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* From the Section of Pulmonary Medicine (Dr. ZuWallack), St. Francis Hospital and Medical Center, Hartford, CT; Dartmouth Hitchcock Medical Center (Dr. Mahler), Lebanon, NH; and Glaxo Wellcome Inc (Mss. Reilly, Church, and Emmett, and Drs. Rickard and Knobil), Research Triangle Park, NC.
Correspondence to: Richard L. ZuWallack, MD, St. Francis Hospital and Medical Center, Pulmonary and Critical Care Medicine, 114 Woodland St, Hartford, CT 06105
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Objectives: To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD.
Methods: Randomized, double-blind, double-dummy, parallel-group trial in 943 patients with COPD. After an open-label theophylline titration period (serum levels, 10 to 20 µg/mL), patients were randomly assigned to receive salmeterol (42 µg bid) plus theophylline, salmeterol (42 µg bid), or theophylline for 12 weeks. Serial pulmonary function tests were completed on day 1 and treatment week 12. Patients kept diary cards and noted their peak flow rates, symptom scores, and albuterol use, and periodically completed quality-of-life and dyspnea questionnaires.
Results: All three groups significantly improved compared
with baseline. Combination treatment with salmeterol plus theophylline
provided significantly (p 
0.045) greater improvements in pulmonary
function; significantly (p 0.048) greater decreases in symptoms,
dyspnea, and albuterol use; and significantly fewer COPD exacerbations
(p = 0.023 vs theophylline). In general, treatment with salmeterol
provided greater improvement in lung function and satisfaction with
treatment compared with theophylline. Salmeterol treatment was also
associated with significantly fewer drug-related adverse events
(p 0.042) than either treatment that included theophylline. The
safety profile (adverse events, vital signs, and ECG findings) of the
two treatments that included theophylline were similar.
Conclusion: Patients with COPD may benefit from combination treatment with salmeterol plus theophylline, without a resulting increase in adverse events or other adverse sequelae.
Key Words: chronic bronchitis • combination therapy • COPD • dyspnea • emphysema • exacerbations • FEV1 • quality of life • salmeterol • theophylline
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Theophylline, a methylxanthine derivative, has been used in the treatment of COPD for many years. Studies3 4 5 6 7 8 have shown that theophylline can increase lung function, decrease symptoms, and improve diaphragmatic muscle function that may translate to reducing fatigue and enhancing endurance during activities of daily living.
Salmeterol xinafoate is a long-acting ß2-agonist that increases lung function and reduces dyspnea and other symptoms of COPD.9 10 11 12 13 14 15 16 17 18 In addition, patients with COPD who receive salmeterol experience significant improvement in health-related quality of life (HRQOL).10 11 Salmeterol has been recommended as first-line maintenance therapy in the treatment of patients with symptomatic COPD.12
The purpose of this randomized, controlled trial was to investigate the combined use of salmeterol and theophylline in the treatment of patients with COPD. The hypothesis was that salmeterol and theophylline would provide greater improvements in lung function and greater reductions in breathlessness compared with either agent alone.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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45 years old with COPD due to
chronic bronchitis or emphysema were recruited to participate from 74
outpatient clinics in the United States. Screening entry criteria
required a smoking history of at least 20 pack-years,
FEV1 0.70 L and 65% of predicted normal
based on standards of Crapo et al,19
and an
FEV1/FVC ratio of 70%. Patients with an
FEV1 < 0.70 L were eligible if their percent
predicted FEV1 was at least 40% of predicted
normal. Patients with a history of asthma, a daily continuous oxygen
requirement, a recent viral or bacterial pulmonary infection,
congestive heart failure, or other clinically active diseases were
excluded. Patients were not permitted to receive inhaled ipratropium
during the study or have any changes in their regular COPD medications
within 4 weeks of the screening visit. Stable doses of inhaled
corticosteroids and/or oral corticosteroid doses ( 10 mg/d of
prednisone or equivalent) were allowed.
Study Design and Conduct
This randomized, double-blind, double-dummy, parallel-group
trial compared the efficacy and safety of three treatments for 12
weeks: (1) salmeterol, 42 µg bid via metered-dose inhaler (MDI) plus
oral sustained-release theophylline twice daily; (2) salmeterol, 42
µg bid; or (3) oral sustained-release theophylline twice daily. The
study protocol was approved by various institutional review boards, and
all patients granted their permission to participate by signing written
informed consent. This article combines the results of two identical,
randomized, double-blind, double-dummy, parallel-group trials.
