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Shellie K. Schoening, MBA, PharmD, RPh
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The Cost Effectiveness of Levalbuterol Versus Racemic Albuterol
Campion Quinn, MD, FACP, MHA
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Grant H. Skrepnek, PhD, RPh; and Stan V. Skrepnek, MD
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Shellie K. Schoening, MBA, PharmD, RPh

The Cost Effectiveness of Levalbuterol Versus Racemic Albuterol

Campion Quinn, MD, FACP, MHA

Albuterol is a selective β2-agonist that is widely used in the prevention and treatment of reactive airway disease. It is formulated as a racemic mixture containing equal parts of the R- and S-isomers. The therapeutic activity of albuterol is due entirely to the R-isomer, whereas the S-isomer may actually have detrimental effects. Because the slowly metabolized S-isomer tends to accumulate in the body, there has been concern that chronic use of racemic albuterol might lead to loss of effectiveness and clinical deterioration, with potentially serious health and cost consequences. Levalbuterol is a formulation containing only the R-isomer of albuterol, and clinical trials have demonstrated that it offers therapeutic advantages over racemic albuterol. The cost effectiveness of levalbuterol derives mainly from reduced need for acute medical care and hospitalization.

(Am J Manag Care. 2004;10:S153-S157)

Asthma is a serious, common, and growing health problem in the United States. During the period 2000-2001, 20.3 million Americans, including 6.3 million children and adolescents, reported having asthma. In these patients, the annual toll attributed to asthma included 12 million acute attacks, over 10 million outpatient visits of which almost 2 million were to emergency departments, almost a half-million hospitalizations, and nearly 5000 deaths.1

Moreover, the burden of asthma has been growing steadily in all age/sex/ethnic groups. The age-adjusted prevalence rose from 30.7 per 1000 in 1980 to 53.8 per 1000 as the 2-year average for 1993-1994–a 75% increase. Among children aged 5 to 14 years, the overall prevalence is higher and the increase since 1980 has been steeper.2 A study examining health claims and prescription data for the year 1987 noted the following: when compared to a cohort of nonasthmatic children, children with asthma accounted for 3.1 times as many prescriptions, 1.9 times as many outpatient visits, 2.2 times as many emergency department visits, 3.5 times as many hospitalizations, and 2.8 times the mean total medical expenditure.3 For the American population in general, total annual asthma-related costs were estimated at $11.3 billion in 1992 and $14 billion in a 2002 report.4 Asthma accounts for 14 million lost school days for pediatric patients and 14.5 million lost work days for adults.5

Costs associated with hospitalizations are the most expensive element in acute asthma management. One positive development is that the rate of hospitalization is decreasing; therefore, the cost of hospitalization represents a declining percentage of total direct medical expenditures.6 This change is due, in large measure, to improved pharmacotherapy.

One class of drugs–short-acting β2-agonists– has emerged as the mainstay of acute asthma management. Albuterol has been the most widely used agent of this class.

In this report, we compare the β2-agonists levalbuterol and albuterol in terms of pharmacology, clinical profile, and cost effectiveness.

Beta-Agonists: A History of Increasing Refinement of Pharmacologic Effects

Beta-adrenergic agonist activity has numerous therapeutic benefits in asthma management, including relaxation of bronchial smooth muscle, reduction in airway reactivity to spasmogens, decreased inflammation, diminished mucosal edema, and improved mucociliary activity to remove allergens and clear the airways.

The first commercial product offering β-agonist activity was synthetic epinephrine. Although it is therapeutically effective, it also produces α-adrenergic effects such as increased heart rate, hypertension, and agitation. Eventually, its clinical role in asthma treatment was restricted to emergency care for acute episodes. Isoproterenol offered β-agonist activity without α activity, but it nevertheless incurred a substantial risk of cardiac side effects. The reason is that its β activity is nonselective–β2 activity provides the therapeutic effects in asthma treatment, whereas β1 activity causes increases in heart rate and contractility.7

Albuterol was the first agent offering selective β2 activity. However, like all the earlier synthetic β-agonists, albuterol is a racemic mixture of R- and S-enantiomers. Although the R- and S-isomers are chemically identical, they may have profoundly different physiologic effects. The therapeutic effects in relieving asthma are delivered entirely by the R-isomer of albuterol.

This process of increasing refinement of pharmacologic effect reached what may be its logical conclusion with levalbuterol, a selective β2-agonist formulated as the pure R-isomer. In 1999, levalbuterol was approved in doses of 0.63 and 1.25 mg for patients aged 12 years and up; in 2002, it was approved in doses of 0.31 and 0.63 mg for children aged 6 through 11.

Pharmacology

The binding of the R-isomer of a β2-agonist to airway smooth muscle receptors activates adenylcyclase and increases cyclic adenosine monophosphate, with 2 effects: (1) lowering of intracellular calcium, leading to muscle relaxation; and (2) inhibiting the release of inflammatory mediators from airway mast cells. These bronchodilatory and protective effects occur throughout the airway system, regardless of the spasmogenic trigger.

