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Cardiovascular Safety of Salmeterol in COPD^*

^* From the Pulmonary Research Institute (Dr. Ferguson) of SouthEast Michigan, Livonia, MI; Hopital Saint Antoine (Dr. Funck-Brentano), Paris, France; and GlaxoSmithKline (Drs. Fischer, Darken, and Reisner), Research Triangle Park, NC.

Correspondence to: Gary T. Ferguson, MD, FCCP, Pulmonary Research Institute of SouthEast Michigan, 28807 Eight Mile Rd, Suite 103, Livonia, MI 48152

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: Patients with COPD have an increased risk of cardiovascular disease. Despite the clinical benefits of long-acting ß-agonist agents in the treatment of COPD, patients may be at an increased risk of cardiovascular toxicity, including tachyarrhythmia due to ß-adrenergic stimulation.

Objective: To evaluate the cardiovascular safety of salmeterol in COPD patients by conducting a pooled analysis of cardiovascular safety data.

Design: Randomized, double-blind, parallel group, multiple-dose studies, which included salmeterol, 50 µg bid, and placebo arms.

Study selection: Seven of a total of 17 studies met the predefined inclusion requirements and were pooled. A total of 1,443 patients received placebo, while 1,410 patients received salmeterol, 50 µg bid. The median duration of treatment was 24 weeks (range, 12 to 52 weeks).

Results: Treatment with salmeterol, 50 µg bid, showed no increased risk of cardiovascular adverse events (AEs) compared with placebo (relative risk, 1.03; 95% confidence interval, 0.8 to 1.3; p = 0.838). Both groups had a similar incidence of cardiovascular events (8%), including cardiovascular deaths. The incidence of cardiovascular AEs increased with age, concurrent cardiovascular conditions, and treatment with antiarrhythmic/bradycardic agents, although increases were comparable in both treatment groups. There were no episodes of sustained ventricular tachycardia, and no clinically significant differences were observed in 24-h heart rate, ventricular and supraventricular ectopic events, qualitative ECGs, QT intervals, or vital signs between the salmeterol, 50 µg bid, group and the placebo group. Similar findings were observed when patients were stratified for age of > 65 years or the known presence of cardiovascular disease.

Conclusions: Treatment with salmeterol, 50 µg bid, does not increase the risk of cardiovascular AEs in this population of COPD patients compared with placebo.

Key Words: cardiovascular safety • COPD • salmeterol

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
COPD is the fourth leading cause of death worldwide, and it is projected to be the third leading cause of death by the year 2020.¹ In an effort to reverse these trends, a Global Initiative for Chronic Obstructive Lung Disease study, with goals of increasing awareness of COPD and decreasing morbidity and mortality, was published in 2001.² Bronchodilator medications are central to the management of COPD and represent the only class of drugs that is currently approved by the US Food and Drug Administration for the treatment of COPD.

The advent of the long-acting inhaled ß₂-adrenergic agonist agents such as salmeterol, with their prolonged duration of action (approximately 12 h) and efficacy in improving airflow obstruction, represents a therapeutic advance in the management of COPD.³ Inhaled salmeterol has been shown to improve symptoms, lung function, and quality of life in patients with COPD,^{4 5 6} and its use as a first-line maintenance bronchodilator has been endorsed in the Global Initiative for Chronic Obstructive Lung Disease guidelines.²

