A Comparison of Levalbuterol and Racemic Albuterol in the Treatment of Acute Severe Asthma Exacerbation in Adults

Design

Randomized, double-blind, multicenter, parallel-group study 

N= 627

Objective

To compare nebulized levalbuterol and racemic albuterol in the treatment of acute asthma

Study Groups

Racemic albuterol 2.5 mg (n= 312)

Levalbuterol 1.25 mg (n= 315)

Inclusion Criteria

Age ≥ 18 years old, presented to clinic/emergency department (ED) with acute asthma exacerbations, FEV₁ between 20-55% predicted, 6-month history of physician-diagnosed asthma, oxygen saturation ≥ 90%, no more than 6 L/min supplemental oxygen, nonpregnant, no other known cause of wheezing or shortness of breath

Exclusion Criteria

Severe respiratory distress, administered therapy other than oxygen after ED/clinic arrival, acute asthma treatment in previous 2 weeks, hospitalization within 1 month of presentation, severe asthma history within previous 12 months, smoking history > 10 pack-years

Methods

All patients were treated with oral prednisone (40 mg). Patients were then randomly allocated to receive in a double-blinded fashion either nebulized levalbuterol (1.25 mg) or racemic albuterol (2.5 mg) administered by mouthpiece. Treatments were administered as clinically necessary approximately every 20 minutes in the first hour and subsequently at 40-minute intervals for up to 3 additional doses. After 3 hours, patients could receive additional asthma therapy as deemed necessary by the investigator. Patients were discontinued from the study if treatment continued beyond 24 hours or if patients were admitted to the hospital.

Duration

Follow-up period: 30 days

Outcome Measures

Primary: time to meet ED discharge criteria (objective functional airway improvement [achieving FEV₁ of ≥ 70% of predicted or 2.1 L, plus no wheeze and good air movement] or sufficient clinical improvement to warrant investigating physician's decision to discharge)

Secondary: FEV₁ change from baseline, proportion of patients hospitalized

Baseline Characteristics

Racemic albuterol 2.5 mg (n= 312) 

Levalbuterol 1.25 mg (n= 315)

Age, years 

Female

Race

African American 

White

Hispanic

192 (61.5%)

74 (23.7%)

37 (11.9%)

214 (67.9%)

64 (20.3%)

28 (8.9%)

FEV₁ % predicted

37.8 ± 10.7

38.0 ± 9.8

Concomitant inhaled steroids within 7 days

103 (33.0%)

126 (40.0%)

Concomitant oral steroids within 7 days

26 (8.3%)

21 (6.7%)

Racemic albuterol canisters per month

1.6 ± 1.1

1.6 ± 1.1

Any racemic albuterol use within 24 h

260 (83.3%)

262 (83.2%)

Racemic albuterol nebulization within 24 h

79 (25.3%)

81 (25.7%)

Salmeterol within 24 h

38 (12.2%)

46 (14.6%)

Theophylline

14 (4.5%)

11 (3.5%)

ED visits within previous 12 months

2.2 ± 2.8

2.5 ± 3.9

Hospitalizations for asthma within previous 12 months

0.4 ± 1.0

0.5 ± 1.2

Results 

Endpoint

Median time to discharge, minutes

Change from baseline in FEV₁, L

Dose 1

Doses 1-3

Doses 1-6

0.43 ± 0.37

0.67 ± 0.49

0.74 ± 0.48

0.50 ± 0.43

0.73 ± 0.51

0.80 ± 0.51

0.021

0.093

0.113

Proportion of patients hospitalized

Among the 60% of patients who reported no corticosteroid use in the preceding 7 days, levalbuterol-treated patients had a greater mean FEV₁ improvement than racemic albuterol-treated patients both after the first dose (0.58 ± 0.47 vs 0.44 ± 0.37 L, respectively; p < 0.01) and after dose 6 (0.90 ± 0.53 vs 0.78 ± 0.48 L, respectively; p= 0.028). No difference in mean FEV1 response was observed between treatment groups for patients who reported corticosteroid use. 

