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A Randomized, Placebo-Controlled Study To Evaluate the Role of Salmeterol in the In-Hospital Management of Asthma^*

^* From the Department of Medicine (Dr. Peters), Division of Pulmonary Diseases/Critical Care Medicine, The Department of Respiratory Care (Drs. Shelledy, Jones, and LeGrand, and Mr. Lawson), and The Department of Surgery (Dr. Davis), The University of Texas Health Science Center at San Antonio, TX.

Correspondence to: Jay I. Peters, MD, FCCP, Pulmonary Disease Section (111E), South Texas Veterans Health Care System, Audie L. Murphy Memorial Veterans Hospital Division, 7400 Merton Minter Blvd, San Antonio, TX 78284; e-mail: peters{at}uthscsa.edu

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Study objectives: To assess the safety and efficacy of salmeterol xinafoate as an adjunct to conventional therapy for the in-hospital management of acute asthma.

Design: A prospective, double-blind, randomized placebo-controlled trial.

Setting: Medical wards of a large university-based hospital.

Patients: Forty-three patients admitted for an acute exacerbation of asthma.

Interventions: Salmeterol (42 µg) or two puffs of placebo every 12 h in addition to standard therapy (short-acting ß-agonists, corticosteroids, and anticholinergic agents).

Results: No clinically adverse effects were seen with the addition of salmeterol to conventional therapy. After salmeterol, there was no difference in pulse, respiratory rate, oxygen saturation by pulse oximetry, severity of symptoms, or dyspnea score. Patients receiving salmeterol had greater FEV₁ percent improvements than the placebo group at 12, 24, 36, and 48 h. These findings were not statistically significant. By paired Student’s t tests, there were significant improvements in FEV₁ (p = 0.03) and FVC (p = 0.03) in the salmeterol group after 48 h of treatment with no comparable improvement in the placebo group. In a subgroup analysis of patients with an initial FEV₁ 1.5 L, the absolute FEV₁ percent improvement for salmeterol vs placebo was 51% vs 16% at 24 h and 54% vs 40% at 48 h. The relative FEV₁ percent improvement for salmeterol vs placebo was 17% vs 8% at 24 h and 18% vs 14% at 48 h.

Conclusion: The addition of salmeterol to conventional therapy is safe and may benefit hospitalized patients with asthma. Further studies are needed to clarify its role in the treatment of acute exacerbation of asthma.

Key Words: asthma • ß-agonists • salmeterol

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
In the hospital emergency department, the primary therapy used in the treatment of acute, severe asthma in adults is repeated administration of inhaled ß₂-agonist bronchodilators.^{1 2} Patients are generally given doses of a relatively short-acting (4 to 6 h) ß₂-agonist every 20 to 30 min for up to 1 h.^{1 2} Thereafter, the frequency of administration varies according to the severity of the patient’s symptoms and the occurrence of adverse medication side effects.^{1 2} In severe exacerbations, inhalation of usual doses of ß₂-agonists may be ineffective.³ Only large doses, frequently applied by nebulizer or metered-dose inhaler (MDI), will alleviate symptoms.^{4 5} The cause of this loss of effectiveness is unknown but may relate to reduction in deposition, desensitization, or a functional antagonism induced by inflammation.⁵

Despite aggressive therapy in the emergency department, approximately 20% of patients will require hospitalization for acute exacerbation of asthma.⁵ Patients with an incomplete response to treatment with either persistent wheezing or shortness of breath or an FEV₁ or peak expiratory flow rate (PEFR) between 50% and 70% of predicted should be considered for hospitalization.^{1 6} Patients with an FEV₁ < 50% after emergency department treatment should be considered for admission to an ICU.¹

The hospital management of adult patients with an acute exacerbation of asthma includes inhaled ß-agonists every 1 to 2 h, systemic corticosteroids, and oxygen.¹ Anticholinergic therapy may also be beneficial in the initial phase of therapy in severe exacerbations.⁷ As the hospitalized asthmatic patient improves, the frequency of inhaled ß₂-agonists is reduced to not more than every 3 to 4 h. Although it is tempting to institute long-acting ß-agonists to reduce the number of nebulizations with short-acting ß-agonists, Shaheen et al⁸ showed that up to 1.5% of patients given salmeterol developed paradoxical bronchospasm. That study demonstrated that the risk of paradoxical response increased with both age and severity of underlying airflow obstruction.

