Original Contributions

Comparison of racemic albuterol and levalbuterol in the treatment of acute asthma in the ED^B,BB

David M. Schreck MD, MS^a,b,c,*, Stephen Babin RN^d

^aSummit medical group, Summit, NJ 07901, USA

^bRobert Wood Johnson Medical School, Piscataway, NJ 08854, USA ^cEmergency Medical Associates, Livingston, NJ 07039, USA ^dMuhlenberg Regional Medical Center, Plainfield, NJ 07060, USA

Accepted 8 April 2005

Abstract

Background: Acute asthma is often treated with racemic albuterol, a 1:1 mixture of (R)-albuterol and (S)-albuterol. Levalbuterol is the single-isomer agent comprised (R)-albuterol, an active bronchodilator, without any effects of (S)-albuterol.

Objective: To compare emergency department (ED) admission rates of patients presenting with acute asthma who were treated with either racemic albuterol or levalbuterol.

Setting: Suburban community teaching hospital.

Design: Retrospective observational case review.

Methods: Emergency department patients presenting with acute asthma at 2 different sites were reviewed over 9- and 3-month consecutive periods. Outcome measures included ED Hospital admission rate, length of stay, arrival acuity, and treatment costs. Patients were excluded if younger than 1 year or if no treatment of acute asthma was rendered.

Results: Of the initial 736 consecutive cases, significantly fewer admissions (4.7% vs 15.1%, respectively; P = .0016) were observed in the levalbuterol vs racemic albuterol group. Of the subsequent

186 consecutive cases, significantly fewer admissions were also observed (13.8% vs 28.9%, respectively; P = .021) in the levalbuterol vs racemic albuterol group. Treatment costs were lower with levalbuterol mainly because of a decrease in hospital admissions.

Conclusion: Levalbuterol treatment in the ED for patients with acute asthma resulted in higher patient discharge rates and may be a cost-effective alternative to racemic albuterol.

D 2005

Presented in part at the American College of Emergency Physicians Research Forum, October 15 to 18, 2001, Chicago, Ill; the National Association of EMS Physicians Annual Scientific Sessions, January 16, 2003, Panama City, Fla; and the Society of Critical Care Medicine 33rd Critical Care Congress, Orlando, Fla, February 22, 2004.

^B This investigation was not funded by any pharmaceutical company. partial funding was obtained from Emergency Medical Associates Research

Foundation.

^BB Dr Schreck has provided post-study consultative services to the manufacturer of levalbuterol, Sepracor, Inc, by serving on the Sepracor Speakers Bureau.

T Corresponding author. 80 Division Ave, Summit, NJ 07901, USA. Tel.: +1 973 740 0607; fax: +1 908 522 0596.

E-mail address: [email protected] (D.M. Schreck).

0735-6757/$ - see front matter D 2005 doi:10.1016/j.ajem.2005.04.003

Introduction

Asthma is one of the most common illnesses treated in the emergency department (ED) setting. It is reported that nearly 15 million Americans have asthma, and the more than 2 million annual ED visits result in costs in excess of

$6 billion with hospitalizations accounting for the largest portion of these costs [1- 4]. In the United States from 1992 to 1999, the absolute number and rate of ED visits for asthma increased by 36% and 29%, respectively [4]. An evaluation of 1 448555 consecutive patients presenting to

15 EDs in northern New Jersey from 1997 to 1999 demonstrated an increasing number of asthma visits (Fig. 1). In addition, an increasing proportion of asthma- related hospital admissions from the ED was also reported. In the calendar year 1999, it was shown that 2.7% of all ED admissions were due to acute asthma and the average acute asthma admission rate from 1997 to 1999 was 16.4% across the 15 northern New Jersey EDs studied (Emergency Medical Associates, Livingston, NJ).

Multiple therapeutic modalities are available to the ED physician to manage acute asthmatic episodes, including b₂-adrenergic agonists and corticosteroids, which are the mainstays of therapy. The most widely prescribed therapy for asthma in the inpatient, outpatient, and ED settings are the b₂-adrenergic agonists. Human b₂-adrenergic receptors are specifically designed to allow a conformational fit with

l-epinephrine,the (R)-stereoisomer. Synthetic b₂-adrenergic agonists such as racemic albuterol structurally mimic epinephrine and bind to the b₂-adrenergic receptor site [5]. Racemic albuterol, the most commonly used b₂- adrenergic agonist, is a 1:1 mixture of (R)- and (S)-albuterol stereoisomers. (R)-albuterol, also known as levalbuterol,

