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Cardiac safety of formoterol 12 μg twice daily in patients with chronic obstructive pulmonary disease
ARTICLE IN PRESS
Pulmonary Pharmacology & Therapeutics 20 (2007) 571–579 www.elsevier.com/locate/ypupt
Cardiac safety of formoterol 12 mg twice daily in patients with chronic obstructive pulmonary disease Sammy C. Campbella,, Gerard J. Crinerb, Bernard E. Levinec, Stuart J. Simond, Jonathan S. Smithe, Chadwick J. Orevillof, Barbara A. Ziehmerf a
Arizona Respiratory Center, University of Arizona and Pulmonary Section, VA Medical Center, Southern Arizona VA Health Care System, Tucson, AZ, USA b Division of Pulmonary & Critical Care Medicine, School of Medicine, Temple University, Philadelphia, PA, USA c Pulmonary Associates, PA, Phoenix, AZ, USA d Radiant Research and Georgia Lung Associates, Austell, GA, USA e Novartis Horsham Research Centre, Horsham, West Sussex, UK f Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Received 11 January 2006; received in revised form 6 June 2006; accepted 18 June 2006
Abstract Background: Some evidence suggests an increased risk of myocardial infarction and dysrhythmia events associated with b2-agonist use in patients with chronic obstructive pulmonary disease (COPD). This prospective, multicenter, randomized, double-blind, placebocontrolled study compared the cardiac safety of formoterol and placebo in patients with COPD. Methods: After a 3–14-day run-in, 204 patients were randomized to receive formoterol 12 mg dry powder inhalation or matching placebo twice daily for 8 weeks. Twenty four-hour continuous electrocardiography (Holter monitoring) was performed at screening and after 2 and 8 weeks of treatment. Results: Only a small number of patients met the predefined criteria for a proarrhythmic event (4 formoterol and 2 placebo patients). No patients had sustained postbaseline ventricular tachycardia events, postbaseline run of ventricular ectopic beats associated with relevant symptoms (e.g. hypotension, syncope), or an episode of ventricular flutter or fibrillation. Holter monitoring data were variable but showed no clinically meaningful differences between the formoterol and placebo groups, respectively, for variables such as (mean7SD at end of treatment): heart rate (8078.6 vs. 80710.6 bpm), number and rate of ventricular premature beats (total 73272685.4 vs. 65072090.6; rate 357131.0 vs. 307101.3 per h), ventricular tachycardia events (total 0.471.70 vs. 1.079.23; rate 0.0270.082 vs. 0.0570.479 per h), and supraventricular premature beats (total 50471844.1 vs. 82372961.8; rate 22780.6 vs. 377129.6 per h). Vital signs and electrocardiogram data, including corrected QT intervals (Bazett and Fridericia), were similar across treatment groups. The overall adverse event experience was similar in the formoterol (n ¼ 26 [27%]) and placebo (n ¼ 33 [31%]) groups. The most common adverse events, infections and respiratory events, were expected for this patient population. The incidence of cardiac adverse events was low (1 formoterol and 4 placebo patients). Conclusions: The results of this study confirm the good cardiovascular safety profile of formoterol in patients with COPD. r 2006 Elsevier Ltd. All rights reserved. Keywords: COPD; Formoterol; Cardiac safety
1. Introduction
Corresponding author. Tel.: +1 520 792 1450x5061; fax: +1 520 882 9811. E-mail address: [email protected] (S.C. Campbell).
1094-5539/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2006.06.003
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality and morbidity in the United States and worldwide [1]. Prevalence estimates vary widely but usually range from about 4%–10% in countries
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where well-designed studies have been conducted [2]. The symptoms of COPD (eg., chronic cough, dyspnea, expectoration, reduced exercise capacity, and repeated exacerbations) cause extensive disability in many patients, imposing a substantial burden on healthcare resources [3]. The Global Initiative for Chronic Obstructive Lung Disease guideline recommends a stepwise approach to disease management with bronchodilators as the mainstay for symptomatic treatment [1]. There are 3 classes of bronchodilators available for the treatment of COPD: b2-adrenoceptor agonists, anticholinergics, and methylxanthines (theophylline). Of these, inhaled b2-agonists and anticholinergics are preferred to oral theophylline which has a narrow therapeutic index. Short-acting b2-agonists, which have a relatively rapid onset of action and short duration of effect (4–6 h), are used primarily as rescue medication for relief of symptoms [4]. Formoterol fumarate is a long-acting b2-agonist with unique pharmacologic properties, including high selectivity to b2-receptors relative to b1-receptors, and high intrinsic activity. Formoterol has been shown to be therapeutically effective, safe and well tolerated in patients participating in clinical trials of up to 12 months’ duration [5–10]. Compared with other long-acting b2-agonists, such as salmeterol, formoterol has a more rapid onset of action (less than 5 min) and similar duration of effect (approximately 12 h) [5,11]. A retrospective review suggests there may be an increased risk of myocardial infarction and dysrhythmia events in patients treated with b2-agonists for obstructive airway disease [12]. The pharmacologic action of b2-agonists on b-adrenergic receptors has the potential to increase heart rate and exacerbate cardiac rhythm disturbances [1]. Development of arrhythmia as a consequence of treatment, often a paradoxical side effect of antiarrhythmic therapy [13], is known as proarrhythmia and is characterized by a poor prognosis [14]. The objective of this prospective study was to compare the electrocardiographic effects, especially a potential influence on cardiac rhythm, of formoterol 12 mg dry powder inhalation with placebo in COPD patients as evaluated by 24-h continuous Holter monitoring. The study was requested by the US Food and Drug Administration (FDA) as a commitment to evaluate further the safety of formoterol dry powder capsules 12 mg twice daily for the maintenance treatment of COPD in adults, following the FDA’s approval of formoterol for use in this setting.
forced expiratory volume in 1 s (FEV1) be o70% of predicted normal value and X0.75 l, with a FEV1/forced vital capacity (FVC) ratio p70%. Main exclusion criteria included a history of asthma, or a respiratory tract infection or hospitalization or emergency room treatment for an acute COPD exacerbation in the previous month. Patients with a history of malignancy in the previous 5 years, a history of untoward reactions to sympathomimetic amines, a corrected QT (QTc) interval 40.46 s at screening (Visit 1), or any clinically significant condition that might compromise the patient’s safety or compliance were excluded. Females who were pregnant or nursing were excluded. Females of childbearing age were required to use a reliable contraception method. The use of b2-agonists (other than formoterol or rescue albuterol), oral or parenteral corticosteroids or inhaled anticholinergics (except inhaled ipratropium bromide) were not allowed unless necessary to treat a COPD exacerbation. Inhaled and nasal corticosteroids, ipratropium bromide or sustained-release theophylline could be continued at a stable dose, but could not be started during the study unless needed for a COPD exacerbation. Patients receiving an inhaled combination of corticosteroid and b2-agonist were switched to a separate formulation of an inhaled corticosteroid (plus a separate inhaled b2-agonist, if required) 3 weeks prior to Visit 1. Short courses of excluded medication (p15 days and not more than twice during the study) for an exacerbation did not result in discontinuation of the patient from the study. Short courses of antibiotics or oxygen were also permitted. Patients taking oral corticosteroids within the previous month, oral or inhaled anticholinergics (other than inhaled ipratropium bromide), long-acting b2-agonists, or inhaled short-acting b2-agonists within 6 h prior to Visit 1 were excluded. Patients receiving b-blockers, antiarrhythmics, non-potassium-sparing diuretics, tricyclic antidepressants, selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors were also excluded. Patients whose screening Holter monitor recording met 1 or more Holter monitoring criteria for discontinuation were excluded (i.e. average heart rate p40 beats per min [bpm] for any 1 h, transient or fixed complete heart block, transient Mobitz II second degree heart block, Mobitz I lasting greater than a continuous 60-min duration, ventricular asystole X2.5-s duration, persistently prolonged QTc interval [consistently 40.5 s], proarrhythmia, investigator’s request). 2.2. Study design
2. Methods 2.1. Patients Patients were male or female, X40 years of age, who were current or ex-smokers of 410 pack-years and had a diagnosis of COPD according to the American Thoracic Society guidelines [15]. Inclusion criteria required that patients’ prebronchodilator (after appropriate washout)
This was a prospective, randomized, multicenter, double-blind, placebo-controlled, parallel-group study. The protocol was reviewed and approved by the appropriate institutional review board for each study site, and all patients gave written informed consent to participate in the study before any study procedures were performed. After screening and a run-in period of 3–14 days, patients were randomized to formoterol 12 mg dry powder inhalation or
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matching placebo administered twice daily via Aerolizers (Novartis, East Hanover, NJ) for 8 weeks. Patients were permitted to take 2 puffs of rescue medication (albuterol pressurized metered dose inhaler [90 mg emitted dose per puff]) as needed during the study, but were not to exceed 8 rescue puffs in any given 24-h period: patients exceeding this or taking 8 puffs on 2 consecutive days were instructed to notify an investigator. Holter monitoring was performed at screening (Visit 1) to provide a baseline recording and after 2 weeks (Visit 3) and 8 weeks (Visit 4) of treatment to determine longitudinal effects. All Holter monitoring recordings were initiated in the morning at approximately the same time; the Visit 3 and Visit 4 Holter monitoring periods were initiated 15–30 min prior to the morning dose of study medication. Holter monitoring recordings were assessed for cardiac arrhythmias by an independent cardiologist. A screening electrocardiogram (ECG) was performed at Visit 1. Further ECGs were obtained at Visits 2 (Day 1), 3, and 4 prior to administration of study medication and at 2 h postdose. At Visit 2, two ECGs were performed predose at least 15 min apart, and the average of the 2 values provided a baseline value. All ECGs included 12 standard leads and a lead II rhythm strip of at least 10-s duration. Vital signs were obtained at all clinic visits, and adverse events were recorded throughout the study. Efficacy was assessed by measuring FEV1 at 2 h postdose, after the first dose of study medication (Visit 2), and after 2 and 8 weeks of treatment (Visits 3 and 4). 2.3. Statistical methods A sample size of 200 was chosen after consideration from the FDA as this would be sufficient to provide a reasonable exposure from a safety perspective. All data were analyzed in the intention to treat (ITT) population, which was defined as all randomized patients who received at least 1 dose of study medication (the safety and ITT populations were defined the same). The continuous electrocardiograph (Holter monitoring) data were summarized by treatment group using descriptive statistics only as it was considered appropriate by the FDA to evaluate the Holter monitoring data without formal statistical analysis. The following variables were analyzed: proarrhythmia, 24-h heart rate, ventricular ectopy (ventricular premature beats [VPBs]), ventricular run events (ventricular tachycardia events [VTE] defined as a run of 3 or more VPBs with X100 bpm, and/or idioventricular run events [IVEs] defined as a run of 3 or more VPBs with a rate o100 bpm), supraventricular ectopy (supraventricular premature beats [SVPBs]), and supraventricular run events defined as a run of SVPBs of 3 or more beats. The 24-h Holter monitor recordings obtained after the start of double-blind treatment were reviewed for the development of, or any increase in the incidence of, cardiac dysrhythmic events that could be considered indicative of proarrhythmic drug effects. The definition of proarrhythmia was based on
573
Table 1 Ventricular tachycardia and ventricular premature beats criteria for proarrhythmia events
Mean VPB/h
Non-sustained VTEs
Baseline
Criteria postbaseline
0–1 1–100 4100 0
X10 mean VPB/h Increase of X10 times baseline Increase of X3 times baseline X5 Events or 415 beats in events/24 h Increase of X10 times baseline events or beats X1
X1 Sustained VTEs
0
Ventricular tachycardia event (VTE) was defined as a run of 3 or more ventricular premature beats (VPBs) with a rate X100 bpm. Sustained VTE was defined as VTE lasting X30 s or X60 beats. Non-sustained VTE was defined as a run of 3 or more VPBs with a rate X100 bpm that did not satisfy the criteria for sustained VTE.
