Oral bambuterol versus terbutaline in patients with asthma

CURRENT TIiEFtAPEUTIC RESEARCH’ VOL. 66, NO. 5, MAY 1995

ORAL BAMBUTEROL VERSUS TERBUTALINE IN PATIENTS WITH ASTHMA GUNNAR

PERSSON,’

OLLE PAHLM,a AND YVONNE

GNOSSPELlUS3

‘Department of Intemul Medicine, Division of Allergy, UniversiCy Hospital of Lund, 2Department of Clinical Physiology, University Hospital of Lund, and sDepartment of Clinical Research & Development, Astm Dmco AR, Lund, Sweden

ABSTRACT

This double-blind, crossover study compared the bronchodilating effects and side-effect profiles, including arrhythmogenic effects, of bambuterol tablets 20 mg once every evening with terbutaline tablets 5 mg three times daily in 22 patients with asthma without concomitant heart disease. Peak expiratory flow, use of inhaled be&agonists, asthma symptoms, and adverse events were recorded daily during each ?-day treatment period. At the end of each period, forced expiratory volume in 1 second and 48-hour ambulatory electrocardiograms were monitored. There was no difference in lung function between treatments; however, the mean score for dyspnea during the night was significantly lower (P < 0.05) for bambuterol than for terbutaline (0.20 f 0.03 vs 0.35 f 0.10, respectively) as was the nighttime use of inhaled be&-agonists (1.7 f 0.5 vs 2.3 f 0.5, respectively). No significant differences between treatments in arrhythmogenic effects were found. Few patients reported adverse events. However, the mean score for daytime uneasiness was significantly lower (P < 0.05) during treatment with bambuterol(O.05 f 0.05) than with terbutaline (0.20 f 0.03). Compared with terbutaline 5 mg three times daily, bambuterol 20 mg once every evening provides greater symptomatic relief of nocturnal asthma with a lower side-effect profile. INTRODUCTION

Asthma is a common condition that affects between 5% and 10% of the adult population in Sweden.’ In most cases, patients are adequately controlled by inhaled corticosteroids and be&-agonists2 Nevertheless, many asthmatic patients still have frequent or persistent symptomatic asthma. In these patients, an oral bronchodilator (like an oral beta,-agonist) might be added to the patients’ therapy. Bambuterol* is a new oral once-daily bronchodilator with several po-

*Trademark Bambece (A&a Draw AB, Lund, Sweden). Address umreapondence to: Gunnar Perason, MD, Department of Internal Medicine, Division of Allergy, University Hospital of Lund, S-221 86, Lund, Sweden. Received forpublicdion on Febnmy lo,1995Printed in the U.S.A. Reproduction in whole or part ia not permitted.

467

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BAMBUTEiROLVSTERBUTALINEIh'ASTHMA

tential advantages over existing oral therapies.3,4 It is a pro-drug of the betas-agonist terbutaline, with high metabolic stability. The terbutaline part of the pro-drug molecule is protected from being metabolized during absorption from the gastrointestinal tract and during first-pass through the liver. Bambuterol can therefore act as an inner depot from which terbutaline is slowly released. 3*4This slow-release mechanism results in a smooth and sustained plasma concentration of generated terbutaline. Fewer side effects could therefore be expected with bambuterol compared with other oral betas-agonists. This theory was supported in an earlier study5 with bambuterol30 mg once daily and terbutaline” controlled-release 10 mg twice daily. However, because the side-effect profile of betas-agonists includes the stimulation of cardiac potential and arrhythmogenic effectq6-s it was interesting to compare the bronchodilating effects and side-effect profiles, including arrhythmogenic effects, of these two drugs at recommended doses. The regimens chosen were 20 mg once every evening for bambuterol and 5 mg three times daily for terbutaline. PATIENTS AND METHODS

