Theophylline and Salbutamol Improve Pulmonary Function in Patients with Irreversible Chronic Obstructive Pulmonary Disease* Peter 'lhomas, M. B., F. C. C. P.; john A. 'Pugsley, Pharm. D.; and john H. Stewart, M.Sc. To investigate the efficacy of bronchodilators in patients with irreversible chronic obstructive pulmonary disease (COPD), we conducted a double-blind, randomized,~ phase, crossover comparison between placebo, oral theophylline, inhaled salbutamol, and a combination of both drugs in 12 patients with stable COPD (mean age, 63 years) whose increase in forced expiratory volume in 1 s (FEV,) was :S 15 percent following 200 p.g of inhale4 salbutamol. Patients received two weeks of therapy with each of the test regimens. Both theophylline and salbutamol resulted in statistically significant improvement in FEV., forced vital capacity (FVC), slow vital capacity (SVC), residual volume (RV), airway resistance (Raw), and maximum expiratory ftow rate at 50 percent of vital capacity (Vso). In most instances, there were no significant differences between theophylline and salbutamol. Combination therapy produced significantly greater improvement in FEV., FVC, Vso, Raw, and RV than either agent alone. The two drugs interacted in an additive fashion. Neither of the drugs, used siqgly, significantly reduced the severity or incidence
of symptoms. The reduction in dyspnea and wheer.e during combination therapy approached statistical signi6cance (p=0.06) and patient preference was significantly in favor of the combination regimen. None of the active treatments produced significantly more side effects than placebo. We conclude that theophylline and inhaled salbutamol produce significant, and approximately equal, improvement in pulmonary function in patients traditionally classified as suffering from "irreversible" COPD. The combination of theophylline and inhaled salbutamol generally results in additional improveqient over that obtained with either drug used alone and this improvement is reftected by reduced symptomatology and treatment preferenee. (Chat 1992; 101:160-65)
The efficacy of bronchodilators in the treatment of nonasthmatic chronic obstructive pulmonary disease (COPD) is a subject of controversy. Results of available studies are difficult to interpret due to differences in the patient populations, therapeutic regimens, duration of therapy, and outcome measures. The term "irreversible" has also likely contributed to the controversy since the diagnosis is often, albeit incorrectly, 1 interpreted as signifying patients whose disease is unresponsive to bronchodilators. It is now better appreciated that many patients with COPD do have a substantial reversible component to their airffow obstruction and will respond to bronchodilator therapy. The efficacy of theophylline and inhaled P-agonists in COPD patients has been evaluated in controlled studies by Taylor et al, 2 Dollinger et al, 3 and Guyatt
et al. 4 Although there were differences in the magnitude of response and statistical significance of their observations, the results were generally complementary and, in aggregate, demonstrated comparable spirometric and symptomatic improvement from Pagonists and theophylline, with ad4itional improvement when the two agents were combined. While these three studies demonstrate that bronchodilators produce both subjective and objective improvement in COPD, tw3·4 allowed entry of patients with an acute forced expiratory volume in 1 s (FEV1) reversibility up to 25 percent and the other2 required an acute reversibility of at least 10 percent. Accordingly, the results of these studies may not be representative of COPD patients with less acute reversibility. Two studies allowed only patients with documented acute FEV1 reversibility of Sl5 percent. Eaton et al5 compared spirometric and subjective breathing improvement following single oral doses of placebo and theophylline. Theophylline, in doses that produced peak concentrations of 9.5 to 120 µmoVL (17 to 22 mWI..), was associated with statistically significant spirometric improvement and some evidence of symptomatic benefit. Mahler et al6 compared theophylline with placebo in a study of ten weeks' duration and
*From the Division of Respiratory Medicine, St. Michael's Hospital (Dr. Thomas): the Faculty of Phann~, University of Toronto, DeFtment of Pharmacy, St. Michaels Hospital (Dr. Pugsley); and the Scientific Department, Purdue Frederick (Dr. Stewart), Toronto, Canada. Supported by a grant from Purdue Frederick. Manuscript received October 2; revision accepted April 12. Reprint requests: Dr. Thomas, 116 Shuter Street, 'Ibronto, Ontario M5A1V8
160
ANOVA=analysis of variance; FRC=func:tional residual capacity; IC= inspiratory capacity; PE~ expiratory flow rate; Baw=airway ~; RV= • vohune; TLC= total hmJE capacity; VZ5 =Bow rate at !5 percent· of vital capacity; Vso= Bow rate at 50 pen:ent of vital capacity
found significant improvement in dyspnea parameters, but not spirometry or exercise performance. Since, to our knowledge, no controlled study has assessed the comparative efficacy of theophylline and p-agonists in patients with a documented acute FEV; reversibility ~as percent, we performed a crossover trial of placebo, inhaled salbutamol, oral theophylline, and combination therapy in carefuQ.y selected patients with "irreversible" COPD.
