6.7 Updates in Stepping Up Asthma Therapy: Increasing ICS Versus Adding LABA

A large body of data exists to assess optimal strategies for increasing therapy when asthma is not controlled on low-dose ICS alone. When stepping up asthma therapy, addition of a LABA as opposed to escalating ICS dose has resulted in better outcomes in randomized, prospective clinical trials with inclusion criteria requiring demonstration of bronchodilator reversibility [47]. However, increased ICS behaved similarly or better than addition of LABA in retrospective and observational studies in which bronchodilator reversibility was not required [48–50]. Although step therapy algorithms in guidelines have endorsed increasing ICS by doubling or quadrupling the dose when control is lost, recent studies have raised questions about the efficacy of this strategy. In 2018, two large, randomized trials assessed the effects from increasing ICS when asthma control worsens [29, 51]. The first was double-blinded and enrolled children ages 5–11 [51]. The second was not blinded, it enrolled adolescents and adults (mean age was 57 ± 15 years old), and participants were on a variety of ICS doses at baseline [29]. Notably, the first study was negative and the second positive.

Controversy regarding interpretation remains. Putting aside the disparate results between the two trials, their alternative designs, and underlying patient populations, one must believe that high doses of ICS have a superior safety profile to oral glucocorticoids before applying this approach. Notably, 22% of patients in in the positive trial were receiving high baseline doses, 1000 ug/day beclomethasone equivalent, of ICS [29, 52]. The authors of the positive trial note that bioequivalence studies are suboptimal, citing data from 1989 that found 1 mg inhaled budesonide is equivalent to 8.7 mg of prednisolone [29, 53]. The median daily dose of beclomethasone equivalent was 800 ug/day. Quadrupling this dose would result in a dose of 3.2 mg/day. Conservative estimates suggest that patients receiving this dose would be subjected to 20 mg prednisolone equivalent per day. The budesonide study concluded that the relative asthma efficacy to side effect profile was superior for ICS but that shouldn’t lead clinicians to consider high doses of ICS risk-free. In the negative trial there was an effect on growth in the intervention group [51], and in the positive one there was a higher incidence of oral candidiasis and dysphonia [29].Adverse systemic effects from ICS are well described and were reviewed earlier in this chapter.

An accompanying editorial and letters to the editor debated the merits of the two trials [54, 55]. Due to differences in study design and the targeted age ranges, there are several factors that may have influenced results. Despite this, those willing to adopt the high-dose ICS approach in the setting of worse asthma control should understand that treatment will not be without side effects, just because it’s inhaled. In addition, as discussed in the first section of this chapter, inhaler type and patient technique should be factors when considering treatment options for loss of asthma control. Lastly, one must consider the risk for further loss of control with ICS for that proportion of patients who will ultimately require oral glucocorticoids to improve symptoms.

6.8 Updates in Stepping Up Asthma Therapy: Addition of LAMA

The Global Initiative for Asthma (GINA) guidelines now include tiotropium, a long-acting muscarinic antagonist (LAMA), as an option for step-up asthma treatment [56]. Tiotropium has been approved for use in COPD and is first-line inhaler treatment for this disease [57]. Studies of tiotropium as treatment for asthma date back to 2007 [58], with two important trials published in the New England Journal of Medicine in 2010 [59] and 2012 [60]. Initial data showed promise for tiotropium as step-up therapy (for patients not controlled on ICS alone) [59] and for asthma uncontrolled on ICS/LABA therapy [60]. In 2015 a meta-analysis published in the CHEST journal summarized the existing literature on tiotropium for asthma. The analysis included 13 studies (4966 patients) and looked at different uses (tiotropium as add-on to ICS monotherapy, for patients poorly controlled on medium-to-high-dose monotherapy, and for patients on ICS/LABA) and outcome measures (peak expiratory flow (PEF) variability, subjective asthma control and quality of life, spirometry, and asthma exacerbations). Tiotropium compared favorably to LABA and ICS/LABA across different outcomes and was particularly effective for improving lung function and reducing exacerbations for patients with severe asthma [61].