The S-isomer of racemic albuterol was long assumed to be pharmacologically inert. However, evidence now suggests that it may cause bronchoconstriction, increased airway hyperreactivity, and increases in eosinophil activity and histamine production. These effects compromise the therapeutic activity of the R-isomer, as demonstrated by research showing that levalbuterol is more effective than racemic albuterol in doses containing the same amount of the R-isomer.8

In addition, because metabolism of the Sisomer is much slower than that of the R-isomer, ongoing treatment with racemic albuterol can lead to an accumulation of the S-isomer. The potential clinical result would be gradually diminishing effectiveness, marked by shorter intervals between treatments, a smaller response to treatment, and even a risk of paradoxical bronchospasm. However, clinical studies have shown inconsistent results concerning detrimental effects from chronic use of racemic albuterol.

Levalbuterol is not free of side effects. β2-receptors are found mainly in the vascular system. The main clinical effect of β2-agonist activity on the cardiovascular system is peripheral vasodilation, which may cause a reflex increase in heart rate; however, the therapeutic improvement in pulmonary function may have the effect of reducing heart rate,7 and the effects of an agonist at these sites are dose-dependent with both levalbuterol and racemic albuterol.

Clinical and Cost Effectiveness

The literature directly comparing levalbuterol and racemic albuterol in terms of cost effectiveness is limited but compelling. Cost effectiveness can also be inferred from clinical data showing a reduced need for hospitalization (Table). Although medication accounts for the greatest portion of direct medical costs for asthma management on a population basis,6 those patients who require hospitalization incur greatly increased costs.



In a randomized, double-blind trial, Milgrom et al9 treated 338 asthmatic children (ages 4-11, FEV1 [forced expiratory volume in 1 second] 40%-85% of expected normal) with 3-times-daily doses of nebulized levalbuterol (0.31 or 0.63 mg), racemic albuterol (1.25 or 2.5 mg), or placebo for 21 days. Immediately after nebulization, median improvements in FEV1 were 2% with placebo, 19% and 18.1% with levalbuterol 0.31 and 0.63 mg, and 12.4% and 15.6% with racemic albuterol 1.25 and 2.5 mg.

Both doses of levalbuterol provided greater bronchodilation compared with racemic albuterol 1.25 mg (P <.05), and higher doses of levalbuterol were more effective in the subset of patients with more severely depressed FEV1 at baseline.

In an open-label dose-escalation trial, Nowak et al10 sequentially assigned 91 asthmatic patients (mean age 33, median baseline FEV1 1.2 L or 39% of predicted) to levalbuterol 0.63, 1.25, 2.5, 3.75, or 5.0 mg, or racemic albuterol 2.5 or 5.0 mg; treatments were given in 3 nebulized doses, 20 minutes apart. Median improvement in FEV1 after the first dose was 56% with levalbuterol 1.25 mg versus 5% and 14% with racemic albuterol 2.5 and 5.0 mg. Better results were observed with levalbuterol 1.25, 2.5, and 5.0 mg (final median FEV1 2.1-2.3 L) than with levalbuterol 0.63 and 3.75 mg and both doses of racemic albuterol (1.5-1.8 L; the relatively poor performance of the 3.75-mg formulation of levalbuterol is difficult to explain). In patients with very low baseline FEV1, the improvement was 10 times greater with levalbuterol than with racemic albuterol (75% vs 3.2%-7.5%), which is important because lack of improvement in FEV1 is associated with an increased likelihood of hospitalization.

In children with asthma, FEV1 values were comparable after treatment with levalbuterol 0.31 and 0.63 mg and racemic albuterol 2.5 mg; in children treated with levalbuterol 1.25 mg, FEV1 values were superior to those in children treated with racemic albuterol.11 Another retrospective comparative study showed that the rate of hospitalization following treatment for acute asthma was significantly lower with levalbuterol than with racemic albuterol (5% vs 15%; P <.002).12

Both levalbuterol and racemic albuterol are generally well tolerated by asthmatic patients.8 Some reports indicate that levalbuterol has fewer β2-mediated side effects.9,11

The cost effectiveness of averting hospitalization for asthma was demonstrated dramatically in the double-blind study by Carl et al,13 in which 482 children aged 1 to 18 years were assigned to levalbuterol 1.25 mg or racemic albuterol 2.5 mg administered every 20 minutes to a maximum of 6 doses in 2 hours. Patients having an inadequate response after 2 hours would then be admitted. There were significantly fewer hospitalizations with levalbuterol than with racemic albuterol (37% vs 45%; P = .02), and the number needed to treat with levalbuterol to avert a hospitalization was 10.6 patients. At the study institution (an urban tertiary-care children's hospital), a 9% reduction in the annual average of 1000 hospitalizations for asthma would save $180 000 minus the additional drug acquisition costs for levalbuterol ($1.25/vial x 4 vials/patient = $5/patient).

Another noteworthy cost-effectiveness analysis was a retrospective study by Truitt et al.14 Among patients hospitalized for asthma or chronic obstructive pulmonary disease (COPD), charts were reviewed from 125 patients treated with racemic albuterol 0.5 mg at 4-hour intervals (July-December 1998) and from 109 patients treated with levalbuterol 1.25 mg at 8-hour intervals (July-December 1999). Injected corticosteroids were given to almost all patients; all COPD patients and asthma patients with infection also received antibiotics, and ipratropium was used as needed. Medication and other hospital costs were calculated using Medicare reimbursement rates and 1999 Red Book listings of wholesale drug costs. The goal was to assess the amount and cost of treatment needed to achieve comparable therapeutic benefit (improvement in FEV1 sufficient for discharge) with each drug.

 
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