- Email: [email protected]
The additive effect of theophylline on a combination of formoterol and tiotropium in stable COPD: A pilot study
ARTICLE IN PRESS Respiratory Medicine (2007) 101, 957–962
The additive effect of theophylline on a combination of formoterol and tiotropium in stable COPD: A pilot study Mario Cazzolaa,,1, Maria Gabriella Materab a
Department of Respiratory Medicine, Unit of Pneumology and Allergology, A. Cardarelli Hospital, Naples, Italy Department of Experimental Medicine, Unit of Pharmacology, 2nd University of Naples, Naples, Italy
b
Received 30 August 2006; accepted 9 September 2006 Available online 23 October 2006
KEYWORDS COPD; Tiotropium; Formoterol; Theophylline; Combination therapy
Summary We explored the additive effect of titrated oral theophylline in patients with stable chronic obstructive pulmonary disease (COPD) who received both tiotropium, 18 mg od, and formoterol, 12 mg bid. Thirty-six patients with moderate-to-severe COPD were enrolled in this two-period trial. They were initially treated with formoterol+tiotropium for 4 weeks. After this first period, they were divided in two groups of 18 patients. Both groups continued with the initial treatment for further 4 weeks, but the first group received also placebo whereas the second group received oral theophylline. The combination therapy with formoterol+tiotropium induced a significant improvement in mean predose FEV1 and FVC at the end of the first period, and a significant reduction in dyspnea score as measure by a visual analogic scale and in use of rescue salbutamol. The second period of treatment elicited a significant further improvement in lung function and reduction in dyspnea score and salbutamol use in both groups. On the contrary, differences in improvements in FEV1 and FVC and reduction in dyspnea score and salbutamol use between theophylline and placebo arms at the end of the second treatment period were not significant, although 5 patients reported an important relief in dyspnea during the theophylline administration period. These findings question the importance of adding theophylline in stable COPD patients already treated with two long-acting bronchodilators, but also indicate the possibility that some of them can benefit from theophylline because of a symptomatic improvement. & 2006 Published by Elsevier Ltd.
Introduction Corresponding author.
E-mail address: [email protected] (M. Cazzola). Present address: Department of Internal Medicine, Unit of Respiratory Diseases, University of Rome Tor Vergata, Rome, Italy. 1
0954-6111/$ - see front matter & 2006 Published by Elsevier Ltd. doi:10.1016/j.rmed.2006.09.012
Current evidence supports the recommendation of the Global Initiative for chronic obstructive lung disease (GOLD) guidelines1 and American Thoracic Society/European
ARTICLE IN PRESS 958 Respiratory Society position paper2 of at least one of the two classes of long-acting inhaled bronchodilators, either oncedaily tiotropium or twice-daily salmeterol or formoterol, as initial maintenance therapy for symptomatic chronic obstructive pulmonary disease (COPD). There is no data supporting the superiority of one of the families of inhaled bronchodilators (i.e., b2 agonists and anti-cholinergic agents) over the other. Thus, the choice has to be based on the individual symptomatic response. In patients who do not respond satisfactorily to tiotropium or a long-acting inhaled b-agonist as the initially prescribed single maintenance agent, the GOLD guidelines recommend the addition of the alternate class of long-acting inhaled bronchodilator as the next step. In effect, an increasing body of evidence3–7 indicates that the combination of a long-acting b2-agonsit and a long-acting anti-muscarinic agent is an effective therapeutic approach for patients suffering from moderate-to-severe COPD. Unfortunately treatments prescribed for COPD patients do not always follow current guidelines, particularly in the primary care setting. Recently, Taskin et al.8 have examined the adherence to GOLD guidelines recommendation among patients entering UPLIFT, a global trial evaluating the efficacy of tiotropium in slowing COPD progression and have observed that the percentage of patients receiving longacting bronchodilators increased as COPD severity increased; however, a substantial number of patients were not receiving long-acting bronchodilators in accordance with GOLD guidelines. In particular, long-acting bronchodilators (anti-cholinergics and/or b-agonists) were used in 67.3% and 69.3% of patients. The use of theophylline in 34.9% and 36.1% patients suffering from severe and very severe COPD, respectively, was another unexpected finding. Theophylline, which used to be part of the mainstay of treatment for COPD, has been relegated to third-line therapy in COPD because of the frequency of side effects and relative low efficacy.9 Nonetheless, it is inexpensive and still has its role. In fact, theophylline tends to be added to these inhaled bronchodilators in more severe patients and has been shown to give additional clinical improvement when added to a long-acting b2-agonist.10,11 Moreover, increasing evidence shows that theophylline has significant anti-inflammatory effects in COPD at lower plasma concentrations.12 In particular, Barnes12 has highlighted that it is the only therapy currently available that is anti-inflammatory in patients with COPD. These findings are important and might justify the body of evidence that supports the use of theophylline together with a b2-agonist and an anti-cholinergic because a number of patients with COPD may respond subjectively to theophylline. In effect, GOLD guidelines1 report that the combination of a b2-agonist, an anti-cholinergic, and theophylline may produce additional improvements in lung function and heath status. We examined the additive effect of oral theophylline in patients with stable COPD who received both tiotropium, 18 mg od, and formoterol, 12 mg bid in a regular manner.