the Morganroth criteria [16,17] as follows: (1) a change from the baseline visit in the number of VPBs/h and/or the frequency of VTEs (non-sustained or sustained) as described in Table 1 (sustained ventricular tachycardia was a ventricular tachycardia event that lasted X30 s or X60 beats; otherwise the VTE was non-sustained), (2) any postbaseline run of ventricular ectopic beats associated with symptoms (e.g. hypotension or syncope) regardless of the rate, and (3) any postbaseline episode of ventricular flutter and/or ventricular fibrillation. Except for proarrhythmic events, only Holter data that satisfied the following rules were considered valid and included in the summaries: (1) at least 14 h of the Holter 24-h monitoring had to be available for analysis, (2) if there were more than 1 Holter for a visit, the recording with the greatest amount of analyzable data was included in the summaries provided rule 1 was satisfied, (3) the baseline Holter had to be completed before start of study drug, (4) Holter ECGs performed 1 day after discontinuation of study drug or later were not accepted for the summaries. Treatment contrasts for QTc interval (Bazett and Fridericia correction), sitting blood pressure, and pulse rate were analyzed at all postbaseline visits using an analysis of covariance model including center, gender, and treatment as factors and the baseline value as covariate. Other safety assessments, including additional ECG variables (uncorrected QT interval, RR interval, PR interval, QRS duration), and adverse events were summarized using descriptive statistics. The 2-h postdose FEV1 measurements after the first dose (Visit 2), after 2 and 8 weeks of treatment (Visits 3 and 4), and at the end of treatment (patient’s last value) were evaluated. Treatment groups were compared using the following analysis of covariance model: FEV1 ¼ center+ gender+treatment+baseline FEV1, where baseline FEV1 was the predose FEV1 measurement taken at Visit 2. All randomized patients who received at least 1 dose of study medication were evaluated.
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3. Results
Table 2 Summary of demographic and baseline data
3.1. Patients The study was conducted between October 2002 and February 2004 at 23 investigational sites in the United States. Of the 346 patients screened, 204 patients were randomized and received study medication (97 received active treatment and 107 received placebo). Of the 142 patients who were screened but not randomized, 15 (10.6%) were not randomized owing to a cardiovascular reason (i.e. Holter finding, ECG finding, cardiovascular concomitant disease, excluded concomitant medication used to treat a cardiovascular disease [such as a beta blocker]). Of the 204 randomized patients, 187 (92%) completed the 8-week treatment period. The most common reasons for discontinuation were protocol violation (5 on active treatment and 2 on placebo) and adverse events (3 on active treatment and 2 on placebo). The most common protocol violations leading to discontinuation of study medication were a prebronchodilator FEV1 value which did not meet the inclusion criteria and an ECG performed X1 day after taking study medication. Of the patients who were randomized and treated, 92 (95%) formoterol and 106 (99%) placebo patients had valid Holter data at baseline and at a postbaseline visit (as defined by prespecified criteria). The treatment groups were balanced with regard to demographics and other baseline characteristics (Table 2). Concomitant COPD and antiarrhythmia (although part of the exclusion criteria) medications were generally well-matched in the treatment groups; the latter was taken by only a small proportion of patients (Table 3). A history of cardiac disorders was noted for 17/97 (17.5%) and 26/107 (24.3%) in the formoterol and placebo groups, respectively. Of those patients in the formoterol group 4/97 (4.1%) and 2/97 (2.1%) patients had a history of myocardial infarction and angina, respectively, and in the placebo group 4/107 (3.7%) and 6 (5.6%) patients had these medical histories, respectively. Hypoxia was present in a total of 3 patients (1/97 patients in the formoterol group and 2/107 patients in the placebo group). Measurements of vital signs and ECGs performed at screening were also similar between treatment groups. 3.2. 24-h Holter monitoring Patients who fulfilled the predefined criteria for proarrhythmic events are presented in Table 4. Of the 4 formoterol and 2 placebo patients with valid Holter recordings who met the criteria for proarrhythmia, none had a postbaseline run of ventricular premature beats associated with relevant symptoms or any postbaseline episode of ventricular flutter or ventricular fibrillation. In addition, for the 2 formoterol patients who experienced relevant increases in ventricular tachycardia, none of the events was sustained. A third placebo patient had an
Age, years Mean7SD Sex, n (%) Male Female Race, n (%) Caucasian Black Other Duration of COPD, years Mean7SD Smoking history Current smoker, n (%) Average number cigarettes/day Mean7SD Spirometry at screening FEV1, l Mean7SD FEV1, % of predicted Mean7SD FEV1/FVC, % Mean7 SD
Formoterol 12 mg bid (n ¼ 97)
Placebo (n ¼ 107)
62.178.85
62.7710.14
50 (51.5) 47 (48.5)
56 (52.3) 51 (47.7)
88 (90.7) 8 (8.2) 1 (1.0)
101 (94.4) 4 (3.7) 2 (1.9)
6.678.46
6.477.37
45 (46.4)
47 (43.9)
22.3710.38
26.7714.60
1.3670.568
1.3670.508
44.4714.09
45.0714.34
51.9711.75
52.9711.57
COPD ¼ chronic obstructive pulmonary disease; FEV1 ¼ forced expiratory volume in 1 s; FVC ¼ forced vital capacity; SD ¼ standard deviation.
Table 3 Number (%) of patients receiving concomitant medication during the study in 42% of patients
COPD medications Ipratropium Salbutamol Salmeterol Salmeterol/fluticasone combination Fluticasone Flunisolide Budesonide Triamcinolone Prednisone
Formoterol 12 mg bid (n ¼ 97) n (%)
Placebo (n ¼ 107) n (%)
22 7 3 3
(22.7) (7.2) (3.1) (3.1)
23 11 4 0
(21.5) (10.3) (3.7) (0.0)
11 4 2 2 2
(11.3) (4.1) (2.1) (2.1) (2.1)
16 3 3 3 5
(15.0) (2.8) (2.8) (2.8) (4.7)
4 2 3 3 1 1 3
(3.7) (1.9) (2.8) (2.8) (0.9) (0.9) (2.8)
Anti-arrhythmia and cardiac stabilizing medications Lisinopril 8 (8.2) Amlodipine 6 (6.2) Verapamil 3 (3.1) Verapamil hydrochloride 0 (0.0) Digoxin 2 (2.1) Irbesartan 2 (2.1) Losartan potassium 0 (0.0) COPD ¼ chronic obstructive pulmonary disease.
increase in mean ventricular premature beats at Visit 4 that met the criteria for proarrhythmia (from 147.7/h at Visit 1 and 123.1/h at Visit 3 to 1170.1/h at Visit 4), but the Holter
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Table 4 Number (%) of patients who satisfied the predefined criteria for proarrhythmic events at any time postbaseline
Patients with valid Holter monitoring data at baseline and postbaseline Any proarrhythmic event By criterion Relevant increase in mean VPB/h since baseline Relevant increase in the number of non-sustained VTEs since baseline Relevant increase in the number of sustained VTEs since baseline Postbaseline run of VPBs associated with symptoms Postbaseline event of ventricular flutter or ventricular fibrillation
Formoterol 12 mg bid (n ¼ 97) N (%)
Placebo (n ¼ 107) n (%)
92 (100.0) 4 (4.3)
106 (100.0) 2 (1.9)
3 (3.3) 2 (2.2) 0 0 0
2 (1.9) 0 0 0 0
Ventricular tachycardia (VTE) was defined as a run of 3 or more ventricular premature beats (VPBs) with X100 bpm. Sustained VTE was a VTE that lasted X30 s or X60 beats. Otherwise the VTE was non-sustained.
recording at this visit was considered invalid because it took place 1 day after the last dose of study medication. None of the Holter monitoring data showed clinically meaningful differences between the formoterol and placebo treatment groups. Summary statistics for the other Holter monitoring variables, predose (Visit 1) and at the end of treatment (patient’s last value), are summarized in Table 5. Heart rate data did not show meaningful changes during the study and were similar for both treatment groups. There was high variability in values for ventricular premature beats, due to the skewed nature of the data, particularly for the placebo group where a few patients with high values at baseline influenced the mean values for the total number and mean and maximum rates. Despite the high variability, the median and 25% and 75% quartile values did not indicate consistent or meaningful differences between treatment groups. No more than 5% of patients in either treatment group experienced a ventricular tachycardia event (a run of 3 or more VPBs with a rate X100 bpm) at any visit, and no more than 12% of patients in either treatment group experienced an idioventricular run event (run of 3 or more VPBs with a rate o100 bpm) at any visit. As a result, the rate of ventricular tachycardia events and idioventricular run events was low in both treatment groups as shown in Table 5. None of the patients with idioventricular run events had a run of 10 or more beats with a rate o100 bpm. Of the patients with ventricular tachycardia events, 2 formoterol and 1 placebo patient had a ventricular tachycardia event rate X10 beats/h. Each of these patients had only 1 ventricular tachycardia event of X10 beats. More than 90% of patients in each treatment group experienced at least 1 supraventricular premature beat. The large variability, due to the skewed nature of the data within each treatment group, influenced the mean values. However, median and 25% and 75% quartile values did not show meaningful differences between treatment groups. The number and rate of supraventricular run events (a run of 3 or more SVBPs) was low and did not show consistent or important differences between treatment groups.
