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Comparative study of extended release albuterol sulfate and long-acting inhaled salmeterol xinafoate in the treatment of nocturnal asthma
Comparative study of extended release albuterol sulfate and long-acting inhaled salmeterol xinafoate in the treatment of nocturnal asthma Richard J Martin, MD*; Monica Kraft, MD*; Wilfred N Beaucher, MD†; Frederic Kiechel, MD‡; James L Sublett, MD¶; Nicole LaVallee, MA§; and Jonathan Shilstone, PhD§
Background: Nocturnal worsening of asthma is a common problem in asthma and is associated with increased morbidity and mortality. Long acting beta-2 agonists are considered long-term symptom control medications, especially for nocturnal symptoms. Objective: To compare efficacy of an extended release oral beta-2 agonist, albuterol sulfate (Volmax威), to a long-acting inhaled agent, salmeterol (Serevent威) in the treatment of nocturnal asthma. Methods: This was a multicenter double-blind, double-dummy, randomized, crossover design with a 1-week baseline period and two 3-week treatment periods separated by a 7 to 9-day washout. An optional 2-week, open-label phase was conducted to evaluate patient preference. Results: A total of 46 patients were included in the efficacy analysis. For the primary outcome variable of morning peak expiratory flow, there were similar and significant improvements over the 3-week treatment period for both medications compared with baseline (P ⬍ .001). Similar improvements were seen in the overnight change in PEF values (P ⬍ .001). The morning and overnight changes in FEV1 were not significantly different between treatment arms (P ⬎ .05). There were significant improvements in both treatment periods in regard to the percentage of nights without awakenings (baseline 53.6 ⫾ 5.3%), extended release albuterol 83.3 ⫾ 3.0% (P ⬍ .001), and salmeterol 88.8 ⫾ 2.4%. The percentage of patients who had no awakenings during treatment did not differ significantly for the two medications. Both treatments also resulted in a decrease in the use of rescue albuterol (extended release 2.66 ⫾ 0.35 puffs per day, salmeterol 1.85 ⫾ 0.29) from baseline (4.57 ⫾ 0.41, P ⬍ .001). There was a significant difference between groups (P ⫽ .001). The reasons why patients preferred one medication over the other varied. Conclusion: Both extended release albuterol tablets and inhaled salmeterol resulted in similar bronchodilation and good control of nocturnal asthma symptoms. Ann Allergy Asthma Immunol 1999;83:121–126.
INTRODUCTION Long acting inhaled beta-2 adrenergic agonists are used extensively in the * National Jewish Medical and Research Center, Denver, Colorado. † Certified Allergy Consultants, Chelmsford, Massachusetts. ‡ Allergy, Asthma and Immunology Associates, Lincoln, Nebraska. ¶ Asthma and Allergy Associates, Louisville, Kentucky. § Biostatistics and Clinical Departments, Muro Pharmaceutical, Inc., Tewksbury, Massachusetts.
VOLUME 83, AUGUST, 1999
treatment of reversible airway disease such as asthma.1–3 Extended release oral albuterol has also been shown to be efficacious in the treatment of asthma.4 – 6 In particular, the nocturnal worsening of asthma appears to be well suited for these types of agents
Funded by a grant from Muro Pharmaceutical, Inc. Received for publication September 22, 1998. Accepted for publication in revised form March 19, 1999.
that have 12-hours of therapeutic effectiveness.7,8 The National Heart Lung Blood Institute (NHLBI) guidelines for management of asthma place long acting beta-agonists in the longterm symptom control category, with special emphasis on their use in nocturnal asthma.9 Since the nocturnal worsening of asthma is a common problem,10 and can be associated with morbidity12,13 and mortality,12,14 it is important to evaluate different therapies in regard to therapeutic benefits. This study compared the twice daily use of inhaled salmeterol to oral extended release albuterol in the treatment of nocturnal asthma. MATERIALS AND METHODS Subjects Asthma was defined according to NHLBI criteria9 and study enrollment included: age range 18 to 65 years, FEV1 ⬎ 50% predicted with a 12% improvement following inhaled albuterol, stable daily asthma regimen for ⱖ30 days, no respiratory or systemic infection during the 4 weeks prior to enrollment, no seasonal allergies during study period, and no systemic disease. The following medications were excluded from use: systemic corticosteroids, beta-2 agonists other than rescue albuterol, ipratropium bromide, once daily sustained release theophylline, sleep aids, and investigational products. Asthma therapy other than noted above (including the use of inhaled steroids) was allowed but was maintained constant throughout the study. Other significant medical problems were also exclusionary. The definition used for nocturnal asthma in this study was a ⱖ15% decrease in
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morning or nighttime awakening peak flow over evening peak flow on at least 3 out of 7 nights immediately prior to randomization in a diurnally active individual. The protocol was approved by an Institutional Review Board (IRB), and all patients signed the IRB approved informed consent prior to enrollment. Study Design This was a 4-center study using a double-blind, double-dummy, randomized, crossover design comparing albuterol sulfate extended-release tablets (Volmax威) to salmeterol xinafoate (Serevent威) inhalation aerosol. Patients on albuterol tablets were to take 4 mg in the morning (between 6 to 8 AM) and 8 mg in the evening (between 6 to 8 PM). This dosing schedule was based on the chronotherapeutic approach of Postma and colleagues.6 Salmeterol was to be delivered via a metered dose inhaler at 2 actuations (42 g) twice daily (between 6 to 8 AM and 6 to 8 PM). The albuterol tablets were blinded in a gelatin capsule with lactose filler while salmeterol was blinded by an inhaler masking device. The albuterol placebo tablet was composed of a gelatin capsule with lactose, while the salmeterol placebo was composed of sorbitan trioleate, Freon 11 and 12. Patients were trained in proper inhaler technique prior to enrollment. After a 1-week baseline period to collect screening data and to establish overnight peak flow variables, eligible patients were randomized to either treatment sequence. The two 3-week treatment periods were separated by a 7 to 9-day washout period. During the study, patients maintained a daily diary of their nighttime asthma symptoms (coughing, shortness of breath, and wheezing), and were instructed to perform PEF and FEV1 measurements each morning (7 AM) and evening (7 PM). PEF measurements were made during the baseline period with the Mini-Wright peak flow meter, but following randomization PEF and FEV1 measurements were made with the AirWatchTM Airway Monitoring System. The best of three
