Reviews Reveal Benefits of LAMAs, LABAs, and SMART in Asthma

Tara Haelle

March 20, 2018

Updated evidence on effective asthma management and step-up therapy provide a more precise understanding of the relative efficacy of regimens involving inhaled corticosteroids, long-acting muscarinic antagonists (LAMAs), long-acting β-agonists (LABAs), and single maintenance and reliever therapy (SMART), according to two meta-analyses and systematic reviews published online today in JAMA.

Adding a LAMA to inhaled corticosteroids reduces the risk for asthma exacerbations compared with placebo plus inhaled corticosteroids, according to one review. However, the combination was no better than adding LABA to inhaled corticosteroids, nor was so-called triple therapy, which combines a LAMA, a LABA, and inhaled corticosteroids.

Meanwhile, the second review shows that SMART with a dry-powder inhaler containing budesonide and the LABA formoterol reduced the risk for asthma exacerbations compared with separate use of LABA controller therapy and high-dose inhaled corticosteroids.

The two systematic reviews and meta-analyses, both led by Diana M. Sobieraj, PharmD, from the University of Connecticut School of Pharmacy in Storrs, arrive as plans are in progress to update the 2007 Expert Panel Report 3 (EPR-3) guidelines by the National Asthma Education and Prevention Program. Limitations in available evidence, however, may reduce the clinical relevance of some findings for US practitioners, as the device studied in nearly all the SMART trials lacks approval by the US Food and Drug Administration (FDA).

"For patients and clinicians, the results from these meta-analyses suggest that dual therapy with scheduled doses of inhaled corticosteroids and LABA or inhaled corticosteroids and LAMA should help reduce the risk of future asthma exacerbations in patients with inadequate asthma control while using inhaled corticosteroids alone," write Jerry A. Krishnan, MD, PhD, from the University of Illinois in Chicago, and David H. Au, MD, from the Veterans Affairs Puget Sound Health Care System and the University of Washington in Seattle, in an accompanying editorial.

"There is no clear difference between these 2 options based on inhaled corticosteroids for dual therapy in reducing the risk of asthma exacerbations, suggesting that patients and clinicians be given flexibility in selecting either option based on the potential for adverse events specific to LABA or LAMA, relative costs, and preference for inhaler device," they conclude.

LAMA as Adjunct Therapy

In the first review, examining LAMAs as adjunct therapy, Sobieraj and colleagues identified 15 randomized controlled trials involving 7122 patients. Most trials restricted enrollment to patients ages 18 years and older except two trials that enrolled 789 patients ages 12 to 17 years.

On the basis of analysis of 8 of the trials, LAMA as an add-on therapy to inhaled corticosteroids resulted in a 33% lower relative risk of needing systemic corticosteroids for asthma exacerbations compared with placebo plus inhaled corticosteroids (risk ratio [RR], 0.67; 95% confidence interval [CI], 0.48 - 0.92). The difference was equivalent to a 2% lower absolute risk.

Adjunctive LAMA also resulted in a 19% reduced risk for asthma worsening compared with adjunctive placebo (RR, 0.81; 95% CI, 0.68 - 0.97), which was a 5% reduction in absolute risk.

However, the benefit of adding LAMA to inhaled corticosteroids was not superior in any way to the benefit of adding LABA to inhaled corticosteroids (RR, 0.87; 95% CI, 0.53 - 1.42), based on 6 trials, plus two others comparing LAMA with montelukast and doxofylline as adjuncts.

Further, the evidence from four trials showed no reduction in exacerbation risk with triple therapy, adding LAMA to combined use of inhaled corticosteroids and LABA, compared with the corticosteroids–LABA combination alone (RR, 0.84; 95% CI, 0.57 - 1.22). In those trials, however, patients could use stable doses of other controllers simultaneously.

"This systematic review did not find sufficient evidence that adding LAMA to inhaled corticosteroids in this population was associated with improvements in clinical outcomes vs adding LABA[,] and the wide 95% CIs around the relative risk does not exclude the possibility that one of these treatments could be superior to the other," write Sobieraj and colleagues. "Triple therapy was associated with some improved outcomes, including spirometry, vs LABA and inhaled corticosteroids although no association with improved exacerbation risk was seen."

Assessing SMART Management Strategy

In the second systematic review, the researchers assessed the benefits of a SMART, using an inhaler with corticosteroids (primarily budesonide) and formoterol against two other therapies: inhaled corticosteroids as a single controller or dual therapy with corticosteroids and twice-daily LABA. They identified 16 trials, involving 22,748 patients, from MEDLINE, EMBASE, the Cochrane Register, and the Cochrane Database of Systematic Reviews through November 2017.

"A SMART strategy containing formoterol combined with inhaled corticosteroids in a single inhaler has the potential to provide quick symptom relief while also delivering inhaled corticosteroids that could reduce the subsequent risk of an exacerbation," the editorialists Krishnan and Au write. "In addition to being convenient for the patient, such a strategy could improve outcomes by titrating the dosage of inhaled corticosteroids to the frequency of the use of a rescue SABA and by eliminating the possibility that a patient would rely on frequent SABA use for symptom relief while not adhering to a separate regimen with an inhaled corticosteroid controller," they explain.