Despite the clinical benefits of inhaled long-acting ß₂-agonist agents in the treatment of patients with COPD, these patients may be at an increased risk of cardiovascular complications.⁷ Since ischemic heart disease, right ventricular hypertrophy, and arrhythmias are relatively common in patients with chronic symptoms of COPD,^{8 9 10} such patients may be at an increased risk of cardiovascular events resulting from ß-adrenergic stimulation with these agents. Therefore, an integrated analysis of cardiovascular safety data from seven clinical trials was conducted to evaluate the cardiovascular safety of salmeterol, 50 µg bid, in patients with COPD. Subgroups of poorly reversible (PR) patients, elderly patients, patients with concurrent cardiovascular disease at baseline, and those patients with concurrent cardiovascular disease who were receiving therapy with antiarrhythmic/bradycardic agents also were evaluated.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
A pooled analysis of cardiovascular safety data was conducted to assess the effects of therapy with salmeterol, 50 µg bid, on the cardiovascular system in patients with COPD. In order to conduct a pooled analysis, individual patient data are required. A total of 17 clinical studies of salmeterol treatment in COPD patients were considered for inclusion because of the availability of individual patient data. Further prospectively defined inclusion criteria included the following: sponsorship by GlaxoSmithKline Research and Development; authorized database by May 1, 2001; randomized, double-blind, parallel-group, multiple-dose studies; and a salmeterol, 50 µg bid, arm (42 µg ex-actuator) administered via metered-dose inhaler (Diskus; GlaxoSmithKline; Research Triangle Park, NC) to patients in whom COPD had been diagnosed (using the American Thoracic Society or European Respiratory Society definition). Non-placebo-controlled trials were considered for inclusion only if the trial had an active comparator that was replicated in a placebo-controlled trial that was included in the analysis. Of the original 17 studies identified, 7 met all the predefined inclusion criteria and were included in the analysis. Ten studies did not meet the criteria for inclusion in the analysis. Two studies did not have a placebo arm and did not have a non-salmeterol treatment arm that was duplicated in a placebo-controlled study included in the analysis. One study was not sponsored by GlaxoSmithKline Research and Development. One study was open-label. The remaining six studies were all of crossover design. There were no cardiovascular safety concerns identified in any of the studies that were excluded from the analysis. Details of the seven studies included in the analysis are provided in Table 1 . Cardiovascular adverse events (AEs) and vital signs were monitored throughout all studies. In addition, each study included at least one of the following cardiovascular end points: 24-h Holter monitoring, including heart rate, occurrence of ventricular ectopic events, supraventricular ectopic events, qualitative ECG assessments, or QT intervals. Patients with any uncontrolled disease were excluded in two of the seven studies (ie, SLGT28 and SFCB3024). In five of the seven studies (ie, SFCA3006, SFCA3007, SLGA4004, SLGA4005, and SFCB3024), patients requiring therapy with ß-blockers were excluded, while patients with clinically significant cardiovascular disease were excluded in four of the seven studies (ie, SFCA3006, SFCA3007, SLGA4004, and SLGA4005). There were no disease-associated exclusion criteria for study SLGF53.

AEs
AEs, including cardiovascular AEs and cardiovascular serious AEs, as well as deaths, were monitored throughout in all studies that were included in this analysis. An AE was defined as any untoward medical occurrence that did not necessarily have a causal relationship with treatment. A serious AE was defined as any event that was fatal, life-threatening, disabling/incapacitating, associated with a congenital anomaly, or resulted in hospitalization or prolonged a hospital stay, or that the investigator regarded as serious.

Vital Signs
Vital signs were measured in all studies (Table 1) . Changes from baseline in systolic and diastolic BPs and heart rate were summarized by time point and treatment group for both predose and postdose values. If baseline data were not available, screening data were used for baseline values.

24-h Holter Monitoring
Holter monitoring was performed in three studies (Table 1) . Holter data from screening and week 4 were pooled for studies SFCA3006, SLGA4004, and SLGA4005. Holter data from day 1 and weeks 8 and 12 were pooled for studies SLGA4004 and SLGA4005. The mean 24-h heart rate, the maximum 24-h heart rate, ventricular ectopic events (including a single premature ventricular contraction [PVC], ventricular couplets (defined as two PVCs preceded or followed by regular beats), ventricular runs (defined as three or more PVCs preceded or followed by regular beats), and sustained ventricular tachycardia (VT) [defined as PVCs lasting > 30 s at a rate > 120 beats/min], and supraventricular ectopic events were summarized by treatment group. Although no commonly recognized standard has been established for heart rate data, a difference of < 5 beats/min is unlikely to be considered clinically significant and was used as a threshold to define a clinically meaningful difference.