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efforts was used for analysis. At each of the study visits, vital signs (including resting pulse rate, blood pressure, and respiratory rate) were measured, and adverse events (recorded by the patients in their diaries during the treatment phase), concomitant medication use, patient diaries, and medication compliance were reviewed. There was an optional 2-week, openlabel randomized crossover phase to evaluate patient preference for the two treatment medications. This consisted of two 1-week treatment periods separated by a 2-day washout. Statistical Methods The primary efficacy variables were morning peak flow and FEV1 measurements. The AM to PM differences of these measurements were also evaluated as well as nocturnal symptoms, percent of nights without awakenings, and average number of puffs of rescue albuterol per day. Symptoms were graded using the following four point scale: 0 ⫽ none, 1 ⫽ mild, 2 ⫽ moderate, and 3 ⫽ severe. Safety analyses were performed for heart rate, respiratory rate, blood pressure, and adverse events. Patients who completed at least 1 week of each treatment and were not replaced due to protocol violations were included in the efficacy analyses. All patients who took study medication were included in the safety analyses. Although comparisons to baseline are problematic in a crossover study beyond the first treatment period in the absence of a placebo arm, improvements in efficacy parameters were evaluated from pretreatment to posttreatment. Treatment comparisons to baseline were first performed for each treatment period separately using paired t-tests. If the results from period 1 and period 2 were homogenous, then the data from the two periods were combined and paired t-tests between baseline and each treatment were performed. These results are presented as mean ⫾ SEM. For comparisons of the extended release albuterol tablets and salmeterol, analysis of variance models appropriate for two-period crossover designs
were used. If carryover (sequence) and treatment-by-site interaction tests were not significant, treatment comparisons were made based on a model with effects for treatment, period, site and patient nested within site and declared statistically significant at the .05 level of significance using two-tailed tests. From these analyses, treatment means were adjusted for the effects in the model, and standard errors of the adjusted means were obtained. The adjusted mean takes into account factors that may influence treatment outcome other than the medication. These results are presented as adjusted mean ⫾ SEM. RESULTS Subjects Of the 56 patients enrolled, 47 were patients initially randomized to treatment sequences, and nine were replacement patients. The efficacy analyses excluded the nine patients who were replaced, as well as one patient who was lost to follow-up after the first treatment period but was not replaced; therefore, 46 patients were evaluated for efficacy. All 56 patients who received study drug were evaluated for safety. Forty-four patients completed all double-blind visits and 31 patients completed the voluntary open-label visits. Five patients were dropped from the study due to adverse events during the double-blind portion, and two patients were discontinued due to adverse events during the openlabel portion. Six of these patients withdrew due to asthma exacerbations and one due to diarrhea. Of the six patients with an asthma exacerbation, one occurred during the first treatment period and was excluded, while 3/6 experienced an asthma exacerbation during the second treatment period and were discontinued from the study. These four patients were excluded from the efficacy analysis. Two of the six patients had their exacerbations during the open-label phase of the study. None of these events were considered by the investigators as related to study drug.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Patient demographic information for the 46 patients evaluated for efficacy outcome is presented in Table 1. Thirty-four (61%) of the 56 patients enrolled in the study were taking inhaled steroids and 15 (27%) had a history of tobacco use. The FEV1 % predicted was 67.4 ⫾ 1.8% with a range between 50% to 98%. The group as a whole fell between 60% to 80% and thus are classified as moderate persistent asthmatics. Efficacy Measurements The weekly morning and overnight percent fall in PEF values at baseline and during the 3 weeks of treatment for each medication are shown in Figures 1 and 2, respectively, and Table 2. Both treatments produced significant improvements (P ⬍ .001) from baseline for morning PEF and overnight percent fall in PEF over the 3-week treatment periods, with no significant differences found between the medications. The morning FEV1 values were similar for each treatment (Fig 3, Table 2) as were the overnight percent decreases in FEV1 (Fig 4, Table 2). Analyses were performed to address whether the as needed albuterol inhalation use affected PEF and FEV1. Measurements of PEF and FEV1 made within 4 hours following rescue albuterol use were thus excluded from the efficacy analyses (approximately 20% of morning readings and 23% of evening readings). The results were similar to those using all measurements. Nocturnal symptoms at baseline were very mild with means of 0.45 ⫾ 0.09 for cough, 0.97 ⫾ 0.11 for shortness of breath, and 0.86 ⫾ 0.11 for wheezing. The composite symptom mean at baseline was 2.29 ⫾ 0.27 compared with the posttreatment means of 1.20 ⫾ 0.18 for the extended release albuterol tablets (P ⬍ .001) and 0.88 ⫾ 0.16 for salmeterol aerosol
Figure 1. Baseline and average weekly morning peak expiratory flow values are demonstrated. Means at weeks 1, 2, and 3 were adjusted for period, site, and patient. Treatment PEF significantly improved compared with baseline (P ⬍ .001). Shaded box ⫽ baseline. Enclosed box ⫽ extended release oral beta agonist. Open box ⫽ long acting inhaled agent.
Figure 2. Baseline and average weekly overnight percent change in peak flow values are shown. Means at weeks 1, 2, and 3 were adjusted for period, site, and patient. The overnight fall in PEF values significantly improved on each treatment arm compared with baseline (P ⬍ .001). Shaded box ⫽ baseline. Enclosed box ⫽ extended release oral beta agonist. Open box ⫽ long acting inhaled agent.