solely binds to the b₂-adrenergic receptor, producing bronchodilation, whereas (S)-albuterol, because of its structural conformation, does not effectively bind to the b₂-adrenergic site and has been considered inert for more than 30 years [6]. Only after the clinical acceptance and use of racemic albuterol was the technology to separate stereo- isomers (enantiomers) developed, enabling the investigation of the individual properties of (R)- and (S)-albuterol. Since then, experiments with animal, tissue, and cell culture models have suggested that (S)-albuterol has proinflamma- tory effects [7,8] and that it enhances airway tissue hyperresponsiveness and contractile responses [9 -11]. Fur- thermore, (S)-albuterol has a 10-fold slower rate of metabolism than (R)-albuterol and, with frequent dosing, can accumulate in patients’ plasma and lung tissue in the absence of (R)-albuterol [12-14]. A more recent report has corroborated the proinflammatory dose- and time-dependent effects of (S)-albuterol and has discussed some of the mechanisms and pathways involved [15].

The development of new technology allowing the separation of the (R)- and (S)-albuterol stereoisomers has resulted in the development of a pure levalbuterol formula- tion (Xopenex, Sepracor, Marlborough, Mass). This formu- lation has been approved for the treatment of bronchoconstriction in patients 6 years and older, but justification of its higher acquisition cost relative to its therapeutic efficacy is controversial. The purpose of this study was to compare the overall disposition and economic impact on patients with acute asthma treated in the ED setting who received either levalbuterol or racemic albuterol as part of their primary therapy.

Materials and methods

20000

18000

16000

14000

Asthma Annual Volume

12000

10000

8000

6000

4000

2000

0

1997 1998 1999

Year

Volume Percent

3.5

3

2.5

Asthma % Volume

2

1.5

1

0.5

0

All consecutive cases of patients presenting to the ED with acute asthma were retrospectively reviewed for

9 months (June 2000 through February 2001) after the addition of levalbuterol to the formulary at Muhlenberg Regional Medical Center in Plainfield, NJ. Patients 1 year or older with a primary or secondary diagnosis of acute asthma who required nebulization with a short-acting b₂-agonist, (R, S)-albuterol (racemic albuterol) or (R)-albuterol (leval- buterol), were included. Patients younger than 1 year were excluded because of the potential for a diagnosis of bronchiolitis. Patients also were excluded if they did not receive b₂-agonist treatment in the ED. Patients received either racemic albuterol 2.5 mg or levalbuterol 1.25 mg delivered via nebulizer in addition to other standard treat- ments including corticosteroids and oxygen. All medica- tions and Treatment regimens were determined by the treating physician.

Each case was stratified by the type of b₂-agonist

Fig. 1 Asthma cases by volume and percentage presenting to 15 EDs in northern New Jersey (courtesy of Emergency Medical Associates of New Jersey).

administered and by age. Patient disposition was assessed (admission vs discharge). Emergency department length of stay (LOS) and objective measures of patient acuity upon

arrival, including respiratory rate, peak flow, and pulse oxygenation, were compared between treatments. v² Test or Fisher exact test was used to determine treatment-related differences in Hospital admission rates. Emergency depart- ment LOS and arrival acuity measures were compared using analysis of variance to identify statistically significant differences between the treatment groups. A pharmacoeco- nomic assessment was performed to quantify the economic charge-based impact of patients in both groups. All hospital charges submitted to patients were collected, assessed, and compared between albuterol and levalbuterol groups.

In an effort to reproduce the disposition results obtained at Muhlenberg Regional Medical Center, a similar retrospec- tive chart review was performed at Mercer Hospital, Trenton, NJ. A total of 186 consecutive cases of acute asthma presenting to the ED were reviewed, with the same inclusion and exclusion criteria, from August 1, 2002, through October 31, 2002. Each case was stratified by the type of b₂-agonist administered and by age. Patient disposition was similarly assessed (admission vs discharge). No pharmacoeconomic data were obtained from Mercer Hospital.

Results

A total of 736 consecutive cases at Muhlenberg Regional Medical Center meeting inclusion and exclusion criteria were reviewed, with 608 patients receiving racemic albu- terol and 128 patients receiving levalbuterol during the 9-month period. Between the 2 treatment groups, there were no significant differences by analysis of variance in patient age, sex, ED LOS, or patient acuity (respiratory rate, peak flow, pulse oxygenation) upon ED arrival (Table 1). There were 98 (13.3%) patients admitted and 638 (86.7%) patients discharged from the ED in this consecutive patient series. Hospital admission rates were significantly lower in the levalbuterol-treated patients vs racemic albuterol-treated patients (4.7% vs 15.1% respectively; P = .0016 by v²; Table 2). The racemic albuterol admission rate was comparable with the 16.4% average admission rate mea- sured at Muhlenberg Regional Medical Center in the pre- vious 3 years. In adult patients (age z18 years; n = 502), the admission rate was 4.5% in those patients treated with

Values are presented as number or number (%).