Male and female outpatients with asthma, aged 20 years or older, who could demonstrate at least a 15% improvement in post bronchodilator forced expiratory volume in 1 second (FEVi) were included in the study. Airflow reversibility was assessed by measuring FEV, before and 15 minutes after giving patients two puffs (0.25 mg/puffl of terbutaline sulfate aerosol through a Nebuhalere (Astra Draco AB, Lund, Sweden). These measurements were made without the influence of the patients’ regular bronchodilator therapy, that is, at least 14 hours after either theophylline or controlled-release terbutaline intake or 10 hours after inhaled bronchodilator use. Patients with either current (or history of) hypertension, angina pectoris, myocardial infarction, and/or abnormal results on electrocardiogram were excluded. Pregnant or lactating women and patients with renal, liver, or thyroid disease were also excluded. The study was performed in accordance with the Declaration of Helsinki and with the approval of the National Board of Health and Welfare and the Committee of Medical Ethics, University of Lund, Lund, Sweden. All patients provided written informed consent. This study was a randomized, double-blind, double-dummy, crossover design that consisted of two consecutive treatment periods, each 7 days long. Randomization was in blocks of four, balanced with respect to order of treatments using computer-generated random numbers. Patients received either active bambuterol and placebo terbutaline or active terbuta*Trademark: Bricanyl@ (A&a

Draco AB, Lund, Sweden). 458

G.PERSSONETAL..

line and placebo bambuterol in each treatment period. One 20-mg bambuterol tablet was taken at 8 PMevery night or one 5-mg terbutaline tablet was taken at 8 AM,2 PM, and 8 PMevery day. Glucocorticoids, both oral and inhaled, were permitted provided the doses did not vary throughout the trial. Patients were allowed to use salbutamol aerosol* at 0.1 mg/ dose when required but were requested not to do so within 5 hours of lung function measurements. No other inhaled bronchodilator use was permitted. Measurements made at the clinic before patient entry and at the same time of day on day 7 of each treatment period included FEVi (using a Vitalograph [Vitalograph, Inc., Lenexa, Kansas]), supine blood pressure, and heart rate, all taken after a lo-minute rest period. Patients used diaries to record morning and evening peak expiratory flow (PEF) before drug intake (using a mini-Wright peak flow meter, Clement Clarke International, London, United Kingdom), daytime and nighttime asthma symptoms (cough, dyspnea, and wheeze), and frequency and time of daytime and nighttime inhaled salbutamol use. Asthma symptoms were scored using a 4-point scale; 0 = none, 1 = mild, 2 = moderate, and 3 = severe. Patients used the same scale to record the following possible side effects every day and night: tremor, uneasiness, palpitations, headache, and skin reactions. These side effects and any other possible adverse events were reviewed by the investigator on day 7 of each treatment period. The arrhythmogenic effects of the two treatment regimens were studied by use of ambulatory electrocardiogram monitoring.g Evaluations were made during two consecutive 24-hour periods using a portable Holter monitor (Oxford MR 10, Oxford Medical Systems, Abingdon, United Kingdom). The monitor was hooked up to the patient on day 5 of both treatment periods. The signal was checked after 24 hours for signal quality, and electrodes were repositioned if necessary. From these recordings the following classes of arrhythmias were reported on an hourly basis: single premature ventricular beats; ventricular bigeminy; ventricular runs (defined as two or more consecutive premature ventricular beats); single premature supraventricular beats; supraventricular bigeminy; and supraventricular runs (defined as two or more consecutive premature supraventricular beats). Statistical Aru&aia Variables associated with lung function and arrhythmias were analyzed with a crossover model using either Student’s t test or, for considerable skew variables (including electrocardiogram and use of inhaled sal*Trademark Vent&n@ (Allen k Hanburys, Research Triangle Park, North Carolina). 459

butamol), Wilcoxon’s sum test. To facilitate analysis at steady-state drug levels and to exclude carryover effects, analysis of diary cards was limited to data collected on day 4 to day 7 of each treatment period. For Holter monitoring, the 48 hours of recording in each period were considered repeated measurements. Because we did not analyze the variation of arrhythmias during each period, means for each 48hour period were calculated, provided each hour had at least 50 minutes of adequate signal quality. Data are expressed as mean * SEM. RESULTS