(P ⬍ .001). There was a significant difference between the adjusted mean for extended release albuterol tablets, 1.43 ⫾ 0.08, and the adjusted mean for salmeterol, 1.13 ⫾ 0.08 (P ⫽ .005). The mean percentage of nights without awakenings during the baseline period was 53.6 ⫾ 5.3%. This was significantly improved during treatment
with extended release albuterol tablets to 83.3 ⫾ 3.0% (P ⬍ .001) and with salmeterol to 88.8 ⫾ 2.4% (P ⬍ .001). A comparison of the adjusted treatment means (Table 2) for the percentage of nights without awakenings favored salmeterol (84.6 ⫾ 1.7 versus 79.4 ⫾ 1.7, P ⫽ .021), however, the percentage of patients who had no
Table 1. Baseline Patient Characterization Number
Male/Female
Age
FEV1 % Pred
24/22
35.1 ⫾ 1.4
67.4 ⫾ 1.8
46
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AM
PEF
352.2 ⫾ 13.4
% Overnight Fall in PEF 14.9 ⫾ 1.1
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Table 2. Outcome Measures
PEFR (L/min) FEV1 (L) % Overnight change PEF % Overnight change FEV1 Rescue albuterol use (puffs/day) % of no nighttime awakenings AM AM
Volmax
Serevent
P
414 2.71 ⫺7.2 ⫺4.0 2.98 79.4
420 2.70 ⫺7.9 ⫺5.1 2.20 84.6
NS NS NS NS .001 .021
Data presented as adjusted means (see text).
when treated with extended release albuterol tablets and 75.9% of the patients when treated with salmeterol (Table 4). Many of the patient-listed adverse effects are not related to study mediations. There were no significant group differences.
Figure 3. Average weekly morning FEV1 values are shown. Means at weeks 1, 2, and 3 were adjusted for period, site and patient. The FEV1 values were similar between albuterol tablets and salmeterol inhaler. Enclosed box ⫽ extended release oral beta agonist. Open box ⫽ long acting inhaled agent.
Figure 4. Average weekly overnight change in FEV1 values are shown. Means at weeks 1, 2, and 3 were adjusted for period, site, and patient. The overnight fall in FEV1 was similar in each treatment arm. Enclosed box ⫽ extended release oral beta agonist. Open box ⫽ long acting inhaled agent.
awakenings during treatment did not differ significantly for the two medications. During baseline, the use of rescue albuterol was 4.57 ⫾ 0.41 puffs/day. This decreased to 2.66 ⫾ 0.35 puffs/ day with the extended release albuterol tablets (P ⬍ .001) and 1.85 ⫾ 0.29 puffs/day with salmeterol (P ⬍ .001). There was a significant difference between the adjusted means for the two
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treatments, 2.98 ⫾ 0.18 puffs/day for albuterol tablets and 2.20 ⫾ 0.18 puffs/ day for salmeterol, P ⫽ .001. Safety Measurements Vital sign measurements taken at baseline and after each treatment are summarized in Table 3. No clinically important differences were observed. Listed adverse effects during treatment occurred in 78.0% of the patients
Open Label Preference Thirty-three patients chose to participate in the open label portion of the study. One of these individuals only completed one arm and thus was not included in the analysis. Twelve of the patients preferred the extended release albuterol tablets, while 18 preferred salmeterol aerosol. Table 5 shows the top 3 reasons patients preferred a given medication. DISCUSSION For symptom relief in the treatment of asthma, beta-2 adrenergic agents are recommended.9 Recent publications have interestingly focused on the use of long acting inhaled beta-agonists in combination with “low-dose” inhaled steroids as being more efficacious than using “high-dose” inhaled steroids15–17 in the treatment of asthma. Since the nocturnal worsening of asthma is a common feature of asthma and is related to sleep disturbance, daytime cognitive function abnormalities and mortality,10 –14 beta-agonists with 12hour effectiveness would be of importance in the therapeutic regimen. Problems that have been reported with inhaled medications include inappropriate inhaler technique in approximately 50% of patients18 and compliance issues in the majority of patients.19 This study was undertaken to determine whether long acting inhaled and oral beta-2 adrenergic ago-
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Table 3. Vital Sign Measurements (Mean ⫾ SEM)
Heart rate Respiratory rate Systolic BP Diastolic BP
Baseline (n ⴝ 56)
Extended Release Albuterol Tablets (n ⴝ 50)
Salmeterol Aerosol (n ⴝ 53)
74.1 ⫾ 1.4 16.2 ⫾ 0.3 115.1 ⫾ 1.6 74.7 ⫾ 1.2
74.5 ⫾ 1.3 16.6 ⫾ 0.3 117.6 ⫾ 1.7 73.5 ⫾ 1.4
76.0 ⫾ 1.4 16.1 ⫾ 0.3 116.3 ⫾ 1.4 74.8 ⫾ 1.4
Table 4. Patient Described Adverse Effects Number (%) of Patients
No adverse event At least one adverse event Headache Pharyngitis Rhinitis Tremor Asthma Dysmenorrhea Pain Dyspepsia
nists would give comparable efficacy outcomes in patients with nocturnal asthma. The choice of how these medications were dosed was based on prior studies involving patients with nocturnal asthma. Fitzgerald and colleagues4 demonstrated that either one or two actuations of salmeterol twice daily improved the overnight fall in lung function. Since two actuations of this formulation given twice daily is the usual dosing regimen, this was used in our study. For an oral beta-agonist, terbutaline, Postma and colleagues6 showed that an unequal dosing schedule of 5 mg in the morning and 10 mg in the evening was a better pharmacologic approach to treating the nocturnal worsening of asthma. We therefore ad-
Volmax (n ⴝ 46)
Serevent (n ⴝ 46)
11 (22.0) 39 (78.0) 28 (56.0) 9 (18.0) 8 (16.0) 5 (10.0) 4 (8.0) 4 (8.0) 3 (6.0) 3 (6.0)
13 (24.1) 41 (75.9) 25 (46.3) 8 (14.8) 9 (16.7) 0 (0.0) 2 (3.7) 3 (5.6) 3 (5.6) 1 (1.9)