3.3. Other safety measurements Less than a third of patients in each treatment group experienced adverse events during the study, and individual events occurred at low incidences (Table 6). As might be expected for this patient population, infections and respiratory events were the most frequently reported. Cardiovascular adverse events were recorded for 1 formoterol patient (atrial flutter) and 4 placebo patients (atrioventricular block, palpitations, sinus bradycardia, supraventricular tachycardia). Vascular disorders were reported for 1 placebo patient (hypertension). Most adverse events were judged by the investigator to be mild or moderate in severity and unrelated to study medication. There were no deaths during this study. Four patients experienced serious adverse events (3 formoterol and 1 placebo patient). Of these, only 1 (atrial flutter in a formoterol patient), which led to discontinuation of study medication, was suspected to be related to the study medication. Two other formoterol patients discontinued study medication due to serious adverse events (both COPD exacerbations), and 2 placebo patients discontinued due to non-serious adverse events (supraventricular tachycardia and sinus bradycardia). There were no important differences between treatment groups in the overall experience of adverse events. There were no clinically meaningful or statistically significant differences between the formoterol and placebo treatment groups in ECG or vital sign measurements. Mean and median QTc measurements and other ECG parameters (uncorrected QT, RR, PR and QRS) were similar in the 2 treatment groups across study visits. The majority of patients (485%) who experienced an increase from baseline in QTc had an increase of less than 30 ms at any visit. Less than 15% of patients experienced an increase from baseline in QTc of X30 ms. One patient in the formoterol group and 2 patients in the placebo group experienced a X60-ms increase in QTc from their pretreatment baseline (Visit 2) value to any postbaseline measurement. The formoterol patient who had a QTc increase X60 ms at Visit 3 (2 h postdose) had a QTc
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Table 5 Holter variables at baseline and end of treatment (patient’s last value)
Maximum heart rate (bpm) Mean7SD Mean heart rate (bpm) Mean7SD Total ventricular premature beats Mean7SD 25% quartile Median 75% quartile Mean ventricular premature beats/h Mean+SD Maximum ventricular premature beats/h Mean7SD Total ventricular tachycardia events Mean7SD Mean ventricular tachycardia events/h Mean7SD Maximum ventricular tachycardia events/h Mean7SD Total idioventricular run events Mean7SD Mean idioventricular run events/h Mean7SD Total supraventricular premature beats Mean7SD 25% quartile Median 75% quartile Mean supraventricular premature beats/h Mean7SD Maximum supraventricular premature beats/h Mean7SD Total supraventricular run events Mean7SD Mean supraventricular events/h Mean7SD
Formoterol 12 mg bid (n ¼ 97)
Placebo (n ¼ 107)
Baseline (n ¼ 96)
End (n ¼ 92)
Baseline (n ¼ 107)
End (n ¼ 106)
124714.7
123713.6
126716.4
123715.8
8179.0
8078.6
81710.3
80710.6
54371253.0 3 11 287
73272685.4 1 9 213
104074112.4 3 61 300
65072090.6 4 40 228
25757.0
357131.0
467181.9
307101.3
617126.7
767199.7
1217484.0
887256.5
0.271.09
0.471.70
1.278.28
1.079.23
0.0170.048
0.0270.082
0.0570.354
0.0570.479
0.170.35
0.270.58
0.774.64
0.371.77
0.070.23
0.070.21
0.170.69
0.170.33
0.0070.010
0.0070.010
0.0070.029
0.0070.017
45871671.1 9 27 99
50471844.1 9 29 124
37371066.6 15 52 146
82372961.8 14 48 186
21781.5
22780.6
17747.5
377129.6
647187.5
757223.5
567126.3
1507635.5
5737.4
7732.3
7728.8
197128.7
0.2671.796
0.2971.359
0.3171.283
0.8475.776
Ventricular tachycardia event ¼ run of 3 or more ventricular premature beats with a rate X100 bpm. Idioventricular run event ¼ run of 3 or more ventricular premature beats with a rate o100 bpm. Supraventricular run event ¼ run of 3 or more supraventricular premature beats.
decrease to a value below baseline at Visit 4 (2 h postdose). One patient in each treatment group had a X60-ms increase in QTc from pre- to postdose during a visit. Few patients experienced newly occurring (i.e. not present at baseline) QTc intervals 4460 ms postbaseline: 6 (6%) formoterol and 9 (9%) placebo patients using Bazett’s correction; 3 (3%) formoterol and 2 (2%) placebo patients using Fridericia’s correction. Mean and median vital sign measurements over time were similar in the 2 treatment groups. There were no clinically meaningful or statistically significant differences between treatment groups for mean vital sign measurements.
dose (Visit 2) and after 2 and 8 weeks of treatment (Visits 3 and 4). As shown in Fig. 1, the bronchodilator effect in the formoterol group was statistically significantly better than in the placebo group at all time points. The use of rescue medication (two 90 mg puffs of albuterol as needed) was recorded 6 h prior to and at any time during each visit. Only 1 formoterol patient required rescue medication during the assessment period (during Visit 3), compared with 4 placebo patients (3 patients during Visit 3, 1 of whom also took rescue medication at Visit 4, and 1 patient during Visit 4). 4. Discussion
3.4. Spirometry The only efficacy variable measured during the study was FEV1 at 2 h postdose, which was measured after the first
The results of this study confirm the good safety profile of 12 mg formoterol dry powder inhalation in patients with COPD. Only a small number of patients with valid Holter
ARTICLE IN PRESS S.C. Campbell et al. / Pulmonary Pharmacology & Therapeutics 20 (2007) 571–579 Table 6 Incidence of adverse events occurring in more than one patient in either treatment group
Total number with adverse events Adverse events Back pain Chronic obstructive airway disease exacerbated Headache Gastroenteritis viral Influenza Nasopharyngitis Oral candidiasis Upper respiratory tract infection Dizziness
Formoterol 12 mg bid (n ¼ 97) n (%)
n (%)
26 (26.8)
33 (30.8)
3 (3.1) 3 (3.1)
0 4 (3.7)
3 2 2 2 2 1
1 (0.9) 2 (1.9) 0 4 (3.7) 0 3 (2.8)
(3.1) (2.1) (2.1) (2.1) (2.1) (1.0) 0
Placebo (n ¼ 107)
2 (1.9)
Fig. 1. 2-h postdose FEV1 least-squares mean measurements over time by treatment group. P values for estimated treatment contrasts (formoterol minus placebo) are based on an analysis of covariance model: 2-h FEV1 ¼ treatment+baseline FEV1+gender+(pooled) center, where baseline FEV1 was the predose FEV1 measurement taken at Day 1 (Visit 2).
monitoring met the predefined criteria for a proarrhythmic event (4 formoterol and 2 placebo patients). These events included increases in the rate of postbaseline ventricular premature beats and/or increases in the rate of nonsustained ventricular tachycardia events. No patients had sustained postbaseline ventricular tachycardia events or met other criteria for a proarrhythmic event, such as a run of ventricular premature beats associated with relevant symptoms (e.g. hypotension or syncope) or an episode of ventricular flutter or ventricular fibrillation. These results provide a good indication of the safety of formoterol (12 mg) in patients with COPD, although larger studies providing more robust statistical power are
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required to elucidate fully the cardiac effects of this treatment. The sample size was chosen to provide reasonable exposure from the safety perspective, and not for considerations of statistical power. A further consideration in adopting an empirical approach for this study was the lack of adequate information available concerning Holter monitoring in COPD patients, which could have been used to estimate sample size with associated power using a predefined hypothesis. Further work is also needed to investigate any long-term cardiac effects of the 24 mg dose of formoterol, which is indicated in some countries for the treatment of patients with COPD. However, it is reassuring to note that heart rate and rhythm disorders were uncommon in 2 large randomized, placebo-controlled studies investigating the use of formoterol 24 mg in a total of more than 1600 patients with COPD [9,10], with an incidence similar to that seen with placebo. Furthermore, clinical trials such as this, for ethical and safety reasons, necessarily select patients at minimal risk of b-agonistinduced complications, and this may limit the application of these results to the wider population of patients in reallife clinical practice. Cardiovascular co-morbidities, most commonly heart failure but including arrhythmias, occur more frequently in patients with COPD, who are at higher risk of hospitalization and death due to these conditions [18–20]. The increasing appreciation of this important comorbidity underlines the need to demonstrate the cardiovascular safety of treatments for COPD. The data obtained in this study in COPD patients are consistent with previously reported Holter monitoring findings in asthma patients treated with formoterol [21,22]. In one 12-week study, Holter monitoring was performed in 217 asthma patients treated with inhaled formoterol (12 and 24 mg bid), albuterol and placebo [22]. For both formoterol doses and placebo, mean total ventricular beats per hour decreased from baseline at Weeks 2 and 8, whereas an increase was observed for albuterol. Similar trends were seen in the mean maximum ventricular beats per hour. There were no meaningful differences between formoterol, albuterol, and placebo with regard to ventricular ectopy, supraventricular ectopy, or heart rate. In both studies, the incidence of clinically significant abnormalities in ECG data was low (o5%) and distributed similarly across treatment groups (formoterol 12 and 24 mg, albuterol, and placebo) [21,22]. Ferguson et al. evaluated the cardiac safety of inhaled salmeterol 50 mg twice-daily in COPD patients using a post hoc pooled analysis across 7 controlled clinical studies [23]. The results of their analysis were similar to our findings. There was no increased risk of cardiovascular adverse events relative to placebo (P ¼ 0.838). Holter monitoring data were obtained from 115 salmeterol and 134 placebo patients, with no reported sustained ventricular tachycardia events and no clinically significant differences between salmeterol and placebo in 24-h heart rate, ventricular or supraventricular ectopy, QTc (Bazett correction) interval, or vital signs.
