Published ahead of print on December 15, 2005, doi:10.1164/rccm.200507-1167OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200507-1167OC
Effects of Esomeprazole 40 mg Twice Daily on AsthmaA Randomized Placebo-controlled TrialDepartment of Pulmonary Diseases, Tampere University Hospital, Tampere, Finland; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Division of Respiratory Medicine, University of Calgary Medical School, Calgary, Alberta, Canada; Allergy Associates of the Palm Beaches, North Palm Beach, Florida; National Jewish Medical and Research Center, Denver, Colorado; AstraZeneca R&D, Lund, Sweden; and AstraZeneca Pharmaceuticals, Wilmington, Delaware Correspondence and requests for reprints should be addressed to Toni Kiljander, M.D., P.O. Box 2000, FIN-33521, Tampere, Finland. E-mail: toni.kiljander{at}fimnet.fi
Rationale: Gastroesophageal reflux disease (GERD) is common in patients with asthma, suggesting an interaction between the two conditions. Objectives: To assess the effect of gastric acid suppression with the proton pump inhibitor esomeprazole on asthma outcomes in subjects with persistent moderate to severe asthma treated with antiinflammatory asthma medication. Methods: In this double-blind study, subjects were randomized to receive esomeprazole 40 mg or placebo twice daily for 16 wk. According to nocturnal respiratory symptoms (NOC) and GERD, subjects were divided into three strata: GERD–/NOC+, GERD+/NOC–, and GERD+/NOC+.
Measurements and Main Results: A total of 770 subjects were randomized. There was no statistically significant improvement in morning peak expiratory flow (PEF) over placebo in the overall study population: 6.3 L/min (p = 0.061). Over the whole treatment period, in GERD+/NOC+ subjects (n = 350), esomeprazole provided an 8.7-L/min improvement (p = 0.03) in morning PEF, and a 10.2-L/min improvement (p = 0.012) in evening PEF over placebo. Among 307 subjects taking long-acting Conclusions: Esomeprazole improved PEF in subjects with asthma who presented with both GERD and NOC. In subjects without both GERD and NOC, no improvement could be detected.
Key Words: asthma • gastric acid • gastroesophageal reflux • peak expiratory flow • proton pump inhibitor Gastroesophageal reflux disease (GERD) is common in adult patients with asthma, with the reported prevalence ranging from 32 to 82%. (1, 2) Although typical GERD symptoms, such as heartburn and regurgitation, are more common in patients with asthma than in control populations (3), substantial acid reflux can be present without the typical reflux symptoms in patients with asthma (4, 5). Acid reflux is a potential trigger of asthma (6) and may also be a complicating factor in difficult-to-control asthma (7). There is also evidence that nocturnal GERD in particular may precipitate asthma symptoms (8, 9). Several studies have investigated the efficacy of different proton pump inhibitors (PPIs) on asthma outcomes in patients with asthma who have GERD (10–18). Many of these studies show improvements in certain asthma variables, although the results are inconsistent, possibly reflecting the relatively small sample sizes and differences in study design. A Cochrane review on the subject concluded that the published data did not consistently support the use of GERD treatment as a means to control asthma, but that improvements were observed in certain subgroups of patients. The authors also concluded, however, that further large, randomized, controlled trials were required (19). Treatment with high doses of PPIs for 2 to 3 mo has been recommended for the management of GERD-related asthma (15, 20). The rationale for this recommendation is that asthma exacerbation may be linked to the acidity of the refluxate and asthma outcomes require lengthy periods of time to show improvement. In healthy volunteers, esomeprazole 40 mg twice daily maintains intragastric pH of more than 4 for over 80% of a 24-h period (21). The primary objective of this study was to investigate the effect of 16 wk of PPI therapy using esomeprazole 40 mg twice daily on pulmonary function in subjects with persistent moderate to severe asthma, who were regularly receiving adequate antiinflammatory asthma medication. To establish the role of GERD in asthma, and to examine the possibility that asymptomatic acid reflux may be linked to respiratory symptoms, subjects were classified according to the presence/absence of GERD and nocturnal respiratory symptoms (NOC). The secondary objective was to assess the safety and tolerability of this high-dose esomeprazole regimen in this asthma population. Data from this study have previously been published in abstract form (22–26).
Subjects Outpatients aged 18 to 70 yr with asthma (27) treated with inhaled glucocorticosteroids (ICS) and/or leukotriene pathway modifiers for 3 mo or more before study entry were enrolled. Subjects had stable asthma (no asthma medication change in the previous 30 d), FEV1 of 50 to 80% predicted with 12% or greater (and  0.20 L) reversibility, and mean morning peak expiratory flow (morning PEF) less than 80% predicted. To be randomized, subjects had to fulfill additional criteria during the run-in period (see online supplement). Exclusion criteria included the following: current smoking or history of 10 pack-years or more; use of oral, rectal, or parenteral glucocorticosteroids less than 30 d before enrollment; previous esophageal or gastric surgery; erosive esophagitis in the 16 wk or fewer before enrollment; PPI use in the 14 d before enrollment; recurrent moderate or severe GERD symptoms in the previous year in subjects older than 40 yr.
