A single high dose of formoterolis as e ective as the same dose administered in a cumulative manner in patients with acute exacerbation of COPD

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1 Vol. 97 (2003) 458 ^ 462 A single high dose of formoterolis as e ective as the same dose administered in a cumulative manner in patients with acute exacerbation of COPD M. CAZZOLA *,P.SANTUS w,m.g.matera z,p.carlucci w,e.belloli w,f.di MARCO w AND S.CENTANNI w * Dipartimento di Medicina Respiratoria, Azienda Ospedaliera di Rilevanza Nazionale A.Cardarelli,Unita' Complessa di Pneumologia e Allergologia, Napoli, Italy, w Unita' di Medicina Respiratoria, Ospedale S. Paolo,Universita' degli Studi di Milano, Milano, Italy, z Dipartimento di Medicina Sperimentale, Facolta' di Medicina e Chirurgia, Seconda Universita' degli Studi di Napoli, Napoli, Italy Abstract Several clinical trials have shown that the inhaled b 2 -agonists with long-acting properties, formoterol and salmeterol, may be effective in acute exacerbations of chronic obstructive pulmonary disease (COPD).However, there is a greatdealofcontroversyregarding thetimingand optimaldose of inhaled b 2 -agonistsin this pathologic condition.in this double-blind, randomised, crossover study, we have compared the bronchodilating effect and the safety of inhaled formoterol administered viaturbuhaler using either a cumulative dose regimen or the equivalent single dose in 16 patients with acute exacerbations of COPD.On the two consecutive days, the patients received, in a randomised order, each of the following active dose regimens: (A): mgofformoterolviaturbuhaler(36mg cumulative delivered dose), or (B): mg of formoterol via Turbuhaler. The three doses on each treatment day were administered at 30-mm intervals, with measurements being made 5 and 30 min after each dose.contemporaneously, we also measured oxygen saturation by pulse oximetry (SpO 2 )and pulse rate. Both the high dose and the cumulative one induced a significant bronchodilation expressed as change in FEV 1.The difference between the two regimens was significant (P=0.0332)only 60 min after the first inhalation.the trend of FVC and IC was similar to that of FEV 1. All treatment regimens were well tolerated and no adverse events were reported. Neither the administration of the high dose nor that of the cumulative one modified heart rate in a significant manner. Also they did not influence SpO 2.This study indicates that a single high dose of formoterol is as effective as the same dose administered in a cumulative manner in patients with acute exacerbation of COPD. r 2002 Elsevier Science Ltd. Allrights reserved. doi: /rmed , available online at INTRODUCTION There is a great deal of controversy regarding the timing and optimal dose of inhaled b 2 -agonists in the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD). Whereas these agents once were administered at a moderate dose every hour, there has been a trend towards increasing frequency and size of dosing for inhaled b-agonists (1). However, one study failed to demonstrate a signi cant advantage by giving salbutamol more frequently than once every 60 min (2). Several clinical trials have shown that the inhaled b 2 - agonists along with long-acting properties, formoterol Received 23 September 2002, accepted in revised form 24 September 2002 Correspondence should be addressed to: Mario Cazzola,Via del Parco Margherita 24, 80121Napoli, Italy. Fax: ; mcazzola@qubisoft.it and salmeterol, may be e ective in acute exacerbations of COPD when administered as cumulative doses (3^5). Rodriguez-Roisin (6) correctly de ned an acute exacerbation of COPD as a sustained worsening of the patient s condition, from the stable state and beyond normal dayto-day variations, that is, acute in onset and necessitating a change in regular medication in a patient with underlying COPD. The sustained worsening of the patient s condition is the best reason to use higher than customary dosage of long-acting b 2 -agonists in the treatment of acute exacerbation of COPD (5). It is now mandatory to examine if high doses of these long-acting inhaled b 2- agonists are as e ective as the same doses administered in a cumulative manner. In this study, we have compared the bronchodilating e ect and the safety of inhaled formoterol administered using either a cumulative dose regimen or the equivalent single dose in patients with acute exacerbations of COPD.