ministered the oral beta-agonist in our study at 4 mg in the morning and 8 mg in the evening. Morning and overnight falls in PEF and FEV1 were similar between the oral and inhaled beta-agonists. In comparison to baseline values of PEF, both agents showed significant improvement for these outcome variables. Although FEV1 values could not be compared to baseline (data not available), the overnight falls in both treatment groups of approximately 5% are within the normal range of circadian alteration for lung function.20 Overall nocturnal symptoms do not always reflect the severity of lung function alterations and this was seen in our study with minimal symptom complaints during the baseline week
with a score of less than 1, ie, mild. During the baseline week, 54% of nights were without nocturnal awakenings due to asthma and it was significantly improved to 83% and 89% on oral and inhaled beta-agonist, respectively. The number of as needed short acting beta-agonist treatments decreased from baseline for both drugs. These differences from baseline were statistically significant for each treatment and greater for salmeterol. For the safety measurements of heart rate, respiratory rate, and blood pressure, there were no significant changes between treatment arms or from baseline. No significant differences were found in regard to side effects, but the oral
Table 5. Main Reasons for Drug Preference During Open Label Phase Albuterol Tablets (12) Greater symptom relief (5)* Longer duration of effect (5) More convenient (5)
Salmeterol Aerosol (18) Fewer side effects (10) Greater symptom relief (8) Less need for prn† medication (6)
*( ) ⫽ number of patients that chose response. † prn ⫽ as needed inhaled beta-agonist. Each patient could select more than one response.
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beta-agonist did have five individuals report the presence of tremor. The open label preference phase of the study showed that more patients preferred the inhaled beta-agonist (18 versus 12). Of interest were the varied reasons for preference of one agent or the other. The top 3 choices for the inhaled beta-agonist were: fewer side effects, greater symptom relief, and less need for as needed inhaled betaagonist. For the oral medication, the top 3 choices were selected with equal frequency and included greater symptom relief, longer duration of effect, and greater convenience. In the era of emphasis on medical economics, it is of interest to compare costs of medication when outcome variables are similar. The cost of inhaled salmeterol at 2 puffs twice a day is $1.84 per day21 or $55.20 per month. For the oral albuterol extended release tablets used in this study at the 4 mg AM/8 mg PM regimen, the cost is essentially identical to salmeterol at $1.86/ day or $55.80 per month.21 In summary, both inhaled salmeterol (Serevent威) and oral extended release albuterol tablets (Volmax威) improved the nocturnal worsening of asthma to similar degrees and without major adverse effects. Costs between the regimens used in this study are equivalent. Why a patient prefers one medication over the other varied greatly; thus, both extended release albuterol tablets and inhaled salmeterol are beneficial in the treatment of nocturnal asthma. ACKNOWLEDGMENTS The authors wish to thank Stacey Wolff for her help in the manuscript preparation. The following aided in the study design development and manuscript review: Elliot F Ellis, MD; John G Karafilidis, RPh; Heidy Russell, PhD; and Miganush Stepanians, PhD. REFERENCES 1. Pearlman DS, Chervinsky P, LaForce C, et al. A comparison of salmeterol
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2.
3.
4.
5.
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8.
9.
10. 11.
with albuterol in the treatment of mildto-moderate asthma. N Engl J Med 1992;327:1420 –1425. Becker AB, Simons FE. Formoterol, a new long-acting selective beta2-adrenergic receptor agonist: double-blind comparison with salbutamol and placebo in children with asthma. J Allergy Clin Immunol 1989;84:891– 895. D’Alonzo GE, Nathan RA, Henochowicz S, et al. Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma. JAMA 1994;271:1412–1416. Pierson WE, LaForce CF, Bell TD, et al. Long-term, double-blind comparison of controlled-release albuterol versus sustained-release theophylline in adolescents and adults with asthma. J Allergy Clin Immunol 1990;85: 618 – 626. Grossman J, Morris RJ, White KD, Cocchetto DM. Improved stability in oral delivery of albuterol provides less variability in bronchodilation in adults with asthma. Ann Allergy 1991;66: 324 –327. Postma DS, Koeter GH, v.d. Mark TW, et al. The effects of oral slowrelease terbutaline on the circadian variation in spirometry and arterial blood gas levels in patients with chronic airflow obstruction. Chest 1985;87:653– 657. Fitzpatrick MF, Mackay T, Driver H, Douglas NJ. Salmeterol in nocturnal asthma: a double blind, placebo controlled trial of a long acting inhaled 2 agonist. Br Med J 1990;301: 1365–1368. Yates DH, Sussman HS, Shaw MJ, et al. Regular formoterol treatment in mild asthma. Effect on bronchial responsiveness during and after treatment. Am J Respir Crit Care Med 1995;152:1170 –1174. NHLBI-NIH. Expert panel report 2. National asthma education and prevention program. Guidelines for the diagnosis and management of asthma. 1997;97– 4051. Turner-Warwick M. Epidemiology of nocturnal asthma. Am J Med 1988; 85(suppl 1B):6 – 8. Dethlefsen U, Repgas R. Ein neues therapieprinzip bei nachtlichen asthma. Klin Med 1985;80:44 – 47.