In patients not taking corticosteroids, those treated with levalbuterol were hospitalized significantly less frequently than those treated with racemic albuterol (3.8% vs 9.3%, respectively; p= 0.03). Among patients taking corticosteroids, no significant differences were evident in the proportion requiring hospitalization between treatment groups.

The difference in the FEV₁ improvement between levalbuterol and racemic albuterol was most pronounced in patients in the highest (S)-albuterol concentration quartile (dose 1: 0.35 ± 0.27 L for levalbuterol vs. 0.25 ± 0.30 L for racemic albuterol, p= 0.017; dose 6 0.69 ± 0.37 vs. 0.42 ± 0.52 L, respectively, p < 0.001).

Common Adverse Events (levalbuterol vs. albuterol): headache (1.0% vs. 3.2%), nervousness (3.2% vs. 2.2%), tremor (2.2% vs. 2.2%), tachycardia (1.9% vs. 2.9%)

Serious Adverse Events: asthma events (4.8% vs. 3.5%)

Percentage Discontinued due to Adverse Events: Not specified

Study Author Conclusions

This study suggests that early, regular nebulized β₂-agonist and systemic corticosteroid therapy may reduce hospitalization and relapse rates in patients with acute severe asthma. Levalbuterol was well-tolerated and compared favorably with racemic albuterol in improving airway function, particularly in those who were not on inhaled or oral corticosteroids and in those who had high plasma (S)-albuterol concentrations at presentation.

InpharmD Researcher Critique

The smaller-than-expected proportion of patients who required admission in this trial may have contributed to an inability to discern meaningful statistical differences in hospitalizations between treatment groups. Discharge decisions made in this trial were based predominantly on subjective physician-investigator assessments rather than patients attaining objective endpoints which may have confounded results. 

Comparison of Levalbuterol and Racemic Albuterol in Hospitalized Patients with Acute Asthma or COPD: A 2-Week, Multicenter, Randomized, Open-Label Study

Design

Prospective, multicenter, randomized, open-label study

N= 479

Objective

Study Groups

Levalbuterol (n= 241)

Albuterol (n= 238)

Inclusion Criteria

Exclusion Criteria

Methods

Duration

Outcome Measures

Primary: Total number of nebulizations (including rescue treatment) during hospital stay

Secondary: length of stay, relapse, improvement in FEV1, respiratory therapy cost

Baseline Characteristics

Levalbuterol (n= 241)

Albuterol (n= 238)

Age, years

Female

Race

White

Black

Hispanic

Asian

Other

60.2%

23.7%

15.4%

0.8%

0

55.5%

22.7%

21.4%

0%

0.4%

Baseline forced expiratory volume in one second (FEV1)

Weight, kg

Results

Endpoint

Levalbuterol (n= 241)

Albuterol (n= 238)

p-value

All nebulizations (interquartile range [IQR])

Scheduled nebulizations (IQR)

Rescue nebulizations (IQR)

10.0 (5-17)

9.0 (5-16)

0 (0-1)

12.0 (6-21)

11.0 (6-20)

0 (0-1)

0.031

0009

0.98

FEV1 change from baseline (standard deviation [SD])

First study day

Final measurement prior to discharge

0.06 (0.43)

0.11 (0.48)

0.10 (0.37)

0.16 (0.52)

Not significant

Length of stay, hours

70.6

65.7

Not significant

Total hospital cost (least squares mean)

$4,869.30 ($343.58)

$4,899.41 ($343.20)

0.94

Adverse Events

Common Adverse Events: Similar between groups. Most commonly reported events were insomnia (10.6%), hyperglycemia (8.6%), constipation (7.7.%), headache (6.9%), anxiety (4.8%), and pain (4.2%).

Serious Adverse Events: 21 (8.7%) in the levalbuterol group and 15 (6.3%) in the racemic albuterol group at 30-day follow-up. Events were deemed unlikely related to treatment. 

