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* From the New England Clinical Studies (Dr. Chervinsky), North Dartmouth, MA; Allergy Asthma and Clinical Immunology Associates (Dr. Goldberg), Indianapolis, IN; Pediatric and Adult Allergy and Clinical Immunology (Dr. Galant), Orange, CA; and Glaxo Wellcome Inc (Drs. Wang, Arledge, Welch, and Stahl), Research Triangle Park, NC.
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Design: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
Setting: Eighteen US clinical centers.
Patients: Three hundred fifty-two patients
(
12 years) with mild persistent asthma (duration 6 months)
requiring pharmacotherapy; with FEV1 of 70 to 90% of
predicted and without abnormal ECG/continuous ambulatory ECG
(Holter).
Interventions: Randomized to twice-daily salmeterol powder (50 µg) or placebo via breath-actuated device for 52 weeks. Backup albuterol was available to control asthma symptoms.
Measurements and results: Cardiovascular safety was regularly assessed by 12-lead ECG with a 15-s lead II rhythm strip, 24-h continuous ambulatory ECG (Holter) monitoring, serial vital sign measurements, and review of adverse cardiovascular events. No deaths occurred during the study. No clinically significant between-group differences were observed in pulse rate, ECG QTc interval, median number of ventricular or supraventricular ectopic events, incidence of ventricular ectopic couplets and runs, or incidence of > 100 ventricular or supraventricular ectopic events in 24 h. No clinically significant between-group differences were observed in arterial BP or incidence of adverse cardiovascular events. Salmeterol was well tolerated throughout the 52-week study period, with a cardiovascular safety profile similar to that of placebo.
Conclusions: Long-term, twice-daily pharmacotherapy with salmeterol powder is safe and is not associated with unfavorable clinically significant changes in cardiac function or increases in cardiovascular adverse effects.
Key Words: asthma • cardiovascular safety • salmeterol powder
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß-Adrenergic stimulation with short-acting ß2-agonists at high doses has been associated with adverse cardiovascular events, including palpitations, changes in BP, and ECG abnormalities.2 ,3 ,4 ,5 ,6 ,7 ,8 In humans, the proportion of ß2-receptors is approximately 20% in the ventricles and 30% in the atria,9 ,10 while the predominant receptors within the vasculature are ß2-adrenoreceptors.10 Thus, most ß-adrenoreceptors in cardiac tissue are ß1-adrenoreceptors. Furthermore, the adverse effects of high-dose ß2-agonists on cardiovascular function are presumably caused by a combination of cross-stimulation of ß1/ß2-adrenoreceptors present in cardiac tissue and stimulation of vascular ß2-adrenoreceptors.10
The development of long-acting ß2-agonists represents a step forward in the treatment of asthma.11 Salmeterol xinafoate (Serevent; Glaxo Wellcome; Research Triangle Park, NC) is a potent, long-acting, highly selective ß2-agonist that provides effective bronchodilation for up to 12 h and is safe and effective for long-term regular use.12 ,13 ,14 ,15 ,16 There is, however, a potential for clinically significant cardiovascular changes, including cardiac arrhythmias and hemodynamic changes, that may result from regular long-term therapy with ß2-agonists.17 The cardiovascular safety concerns relate to the affinity of salmeterol for ß2-adrenoreceptors and, to a lesser extent, to the cross-reactivity with ß1-adrenoreceptors present in cardiac muscle and vascular tissue.9 ,10 Clinically, however, salmeterol has not been associated with any significant increases in the incidence of adverse cardiovascular events, laboratory value abnormalities, or changes in vital signs.12 ,13 ,15 ,17 ,18
Although the cardiovascular safety of short-term and long-term therapy with salmeterol aerosol has been documented, long-term studies with salmeterol powder are limited. Previous studies by D'Alonzo et al14 and Pearlman et al16 using continuous ambulatory monitoring (ie, Holter monitor) to assess cardiovascular safety were limited to 3 months. Therefore, the current study sought to investigate the long-term safety, and in particular the cardiovascular safety, of twice-daily therapy with salmeterol powder (50 µg) for a period of 1 year.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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12 years of age with a 6-month
history of mild persistent asthma (American Thoracic Society
criteria)19
that required pharmacotherapy. Eligible
patients were required to have a nonmedicated baseline FEV1
of 70 to 90% of the predicted value and to demonstrate either a
15% reversibility of airway obstruction or a return of
FEV1 to 100% of predicted within 30 min following
inhalation of 180 to 360 µg albuterol. Patients had to demonstrate
bronchial hyperresponsiveness such that a 20% reduction in
FEV1 could be achieved at a methacholine concentration
7.5 mg/mL. Patient use of concomitant medications had to start 3
months before screening and remain stable throughout the posttreatment
period. Terfenadine and other long-acting antihistamines were
prohibited during the study.