2 (5.0) 19 (9.8) .01

194

40

4 (4.5) 73 (17.6) .00085

414

88

6 (4.7) 92 (15.1) .0016

Rac Alb P

608

Lev

128

All patients (N = 736)

Admission to hospital from ED Adult (age N18 y) (n = 502) Admission to hospital from ED Children (age b18 y) (n = 234) Admission to hospital from ED

Table 2 Muhlenberg Regional Medical Center patient

disposition results: levalbuterol vs racemic albuterol

levalbuterol vs 17.6% admit rate for those treated with the racemate ( P = .00085 by Fisher exact test). In pediatric patients (age b18 years; n = 234), the admission rate was also significantly lower for those treated with levalbuterol compared with those treated with racemic albuterol (5.0% vs 9.8%; P = .01 by Fisher exact test; Table 2).

The mean patient hospital charges for ED treatment in each treatment group (Table 3) were $404.56 F $193.56 and

$422.30 F $230.61 for levalbuterol and racemic albuterol, respectively, but this difference was not statistically signif- icant ( P = .467). A medical chart and billing review of the

98 patients who were admitted to Muhlenberg Regional Medical Center during the study period determined that the mean LOS was 3.8 days with an average per diem cost of $945 resulting in a mean hospitalization cost of

$3625 per admitted patient. Muhlenberg Regional Medical Center received approximately 1000 patients in the calendar year 2000 (approximately 3.0% of total ED volume) with acute asthma. An average of 4 nebulized b₂-agonist treat- ments were given to each asthmatic patient in the ED during this review. Data review from the pharmacy revealed that the cost of racemic albuterol was $0.26 per 2.5-mg dose (approximately $1.00 per ED patient treatment) and the cost of levalbuterol was $1.47 per 1.25-mg dose (approximately

$6.00 per ED patient treatment). The ED admission rates for levalbuterol and racemic albuterol approximated 5% and 15%, respectively. Using a per diem rate of approximately

$1000 and an approximate LOS of 4 days, the average asthma hospital stay costs approximately $4000. When one considers 1000 ED asthmatic patients presenting to the ED annually, the overall drug cost per 1000 albuterol-treated patients

Table 1 Patient characteristics and ED statistics
	Rac Alb admitted	Rac Alb discharged	Lev admitted	Lev discharged	P
Age b18 y	6.7 F 4.9	6.8 F 4.8	7.4 F 5.0	7.2 F 5.0	.88
Age z18 y	49.8 F 17.0	49.2 F 19.0	40.2 F 14.1	39.9 F 13.4	.957
Male (%)	48.4	33.3	50.0	41.0	.668
LOS (min)	331 F 195	335 F 212	181 F 113	196 F 107	.762
RR0	29.8 F 8.1	39.8 F 14.2	25.6 F 8.5	30.2 F 10.3	.143
PF0	200 F 70	200 F 80	265 F 102	182 F 70	.433
SAT0 (%)	92.8 F 10.9	94.0 F 3.5	97.3 F 2.4	96.7 F 3.2	.407
Values are presented as mean F SD unless noted otherwise. Rac Alb indicates racemic albuterol; Lev, levalbuterol; RR0, respiratory rate; PF0, peak flow; SAT0, oxygenation saturation.

Table 3 Calculated costs of ED treatment
	Lev	Rac Alb	P
All patients (N = 736) Hospital charges	128 $404.56 F $192.56	608 $422.30 F $230.61	.467
Collected funds	$211.90 F $107.56	$207.16 F $157.47
Admitted patients (n = 98)	6	92	.0001
Total hospital costsT	$21750	$333500
Values are presented as mean F SD unless noted otherwise. T In the patient charts reviewed in this study, the mean hospital cost for the 98 admitted patients was $3625. This value was used to project the total hospital costs of admitted patients in each group.

is approximately $1000 ($1.00 per patient treatment x 1000 patients). If levalbuterol is substituted, the overall drug cost per 1000 ED asthmatic patients is $6000 ($6.00 per patient treatment x 1000 patients). Thus, an economic investment of $5000 occurs annually for the use of leval- buterol in all ED patients with acute asthma. However, the return on this investment is clearly demonstrated by examining the admission Costs of care. It is projected that approximately 150 patients will be admitted for each 1000 patients treated with racemic albuterol (1000 patients x 0.15 admit rate) vs 50 admissions (1000 patients x 0.05 admit rate) for those patients treated with levalbuterol. Thus, the Total costs for admission in the racemic albuterol group is

$600000 (150 admitted patients x $4000 total hospital stay costs for 4 day LOS) vs $200000 (50 admitted patients x

$4000) for patients treated with levalbuterol. The inpatient cost savings of $400000 resulting from an investment of

$5000 cost for levalbuterol results in an 80:1 Risk-benefit ratio favoring levalbuterol.