Patient Chamctertstics Twenty-two patients were recruited into and completed the study. Their mean age was 39 years (range, 21 to 66 years), duration of asthma was 18 years (range, 3 to 50 years), basal FEVl was 1.99 L (range, 0.80 to 3.90 L), and reversibility was 51% (range, 15% to 288%). Fourteen patients were nonsmokers, seven were ex-smokers, and one was a current smoker. One patient withdrew from treatment during period 1 (bambuterol) after 2 days because of a respiratory infection but was re-entered on recovery. Although the protoaol stipulated that salbutamol was the only bronchodilator permitted during the study, two patients retained fenoterol as their standard bronchodilator therapy. Fenoterol was converted to a salbutamol equivalent by multiplying the number of inhalations by a factor of 2.

Pulmonary Function Variables and S&ptom

Scores

Mean (+SEM) baseline FEV, values were 2.0 ? 0.2 L. On day 7, patients treated with bambuterol showed FEVl values of 2.4 & 0.2 L, and patients treated with terbutaline showed values of 2.4 + 0.2 L. These changes were not statistically significant. Given that baseline FEVr values were on average 18% lower than treatment values, it is surprising that no statistically significant differences were found. This lack may be a consequence of sample size. Neither daily morning nor evening PEF values for the bambuterol period (404 4 22 Umin and 423 2 22 Wmin, respectively) differed from values for the terbutaline period (400 + 22 L/min and 431 5 22 Umin, respectively). Although there were no significant differences between treatments for PEF, during the night patients taking bambuterol used significantly less inhaled salbutamol than patients taking terbutaline (1.7 + 0.5compared with 2.3 + 0.5 inhalations, respectively; P < 0.05) (Figure 1). 460

G.

n 0

PERSSON ET AL

Terbutaline (5 mg TID) Bambuterol (20 mg once daily)

T

Night

Figure 1. Mean (+SEM) number of be&-agonist inhalations (n = 22). TID = three times daily. *P < 0.05.

The mean score for nighttime dyspnea was significantly lower (P < 0.05) with bambuterol than terbutaline (0.20 + 0.09 compared with 0.36 + 0.10, respectively) (Figure 2). There were no significant differences in the mean scores for daytime or nighttime cough and wheeze or daytime dyspnea, although scores were lower with bambuterol for these variables.

Cardiac Effects As shown in the table, the frequency of arrhythmias with both treatTerbutaline (5 mg TID) Eambuterol (20 mg once daily)

muI

0.4 I-; : 6 c I I

T

T

T

0.3 -

O.P-

0.1 -

Night Day Cough

Night Day Dyspnea

Night Day Wheeze

Figure 2. Patient-rated (mean f SEMI asthma symptoms (n = 22). 0 = none; 1 = mild; 2 = moderate; and 3 = severe. TID = three times daily. *P < 0.05. 461

BAMBUTEROL

VS TFJtBUTALINE

IN ASTHMA

ments was low and of no clinical significance (ie, was within the normal range). The results are thus unremarkable. There were no significant differences between treatments. The mean heart rate did not differ between bambuterol (80.5 + 2.1 beats/min) and terbutaline (80.5 + 1.7 beats/min) treatments; however, rates for both drugs were significantly greater (P < 0.05) than rates at study entry (75.5 + 1.9 beats/min). Neither systolic nor diastolic blood pressure differed between bambuterol(122.5 + 1.9 mm Hg and 82.0 + 2.0 mm Hg, respectively) and terbutaline (120.2 ? 2.4 mm Hg and 81.6 + 1.6 mm Hg, respectively). Changes in blood pressure did not differ significantly from study entry with either drug (121 + 2.4 mm Hg and 82.5 ? 2.2 mm Hg, respectively).

Adverse Events Patients scored uneasiness during the day significantly lower (P < 0.05) during the bambuterol period than during the terbutaline period (0.05 + 0.05 compared with 0.20 + 0.09, respectively) (Figure 3). Palpitations and tremor were also scored lower during bambuterol treatment, although this finding was not statistically significant. Headache was reported equally in both treatment groups. There were few other adverse events, none of them serious; the most common of these adverse events were muscle cramps (three patients, terbutaline period) and nausea (two patients, terbutaline period). No other event was experienced by more than one individual. Mild skin reactions were reported by one patient.