Qualitative ECG
Qualitative ECGs were performed in five studies (Table 1) . Assessments included the determination of normal or abnormal ECGs at screening or baseline. At postbaseline visits, three categories of qualitative ECG assessments were prospectively defined in each study, as follows: normal; abnormal without a clinically significant change; and abnormal with a clinically significant change. Pretreatment assessments were summarized separately from posttreatment assessments.

QT Intervals
QT intervals from ECGs were measured in two studies (Table 1) . QT intervals (in milliseconds) were corrected by the Bazett square root formula, as follows: QTcB = QT* square root (heart rate/60) = QT/square root (RR/1,000). The 95% confidence interval (CI) on the treatment difference between the salmeterol, 50 µg bid, group and the placebo group was compared to a clinically meaningful effect of 30 ms.^{11 12} The frequency of increases from baseline of ≤ 30, 31 to 40, 41 to 50, 51 to 60, and > 60 ms, and the frequency of raw values of ≤ 430, 431 to 450, 451 to 470, and > 470 ms were summarized.

Statistical Methods
The primary comparison for all measures was salmeterol, 50 µg bid, vs placebo. Two-sided p values of < 0.05 were considered to be statistically significant. For the QTcB interval data, the 95% CI on the treatment difference between the salmeterol, 50 µg bid, group and the placebo group was compared to a clinically meaningful effect of 30 ms. For the heart rate data obtained from 24-h Holter monitoring, the 95% CI on the treatment difference between the salmeterol, 50 µg bid, group and the placebo group was compared to 5 beats/min. Because of their potential association with cardiovascular measures, the following covariates were included in models of inferential analyses of Holter, QT interval, and AE data: baseline (except for AE); age; sex; smoking status; baseline percent predicted FEV₁; bronchodilator response; protocol; and treatment. The investigator was not included in models since the Holter monitors and ECGs were read centrally (except in study SFCB3024), and there were generally small numbers of patients per site.

Poisson regression with exposure as an offset variable, and the covariates listed above that were included in the model, were used to compare the incidence of cardiovascular AEs among treatment groups. Additionally, survival analysis using a Cox proportional hazards model with the same covariates was used to compare the time to first cardiovascular AE. Treatment comparisons for QTcB intervals, and for the mean and maximum heart rates were made using contrasts constructed from a general linear model fit using standard least squares with covariates, as listed above. Log-transformed values were used to compare the number of ventricular ectopic events and supraventricular ectopic events between treatment groups, and a nonparametric analysis of covariance was used to confirm the results of the analyses. Interactions between the treatment and each of the variables used to divide patients into subgroups also were tested for each of the measures in which inferential analyses were performed.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
A total of 1,443 patients received placebo, while 1,410 patients were treated with salmeterol, 50 µg bid. The data are presented only for the ITT population since the findings in the PR population were similar to those in the ITT population. Although some differences were observed among subgroups when compared to the overall ITT population (data for these differences are presented), the findings across subgroups were comparable between the salmeterol and placebo groups. Only significant results from interaction testing between treatment group and these subgroups at the end point are reported. Demographic and baseline characteristics were comparable in the placebo and salmeterol, 50 µg bid, groups (Table 2 ). Patients in these two groups were between 35 and 90 years old, had extensive smoking histories (mean, 52 pack-years), had impaired lung function (mean FEV₁, 42% of predicted), and 40 to 42% of patients had an underlying cardiac condition at baseline. Of these, 25 to 29% were receiving therapy with antiarrhythmic or bradycardic agents. The duration of treatment in the studies included in this analysis ranged from a minimum of 12 weeks to a maximum of 52 weeks. The mean (± SD) exposure to treatment was 24 ± 15 weeks in the salmeterol, 50 µg bid, group and 22 ± 16 weeks in the placebo group, which represented 651 and 614 patient-years, respectively, of exposure. One hundred sixty-eight patients (12%) in the placebo group and 197 patients (14%) in the salmeterol, 50 µg bid, group had treatment exposures of ≥ 52 weeks.