Another systematic review and meta-analysis published in the Journal of the American Medical Association (JAMA) in 2018, conducted differently, reached similar conclusions. It found LAMA was superior to placebo but equivalent to LABA as add-on therapy to ICS when asthma is sub-optimally controlled. This review found some improvement in lung function and asthma control when LAMA was added to ICS/LABA (triple therapy) in patients with persistent symptoms from asthma. However, there was no significant difference in asthma-related quality of life (although associations were generally positive), rescue-inhaler use, or exacerbations with use of triple therapy [62]. It is possible that the asthma population that might benefit from triple therapy has not yet been identified, and use of triple therapy either in separate inhalers, or as a single inhaler will be an active area of investigation going forward.

6.9 Using Biomarkers for Adjusting Asthma Therapy

To date, most studies evaluating step-up therapy of uncontrolled asthma have approached lack of control as a uniform trait without accounting for heterogeneity of disease. For patients with evidence of ongoing type 2 inflammation based on biomarkers, such as elevated fraction of exhaled nitric oxide (FeNo) > 50 parts per billion (ppb) or elevated blood or sputum eosinophil count, the ICS dose may need to be increased. Conversely, if inflammation is suppressed and persistent symptoms are related to ongoing bronchial hyper-reactivity or persistent airflow limitation, addition of a long-acting bronchodilator would be more reasonable. It is possible that strategies that distinguish lack of control or deterioration due to type 2 airway inflammation, non-type 2 inflammation, or increased bronchial reactivity will help identify the optimal approach to stepping up controller therapy. Given that up to 50% of patients with mild asthma lack overt type 2 biology, it is possible that inclusion of low type 2 patients may have offset biomarker efficacy in studies of heterogeneous populations [63]. Although conflicting studies exist, recent data show increasing support for use of FeNo, sputum eosinophilia, and blood eosinophilia in adjusting steroid dosing in patients with asthma [64, 65]. Data showing discontinuation of ICS in patients with COPD can be guided by absolute eosinophil count suggest that step-up and perhaps step-down strategies in asthmatics according to biomarker status need further investigation [66].

6.10 Updates to Stepping Down Fixed-Dose ICS/LABA Therapy

Guidelines also recommend stepping down therapy once asthma control is achieved for at least 3 months. This can typically be accomplished safely by reducing ICS dose by 50% when using ICS therapy alone, but the step-down approach when using combination ICS/LABA therapy is less clear [67]. In the USA, regulatory authorities have suggested discontinuing LABA when asthma is stable but guidelines suggest reducing ICS dose by 50%, while maintaining the LABA, is the optimal strategy [55, 68]. Systematic reviews comparing treatment reduction strategies found worse symptom control and quality of life when LABAs were stopped, but differences were small and of unclear clinical significance [69, 70]. These reviews included studies where the primary outcome was peak flow, and studies were of short duration and were underpowered to assess important endpoints such as urgent care visits and hospitalizations.

More recently, a 56-week, multi-center, randomized, double-masked three-arm parallel group study was performed where 459 participants continued medium dose ICS/LABA, reduced dose ICS/ LABA, or discontinued LABA (LABA step-off) using a composite endpoint of treatment failure as the primary outcome. The authors found that the two step-down regimens did not differ significantly from stable ICS/LABA in terms of treatment failure, although stopping LABA was associated with more all cause hospitalizations and lower lung function. In terms of serious adverse events, there were no deaths or intubations in this study, and the few asthma-specific hospitalizations all occurred in the LABA-step-off group with none in groups who continued LABA [71]. These results suggest similar outcomes with use of either strategy of reducing asthma therapy. In the recent FDA-mandated LABA safety studies, adults and adolescents well controlled on ICS/LABA at baseline had a greater risk of exacerbation on LABA-step-off versus continuation of ICS/LABA [46]. In light of recent reassuring LABA safety data, an ICS reduction rather than a LABA-step-off approach when reducing combination therapy is likely preferable.

6.11 Fixed Versus Variable Dosing of ICS/LABA

Currently ICS/LABA combination therapy can be prescribed as fixed-dose therapy, such as with combination inhalers including the LABAs salmeterol or vilanterol, or with variable dosing using formoterol-containing combinations. The former strategy is most commonly used in the USA. Elsewhere in the world, there has been increasing investigation and clinical use of variable doing with formoterol containing combination inhalers in recent years. Variable dosing can consist of use of ICS/formoterol combination based on symptoms as needed, capitalizing on the rapid onset of action of formoterol, or use as maintenance therapy with additional dosing for quick relief (referred to as single maintenance and reliever therapy, referred to as SMART or MART, or single inhaler therapy, SIT). Most data on safety and efficacy of variable dosing has been performed using budesonide-formoterol, particularly the DPI formulation available only outside of the USA [72]. Older systematic reviews found MART to be effective at reducing risk of exacerbations requiring OCS, including those resulting in ED visits or hospitalizations [73].