Exclusion criteria included the following: infection of the upper or
lower respiratory tract or middle ear within 6 weeks of study entry;
abnormal ECG from 12-lead ECG or continuous ambulatory ECG (Holter)
monitoring; and tobacco use within the previous year, 10 pack-years
of cigarette use, 10 years of cigar or pipe use, or 4 h/d of
ongoing passive exposure to tobacco smoke. Informed consent was
obtained in writing from all study participants.
Study Design and Procedures
This multicenter, randomized, double-blind, placebo-controlled,
parallel-group clinical trial was conducted at 18 centers in the United
States and was approved by the Investigational Review Board of each
participating study site. The study was divided into three phases: an
18- to 30-day screening phase, a 52-week treatment phase, and a 14-day
posttreatment phase.
Patient eligibility assessment took place at the initial screening visit and included medical history, physical examination, determination of vital signs, chest radiographic examination, serum pregnancy test for female patients, 12-lead ECG, clinical laboratory tests, pulmonary function tests, global symptom assessment, assessment of airway reversibility and hyperresponsiveness, and Holter monitoring (at eight selected sites). At this time, eligible patients began single-blind placebo treatment with supplemental albuterol via metered-dose inhaler to control breakthrough asthma symptoms.
Patients were randomized on treatment day 1 to twice-daily salmeterol powder (50 µg) or placebo powder via a breath-actuated multidose powder inhaler using a computer-generated randomization schedule. Active drug and placebo were supplied in identical packages. Detailed instructions on how to use the device were given to each patient, and each patient became familiar with the operation of the device and the delivery of the study medication at the initial treatment visit. The initial dose of study drug was administered during this clinic visit to ensure that the patients used the device properly. Medical evaluations were performed on treatment day 1 and every 4 weeks during the 52-week treatment phase and on days 1, 2, 7, and 14 after discontinuation of treatment with the study drug (posttreatment phase). Clinical laboratory evaluations were made for each patient at the screening visit, and at treatment weeks 12, 24, 36, and 52. Blood samples were collected either before dosing or before the methacholine challenge to measure serum electrolytes. Patients were required to return all used and unused devices at each study visit and at the end of the trial, and the numbers of used blisters were counted and recorded to document patient compliance with the dosing regimen.
Cardiovascular Safety Evaluations
The cardiovascular safety of both treatments was assessed in all
patients at each clinic visit throughout the 52-week treatment period
by monitoring pulse rate, arterial systolic and diastolic BP, and
clinical adverse events. Twelve-lead ECGs, including QTc evaluations
and 15-s rhythm strips, were obtained at screening, predose, and
1.5 h postdose on treatment day 1, and again at weeks 8, 20, and
48. Pulse rate and arterial BP were assessed during 12-h serial
monitoring on day 1, and again at weeks 8, 20, and 48.
Holter monitoring was performed at screening, day 1, and at weeks 20 and 48 for all patients at eight investigational sites. Approximately 50% of patients from each treatment group were evaluated via Holter monitoring at screening (placebo, n = 82; salmeterol, n = 83). Holter monitors were attached predose and worn for approximately 24 h. Patient ECG and Holter monitor data were evaluated by an independent cardiologist blinded to the treatment assignment. Cardiovascular adverse events were monitored and/or collected at each visit to the clinic.
Statistical Methods
All clinical adverse events and adverse events considered drug
related by the investigators were tabulated. Events were categorized
according to adverse event class, and testing was performed on selected
individual adverse event categories. A two-sided Fisher's Exact Test
was performed between treatment groups and for each pairwise
comparison. For vital signs (pulse rate and systolic/diastolic BP),
mean values and mean change from baseline were calculated at each time
point over the 12-h evaluation period, and treatment differences were
compared using analysis of variance (ANOVA) F tests.