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Although a number of studies have shown that inhaled formoterol exhibits a good safety profile in both COPD [9,10] and asthma [21,22], b2-adrenoceptor stimulation has the potential to induce cardiac rhythm disturbances. Recently, Salpeter et al. performed a pooled analysis of published, randomized, placebo-controlled trials to evaluate the cardiovascular effects of b2-agonists in patients with asthma or COPD [12]. Data were obtained from 13 single-dose studies and 20 multiple-dose trials ranging from 3 days to 1 year in duration. The retrospective analysis found that single doses of b2-agonist significantly increased heart rate and decreased potassium concentration relative to placebo [12]. Further, the analysis of multiple-dose trials suggested that b2-agonists increased the risk of sinus tachycardia and cardiovascular events overall compared with placebo. The authors concluded that b2-agonists increase the risk for adverse cardiovascular events in patients with obstructive airway disease and speculated that this class of drugs may precipitate ischemia, congestive heart failure arrhythmias and sudden death. The clinical significance of the analysis is unclear as the pooled data included patients with asthma or COPD treated with a variety of b2-agonists via different modes of administration in studies published up to 27 years ago [12]. The analysis did not show a significantly increased risk of major cardiovascular events associated with b2-agonists (relative risk [RR], 1.66; 95% CI, 0.76–3.6). The risk for sinus tachycardia was not significantly increased with b2-agonists relative to placebo in any of the studies of COPD patients (i.e. the 95% CI for RR included 1 for all studies). In fact, although the relative risk for sinus tachycardia was 3.06 (95% CI, 1.70–5.50) in the pooled analysis, only 1 of the studies showed a statistically significant increased risk for sinus tachycardia with b2-agonists relative to placebo (i.e. the 95% CI for RR included 1 for all except 1 study). Cazzola et al. found that single doses of formoterol (12 and 24 mg) and salmeterol (50 mg), increased mean heart rate and decreased mean potassium concentrations compared with placebo in a single-blind, randomized, crossover study of patients with COPD and preexisting cardiac arrhythmias and hypoxemia [24]. There were no meaningful differences between formoterol 12 mg and salmeterol 50 mg in any of the reported Holter monitoring variables. No baseline Holter monitoring data were available and the number of patients (12) was small. Recently, a nested casecontrol study found an association between inhaled b2-agonist use and rehospitalization for chronic heart failure (CHF) among patients with a prior diagnosis of CHF. There was no apparent association between b2-agonists and risk of incident heart failure [25]. Only 3 patients overall had preexisting hypoxia and patients with preexisting clinically significant conditions (including arrhythmia) were generally excluded from our study. Further research is needed to assess the cardiac effects of b2-agonists in COPD patients with preexisting cardiac disorders.
Likewise, no conclusion can be drawn as to the possible influence of concomitant medications, as the data were not stratified to analyze this sub-population. A previous study [26] in a small group of healthy subjects showed that inhaled corticosteroids (ICS) and b2-agonist may lead to increased cardiac risk as a consequence of resensitization of cardiac b2-receptors by ICS. As similar proportions of patients in each treatment group in the current study took ICS concomitantly, it is unlikely that the results would have been affected. Other concomitant medications such as antiarrhythmia drugs, which have the potential to cause proarrhythmia [13], were taken by a small proportion of patients, and as a result, are unlikely to have influenced the data significantly. Although our study was primarily a safety study, spirometry (FEV1 2 h postdose) was measured after the first dose and after 2 and 8 weeks of treatment. Treatmentgroup comparisons showed that 2-h postdose FEV1 was statistically significantly improved in the formoterol group compared with the placebo group at all visits during the treatment period (Po0.001 for estimated treatment contrasts at each visit). These findings are consistent with previous reports where formoterol demonstrated significantly better spirometric efficacy than placebo, ipratropium, and theophylline, and was shown to improve healthrelated quality of life [9,10]. 5. Conclusions The results of this study indicate that twice-daily use of 12 mg formoterol dry powder inhalation capsules delivered by the Aerolizer device has an acceptable cardiovascular safety profile in patients with COPD. The data showed no clinically meaningful increase in cardiac rhythm events for patients treated with formoterol compared with matching placebo. This study screened out patients with significant cardiovascular disease and arrhythmia, which are common co-morbidities in COPD patients. Vital signs and ECG data, including QTc interval, were similar for active and placebo groups. The pattern of reported adverse events was consistent with the expected profile for COPD patients. Acknowledgments This study was supported by Novartis, East Hanover, NJ. Novartis was responsible for the design and conduct of the study, data collection, management and analysis. Novartis was also involved in the interpretation of the data, and preparation, review and approval of the manuscript. Dr Ziehmer, Mr Orevillo, and Mr Smith are employed by Novartis; Dr Ziehmer and Mr Orevillo received stock options and shares in Novartis as part of their employee compensation package during the time of their contribution to the study. Drs Campbell and Levine have received research funding and honoraria and have acted as consultants to Novartis. Dr Criner has received honoraria
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from Novartis. Dr Simon does not have any conflict of financial interest with the subject matter of this manuscript. The authors would like to thank the investigators and staff at the study sites. We also thank Karen M. Miner, PhD, for her help in preparing this manuscript. The principal investigators and site locations were as follows: George W. Bensch, MD, Bensch Clinical Research Associates, Stockton, CA; Laurie Dubois (study coordinator), CCRC, Heartland Clinical Research, Inc., Omaha, NE; Frank C. Hampel, Jr., MD, Central Texas Health Research, New Braunfels, TX; Terence Isakov, MD, Ohio Clinical Research, LLC, Lyndhurst, OH; Craig F. LaForce, MD, North Carolina Clinical Research, Raleigh, NC; David Ostransky, DO, North Texas Lung & Sleep Center, Fort Worth, TX; Thomas C. Klein, MD, Heartland Research Associates, LLC, Wichita, KS; Jahn A. Pothier, MD, Hawthorne Medical Associates, LLC, North Dartmouth, MA; Stephen I. Rennard, MD, Pulmonary Research, University of Nebraska Medical Center, Omaha, NE; James E. Turek, MD, Med Plus South Strand Family Practice, Garden City, SC. References [1] Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/ WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary. Am J Respir Crit Care Med 2001;163:1256–76 (updated 2003. Available at http://www.goldcopd. com. Accessed August 4, 2004. [2] Halbert RJ, Isonaka S, George D, Iqbal A. Interpreting COPD prevalence estimates: what is the true burden of disease? Chest 2003;123:1684–92. [3] Sullivan SD, Ramsey SD, Lee TA. The economic burden of COPD. Chest 2000;117(2 Suppl):5S–9S. [4] Tashkin DP, Cooper CB. The role of long-acting bronchodilators in the management of stable COPD. Chest 2004;125:249–59. [5] Kottakis J, Cioppa GD, Creemers J, Greefhorst L, Leclerc V, Pistelli R, et al. Faster onset of bronchodilation with formoterol than with salmeterol in patients with stable, moderate to severe COPD: results of a randomized, double-blind clinical study. Can Respir J 2002; 9:107–15. [6] Maesen BL, Westermann CJ, Duurkens VA, van den Bosch JM. Effects of formoterol in apparently poorly reversible chronic obstructive pulmonary disease. Eur Respir J 1999;13:1103–8. [7] Celik G, Kayacan O, Beder S, Durmaz G. Formoterol and salmeterol in partially reversible chronic obstructive pulmonary disease: a crossover, placebo-controlled comparison of onset and duration of action. Respiration 1999;66:434–9. [8] Benhamou D, Cuvelier A, Muir JF, Leclerc V, Le Gros V, Kottakis J, et al. Rapid onset of bronchodilation in COPD: a placebo-controlled study comparing formoterol (Foradils AerolizerTM) with salbutamol (VentodiskTM). Respir Med 2001;95:817–21.
