Albuterol is a selective β2-agonist that is widelyused in the prevention and treatment of reactive airwaydisease. It is formulated as a racemic mixturecontaining equal parts of the R- and S-isomers. Thetherapeutic activity of albuterol is due entirely to theR-isomer, whereas the S-isomer may actually havedetrimental effects. Because the slowly metabolizedS-isomer tends to accumulate in the body, there hasbeen concern that chronic use of racemic albuterolmight lead to loss of effectiveness and clinical deterioration,with potentially serious health and costconsequences. Levalbuterol is a formulation containingonly the R-isomer of albuterol, and clinicaltrials have demonstrated that it offers therapeuticadvantages over racemic albuterol. The cost effectivenessof levalbuterol derives mainly from reducedneed for acute medical care and hospitalization.
(Am J Manag Care. 2004;10:S153-S157)
Asthma is a serious, common, andgrowing health problem in the UnitedStates. During the period 2000-2001,20.3 million Americans, including 6.3 millionchildren and adolescents, reported havingasthma. In these patients, the annual tollattributed to asthma included 12 millionacute attacks, over 10 million outpatient visitsof which almost 2 million were to emergencydepartments, almost a half-millionhospitalizations, and nearly 5000 deaths.1
Moreover, the burden of asthma has beengrowing steadily in all age/sex/ethnic groups.The age-adjusted prevalence rose from 30.7per 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 overallprevalence is higher and the increasesince 1980 has been steeper.2 A study examininghealth claims and prescription data forthe year 1987 noted the following: whencompared to a cohort of nonasthmatic children,children with asthma accounted for3.1 times as many prescriptions, 1.9 timesas many outpatient visits, 2.2 times as manyemergency department visits, 3.5 times asmany hospitalizations, and 2.8 times themean total medical expenditure.3 For theAmerican population in general, total annualasthma-related costs were estimated at$11.3 billion in 1992 and $14 billion in a2002 report.4 Asthma accounts for 14 millionlost school days for pediatric patientsand 14.5 million lost work days for adults.5
Costs associated with hospitalizationsare the most expensive element in acuteasthma management. One positive developmentis that the rate of hospitalization isdecreasing; therefore, the cost of hospitalizationrepresents a declining percentage oftotal direct medical expenditures.6 Thischange is due, in large measure, to improvedpharmacotherapy.
One class of drugs–short-acting β2-agonists–has emerged as the mainstay of acuteasthma management. Albuterol has been themost widely used agent of this class.
In this report, we compare the β2-agonistslevalbuterol and albuterol in terms of pharmacology,clinical profile, and cost effectiveness.
Beta-Agonists: A History of IncreasingRefinement of Pharmacologic Effects
Beta-adrenergic agonist activity hasnumerous therapeutic benefits in asthmamanagement, including relaxation ofbronchial smooth muscle, reduction in airwayreactivity to spasmogens, decreasedinflammation, diminished mucosal edema,and improved mucociliary activity toremove allergens and clear the airways.
The first commercial product offering β-agonist activity was synthetic epinephrine.Although it is therapeutically effective, italso produces α-adrenergic effects such asincreased heart rate, hypertension, and agitation.Eventually, its clinical role in asthmatreatment was restricted to emergency carefor acute episodes.Isoproterenol offered β-agonist activitywithout α activity, but it neverthelessincurred a substantial risk of cardiac sideeffects. The reason is that its β activity isnonselective–β2 activity provides the therapeuticeffects in asthma treatment, whereasβ1 activity causes increases in heart rate andcontractility.7
Albuterol was the first agent offeringselective β2 activity. However, like all theearlier synthetic β-agonists, albuterol is aracemic mixture of R- and S-enantiomers.Although the R- and S-isomers are chemicallyidentical, they may have profoundlydifferent physiologic effects. The therapeuticeffects in relieving asthma are deliveredentirely by the R-isomer of albuterol.
This process of increasing refinement ofpharmacologic effect reached what may beits logical conclusion with levalbuterol, aselective β2-agonist formulated as the pureR-isomer. In 1999, levalbuterol was approvedin doses of 0.63 and 1.25 mg for patientsaged 12 years and up; in 2002, it wasapproved in doses of 0.31 and 0.63 mg forchildren aged 6 through 11.
The binding of the R-isomer of a β2-agonistto airway smooth muscle receptors activatesadenylcyclase and increases cyclic adenosinemonophosphate, with 2 effects: (1) loweringof intracellular calcium, leading tomuscle relaxation; and (2) inhibiting therelease of inflammatory mediators from airwaymast cells. These bronchodilatory andprotective effects occur throughout the airwaysystem, regardless of the spasmogenictrigger.