12. Hetzel MR, Clark TJH, Branthwaite MA. Asthma: analysis of sudden deaths and ventilatory arrest in hospital. Br Med J 1977;1:808 – 811. 13. Weersink EJM, vanZomeren EH, Koeter CH, Postma DS. Treatment of nocturnal airway obstruction improves daytime cognitive performance in asthmatics. Am J Respir Crit Care Med 1997;156:1144 –1150. 14. Robertson CE, Rubinfeld AR, Bowej G. Deaths from asthma in Victoria: a 12-month study. Med J Australia 1990; 152:511–517. 15. Greening AP, Wind P, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344: 219 –224. 16. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroid. Am J Respir Crit Care Med 1996;153: 1481–1488. 17. Pauwels RA, Lofdahl C-G, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337: 1405–1411. 18. Shim C, Williams MH, Jr. The adequacy of inhalation of aerosol from canister nebulizers. Am J Med 1980; 69:891– 894. 19. Spector SL, Kinsman R, Mawhinney H, et al. Compliance of patients with asthma with an experimental aerosolized medication: implications for controlled clinical trials. Allergy Clin Immunol 1986;77:65–70. 20. Hetzel MR, Clark TJH. Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate. Thorax 1980;35:732–738. 21. Medi-Span. Hospital Formulary Pricing Guide. Indianapolis: Medi-Span, Inc, 1997.
Request for reprints should be addressed to: Richard J Martin, MD National Jewish Medical & Research Center 1400 Jackson St Denver, CO 80206
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Background: Nocturnal worsening of asthma is a common problem in asthma and is associated with increased morbidity and mortality. Long acting beta-2 agonists are considered long-term symptom control medications, especially for nocturnal symptoms. Objective: To compare efficacy of an extended release oral beta-2 agonist, albuterol sulfate (Volmax威), to a long-acting inhaled agent, salmeterol (Serevent威) in the treatment of nocturnal asthma. Methods: This was a multicenter double-blind, double-dummy, randomized, crossover design with a 1-week baseline period and two 3-week treatment periods separated by a 7 to 9-day washout. An optional 2-week, open-label phase was conducted to evaluate patient preference. Results: A total of 46 patients were included in the efficacy analysis. For the primary outcome variable of morning peak expiratory flow, there were similar and significant improvements over the 3-week treatment period for both medications compared with baseline (P ⬍ .001). Similar improvements were seen in the overnight change in PEF values (P ⬍ .001). The morning and overnight changes in FEV1 were not significantly different between treatment arms (P ⬎ .05). There were significant improvements in both treatment periods in regard to the percentage of nights without awakenings (baseline 53.6 ⫾ 5.3%), extended release albuterol 83.3 ⫾ 3.0% (P ⬍ .001), and salmeterol 88.8 ⫾ 2.4%. The percentage of patients who had no awakenings during treatment did not differ significantly for the two medications. Both treatments also resulted in a decrease in the use of rescue albuterol (extended release 2.66 ⫾ 0.35 puffs per day, salmeterol 1.85 ⫾ 0.29) from baseline (4.57 ⫾ 0.41, P ⬍ .001). There was a significant difference between groups (P ⫽ .001). The reasons why patients preferred one medication over the other varied. Conclusion: Both extended release albuterol tablets and inhaled salmeterol resulted in similar bronchodilation and good control of nocturnal asthma symptoms. Ann Allergy Asthma Immunol 1999;83:121–126.
INTRODUCTION Long acting inhaled beta-2 adrenergic agonists are used extensively in the * National Jewish Medical and Research Center, Denver, Colorado. † Certified Allergy Consultants, Chelmsford, Massachusetts. ‡ Allergy, Asthma and Immunology Associates, Lincoln, Nebraska. ¶ Asthma and Allergy Associates, Louisville, Kentucky. § Biostatistics and Clinical Departments, Muro Pharmaceutical, Inc., Tewksbury, Massachusetts.
VOLUME 83, AUGUST, 1999
treatment of reversible airway disease such as asthma.1–3 Extended release oral albuterol has also been shown to be efficacious in the treatment of asthma.4 – 6 In particular, the nocturnal worsening of asthma appears to be well suited for these types of agents
Funded by a grant from Muro Pharmaceutical, Inc. Received for publication September 22, 1998. Accepted for publication in revised form March 19, 1999.
that have 12-hours of therapeutic effectiveness.7,8 The National Heart Lung Blood Institute (NHLBI) guidelines for management of asthma place long acting beta-agonists in the longterm symptom control category, with special emphasis on their use in nocturnal asthma.9 Since the nocturnal worsening of asthma is a common problem,10 and can be associated with morbidity12,13 and mortality,12,14 it is important to evaluate different therapies in regard to therapeutic benefits. This study compared the twice daily use of inhaled salmeterol to oral extended release albuterol in the treatment of nocturnal asthma. MATERIALS AND METHODS Subjects Asthma was defined according to NHLBI criteria9 and study enrollment included: age range 18 to 65 years, FEV1 ⬎ 50% predicted with a 12% improvement following inhaled albuterol, stable daily asthma regimen for ⱖ30 days, no respiratory or systemic infection during the 4 weeks prior to enrollment, no seasonal allergies during study period, and no systemic disease. The following medications were excluded from use: systemic corticosteroids, beta-2 agonists other than rescue albuterol, ipratropium bromide, once daily sustained release theophylline, sleep aids, and investigational products. Asthma therapy other than noted above (including the use of inhaled steroids) was allowed but was maintained constant throughout the study. Other significant medical problems were also exclusionary. The definition used for nocturnal asthma in this study was a ⱖ15% decrease in
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morning or nighttime awakening peak flow over evening peak flow on at least 3 out of 7 nights immediately prior to randomization in a diurnally active individual. The protocol was approved by an Institutional Review Board (IRB), and all patients signed the IRB approved informed consent prior to enrollment. Study Design This was a 4-center study using a double-blind, double-dummy, randomized, crossover design comparing albuterol sulfate extended-release tablets (Volmax威) to salmeterol xinafoate (Serevent威) inhalation aerosol. Patients on albuterol tablets were to take 4 mg in the morning (between 6 to 8 AM) and 8 mg in the evening (between 6 to 8 PM). This dosing schedule was based on the chronotherapeutic approach of Postma and colleagues.6 Salmeterol was to be delivered via a metered dose inhaler at 2 actuations (42 g) twice daily (between 6 to 8 AM and 6 to 8 PM). The albuterol tablets were blinded in a gelatin capsule with lactose filler while salmeterol was blinded by an inhaler masking device. The albuterol placebo tablet was composed of a gelatin capsule with lactose, while the salmeterol placebo was composed of sorbitan trioleate, Freon 11 and 12. Patients were trained in proper inhaler technique prior to enrollment. After a 1-week baseline period to collect screening data and to establish overnight peak flow variables, eligible patients were randomized to either treatment sequence. The two 3-week treatment periods were separated by a 7 to 9-day washout period. During the study, patients maintained a daily diary of their nighttime asthma symptoms (coughing, shortness of breath, and wheezing), and were instructed to perform PEF and FEV1 measurements each morning (7 AM) and evening (7 PM). PEF measurements were made during the baseline period with the Mini-Wright peak flow meter, but following randomization PEF and FEV1 measurements were made with the AirWatchTM Airway Monitoring System. The best of three