Table. Mean (*SD) hourly frequency of cardiac arrhythmias recorded over 48 consecutive hours with Halter monitoring.

Bambuieml

(20 mg once daily)

N

Terbutaline (5 mg no)

N

1.6 + 4.2

17

1.6 +- 3.9

16

0.0 ? 0.1 1.6 f 4.3

1;

0.0 1.7 If: k 0.1 4.1

1:

No. of episodes Duration of beats in the longest episode PSVBs Su raventricular bigeminy Ro. of episodes CV!’ psvBs

0.1 * 0.2 0.1 + 0.2 0.6 2 1.7

19

No. of episodes Duration of beats in longest episode

0.0 f 0.1 0.1 f 0.2

PVBs Ventricular bigeminy No. of episodes Eta’ pvBs

:

;:1f “0:: 16t

0.3 IO.5

0.0 * 0.1 0.6 2 1.7

TID = three times daily; PVBs = single remature ventricular beats; VR = ventricular runs; PSVBs = single premature supraventricular beats; S& R = supraventricular runs.

G.PER.WONETAL.

I

W UN

T

Night Day Tremor

Night Day Uneasiness

Terbutaline (5 mg TID) Bambuterol (20 mg once daily)

Night Day Palpitation

Night Day Headache

Figure 3. Patient-rated (mean k SEMI adverse events (n = 22). 0 = none; 1 = mild; 2 = moderate; and 3 = severe. TID = three times daily. *P < 0.05. DISCUSSION AND CONCLUSIONS

This study compared the bronchodilating effects and side-effect profiles of bambuterol 20 mg once every evening and terbutaline 5 mg three times daily. Although lung function parameters (clinic FEV, and diary PEF) did not differ between treatments, patients experienced significantly less nocturnal dyspnea with bambuterol than with terbutaline. The higher level of nocturnal dyspnea experienced with terbutaline was reflected by a greater nocturnal requirement for inhaled bronchodilator use. All other asthma symptoms (daytime and nighttime cough and wheeze and daytime dyspnea) were consistently scored higher during the terbutaline period, although differences were not significant. This finding may reflect a trend; with a larger sample size it is possible that significant differences between treatments may have been discernible. At least 73% of asthmatic patients wake with asthma symptoms at least once a week and 39% wake nightly. lo It is thus desirable for an antiasthmatic drug to relieve or prevent nocturnal asthma. The beneficial effects of bambuterol on nocturnal asthma symptoms and the reduced need for inhaled beta,-agonists have been confirmed in other studies.“*” Bambuterol20 mg in addition to regularly inhaled steroids and inhaled betazagonists as needed have been shown to improve nocturnal asthma symptoms, general well-being, and daily PEF, and reduce the frequency of nocturnal awakening in patients with nocturnal asthma symptoms.ll It has also been demonstrated that bambuterol achieves its maximal effect during the night.12 In this study patients experienced significantly less daytime uneasi463