Patients and methods Thirty-six patients with well-controlled moderate-to-very severe COPD were enrolled. All of them were 50 years of age
M. Cazzola, M.G. Matera or older, and were current or former smokers with a 20 packyear or more history. Inclusion criteria required a baseline FEV1 of less than 70% of predicted but more than 0.50 L, and a postbronchodilator FEV1/FVC o70% following salbutamol, 400 mg. Exclusion criteria were as follows: current evidence of asthma as primary diagnosis; unstable respiratory disease requiring oral/parenteral corticosteroids within 4 weeks prior to beginning the study; upper or lower respiratory tract infection within 4 weeks of the screening visit; unstable angina or unstable arrhythmias; concurrent use of medications that affected COPD or interacted with methylxanthine products, such as macrolides or fluoroquinolones; and evidence of alcohol abuse. All patients were not taking theophylline at the time of recruitment in order to avoid the well-known effects of theophylline withdrawal in COPD.13 Table 1 outlines some characteristics and the smoking history of the population studied. This was a single-blind, placebo-controlled, randomized, two-period trial. Following an initial screening visit, all eligible patients entered a 7 days inhaled placebo run-in during which their regular treatment for COPD was stopped and they received salbutamol for relief of breakthrough symptoms and inhaled corticosteroids when already used. Thereafter, all patients were treated with formoterol 12 mg bid+tiotropium 18 mg od for 4 weeks. After this first period, they were divided in two groups of 18 patients each in a random manner. Both groups continued with the initial treatment for further 4 weeks, but the first group also oral received placebo twice whereas the second group received oral theophylline (i.e., 200 or 300 mg twice daily throughout the 4 weeks [the 300-mg dose was only for patients weighing480 kg, and these patients received 200 mg bid for first week and the higher 300-mg dose bid for the remaining 3 weeks]). The patients were blinded to the nature of the oral medications. After the initial screening visit, patients returned to the clinic at the end of the 7-day placebo run-in period for visit 2, at which time they started the treatment regimen with formoterol+tiotropium. Afterwards, they attended the clinic after 4 weeks of treatment when they were randomized to placebo or theophylline, and after 4 further weeks of treatment for evaluations of pulmonary function. Patients withheld from taking their study medication on the morning of each visit, so all measurements were made at trough (i.e., approximately 12 h after their preceding evening dose was received). At each visit, three FEV1 and FVC measurements were taken, and the highest of each was recorded. Changes in the perception of dyspnea assessed through use of a bipolar visual anagogic scale (VAS), and supplemental salbutamol use were also monitored at each visit. The VAS consisted of a 20-cm horizontal line scoring between 0 (very much better) at the left end, and 10 (very much worse) at the right, with ‘no change’ in the middle. All patients were familiarized with the VAS before the study. The supplemental salbutamol use was recorded by the patient daily throughout the 2-month treatment period. At the end of the second 4-week-treatment, we checked the serum theophylline concentration in all patients included in the theophylline arm. Adverse events were collected through non-specific questioning or direct observation by investigators at each clinic visit and through spontaneous reports by patients.
ARTICLE IN PRESS Effect of theophylline on a combination of formoterol and tiotropium in stable COPD
Table 1
959
Demographics of the population studied.
Variables
Placebo arm
Theophylline arm
Age (year) Sex (no.) Smoking (pack-year) Current smokers, n (%) FEV1, predicted (%) FEV1/FVC ratio (before bronchodilator) Inhaled corticosteroid use, n (%) Tiotropium use, n (%) Long-acting b2-agonist use, n (%) Theophylline use, n (%)
63.873.1 15 M–3 F 4874.7 12 (72) 42 (1.7) 5073.2 9 (50) 7 (39) 18 (100) 2 (11)
66.274.0 17 M–1 F 5575.2 11 (61) 39 (1.4) 5173.7 11 (61) 6 (33) 18 (100) 1 (6)
Data are presented as mean7SE unless otherwise indicated. M, male; F, female.
Patients who experienced exacerbation resulting in hospitalization or, at least, treatment with an oral corticosteroid and/or antibiotic during the study period were withdrawn. The definition of exacerbation used in the present study was ‘‘a worsening of respiratory symptoms, which requires treatment with oral corticosteroids or antibiotics, or both’’.14 This was a pilot study and the first known evaluation of the additive effect of theophylline on a combination of formoterol and tiotropium in stable COPD. In view of the lack of previous experiences, no statistical hypotheses were drawn and consequently no formal sample size calculation was made. The use of a pilot study such as the current study in clinical research is a well-established scientific procedure and only through the use of a pilot study can statisticians clarify data distributions and determine appropriate sample sizes for full-scale clinical trials.3 The primary efficacy measure was the mean change from baseline in predose FEV1 at the end of the study. Secondary efficacy measures included change from baseline in FVC, VAS score assessing dyspnea and in supplemental salbutamol. Student’s t-test for paired data and repeated ANOVA measurements were used for statistical analysis. Values of po0:05 were considered as significant.
