Acute and short-term effect of an extra dose of
formoterol in COPD patients
Fernando Se
´rgio Studart
a, Meyer Izbicki
a, Luiz Eduardo Nery
a,
Luı´s Vicente Franco Oliveira
b, Claudio F. Donner
c,*, Jose
´ Roberto Jardim
a,
Oliver Augusto Nascimento
aaRespiratory Division of Federal University of Sa˜o Paulo, Sa˜o Paulo, SP, Brazil
bRehabilitation Sciences Master’s Program Department, Nove de Julho University, Sao Paulo, SP, Brazil cMondo Medico, Multidisciplinary and Rehabilitation Outpatient Clinic, Via Monsignor Caviglioli 10, Borgomanero (NO) 28021, Italy
Received 9 November 2011; accepted 21 December 2011 Available online 14 February 2012
KEYWORDS
COPD; Formoterol; Hyperinflation
Summary
Rationale:Formoterol action may decrease progressively after its inhalation. It is unknown if this decrease of bronchodilation following formoterol use could be associated with worsening hyperinflation.
Objectives:To investigate whether the use of an extra daily dose of formoterol could promote a greater reduction in lung hyperinflation and a greater improvement in inspiratory capacity (IC) compared to usual doses.
Methods:56 hyperinflated COPD patients were divided into two groups: F2 and F3. Basal eval-uation was carried out after 5 days of formoterol washout. In order to evaluate the acute effect, spirometry and body plethysmography were performed 8 h after the first formoterol dose in both groups and repeated 1 h after an additional formoterol dose (F3) or placebo (F2). The short-term effect was evaluated by measuring the resting lung function after a 14-day period of formoterol t.i.d. (F3) or formoterol b.i.d.þplacebo (F2).
Measurements and main results:A second formoterol dose inhaled 8 h after the previous dose promoted additional improvements in lung function, as demonstrated by higher IC (118140 mL,p<0.001) and lower functional residual capacity (FRC) (383 367 mL, p<0.001). On day 15, the mean differences from baseline regarding all lung function variables
were similar between the groups.
* Corresponding author. Tel.:þ39 0322 836718,þ39 0322 846549; fax:þ39 0322 869950. E-mail address:[email protected](C.F. Donner).
0954-6111/$ - see front matterª2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2011.12.015
Available online atwww.sciencedirect.com
Conclusion:An extra daily dose of formoterol inhaled 8 h after a previous dose could result in an acute additional peak of bronchodilation. However, short-term formoterol t.i.d. showed no advantages over formoterol b.i.d. concerning reduction of hyperinflation in resting lung function.
ª2012 Elsevier Ltd. All rights reserved.
Introduction
Chronic obstructive pulmonary disease (COPD) is charac-terized by progressive airflow limitation and decreased elasticity of the lung parenchyma resulting in hyperinflation and gas trapping, particularly in moderate to severe patients.1As a consequence, during exercise, as ventilatory demands increase in flow-limited patients, progressive air trapping and further dynamic lung hyperinflation above the already increased resting values is inevitable.2,3Moreover,
it is known that measurements of forced expiratory volume in 1st second (FEV1) is not always reliable as a surrogate
marker of pulmonary function improvement following bronchodilator use, as reductions in lung hyperinflation in COPD patients can occur with almost no change in FEV1.3e7
Long-actingb2-agonists (LABA), such as formoterol, are
widely used bronchodilators in the management of COPD, usually prescribed twice a day.8e10 However, previous
studies have shown that formoterol action may decrease progressively 8 h after its inhalation.11e13 It is unknown if
this decrease in bronchodilation following formoterol use could be associated with worsening hyperinflation.
The purpose of this study was to investigate whether the administration of an extra dose of formoterol could result in a greater increase in inspiratory capacity (IC) and a greater reduction in static hyperinflation in two different situations: acutely, eight hours after a previous formoterol dose vs. placebo; and in the short-term, after a 14-day period of formoterol t.i.d. (three times daily) vs. for-moterol b.i.d. (twice daily).