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[9] Dahl R, Greefhorst LA, Nowak D, Nonikov V, Byrne AM, Thomson MH, for the Formoterol in Chronic Obstructive Pulmonary Disease I (FICOPD I) Study Group, et al. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:778–84. [10] Rossi A, Kristufek P, Levine BE, Thomson MH, Till D, Kottakis J, et al. For the Formoterol in Chronic Obstructive Pulmonary Disease (FICOPD) II Study Group. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Chest 2002;121:1058–69. [11] Rabe KF. State of the art in b2-agonist therapy: a safety review of long-acting agents. Int J Clin Pract 2003;57:689–97. [12] Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of b-agonists in patients with asthma and COPD. A meta-analysis. Chest 2004;125:2309–21. [13] Mackstaller LL, Alpert JS. Atrial fibrillation: a review of mechanism, etiology, and therapy. Clin Cardiol 1997;20:640–50. [14] Naccarelli GV, Wolbrette DL, Luck JC. Proarrhythmia. Med Clin North Am 2001;85:503–26 xii. [15] American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152:S77–S121. [16] Morganroth J, Borland M, Chao G. Application of a frequency definition of ventricular proarrhythmia. Am J Cardiol 1987;59:97–9. [17] Morganroth J, Horowitz LN. Flecainide: its proarrhythmic effect and expected changes on the surface electrocardiogram. Am J Cardiol 1984;53:89B–94B. [18] Rutten FH, Cramer MJ, Grobbee DE, Sachs AP, Kirkels JH, Lammers JW, et al. Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease. Eur Heart J 2005;26:1887–94. [19] Curkendall SM, DeLuise C, Jones JK, Lanes S, Stang MR, Goehring Jr. E, et al. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol 2006;16:63–70. [20] Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD. Chest 2005;128:2640–6. [21] Bensch G, Lapidus RJ, Levine BE, Lumry W, Yegen U, Kiselev P, et al. A randomized, 12-week, double-blind, placebo-controlled study comparing formoterol dry powder inhaler with albuterol metereddose inhaler. Ann Allergy Asthma Immunol 2001;86:19–27. [22] Pleskow W, LaForce CF, Yegen U¨, Matos D, Della Cioppa G. Formoterol delivered via the dry powder Aerolizers inhaler versus albuterol MDI and placebo in mild-to-moderate asthma: a randomized, double-blind, double-dummy trial. J Asthma 2003;40:505–14. [23] Ferguson GT, Funck-Brentano C, Fischer T, Darken P, Reisner C. Cardiovascular safety of salmeterol in COPD. Chest 2003;123: 1817–24. [24] Cazzola M, Imperatore F, Salzillo A, Di Perna F, Calderaro F, Imperatore A, et al. Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia. Chest 1998;114:411–5. [25] Au DH, Udris EM, Curtis JR, McDonell MB, Fihn SD. Association between chronic heart failure and inhaled b-2-adrenoceptor agonists. Am Heart J 2004;148:915–20. [26] Aziz I, McFarlane LC, Lipworth BJ. Concomitant inhaled corticosteroid resensitises cardiac beta2-adrenoceptors in the presence of long-acting beta2-agonist therapy. Eur J Clin Pharmacol 1998; 54:377–81.
Pulmonary Pharmacology & Therapeutics 20 (2007) 571–579 www.elsevier.com/locate/ypupt
Cardiac safety of formoterol 12 mg twice daily in patients with chronic obstructive pulmonary disease Sammy C. Campbella,, Gerard J. Crinerb, Bernard E. Levinec, Stuart J. Simond, Jonathan S. Smithe, Chadwick J. Orevillof, Barbara A. Ziehmerf a
Arizona Respiratory Center, University of Arizona and Pulmonary Section, VA Medical Center, Southern Arizona VA Health Care System, Tucson, AZ, USA b Division of Pulmonary & Critical Care Medicine, School of Medicine, Temple University, Philadelphia, PA, USA c Pulmonary Associates, PA, Phoenix, AZ, USA d Radiant Research and Georgia Lung Associates, Austell, GA, USA e Novartis Horsham Research Centre, Horsham, West Sussex, UK f Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Received 11 January 2006; received in revised form 6 June 2006; accepted 18 June 2006
Abstract Background: Some evidence suggests an increased risk of myocardial infarction and dysrhythmia events associated with b2-agonist use in patients with chronic obstructive pulmonary disease (COPD). This prospective, multicenter, randomized, double-blind, placebocontrolled study compared the cardiac safety of formoterol and placebo in patients with COPD. Methods: After a 3–14-day run-in, 204 patients were randomized to receive formoterol 12 mg dry powder inhalation or matching placebo twice daily for 8 weeks. Twenty four-hour continuous electrocardiography (Holter monitoring) was performed at screening and after 2 and 8 weeks of treatment. Results: Only a small number of patients met the predefined criteria for a proarrhythmic event (4 formoterol and 2 placebo patients). No patients had sustained postbaseline ventricular tachycardia events, postbaseline run of ventricular ectopic beats associated with relevant symptoms (e.g. hypotension, syncope), or an episode of ventricular flutter or fibrillation. Holter monitoring data were variable but showed no clinically meaningful differences between the formoterol and placebo groups, respectively, for variables such as (mean7SD at end of treatment): heart rate (8078.6 vs. 80710.6 bpm), number and rate of ventricular premature beats (total 73272685.4 vs. 65072090.6; rate 357131.0 vs. 307101.3 per h), ventricular tachycardia events (total 0.471.70 vs. 1.079.23; rate 0.0270.082 vs. 0.0570.479 per h), and supraventricular premature beats (total 50471844.1 vs. 82372961.8; rate 22780.6 vs. 377129.6 per h). Vital signs and electrocardiogram data, including corrected QT intervals (Bazett and Fridericia), were similar across treatment groups. The overall adverse event experience was similar in the formoterol (n ¼ 26 [27%]) and placebo (n ¼ 33 [31%]) groups. The most common adverse events, infections and respiratory events, were expected for this patient population. The incidence of cardiac adverse events was low (1 formoterol and 4 placebo patients). Conclusions: The results of this study confirm the good cardiovascular safety profile of formoterol in patients with COPD. r 2006 Elsevier Ltd. All rights reserved. Keywords: COPD; Formoterol; Cardiac safety
1. Introduction
Corresponding author. Tel.: +1 520 792 1450x5061; fax: +1 520 882 9811. E-mail address: [email protected] (S.C. Campbell).
1094-5539/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2006.06.003
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality and morbidity in the United States and worldwide [1]. Prevalence estimates vary widely but usually range from about 4%–10% in countries
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where well-designed studies have been conducted [2]. The symptoms of COPD (eg., chronic cough, dyspnea, expectoration, reduced exercise capacity, and repeated exacerbations) cause extensive disability in many patients, imposing a substantial burden on healthcare resources [3]. The Global Initiative for Chronic Obstructive Lung Disease guideline recommends a stepwise approach to disease management with bronchodilators as the mainstay for symptomatic treatment [1]. There are 3 classes of bronchodilators available for the treatment of COPD: b2-adrenoceptor agonists, anticholinergics, and methylxanthines (theophylline). Of these, inhaled b2-agonists and anticholinergics are preferred to oral theophylline which has a narrow therapeutic index. Short-acting b2-agonists, which have a relatively rapid onset of action and short duration of effect (4–6 h), are used primarily as rescue medication for relief of symptoms [4]. Formoterol fumarate is a long-acting b2-agonist with unique pharmacologic properties, including high selectivity to b2-receptors relative to b1-receptors, and high intrinsic activity. Formoterol has been shown to be therapeutically effective, safe and well tolerated in patients participating in clinical trials of up to 12 months’ duration [5–10]. Compared with other long-acting b2-agonists, such as salmeterol, formoterol has a more rapid onset of action (less than 5 min) and similar duration of effect (approximately 12 h) [5,11]. A retrospective review suggests there may be an increased risk of myocardial infarction and dysrhythmia events in patients treated with b2-agonists for obstructive airway disease [12]. The pharmacologic action of b2-agonists on b-adrenergic receptors has the potential to increase heart rate and exacerbate cardiac rhythm disturbances [1]. Development of arrhythmia as a consequence of treatment, often a paradoxical side effect of antiarrhythmic therapy [13], is known as proarrhythmia and is characterized by a poor prognosis [14]. The objective of this prospective study was to compare the electrocardiographic effects, especially a potential influence on cardiac rhythm, of formoterol 12 mg dry powder inhalation with placebo in COPD patients as evaluated by 24-h continuous Holter monitoring. The study was requested by the US Food and Drug Administration (FDA) as a commitment to evaluate further the safety of formoterol dry powder capsules 12 mg twice daily for the maintenance treatment of COPD in adults, following the FDA’s approval of formoterol for use in this setting.