Results All patients completed the first treatment period with formoterol+tiotropium. Thirty-three patients completed the second treatment period: 17 patients in the placebo arm, and 16 patients in the theophylline arm. The patient in the placebo arm was withdrawn for COPD exacerbation resulting in hospitalization. The two patients in the theophylline were withdrawn for severe headache and rhythm disturbances, respectively. There was no significant difference among the post run-in baseline spirometric values of the two treatment groups (FEV1, P40.05)). The mean7SE baseline FEV1 and FVC at the start of the treatment periods were 1.01770.07 L and 1.99270.130 L, respectively in the placebo arm and 0.94170.07 L and 1.86470.129 L, respectively, in the theophylline arm. Mean predose FEV1 and FVC values significantly (Po0.001) improved compared to baseline at the end of the first 4week treatment in both arms (Fig. 1). At the end of the
second 4-week treatment, FEV1 (Po0.001 both in the placebo arm and in the theophylline arm, respectively) and FVC (Po0.05 in the placebo arm and Po0.001 in the theophylline arm, respectively) values further significantly improved in both arms (Fig. 1). On the contrary, differences in improvements in FEV1 and FVC between theophylline and placebo arms at the end of the second treatment period were not significant (P ¼ 0.779 and P ¼ 0.638, respectively). The initial 4-week treatment with formoterol+tiotropium induced a significant (Po0.001) improvement in dyspnea and induced a significant (Po0.001) reduction in the use of supplemental salbutamol (Fig. 2). At the end of the second 4-week treatment with formoterol+tiotropium, we observed an additional significant improvement in dyspnea (Po0.01 in the placebo arm and Po0.001 in the theophylline arm, respectively) and a further significant (Po0.05, both in the placebo arm and in the theophylline arm) reduction in the use of salbutamol as rescue medication (Fig. 2). Differences in changes in dyspnea score and use of supplemental salbutamol between theophylline and placebo arms at the end of the second treatment period were not significant (P ¼ 0.436 and P ¼ 0.975, respectively). In any case, 5 patients reported an important relief in dyspnea at the end the theophylline administration period. Ten out of 16 patients had a theophylline concentration above the lower limit of 10 mg/mL, only one had a serum theophylline concentration 420 mg/mL, and in the other five patients theophylline concentration was in the 7–10 mg/ mL range. A part the three patients that were withdrawn for severe adverse events, two patients in the theophylline arm suffered from a mild gastrointestinal adverse event and another from insomnia.
Discussion Theophylline is still widely used as a bronchodilator in COPD, although inhaled bronchodilators are preferred.1,2 Usually theophylline tends to be added to these inhaled bronchodilators in patients with more severe COPD.15 In a crossover study, 16 patients with severe COPD received high-dose salbutamol followed by high-dose theophylline, and the opposite regimen.16 The increase in FEV1 with salbutamol
ARTICLE IN PRESS 960
M. Cazzola, M.G. Matera FEV1 1.25
VAS
§§§
1.10 L
§§§
score
7
5
§§§
3
§§
0.95
0.80 0
4 weeks
8
0
FVC 5.5
§ 1.85 1.70 0
4 weeks
8
Figure 1 Mean FEV1 and FVC values during 8 weeks of therapy with formoterol 12 mg bid+tiotropium 18 mg od plus, in the second 4-week treatment, placebo (n 17, squares) or theophylline (n 16, triangles), respectively. Values are mean7SE. Po0:001 versus time point 0 (end of the run-in); y Po0:05, and yyy Po0:001 vs. 4-week time point.
alone was 24% of the baseline value, versus 17% with theophylline alone. The responses to the two agents were additive regardless of which drug was given first. Interestingly, patients with reversibility to salbutamol showed a large increase in FEV1 when theophylline was added (32% of baseline), whereas those with poorly reversible obstruction showed no additional benefit when theophylline was added. These observations raise the question of the risk–benefit ratio of theophylline therapy for patients with poorly reversible obstruction. Others have recommended the opposite: that theophylline must be reserved for patients with bronchodilator irreversibility.17 Interestingly, many studies have shown that combinations of b2-agonists, anticholinergic agents, and theophylline can achieve additional improvements in lung function and health status.18–20 Nonetheless, Lefcoe et al.21, who compared the bronchodilator effects of ipratropium 40 mg plus oral fenoterol 5 mg, plus oral oxtriphylline 400 mg, and ipratropium 40 mg, plus fenoterol 5 mg, plus oxtriphylline 400 mg in a double-blind, single-dose study of 15 bronchitis patients, documented that the three-drug and the fenoterol–oxtriphylline regimens were not significantly better than ipratropium alone.
number of puffs
L
2.00
8
Supplemental salbutamol
§§§ 2.30 2.15
4 weeks
4.0
2.5
§§
1.0
§ 0
4 weeks
8
Figure 2 Mean VAS score and daily numbers of puffs of salbutamol as rescue medication averaged over the 7 days of the run-in period (time point 0) and over the week preceding each visit, during 8 weeks of therapy with formoterol 12 mg bid+tiotropium 18 mg od plus, in the second 4-week treatment, placebo (n 17, squares) or theophylline (n 16, triangles), respectively. Values are mean7SE. po0:001 vs. time point 0; y Po0:05, yy Po0:01 and yyy Po0:001 vs. 4-week time point.