ness during treatment with bambuterol. Nighttime and daytime palpitations and tremor and nighttime uneasiness were scored lower during the bambuterol period, but the differences reported were not statistically significant. However, as with the asthma symptom scores, these results may reflect a trend. In addition, these results are in accordance with a study on healthy subjects, where bambuterol20 mg produced less tremor than terbutaline controlled-release 7.5 mg twice daily.13 Bambuterol provided significantly better control of symptomatic asthma at night with a lower side-effect profile. It is thus possible, as found here and elsewhere,g to produce a similar bronchodilating effect with a lower side-effect profile with bambuterol compared with terbutaline. This improved ratio may be due to the smooth and sustained plasma level of generated terbutaline that occurs with bambuterol. The frequency of arrhythmias found with both treatments was low and within levels reported for normal populations.” Thus, with respect to arrhythmogenic effects, both treatment regimens produce clinically insignificant frequencies of arrhythmias. This finding and the frequency of arrhythmias reported here is in agreement with that reported by Conradson et al.” The only cardiac effect we found was a small but statistically significant increase in heart rate (5 beats/min). This increase occurred with both drugs and is typical of betaa-agonists.16 Blood pressure (both systolic and diastolic) was unaffected by both treatments. We can thus conclude that neither treatment has any significant cardiac effect-at least for patients with asthma without concomitant heart disease. Current guidelines recommend inhaled betas-agonist therapy as needed and regular inhaled steroids as a mainstay in the treatment of patients with asthma. l7 If adequate control of symptoms is not achieved, addition of oral bronchodilators may be considered. When a patient has nocturnal asthma symptoms, a long-acting bronchodilator may be effective. Bambuterol20 mg once every evening decreases nocturnal symptoms and reduces patient dependence on nocturnal inhaler use. Furthermore, it has a lower side-effect profile than oral terbutaline 5 mg three times daily. References: 1. Barnes PJ. New concepts in the pathogeneeis of bronchial hyperreaponeiveneas and asthma. J Allergy Clin Immurwl. 1989;83:1013-1026. 2. Barnes PJ. Difficult asthma. BMJ. 1989;299:695-698. 3. Oleson OA, Sveneeon Q. New lipophilic terbutaline ester prodruge with long effect duration. Phurm Res. 1984$anuary:19-23. 4. Nyberg L. Pharmacokinetic properties of bambuterol in solution and tablet-basis once-daily dosage in asthma. Actu Pharmacol Toxicol. 1989;SS(Suppl 5):229.

for

5. Peraeon G, Gnoeepelius Y, Anehus S. Comparison between a new once-daily anti464

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asthmatic drug, bambuterol, and terbutaline sustained release, twice daily. Eur Respir J. 1988;1:223-226. 6. Al-Hillawi AH, Hayward R, Johnson NM. Incidence of cardiac arrhythmias in patients taking slow release aalbutamol and slow release terbutaline for asthma. BMJ. 1984,288: 367. 7. Banner AS, Sunderrajan EV, Agarwal MK, Addington WW. Arrhytbmogenic effect9 of orally administered bronchodilators. Arch Zntem Med. 1979;139:434-437. 8. Pierson DJ, Hudson LD, Stark K, Hedgecock M. Cardiopulmonary effects of terbutaline and bronchodilator combination in chronic obstructive pulmonary disease. Chest. 1980; 77:176-182. 9. Van den Berg W, Alar&o K, Sahlstrom K, et al. Bambuterol once every evening in combination with terbutaline t.i.d. in asthmatic patients. Clin Exp Allergy. 1990; 2O(Suppl 035. 10. Turner-Wanvich M. Nocturnal asthma: A study in general practice. JR CoZZGen Pmct. 1989;39:239-243. 11. Petrie GR, Chookang J, Hassan WU. Bambuterol: Effective in nocturnal asthma. Respir Med. 1993;87:581-585. 12. Alonao GE, Smolensky MH, Feldman S, et al. Bambuterol in the treatment of asthma: A placebo controlled comparison of once-daily morning versus evening administration. Chest. 1995;107:406-412. 13. Larsen K, Schmekel B. Tremor in healthy volunteers after Bambece (bambuterol) and Bricanyle CR-tablets (terbutaline). Eur J Clin Phunnaco 1.1993;45:303-305. 14. Morganroth J. Premature ventricular complexes. Diagnosis and indications for therapy. JAMA. 1984,252:673-676. 15. Conradaon T-B, Eklundh G, Olofaaon B, et al. Cardiac arrhythmias in patiente with mild-to-moderate ob&ructive lung disease. Comparison of beta-agonist therapy alone and in combination with a xanthine derivative, enprofylline or theophylline. Chest. 1985;88: 537-542. 16. Popa V. Beta-adrenergic drugs. Clin Chest Med. 1986;7:313-329. 17. British Thoracic Society and others. Guidelines on the management of asthma. Thorax. 1993;48(Suppl):Sl-s24.

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