The incidence of cardiovascular AEs is provided in Table 3 . The number of patients experiencing any cardiovascular AE was similar in the placebo and salmeterol, 50 µg bid, groups. There were no significant differences between salmeterol, 50 µg bid, and placebo for the incidence of cardiovascular AEs (relative rate, 1.03; 95% CI, 0.81 to 1.31; p = 0.796) or for the time to first cardiovascular AE (p = 0.944).

24-h Holter Monitoring
Holter monitoring data were obtained from 134 placebo patients and 115 salmeterol patients at baseline and at the end point. The mean 24-h heart rates at screening and at the end point were 81.4 and 79.6 beats/min, respectively, in the placebo group, and 80.5 and 79.9 beats/min, respectively, in the salmeterol group, with no differences detected at the end point (Fig 1 ). Inferential analysis of the 24-h Holter monitoring data showed no significant differences between the salmeterol, 50 µg bid, group and the placebo group at the end point for mean 24-h heart rate (estimated difference, 1.2 beats/min; 95% CI, -0.64 to 2.95; p = 0.207), maximum 24-heart rate (estimated difference, 1.3 beats/min; 95% CI, -0.83 to 3.53; p = 0.225), number of ventricular ectopic events (estimated difference, 0.3 events; 95% CI, -0.09 to 0.67; p = 0.131), and number of supraventricular ectopic events (estimated difference, -0.2; 95% CI, -0.53 to 0.21; p = 0.388). The upper interval for the mean and maximum 24-h heart rate was < 5 beats/min. The number of patients with ventricular ectopic events are summarized in Table 6 . The number of patients with single PVCs, ventricular couplets, and ventricular runs were similar between the salmeterol and placebo groups. There were no occurrences of sustained VT.

View larger version (10K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Mean (± SD) 24-h heart rate measured by Holter monitoring in the salmeterol, 50 µg bid, group and the placebo group. bpm = beats per minute.

QTcB Intervals
QTcB intervals at screening and at the end point, and change from baseline values were similar between the placebo and salmeterol, 50 µg bid, groups (Fig 2 ). At the end point, one patient who was receiving salmeterol, 50 µg bid, had a > 60-ms change in QTcB interval compared with two patients receiving placebo. The estimated difference of 0.1 ms, corresponding to a 95% CI of -2.4 to 2.6 in QTcB interval between salmeterol, 50 µg bid, and placebo at the end point, was not clinically meaningful or significantly different (p = 0.940).

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Mean (± SD) QTcB intervals in the salmeterol, 50 µg bid, group and the placebo group. msec = milliseconds.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

Most patients with COPD are current or ex-smokers and are, therefore, at an increased risk for coronary artery disease and peripheral vascular disease. However, the major cardiovascular consequence of COPD is pulmonary arterial hypertension, which is associated with the development of right ventricular hypertrophy and edema (ie, cor pulmonale), which predicts a poor prognosis.⁸ The most common cardiac arrhythmia seen in patients with respiratory failure due to COPD is sinus tachycardia, but premature atrial complexes, atrial fibrillation, premature ventricular complexes, and VT often are reported.^{9 16}

Factors reported to be potentially arrhythmogenic in these patients include the presence of cor pulmonale, hypoxemia, hypokalemia, increased levels of catecholamines, coexisting ischemic heart disease, and treatment with drugs such as digoxin, theophylline agents, and ß-agonist agents.^{9 17} Patients with hypoxemic COPD, in particular, have been reported to have subclinical autonomic neuropathy associated with prolonged QTc interval and associated risk of ventricular arrhythmias.¹⁰ The examination of some of these potential risk factors in patients with COPD and concurrent ischemic heart disease have revealed no significant increases in cardiac arrhythmias with the use of inhaled nebulized bronchodilators,¹⁸ the use of oral theophylline in conjunction with albuterol,¹⁹ or in the presence of hypokalemia induced by nebulized bronchodilator therapy.²⁰