The study consisted of a screening visit, a 7- to 10-day baseline period, and 12 weeks of double-blind treatment. During the baseline period, patients continued to receive their regular COPD medications (not otherwise excluded) and complete diary cards. After at least 5 days, patients began the open-label theophylline titration period by taking the theophylline dose prescribed by the investigator. Patients returned to the clinic for serum theophylline concentration checks and had the dose adjusted as necessary until the target peak serum theophylline concentration of 10 to 20 µg/mL was achieved. Patients unable to reach the target theophylline concentration in three visits were withdrawn.
At visit 1 (after the theophylline titration), patients discontinued the use of the open-label theophylline and were randomly assigned to the oral medication component of their double-blind treatment using the dose identified during the titration period. Reversible patients (ie, those with at least a 200-mL and 12% improvement in FEV1 within 30 min of inhalation of two puffs of albuterol) and nonreversible patients were stratified in order to ensure balance between the treatment groups.
Patients returned to the clinic within 3 to 5 days for visit 2, at which time they were randomized to the inhaled medication component of their treatment regimen. The purpose of this staggered randomization period was to permit a washout of the effects of theophylline for those patients assigned to salmeterol treatment alone. Serial spirometric assessments were obtained immediately predose (time 0, prior to the first dose of inhaled study medication) and at 0.5, 1, 2, 4, 6, 8, 10, and 12 h postdose.
Patients attended the clinic after 4 weeks, 8 weeks, and 12 weeks of treatment for evaluations of pulmonary function, dyspnea, HRQOL, and satisfaction with treatment. Dyspnea was assessed using the baseline dyspnea index (BDI) and the transitional dyspnea index (TDI).20 HRQOL was assessed by the chronic respiratory disease questionnaire (CRDQ), a 20-item questionnaire with four components (dyspnea, fatigue, emotional function, and the feeling of mastery over disease).21 22 The satisfaction with treatment questionnaire evaluated the patient’s overall satisfaction with his/her medication as well as attributes of satisfaction, including how well the medication worked, how fast it worked, how long it worked, how good it made the patient feel, and side effects using a 7-point scale, from 0 = very dissatisfied to 6= very satisfied.
Patients recorded on diary cards their morning and evening peak expiratory flow (PEF), daily COPD symptoms, and albuterol use. COPD symptoms were rated by the patients with a 5-point scale, from 0 = no symptoms at all during the day to 4 = symptoms so severe that the patient was not able to do most daily activities. An albuterol treatment was defined as inhalation of two puffs from an MDI or one nebule of solution for nebulization. Compliance was assessed via patient report of medication use and by pill counts.
A COPD exacerbation was defined as a worsening of symptoms requiring an
increase in drug therapy (not including albuterol). Exacerbations could
be treated with oral/parenteral corticosteroids for 14 days.
Patients who required hospitalization or who experienced more than one
exacerbation during the study were withdrawn.
Treatments
Blinded study treatments were an MDI (salmeterol, 42 µg bid;
Serevent Inhalation Aerosol; Glaxo Wellcome Inc; Research Triangle
Park, NC) or matching placebo, and an oral theophylline capsule, 100 mg
(Slo-Bid Gyrocaps; Aventis Pharma; Parsippany, NJ) or matching
placebo. Patients were randomly assigned in a 1:1:1 ratio to receive
salmeterol twice daily plus theophylline twice daily (SALM + THEO),
salmeterol twice daily (SALM), or theophylline twice daily (THEO). All
patients received albuterol (Ventolin Inhalation Aerosol and/or
Ventolin Inhalation Solution, 0.5%; Glaxo
Wellcome Inc) to use as necessary.
Statistical Methods
Data from five patients at one site were excluded from analyses
of efficacy due to concerns about study conduct, but all data from all
sites were included in the analyses of safety. Data from patients
withdrawn early were included in the analyses up to the time of study
discontinuation. No interpolation was used for missing data.
Statistical analyses were based on two-sided tests conducted at the
0.05 significance level and compared differences between pairs of
treatment groups.