Salmeterol xinafoate is the first long-acting inhaled ß₂-agonist to be available in the United States.⁹ Salmeterol xinafoate is indicated for long-term, twice daily (morning and evening) administration in the maintenance of chronic persistent asthma and is currently not recommended for the treatment of acute asthma symptoms.^{9 10 11 12 13}

It is not clear, however, what role salmeterol should play after an acute exacerbation of chronic asthma as an adjunct to shorter-acting ß₂-agonist drugs. The addition of salmeterol, begun in the immediate post–emergency department phase of an asthma exacerbation, has the potential to reduce the need for more-frequent conventional ß₂-agonist administration and the associated costs.¹⁴ Salmeterol has been shown to offer better control of bronchospasm than shorter-acting bronchodilators in the maintenance treatment of chronic asthma.¹⁴ As an adjunct to conventional ß₂-agonist therapy in acute asthma, salmeterol may improve patient outcomes.

The purpose of this study was to assess the safety of salmeterol xinafoate in patients hospitalized for an acute asthma exacerbation as an adjunct to conventional therapy by comparing the frequency of reported side effects, heart rate, respirations, severity of symptoms, dyspnea index, pulse oximetry, and FEV₁ with salmeterol vs placebo treatment. The second objective of this study was to test the hypothesis that the addition of inhaled salmeterol xinafoate to conventional therapy of acute severe asthma would improve pulmonary function better, reduce the required doses of albuterol, and shorten the length of hospitalization.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
A double-blind, placebo-controlled, randomized study design was used to assess the safety and efficacy of adding aerosolized salmeterol to conventional therapy. All patients gave written informed consent, as approved by The University of Texas Health Science Center’s Institutional Review Board.

Patients admitted from the emergency department for acute exacerbation of asthma were eligible if they met the following criteria: (1) American Thoracic Society’s definition of asthma; (2) 18 to 60 years of age; and (3) able to perform a forced expiratory maneuver.

Patients were excluded from the study if they had the following: (1) concomitant life-threatening illness; (2) active pulmonary disease other than asthma; (3) ventilatory failure requiring admission to the ICU; (4) female patients known or suspected to be pregnant or nursing; (5) a history of hypersensitivity to salmeterol or any of its components; or (6) prior salmeterol use within 24 h of entering the study.

Randomization codes were computer generated and sealed in an opaque envelope. Envelopes were opened by the hospital pharmacist who dispensed identical canisters of either salmeterol xinafoate or placebo.

On entry to the hospital emergency department, patients were initially evaluated and treated by a protocol that included aerosolized albuterol 2.5 to 5.0 mg every 20 min for a maximum of three doses, then hourly aerosolized albuterol. Patients with PEFR or FEV₁ < 50% predicted were treated with ipratropium bromide 0.5 mg via nebulization or eight puffs via MDI with spacer (ACE holding chamber; DHO Healthcare; Syracuse, NY). Methylprednisolone (Solu-Medrol; Pharmacia & Upjohn; Kalamazoo, MI), 125 mg IV, was administered during the first hour of therapy. Patients were then evaluated by the academic hospital physician, and those showing an incomplete or poor response after 4 to 6 h of ß-agonist, oxygen, and corticosteroids were admitted to the hospital.