Twelve-lead ECGs and pulse rates were summarized by treatment and time of evaluation. The QTc intervals (in milliseconds) were summarized by treatment, with the mean change from baseline (day 1 predose) tested by using an ANOVA F test. Statistical tests for ventricular ectopic (VE) and supraventricular ectopic (SVE) events were based on the nonparametric van Elteren20 test, controlling for investigator effect, and tests of pulse rate were based on ANOVA F tests.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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12-h Serial Vital Signs
Pulse Rate:
Mean baseline pulse rates (beats per minute) were similar in both
treatment groups prior to medication on treatment day 1, averaging 70
beats/min in the placebo group and 71 beats/min in the salmeterol
group. Serial pulse rate measurements performed over 12 h
demonstrated no significant between-group differences in mean pulse
rate on treatment day 1 and at treatment week 48. Furthermore, there
were no between-group differences in mean pulse rate at treatment weeks
8 and 20. Minor increases (approximately 4 beats/min) in pulse rate
were observed during the 12-h monitoring period in both treatment
groups, and were comparable between treatment groups at each postdose
evaluation time point. These small changes in pulse rate were
considered clinically insignificant.
One patient in each treatment group (< 1%) developed heart palpitations. Both events were mild to moderate in severity, and required no intervention on the part of the investigator.
Arterial BP:
Baseline systolic/diastolic BP measurements were similar between
treatment groups, averaging 113/72 mm Hg for the salmeterol group and
114/71 mm Hg for the placebo group. Postdose increases in systolic BP
on day 1 and at weeks 8, 20, and 48 were slightly higher (1 to 2 mm Hg)
for the salmeterol group than for the placebo group (p 0.031),
although these modest increases in systolic BP were not considered to
be clinically significant. Changes in diastolic BP were similar (± 2
mm Hg) for both treatment groups, and no statistically significant
between-group differences were observed.
One patient from each treatment group exhibited an increase in arterial BP. In both instances, the severity of hypertension was mild to moderate, and required no intervention.
Electrocardiograms
All ECGs were reviewed by an independent cardiologist blinded to
patient treatment assignment. At screening, QTc intervals were similar
in both treatment groups. During treatment, mean predose and postdose
QTc intervals were comparable for both groups at all evaluation time
points (Table 2
).
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1% of patients treated with salmeterol powder exhibited abnormal
ECGs that were considered clinically significant. No patient
discontinued treatment with the study medication, withdrew from the
study, or required intervention for any ECG abnormality, and these
patients had normal ECGs at other time points. These findings were
observed in four patients in the salmeterol group who exhibited changes
in ECG results that were considered by the investigators to be adverse
events over the year-long study period (Table 3
).
Two of the four events were considered related to treatment. One
patient exhibited nonspecific T-wave abnormalities postdose on
treatment day 1 that were considered possibly related to the study
drug, and one patient exhibited nonspecific ST-T-wave abnormalities
postdose at treatment week 20 that were considered probably related to
the study drug.
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The median number of VE and SVE events recorded for each treatment group was minimal at each Holter monitoring session. Patients in the placebo group had a median of 1, 1, and 1 VE event at screening, week 20, and week 48, respectively, compared with a median of 0, 0, and 1 VE events at the same time points for patients in the salmeterol group. Patients in the placebo group had a median of 1, 2, and 3 SVE events at screening, week 20, and week 48, respectively, compared with 2, 1, and 3 SVE events for patients in the salmeterol group. There were no significant differences between the treatment groups in the frequency of VE or SVE events over the 24-h monitoring periods.
Electrolyte/Potassium Monitoring
Less than 1% of the patients in each treatment group demonstrated
abnormal laboratory values during the study period. There were no
clinically significant differences in electrolyte values between
treatment groups. In the salmeterol treatment group, serum potassium
concentration was below threshold ( 3 mmol/L) on one occasion in two
patients (1%). Both patients had potassium values within threshold
limits on retest at the same visit, and no intervention was required.