Methods
Study design
This study was a randomized, double blind, placebo-controlled, parallel-group trial. Randomization was con-ducted by envelopes in blocks of four patients, with patients
being randomly divided into two groups: F2 and F3. The primary outcome was an increase from baseline in IC on days 1 and 15. Secondary outcomes on day 15 included the difference from baseline in other lung function parameters, namely forced vital capacity (FVC), FEV1, slow vital capacity (SVC),
residual volume (RV), functional residual capacity (FRC) and total lung capacity (TLC). We also evaluated the improvement in basal dyspnea scores, incidence of side effects and the use of relief medication as secondary outcomes. The study was approved by the local ethics committees, and all patients signed an informed consent prior to participation.
Subjects
Patients referring to the pulmonary division of a tertiary hospital in Brazil from July 2007 to May 2009 who met the following inclusion criteria were invited to participate in the study: moderate to very severe COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) guidelines1 with post-bronchodilator FEV1 60% of
pre-dicted values, former smokers (10 pack-years), absence of FEV1 reversibility after albuterol in spirometry, age 40
years or older, clinical stability within four weeks prior to randomization (no occurrence of increased dyspnea, increased sputum and/or change in sputum purulence or change in medication use),2,14 hyperinflation as
demon-strated by FRC 130% or RV 140% or TLC 120% of predicted values.15 Exclusion criteria were: presence of
asthma or any other active pulmonary disease and the inability to perform pulmonary function tests or carry out reproducible maneuvers.
Measurements
Screening visit (Day-5): Patients were screened for eligi-bility and familiarized with the pulmonary lung function tests, and instructed to discontinue all bronchodilators (LABAs, tiotropium or methylxantines)(Fig. 1). They were,
At a Glance Commentary
Formoterol is widely used in the management of COPD, usually prescribed b.i.d. However, studies have shown that its action may decrease progressively 8 h after inhalation. It is unknown if this decrease in bronchodilation following formoterol use could be associated with worsening hyperinflation.
What This Study Adds to the Field
however, permitted to use albuterol 200mg, via a metered dose inhaler (MDI) device, every 6 h or as needed for symptom relief up until 12 h before baseline examinations.
Baseline visit (Day 0): patients were randomized and lung function tests were performed (spirometry and body plethysmography), following discontinuation of albuterol 12 h prior. They were then sent home with instructions to inhale a single dose of formoterol 12 mg at midnight and return to the laboratory the next day.
Acute bronchodilator effect evaluation (Day 1): patients underwent a body plethysmography at 8.00 a.m. in order to detect any improvements in lung function 8 h after for-moterol use. Following these tests, patients inhaled an additional dose of formoterol (F3 group) or placebo (F2 group), and lung function was reevaluated by body plethysmography 1 h later (10.00 a.m.).
Short-term effect bronchodilator evaluation (Day 15): between days 2e14, both groups inhaled three capsules per
day in a regimen chosen to suit as best as possible their normal daily routine (6.00e7.00 a.m., 1.00e2.00 p.m.,
8.00e9.00 p.m.), with morning and evening capsules
con-taining formoterol 12mg in both groups, and the afternoon capsule containing an additional dose of formoterol 12mg (F3 group) or placebo (F2 group). During this visit, patients underwent spirometry and body plethysmography, with formoterol having been withdrawn 12 h before. All for-moterol or placebo doses were administered via a single-dose, breath-activated device inhaler (Aerolizer), with all capsules being provided by Mantecorp Pharmaceutical Company
; Sa˜o Paulo; Brazil.
Lung function tests: Spirometry included both forced and slow vital capacity maneuvers, in accordance with the
American Thoracic Society (ATS) criteria.16 Functional
residual capacity was measured by body plethysmography17 using a volume variable pressure body plethysmograph (Elite Series Breeze PF System
, MGC, St. Paul, USA). IC was calculated as SVCeERV (expiratory reserve volume).