The primary efficacy measure was the mean change from baseline in the area under the FEV1 vs time curve during 12-h serial pulmonary function testing (PFT) on day 1 and week 12. Secondary efficacy measures included other pulmonary function parameters (predose FEV1, FEV1, and FVC over the 12 h of serial testing), TDI focal scores, morning and evening PEF, symptom scores, albuterol use, COPD exacerbations, HRQOL, and treatment satisfaction.
Baseline FEV1 area under the curve (AUC) was the screening FEV1 value times 12 h. Baseline values for PEF, symptoms, and supplemental albuterol use were obtained from the 5 days of the screening period prior to theophylline titration. Comparisons among treatment groups for serial pulmonary function, PEF, dyspnea ratings (BDI/TDI), and albuterol use were made by analysis of variance (ANOVA) including terms for treatment, investigator, and baseline. Comparisons among treatment groups for symptoms, albuterol use, and percentage of symptom-free and albuterol-free days were made using a van Elteren test controlling for investigator. Ninety-five percent confidence intervals (CIs) for treatment differences were also calculated using analysis of covariance with treatment, investigator, and baseline in the model.
The mean changes from baseline in the CRDQ data and satisfaction with
treatment data were compared among treatments using an ANOVA
controlling for baseline and investigator. In addition to analyzing the
mean changes from baseline in the CRDQ data, the proportion of patients
with a clinically significant improvement21
in the overall
and component parts of the CRDQ were compared between treatments using
a Cochran-Mantel-Haenszel test controlling for investigator. A total
improvement score of 10 points was considered clinically
significant.
Safety was assessed by clinical adverse events, vital signs, ECG, and theophylline concentrations. Adverse events, reported either spontaneously by the patient or elicited during clinic visits, were recorded regardless of the suspected relationship with study treatment. The proportion of patients with adverse events, COPD exacerbations, and clinically significant ECG changes from baseline were compared using the Fisher’s Exact Test. Mean changes from baseline in vital signs and mean theophylline concentrations were compared between treatment groups using an ANOVA controlling for investigator and baseline.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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0.021), with the exception
of the predose FVC assessment at week 12. The SALM + THEO group
experienced significantly greater improvement in
FEV1 and FVC than either the SALM group or the
THEO group (p 0.020; Table 3
). Although the improvements in the SALM group were slightly greater
than those in the THEO group for both FEV1 and
FVC, the differences were not significant.
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0.045). At week 12, the 95% CIs for predose
FEV1 mean change from baseline treatment
differences were 0.04 to 0.13 and 0.07 to 0.16 for the
SALM + THEO - SALM groups and the SALM + THEO - THEO groups,
respectively. With predose FVC at week 12, the 95% CIs for treatment
differences were 0.04 to 0.21 and 0.09 to 0.26, respectively. The SALM
group experienced significantly greater improvement than the THEO group
in FEV1 and FVC during the first several hours
postdose, most notably on day 1 (p 0.046). The rank order of
improvement (SALM + THEO > SALM > THEO) was similar in the
reversible and nonreversible patients. Evaluations of the
FEV1 AUC showed that the SALM + THEO group
experienced significantly greater improvement than the SALM group or
the THEO group overall (all patients) and also for the subgroups of
reversible and nonreversible patients on day 1 and week 12
(p 0.002; Fig 4
). On day 1, the SALM group experienced significantly greater
improvement than the THEO group overall and in the reversible patients
(p 0.011). There was no difference between the SALM group and the
THEO group at week 12. A similar pattern was observed for serial FVC
results in the reversible and nonreversible patients (data not shown).
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0.048). Furthermore,
the SALM + THEO group experienced significantly more symptom-free
days (p = 0.023) compared with the THEO group. COPD exacerbations
were experienced by significantly fewer patients in the SALM + THEO
group (40 patients, 48 exacerbations) compared with the THEO group (62
patients, 96 exacerbations; p = 0.023), but not the SALM group (56
patients, 71 exacerbations; p = 0.076).
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10
points) and was significantly greater (p 0.019) at week 4 compared
to the SALM group and the THEO group (+ 6.3 points for the SALM group;
+ 5.1 points for the THEO group). At week 12, mean improvements in
overall CRDQ scores were + 12.7 points in the SALM + THEO group,
+ 7.6 points in the SALM group, and + 8.6 points in the THEO group
(p 0.052). A significantly higher percentage of patients in the
SALM + THEO group (52 to 54%) experienced a clinically important
improvement overall compared with the SALM group (36 to 45%) or the
THEO group (31 to 42%) at week 4 and week 12 (p 0.014).