The results from Mercer Hospital also revealed signifi- cant decreases in hospital admission rates with levalbuterol in comparison with the racemic drug (13.8% vs 28.9%; P = .021 by v²; Table 4). Although not powered for appropriate sample sizing when stratified by age, trends toward statistical significance were noted in both adult and pediatric age groups.

Discussion

drug therapy with isomeric derivatives of racemic compounds is not a new concept. Many single-isomer

Table 4 Mercer Hospital patient disposition results: levalbuterol vs racemic albuterol

Lev Rac Alb P

All patients (N = 186) 65 121

Admissions from ED 9 (13.8) 35 (28.9) .021

Adults (age z18 y) (n = 119) 29 90

Admissions from ED 4 (13.8) 25 (27.7) .127

Children (age b18 y) (n = 67) 36 31

Admissions from ED 5 (13.9) 10 (32.3) .066

Values are presented as number or number (%).

drugs are now available for clinical use such as levoflox- acin, simvastatin, and enalapril. Although the (R)- and (S)-albuterol isomers have the same molecular weight and other similar physiochemical properties, they are nonsuper- imposable images with regard to their 3-dimensional structure. This conformational stereochemistry confers dif- ferent and distinctive properties to each isomer such that they are considered different compounds, and thus, regulatory authorities have mandated that the potential risks associated with racemic mixtures should be quantified [16]. To this end, levalbuterol was developed to maximize Therapeutic effects and potentially minimize untoward effects that may be related to (S)-albuterol.

The findings shown in this study demonstrate that the use of levalbuterol when compared against racemic albuterol for the treatment of patients presenting to the ED with acute asthma significantly reduces hospital admission rates (4.7% vs 15.1%; P = .0016) and suggest that levalbuterol has clinical advantages over racemic albuterol in critical care settings. This clinical benefit was evident in both the pediatric and adult asthmatic patients who had been treated with levalbuterol. Similar observations of the data collected from Muhlenberg Regional Medical Center, performed on consecutive patients (N = 186) presenting with acute asthma to the Mercer Hospital ED, also found significant decreases in hospital admission rates with levalbuterol in comparison with the racemic drug. Thus, in geographically distinct ED settings, with varying physicians, patient populations, and socioEconomic conditions, the substitution of racemic albuterol with levalbuterol improved patient outcomes by reducing hospital admission rates. The observational pooled data include 922 patients with composite admission rate of 17.4% for patients treated with racemic albuterol and 7.8% for those patients treated with levalbuterol ( P = .001; v²). The comparison of admission rates by site of study is shown in Fig. 2.

Previous ED studies have suggested that levalbuterol produces greater bronchodilation than racemic albuterol and improves health resource use and discharge rates [17-21]. Compared with racemic albuterol 2.5 mg, levalbuterol

1.25 mg significantly improved Forced expiratory volume in 1 second percent change from baseline in adults with acute asthma (39% vs 74%, respectively; P b .05), although levalbuterol 0.63 mg was no different from 2.5 mg of the

35

P = 0.0016

P = 0.021

P = 0.001

30

25

Admission Rate (%)

20

15

10

5

0

Muhlenberg Mercer Pooled

Site

Fig. 2 Comparison of racemic albuterol vs levalbuterol admis- sion rates (pooled data from 2 consecutive studies).

racemate (37% vs 39%, respectively) [19]. Furthermore, a post hoc analysis found that patients’ baseline (S)-albuterol plasma levels negatively impacted patients’ baseline forced expiratory volume in 1 second as well as pulmonary function

1 hour after ED treatment was begun [19]. In another randomized double-blind study, Carl et al [18] compared treatment with levalbuterol 1.25 mg with racemic albuterol

2.5 mg in more than 500 pediatric patients reporting to the ED of a major children’s hospital. Patients receiving levalbuterol had significantly reduced hospital admission rates in comparison with those receiving racemic albuterol (36% vs 45%; P = .021). However, there was no significant difference between treatment groups for number of nebu- lizED treatments received in the ED or ED LOS, and upon admission to the hospital, the LOS in the hospital’s asthma care unit was not significantly different between treatment groups.