None of the patients in the placebo group had serum potassium values
below threshold limits.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cardiovascular monitoring in the current study revealed no clinically significant cardiovascular changes or arrhythmias associated with regular use of salmeterol powder for 1 year. Four patients in the salmeterol group did have abnormal ECG changes that were reported as adverse events, but these events required no additional therapy and study drug therapy was continued. Only minor changes in pulse rate of approximately 4 beats/min were observed over the 12-h evaluation period. These results were expected given the high selectivity of salmeterol for ß2-adrenoreceptors and the minimal effect of salmeterol at ß1-adrenoreceptors such as those mediating cardiac chronotropic and inotropic activity.10 ,21 ,22 One patient from each treatment group (< 1%) exhibited heart palpitations; however, both events were considered mild to moderate, required no intervention, and resolved on the day of occurrence. These observations are consistent with those of other investigators who have assessed the cardiac safety of salmeterol.23 Changes in arterial BP were similar between salmeterol and placebo treatment groups, and only one patient from each treatment group developed hypertension during the study. The severity of hypertension was mild to moderate, and was considered unrelated to study medication.
ß-Agonists, as well as other asthma medications, have dose-related systemic effects that may include a reduction in serum potassium level.3 Worsening hypokalemia, in turn, may potentiate cardiac arrhythmias.24 Therefore, serum potassium level was closely monitored in the current study. In our study population in whom salmeterol was administered at the recommended dosage for 1 year, serum potassium level decreased below a threshold value of 3 mmol/L in only two patients. Both events were within threshold limits on retest at the same visit, and no therapeutic intervention was required. These data indicate that inhaled salmeterol powder at the recommended dosage is unlikely to induce hypokalemia.
Because of known cardiovascular side effects associated with ß-agonists,25 investigators have questioned whether an increase in cardiovascular mortality is associated with their long-term use.26 In a retrospective study of 12,301 asthmatic patients between 1978 and 1987, 30 cardiovascular deaths were reported. Results of the analyses demonstrated that users of theophylline and ß-agonists either orally or by nebulization were at a higher risk of cardiovascular mortality.26 In contrast, patients who used ß-agonists via metered-dose inhaler were not at increased risk of cardiovascular death.
Though no significant cardiovascular toxicity related to the use of salmeterol was observed in this study, risks of cardiovascular complications from ß-agonists can increase under certain circumstances. The most important risk factor for ß-agonist-induced serious cardiovascular adverse events is coexisting cardiac disease. In patients with cardiac disease or who are at high risk of cardiac disease, any ß-agonist, even when administered by the inhaled route at approved dosages, should be prescribed with caution. Other potential risk factors associated with the use of ß-agonists include hypoxemia during acute exacerbations of asthma, coadministration of theophylline, and cardiac medications or medications that can induce hypokalemia (eg, systemic glucocorticosteroids or diuretics).
Current recommendations for the appropriate use of salmeterol in patients with mild-to-moderate persistent asthma include its use on a fixed dosing schedule not to exceed 50 µg twice a day. Concurrent as-needed use of a short-acting ß-agonist with salmeterol is also considered appropriate for breakthrough/rescue therapy. Current guidelines for the diagnosis and management of asthma recommend that inhaled anti-inflammatory therapy with cromolyn/nedocromil or inhaled corticosteroids be prescribed to address the inflammatory component of asthma and that long-acting ß-agonists be added to this regimen if control of symptoms is not achieved.27 Guidelines indicate that leukotriene modifiers may also have a place in the treatment of mild asthma, although further study is needed before their role can be established.
In summary, long-term, twice-daily pharmacotherapy with salmeterol powder is not associated with unfavorable clinically significant changes in cardiac function or increases in cardiovascular adverse effects. Results of this study are in agreement with extensive safety data from studies involving > 4,000 patients treated with salmeterol.12 ,15 ,16 ,28 ,29 ,30 ,31 ,32 ,33 ,34 With the addition of the data from the current study, the long-term cardiovascular safety of salmeterol powder has been well documented.
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Acknowledgements |
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Footnotes |
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Correspondence to: Paul Chervinsky, MD, New England Clinical Studies, Dartmouth Place, 49 State Rd, Wattupa Bldg, Suite 203, North Dartmouth, MA 02747
Abbreviations: ANOVA = analysis of variance; SVE = supraventricular ectopic; VE = ventricular ectopic
Received for publication July 14, 1998. Accepted for publication October 28, 1998.
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