Study Design Figure 1 shows the study design. Study medication was taken with a glass of water 30 min before breakfast and dinner. At randomization, subjects were classified into one of three strata according to the presence of GERD and/or NOC. NOC was defined as the presence of nighttime awakening with associated respiratory symptoms on one or more occasion, or PEF overnight variability of 15% or more on two or more occasions during the last week of the run-in period. GERD was considered present if the subject had any of the following: a mean of two or more episodes per week of heartburn, or one episode per week of acid regurgitation in the 3 mo before enrollment; a documented history of erosive esophagitis or Barrett's esophagus (without dysplasia) in the previous 12 mo; or a documented history of abnormal 24-h esophageal pH. Also, subjects who could correlate heartburn with subsequent asthma symptoms (within 1 h) on two or more occasions in the previous 3 mo were considered to have GERD.
Assessments The primary variable was the change in the mean morning PEF from baseline (last 7 d of run-in) to the end of the treatment period (last 28 d of the study). Change in morning PEF was also assessed over the entire treatment period. PEF was measured at home by subjects using a Mini-Wright PEF meter (Clement Clark, Harlow, UK). Secondary outcome variables are detailed in the online supplement.
Statistical Analyses
The flow of subjects through the study is shown in Figure 2. A total of 770 subjects were randomized to treatment with the study medication.
Baseline clinical and demographic characteristics of the two treatment groups were similar in each stratum and for all subjects (Table 1). The vast majority of subjects (98%) were using ICS at baseline. Throughout the study, the use of antacids as rescue medication for GERD was low, with a mean daily usage of 0.47 and 0.58 tablets per subject in the esomeprazole and placebo groups, respectively. Among those subjects with GERD, the respective daily usage was 0.52 and 0.68 tablets.
Efficacy Change in morning PEF. For the primary variable (change in morning PEF from baseline to the last 28 d of the study), a difference of 6.3 L/min was observed between esomeprazole and placebo (p = 0.061). The adjusted mean improvement in morning PEF from baseline to the last 28 d was 22.3 L/min in the esomeprazole group (n = 386) and 16.0 L/min in the placebo group (n = 374). A statistically significant difference was observed (5.6 L/min, p = 0.042) when data were analyzed using the change in morning PEF observed over the entire treatment period. The morning PEF values at baseline and after treatment are shown in Table E1 of the online supplement. Changes in morning PEF values for subjects classified according to GERD and NOC are shown in Figure 3. Intertreatment differences in morning PEF values among these subjects are shown in Table 2. When changes in morning PEF were assessed over the entire treatment period, esomeprazole significantly increased morning PEF, compared with placebo, in subjects with GERD and NOC (8.7 L/min, p = 0.03). Among these subjects, a difference was apparent between esomeprazole and placebo within the first few weeks of the study (Figure 3).
Change in evening PEF. For the overall study population, the mean treatment difference in evening PEF was 5.9 L/min (p = 0.078) and 5.4 L/min (p = 0.053) over the last 28 d and for the whole treatment period, respectively. Statistically significant differences between esomeprazole and placebo were observed in evening PEF values among subjects with GERD and NOC, regardless of whether the change was analyzed over the last 28 d of the study (difference: 11.2 L/min, p = 0.02) or over the entire study period (difference: 10.2 L/min, p = 0.012; Table 2). The evening PEF values at baseline and after 16 wk of treatment are shown in Table E2.
Other asthma outcome variables. Over the entire treatment period, there were 22 and 24 asthma exacerbations in the esomeprazole and placebo groups, and the median times to exacerbation were 42 and 67 d, respectively. There was no significant difference with respect to time to asthma exacerbation between the two treatment groups (p = 0.70).
LABAs.
Safety and Tolerability Esomeprazole and placebo were similarly well tolerated with 6 and 8% of subjects, respectively, discontinuing from the randomized treatment prematurely because of adverse events. Only 1% of subjects in each treatment group experienced serious adverse events. There were no deaths and none of the serious adverse events were considered to be related to the study drug. There were no cases of pneumonia reported during the study period in either treatment group. In esomeprazole-treated subjects, 306 nonserious adverse events were reported in 166 subjects (43%), compared with 288 among 171 placebo recipients (45%). The causality of these adverse events was not established (i.e., includes both non–drug-related and potentially drug-related adverse events). The most commonly reported adverse events in both treatment groups were asthma and nasopharyngitis (Table 4), reflecting the susceptibility of the study population to these events. The majority of nonserious adverse events were of mild or moderate severity (> 96% in both treatment groups). Only minor changes in hematologic and clinical chemistry parameters were observed. None of the changes were considered to be clinically relevant and these changes occurred with similar frequency in both treatment groups.