More recently, theophylline has been shown to give additional clinical improvement when added to salmeterol,10,11 but Yildiz et al.22 have documented that the addition of theophylline to formoterol had similar effects on St. George’s Respiratory Questionnaire scores and lung functions when compared to formoterol+ipratropium. It has also been reported that the combined use of theophylline with inhaled tiotropium bromide produces better exercise capacity than the tiotropium alone in patients with stable COPD.23 Our study documented that the addition of theophylline on a combination of formoterol and tiotropium in stable COPD did not induced a significant further improvement in lung function and in dyspnea. We must underline that this was a pilot study and, consequently, associated with an insufficient statistical power. It is likely that the failure to show a statistically significant difference between treatments when we explored the impact of different therapies on dyspnea and salbutamol use was likely associated with an insufficient statistical power in the study, although the differences between treatments were small. Obviously,
ARTICLE IN PRESS Effect of theophylline on a combination of formoterol and tiotropium in stable COPD there was a possibility of a type II error, which supported the lack of significance that we have repeatedly observed24 and, perhaps, a study with a larger sample would likely have reached statistical significance. In any case, our study questions the importance of adding theophylline in stable COPD patients already treated with two long-acting bronchodilators, although it indicates the possibility that some of them can benefit from theophylline because of a symptomatic improvement. A systematic review and meta-analysis of efficacy of theophylline in people with stable COPD has documented that beneficial effects may be obtained in individuals who remain symptomatic from COPD, despite first-line bronchodilator therapy.25 We cannot confirm this finding because we have observed improvement in dyspnea in both groups, but differences between theophylline and placebo groups were not significant. In any case, the fact that five patients reported an important relief in dyspnea during the theophylline administration period and these patients were between those with more severe dyspnea at the end of the first 4-week treatment with formoterol+tiotropium supports this opinion. It is evident that larger parallel, randomized-controlled trials with explicit clinical and diagnostic criteria, sufficient duration of follow-up and description of all relevant clinical outcome measures are warranted in order to understand when the addition of theophylline is really needed. In any case, theophylline possesses anti-inflammatory and immunomodulatory effects in addition to its well-recognized effects as a bronchodilator when administered at doses that are not associated with unacceptable side effects and which may be used in selected patients without serum monitoring.26,27 Therefore, we believe that a combination therapy with tiotropium and a long-acting b2-agonist may serve as a basis for improved ‘triple therapy’ combinations with lowdose theophylline with the aim of delivering three complementary therapeutic effects for patients with COPD. In order to explore this possibility, a trial of longer duration (at least 1 year) is mandatory.
References 1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, 2005 [accessed August 26, 2006]. Available at: /http://www.goldcopd.comS. 2. Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932–46. 3. Cazzola M, Di Marco F, Santus P, Boveri B, Verga M, Matera MG, et al. The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD. Pulm Pharmacol Ther 2004;17:35–9. 4. Cazzola M, Centanni S, Santus P, Verga M, Mondoni M, di Marco F, et al. The functional impact of adding salmeterol and tiotropium in patients with stable COPD. Respir Med 2004;98: 1214–21. 5. Cazzola M, Noschese P, Salzillo A, De Giglio C, D’Amato G, Matera MG. Bronchodilator response to formoterol after regular tiotropium or to tiotropium after regular formoterol in COPD patients. Respir Med 2005;99:524–8. 6. van Noord JA, Aumann JL, Janssens E, Smeets JJ, Verhaert J, Disse B, et al. Comparison of tiotropium once daily, formoterol
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twice daily and both combined once daily in patients with COPD. Eur Respir J 2005;26:214–22. van Noord JA, Aumann JL, Janssens E, Verhaert J, Smeets JJ, Mueller A, et al. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest 2006;129:509–17. Tashkin D, Celli B, Decramer M, Burkhart D, Kesten S, Cassino C. Prescribing patterns according to COPD treatment guidelines in patients enrolled in a global clinical trial [abstract]. Proc Am Thorac Soc 2006;3:A111. Cazzola M, Matera MG, Donner CF. Long-acting b2 agonists and theophylline in stable chronic obstructive pulmonary disease. Thorax 1999;54:730–6. Cazzola M, Di Lorenzo G, Di Perna F, Calderaro F, Testi R, Centanni S. Additive effects of salmeterol and fluticasone or theophylline in COPD. Chest 2000;118:1576–81. ZuWallack RL, Mahler DA, Reilly D, Church N, Emmett A, Rickard K, et al. Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest 2001;119:1661–70. Barnes PJ. Theophylline in chronic obstructive pulmonary disease: new horizons. Proc Am Thorac Soc 2005;2:334–9. Kirsten DK, Wegner RE, Jorres RA, Magnussen H. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993;104:1101–7. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br Med J 2000;320:1297–303. Donohue JF. Combination therapy for chronic obstructive pulmonary disease: clinical aspects. Proc Am Thorac Soc 2005; 2:272–81. Filuk RB, Easton PA, Anthonisen NR. Responses to large doses of salbutamol and theophylline in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;132: 871–4. Thomas P, Pugsley JA, Stewart JH. Theophylline and salbutamol improve pulmonary function in patients with irreversible chronic obstructive pulmonary disease. Chest 1992;101: 160–5. Nishimura K, Koyama H, Ikeda A, Izumi T. Is oral theophylline effective in combination with both inhaled anticholinergic agent inhaled b2-agonist in the treatment of stable COPD? Chest 1993;104:179–84. Karpel JP, Kotch A, Zinny M, Pesin J, Alleyne W. A comparison of inhaled ipratropium, oral theophylline plus inhaled b-agonist, and the combination of all three in patients with COPD. Chest 1994;105:1089–94. Nishimura K, Koyama H, Ikeda A, Sugiura N, Kawakatsu K, Izumi T. The additive effect of theophylline on a high-dose combination of inhaled salbutamol and ipratropium bromide in stable COPD. Chest 1995;107:718–23. Lefcoe NM, Toogood JH, Blennerhassett G, Baskerville J, Paterson NA. The addition of an aerosol anticholinergic to an oral beta agonist plus theophylline in asthma and bronchitis: a double-blind single dose study. Chest 1982;82(3):300–5. Yildiz F, Basyigit I, Yildirim E, Boyaci H, Ilgazli A. Different bronchodilator combinations have similar effects on health status in COPD. Pulm Pharmacol Ther 2006;19:101–6. Hanaoka Y, Teramoto S, Yamamoto H, Yamaguchi Y, Ouchi Y. Effects of the sustained release of theophylline, UnifilR, and tiotropium bromide on pulmonary function and exercise performance in patients with stable chronic obstructive pulmonary disease [abstract]. Proc Am Thorac Soc 2006; 3:A114. Freiman JA, Chalmers TC, Smith H, Kuebler RR. The importance of b, the type II error, and sample size in the design and interpretation of the randomized controlled trial. In: Bailar JC,
ARTICLE IN PRESS 962 Mosteller F, editors. Medical uses of statistics. Boston, USA: NEJM Books; 1992. p. 357–73. 25. Ram FS, Jardin JR, Atallah A, Castro AA, Mazzini R, Goldstein R, et al. Efficacy of theophylline in people with stable chronic obstructive pulmonary disease: a systematic review and metaanalysis. Respir Med 2005;99:135–44.
M. Cazzola, M.G. Matera 26. Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J. Antiinflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 1994;343:1006–8. 27. Boswell-Smith V, Cazzola M, Page CP. Are phosphodiesterase 4 inhibitors just more theophylline? J Allergy Clin Immunol 2006;117:1237–43.
The additive effect of theophylline on a combination of formoterol and tiotropium in stable COPD: A pilot study Mario Cazzolaa,,1, Maria Gabriella Materab a
Department of Respiratory Medicine, Unit of Pneumology and Allergology, A. Cardarelli Hospital, Naples, Italy Department of Experimental Medicine, Unit of Pharmacology, 2nd University of Naples, Naples, Italy
b
Received 30 August 2006; accepted 9 September 2006 Available online 23 October 2006
KEYWORDS COPD; Tiotropium; Formoterol; Theophylline; Combination therapy
Summary We explored the additive effect of titrated oral theophylline in patients with stable chronic obstructive pulmonary disease (COPD) who received both tiotropium, 18 mg od, and formoterol, 12 mg bid. Thirty-six patients with moderate-to-severe COPD were enrolled in this two-period trial. They were initially treated with formoterol+tiotropium for 4 weeks. After this first period, they were divided in two groups of 18 patients. Both groups continued with the initial treatment for further 4 weeks, but the first group received also placebo whereas the second group received oral theophylline. The combination therapy with formoterol+tiotropium induced a significant improvement in mean predose FEV1 and FVC at the end of the first period, and a significant reduction in dyspnea score as measure by a visual analogic scale and in use of rescue salbutamol. The second period of treatment elicited a significant further improvement in lung function and reduction in dyspnea score and salbutamol use in both groups. On the contrary, differences in improvements in FEV1 and FVC and reduction in dyspnea score and salbutamol use between theophylline and placebo arms at the end of the second treatment period were not significant, although 5 patients reported an important relief in dyspnea during the theophylline administration period. These findings question the importance of adding theophylline in stable COPD patients already treated with two long-acting bronchodilators, but also indicate the possibility that some of them can benefit from theophylline because of a symptomatic improvement. & 2006 Published by Elsevier Ltd.
Introduction Corresponding author.