METHODS Ibfients
The study population consisted of patients with stable, nonasthmatic, irreversible, COPD. Patients younger than 70 years of age with a clinical diagnosis of COPD, FEV,
of symptoms. The reduction in dyspnea and wheer.e during combination therapy approached statistical signi6cance (p=0.06) and patient preference was significantly in favor of the combination regimen. None of the active treatments produced significantly more side effects than placebo. We conclude that theophylline and inhaled salbutamol produce significant, and approximately equal, improvement in pulmonary function in patients traditionally classified as suffering from "irreversible" COPD. The combination of theophylline and inhaled salbutamol generally results in additional improveqient over that obtained with either drug used alone and this improvement is reftected by reduced symptomatology and treatment preferenee. (Chat 1992; 101:160-65)
The efficacy of bronchodilators in the treatment of nonasthmatic chronic obstructive pulmonary disease (COPD) is a subject of controversy. Results of available studies are difficult to interpret due to differences in the patient populations, therapeutic regimens, duration of therapy, and outcome measures. The term "irreversible" has also likely contributed to the controversy since the diagnosis is often, albeit incorrectly, 1 interpreted as signifying patients whose disease is unresponsive to bronchodilators. It is now better appreciated that many patients with COPD do have a substantial reversible component to their airffow obstruction and will respond to bronchodilator therapy. The efficacy of theophylline and inhaled P-agonists in COPD patients has been evaluated in controlled studies by Taylor et al, 2 Dollinger et al, 3 and Guyatt
et al. 4 Although there were differences in the magnitude of response and statistical significance of their observations, the results were generally complementary and, in aggregate, demonstrated comparable spirometric and symptomatic improvement from Pagonists and theophylline, with ad4itional improvement when the two agents were combined. While these three studies demonstrate that bronchodilators produce both subjective and objective improvement in COPD, tw3·4 allowed entry of patients with an acute forced expiratory volume in 1 s (FEV1) reversibility up to 25 percent and the other2 required an acute reversibility of at least 10 percent. Accordingly, the results of these studies may not be representative of COPD patients with less acute reversibility. Two studies allowed only patients with documented acute FEV1 reversibility of Sl5 percent. Eaton et al5 compared spirometric and subjective breathing improvement following single oral doses of placebo and theophylline. Theophylline, in doses that produced peak concentrations of 9.5 to 120 µmoVL (17 to 22 mWI..), was associated with statistically significant spirometric improvement and some evidence of symptomatic benefit. Mahler et al6 compared theophylline with placebo in a study of ten weeks' duration and
*From the Division of Respiratory Medicine, St. Michael's Hospital (Dr. Thomas): the Faculty of Phann~, University of Toronto, DeFtment of Pharmacy, St. Michaels Hospital (Dr. Pugsley); and the Scientific Department, Purdue Frederick (Dr. Stewart), Toronto, Canada. Supported by a grant from Purdue Frederick. Manuscript received October 2; revision accepted April 12. Reprint requests: Dr. Thomas, 116 Shuter Street, 'Ibronto, Ontario M5A1V8
160
ANOVA=analysis of variance; FRC=func:tional residual capacity; IC= inspiratory capacity; PE~ expiratory flow rate; Baw=airway ~; RV= • vohune; TLC= total hmJE capacity; VZ5 =Bow rate at !5 percent· of vital capacity; Vso= Bow rate at 50 pen:ent of vital capacity
found significant improvement in dyspnea parameters, but not spirometry or exercise performance. Since, to our knowledge, no controlled study has assessed the comparative efficacy of theophylline and p-agonists in patients with a documented acute FEV; reversibility ~as percent, we performed a crossover trial of placebo, inhaled salbutamol, oral theophylline, and combination therapy in carefuQ.y selected patients with "irreversible" COPD.
METHODS Ibfients
The study population consisted of patients with stable, nonasthmatic, irreversible, COPD. Patients younger than 70 years of age with a clinical diagnosis of COPD, FEV,