Improvements in pulmonary function were contrasted with improvements in
HRQOL and TDI scores and found to be positively, but weakly, correlated
(r = 0.2 and r = 0.11 for
FEV1 AUC and FVC vs HRQOL, respectively, and
r = 0.19 and r = 0.14 for
FEV1 AUC and FVC vs TDI, respectively).
SALM + THEO treatment was rated as providing significantly greater
overall satisfaction with treatment compared with the THEO group at all
time points (p 0.012) and compared with the SALM group at week 8
and week 12 (p 0.041). SALM treatment provided significantly
greater satisfaction with treatment with respect to side effects than
either treatment involving theophylline (p 0.028).
Adverse Events
The proportion of patients reporting adverse events (regardless of
causality) was not significantly different among treatment groups.
However, the proportion of patients reporting adverse events that were
judged to be related to study drug was significantly higher in both of
the groups that received theophylline compared with the SALM group,
most notably for GI events (p 0.042; Table 5 ). Drug-related cardiovascular events were reported relatively rarely (1
to 4% overall) and were similar among treatment groups.
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Cardiovascular Effects
Mean heart rate significantly (p 0.004) increased relative to
baseline for all patients during the theophylline titration period
(range, 5 to 7 beats/min). Once randomized to study treatment, however,
mean heart rates returned to baseline levels in the SALM group, but
remained significantly elevated relative to baseline (range, 2 to 5
beats/min; p 0.002) in both groups receiving theophylline. There
were no clinically significant changes in BP. Clinically significant
changes from baseline on ECG were rare, comparable between the
treatment groups, and generally limited to increases in premature
ventricular contractions (three patients in the SALM + THEO group,
three patients in the THEO group) and nonspecific ST-T segment wave
changes (four patients in SALM + THEO group, two patients in SALM
group, and one patient in THEO group).
Theophylline Concentrations
Mean peak serum theophylline concentrations remained within the
target range of 10 to 20 µg/mL during the study. Thirty-four to 37%
of patients had a theophylline concentration below the lower limit of
10 µg/mL; however, of these, the majority had theophylline
concentrations in the 8- to 10-µg/mL range. One patient in the
SALM + THEO group had a serum theophylline concentration > 20
µg/mL.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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National and international guidelines have proposed a stepwise approach to medications for the treatment of COPD.1 2 Salmeterol, a relatively new agent indicated for COPD, is considered by some to be a first-line treatment. Although theophylline is considered to be a third-line agent after the use of ß2-agonists and anticholinergics, it is more widely used than might be expected, perhaps because of its long, established history of use. Combination therapy with these agents has been observed to provide significantly greater improvement than monotherapy in numerous studies, including theophylline added to other ß2-agonists23 24 25 26 27 and theophylline added to anticholinergic therapy.23 28 29 30 Anticholinergic therapy added to albuterol provided significantly greater improvement in FEV1 compared with either agent alone31 32 33 34 as did salmeterol plus ipratropium.35 This study extends these findings to include combination treatment with salmeterol plus theophylline.
The specific actions of salmeterol and theophylline in the treatment of COPD have not been as well characterized as they have in asthma, but the greater improvements in physiologic and clinical outcomes observed with combination treatment are likely due to the contribution of two different pharmacologic classes. COPD is characterized by predominantly neutrophilic inflammation, as opposed to the eosinophilic inflammation of asthma, with parenchymal destruction leading to airflow obstruction through dynamic compression.36 Although both salmeterol and theophylline are considered bronchodilators, theophylline may also increase respiratory muscle strength and delay the occurrence of diaphragmatic fatigue4 5 8 and may possess some anti-inflammatory properties.37 38 39 In addition to providing a long-acting bronchodilatory effect on airways, salmeterol has been shown to decrease vascular permeability,40 decrease adhesion of neutrophils to airway epithelium,41 decrease release of inflammatory mediators,42 43 44 45 and improve mucociliary clearance.46 Salmeterol has also been shown to protect the respiratory epithelium against Pseudomonas aeruginosa-induced and Haemophilus influenzae-induced damage.47 48 Further research is warranted to more fully understand not only the mechanisms of action of current treatments specific to COPD, but to develop new treatments that not only relieve symptoms, but also address the underlying disease.