forced expiratory volume in 1 s (FEV1) be o70% of predicted normal value and X0.75 l, with a FEV1/forced vital capacity (FVC) ratio p70%. Main exclusion criteria included a history of asthma, or a respiratory tract infection or hospitalization or emergency room treatment for an acute COPD exacerbation in the previous month. Patients with a history of malignancy in the previous 5 years, a history of untoward reactions to sympathomimetic amines, a corrected QT (QTc) interval 40.46 s at screening (Visit 1), or any clinically significant condition that might compromise the patient’s safety or compliance were excluded. Females who were pregnant or nursing were excluded. Females of childbearing age were required to use a reliable contraception method. The use of b2-agonists (other than formoterol or rescue albuterol), oral or parenteral corticosteroids or inhaled anticholinergics (except inhaled ipratropium bromide) were not allowed unless necessary to treat a COPD exacerbation. Inhaled and nasal corticosteroids, ipratropium bromide or sustained-release theophylline could be continued at a stable dose, but could not be started during the study unless needed for a COPD exacerbation. Patients receiving an inhaled combination of corticosteroid and b2-agonist were switched to a separate formulation of an inhaled corticosteroid (plus a separate inhaled b2-agonist, if required) 3 weeks prior to Visit 1. Short courses of excluded medication (p15 days and not more than twice during the study) for an exacerbation did not result in discontinuation of the patient from the study. Short courses of antibiotics or oxygen were also permitted. Patients taking oral corticosteroids within the previous month, oral or inhaled anticholinergics (other than inhaled ipratropium bromide), long-acting b2-agonists, or inhaled short-acting b2-agonists within 6 h prior to Visit 1 were excluded. Patients receiving b-blockers, antiarrhythmics, non-potassium-sparing diuretics, tricyclic antidepressants, selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors were also excluded. Patients whose screening Holter monitor recording met 1 or more Holter monitoring criteria for discontinuation were excluded (i.e. average heart rate p40 beats per min [bpm] for any 1 h, transient or fixed complete heart block, transient Mobitz II second degree heart block, Mobitz I lasting greater than a continuous 60-min duration, ventricular asystole X2.5-s duration, persistently prolonged QTc interval [consistently 40.5 s], proarrhythmia, investigator’s request). 2.2. Study design
2. Methods 2.1. Patients Patients were male or female, X40 years of age, who were current or ex-smokers of 410 pack-years and had a diagnosis of COPD according to the American Thoracic Society guidelines [15]. Inclusion criteria required that patients’ prebronchodilator (after appropriate washout)
This was a prospective, randomized, multicenter, double-blind, placebo-controlled, parallel-group study. The protocol was reviewed and approved by the appropriate institutional review board for each study site, and all patients gave written informed consent to participate in the study before any study procedures were performed. After screening and a run-in period of 3–14 days, patients were randomized to formoterol 12 mg dry powder inhalation or
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matching placebo administered twice daily via Aerolizers (Novartis, East Hanover, NJ) for 8 weeks. Patients were permitted to take 2 puffs of rescue medication (albuterol pressurized metered dose inhaler [90 mg emitted dose per puff]) as needed during the study, but were not to exceed 8 rescue puffs in any given 24-h period: patients exceeding this or taking 8 puffs on 2 consecutive days were instructed to notify an investigator. Holter monitoring was performed at screening (Visit 1) to provide a baseline recording and after 2 weeks (Visit 3) and 8 weeks (Visit 4) of treatment to determine longitudinal effects. All Holter monitoring recordings were initiated in the morning at approximately the same time; the Visit 3 and Visit 4 Holter monitoring periods were initiated 15–30 min prior to the morning dose of study medication. Holter monitoring recordings were assessed for cardiac arrhythmias by an independent cardiologist. A screening electrocardiogram (ECG) was performed at Visit 1. Further ECGs were obtained at Visits 2 (Day 1), 3, and 4 prior to administration of study medication and at 2 h postdose. At Visit 2, two ECGs were performed predose at least 15 min apart, and the average of the 2 values provided a baseline value. All ECGs included 12 standard leads and a lead II rhythm strip of at least 10-s duration. Vital signs were obtained at all clinic visits, and adverse events were recorded throughout the study. Efficacy was assessed by measuring FEV1 at 2 h postdose, after the first dose of study medication (Visit 2), and after 2 and 8 weeks of treatment (Visits 3 and 4). 2.3. Statistical methods A sample size of 200 was chosen after consideration from the FDA as this would be sufficient to provide a reasonable exposure from a safety perspective. All data were analyzed in the intention to treat (ITT) population, which was defined as all randomized patients who received at least 1 dose of study medication (the safety and ITT populations were defined the same). The continuous electrocardiograph (Holter monitoring) data were summarized by treatment group using descriptive statistics only as it was considered appropriate by the FDA to evaluate the Holter monitoring data without formal statistical analysis. The following variables were analyzed: proarrhythmia, 24-h heart rate, ventricular ectopy (ventricular premature beats [VPBs]), ventricular run events (ventricular tachycardia events [VTE] defined as a run of 3 or more VPBs with X100 bpm, and/or idioventricular run events [IVEs] defined as a run of 3 or more VPBs with a rate o100 bpm), supraventricular ectopy (supraventricular premature beats [SVPBs]), and supraventricular run events defined as a run of SVPBs of 3 or more beats. The 24-h Holter monitor recordings obtained after the start of double-blind treatment were reviewed for the development of, or any increase in the incidence of, cardiac dysrhythmic events that could be considered indicative of proarrhythmic drug effects. The definition of proarrhythmia was based on
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Table 1 Ventricular tachycardia and ventricular premature beats criteria for proarrhythmia events
Mean VPB/h
Non-sustained VTEs
Baseline
Criteria postbaseline
0–1 1–100 4100 0
X10 mean VPB/h Increase of X10 times baseline Increase of X3 times baseline X5 Events or 415 beats in events/24 h Increase of X10 times baseline events or beats X1
X1 Sustained VTEs
0
Ventricular tachycardia event (VTE) was defined as a run of 3 or more ventricular premature beats (VPBs) with a rate X100 bpm. Sustained VTE was defined as VTE lasting X30 s or X60 beats. Non-sustained VTE was defined as a run of 3 or more VPBs with a rate X100 bpm that did not satisfy the criteria for sustained VTE.
the Morganroth criteria [16,17] as follows: (1) a change from the baseline visit in the number of VPBs/h and/or the frequency of VTEs (non-sustained or sustained) as described in Table 1 (sustained ventricular tachycardia was a ventricular tachycardia event that lasted X30 s or X60 beats; otherwise the VTE was non-sustained), (2) any postbaseline run of ventricular ectopic beats associated with symptoms (e.g. hypotension or syncope) regardless of the rate, and (3) any postbaseline episode of ventricular flutter and/or ventricular fibrillation. Except for proarrhythmic events, only Holter data that satisfied the following rules were considered valid and included in the summaries: (1) at least 14 h of the Holter 24-h monitoring had to be available for analysis, (2) if there were more than 1 Holter for a visit, the recording with the greatest amount of analyzable data was included in the summaries provided rule 1 was satisfied, (3) the baseline Holter had to be completed before start of study drug, (4) Holter ECGs performed 1 day after discontinuation of study drug or later were not accepted for the summaries. Treatment contrasts for QTc interval (Bazett and Fridericia correction), sitting blood pressure, and pulse rate were analyzed at all postbaseline visits using an analysis of covariance model including center, gender, and treatment as factors and the baseline value as covariate. Other safety assessments, including additional ECG variables (uncorrected QT interval, RR interval, PR interval, QRS duration), and adverse events were summarized using descriptive statistics. The 2-h postdose FEV1 measurements after the first dose (Visit 2), after 2 and 8 weeks of treatment (Visits 3 and 4), and at the end of treatment (patient’s last value) were evaluated. Treatment groups were compared using the following analysis of covariance model: FEV1 ¼ center+ gender+treatment+baseline FEV1, where baseline FEV1 was the predose FEV1 measurement taken at Visit 2. All randomized patients who received at least 1 dose of study medication were evaluated.
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3. Results
Table 2 Summary of demographic and baseline data
3.1. Patients The study was conducted between October 2002 and February 2004 at 23 investigational sites in the United States. Of the 346 patients screened, 204 patients were randomized and received study medication (97 received active treatment and 107 received placebo). Of the 142 patients who were screened but not randomized, 15 (10.6%) were not randomized owing to a cardiovascular reason (i.e. Holter finding, ECG finding, cardiovascular concomitant disease, excluded concomitant medication used to treat a cardiovascular disease [such as a beta blocker]). Of the 204 randomized patients, 187 (92%) completed the 8-week treatment period. The most common reasons for discontinuation were protocol violation (5 on active treatment and 2 on placebo) and adverse events (3 on active treatment and 2 on placebo). The most common protocol violations leading to discontinuation of study medication were a prebronchodilator FEV1 value which did not meet the inclusion criteria and an ECG performed X1 day after taking study medication. Of the patients who were randomized and treated, 92 (95%) formoterol and 106 (99%) placebo patients had valid Holter data at baseline and at a postbaseline visit (as defined by prespecified criteria). The treatment groups were balanced with regard to demographics and other baseline characteristics (Table 2). Concomitant COPD and antiarrhythmia (although part of the exclusion criteria) medications were generally well-matched in the treatment groups; the latter was taken by only a small proportion of patients (Table 3). A history of cardiac disorders was noted for 17/97 (17.5%) and 26/107 (24.3%) in the formoterol and placebo groups, respectively. Of those patients in the formoterol group 4/97 (4.1%) and 2/97 (2.1%) patients had a history of myocardial infarction and angina, respectively, and in the placebo group 4/107 (3.7%) and 6 (5.6%) patients had these medical histories, respectively. Hypoxia was present in a total of 3 patients (1/97 patients in the formoterol group and 2/107 patients in the placebo group). Measurements of vital signs and ECGs performed at screening were also similar between treatment groups. 3.2. 24-h Holter monitoring Patients who fulfilled the predefined criteria for proarrhythmic events are presented in Table 4. Of the 4 formoterol and 2 placebo patients with valid Holter recordings who met the criteria for proarrhythmia, none had a postbaseline run of ventricular premature beats associated with relevant symptoms or any postbaseline episode of ventricular flutter or ventricular fibrillation. In addition, for the 2 formoterol patients who experienced relevant increases in ventricular tachycardia, none of the events was sustained. A third placebo patient had an
Age, years Mean7SD Sex, n (%) Male Female Race, n (%) Caucasian Black Other Duration of COPD, years Mean7SD Smoking history Current smoker, n (%) Average number cigarettes/day Mean7SD Spirometry at screening FEV1, l Mean7SD FEV1, % of predicted Mean7SD FEV1/FVC, % Mean7 SD
Formoterol 12 mg bid (n ¼ 97)
Placebo (n ¼ 107)
62.178.85
62.7710.14
50 (51.5) 47 (48.5)
56 (52.3) 51 (47.7)
88 (90.7) 8 (8.2) 1 (1.0)
101 (94.4) 4 (3.7) 2 (1.9)
6.678.46
6.477.37
45 (46.4)
47 (43.9)
22.3710.38
26.7714.60
1.3670.568
1.3670.508
44.4714.09
45.0714.34
51.9711.75
52.9711.57
COPD ¼ chronic obstructive pulmonary disease; FEV1 ¼ forced expiratory volume in 1 s; FVC ¼ forced vital capacity; SD ¼ standard deviation.