2 CUMULATIVE DOSE STUDY IN PATIENTS WITH COPD 459 METHODS Study design The study was of a double-blind, double-dummy, randomised, crossover design taking place over two consecutive days. All work was conducted according to the rules of the Declaration of Helsinki. An independent review board for human studies approved the protocol. Informed written consent was obtained from the patients. Patients Sixteen patients with acute exacerbation of COPD (anthonisen exacerbation type I or II), and who were willing to participate, were recruited (Table 1). Their ages ranged from 51 to 77 years. Six of them were smokers and 10 ex-smokers. The diagnosis of COPD was consistent with the diagnostic standards of European Respiratory Society (ERS) for the management of COPD (7). Acute exacerbation was de ned as a sustained worsening of the patient s condition, from the stable state and beyond normal day-to-day variations [current FEV 1 (forced expiratory volume in one second) always less than 70% of their best], that is, acute in onset and necessitating a change in regular medication in a patient with underlying COPD (6). All patients had no indication for hospitalisation, according to the British Thoracic Society (BTS) Guidelines (8). The number of patients for this study was not calculated because it was a pilot investigation. A bronchodilator response prior to entry into the study was not required, but all patients were able to perform a forced expiratory manoeuvre. Patients with a history of asthma, allergic rhinitis, atopy, or with a total blood eosinophil count over 400/mm 3 were excluded. Patients were also excluded if they had comorbidities (such as congestive heart failure or pulmonary embolus) or complications of COPD (e.g. pneumothorax) as the aetiology of exacerbation of their symptoms. No patient was su ering from febrile tracheobronchitis. Additional medication Oral bronchodilators were not permitted during the study. Short-acting inhaled b 2 -agonists were permitted soon after each test when required. All patients received a treatment with an oral antibiotic (co-amoxiclav or levo- oxacin) and an inhaled steroid (budesonide 400 mg or uticasone 250 mg twice daily), Patients were asked not to consume cola drinks, co ee or tea and not to smoke in the hours before and during the investigation. Treatment On the two consecutive days, the patients received, in a randomised order, each of the following active dose regimens: (A): mg of formoterol via Turbuhaler (36 mg cumulative delivered dose equivalent to cumulative metered dose of 48 mg). (B): mg of formoterol viaturbuhaler (delivered dose). Treatments were double-blinded, using Turbuhaler placebo inhalers; active inhalation was performed rst. Patients always inhaled four consecutive doses. All inhalations were made by administering either formoterol (9 mg/inhalation) or placebo. TABLE 1. Demographic data and pulmonary function of patients Patient Sex Age (years)height (cm)weight (kg)smoking habit 1 M ex;50p/y 2 F die;45p/y 3 M ex;44p/y 4 M ex;60p/y 5 M ex;39p/y 6 M ex;50p/y 7 M ex;40p/y 8 M die;45p/y 9 M ex;40p/y 10 M ex; 60 p/y 11 M ex; 40 p/y 12 M ex; 30 p/y 13 M die, 25p/y 14 M ex, 40 p/y 15 F die, 20 p/y 16 M ex,45p/y

3 460 RESPIRATORY MEDICINE Eight patients received treatment (A) on the rst day and treatment (B) on the second day, while the other eight received treatment (B) on the rst day and treatment (A) on the second day. The three doses on each treatment day were administered at 30-mm intervals, with measurements being made 5 and 30 min after each dose. Spirometric testing was performed according to the procedures described in the AmericanThoracic Society s (ATS) 1987 update (9). Two acceptable forced expiratory manoeuvres were performed. The highest FVC (forced vital capacity), IC (inspiratory capacity) and FEV 1,obtained from one of the curves, were kept for analysis. Contemporaneously, we also measured oxygen saturation by pulse oximetry (SpO 2 ) and pulse rate.pulse oximetry was performed with the patient breathing room air. FIG. 1. Changes in FEV 1 induced by the inhalation of a single 36 mg dose of formoterol Turbuhaler or the same dose administered in a cumulative manner.values are mean 7S.E. Statistics The maximum FEV 1 value during the dose ^response curve to formoterol or salmeterol was chosen as the primary outcome variable to compare the two treatments. Spirometric data, heart rate and SpO 2 values for each treatment were analysed using the Student s t-test for paired variables. Mean responses were also compared by multifactorial analysis of variance (ANOVA) to establish any signi cant overall e ect between the two treatments. In the presence of a signi cant overall ANOVA, Duncan s multiple range testing with 95% con dence limits was used to Identify where di erences were significant. A probability level of Po0.05 was considered as signi cant for all tests. All data analysis were performed using computer software (GB-STAT, Version 8.0, Dynamic Microsystems, Inc, Silver Spring, MD 20904, U.S.A). RESULTS All patients completed the two-day study. No signi cant di erences occurred between the baseline spirometric values of the two treatment groups for FEV 1 [mean difference = l (95% CI: to 0.061l); P=0.496]. The mean changes in FEV 1 from baseline for each treatmeht regimen are shown in Fig.1. Both the high dose and the cumulative one have induced a signi cant