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efforts was used for analysis. At each of the study visits, vital signs (including resting pulse rate, blood pressure, and respiratory rate) were measured, and adverse events (recorded by the patients in their diaries during the treatment phase), concomitant medication use, patient diaries, and medication compliance were reviewed. There was an optional 2-week, openlabel randomized crossover phase to evaluate patient preference for the two treatment medications. This consisted of two 1-week treatment periods separated by a 2-day washout. Statistical Methods The primary efficacy variables were morning peak flow and FEV1 measurements. The AM to PM differences of these measurements were also evaluated as well as nocturnal symptoms, percent of nights without awakenings, and average number of puffs of rescue albuterol per day. Symptoms were graded using the following four point scale: 0 ⫽ none, 1 ⫽ mild, 2 ⫽ moderate, and 3 ⫽ severe. Safety analyses were performed for heart rate, respiratory rate, blood pressure, and adverse events. Patients who completed at least 1 week of each treatment and were not replaced due to protocol violations were included in the efficacy analyses. All patients who took study medication were included in the safety analyses. Although comparisons to baseline are problematic in a crossover study beyond the first treatment period in the absence of a placebo arm, improvements in efficacy parameters were evaluated from pretreatment to posttreatment. Treatment comparisons to baseline were first performed for each treatment period separately using paired t-tests. If the results from period 1 and period 2 were homogenous, then the data from the two periods were combined and paired t-tests between baseline and each treatment were performed. These results are presented as mean ⫾ SEM. For comparisons of the extended release albuterol tablets and salmeterol, analysis of variance models appropriate for two-period crossover designs
were used. If carryover (sequence) and treatment-by-site interaction tests were not significant, treatment comparisons were made based on a model with effects for treatment, period, site and patient nested within site and declared statistically significant at the .05 level of significance using two-tailed tests. From these analyses, treatment means were adjusted for the effects in the model, and standard errors of the adjusted means were obtained. The adjusted mean takes into account factors that may influence treatment outcome other than the medication. These results are presented as adjusted mean ⫾ SEM. RESULTS Subjects Of the 56 patients enrolled, 47 were patients initially randomized to treatment sequences, and nine were replacement patients. The efficacy analyses excluded the nine patients who were replaced, as well as one patient who was lost to follow-up after the first treatment period but was not replaced; therefore, 46 patients were evaluated for efficacy. All 56 patients who received study drug were evaluated for safety. Forty-four patients completed all double-blind visits and 31 patients completed the voluntary open-label visits. Five patients were dropped from the study due to adverse events during the double-blind portion, and two patients were discontinued due to adverse events during the openlabel portion. Six of these patients withdrew due to asthma exacerbations and one due to diarrhea. Of the six patients with an asthma exacerbation, one occurred during the first treatment period and was excluded, while 3/6 experienced an asthma exacerbation during the second treatment period and were discontinued from the study. These four patients were excluded from the efficacy analysis. Two of the six patients had their exacerbations during the open-label phase of the study. None of these events were considered by the investigators as related to study drug.
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Patient demographic information for the 46 patients evaluated for efficacy outcome is presented in Table 1. Thirty-four (61%) of the 56 patients enrolled in the study were taking inhaled steroids and 15 (27%) had a history of tobacco use. The FEV1 % predicted was 67.4 ⫾ 1.8% with a range between 50% to 98%. The group as a whole fell between 60% to 80% and thus are classified as moderate persistent asthmatics. Efficacy Measurements The weekly morning and overnight percent fall in PEF values at baseline and during the 3 weeks of treatment for each medication are shown in Figures 1 and 2, respectively, and Table 2. Both treatments produced significant improvements (P ⬍ .001) from baseline for morning PEF and overnight percent fall in PEF over the 3-week treatment periods, with no significant differences found between the medications. The morning FEV1 values were similar for each treatment (Fig 3, Table 2) as were the overnight percent decreases in FEV1 (Fig 4, Table 2). Analyses were performed to address whether the as needed albuterol inhalation use affected PEF and FEV1. Measurements of PEF and FEV1 made within 4 hours following rescue albuterol use were thus excluded from the efficacy analyses (approximately 20% of morning readings and 23% of evening readings). The results were similar to those using all measurements. Nocturnal symptoms at baseline were very mild with means of 0.45 ⫾ 0.09 for cough, 0.97 ⫾ 0.11 for shortness of breath, and 0.86 ⫾ 0.11 for wheezing. The composite symptom mean at baseline was 2.29 ⫾ 0.27 compared with the posttreatment means of 1.20 ⫾ 0.18 for the extended release albuterol tablets (P ⬍ .001) and 0.88 ⫾ 0.16 for salmeterol aerosol
Figure 1. Baseline and average weekly morning peak expiratory flow values are demonstrated. Means at weeks 1, 2, and 3 were adjusted for period, site, and patient. Treatment PEF significantly improved compared with baseline (P ⬍ .001). Shaded box ⫽ baseline. Enclosed box ⫽ extended release oral beta agonist. Open box ⫽ long acting inhaled agent.