During the initial hospitalization phase, patients continued to receive aerosolized albuterol every 1 to 4 h, depending on severity of symptoms. All patients received conventional therapy based on the 1994 guidelines of the National Institutes of Health for the diagnosis and management of asthma. This included aerosolized albuterol 2.5 mg in 3 mL of normal saline solution via small volume nebulizer every 1 to 2 h, increasing to every 4 to 6 h, and as needed as the patient’s condition improved. Methylprednisolone 125 mg every 6 h, was given for 24 h followed by 40 mg every 6 h until the patient demonstrated significant improvement in PEFR. Oxygen therapy was titrated to maintain an oxygen saturation by pulse oximetry (SpO₂) 92%. Only two patients received theophylline (one salmeterol patient, one placebo patient).

After informed consent was obtained, 43 patients admitted to the hospital were randomized to either the treatment or control group. Treatment began the first day of admission (approximately 8 to 12 h after emergency department presentation) and continued until discharge from the hospital. Patients received either two puffs (42 µg) of salmeterol or placebo administered from an MDI with a spacer every 12 h by a coinvestigator or research associate. Before and after each administration of salmeterol or placebo, patients were assessed for heart rate, respirations, and breath sounds. Severity of asthma symptoms, dyspnea, and SpO₂ were also assessed after salmeterol or placebo administration. Asthma symptoms were assessed by a coinvestigator or research associate using the following scale: 0 (no symptoms), 1 (mild symptoms), 2 (moderate symptoms), 3 (moderately severe symptoms), 4 (severe symptoms), and 5 (very severe symptoms). Dyspnea was assessed using the Borg dyspnea scale.

Before and 5 min after each aerosol administration of salmeterol or placebo, a bedside pulmonary function screen was performed, and the patient’s FVC, FEV₁, forced expiratory flow at 25 to 75% of exhalation, and PEFR were recorded. After aerosol administration, the patients’ heart rate, respirations, and breath sounds were reassessed. FEV₁ percent improvement was then calculated as follows: the absolute FEV₁ percent improvement over baseline equals the FEV₁ measured minus the FEV₁ at the time of initial treatment divided by the initial FEV₁. Relative FEV₁ percent improvement adjusted for predicted values was also calculated according to the method of Tinkleman et al¹⁵ as follows: the relative FEV₁ percent improvement equals the FEV₁ measured minus the baseline FEV₁ divided by the predicted FEV₁ minus the baseline FEV₁. Many authors feel this is the most stringent method because it allows for calculation of the maximum possible improvement in FEV₁ for each subject.

All data were verified by the principal investigator or coinvestigator. Mean age, number of previous emergency department visits (last 12 months), number of previous hospitalizations (last 12 months), and FEV₁, FVC, PEFR, heart rate, respiratory rate, severity of symptoms scores, dyspnea scores, and SpO₂ for the salmeterol and placebo groups on entry to the study were compared using a two-tailed Student’s t test for independent samples.

The salmeterol and placebo groups were also compared for significant differences (p < 0.05) in pulse, respirations, severity of symptoms, dyspnea scores, or SpO₂ on initial entry to the study and at 12, 24, 36, and 48 h after salmeterol or placebo treatment using the Student’s t test for independent samples.

Differences in mean FEV₁, FVC, PEFR, and FEV₁ percent improvement between the placebo and salmeterol groups on initial treatment and at 12, 24, 36, and 48 h were also evaluated using the Student’s t test for independent samples. A paired Student’s t test was used to compare initial FEV₁, FVC, and FEV₁/FVC ratio at 12, 24, 36, and 48 h to determine whether there were significant improvements (p < 0.05) in either group on these measures. All data analysis was performed using computer software (CSS: Statistica; Statsoft; Tulsa, OK).

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Table 1 compares the salmeterol and placebo groups on entry into the study. There were no significant differences (p > 0.05) between the two groups in age, height, number of emergency department visits, hospital admissions, FVC, FEV₁, PEFR, heart rate, respiratory rate, severity of symptoms score, Borg dyspnea index, or SpO₂ values. The distribution of men and women in the two groups was similar. Twenty-two patients received anticholinergic therapy (11 in the salmeterol group and 11 in the placebo group). The initial mean FEV₁ (± SD) vs placebo was 1.51 ± 0.7 vs 1.69 ± 0.7 L; FVC was 2.26 ± 1.1 vs 2.48 ± 0.7 L.