This study revealed that esomeprazole treatment does not universally improve asthma outcome in patients with moderate to severe asthma. However, the current study demonstrated that esomeprazole can improve PEF in patients with asthma who present with both GERD and NOC. In the current study population, the improvements were of borderline clinical significance. The authors believe that the most important analyses of the current study were those by stratum, which revealed that esomeprazole treatment can affect PEF, and indicated which groups of patients are more likely to respond to esomeprazole treatment. Of the three subgroups analyzed, statistically significant improvements in morning PEF and evening PEF were only observed in subjects presenting with NOC and GERD. This observation may support the previously reported link between nocturnal gastroesophageal reflux and asthma (8, 9). It is of interest that nocturnal asthma symptoms are a classical sign of difficult-to-control asthma (28), and therefore our results indirectly suggest that GERD may be a factor that makes these subjects' asthma more difficult to control. Furthermore, a post hoc analysis revealed improvements in morning PEF and evening PEF in subjects taking LABAs, which are often used to manage asthma that is poorly controlled by other treatments. Also, within the LABA subgroup, the largest improvements in evening PEF were also observed in subjects who presented with both GERD and NOC. Improvements in morning and evening PEF among patients with both GERD and NOC were 8.7 and 10.2 L/min, respectively, which may be considered of only borderline clinical significance. There are several possible explanations for this. First, there is evidence that PPI therapy provides greater benefit in patients with asthma with more severe GERD (15, 29). Subjects with severe GERD were excluded from the current study. The mild nature of GERD experienced by subjects was demonstrated by the low use of antacids as rescue medication (mean daily usage of 0.68 tablets among placebo recipients in the GERD groups). This is lower than has been observed previously in subjects with mild GERD, where mean daily antacid use among placebo recipients was 1.06 tablets (30). Second, the duration of the study was 16 wk, and not 24 wk, as suggested by the Cochrane review (19), although improvements in morning PEF were apparent already within the first few weeks of the study. Third, there may be a link between nonacidic reflux and asthma in some subjects, and PPI therapy would not be expected to provide any therapeutic benefit in these subjects. Finally, because no objective measure of GERD was performed, we cannot be certain how many subjects actually had GERD and in how many subjects asthma symptoms were temporally associated with a reflux episode. When analyzing the entire study population, the improvements in PEF cannot be considered as clinically significant. This reflects the lack of benefit with esomeprazole treatment in subjects without GERD symptoms (and those with GERD but without NOC). This may support the previous suggestion that mild reflux often found in patients with asthma is actually caused by asthma rather than being a trigger for asthma (4). A statistically significant improvement in morning PEF was observed, however, when the data were observed over the entire treatment period (p = 0.042). This reflects the fact that, in the current study, improvement in morning PEF, where present, was apparent within the first few weeks of the study. Recently, Littner and colleagues (10) performed a placebo-controlled study where the effect of lansoprazole on asthma outcome was investigated in 207 patients with moderate to severe asthma who presented with GERD and nocturnal asthma symptoms. The Littner study revealed that PPI treatment may reduce asthma exacerbations. In accordance with our results, the finding was more pronounced among patients who required more than one asthma control medication. In contrast with the current study, no improvements in PEF values could be detected in the Littner study. Esomeprazole has been shown to be well tolerated when administered at a dosage of 40 mg once daily (31). Fewer data exist examining the safety profile of esomeprazole 40 mg twice daily. To date, the study reported here is the longest study to assess the effect of this high-dose regimen, demonstrating that esomeprazole 40 mg twice daily is well tolerated and that no safety concerns were raised in this asthma population. In conclusion, gastric acid suppression provided by treatment with esomeprazole 40 mg twice daily over 16 wk improves morning and evening PEF in subjects with moderate to severe asthma who present with GERD symptoms and NOC. Also, subjects taking LABAs may benefit from esomeprazole treatment. Patients who do not suffer from GERD symptoms and NOC do not appear to benefit from esomeprazole treatment. Future studies are required to define more precisely the optimal target asthma population and to clarify the clinical significance of improvements in asthma outcomes with acid suppressive therapy.