Figure 2. Baseline and average weekly overnight percent change in peak flow values are shown. Means at weeks 1, 2, and 3 were adjusted for period, site, and patient. The overnight fall in PEF values significantly improved on each treatment arm compared with baseline (P ⬍ .001). Shaded box ⫽ baseline. Enclosed box ⫽ extended release oral beta agonist. Open box ⫽ long acting inhaled agent.
(P ⬍ .001). There was a significant difference between the adjusted mean for extended release albuterol tablets, 1.43 ⫾ 0.08, and the adjusted mean for salmeterol, 1.13 ⫾ 0.08 (P ⫽ .005). The mean percentage of nights without awakenings during the baseline period was 53.6 ⫾ 5.3%. This was significantly improved during treatment
with extended release albuterol tablets to 83.3 ⫾ 3.0% (P ⬍ .001) and with salmeterol to 88.8 ⫾ 2.4% (P ⬍ .001). A comparison of the adjusted treatment means (Table 2) for the percentage of nights without awakenings favored salmeterol (84.6 ⫾ 1.7 versus 79.4 ⫾ 1.7, P ⫽ .021), however, the percentage of patients who had no
Table 1. Baseline Patient Characterization Number
Male/Female
Age
FEV1 % Pred
24/22
35.1 ⫾ 1.4
67.4 ⫾ 1.8
46
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AM
PEF
352.2 ⫾ 13.4
% Overnight Fall in PEF 14.9 ⫾ 1.1
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Table 2. Outcome Measures
PEFR (L/min) FEV1 (L) % Overnight change PEF % Overnight change FEV1 Rescue albuterol use (puffs/day) % of no nighttime awakenings AM AM
Volmax
Serevent
P
414 2.71 ⫺7.2 ⫺4.0 2.98 79.4
420 2.70 ⫺7.9 ⫺5.1 2.20 84.6
NS NS NS NS .001 .021
Data presented as adjusted means (see text).
when treated with extended release albuterol tablets and 75.9% of the patients when treated with salmeterol (Table 4). Many of the patient-listed adverse effects are not related to study mediations. There were no significant group differences.
Figure 3. Average weekly morning FEV1 values are shown. Means at weeks 1, 2, and 3 were adjusted for period, site and patient. The FEV1 values were similar between albuterol tablets and salmeterol inhaler. Enclosed box ⫽ extended release oral beta agonist. Open box ⫽ long acting inhaled agent.
Figure 4. Average weekly overnight change in FEV1 values are shown. Means at weeks 1, 2, and 3 were adjusted for period, site, and patient. The overnight fall in FEV1 was similar in each treatment arm. Enclosed box ⫽ extended release oral beta agonist. Open box ⫽ long acting inhaled agent.
awakenings during treatment did not differ significantly for the two medications. During baseline, the use of rescue albuterol was 4.57 ⫾ 0.41 puffs/day. This decreased to 2.66 ⫾ 0.35 puffs/ day with the extended release albuterol tablets (P ⬍ .001) and 1.85 ⫾ 0.29 puffs/day with salmeterol (P ⬍ .001). There was a significant difference between the adjusted means for the two
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treatments, 2.98 ⫾ 0.18 puffs/day for albuterol tablets and 2.20 ⫾ 0.18 puffs/ day for salmeterol, P ⫽ .001. Safety Measurements Vital sign measurements taken at baseline and after each treatment are summarized in Table 3. No clinically important differences were observed. Listed adverse effects during treatment occurred in 78.0% of the patients
Open Label Preference Thirty-three patients chose to participate in the open label portion of the study. One of these individuals only completed one arm and thus was not included in the analysis. Twelve of the patients preferred the extended release albuterol tablets, while 18 preferred salmeterol aerosol. Table 5 shows the top 3 reasons patients preferred a given medication. DISCUSSION For symptom relief in the treatment of asthma, beta-2 adrenergic agents are recommended.9 Recent publications have interestingly focused on the use of long acting inhaled beta-agonists in combination with “low-dose” inhaled steroids as being more efficacious than using “high-dose” inhaled steroids15–17 in the treatment of asthma. Since the nocturnal worsening of asthma is a common feature of asthma and is related to sleep disturbance, daytime cognitive function abnormalities and mortality,10 –14 beta-agonists with 12hour effectiveness would be of importance in the therapeutic regimen. Problems that have been reported with inhaled medications include inappropriate inhaler technique in approximately 50% of patients18 and compliance issues in the majority of patients.19 This study was undertaken to determine whether long acting inhaled and oral beta-2 adrenergic ago-
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Table 3. Vital Sign Measurements (Mean ⫾ SEM)
Heart rate Respiratory rate Systolic BP Diastolic BP
Baseline (n ⴝ 56)
Extended Release Albuterol Tablets (n ⴝ 50)
Salmeterol Aerosol (n ⴝ 53)
74.1 ⫾ 1.4 16.2 ⫾ 0.3 115.1 ⫾ 1.6 74.7 ⫾ 1.2
74.5 ⫾ 1.3 16.6 ⫾ 0.3 117.6 ⫾ 1.7 73.5 ⫾ 1.4
76.0 ⫾ 1.4 16.1 ⫾ 0.3 116.3 ⫾ 1.4 74.8 ⫾ 1.4
Table 4. Patient Described Adverse Effects Number (%) of Patients
No adverse event At least one adverse event Headache Pharyngitis Rhinitis Tremor Asthma Dysmenorrhea Pain Dyspepsia
nists would give comparable efficacy outcomes in patients with nocturnal asthma. The choice of how these medications were dosed was based on prior studies involving patients with nocturnal asthma. Fitzgerald and colleagues4 demonstrated that either one or two actuations of salmeterol twice daily improved the overnight fall in lung function. Since two actuations of this formulation given twice daily is the usual dosing regimen, this was used in our study. For an oral beta-agonist, terbutaline, Postma and colleagues6 showed that an unequal dosing schedule of 5 mg in the morning and 10 mg in the evening was a better pharmacologic approach to treating the nocturnal worsening of asthma. We therefore ad-