There were no differences (p > 0.05) between the two groups on FVC, FEV₁, or PEFR. The salmeterol group tended to have a greater FEV₁ percent improvement than the placebo group; however, the difference was not statistically significant.

For those patients remaining in the hospital at least 48 h (n = 20), the FEV₁ for the salmeterol group (n = 11) increased from 1.39 ± 0.65 to 1.77 ± 0.78 L vs 1.46 ± 0.68 to 1.68 ± 0.64 L for the placebo group (n = 9). FVC increased from 1.91 ± 0.82 to 2.41 ± 0.99 L for the salmeterol group vs 2.29 ± 0.7 to 2.32 ± 0.84 L for the placebo group.

A paired Student’s t test for dependent samples was performed to compare the initial FEV₁ and FVC to that at 48 h of treatment for each group. The salmeterol group had a significant improvement in FEV₁ (p = 0.03) and FVC (p = 0.03) at 48 h when compared with the initial values. There was no such improvement in the placebo group for FEV₁ (p = 0.15) or FVC (p = 0.82).

Figure 1 compares absolute FEV₁ percent improvement and relative FEV₁ percent improvement for the two groups for patients hospitalized for 48 h. FEV₁ percent improvement for the salmeterol group was greater than placebo at each time.

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Percent improvement in absolute FEV1 over initial values (top) and relative percent improvements in FEV1 (bottom) after salmeterol (closed circles) and placebo (open circles) treatments for patients hospitalized 48 h. Values given as mean ± SE.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Salmeterol xinafoate, the first long-acting inhaled ß₂-agonist available in the United States, was developed to be used in conjunction with short-acting ß-agonists and approved only for the control of chronic persistent asthma. Studies of salmeterol in chronic asthmatics who were considered candidates for maintenance oral corticosteroid therapy demonstrated not only an improvement in peak flow rates and symptoms, but also a significant reduction in the need for short-acting ß-agonists.^{16 17} Long-acting ß-agonists are highly effective therapeutic agents for asthmatics who experience physiologic impairment or excessive symptoms despite the regular administration of inhaled corticosteroids.^{17 18 19} Although the addition of salmeterol to the therapeutic regimen is often used for mild to moderate outpatient exacerbations of asthma, there are no reports on the safety or efficacy of using salmeterol in the management of an acute exacerbation of asthma requiring hospitalization. This is especially problematic because many patients admitted to the hospital for an acute exacerbation of asthma are chronically maintained on salmeterol, and there are no data to guide the clinician on the risks and benefits of continuing salmeterol in this setting.

One of our primary objectives was to assess the safety of salmeterol as an adjunct to conventional therapy in the hospital setting. An investigator or coinvestigator was present during and after each dose of salmeterol or placebo to clinically assess the patient for potential side effects. No patient had any clinical adverse effects throughout the study. Although symptomatic, paradoxical reactions to ß-agonists are reported to be four times higher in patients with PEFR or FEV₁ < 50% predicted,⁸ the respiratory rate (22 ± 7 vs 22 ± 8 breaths/min) and pulse rate (109 ± 16 vs 109 ± 19 breaths/min) remained essentially the same before and after the first dose of salmeterol when the patients’ airflow obstruction was maximal (FEV₁, 1.5 ± 0.7 L). Similarly, there were no significant differences in patient’s Borg score, SpO₂, or the investigators’ assessment of severity of symptoms between the salmeterol and the placebo groups. Throughout the entire study, there were no significant differences between the salmeterol and placebo groups in any of these clinical measurements designed to detect paradoxical bronchospasm. Although the investigators remained at the patient’s bedside for 20 to 30 min, the measurements were recorded 5 min after salmeterol or placebo because prior reports have documented that paradoxical responses occur almost immediately and start to resolve spontaneously within 5 min to 3 h.^{8 20}

Our findings support prior reports documenting the safety profile of salmeterol.^{21 22} Because salmeterol was developed during the ß-agonist debate,^{23 24} it underwent perhaps the greatest scrutiny of any asthma therapy previously cleared for marketing by the US Food and Drug Administration.