Physiologic improvements traditionally used to evaluate the benefits of
therapies in COPD do not generally correlate well with clinical
outcomes. Although both the lung function and clinical measures of COPD
improved with combination therapy (SALM + THEO), the correlation
coefficients for FEV1 and FVC vs measures of
dyspnea (TDI) and HRQOL were low ( 0.2). The development of dynamic
hyperinflation has been recently reported49
to correlate
better with the severity of dyspnea than with spirometric measures.
Clinical outcomes such as improvement in dyspnea, HRQOL, and treatment
satisfaction are at least as important as physiologic measures when
evaluating therapies for COPD.50
Dyspnea is perhaps the
most important symptom from the patient’s perspective and one of the
most common reasons that patients seek medical
attention.1
51
In a small 4-week study, salmeterol had a
small, statistically significant increase in
FEV1, and while there was no significant increase
in FVC or in the distance walked in 6 min, patients reported a
significant decrease in dyspnea when compared to
placebo.18
In the current study, combination treatment
with salmeterol plus theophylline provided significantly greater relief
in dyspnea compared with either treatment alone as measured by the
BDI/TDI instrument, and the magnitude of this improvement (improvement
of 1.9 points on the TDI) was greater than what has been observed
previously with inhaled bronchodilator therapy.12
Similarly, the improvement in overall HRQOL, particularly the
proportion of patients with a clinically significant improvement in
CRDQ scores ( 10 points), was more marked with combination treatment
of salmeterol plus theophylline (52%) than has been previously
reported with either salmeterol (46% with 10 point improvement) or
ipratropium bromide (39% with 10 point
improvement).12
Additionally, combination treatment with
salmeterol plus theophylline provided significantly higher overall
satisfaction scores compared with either treatment alone, despite the
fact that patients treated with salmeterol alone had significantly
higher treatment satisfaction scores for side effects (and
significantly fewer adverse events) than either of the two groups that
received theophylline.
The magnitude of the response among the "nonreversible" subjects treated with the combination of salmeterol plus theophylline is perhaps the most intriguing aspect of these results. The underlying mechanistic actions to explain why these subjects should have such a marked improvement in FEV1 with combination therapy is not currently understood, but has been observed before when theophylline has been taken in combination with other therapies.24 52 53 These results highlight that the lack of an acute response to albuterol in patients with COPD is not always a reliable predictor of subsequent responses to long-acting ß-agonists (alone or in combination) and underscores the importance of not undertreating patients who are believed to have little chance of benefiting from bronchodilators.
Issues with tolerability have always been a consistent limitation to the use of theophylline, particularly in elderly patients. The results of the current study underscore this concern. Nearly 16% of patients withdrew during the theophylline titration period and prior to randomization due to adverse events commonly associated with theophylline or an inability to tolerate the dose during titration. The patients who were then randomized were, by definition, relatively theophylline tolerant. Nevertheless, adverse events attributable to theophylline therapy were considerable. Theophylline concentrations were titrated to a dose of 10 to 20 µg/mL in this study, which is the level suggested in the package insert. However, by the end of the study, more than one third of the patients had concentrations < 10 µg/mL. Most of these "low" theophylline concentrations were still within what is considered to be a therapeutic range of 8 to 10 µg/mL.2 Whether the tolerability of combination therapy could be improved (without an accompanying loss of efficacy) by titrating the theophylline dose downward requires further research.
In conclusion, patients with COPD treated with salmeterol alone, theophylline alone, or a combination of salmeterol plus theophylline experienced significant improvements in multiple outcomes. Patients receiving combination treatment experienced both statistically significant and clinically relevant improvements in objective measures of pulmonary function and subjective measures (dyspnea, HRQOL, and patient satisfaction) compared to either treatment alone. Our results suggest that combination therapy with salmeterol and theophylline may provide substantial benefits in both physiologic and clinical outcomes in symptomatic patients with COPD.
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Acknowledgements |
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Footnotes |
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Presented in abstract form at the 2000 American Thoracic Society Meeting, Toronto, Canada, May 8, 2000.
This study was supported by a grant from Glaxo Wellcome Inc, Research Triangle Park, NC.
Dr. Mahler is a consultant to Glaxo Wellcome Inc.
Received for publication August 24, 2000. Accepted for publication December 12, 2000.
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References |
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release from human mast cells. J Allergy Clin Immunol 100,825-831[CrossRef][ISI][Medline]
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