Pikarsky and Acevedo [20] recently reported data from a levalbuterol hospital conversion where racemic albuterol

2.5 mg every 4 hours was replaced with levalbuterol

0.63 mg every 6 hours or levalbuterol 1.25 mg every 8 hours. Despite that levalbuterol treatments were less frequent, these patients required fewer rescue treatments for breakthrough symptoms than did those treated with racemic albuterol (with or without concomitant ipratropium bromide). Furthermore, less frequently scheduled treatments reduced workload demands on Respiratory therapists and reduced the number of missed treatments because of unavailability of the therapist [21].

Questions have been raised over the cost of levalbuterol and racemic albuterol, which has generic formulations [22]. Data presented here indicate that levalbuterol is effective for

the treatment of acute asthma in the ED and that, despite the higher drug cost of levalbuterol, when total system costs are considered, overall ED treatment costs were similar (5% decrease in cost in the levalbuterol group vs racemic albuterol group was not significant; P = .467). When considering the expenses related to asthma treatment, our findings are consistent with other reports that examine parameters besides drug cost alone [21,23 - 25]. Truitt et al

[23] reported that levalbuterol-treated inpatients with acute asthma or chronic obstructive pulmonary disease required significantly fewer b₂-agonist treatments and a 67% decrease in readmissions within 30 days of discharge compared with racemic albuterol ( P = .056). Hospital use of levalbuterol translated into a nearly 1-day shorter hospital stay ( P = .015) and an average cost savings of $556 per levalbuterol-treated patient ( P = .013) [23]. In a case- controlled assessment of Claims data, levalbuterol was associated with a $435 reduction in mean charges compared with a $311 increase for albuterol in outpatients receiving

2 controller medications or more [26]. Additional cost reductions associated with levalbuterol were noted with increasing Asthma severity [26]. Other studies comparing levalbuterol with racemic albuterol as the primary short- acting b₂-agonist therapy have reported decreased numbers of daily treatments, fewer as-needed treatments, and reduc- tions in staffing requirements [21,25]. Therefore, in addition to cost savings associated with less frequent dosing of levalbuterol compared with racemic albuterol [27,28], levalbuterol appears to be cost-effective in the treatment of acute asthma in the ED, despite its higher drug cost. Data presented here demonstrate that the overall ED treatment costs were similar in the levalbuterol vs racemic albuterol group ( P = .467); however, significant cost savings were attained by reducing hospital admissions.

The number needed-to-treat (NNT) required to achieve clinical benefit using levalbuterol in this retrospective review is 9.6 patients (NNT = 1/0.151 — 0.047). Thus, approximately 10 patients would need to be treated with levalbuterol instead of racemic albuterol to achieve one more discharge than expected, and for every $50 ($5.00 per patient in increased levalbuterol costs) invested in treating

10 patients with levalbuterol, $4000 is saved from a resulting extra discharge. The NNT reported in this study is similar to that of other investigators [18,29] and was similarly observed in the repeat study of an additional 186 consecutive ED patients with acute asthma reported by Schreck et al [30] (Table 4).

It is very interesting that the clinical and preclinical benefits of levalbuterol compared with racemic albuterol reported in the literature cited in this investigation have occurred when the only difference between the 2 agents is the presence of the S-isomer in the racemic mixture. This suggests that the S-isomer may not be inert and instead may have some proinflammatory effect.

Limitations of this study include its retrospective design, lack of standardization in treatment regimens, smaller

numbers of patients in the levalbuterol group relative to the racemic albuterol group, and lack of postdosing efficacy comparisons regarding parameters such as peak expiratory flow rates and respiratory rates. Because of the retrospective design, no cause and effect conclusions can be drawn from the data. In addition, other treatments were not considered in our evaluation of the patient disposition of each treatment group including corticosteroids and ipratropium bromide. It should also be stated that the diagnoses of asthma for patients in this investigation are based on the reported physician diagnosis as listed in the medical record as noted on chart review. It is conceivable that some older patients, although a small portion of the sample size (11% of the racemic albuterol group was older than 60 years vs 9% in the levalbuterol group), may have actually had chronic obstructive pulmo- nary disease. However, the large size of this observational study has hopefully allowed any treatment selection bias to be randomly distributed between the 2 study groups.

Conclusion

Our findings suggest that levalbuterol, when used in place of racemic albuterol, is cost-effective and reduces the number hospital admissions in the treatment of acute asthma in the ED setting. This observation is provocative because the only difference between the 2 agents is that of the presence of the S-isomer in the racemic mixture. A prospective trial is warranted to further validate these findings.

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