More recently a series of studies have cemented the role of variable dosing. In a recent systematic review, the authors identified 16 trials involving over 20, 000 children, adolescents, and adults that compared either ICS or variable ICS/LABA as maintenance, with SABA for rescue therapy. Importantly, 15 of the trials used the ICS/LABA budesonide/formoterol delivered via DPI, and for this reason, caution is advised before generalizing findings to other ICS/LABA combination drugs. MART was associated with a lower rate of exacerbations when compared to fixed-dose ICS/LABA treatment and when compared to either a same (RR, 0.38 [95%CI, 0.23 to 0.63]; RD, −23.2%[95%CI, −33.6%to −12.1%]) or higher dose ICS (RR, 0.55 [95%CI, 0.32 to 0.94]; RD, −12.0% [95%CI, −22.5%to −1.5%]), and this finding held across age groups (although children under 12 formed a smaller portion (1%) of the cohort) [74]. The authors concluded that budesonide/formoterol effectively decreases the risk for a composite outcome centered around exacerbations (need for systemic corticosteroid therapy, hospitalization, or visits to the emergency department). Improvements in symptoms and asthma-related quality of life were less impressive, and conclusions for younger patients (5–11 years old) were less robust given smaller sample size [62]..

Additional support for this strategy was provided by a recent analysis of studies in adolescents and two large international studies in adolescents and adults. In adolescents, MART was found to be more effective in reducing exacerbations, ED visits, and hospitalization when compared to same dose or a doubled dose of ICS used in the MART regimen [75].^. In both adolescents and adults, the SYGMA 1 study compared intermittent ICS/LABA to fixed-dose maintenance ICS and SABA alone. Intermittent ICS/LABA was superior to SABA alone and non-inferior to fixed-dose ICS in preventing exacerbations, although superior symptom control was achieved with fixed-dose ICS [76]. Using a weekly diary, the difference in symptom control was 34.4% vs. 44.4% well-controlled weeks in ICS fixed dose vs. ICS/LABA as needed (odds ratio 0.64, 95% CI, 0.57 to 0.73).

A companion study, SYGMA 2, had a similar study design with a more pragmatic approach. There were fewer study visits, no reminders for study medication, and fewer study center visits, with the intent to closely mimic clinical practice [77]. Findings were similar to SYGMA 1; there was non-inferiority for preventing exacerbations. Symptom control in SYGMA 2 was better with fixed-dose ICS similar to findings in SYGMA 1, but the difference in ACQ-5 was 0.11 units (95% CI 0.07–0.15), less than the minimal clinically important difference for this measure. Of note, the dose of inhaled steroid in the as needed ICS/LABA group in both SYGMA 1 and 2 was less than ¼ of the dose in the fixed dosing group, offering possible advantages for minimizing adverse effects, particularly in children, and cost of treatment [76, 77]. The updated 2019 GINA guidelines have replaced as-needed SABA with as-needed low dose ICS/fortomoterol as the preferred step 1 therapy [78]. Although using ICS/LABA for rescue therapy is endorsed by guidelines, the authors note that no ICS/LABA combination is currently approved by the FDA for this purpose [79, 80]. Despite the recent data supporting the role of this treatment approach, wider use of MART has been limited by the lack of regulatory approval of this dosing strategy in some jurisdictions [55].

6.12 Summing It All Up: Advances in Traditional Asthma Therapies

Recent advances in our knowledge of traditional asthma therapies are summarized in Table 6.2. Inhaler design, delivery mechanisms, propellants, and particle sizes provide physicians with numerous choices for each patient. While we’re not currently able to predict adherence and efficacy prior to use, it’s important that providers understand the barriers patients face with using different inhaler designs. Small particle medicines may be preferred when side effects limit use or small airways disease is driving symptoms.

Table 6.2

Advances in traditional asthma therapies

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