The Acid Asthma Study investigators were as follows: from Argentina: M. Bosio, J. Figueroa Casas, D. Pérez Chada, F. Julio Chertcoff, C. Di Bartolo, R. Gené, A. María López, L. Nannini, E. Prieto, R. Herberto Re, E. Rhodius, X. Bocca Ruiz; from Brazil: J. Carlos Corrêa; Á. Cruz, A. Luisa Godoy Fernandes, J. César Abreu de Oliveira, R. Stelmach, R. Stirbulov; from Bulgaria: V. Dimitrov, D. Dimova, O. Georgiev, Y. Ivanov, H. Metev, D. Osmanliev, D. Popov; from Canada: A. Atkinson, A. Cheema, S. Field, G. Fox, C. Licskai, R. Olivenstein, R. Maleki-Yazdi; from the Czech Republic: P. Fousek, R. Kolariková, J. Lahovsk  , E. Ohnútková, H. Pauková, A. Popelková, J. Urbanová, J. Veverka; from Finland: R. Backman, J. Jaakkola, E. Kallonen, T. Kiljander, L.-H. Plathin; from Hungary: M. Bisits, M. Csányi, Z. Cseke, M. Hegedus, G. Kelen, É. Radeczky; from Italy: M. Boccieri, S. Centanni, A. Cirillo, R. Claudio, G. Marone, F. Mazza, P. Melchiorre, P. Paggiaro, G. Petrigni, M. Polverino; from Mexico: N. Martínez Aguilar, A. Gazca Aguilar, B. Bello-Rivera, O. Priego Feria, S. González; from Romania: M. Abobului, I. Agache, D.M. Dumitrascu, D. Isacoff, T. Mihaescu, D. Moldovan, C. Ureche, O. Verescu; from Sweden: L. Boman, I. Vinge; from the United States: J. Angeloni, G. Ayars, C. Banov, D. Bernstein, M. Blumberg, B. Castillo, L. Charous, R. Cofman, J. Corren, E. Delfin, Jr., D. Elkayam, W. Gamel, S. Gawchick, A. Goldsobel, G. Gross, N. Hanania, S. Harding, T. Harper, E. Kerwin, J. King, P. Korenblat, K. Lampl, M. Littner, M. Manning, L. Mansfield, P. Marcus, J. Matz, R. Menendez, D. Miller, A. Nayak, H. Nelson, M. Neustrom, M. Noonan, N. Ostrum, M. Pacin, J. Pinnas, J. Ramsdell, R. Saff, K. Schaffer, E. Schwartz, P. Shapero, T. Sim, W. Sokol, M. Stein, G. Steven, S. Tilles, J. Wald, S. Weakley, J. Winder, R. Zielinski. The authors thank Noel Curtis from Adis Communications who provided medical writing support on behalf of AstraZeneca.
Supported by a research grant from AstraZeneca, which designed and funded the study, and provided study drug. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200507-1167OC on December 15, 2005 Conflict of Interest Statement: T.O.K. has received lecturing fees from AstraZeneca (AZ) and Wyeth, and is a member of an advisory board for AZ. S.M.H. received $3,500 in 2002, $1,000 in 2003, and $1,000 in 2004, all related to speaker honoraria or participation in research symposia from AZ. She has received a direct payment of $8,000 to organize and conduct a workshop for AZ scientists and $11,500 was paid to her division at the University of Alabama at Birmingham for costs associated with two other scientific workshops held on campus. In 2003, she received a $500 honorarium from TAP Pharmaceuticals for lecturing at a local CME event. In 2002, she received a $2,000 honorarium for work on a medical advisory board for Wyeth-Ayerst Pharmaceuticals. She also receives biannual royalties since 1996 from Up-To-Date for authoring a card. The amount of the money varies from a few dollars to less than $100/yr. S.K.F. received Can $86,000 as research grants for participating in multicenter clinical trials and Can $8,000 for serving on advisory boards from 2002 until 2004 from AZ. M.R.S. has received speaker lecture fees of $8,000 (Merck), $4,000 (Glaxo), $2,000 (Schering), $2,000 (Aventis), and $2,000 (Pfizer) in 2004 and about the same in 2003 and 2002. H.S.N. received $3,000 in 2002 and $2,000 in 2003 for speaking at meetings sponsored by AZ and $203,916 in 2003–2005 from AZ as a research grant for participation in multicenter clinical trials. J.E. is an employee of AZ. M.I. is a full-time employee of AZ. O.B. is a full-time employee of AZ and a shareholder. M.B.S. is a full-time employee of AZ. Received in original form July 28, 2005; accepted in final form December 15, 2005
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ABSTRACT
METHODS
2-agonists, improvements over placebo were observed in morning PEF (12.2 L/min, p = 0.017) and in evening PEF (11.1 L/min, p = 0.024); these improvements were more pronounced in GERD+/NOC+ subjects. Esomeprazole 40 mg twice daily was well tolerated and no safety concerns were noted. 