bronchodilation, expressed as change in FEV 1 [mean increases (95% CI) in litres 5, 30, 35, 60, 65 and 90 min after the inhalation of the high dose: (0.080 ^ 0.154), (0.093^ 0.174), (0.100 ^ 0.177), (0.138 ^ 0.219), (0.154 ^ 0.249), (0.145^ 0.214); at the same times after inhalation of the cumulative dose: (0.066 ^ 0.133), (0.064 ^ 0.156), (0.097^ 0.212), (0.096^ 0.186), (0.153^ 0.229), (0.162^ 0.223)]. In particular, for the cumulative treatment regimen, each new dose produced an increase in FEV 1 suggesting FIG. 2. Changesin IC or FVCinduced by the inhalation of a single 36 mg dose of formoterol Turbuhaler or the same dose administered in a cumulative manner.values are mean 7S.E. that the dose ^ response plateau had not been reached. The di erence between the two regimens was signi cant (P=0.0332) only 60 min after the rst inhalation. The trendoffvcandicwassimilartothatoffev 1 (Fig. 2). All treatment regimens were well tolerated and no adverse events were reported. Neither the administration of the high dose nor that of the cumulative one modi ed heart rate in a signi cant manner. Also, they did not in uence SpO 2 (Table 2). Di erences between the two manners of administration of the same dose of formoterol were not signi cant.

4 CUMULATIVE DOSE STUDY IN PATIENTS WITH COPD 461 TABLE 2. Changesinpulserate and SpO 2 induced by theinhalation of a single 36mgdose offormoterol Turbuhaleror the same dose administered in a cumulative manner.values are mean and 95% CI Pulse rate (beats/mm)0 mm 5 mm 30 mm 35 mm 60 mm 65 mm 90 mm Single dose Cumulative dose SpO 2 (%) Single dose Cumulative dose DISCUSSION This study indicates that a single high dose of formoterol is as e ective as the same dose administered in a cumulative manner in patients with acute exacerbation of COPD. This nding was unexpected considering that it has been suggested that the use of a cumulative technique to obtain bronchodilator dose ^ response curves will cause a greater response than a non-cumulative technique, because sequential doses of drug will penetrate further into the lung (10,11). Practically, Britton and Tatters eld observed that the bronchodilator response to isoprenaline was less when administered as single doses of 10, 20, 80, and 400 mg when compared with the same doses given according to a cumulative regimen in patients with asthma (11). Recently, it has been documented that the e ect on FEV 1 of 400 mg inhaled salbutamol administered viaturbuhaler using a cumulative dose regimen was (also) greater than the equivalent single dose, always in subjects with asthma (12). It is di cult to explain the di erences between the responses in patients with acute exacerbation of COPD that we have observed in this study, and those in asthmatic subjects documented by other researchers (10 ^12). We could hypothesise that the use of di erent agents induces di erent pharmacodynamic behaviours independently from the treated pathology. In e ect, in vitro estimates suggest that the bronchodilating potency of formoterol may be 100 ^200 times greater than that of salbutamol on a molar basis (13,14) i.e. about 60 ^ 120 times greater on a weight basis. If this nding is true also in humansin vivo,itmeansthat48mgofformoterolis a more potent dose than 400 mg ofsalbutamolandis a dose able to induce a fast and generalised bronchodilation. In other words, this dose, which we could call relative saturation dose, would be great enough to open the majority of those pulmonary areas that are without anatomical damage. On the contrary, 400 mg of salbutamol might not be su cient to elicit the same e ect and, for this reason, patients could draw bene t from the progressive opening of new pulmonary areas that is subsequent to the inhalation of increasing doses of this bronchodilator. In e ect, as correctly described by Fishwick et al. (12), the rst dose partially opens up the constricted lung, but the dose needed for this rst maximal bronchodilation is far below the doses usually given.the next dose given will reach new areas of the lung and thus the bronchodilator e ect will increase further. This will result in a dose ^ response curve that gradually approaches a maximum. However, we have documented that there was no signi cant di erence between FEV 1, IC and FVC values after 48 mg formoteroland800mg salbutamol in patients su ering from acute exacerbation of COPD (4) when a dose-response curve has been constructed. It is also possible that the di erence in the treated pathology might be another reason of the di erent behaviour between patients with asthma and those su ering from acute exacerbation of COPD. It might be hypothesised that the non-cumulative technique causes a greater response than the dose ^ response curves patients with COPD, contrary to what is observed in asthma because in COPD air ow is limited mainly by structural alterations within and around peripheral airways (15). These anatomic changes prevent access of b-agonists to the periphery of the lung where the highest concentration of b-adrenoceptors is found (16). Consequently, better penetration of aerosol into the airways partially dilated by preceding treatment is unimportant in this case. On the contrary, the non-cumulative technique permits the inhalation of a high amount of drug that reaches b 2 -adrenoceptors which are present also in the larger airways, and activates a larger number of these receptors.