Other measurements: Dyspnea was evaluated using the modified Medical Research Council (mMRC) scale18 and
Baseline Dyspnea Index (BDI).19The response to therapy in
terms of dyspnea was evaluated by the Transition Dyspnea Index (TDI) with a 1-point difference considered as the minimal significant difference.19 Incidence of side effects and the use of relief medication were recorded on a diary card. Compliance was evaluated by counting unused capsules in both devices on day 15.
Statistical analysis
SPSS Version 16.0 statistical software was used for data analysis (IBM, Chicago, IL). Sample size was calculated in order to have an 80% power to detect a mean difference of 0.150 L20in resting IC between F3 and F2 groups on day 15, assuming two-sidedaZ5% and a standard deviation (SD) of
0.190 L according to a pilot study. The minimal number of patients required in each group was set at 26. Descriptive and numerical data were reported as means SD or means CI 95%. Comparisons between groups were per-formed using Student’s t test or ManneWhitney U test
according to the type of distribution. For the comparison of variables within the same group, Pairedtor Wilcoxon tests were used as appropriate. The level of statistical signifi-cance was set atp<0.05 for all tests.
Results
A total of 90 patients were evaluated. Fifty-six patients were considered eligible and subsequently entered the study. The main reason that 34 patients were not included was that they were unable to perform reproducible FRC maneuvers during the screening visit. The average age of patients was 64 years (range, 50e83), and 86% were males.
Mean FEV1 was 1.10 0.35 L (39 11% of predicted).
Hyperinflation was demonstrated by abnormally high mean values of FRC (15727% of predicted) and RV (20945% of predicted). The mean TLC was 11615% of predicted, with 20 patients presenting TLC 120% of predicted values (9 patients in the F3 group). The sample included 11 patients (19.6%) in GOLD Stage 2, 36 in GOLD Stage 3 (64.3%) and 9 in GOLD Stage 4 (16.1%). The baseline characteristics of the two treatment groups were similar (Table 1).
Day 1eacute effect of an additional formoterol dose vs. placebo 8 h after a previous formoterol dose
Eight hours (8.00 a.m.) after inhalation of the first for-moterol dose, the measurement of lung function variables (SVC, IC, RV, FRC) still showed a statistical improvement from baseline in both groups. These results did not differ between the two groups. At 10.00 a.m., the group that inhaled an extra formoterol dose showed an additional
improvement in lung function, achieving higher SVC (122 215 mL, p Z 0.006), higher IC (118 140 mL, p<0.001), lower FRC (383367 mL,p<0.001), lower
RV (371 460 mL, p < 0.001) and lower TLC
(263376 mL,pZ0.001). On the other hand, the group
that received placebo showed no statistical change in SVC, IC, FRC, RV and TLC, with all differences between the two groups being statistically significant (Fig. 2). The cumula-tive bronchodilator effect from baseline after two for-moterol doses (F3 group) compared to that after a single formoterol dose plus placebo (F2 group) is shown inFig. 3, with the former showing a greater decrease in RV (768 483 ml vs. 385 621 ml,pZ 0.014) and TLC
(386357 mL vs.152343 mL,pZ0.016).
Day 15eshort-term effect of formoterol t.i.d. vs. formoterol b.i.d
Lung function: The mean differences from baseline regarding all lung function variables were similar between
Table 1 Baseline characteristics of the study population.
