cohort design:
1) The target exposure cohort:
Patients with asthma (age: 12 – 50 years) exposed to LAMA without ICS;
Either (A) monotherapy with LAMA, or (B) therapy with LAMA and (LABA and/or LTRA).
2) The comparator cohort:
Patients with asthma (age: 12 – 50 years) exposed to LAMA and ICS;
Either (A) therapy with LAMA and ICS only, or (B) therapy with LAMA and ICS and (LABA and/or LTRA).
3) The outcome (cohort):
Mortality (all-cause mortality);
eventually in a second stage: respiratory mortality (asthma-related mortality).
4) A time-at-risk period:
From the first day of treatment with LAMA or LAMA and ICS till end of cohort study, end of follow-up or death.
5) A model specification:
Matching of subjects of the comparator cohort with subjects in the target exposure cohort on age, gender and propensity score (e.g. smoking, asthma severity, asthma control, previous asthma exacerbations, previous asthma hospitalizations …).
The choice of the age range (12 - 50 years) is based upon the following rationale:
- The LAMA tiotropium is indicated for the (add-on) treatment of
asthma from the age of 12 years onwards;
- LAMA monotherapy
(without ICS) and LAMA + LABA combination therapy (loose or fixed
combination inhalers; with or without ICS) are indicated for the
maintenance treatment of COPD, which mainly affects subjects older
than 50 years.