5 462 RESPIRATORY MEDICINE Leaving out of consideration the reasons that justify the described behaviour in patients with acute exacerbations of COPD, we must underline that the single highdose regimen also seems to be as safe as the cumulative one. This nding has important clinical implications with respect to the utilization of bronchodilator aerosols in the treatment of acute exacerbation of COPD. In fact, because side e ects are minimal, it would be reasonable to use 36 mg of nebulised formoterol as initial therapy of acute exacerbation of COPD. In our opinion, this posologic approach is preferable to prescription of the equivalent cumulative dose regimen when it does not involves additional risks because it simpli es the assumption of bronchodilator. Alternatively, if there are potential risks for side e ects, dose ^ response titration with formoterol would be advantageous although some degree of side e ects from b-agonist use is tolerable in an acute situation to achieve a critical therapeutic e ect (17). REFERENCES 1. NHLBI/WHO. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease (GOLD). NHLBI/ WHO Workshop Report Emerman CL, Cydulka RK. Effect of different albuterol dosing regimens in the treatment of acute exacerbation of chronic obstructive pulmonary disease. Ann Emerg Med 1997; 29: Cazzola M, Di Perna F, D Amato M, Califano C, Matera MG, D Amato G. Formoterol Turbuhaler for as-needed therapy in patients with mild acute exacerbations of COPD. Respir Med 2001; 95: Cazzola M, D Amato M, Califano C, Di Perna F, Catderaro F, Matera MG, D Amato G. Formoterol as dry powder oral inhalation in comparison with salbutamol metered dose inhaler in acute exacerbations of chronic obstructive pulmonary disease. ClinTher 2002; 24: Cazzola M, Matera MG, D Amato M, Noschese P, Califano C, Di Perna F, Terzano C, D Amato G. Long-acting b 2 agonists in the treatment of acute exacerbations of COPD. Clin Drug Invest 2002; 22: Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest 2000; 117: 398S 401S. 7. Siafakas NM, Vermeire P, Pride NB, et at. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). EurRespirJ 1995; 8: The COPD Guidelines Group of the Standards of Care Committee of the BTS. BTS guidelines for the management of chronic obstructive pulmonary disease. Thorax 1997; 52 (Suppl 5): S1 S American Thoracic Society. Standardization of spirometryf1987 update. Am Rev Respir Dis 1987; 136: Heimer D, Shim C, Williams M. The effect of sequential inhalations of metaproterenol aerosol in asthma. J AllergyClin Immunol 1980; 66: Britton J, Tattersfield A. Comparison of cumulative and non-cumulative techniques to measure dose-response curves for beta agonists in patients with asthma. Thorax 1984; 39: Fishwick D, Bradshaw L, Macdonald C, Beasley R, Gash D, Bengtsson T, Bondesson E, Borgstrom L. Cumulative and singledose design to assess the bronchodilator effects of b 2 -agonists in individuals with asthma. Am J Respir Crit Care Med 2001; 163: Nials AT, Coleman RA, Johnson M, Magnussen H, Rabe KF, Vardey CJ. Effects of beta-adrenoceptor agonists in human bronchial smooth muscle. Br J Pharmacol 1993; 110: Naline E, Zhang Y, Qian Y, et al. Relaxant effects and durations of action of formoterol and salmeterol on the isolated human bronchus.eurrespirj1994; 7: Wright JL. Small airway disease: structure and function. In: Hensley MJ, Saunders NA (eds), Clinical Epidemiology of Chronic Obstructive Pulmonary Disease. New York: Marcell Dekker, 1989: Ohrui T, Yanei M, Sekiwzawa K, et al. Effective site of bronchodilation by beta adrenergic and anticholinergic agents in patients with chronic obstructive pulmonary disease: direct measurement of intrabronchial pressure with a new catheter. Am Rev Respir Dis 1992; 146: Hanania NA, Sharafkhaneh A, Barber R, Dickey BF. b 2 -agonists Intrinsic efficacy: measurement and clinical significance. Am JRespir Crit Care Med 2002; 165: