The assessment of asthma control is based on the use of various questionnaires;the most widely used are the St. George respiratory questionnaire (SGRQ) ^[1][22], the asthma control questionnaire (ACQ) ^[2][23], the asthma quality of life questionnaire (AQLQ) ^[3][24], and the asthma control test (ACT) ^[4][25]. The total score of each test is calculated according to the patient’sanswers, and subsequently, the level of asthma control is classified ^[5][6][7][8][26,27,28,29].

A retrospective observational study demonstrated that severe asthmatics under treatment with LAMAs used to experience significantly worse asthma control and worse disease-related quality of life before LAMA initiation, based on the results of ACT, ACQ, and AQLQ ^[9][10]. These patients tended to be ex-smokers and had later-onset asthma in comparison to patients who did not receive LAMAs. Moreover, they were often diagnosed with concomitant bronchiectasis and used to receive oral corticosteroid (OCS) treatment courses and long-term treatment with monoclonal antibodies more frequently compared with non-LAMAusers ^[9][10].

In the TRIGGER study, a randomized controlled trial (RCT) on patients with uncontrolled asthma, which compared standard high-dose ICS + LABA treatment to open and closed triple inhaler therapy (ICS + LABA + LAMA), participants on close triple therapy experienced considerable improvement in their ACQ score and in the proportion of days free of asthma symptoms, at 52 weeks, but not in rescue medication use ^[10][30]. However, in the TRIMARAN study, a twin study with TRIGGER but with a medium ICS dose, no significant differences between the study groups in any of the aforementioned parameters were observed ^[10][30]. Similarly, no differences were found in the TRIGGER study between open and closed triple inhaler therapy arms ^[10][30]. In another randomized, non-inferiority study, the ARGON study, single-triple inhaler therapy was non-inferior to open triple inhaler use as far as the AQLQ improvement at 24 weeks is concerned. The single triple inhaler therapy was superior in the ACQ and SGRQ improvement compared to open triple inhaler therapy in the ARGON study ^[11][31].

In the CAPTAIN study, an RCT like TRIMARAN, with a study period of 24 weeks, showed no clinically important improvement in SGRQ between study arms ^[12][32]. However, the minimal clinically important improvement in the ACQ was significantly greater regarding closed triple inhaler therapy, but this effect was only evident in the higher LAMA dosage study arm ^[12][32]. In the IRIDIUM study, another similar 52-week RCT, improvement in the ACQ questionnaire was significantly greater in the closed triple inhaler therapy group compared to the group that received only ICS + LABA therapy ^[13][33].

As far as asthma COPD overlap (ACO) is concerned, two studies showed no statistically significant difference in asthma control, measured with ACT, when a LAMA was added to the treatment with ICS + LABA ^[14][15][34,35]. It is noteworthy that the choice of rescue medication is different in patients receiving single-triple versus open-triple treatment. According to GINA guidelines, patients in single triple or open triple with no formoterol-containing regimen should use SABA as a reliever therapy and move to track 2 ^[16][3]. Nevertheless, there is no adequate evidence to advise in favor of using SABA combined with ICS (same or separate device) in these therapeutic categories ^[16][3].

Summarizing the existing evidence, it seems plausible to suggest the addition of a LAMA, for asthma symptom control, in patients with persistent asthma, uncontrolled with medium or high dose ICS + LABA treatment, either in a separate or the same inhaler device, which is more cost-effective ^[17][36]. Also, the use of a single triple inhaler simplifies the treatment in contrast to an open triple inhaler, and that fact could strengthen adherence. Multiple inhaler devices could be one of the reasons for suboptimal adherence because it is challenging for the patients to establish and sustain the correct technique for each inhaler ^[18][37].

The prevention of exacerbations, along with symptom control, are the two main indices of asthma management. Even patients with mild asthma or well-controlled asthma symptoms could experience severe exacerbations ^[19][20][38,39], which could be fatal ^{[21][22][23][24]}[40,41,42,43].