In a study by Smyth et al,²⁵ asthmatic patients received 50, 100, and 200 µg of salmeterol on separate days followed 2 h later by inhaled albuterol in cumulative doses up to 3,600 µg. Despite an increasing FEV₁ with cumulative doses of salmeterol, the mean change in heart rate was only 1.6 ± 1.9 beats/min, and the change in serum potassium, -0.05 ± 0.08 mmol/L. After the addition of 3,600 µg albuterol, the change in heart rate was 14.4 ± 1.7 beats/min, and the serum potassium level was -0.48 ± 0.05 mmol/L.

In a double-blind, six-way crossover study by Kemp et al,²⁶ single doses of salmeterol (12.5, 25, 50, and 100 µg) were compared with albuterol aerosol (200 µg) or placebo with pulmonary function testing and 24-h Holter monitoring. Salmeterol at each dose showed a greater increase in FEV₁ above baseline than albuterol, but no significant difference in atrial or ventricular premature beats. Tremors and palpitations were the most frequent adverse effects and increased with increasing doses of salmeterol (15 to 20% with 100 µg). Neither tremor nor palpitation developed in any of our patients after a standard dose of salmeterol.

In our study, eight patients experienced a decline in FEV₁ of 20% after salmeterol or placebo. In all but one patient, this decline in FEV₁ occurred after the first or second dose of salmeterol (n = 5) or placebo (n = 2) and was an isolated finding in all patients in the salmeterol group. In the placebo group, one patient had an isolated decline in FEV₁ after the sixth dose, and one patient had declines after the second and third doses. Surprisingly, none of the patients exhibited symptoms with these declines in FEV₁, and no changes in the Borg dyspnea index, severity of asthma score, or desaturations were noted. One possible explanation relates to the fact that these patients were directed to perform six forced maneuvers within a 5-min period because we obtained three determinations of FEV₁ at baseline and three after salmeterol or placebo. Although deep inspiration and forced expiration²⁷ have been shown to increase bronchoconstriction, our literature review was unsuccessful in documenting the extent and duration of this effect in patients with an acute asthmatic exacerbation. Many of our patients demonstrated their best peak flow rates and forced expiratory volumes on their first effort with declining values on subsequent efforts; however, this explanation for the decline in FEV₁ is purely speculative. Inasmuch as there was no difference in the frequency of episodes between the salmeterol and the placebo groups (p = 0.24), another explanation could be a bronchoconstrictor response to either the propellant or the dispersant in the MDI. Both canisters contained the propellants trichloromonofluoromethane and dichlorodifluoromethane, with a lecithin dispersant. A study by Shaheen et al⁸ supports this concept. This multicenter, double-blind study evaluated 11,850 asthmatic patients to investigate and compare the incidence of MDI-associated bronchoconstriction. All patients received the same chlorofluorocarbons, but one group received an oleic acid dispersant (n = 3,960), one group received a lecithin dispersant (n = 3,942), and one group received salmeterol xinafoate (25 µg) with the lecithin dispersant (n = 3,948). Overall, 1.5% of patients demonstrated bronchoconstriction (fall in peak flow of 20% at 5 min), but there was a significantly lower incidence of bronchoconstriction with the salmeterol-MDI group than either of the other two preparations. Although the median time to show a mean FEV₁ improvement of 15% has been reported to be 14 min with salmeterol,¹⁶ the authors thought that the bronchodilator activation of salmeterol was sufficient to counteract the bronchoconstricting effect produced by the chemical irritants. Tattersfield’s review²⁸ on long-acting ß-receptor agonists concurs with this concept and points out that the bronchoconstrictor effect is most certainly caused by the other constituents in the MDI inasmuch as bronchoconstriction has not been reported with salmeterol by dry-powder inhaler, but does occur with the placebo-MDI.²⁹