Percentage that Discontinued due to Adverse Events: 6 (2.5%) in the levalbuterol group versus 9 (3.8%) in the racemic albuterol group, most commonly due to dyspnea and apnea

Study Author Conclusions

InpharmD Researcher Critique

Evaluation of the Efficacy and Safety of Levalbuterol in Subjects with COPD

Design

Randomized, double-blind, multicenter, parallel-group trial

N= 171

Objective

To evaluate the bronchodilator response and safety parameters of patients with chronic obstructive pulmonary disease (COPD) to levalbuterol, racemic albuterol, or placebo in combination with ipratropium bromide

Study Groups

Placebo (n= 52)

Levalbuterol 0.63 mg (n= 43)

Levalbuterol 1.25 mg (n= 36)

Racemic albuterol (n= 36)

Inclusion Criteria

Adults aged ≥35 years; had a clinical diagnosis of COPD; baseline forced expiratory volume in the first second (FEV₁) ≤65% of predicted and >0.70 L, FEV₁/forced vital capacity (FVC) ratio ≤70%; ≥15 pack-year smoking history; history of breathlessness severity grade from the medical research council dyspnea scale score of ≥2

Exclusion Criteria

Taking corticosteroids (inhaled, oral, or nasal), xanthines, or leukotriene antagonists at non-stable doses (i.e., doses needed adjustments 30 days prior or during the study period)

Methods

After a 2-week run-in period, patients were randomized to receive nebulized treatment with either levalbuterol 0.63 mg, levalbuterol 1.25 mg, racemic albuterol 2.5 mg, or placebo TID for 6 weeks. Subjects received the initial dose of study medication on the day of random allocation and returned every 2 weeks for follow-up. All treatments were supplied in unit dose vials that delivered 3 mL of inhalation solution to be administered via a PARI LC Plus Nebulizer (with a mouthpiece or face mask) and a DURA-NEB 3000 compressor.

All participants also received open-label ipratropium bromide 18 mcg metered dose inhalers to use as supplemental therapy PRN. Participants were also given a blinded rescue metered dose inhaler of levalbuterol 45 mcg/actuation for the patients randomized to the levalbuterol groups or racemic albuterol 90 mcg/actuation (Ventolin) for patients allocated to albuterol or placebo. Rescue and supplemental inhalers were withheld for at least 8 hours before study visits.

Duration

Outcome Measures

Primary: average of the time-normalized percent change (from visit pre-dose) in FEV₁ area under the curve (FEV₁ AUC_{(0–8 hrs)}) from serial spirometry

Secondary: COPD exacerbations; safety

Baseline Characteristics

Placebo (n= 55)

Levalbuterol 0.63 mg (n= 53)

Levalbuterol 1.25 mg (n= 49)

Albuterol (n= 52)

Age, years

Male

Corticosteroid use

Mean FEV1 predicted, %

Results

Placebo (n= 52)

Levalbuterol 0.63 mg (n= 43)

Levalbuterol 1.25 mg (n= 36)

Albuterol (n= 36)

Time-normalized AUC_0-8h % change in FEV₁

Week 0

Week 2

Week 4

Week 6

1.93 ± 1.38

3.70 ± 1.47

17.70 ± 2.22

1.64 ± 1.19

16.56 ± 1.80**

14.12 ± 1.72**

22.29 ± 2.20

10.47 ± 1.59**

15.65 ± 1.61**

11.56 ± 1.61**

24.19 ± 3.45

9.19 ± 1.96*,**

22.54 ± 3.18**

12.65 ± 2.02**

23.00 ± 2.46

15.29 ± 1.93**

Patients with COPD exacerbations

Adverse events

Chest pain

Cardiovascular-related events

Headache

Dry mouth

Insomnia

Nervousness

Tremor

Increased cough

56.4%

3.6%

10.9%

12.7%

3.6%

5.5%

0

0

5.5%

56.6%

3.8%

3.8%

3.8%

1.9%

0

0

1.9%

3.8%

67.3%

8.2%

8.2%

8.2%

2.0%

0

6.1%

2.0%

8.2%

65.4%

0

9.6%

9.6%

5.8%

1.9%

3.8%

7.7%

7.7%

Discontinued due to adverse event(s)

5.5%

18.9%

18.4%

30.8%

Change in heart rate 30 minutes after the first study dose, beats/minute

-3.8 ± 6.8

-1.2 ± 6.3

+1.4 ± 6.5**

+2.8 ± 8.6**

*p=0.025 vs racemic albuterol; no other values were significantly different versus albuterol

**p<0.001 vs placebo

Adverse Events

Beta-adrenergic mediated adverse events were similar in all treatment groups with the exception of ventricular heart rate. Changes in serum potassium, glucose, and heart rate were similar in all active treatment groups.

Study Author Conclusions

Levalbuterol treatment in subjects with COPD was generally well tolerated, produced significant bronchodilation compared with placebo, and improved clinical control of COPD as evidenced by reductions in rescue medication use compared with placebo and/or racemic albuterol.

InpharmD Researcher Critique

This study had a small sample size with a fair amount of drop-outs (mainly due to adverse events or withdrawing consent); however, the study was adequately powered for the primary endpoint. This was a relatively short-term study, and more COPD exacerbations may have been observed with a longer duration. Additionally, there were uneven baseline demographics in terms of sex and corticosteroid (oral or inhaled) use.

Clinical outcomes and treatment cost comparison of levalbuterol versus albuterol in hospitalized adults with chronic obstructive pulmonary disease or asthma

Design

Single-center, randomized, prospective, open-label study

N= 112

Objective

To compare clinical outcomes and costs of levalbuterol versus albuterol therapy for exacerbations of asthma or chronic obstructive pulmonary disease (COPD)

Study Groups

Levalbuterol (n= 55) 

Albuterol (n= 57)

Inclusion Criteria

Aged ≥ 18 years, with a hospital admission related to COPD or asthma, a documented history of COPD or asthma, and an oxygen saturation of at least 90% at the time of enrollment

Exclusion Criteria

Malignancy, hyperthyroidism, uncontrolled dysrhythmias, pregnancy, cognitive impairment, a history of seizures, a baseline heart rate greater than 120 beats/min, pulmonary symptoms related to embolism, cystic fibrosis, angioedema, acute exacerbation of heart failure

Methods

Eligible patients were randomly assigned (1:1) to receive either albuterol 2.5 mg four times daily or levalbuterol 1.25 mg three times daily via high-flow nebulization. Patients might have received standard treatment according to physician preference for periods of less than 48 hours before consent and randomization. All patients also received albuterol 2.5 mg via nebulization every 4 hours as needed for dyspnea or wheezing. As clinically indicated, doses of albuterol and levalbuterol could be reduced to 1.25 mg every 6 hours and 0.63 mg every 8 hours, respectively. During the study period, use of other treatments required for the management of respiratory disease was also allowed. Heart rate was measured immediately before administration of scheduled nebulizer therapy and 15 minutes after completion of dose administration.

Data analyses stratified by the presence or absence of cardiovascular disease (CVD) and by disease states (COPD versus asthma) were also conducted. CVD was defined as a documented history of angina, coronary artery disease, coronary heart disease, dyslipidemia, heart failure, hypertension, ischemic heart disease, myocardial infarction, or valvular heart disease. 

Duration

Between December 2009 and September 2011

Follow-up: throughout the hospital stay 

Outcome Measures

Primary: numbers of scheduled and rescue β-agonist nebulization treatments received, total treatment costs (defined as costs associated with hospitalization and drugs)

Secondary: total treatment costs per patient, change in heart rate from baseline, and length of hospital stay 

Baseline Characteristics

Levalbuterol (n= 55) 

Albuterol (n= 57)

Age, years

Female

White

Black

76.4%

14.5%

75.4%

15.8%

No toxic exposure 

Comorbidities 

CVD*

Hypertension*

Diabetes mellitus 

Obstructive sleep apnea 

56.4%

70.9%

34.6%

29.1%

35.1%

52.6%

24.6%

43.9%

Concomitant respiratory medications

Corticosteroids

Leukotriene modifiers

Ipratropium

Beta-blocker

100%

60%

94.6%

32.7%

100%

59.7%

91.2%

18.1%

Readmission within 30 days

Heart rate, beats/min

*p< 0.05
In patients without CVD, 24 received levalbuterol and 37 received albuterol; in patients with CVD, 31 received levalbuterol and 20 received albuterol. 

Results

Endpoint

Levalbuterol (n= 55) 

Albuterol (n= 57)

p-value

Overall Study Population

Nebulizations

Scheduled

Received

Used as needed 

Total

Heart rate, beats/min

After dose administration

Change from baseline 

Length of stay, days 

-

-

21.1 ± 14.9

18.9 ± 13.1

0.7 ± 1.4

19.6 ± 13.4

-

83.2 ± 9.8

0.8 ± 1.2 (< 0.001)

8.5 ± 5.2 

-

-

21.2 ± 13.7

19.9 ± 13.1

0.8 ± 2.0

20.7 ± 14.4

-

80.5 ± 7.3

0.6 ± 1.5 (0.003)

6.8 ± 3.6 

-

-

0.970

0.692

0.849

0.692

-

0.112

0.499

0.040

Patients Without CVD

Nebulizations

Scheduled

Received

Used as needed 

Total

Heart rate, beats/min

Change from baseline 

Length of stay, days 

-

-

19.7 ± 15.5

17.7 ± 13.9

0.5 ± 0.7

18.2 ± 14.1

-

0.7 ± 1.1 (0.008)

8.0 ± 5.1

-

-

19.8 ± 12.4

18.4 ± 11.7

0.6 ± 1.6

19.0 ± 12.5

-

0.8 ± 1.4 (0.003)

6.4 ± 3.3

-

-

0.713

0.643

0.806

0.670

-

0.558

0.312

Patients With CVD

Nebulizations

Scheduled

Received

Used as needed 

Total

Heart rate, beats/min

Change from baseline 

Length of stay, days 

-

-

22.2 ± 14.6

19.9 ± 12.6

0.9 ± 1.8

20.7 ± 12.9

-

0.9 ± 1.2 (​< 0.001)

8.9 ± 5.3

-

-

23.8 ± 15.8

22.8 ± 15.4

1.0 ± 2.7

23.7 ± 17.4

-

0.4 ± 1.5 (0.283)

7.4 ± 4.1

-

-

0.730

0.595

0.349

0.743

-

0.533

0.349

Mean total treatment costs per patient were significantly greater with the use of levalbuterol ($8,003, bootstrap 95% confidence interval [CI], $6,628 to $9,379) versus albuterol ($5,772, bootstrap 95% CI, $5,051 to $6,494; p= 0.006). Mean treatment costs did not differ significantly between patients with and patients without CVD; mean costs were significantly higher in female patients.

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: One patient in the levalbuterol group discontinued the intervention due to the development of atrial fibrillation. 

Study Author Conclusions

Clinical outcomes were similar with the use of levalbuterol versus albuterol for exacerbations of COPD or asthma. On average, patients receiving levalbuterol had longer and more costly hospital stays

InpharmD Researcher Critique

Findings of cost analysis conducted in 2015 at a single institution may not readily apply to current practice settings. Other clinically relevant outcomes, such as quality of life, FEV₁, or β-mediated adverse reactions (besides the change in heart rates), were not evaluated. 

Efficacy of Racemic Albuterol versus Levalbuterol Used as a Continuous Nebulization for the Treatment of Acute Asthma Exacerbations: A Randomized, Double-Blind, Clinical Trial

Design

Prospective, double-blind, randomized controlled trial

N= 99

Objective

To compare racemic albuterol (RAC) with levalbuterol (LEV) in continuous form for the treatment of acute pediatric asthma exacerbations in the emergency department (ED)

Study Groups

Albuterol (n= 44)

Levalbuterol (n= 55)

Inclusion Criteria

Ages 6 to 17 years, a history of asthma, presented to the ED with a moderate to severe acute asthma exacerbation as determined by the attending physician

Exclusion Criteria

Baseline forced expiratory volume in 1 second (FEV1) ≥ 70% predicted, a history of chronic lung disease (e.g., cystic fibrosis), uncorrected congenital heart disease, suspected intrathoracic foreign body, needed immediate resuscitation, pregnant, had already received oral or intravenous/intramuscular (IV/IM) steroids before arrival in the ED

Methods

To avoid adverse patient outcomes, if the consent process was not completed within the first 15 minutes upon arrival to the ED, patients would receive a standard dose (2.5 mg) of albuterol as per standing ED orders. Eligible pediatric patients were randomly assigned to receive 7.5 mg of racemic albuterol (0.5%, 2.5 mg/0.5 mL) in normal saline (total volume = 20 ml) or 3.75 mg of levalbuterol in the same volume of normal saline, both nebulized over 1 hour. 

All children also received 2 mg/kg of oral prednisolone or prednisone, up to a maximum dose of 60 mg within the first 20 minutes of treatment, along with two unit doses of ipratropium bromide (1,000 mcg) in the first hour of nebulization therapy. Spirometry was performed at baseline and after each hour of bronchodilator treatment until the child was discharged home or admitted to an inpatient unit. If clinically indicated, a second continuous nebulization with the same drug used in the first treatment was given.

Duration

Follow-up: 30 days post-discharge 

Outcome Measures

Primary: percent change in the FEV1 and the asthma scores from baseline

Secondary: percent changes in heart rate (HR), respiratory rate (RR), oxygen saturation, and hospitalization rates

Baseline Characteristics

Albuterol (n= 44)

Levalbuterol (n= 57)

Age, years

Male 

Ethnicity 

Hispanic

African-Amerian

Caucasian

59.1%

22.7%

11.4%

57.9%

22.8%

17.5%

Mean initial asthma score^#*

Mean initial FEV1

Home Medications

Albuterol

Last 24 hours^*

Levalbuterol

Last 24 hours 

Inhaled steroids

Leukotriene receptor antagonist

Long-acting β-agonist

Total previous admissions

90.9% 

3.3 ± 3.3

4.65%

0.07 ± 0.46

31.8%

16.3%

11.6%

1

98.3%

4.7 ± 3.3

5.4%

0.27 ± 1.4

42.1%

22.8%

19.6%

2

^#Calculated based on respiratory rate, oxygen saturation, auscultation, retractions, and dyspnea; *p< 0.05

Results

Endpoint

Albuterol (n= 44)

Levalbuterol (n= 55)

p-value

Receiving first nebulizer

Change in FEV1 (n= 35)

Change in asthma score, %

Change in HR, beats/min

Change in RR, breaths/minutes

Change in O2 sat, %

55.2 (28.0, 75.7)

−30.3 (−39.2, −11.8)

7.56 (0.77, 18.0)

−1.5 (−18.8, 16.7)

1.6 (−2.1, 3.2) 

19.8 (14.4, 67.0)

−16.7 (−28.6, 0)

12.1 (6.3, 20.6)

−4.2 (−20.8, 9.1)

1.0 (−2.1, 2.1)

0.043

0.010

0.215

0.514

0.234

Admitted 

Intensive care unit 

30.95%

27.9%

29.1%

23.2%

0.843

0.594

Length of stay, days 

Fifty-six (56.6%) children required a second hour of continuous therapy; 24 (42.9%) were in the albuterol group. After receiving the second nebulizer, only change in asthma score (%) was significantly different between the albuterol(-35.4 [IQR -50 to -19.4]) and levalbuterol group (-16.7 [IQR -27.3 to 0]).  

*Numbers in parentheses are interquartile ranges (IQR) (25th percentile, 75th percentile). 

Adverse Events

Common Adverse Events (albuterol vs. levalbuterol): differences were not significantly different between the two groups 

Receiving first nebulizer: nausea (15.9% vs. 19.3%), vomiting (6.8% vs. 3.5%), headache (9.1% vs. 15.8%), jitteriness (50% vs. 42.1%)

Receiving second nebulizer: nausea (4.6% vs. 5.3%), vomiting (0 vs. 1.8%), headache (0 vs. 7%), jitteriness (25% vs. 24.6%) 

Study Author Conclusions

At the doses used, RAC appears to be superior to LEV with respect to changes in FEV1 and asthma score. There was no significant difference between the drugs with respect to admission rates or side-effect profiles.

InpharmD Researcher Critique

As the study was potentially underpowered due to the inability to perform adequate spirometry in some children, small differences in certain efficacy outcomes and side effects could not be detected.