E-mail address: [email protected] (M. Cazzola). Present address: Department of Internal Medicine, Unit of Respiratory Diseases, University of Rome Tor Vergata, Rome, Italy. 1
0954-6111/$ - see front matter & 2006 Published by Elsevier Ltd. doi:10.1016/j.rmed.2006.09.012
Current evidence supports the recommendation of the Global Initiative for chronic obstructive lung disease (GOLD) guidelines1 and American Thoracic Society/European
ARTICLE IN PRESS 958 Respiratory Society position paper2 of at least one of the two classes of long-acting inhaled bronchodilators, either oncedaily tiotropium or twice-daily salmeterol or formoterol, as initial maintenance therapy for symptomatic chronic obstructive pulmonary disease (COPD). There is no data supporting the superiority of one of the families of inhaled bronchodilators (i.e., b2 agonists and anti-cholinergic agents) over the other. Thus, the choice has to be based on the individual symptomatic response. In patients who do not respond satisfactorily to tiotropium or a long-acting inhaled b-agonist as the initially prescribed single maintenance agent, the GOLD guidelines recommend the addition of the alternate class of long-acting inhaled bronchodilator as the next step. In effect, an increasing body of evidence3–7 indicates that the combination of a long-acting b2-agonsit and a long-acting anti-muscarinic agent is an effective therapeutic approach for patients suffering from moderate-to-severe COPD. Unfortunately treatments prescribed for COPD patients do not always follow current guidelines, particularly in the primary care setting. Recently, Taskin et al.8 have examined the adherence to GOLD guidelines recommendation among patients entering UPLIFT, a global trial evaluating the efficacy of tiotropium in slowing COPD progression and have observed that the percentage of patients receiving longacting bronchodilators increased as COPD severity increased; however, a substantial number of patients were not receiving long-acting bronchodilators in accordance with GOLD guidelines. In particular, long-acting bronchodilators (anti-cholinergics and/or b-agonists) were used in 67.3% and 69.3% of patients. The use of theophylline in 34.9% and 36.1% patients suffering from severe and very severe COPD, respectively, was another unexpected finding. Theophylline, which used to be part of the mainstay of treatment for COPD, has been relegated to third-line therapy in COPD because of the frequency of side effects and relative low efficacy.9 Nonetheless, it is inexpensive and still has its role. In fact, theophylline tends to be added to these inhaled bronchodilators in more severe patients and has been shown to give additional clinical improvement when added to a long-acting b2-agonist.10,11 Moreover, increasing evidence shows that theophylline has significant anti-inflammatory effects in COPD at lower plasma concentrations.12 In particular, Barnes12 has highlighted that it is the only therapy currently available that is anti-inflammatory in patients with COPD. These findings are important and might justify the body of evidence that supports the use of theophylline together with a b2-agonist and an anti-cholinergic because a number of patients with COPD may respond subjectively to theophylline. In effect, GOLD guidelines1 report that the combination of a b2-agonist, an anti-cholinergic, and theophylline may produce additional improvements in lung function and heath status. We examined the additive effect of oral theophylline in patients with stable COPD who received both tiotropium, 18 mg od, and formoterol, 12 mg bid in a regular manner.
Patients and methods Thirty-six patients with well-controlled moderate-to-very severe COPD were enrolled. All of them were 50 years of age
M. Cazzola, M.G. Matera or older, and were current or former smokers with a 20 packyear or more history. Inclusion criteria required a baseline FEV1 of less than 70% of predicted but more than 0.50 L, and a postbronchodilator FEV1/FVC o70% following salbutamol, 400 mg. Exclusion criteria were as follows: current evidence of asthma as primary diagnosis; unstable respiratory disease requiring oral/parenteral corticosteroids within 4 weeks prior to beginning the study; upper or lower respiratory tract infection within 4 weeks of the screening visit; unstable angina or unstable arrhythmias; concurrent use of medications that affected COPD or interacted with methylxanthine products, such as macrolides or fluoroquinolones; and evidence of alcohol abuse. All patients were not taking theophylline at the time of recruitment in order to avoid the well-known effects of theophylline withdrawal in COPD.13 Table 1 outlines some characteristics and the smoking history of the population studied. This was a single-blind, placebo-controlled, randomized, two-period trial. Following an initial screening visit, all eligible patients entered a 7 days inhaled placebo run-in during which their regular treatment for COPD was stopped and they received salbutamol for relief of breakthrough symptoms and inhaled corticosteroids when already used. Thereafter, all patients were treated with formoterol 12 mg bid+tiotropium 18 mg od for 4 weeks. After this first period, they were divided in two groups of 18 patients each in a random manner. Both groups continued with the initial treatment for further 4 weeks, but the first group also oral received placebo twice whereas the second group received oral theophylline (i.e., 200 or 300 mg twice daily throughout the 4 weeks [the 300-mg dose was only for patients weighing480 kg, and these patients received 200 mg bid for first week and the higher 300-mg dose bid for the remaining 3 weeks]). The patients were blinded to the nature of the oral medications. After the initial screening visit, patients returned to the clinic at the end of the 7-day placebo run-in period for visit 2, at which time they started the treatment regimen with formoterol+tiotropium. Afterwards, they attended the clinic after 4 weeks of treatment when they were randomized to placebo or theophylline, and after 4 further weeks of treatment for evaluations of pulmonary function. Patients withheld from taking their study medication on the morning of each visit, so all measurements were made at trough (i.e., approximately 12 h after their preceding evening dose was received). At each visit, three FEV1 and FVC measurements were taken, and the highest of each was recorded. Changes in the perception of dyspnea assessed through use of a bipolar visual anagogic scale (VAS), and supplemental salbutamol use were also monitored at each visit. The VAS consisted of a 20-cm horizontal line scoring between 0 (very much better) at the left end, and 10 (very much worse) at the right, with ‘no change’ in the middle. All patients were familiarized with the VAS before the study. The supplemental salbutamol use was recorded by the patient daily throughout the 2-month treatment period. At the end of the second 4-week-treatment, we checked the serum theophylline concentration in all patients included in the theophylline arm. Adverse events were collected through non-specific questioning or direct observation by investigators at each clinic visit and through spontaneous reports by patients.
ARTICLE IN PRESS Effect of theophylline on a combination of formoterol and tiotropium in stable COPD
Table 1
959
Demographics of the population studied.
Variables
Placebo arm
Theophylline arm
Age (year) Sex (no.) Smoking (pack-year) Current smokers, n (%) FEV1, predicted (%) FEV1/FVC ratio (before bronchodilator) Inhaled corticosteroid use, n (%) Tiotropium use, n (%) Long-acting b2-agonist use, n (%) Theophylline use, n (%)
63.873.1 15 M–3 F 4874.7 12 (72) 42 (1.7) 5073.2 9 (50) 7 (39) 18 (100) 2 (11)
66.274.0 17 M–1 F 5575.2 11 (61) 39 (1.4) 5173.7 11 (61) 6 (33) 18 (100) 1 (6)
Data are presented as mean7SE unless otherwise indicated. M, male; F, female.
Patients who experienced exacerbation resulting in hospitalization or, at least, treatment with an oral corticosteroid and/or antibiotic during the study period were withdrawn. The definition of exacerbation used in the present study was ‘‘a worsening of respiratory symptoms, which requires treatment with oral corticosteroids or antibiotics, or both’’.14 This was a pilot study and the first known evaluation of the additive effect of theophylline on a combination of formoterol and tiotropium in stable COPD. In view of the lack of previous experiences, no statistical hypotheses were drawn and consequently no formal sample size calculation was made. The use of a pilot study such as the current study in clinical research is a well-established scientific procedure and only through the use of a pilot study can statisticians clarify data distributions and determine appropriate sample sizes for full-scale clinical trials.3 The primary efficacy measure was the mean change from baseline in predose FEV1 at the end of the study. Secondary efficacy measures included change from baseline in FVC, VAS score assessing dyspnea and in supplemental salbutamol. Student’s t-test for paired data and repeated ANOVA measurements were used for statistical analysis. Values of po0:05 were considered as significant.
Results All patients completed the first treatment period with formoterol+tiotropium. Thirty-three patients completed the second treatment period: 17 patients in the placebo arm, and 16 patients in the theophylline arm. The patient in the placebo arm was withdrawn for COPD exacerbation resulting in hospitalization. The two patients in the theophylline were withdrawn for severe headache and rhythm disturbances, respectively. There was no significant difference among the post run-in baseline spirometric values of the two treatment groups (FEV1, P40.05)). The mean7SE baseline FEV1 and FVC at the start of the treatment periods were 1.01770.07 L and 1.99270.130 L, respectively in the placebo arm and 0.94170.07 L and 1.86470.129 L, respectively, in the theophylline arm. Mean predose FEV1 and FVC values significantly (Po0.001) improved compared to baseline at the end of the first 4week treatment in both arms (Fig. 1). At the end of the
second 4-week treatment, FEV1 (Po0.001 both in the placebo arm and in the theophylline arm, respectively) and FVC (Po0.05 in the placebo arm and Po0.001 in the theophylline arm, respectively) values further significantly improved in both arms (Fig. 1). On the contrary, differences in improvements in FEV1 and FVC between theophylline and placebo arms at the end of the second treatment period were not significant (P ¼ 0.779 and P ¼ 0.638, respectively). The initial 4-week treatment with formoterol+tiotropium induced a significant (Po0.001) improvement in dyspnea and induced a significant (Po0.001) reduction in the use of supplemental salbutamol (Fig. 2). At the end of the second 4-week treatment with formoterol+tiotropium, we observed an additional significant improvement in dyspnea (Po0.01 in the placebo arm and Po0.001 in the theophylline arm, respectively) and a further significant (Po0.05, both in the placebo arm and in the theophylline arm) reduction in the use of salbutamol as rescue medication (Fig. 2). Differences in changes in dyspnea score and use of supplemental salbutamol between theophylline and placebo arms at the end of the second treatment period were not significant (P ¼ 0.436 and P ¼ 0.975, respectively). In any case, 5 patients reported an important relief in dyspnea at the end the theophylline administration period. Ten out of 16 patients had a theophylline concentration above the lower limit of 10 mg/mL, only one had a serum theophylline concentration 420 mg/mL, and in the other five patients theophylline concentration was in the 7–10 mg/ mL range. A part the three patients that were withdrawn for severe adverse events, two patients in the theophylline arm suffered from a mild gastrointestinal adverse event and another from insomnia.