The study byPuggioni et al. showed that asthmatic patients, who are already on LAMA treatment, have a significantly higher annual exacerbation rate ^[9][10]. In another retrospective observational study, Averell et al. demonstrated that asthma exacerbations were more frequent in patients receiving various control medications, including LAMAs ^[25][44]. Another study from Japan also showed that patients on triple inhaler therapy experienced an exacerbation in the year prior to triple treatment initiation significantly more frequently than those on ICS + LABA alone. However, this frequency was significantly lower in the year following the triple treatment initiation ^[26][45].

The patients under triple inhaler treatment (open or closed) in the TRIMARAN and TRIGGER studies demonstrated a significant reduction in the rate of moderate and severe exacerbations compared to those on ICS + LABA alone, by 15% and 12%, respectively, with no significant differences between the open and closed treatment combinations ^[10][30]. These reductions, however, showed a significant seasonal variation, as they were greater in winter, when the reduction in the rate of moderate and severe exacerbations with triple inhaler treatment was 20.3% compared to ICS + LABA alone, while in the other seasons of the year the corresponding reductions varied between 8.6% and 12.0% ^[27][46]. Furthermore, patients with higher reversibility in post-bronchodilator forced expiratory volume in 1 s (post-FEV₁) (>400 mL) experienced greater exacerbation reduction benefit. Nevertheless, no differences were observed between patients with different blood eosinophil levels ^[28][47].

In two older RCTs, the addition of a LAMA to ICS + LABA increased the time to the first severe exacerbation by 56 days and significantly reduced the risk for a severe exacerbation by 21% ^[29][48]. In the IRIDIUM study, the addition of a LAMA reduced the overall risk for an exacerbation along with the risk for moderate and/or severe exacerbation. Interestingly, this reduction was more evident in high ICS dosages ^[13][33], while in the CAPTAIN study, only non-significant reductions were observed in moderate and/or severe exacerbation rates. Similarly, those reductions were more evident in the study arms of higher ICS doses ^[12][32]. Regarding ACO, there is no clear evidence whether ICS + LABA + LAMA treatment reduces the time to first exacerbation ^[15][35].

As a result, the addition of a LAMA to the standard treatment with ICS + LABA probably reduces the risk of moderate and/or severe asthma exacerbations and should be used in cases wheredual treatment is inadequate in the prevention of the asthma exacerbations ^[17][30][21,36].

Lung function is another key aspect of asthma, as it might mirror disease control. In contrast to asthma symptoms and exacerbation control, the addition of a LAMA to the dual therapy of ICS + LABA in patients with asthma that remains uncontrolled leads to a clearly beneficial effect on lung function ^[27][46]. For this reason, patients on LAMA + ICS + LABA usually presented with worse lung function during the initial clinical assessment ^[9][10].

In the CAPTAIN study, the addition of LAMA to ICS + LABA increased the FEV₁, between 82 and 110 mL in the different study arms, with different drug doses—and these differences were statistically significant across all study arms and supported by the analysis of FEV₁ at 3 h post-dose ^[23][42]. Similar results were also seen in the IRIDIUM study, in which the statistically significant increase in trough FEV₁ varied between 65 and 119 mL ^[13][33]. In two older RCTs by Kerstjens et al., both pre-dose (trough) and peak FEV₁ were significantly increased after LAMA initiation ^[29][48].

In the two parallel-group RCTs, the TRIMARAN and TRIGGER studies, the participants in the LAMA study arms experienced significant improvement in both pre-dose and peak FEV₁, as well as in morning peak expiratory flow (PEF) ^[10][30]; moreover, in the TRIMARAN study, the sub-group of patients with low eosinophil blood count (<300 cells/μL), experienced greater benefit, although this was not evident in the TRIGGER study ^[28][47]. The latter also showed no differences between the open and the closed triple inhaler therapy study arms ^[10][30]. Nevertheless, in the ARGON study, closed triple inhaler therapy with a high ICS dose was superior to the open triple inhaler therapy regarding the improvement of trough FEV₁ and of morning and evening PEF. The corresponding results between the medium ICS dose closed triple inhaler therapy and open triple inhaler therapy were comparable ^[11][31].