The second objective of this study was to test the hypothesis that salmeterol would be either synergistic or additive to standard albuterol therapy and improve a patient’s pulmonary function, reduce the required doses of albuterol, and shorten the length of hospitalization. Although more potent than albuterol on human airways, salmeterol is only a partial agonist, achieving approximately 70% of maximum effect seen with albuterol.³⁰ This raises the theoretical concern that a partial agonist (salmeterol) could occupy receptors and decrease the effectiveness of a full agonist (albuterol), especially during a severe exacerbation of asthma.²⁵ Our data (Fig 1) clearly show this theoretical concern to be invalid because the FEV₁ percent improvement compared with placebo at each time during the study was higher in the salmeterol group when compared with the placebo group.

Although the pulmonary function data for the two groups were not significantly different for FVC, FEV₁, or PEFR by Student’s t test analysis, the salmeterol group tended to have a greater FEV₁ percent improvement than the placebo group. The design of this study was established to assure maximum safety for the patients, and measurements of pulmonary functions were obtained 12 h after each dose of salmeterol or placebo to assure an investigator was present during each dosing interval. In chronic stable asthma, maximum bronchodilation with salmeterol occurs 2 to 4 h after administration, with 90% of the maximum effect seen within 1 h.^{31 32} Pulmonary function studies may have shown a significant difference had we measured expiratory flows 4 to 6 h after administration. Also, bronchodilators may demonstrate different pharmacodynamic and pharmacokinetic characteristics during an acute exacerbation of asthma. Contrary to studies in stable asthma, Bryant and Rogers⁷ detected a significant response to ipratropium, another slow-onset, long-acting bronchodilator, within 1 min and a mean time to reach the peak effect of FEV₁ within 17 min in patients with acute asthma. The optimal dose and dosing interval for salmeterol in patients with acute asthma are not known.

When a paired Student’s t test for dependent samples was performed to compare the initial FVC and FEV₁ with that at 48 h of treatment, the salmeterol group demonstrated a significant improvement in FVC (p = 0.03) and FEV₁ (p = 0.03). There was no such improvement in the placebo group for FEV₁ (p = 0.15) or FVC (p = 0.82). This difference could be explained in two ways. The addition of salmeterol to conventional therapy had some beneficial effect, albeit too small to be detected by a direct comparison between groups. Supporting this explanation is the large variation in FEV₁ percent improvement in both groups and the relatively small sample size. A second explanation could be that the differences in the baseline FVC and FEV₁ were too great despite the homogeneity of the group by statistical analysis (Table 1) . To investigate this possibility, we performed a subgroup analysis of all patients with an FEV₁ at baseline of 1.5 L. This value was chosen because it represented the mean FEV₁ for the salmeterol group. The mean FEV₁ percent improvements for the salmeterol vs placebo groups were the following: 51 vs 16% at 24 h; 64 vs 34% at 36 h; and 53 vs 40% at 48 h. Even though these changes appear large, the p value at 24 h, the time of maximal difference, was only 0.19, secondary to the small number of subjects (eight per group) analyzed in each group.

One must always be cautious of subgroup analysis and use such information as a guide for larger studies designed to establish the efficacy of salmeterol as an adjunct to conventional therapy. Our post hoc power analysis revealed at least 50 patients per group would be necessary to prove the benefit of salmeterol in the treatment of acute asthmatic exacerbations.

In conclusion, we believe this study helps clarify the risk of continuing salmeterol in the hospital setting of an acute exacerbation of asthma. No clinical adverse effects were noted in any patient in the postemergency department treatment with salmeterol. We believe that the addition of salmeterol to conventional therapy may benefit hospitalized patients with asthmatic exacerbations and suggest that future studies are warranted to evaluate the role of salmeterol in this clinical setting.

	Footnotes

 
Abbreviations: MDI = metered-dose inhaler; PEFR = peak expiratory flow rate; SpO₂ = oxygen saturation by pulse oximetry

Funded by a research grant from Glaxo Wellcome. No author has any financial interest in this company or their products.

Received for publication June 1, 1999. Accepted for publication April 3, 2000.

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