Table 3 Number (%) of patients receiving concomitant medication during the study in 42% of patients
COPD medications Ipratropium Salbutamol Salmeterol Salmeterol/fluticasone combination Fluticasone Flunisolide Budesonide Triamcinolone Prednisone
Formoterol 12 mg bid (n ¼ 97) n (%)
Placebo (n ¼ 107) n (%)
22 7 3 3
(22.7) (7.2) (3.1) (3.1)
23 11 4 0
(21.5) (10.3) (3.7) (0.0)
11 4 2 2 2
(11.3) (4.1) (2.1) (2.1) (2.1)
16 3 3 3 5
(15.0) (2.8) (2.8) (2.8) (4.7)
4 2 3 3 1 1 3
(3.7) (1.9) (2.8) (2.8) (0.9) (0.9) (2.8)
Anti-arrhythmia and cardiac stabilizing medications Lisinopril 8 (8.2) Amlodipine 6 (6.2) Verapamil 3 (3.1) Verapamil hydrochloride 0 (0.0) Digoxin 2 (2.1) Irbesartan 2 (2.1) Losartan potassium 0 (0.0) COPD ¼ chronic obstructive pulmonary disease.
increase in mean ventricular premature beats at Visit 4 that met the criteria for proarrhythmia (from 147.7/h at Visit 1 and 123.1/h at Visit 3 to 1170.1/h at Visit 4), but the Holter
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Table 4 Number (%) of patients who satisfied the predefined criteria for proarrhythmic events at any time postbaseline
Patients with valid Holter monitoring data at baseline and postbaseline Any proarrhythmic event By criterion Relevant increase in mean VPB/h since baseline Relevant increase in the number of non-sustained VTEs since baseline Relevant increase in the number of sustained VTEs since baseline Postbaseline run of VPBs associated with symptoms Postbaseline event of ventricular flutter or ventricular fibrillation
Formoterol 12 mg bid (n ¼ 97) N (%)
Placebo (n ¼ 107) n (%)
92 (100.0) 4 (4.3)
106 (100.0) 2 (1.9)
3 (3.3) 2 (2.2) 0 0 0
2 (1.9) 0 0 0 0
Ventricular tachycardia (VTE) was defined as a run of 3 or more ventricular premature beats (VPBs) with X100 bpm. Sustained VTE was a VTE that lasted X30 s or X60 beats. Otherwise the VTE was non-sustained.
recording at this visit was considered invalid because it took place 1 day after the last dose of study medication. None of the Holter monitoring data showed clinically meaningful differences between the formoterol and placebo treatment groups. Summary statistics for the other Holter monitoring variables, predose (Visit 1) and at the end of treatment (patient’s last value), are summarized in Table 5. Heart rate data did not show meaningful changes during the study and were similar for both treatment groups. There was high variability in values for ventricular premature beats, due to the skewed nature of the data, particularly for the placebo group where a few patients with high values at baseline influenced the mean values for the total number and mean and maximum rates. Despite the high variability, the median and 25% and 75% quartile values did not indicate consistent or meaningful differences between treatment groups. No more than 5% of patients in either treatment group experienced a ventricular tachycardia event (a run of 3 or more VPBs with a rate X100 bpm) at any visit, and no more than 12% of patients in either treatment group experienced an idioventricular run event (run of 3 or more VPBs with a rate o100 bpm) at any visit. As a result, the rate of ventricular tachycardia events and idioventricular run events was low in both treatment groups as shown in Table 5. None of the patients with idioventricular run events had a run of 10 or more beats with a rate o100 bpm. Of the patients with ventricular tachycardia events, 2 formoterol and 1 placebo patient had a ventricular tachycardia event rate X10 beats/h. Each of these patients had only 1 ventricular tachycardia event of X10 beats. More than 90% of patients in each treatment group experienced at least 1 supraventricular premature beat. The large variability, due to the skewed nature of the data within each treatment group, influenced the mean values. However, median and 25% and 75% quartile values did not show meaningful differences between treatment groups. The number and rate of supraventricular run events (a run of 3 or more SVBPs) was low and did not show consistent or important differences between treatment groups.
3.3. Other safety measurements Less than a third of patients in each treatment group experienced adverse events during the study, and individual events occurred at low incidences (Table 6). As might be expected for this patient population, infections and respiratory events were the most frequently reported. Cardiovascular adverse events were recorded for 1 formoterol patient (atrial flutter) and 4 placebo patients (atrioventricular block, palpitations, sinus bradycardia, supraventricular tachycardia). Vascular disorders were reported for 1 placebo patient (hypertension). Most adverse events were judged by the investigator to be mild or moderate in severity and unrelated to study medication. There were no deaths during this study. Four patients experienced serious adverse events (3 formoterol and 1 placebo patient). Of these, only 1 (atrial flutter in a formoterol patient), which led to discontinuation of study medication, was suspected to be related to the study medication. Two other formoterol patients discontinued study medication due to serious adverse events (both COPD exacerbations), and 2 placebo patients discontinued due to non-serious adverse events (supraventricular tachycardia and sinus bradycardia). There were no important differences between treatment groups in the overall experience of adverse events. There were no clinically meaningful or statistically significant differences between the formoterol and placebo treatment groups in ECG or vital sign measurements. Mean and median QTc measurements and other ECG parameters (uncorrected QT, RR, PR and QRS) were similar in the 2 treatment groups across study visits. The majority of patients (485%) who experienced an increase from baseline in QTc had an increase of less than 30 ms at any visit. Less than 15% of patients experienced an increase from baseline in QTc of X30 ms. One patient in the formoterol group and 2 patients in the placebo group experienced a X60-ms increase in QTc from their pretreatment baseline (Visit 2) value to any postbaseline measurement. The formoterol patient who had a QTc increase X60 ms at Visit 3 (2 h postdose) had a QTc
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Table 5 Holter variables at baseline and end of treatment (patient’s last value)
Maximum heart rate (bpm) Mean7SD Mean heart rate (bpm) Mean7SD Total ventricular premature beats Mean7SD 25% quartile Median 75% quartile Mean ventricular premature beats/h Mean+SD Maximum ventricular premature beats/h Mean7SD Total ventricular tachycardia events Mean7SD Mean ventricular tachycardia events/h Mean7SD Maximum ventricular tachycardia events/h Mean7SD Total idioventricular run events Mean7SD Mean idioventricular run events/h Mean7SD Total supraventricular premature beats Mean7SD 25% quartile Median 75% quartile Mean supraventricular premature beats/h Mean7SD Maximum supraventricular premature beats/h Mean7SD Total supraventricular run events Mean7SD Mean supraventricular events/h Mean7SD
Formoterol 12 mg bid (n ¼ 97)
Placebo (n ¼ 107)
Baseline (n ¼ 96)
End (n ¼ 92)
Baseline (n ¼ 107)
End (n ¼ 106)
124714.7
123713.6
126716.4
123715.8
8179.0
8078.6
81710.3
80710.6
54371253.0 3 11 287
73272685.4 1 9 213
104074112.4 3 61 300
65072090.6 4 40 228
25757.0
357131.0
467181.9
307101.3
617126.7
767199.7
1217484.0
887256.5
0.271.09
0.471.70
1.278.28
1.079.23
0.0170.048
0.0270.082
0.0570.354
0.0570.479
0.170.35
0.270.58
0.774.64
0.371.77
0.070.23
0.070.21
0.170.69
0.170.33
0.0070.010
0.0070.010
0.0070.029
0.0070.017
45871671.1 9 27 99
50471844.1 9 29 124
37371066.6 15 52 146
82372961.8 14 48 186
21781.5
22780.6
17747.5
377129.6
647187.5
757223.5
567126.3
1507635.5
5737.4
7732.3
7728.8
197128.7
0.2671.796
0.2971.359
0.3171.283
0.8475.776
Ventricular tachycardia event ¼ run of 3 or more ventricular premature beats with a rate X100 bpm. Idioventricular run event ¼ run of 3 or more ventricular premature beats with a rate o100 bpm. Supraventricular run event ¼ run of 3 or more supraventricular premature beats.
decrease to a value below baseline at Visit 4 (2 h postdose). One patient in each treatment group had a X60-ms increase in QTc from pre- to postdose during a visit. Few patients experienced newly occurring (i.e. not present at baseline) QTc intervals 4460 ms postbaseline: 6 (6%) formoterol and 9 (9%) placebo patients using Bazett’s correction; 3 (3%) formoterol and 2 (2%) placebo patients using Fridericia’s correction. Mean and median vital sign measurements over time were similar in the 2 treatment groups. There were no clinically meaningful or statistically significant differences between treatment groups for mean vital sign measurements.
dose (Visit 2) and after 2 and 8 weeks of treatment (Visits 3 and 4). As shown in Fig. 1, the bronchodilator effect in the formoterol group was statistically significantly better than in the placebo group at all time points. The use of rescue medication (two 90 mg puffs of albuterol as needed) was recorded 6 h prior to and at any time during each visit. Only 1 formoterol patient required rescue medication during the assessment period (during Visit 3), compared with 4 placebo patients (3 patients during Visit 3, 1 of whom also took rescue medication at Visit 4, and 1 patient during Visit 4). 4. Discussion
3.4. Spirometry The only efficacy variable measured during the study was FEV1 at 2 h postdose, which was measured after the first
The results of this study confirm the good safety profile of 12 mg formoterol dry powder inhalation in patients with COPD. Only a small number of patients with valid Holter
ARTICLE IN PRESS S.C. Campbell et al. / Pulmonary Pharmacology & Therapeutics 20 (2007) 571–579 Table 6 Incidence of adverse events occurring in more than one patient in either treatment group
Total number with adverse events Adverse events Back pain Chronic obstructive airway disease exacerbated Headache Gastroenteritis viral Influenza Nasopharyngitis Oral candidiasis Upper respiratory tract infection Dizziness
Formoterol 12 mg bid (n ¼ 97) n (%)
n (%)
26 (26.8)
33 (30.8)
3 (3.1) 3 (3.1)
0 4 (3.7)
3 2 2 2 2 1
1 (0.9) 2 (1.9) 0 4 (3.7) 0 3 (2.8)
(3.1) (2.1) (2.1) (2.1) (2.1) (1.0) 0
Placebo (n ¼ 107)
2 (1.9)
Fig. 1. 2-h postdose FEV1 least-squares mean measurements over time by treatment group. P values for estimated treatment contrasts (formoterol minus placebo) are based on an analysis of covariance model: 2-h FEV1 ¼ treatment+baseline FEV1+gender+(pooled) center, where baseline FEV1 was the predose FEV1 measurement taken at Day 1 (Visit 2).