The addition of LAMA to the ICS + LABA regimen seems to improve lung function in patients with ACO. This fact is supported by the results of two studies that showed a significant improvement in multiple pulmonary function tests (PFTs) and impulse oscillometry (IOS) parameters after LAMA treatment initiation ^[14][15][34,35].

To sum up, the addition of LAMA to the standard ICS + LABA treatment regimen undoubtedly significantly improves lung function in patients with inadequately controlled asthma ^[17][30][21,36].

There is a great challenge in deciding the next step of treatment in patients with severe, uncontrolled asthma between the choices to addon LAMA on ICS + LABA treatment or to increase the ICS dose in the ICS + LABA regimen. In a retrospective cohort study, the addition of LAMA to ICS + LABA decreased the risk of exacerbations by 35% versus ICS dose escalation ^[31][49]. As discussed in previous sections, the addition of LAMA improved lung function and daily symptom control ^[32][50]. It would be helpful to have asthma biomarkers that could detect patients who could benefit the most from LAMA add-on therapy.

Data from national registries of patients with severe asthma have shown that patients on LAMA treatment have higher eosinophil blood count levels. However, a fraction of exhaled nitric oxide (FeNO) and serum total IgE levels are comparable with those of non-LAMAusers ^[9][10]. There is a limited number of studies thatinvestigate the eligible profile of severe, refractory asthma patients for LAMA initiation. As mentioned above, in the TRIMARAN study, the sub-group of patients with low eosinophil blood count (<300 cells/μL) experienced greater improvement in lung function after LAMA initiation ^[28][47]. This was not the case in the TRIGGER study. In this researchtudy, eosinophil blood count was not associated with the rate of exacerbations ^[28][47]. Moreover, in the CAPTAIN study, clinic trough FEV₁ and annual moderate and/or severe exacerbation rates were not affected by LAMA initiation. They were affected by ICS dosage in the patient groups with higher baseline FeNO and blood eosinophil count ^[12][32]. Furthermore, the beneficial effect of LAMA in patients with ACO seems to be independent of FeNO level, total serumIgE, or eosinophil blood count ^[14][34].

Currently, there are no reliable biomarkers that could identify patients with severe refractory asthma eligible for LAMA treatment initiation. Some asthma traits that might be predictive ofbetter response to treatment with LAMA could be a previous smoking history and fixed airway obstruction ^[17][36]. The role of other recognizable disease traits is still under investigation ^[30][21].

5. Safety

There have been several concerns about LAMAs’ safety, especially due to the cardiovascular adverse effects following their anticholinergic action. However, several studies have shown that in asthmatic patients, they demonstrate a particularly favorable safety profile. In the CAPTAIN study, adverse events, as well as serious adverse events, were comparable among study groups, with only one death to be considered as related toa study drug in the study arm of the triple therapy with the low concentration of umeclidinium ^[12][32]. The same trend in adverse events was also reported in the IRIDIUM study, in which seven deaths were reported, which were balanced between LAMA and non-LAMA treatment arms, and none of them was considered, by the investigators, to be related toany of the study drugs ^[13][33]. Similar safety outcomes were also reported in the TRIMARAN and TRIGGER studies ^[10][30], while Kerstjens et al. reported no deaths in their RCT a few years earlier ^[29][48]. In addition, in the ARGON study, mild adverse events were comparable between treatment groups. The most frequent serious adverse event was pneumonia, which was correlated with the increased dose of ICS rather than the addition of LAMAs. Also, the only death that occurred was caused by a hemorrhagic stroke and was not considered to be study drug-related ^[11][31].