Indeed, Sobieraj and colleagues report that the risk for asthma exacerbations was 32% lower compared with the same dose of inhaled corticosteroids with a LABA controller (RR, 0.68; 95% CI, 0.58 - 0.80), which translated to a 6.4% lower absolute risk. Even compared with a higher dose of corticosteroids with a LABA controller, SMART resulted in 23% lower relative risk, and a 2.7% lower absolute risk, of exacerbations (RR, 0.77; 95% CI, 0.60 - 0.98).

Three trials assessed SMART against a corticosteroid inhaler as controller alone, but could not be combined because of heterogeneity in the populations and participant criteria. In one of them, "SMART was associated with a decreased risk for asthma exacerbations defined as a composite of those requiring use of systemic corticosteroids, hospitalization, or [emergency department] visit compared with the same dose of inhaled corticosteroids alone as the controller therapy," the authors report. The relative risk was reduced by 36% (RR, 0.64; 95% CI, 0.53 - 0.78), which translated to an 8.1% reduction in absolute risk.

Compared with a higher comparative dose of inhaled corticosteroids in a different trial, SMART reduced asthma exacerbations by 41% (RR, 0.59; 95% CI, 0.49 - 0.71), which was an 11% reduction in absolute risk.

SMART was not, however, associated with improvements in forced expiratory volume in the first second of expiration, forced vital capacity, or percentage of predicted forced expiratory volume in the first second of expiration compared with LABA as controller with the same or a higher dose of inhaled corticosteroids. The two trials that assessed asthma-related quality of life showed no benefit from SMART relative to standard care.

SMART in Pediatric Populations

Far fewer data were available on children ages 4 to 11 years, who comprised only about 1% of the total participants in the trials (341 patients). Based on that small group, however, SMART reduced asthma exacerbation risk by 45% compared with higher-dose inhaled corticosteroids as controller therapy (RR, 0.55; 95% CI, 0.32 - 0.94). Compared with LABA as controller and the same dose of corticosteroids, the pediatric patients had a 62% reduced risk for exacerbations with SMART (RR, 0.38; 95% CI, 0.23 - 0.63).

"Given the relatively few children aged 4 to 11 years included in this study, there is less confidence regarding the benefits of SMART in this population than among adolescents and adults," write Krishnan and Au.

Good Information…With Limitations

In the editorial, Krishnan and Au note limitations in both systematic reviews, including that neither analysis assessed potential harms or relative costs of different therapies.

"LAMAs have the potential to worsen narrow-angle glaucoma and urinary retention, especially in individuals who may be using other anticholinergic medications," write Krishnan and Au. "The FDA-approved prescribing information for the combination of formoterol and budesonide via a metered-dose inhaler indicates the potential for several adverse effects, including nasopharyngitis, oral candidiasis, and (among children) a reduction in growth velocity."

Deaths were rare in both groups of studies, but neither was powered to detect death outcomes. Yet, they add, four FDA-mandate postmarketing randomized clinical trials in 41,000 children, teenagers, and adults did not find a greater risk for deaths or other serious events from taking LABAs with inhaled corticosteroids.

The medications included in the trials also limited the applicability or generalizability of the results. Most clinical trials in the LAMA meta-analysis used tiotropium, so the benefit of other LAMAs in this regimen is unclear, Krishnan and Au note.

In addition, all but one of the trials testing SMART used inhalers with a dry-powder combination of formoterol and budesonide. "However, the combination of formoterol and budesonide is delivered only via a metered-dose inhaler in the United States," Krishnan and Au wrote. "[T]herefore, the applicability to a US population of SMART studies based on the use of a dry-powder inhaler is less clear."

With respect to the planned EPR-3 update, Krishnan and Au say the findings on tiotropium suggest LAMA should be included as treatment options in steps 3 to 6 of step-up therapy. "Such changes to the EPR-3 guidelines would help to harmonize the approval by the FDA for inhaled tiotropium and the clinical guidelines in the United States," they write.

However, the SMART findings are more problematic, because the FDA has not approved the dry-powder inhaler device containing combination formoterol and budesonide. "Dry-powder and metered-dose inhaler devices require different techniques that could contribute to different types of errors in inhaler use, differences in drug deposition in the airways and different clinical outcomes," Krishnan and Au write. "Thus, the efficacy and safety of medications using one type of inhaler device should not be presumed to be equally efficacious using another device."

Both meta-analyses were funded by the Agency for Healthcare Research and Quality, and no authors in either study had industry-related disclosures. Krishnan and Au reported compensation for participation on data monitoring committees from Sanofi and Novartis, respectively, and Au has consulted for Gilead Sciences.

JAMA. Published online March 19, 2018. LAMA study, SMART study, Editorial

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