Variablesa F3 group
(nZ28)
F2 group (nZ28)
pc
Demographics
Age (years) 64.77.7 64.07.4 0.72
Male gender, N(%)
24 (85.7) 23 (82.1) 0.90
Body mass index (kg/m2)
23.64.9 24.84.7 0.34
Dyspnea
mMRC 1.90.7 2.10.6 0.23
BDI 6.51.7 6.01.7 0.32
Pulmonary functionb
FVC (L) 2.680.61 2.600.72 0.66
FVC, % predicted 7314 7215 0.54
FEV1(L) 1.090.34 1.100.36 0.87
FEV1, % predicted 3913 399 0.90
SVC (L) 2.970.74 3.040.79 0.74
SVC, % predicted 8115 8416 0.51
IC (L) 1.940.40 1.940.49 0.95
IC, % predicted 6814 6913 0.84
FRC (L) 5.441.05 5.051.11 0.19
FRC, % predicted 16224 15329 0.21
RV (L) 4.410.93 3.930.79 0.04
RV, % predicted 21847 20043 0.13
TLC (L) 7.381.17 7.001.28 0.24
TLC, % predicted 11814 11416 0.29
IC/TLC, % 26.55.2 28.16.1 0.31
Definitions of abbreviations: FVC Z forced vital capacity; FEV1Zforced expiratory volume in the 1st second; SVCZslow vital capacity; IC Z inspiratory capacity; FRC Z functional residual capacity; RV Z residual volume; TLC Z total lung capacity; mMRC Zmodified Medical Research Council scale; BDIZBasal Dyspnea Index.
a Values presented as meansSD. b Prebronchodilator lung function. c Student’s ttest or Mann
the groups. However, only the F3 group showed a statisti-cally significant reduction from baseline in RV (p<0.001)
and in TLC (pZ0.01) (Table 2).
Dyspnea: scores in TDI scale showed a clinically signifi-cant improvement in both F3 and F2 groups, 3.41.6 units and 3.4 1.4 units, respectively, with no difference between the two groups (pZ0.95).
Other measurements: High treatment compliance was observed. Only one patient in the F3 group and two patients in the F2 group forgot to inhale one afternoon capsule (formoterol or placebo) during the study.
Relief medication: Fourteen patients in the F3 group (51.7%) and 15 patients in the F2 group (53.5%) did not use any albuterol during the trial. The average number of doses of albuterol per day was similar, 0.69 1.11 puffs and 0.70 1.58 puffs in the F3 and F2 groups, respectively (pZ0.78).
Side effects: these were quite rare and similar in both groups, with no episodes of hospitalization, death, arrhythmias or palpitation being detected or self-reported by patients. The most common adverse event was COPD exacerbation, which occurred in two patients in the F3 group and one patient in the F2 group, requiring a course of antibiotics and prednisone. One patient in the F3 group reported an episode of tremors on day 2 after using a for-moterol dose, with no recurrence during the trial. A headache was also reported by a patient in the F3 group; however this cannot necessarily be associated with for-moterol use.
Discussion
There is a great deal of controversy regarding the timing and optimal dose of inhaledb2eagonists in the treatment of
COPD. In a study by Cazzola et al. it was demonstrated that a single high dose of formoterol is as effective as the same dose administered in a cumulative manner, with the same tolerability.21 In spite of this interesting finding we
preferred to test the cumulative approach, considering the relatively advanced age of our case series, to privilege as much as possible the aspect of safety.
The objective of this study was to evaluate the acute and short-term effects of an additional dose of formoterol on lung volumes in hyperinflated COPD patients. Our results clearly demonstrate that an extra dose of formoterol inhaled 8 h after a previous dose resulted in a greater increase of IC and a greater reduction of hyperinflation. However, after a 14-day treatment of formoterol t.i.d. vs.
Table 2 Prebronchodilator lung function after a short-term period of formoterol t.i.d. versus usual therapy b.i.d.