The evaluation of safety data from several clinical studies with salmeterol demonstrates no clinically significant effect on heart rate or BP in patients with COPD.^{3 6 13} However, significant increases in mean heart rate relative to placebo were reported with single doses of formoterol, 12 or 24 µg, or salmeterol, 50 µg, in a study⁷ of 12 high-risk patients with COPD who had preexisting cardiac arrhythmias and hypoxemia (PaO₂, <60 mm Hg). This effect was greatest with formoterol, 24 µg. The notable limitations of this study were that it evaluated a small number of patients and that there was no baseline Holter monitoring conducted. Few differences were noted between the salmeterol and placebo groups, and the incidence of supraventricular and ventricular premature beats was similar in both groups.

The strengths of our pooled analysis include the use of an extensive safety database that is highly representative of the COPD population, including a broad range of patients with COPD across the full range of disease severity, smokers, elderly patients, and those with concomitant cardiovascular conditions. The use of a larger population in this analysis than those included in individual trials increased the power of the analysis, and therefore, the ability to detect less common events. Most of the studies were of similar design, although the different inclusion criteria in the US vs the non-US studies led to the analysis of two populations, namely, the ITT and PR populations. Differences in the duration of the studies included in this analysis meant that the incidence of AEs varied slightly, but these differences were considered to be minor.

This analysis could be considered to be limited by the fact that some of the studies excluded patients who had been treated with ß-blockers because of the possible induction of bronchospasms by these agents,^{21 22} and also excluded patients with severe underlying cardiovascular conditions for potential ethical reasons. However, the stratification of our patients by cardiovascular condition at baseline with or without the use of bradycardic and/or antiarrhythmic agents does not show an increased risk in this population. Another potential limitation of this analysis was the limited duration of follow-up in these studies. The duration of the studies in this pooled analysis ranged from 12 weeks to 1 year. Since COPD is a chronic disease, subjects may require salmeterol therapy for several years or even decades. The extrapolation of these data to long-term outcome data is not possible. Reassuringly, a large epidemiologic study²³ evaluating the safety of salmeterol administration to subjects with COPD for 3 years revealed no increased risk of death when compared with a control group of COPD patients not using long-acting ß-agonist agents or inhaled corticosteroids.

The results of our pooled analysis revealed no significant differences between salmeterol and placebo in any of the safety parameters evaluated. Holter monitoring showed no evidence of an effect on the mean or maximum 24-h heart rates, indicating that salmeterol does not induce significant sympathetic stimulation of the heart in patients with COPD. Additionally, no clinically relevant differences were observed between the two groups in the incidence of ventricular or supraventricular ectopy. No cases of sustained VT were reported. No differences were observed in qualitative ECG measurements, QT intervals, pulse rates, and BPs between the salmeterol and placebo groups. No significant differences were observed in the overall incidence of cardiovascular AEs between salmeterol and placebo. Although these events increased with age, concurrent cardiovascular disease at baseline, and treatment with antiarrhythmic/bradycardic agents, the increases were comparable in the salmeterol and placebo groups.

The results of this pooled analysis of salmeterol cardiovascular safety data indicate that salmeterol confers a similar cardiovascular safety profile to placebo in this population of COPD patients. Therefore, salmeterol can be used safely to manage symptoms, improve lung function, potentially decrease exacerbations and improve the quality of life in patients with COPD.

	Acknowledgements

 
We thank Tracy Weeks and Shehnaz Gangjee, PhD, for assistance with the preparation of this manuscript.

	Footnotes

 
Abbreviations: AE = adverse event; CI = confidence interval; ITT = intent to treat; PR = poorly reversible; PVC = premature ventricular contraction; VT = ventricular tachycardia

The studies reported in this manuscript were supported by GlaxoSmithKline.

Received for publication June 26, 2002. Accepted for publication December 12, 2002.

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TOP Abstract Introduction Materials and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (24) Citing Articles via Google Scholar Google Scholar Articles by Ferguson, G. T. Articles by Reisner, C. Search for Related Content PubMed PubMed Citation Articles by Ferguson, G. T. Articles by Reisner, C.