monitoring met the predefined criteria for a proarrhythmic event (4 formoterol and 2 placebo patients). These events included increases in the rate of postbaseline ventricular premature beats and/or increases in the rate of nonsustained ventricular tachycardia events. No patients had sustained postbaseline ventricular tachycardia events or met other criteria for a proarrhythmic event, such as a run of ventricular premature beats associated with relevant symptoms (e.g. hypotension or syncope) or an episode of ventricular flutter or ventricular fibrillation. These results provide a good indication of the safety of formoterol (12 mg) in patients with COPD, although larger studies providing more robust statistical power are
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required to elucidate fully the cardiac effects of this treatment. The sample size was chosen to provide reasonable exposure from the safety perspective, and not for considerations of statistical power. A further consideration in adopting an empirical approach for this study was the lack of adequate information available concerning Holter monitoring in COPD patients, which could have been used to estimate sample size with associated power using a predefined hypothesis. Further work is also needed to investigate any long-term cardiac effects of the 24 mg dose of formoterol, which is indicated in some countries for the treatment of patients with COPD. However, it is reassuring to note that heart rate and rhythm disorders were uncommon in 2 large randomized, placebo-controlled studies investigating the use of formoterol 24 mg in a total of more than 1600 patients with COPD [9,10], with an incidence similar to that seen with placebo. Furthermore, clinical trials such as this, for ethical and safety reasons, necessarily select patients at minimal risk of b-agonistinduced complications, and this may limit the application of these results to the wider population of patients in reallife clinical practice. Cardiovascular co-morbidities, most commonly heart failure but including arrhythmias, occur more frequently in patients with COPD, who are at higher risk of hospitalization and death due to these conditions [18–20]. The increasing appreciation of this important comorbidity underlines the need to demonstrate the cardiovascular safety of treatments for COPD. The data obtained in this study in COPD patients are consistent with previously reported Holter monitoring findings in asthma patients treated with formoterol [21,22]. In one 12-week study, Holter monitoring was performed in 217 asthma patients treated with inhaled formoterol (12 and 24 mg bid), albuterol and placebo [22]. For both formoterol doses and placebo, mean total ventricular beats per hour decreased from baseline at Weeks 2 and 8, whereas an increase was observed for albuterol. Similar trends were seen in the mean maximum ventricular beats per hour. There were no meaningful differences between formoterol, albuterol, and placebo with regard to ventricular ectopy, supraventricular ectopy, or heart rate. In both studies, the incidence of clinically significant abnormalities in ECG data was low (o5%) and distributed similarly across treatment groups (formoterol 12 and 24 mg, albuterol, and placebo) [21,22]. Ferguson et al. evaluated the cardiac safety of inhaled salmeterol 50 mg twice-daily in COPD patients using a post hoc pooled analysis across 7 controlled clinical studies [23]. The results of their analysis were similar to our findings. There was no increased risk of cardiovascular adverse events relative to placebo (P ¼ 0.838). Holter monitoring data were obtained from 115 salmeterol and 134 placebo patients, with no reported sustained ventricular tachycardia events and no clinically significant differences between salmeterol and placebo in 24-h heart rate, ventricular or supraventricular ectopy, QTc (Bazett correction) interval, or vital signs.
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Although a number of studies have shown that inhaled formoterol exhibits a good safety profile in both COPD [9,10] and asthma [21,22], b2-adrenoceptor stimulation has the potential to induce cardiac rhythm disturbances. Recently, Salpeter et al. performed a pooled analysis of published, randomized, placebo-controlled trials to evaluate the cardiovascular effects of b2-agonists in patients with asthma or COPD [12]. Data were obtained from 13 single-dose studies and 20 multiple-dose trials ranging from 3 days to 1 year in duration. The retrospective analysis found that single doses of b2-agonist significantly increased heart rate and decreased potassium concentration relative to placebo [12]. Further, the analysis of multiple-dose trials suggested that b2-agonists increased the risk of sinus tachycardia and cardiovascular events overall compared with placebo. The authors concluded that b2-agonists increase the risk for adverse cardiovascular events in patients with obstructive airway disease and speculated that this class of drugs may precipitate ischemia, congestive heart failure arrhythmias and sudden death. The clinical significance of the analysis is unclear as the pooled data included patients with asthma or COPD treated with a variety of b2-agonists via different modes of administration in studies published up to 27 years ago [12]. The analysis did not show a significantly increased risk of major cardiovascular events associated with b2-agonists (relative risk [RR], 1.66; 95% CI, 0.76–3.6). The risk for sinus tachycardia was not significantly increased with b2-agonists relative to placebo in any of the studies of COPD patients (i.e. the 95% CI for RR included 1 for all studies). In fact, although the relative risk for sinus tachycardia was 3.06 (95% CI, 1.70–5.50) in the pooled analysis, only 1 of the studies showed a statistically significant increased risk for sinus tachycardia with b2-agonists relative to placebo (i.e. the 95% CI for RR included 1 for all except 1 study). Cazzola et al. found that single doses of formoterol (12 and 24 mg) and salmeterol (50 mg), increased mean heart rate and decreased mean potassium concentrations compared with placebo in a single-blind, randomized, crossover study of patients with COPD and preexisting cardiac arrhythmias and hypoxemia [24]. There were no meaningful differences between formoterol 12 mg and salmeterol 50 mg in any of the reported Holter monitoring variables. No baseline Holter monitoring data were available and the number of patients (12) was small. Recently, a nested casecontrol study found an association between inhaled b2-agonist use and rehospitalization for chronic heart failure (CHF) among patients with a prior diagnosis of CHF. There was no apparent association between b2-agonists and risk of incident heart failure [25]. Only 3 patients overall had preexisting hypoxia and patients with preexisting clinically significant conditions (including arrhythmia) were generally excluded from our study. Further research is needed to assess the cardiac effects of b2-agonists in COPD patients with preexisting cardiac disorders.
Likewise, no conclusion can be drawn as to the possible influence of concomitant medications, as the data were not stratified to analyze this sub-population. A previous study [26] in a small group of healthy subjects showed that inhaled corticosteroids (ICS) and b2-agonist may lead to increased cardiac risk as a consequence of resensitization of cardiac b2-receptors by ICS. As similar proportions of patients in each treatment group in the current study took ICS concomitantly, it is unlikely that the results would have been affected. Other concomitant medications such as antiarrhythmia drugs, which have the potential to cause proarrhythmia [13], were taken by a small proportion of patients, and as a result, are unlikely to have influenced the data significantly. Although our study was primarily a safety study, spirometry (FEV1 2 h postdose) was measured after the first dose and after 2 and 8 weeks of treatment. Treatmentgroup comparisons showed that 2-h postdose FEV1 was statistically significantly improved in the formoterol group compared with the placebo group at all visits during the treatment period (Po0.001 for estimated treatment contrasts at each visit). These findings are consistent with previous reports where formoterol demonstrated significantly better spirometric efficacy than placebo, ipratropium, and theophylline, and was shown to improve healthrelated quality of life [9,10]. 5. Conclusions The results of this study indicate that twice-daily use of 12 mg formoterol dry powder inhalation capsules delivered by the Aerolizer device has an acceptable cardiovascular safety profile in patients with COPD. The data showed no clinically meaningful increase in cardiac rhythm events for patients treated with formoterol compared with matching placebo. This study screened out patients with significant cardiovascular disease and arrhythmia, which are common co-morbidities in COPD patients. Vital signs and ECG data, including QTc interval, were similar for active and placebo groups. The pattern of reported adverse events was consistent with the expected profile for COPD patients. Acknowledgments This study was supported by Novartis, East Hanover, NJ. Novartis was responsible for the design and conduct of the study, data collection, management and analysis. Novartis was also involved in the interpretation of the data, and preparation, review and approval of the manuscript. Dr Ziehmer, Mr Orevillo, and Mr Smith are employed by Novartis; Dr Ziehmer and Mr Orevillo received stock options and shares in Novartis as part of their employee compensation package during the time of their contribution to the study. Drs Campbell and Levine have received research funding and honoraria and have acted as consultants to Novartis. Dr Criner has received honoraria
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from Novartis. Dr Simon does not have any conflict of financial interest with the subject matter of this manuscript. The authors would like to thank the investigators and staff at the study sites. We also thank Karen M. Miner, PhD, for her help in preparing this manuscript. The principal investigators and site locations were as follows: George W. Bensch, MD, Bensch Clinical Research Associates, Stockton, CA; Laurie Dubois (study coordinator), CCRC, Heartland Clinical Research, Inc., Omaha, NE; Frank C. Hampel, Jr., MD, Central Texas Health Research, New Braunfels, TX; Terence Isakov, MD, Ohio Clinical Research, LLC, Lyndhurst, OH; Craig F. LaForce, MD, North Carolina Clinical Research, Raleigh, NC; David Ostransky, DO, North Texas Lung & Sleep Center, Fort Worth, TX; Thomas C. Klein, MD, Heartland Research Associates, LLC, Wichita, KS; Jahn A. Pothier, MD, Hawthorne Medical Associates, LLC, North Dartmouth, MA; Stephen I. Rennard, MD, Pulmonary Research, University of Nebraska Medical Center, Omaha, NE; James E. Turek, MD, Med Plus South Strand Family Practice, Garden City, SC. References [1] Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/ WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary. Am J Respir Crit Care Med 2001;163:1256–76 (updated 2003. Available at http://www.goldcopd. com. Accessed August 4, 2004. [2] Halbert RJ, Isonaka S, George D, Iqbal A. Interpreting COPD prevalence estimates: what is the true burden of disease? Chest 2003;123:1684–92. [3] Sullivan SD, Ramsey SD, Lee TA. The economic burden of COPD. Chest 2000;117(2 Suppl):5S–9S. [4] Tashkin DP, Cooper CB. The role of long-acting bronchodilators in the management of stable COPD. Chest 2004;125:249–59. [5] Kottakis J, Cioppa GD, Creemers J, Greefhorst L, Leclerc V, Pistelli R, et al. Faster onset of bronchodilation with formoterol than with salmeterol in patients with stable, moderate to severe COPD: results of a randomized, double-blind clinical study. Can Respir J 2002; 9:107–15. [6] Maesen BL, Westermann CJ, Duurkens VA, van den Bosch JM. Effects of formoterol in apparently poorly reversible chronic obstructive pulmonary disease. Eur Respir J 1999;13:1103–8. [7] Celik G, Kayacan O, Beder S, Durmaz G. Formoterol and salmeterol in partially reversible chronic obstructive pulmonary disease: a crossover, placebo-controlled comparison of onset and duration of action. Respiration 1999;66:434–9. [8] Benhamou D, Cuvelier A, Muir JF, Leclerc V, Le Gros V, Kottakis J, et al. Rapid onset of bronchodilation in COPD: a placebo-controlled study comparing formoterol (Foradils AerolizerTM) with salbutamol (VentodiskTM). Respir Med 2001;95:817–21.
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