Variablesa F3 group (n
Z26) F2 group (nZ28) F3 vs. F2 (Day 15)
Baseline Day 15 Baseline Day 15 pd
FVC (L) 2.760.6 2.890.7b 2.600.7 2.840.8b 0.84
FEV1(L) 1.120.3 1.200.4b 1.100.4 1.240.4b 0.73
FEV1/FVC 0.400.1 0.420.1 0.420.1 0.430.1 0.59
SVC (L) 3.040.7 3.210.8b 3.040.8 3.190.8b 0.93
IC (L) 1.980.4 2.090.5c 1.940.5 2.100.5b 0.97
FRC (L) 5.451.1 5.121.0b 5.051.1 4.831.1b 0.33
RV (L) 4.390.9 4.001.0b 3.93
0.8 3.740.9 0.32
TLC (L) 7.431.2 7.231.3 6.991.3 6.941.3 0.41
RV/TLC (%) 59.07.7 55.38.9b 56.6
7.3 54.08.2b 0.58
IC/TLC (%) 27.05.1 29.25.3b 28.16.1 30.66.0b 0.37
Definitions of abbreviations: FVCZforced vital capacity; FEV1Zforced expiratory volume in the 1st second; SVCZslow vital capacity; ICZinspiratory capacity; FRCZfunctional residual capacity; RVZresidual volume; TLCZtotal lung capacity.
a Values presented as meansSD. b p<0.01.
c p
Z0.06, related to differences within the same group from baseline to day 15 after formoterol treatment (pairedtor Wilcoxon tests according to the type of distribution).
d Differences on resting lung function between groups F3 and F2 on day 15 (Student’sttest).
Figure 2 Mean difference in lung function 1 h after an
additional formoterol dose (F3 group) or placebo (F2 group) following a previous formoterol dose inhaled 8 h earlier. Values as meansCI 95%. Legend:CF3 group;,F2 group. Defini-tions of abbreviations: SVC Z slow vital capacity;
ICZinspiratory capacity; FRCZfunctional residual capacity;
RVZresidual volume; TLCZtotal lung capacity.p<0.001 for
formoterol b.i.d., no difference in prebronchodilator lung function was found between groups.
In order to evaluate the acute effect of an additional dose of formoterol on lung volumes, patients were asked to inhale a dose of formoterol at midnight (first dose), having pulmonary function tests performed an hour after the inhalation of an additional dose of formoterol (second dose) or placebo, both administered 8 h after the first dose of formoterol.
Significant improvements in lung function were still observed 8 h after the inhalation of the first dose of for-moterol in both groups, as forfor-moterol action is expected to last for 12 h.8,10However, only the group that received the second dose of formoterol evolved with a significant increase in IC and a reduction of hyperinflation, confirming the existence of a formoterol dose-response curve (Fig. 2). In line with these data Cazzola et al. also observed a greater bronchodilation effect (FEV1increase) following
progressive doses of formoterol (12, 24 and 36mg) in COPD patients13 and they observed, in a subsequent study, a dose-dependent increase in FEV1 with formoterol, with
a maximum mean increase from the 2-h value, showing that regular treatment with formoterol does not compromise the bronchodilator response to further cumulative inhala-tions of formoterol.22
All these previous data support the rationale of our study, but to the best of our knowledge, no previous studies have evaluated this specific pharmacological strategy (two formoterol doses, administered at an 8-h interval), allowing a marked increase of IC of 280 mL and a decrease of FRC of approximately 700 mL compared to the baseline. These results are similar to findings of Celli et al. who found an increase of 350 mL in IC and a decrease of 600 mL in FRC at the peak bronchodilator effect of tiotropium.23 As this
additional dose of formoterol was administered in the
morning (at 9.00 a.m.), with important reductions in static hyperinflation, it is reasonable to also expect a lesser degree of dynamic hyperinflation and, probably, a better exercise capacity. This could be corroborated by the study of Partridge et al. who demonstrated that formoterol/ budesonide combination, due to a more rapid onset of bronchodilation compared to salmeterol/fluticasone, was associated with greater improvements in the ability of COPD patients to perform morning activities.24
On day 15, no differences in resting lung function, use of relief medication or dyspnea scores were observed between the two groups. One possible explanation for these results is that the use of a third daily dose of for-moterol is not able to promote a greater reduction in resting airway smooth muscle tone compared to a twice-daily dose, with any additional benefits disappearing as soon as formoterol finishes its bronchodilator effect. Tachyphylaxis is a possibility in this context; however as we used a short duration protocol, and as a reduction of formoterol-related bronchodilation effects in COPD patients, even after longer periods of treatment,11,13 has
not been reported by other authors, this is unlikely. On the other hand, this does not necessarily mean that a patient from the F3 group would not benefit from this intervention. A clinical follow up could help to discern which patients would really benefit from the use of formoterol three times a day. Furthermore, in the same way that an acute reduc-tion of the lung hyperinflareduc-tion was noticed in the morning after the use of an additional dose of formoterol, it is also possible to infer that this same benefit could occur an hour after the use of an extra dose of formoterol in the afternoon.