Volmax (n ⴝ 46)
Serevent (n ⴝ 46)
11 (22.0) 39 (78.0) 28 (56.0) 9 (18.0) 8 (16.0) 5 (10.0) 4 (8.0) 4 (8.0) 3 (6.0) 3 (6.0)
13 (24.1) 41 (75.9) 25 (46.3) 8 (14.8) 9 (16.7) 0 (0.0) 2 (3.7) 3 (5.6) 3 (5.6) 1 (1.9)
ministered the oral beta-agonist in our study at 4 mg in the morning and 8 mg in the evening. Morning and overnight falls in PEF and FEV1 were similar between the oral and inhaled beta-agonists. In comparison to baseline values of PEF, both agents showed significant improvement for these outcome variables. Although FEV1 values could not be compared to baseline (data not available), the overnight falls in both treatment groups of approximately 5% are within the normal range of circadian alteration for lung function.20 Overall nocturnal symptoms do not always reflect the severity of lung function alterations and this was seen in our study with minimal symptom complaints during the baseline week
with a score of less than 1, ie, mild. During the baseline week, 54% of nights were without nocturnal awakenings due to asthma and it was significantly improved to 83% and 89% on oral and inhaled beta-agonist, respectively. The number of as needed short acting beta-agonist treatments decreased from baseline for both drugs. These differences from baseline were statistically significant for each treatment and greater for salmeterol. For the safety measurements of heart rate, respiratory rate, and blood pressure, there were no significant changes between treatment arms or from baseline. No significant differences were found in regard to side effects, but the oral
Table 5. Main Reasons for Drug Preference During Open Label Phase Albuterol Tablets (12) Greater symptom relief (5)* Longer duration of effect (5) More convenient (5)
Salmeterol Aerosol (18) Fewer side effects (10) Greater symptom relief (8) Less need for prn† medication (6)
*( ) ⫽ number of patients that chose response. † prn ⫽ as needed inhaled beta-agonist. Each patient could select more than one response.
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beta-agonist did have five individuals report the presence of tremor. The open label preference phase of the study showed that more patients preferred the inhaled beta-agonist (18 versus 12). Of interest were the varied reasons for preference of one agent or the other. The top 3 choices for the inhaled beta-agonist were: fewer side effects, greater symptom relief, and less need for as needed inhaled betaagonist. For the oral medication, the top 3 choices were selected with equal frequency and included greater symptom relief, longer duration of effect, and greater convenience. In the era of emphasis on medical economics, it is of interest to compare costs of medication when outcome variables are similar. The cost of inhaled salmeterol at 2 puffs twice a day is $1.84 per day21 or $55.20 per month. For the oral albuterol extended release tablets used in this study at the 4 mg AM/8 mg PM regimen, the cost is essentially identical to salmeterol at $1.86/ day or $55.80 per month.21 In summary, both inhaled salmeterol (Serevent威) and oral extended release albuterol tablets (Volmax威) improved the nocturnal worsening of asthma to similar degrees and without major adverse effects. Costs between the regimens used in this study are equivalent. Why a patient prefers one medication over the other varied greatly; thus, both extended release albuterol tablets and inhaled salmeterol are beneficial in the treatment of nocturnal asthma. ACKNOWLEDGMENTS The authors wish to thank Stacey Wolff for her help in the manuscript preparation. The following aided in the study design development and manuscript review: Elliot F Ellis, MD; John G Karafilidis, RPh; Heidy Russell, PhD; and Miganush Stepanians, PhD. REFERENCES 1. Pearlman DS, Chervinsky P, LaForce C, et al. A comparison of salmeterol
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12. Hetzel MR, Clark TJH, Branthwaite MA. Asthma: analysis of sudden deaths and ventilatory arrest in hospital. Br Med J 1977;1:808 – 811. 13. Weersink EJM, vanZomeren EH, Koeter CH, Postma DS. Treatment of nocturnal airway obstruction improves daytime cognitive performance in asthmatics. Am J Respir Crit Care Med 1997;156:1144 –1150. 14. Robertson CE, Rubinfeld AR, Bowej G. Deaths from asthma in Victoria: a 12-month study. Med J Australia 1990; 152:511–517. 15. Greening AP, Wind P, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344: 219 –224. 16. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroid. Am J Respir Crit Care Med 1996;153: 1481–1488. 17. Pauwels RA, Lofdahl C-G, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337: 1405–1411. 18. Shim C, Williams MH, Jr. The adequacy of inhalation of aerosol from canister nebulizers. Am J Med 1980; 69:891– 894. 19. Spector SL, Kinsman R, Mawhinney H, et al. Compliance of patients with asthma with an experimental aerosolized medication: implications for controlled clinical trials. Allergy Clin Immunol 1986;77:65–70. 20. Hetzel MR, Clark TJH. Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate. Thorax 1980;35:732–738. 21. Medi-Span. Hospital Formulary Pricing Guide. Indianapolis: Medi-Span, Inc, 1997.
Request for reprints should be addressed to: Richard J Martin, MD National Jewish Medical & Research Center 1400 Jackson St Denver, CO 80206
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