Discussion Theophylline is still widely used as a bronchodilator in COPD, although inhaled bronchodilators are preferred.1,2 Usually theophylline tends to be added to these inhaled bronchodilators in patients with more severe COPD.15 In a crossover study, 16 patients with severe COPD received high-dose salbutamol followed by high-dose theophylline, and the opposite regimen.16 The increase in FEV1 with salbutamol
ARTICLE IN PRESS 960
M. Cazzola, M.G. Matera FEV1 1.25
VAS
§§§
1.10 L
§§§
score
7
5
§§§
3
§§
0.95
0.80 0
4 weeks
8
0
FVC 5.5
§ 1.85 1.70 0
4 weeks
8
Figure 1 Mean FEV1 and FVC values during 8 weeks of therapy with formoterol 12 mg bid+tiotropium 18 mg od plus, in the second 4-week treatment, placebo (n 17, squares) or theophylline (n 16, triangles), respectively. Values are mean7SE. Po0:001 versus time point 0 (end of the run-in); y Po0:05, and yyy Po0:001 vs. 4-week time point.
alone was 24% of the baseline value, versus 17% with theophylline alone. The responses to the two agents were additive regardless of which drug was given first. Interestingly, patients with reversibility to salbutamol showed a large increase in FEV1 when theophylline was added (32% of baseline), whereas those with poorly reversible obstruction showed no additional benefit when theophylline was added. These observations raise the question of the risk–benefit ratio of theophylline therapy for patients with poorly reversible obstruction. Others have recommended the opposite: that theophylline must be reserved for patients with bronchodilator irreversibility.17 Interestingly, many studies have shown that combinations of b2-agonists, anticholinergic agents, and theophylline can achieve additional improvements in lung function and health status.18–20 Nonetheless, Lefcoe et al.21, who compared the bronchodilator effects of ipratropium 40 mg plus oral fenoterol 5 mg, plus oral oxtriphylline 400 mg, and ipratropium 40 mg, plus fenoterol 5 mg, plus oxtriphylline 400 mg in a double-blind, single-dose study of 15 bronchitis patients, documented that the three-drug and the fenoterol–oxtriphylline regimens were not significantly better than ipratropium alone.
number of puffs
L
2.00
8
Supplemental salbutamol
§§§ 2.30 2.15
4 weeks
4.0
2.5
§§
1.0
§ 0
4 weeks
8
Figure 2 Mean VAS score and daily numbers of puffs of salbutamol as rescue medication averaged over the 7 days of the run-in period (time point 0) and over the week preceding each visit, during 8 weeks of therapy with formoterol 12 mg bid+tiotropium 18 mg od plus, in the second 4-week treatment, placebo (n 17, squares) or theophylline (n 16, triangles), respectively. Values are mean7SE. po0:001 vs. time point 0; y Po0:05, yy Po0:01 and yyy Po0:001 vs. 4-week time point.
More recently, theophylline has been shown to give additional clinical improvement when added to salmeterol,10,11 but Yildiz et al.22 have documented that the addition of theophylline to formoterol had similar effects on St. George’s Respiratory Questionnaire scores and lung functions when compared to formoterol+ipratropium. It has also been reported that the combined use of theophylline with inhaled tiotropium bromide produces better exercise capacity than the tiotropium alone in patients with stable COPD.23 Our study documented that the addition of theophylline on a combination of formoterol and tiotropium in stable COPD did not induced a significant further improvement in lung function and in dyspnea. We must underline that this was a pilot study and, consequently, associated with an insufficient statistical power. It is likely that the failure to show a statistically significant difference between treatments when we explored the impact of different therapies on dyspnea and salbutamol use was likely associated with an insufficient statistical power in the study, although the differences between treatments were small. Obviously,
ARTICLE IN PRESS Effect of theophylline on a combination of formoterol and tiotropium in stable COPD there was a possibility of a type II error, which supported the lack of significance that we have repeatedly observed24 and, perhaps, a study with a larger sample would likely have reached statistical significance. In any case, our study questions the importance of adding theophylline in stable COPD patients already treated with two long-acting bronchodilators, although it indicates the possibility that some of them can benefit from theophylline because of a symptomatic improvement. A systematic review and meta-analysis of efficacy of theophylline in people with stable COPD has documented that beneficial effects may be obtained in individuals who remain symptomatic from COPD, despite first-line bronchodilator therapy.25 We cannot confirm this finding because we have observed improvement in dyspnea in both groups, but differences between theophylline and placebo groups were not significant. In any case, the fact that five patients reported an important relief in dyspnea during the theophylline administration period and these patients were between those with more severe dyspnea at the end of the first 4-week treatment with formoterol+tiotropium supports this opinion. It is evident that larger parallel, randomized-controlled trials with explicit clinical and diagnostic criteria, sufficient duration of follow-up and description of all relevant clinical outcome measures are warranted in order to understand when the addition of theophylline is really needed. In any case, theophylline possesses anti-inflammatory and immunomodulatory effects in addition to its well-recognized effects as a bronchodilator when administered at doses that are not associated with unacceptable side effects and which may be used in selected patients without serum monitoring.26,27 Therefore, we believe that a combination therapy with tiotropium and a long-acting b2-agonist may serve as a basis for improved ‘triple therapy’ combinations with lowdose theophylline with the aim of delivering three complementary therapeutic effects for patients with COPD. In order to explore this possibility, a trial of longer duration (at least 1 year) is mandatory.
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