One important concern of our trial was that the use of higher formoterol doses in elderly patients could result in possible side effects. Our data showed that the prescription of formoterol t.i.d. or b.i.d. appeared to be a safe inter-vention, with the incidence of side effects being similar in both groups. Rossi et al. did not also observe a higher incidence of side effects in COPD patients receiving for-moterol 24mg b.i.d. vs. formoterol 12mg b.i.d.11 In other
studies evaluating formoterol, no clinically significant changes in potassium levels, heart rate, or electrocardi-ography measurements were associated with the use of formoterol, regardless of dose or treatment duration.25e28
Our study presents some limitations. Firstly, our findings should not be extrapolated to other subgroups of COPD, such as patients in GOLD stage I. It is well noted that even mild COPD patients have some degree of air trapping which is decreased by bronchodilator use.29,30 Similarly, COPD
patients may develop acute exacerbations; further aggra-vating lung hyperinflation and dyspnea. Our results, nevertheless, may not be applied to these situations, as we analyzed only stable COPD patients. Another limitation of our study was that we did not perform a more detailed surveillance of possible known side effects related to for-moterol use, which could have included, for example, measurement of corrected QT interval in the electrocardiogram.
In conclusion, an additional dose of formoterol was able to reduce acutely the static hyperinflation in patients with COPD. Hence, considering the low incidence of side effects, it is reasonable to consider prescribing formoterol t.i.d. for
Figure 3 Mean cumulative difference in lung function from
baseline after two formoterol doses (F3 group) compared to that after a single formoterol dose plus placebo (F2 group). Values as meansCI 95%. Legend:CF3 group;,F2 group. Definitions of abbreviations: SVC Z slow vital capacity;
ICZinspiratory capacity; FRCZfunctional residual capacity;
RVZ residual volume; TLCZ total lung capacity.*p Z NS; xp
stable COPD patients who experience significant continued breathlessness despite inhaling formoterol twice a day. Naturally, this strategy needs to be targeted to the indi-vidual, and in cases displaying clinical improvement, the clinician could evaluate the possibility of maintaining it. Other trials with a larger sample of patients could provide better evidence in support of this strategy.
Sources of support
Mantecorp Pharmaceutical Company
supplied all drugs (formoterol 12mg or placebo) used in this trial.
Authorship
Conception and design: FSS, LEN, JRJ, OAN
Analysis and interpretation: FSS, MI, JRJ, LVFO, OAN Drafting the manuscript for important intellectual content: FSS, MI, LEN, CFD, LVFO, JRJ, OAN
Acknowledgments
The authors thank all colleagues from the Respiratory Division of Federal University of Sa˜o Paulo for their collaboration; Mrs. Michele Regina and Gabriela Siqueira for her technical support during pulmonary function tests; Mantecorp Pharmaceutical Company
for supplying the drugs used in this trial (formoterol or placebo capsules) and the patients for their effort and enthusiastic cooperation throughout the study.
Conflict of interest statement
The authors have all read and approved the enclosed version of the manuscript, and declare that there are no conflicts of interest related to the subject treated in this paper.
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