The S-isomer of racemic albuterol waslong assumed to be pharmacologically inert.However, evidence now suggests that it maycause bronchoconstriction, increased airwayhyperreactivity, and increases ineosinophil activity and histamine production.These effects compromise the therapeuticactivity of the R-isomer, as demonstratedby research showing that levalbuterol ismore effective than racemic albuterol indoses containing the same amount of theR-isomer.8
In addition, because metabolism of the Sisomeris much slower than that of the R-isomer,ongoing treatment with racemicalbuterol can lead to an accumulation of theS-isomer. The potential clinical result wouldbe gradually diminishing effectiveness,marked by shorter intervals between treatments,a smaller response to treatment, andeven a risk of paradoxical bronchospasm.However, clinical studies have shown inconsistentresults concerning detrimental effectsfrom chronic use of racemic albuterol.
Levalbuterol is not free of side effects.β2-receptors are found mainly in the vascularsystem. The main clinical effect of β2-agonist activity on the cardiovascular systemis peripheral vasodilation, which may cause areflex increase in heart rate; however, thetherapeutic improvement in pulmonary functionmay have the effect of reducing heartrate,7 and the effects of an agonist at thesesites are dose-dependent with both levalbuteroland racemic albuterol.
Clinical and Cost Effectiveness
The literature directly comparing levalbuteroland racemic albuterol in terms ofcost effectiveness is limited but compelling.Cost effectiveness can also be inferred fromclinical data showing a reduced need forhospitalization (Table). Although medicationaccounts for the greatest portion ofdirect medical costs for asthma managementon a population basis,6 those patients who requirehospitalization incur greatly increasedcosts.
In a randomized, double-blind trial,Milgrom et al9 treated 338 asthmatic children(ages 4-11, FEV1 [forced expiratoryvolume in 1 second] 40%-85% of expectednormal) with 3-times-daily doses of nebulizedlevalbuterol (0.31 or 0.63 mg),racemic albuterol (1.25 or 2.5 mg), orplacebo for 21 days. Immediately after nebulization,median improvements in FEV1were 2% with placebo, 19% and 18.1% withlevalbuterol 0.31 and 0.63 mg, and 12.4%and 15.6% with racemic albuterol 1.25 and2.5 mg.
Both doses of levalbuterol providedgreater bronchodilation compared withracemic albuterol 1.25 mg ( <.05), andhigher doses of levalbuterol were more effectivein the subset of patients with moreseverely depressed FEV1 at baseline.
In an open-label dose-escalation trial,Nowak et al10 sequentially assigned 91 asthmaticpatients (mean age 33, median baselineFEV1 1.2 L or 39% of predicted) tolevalbuterol 0.63, 1.25, 2.5, 3.75, or 5.0 mg,or racemic albuterol 2.5 or 5.0 mg; treatmentswere given in 3 nebulized doses, 20minutes apart. Median improvement inFEV1 after the first dose was 56% with levalbuterol1.25 mg versus 5% and 14% withracemic albuterol 2.5 and 5.0 mg. Betterresults were observed with levalbuterol1.25, 2.5, and 5.0 mg (final median FEV12.1-2.3 L) than with levalbuterol 0.63 and3.75 mg and both doses of racemic albuterol(1.5-1.8 L; the relatively poor performanceof the 3.75-mg formulation of levalbuterolis difficult to explain). In patients with verylow baseline FEV1, the improvement was 10times greater with levalbuterol than withracemic albuterol (75% vs 3.2%-7.5%),which is important because lack ofimprovement in FEV1 is associated with anincreased likelihood of hospitalization.
In children with asthma, FEV1 valueswere comparable after treatment with levalbuterol0.31 and 0.63 mg and racemicalbuterol 2.5 mg; in children treated withlevalbuterol 1.25 mg, FEV1 values were superiorto those in children treated with racemicalbuterol.11 Another retrospective comparativestudy showed that the rate of hospitalizationfollowing treatment for acute asthma wassignificantly lower with levalbuterol than withracemic albuterol (5% vs 15%; <.002).12
Both levalbuterol and racemic albuterolare generally well tolerated by asthmaticpatients.8 Some reports indicate that levalbuterolhas fewer β2-mediated side effects.9,11
The cost effectiveness of averting hospitalizationfor asthma was demonstrated dramaticallyin the double-blind study by Carlet al,13 in which 482 children aged 1 to 18years were assigned to levalbuterol 1.25 mgor racemic albuterol 2.5 mg administeredevery 20 minutes to a maximum of 6 dosesin 2 hours. Patients having an inadequate responseafter 2 hours would then be admitted.There were significantly fewer hospitalizationswith levalbuterol than with racemicalbuterol (37% vs 45%; = .02), and thenumber needed to treat with levalbuterol toavert a hospitalization was 10.6 patients. Atthe study institution (an urban tertiary-carechildren's hospital), a 9% reduction in theannual average of 1000 hospitalizations forasthma would save $180 000 minus theadditional drug acquisition costs for levalbuterol($1.25/vial x 4 vials/patient = $5/patient).
Another noteworthy cost-effectivenessanalysis was a retrospective study by Truittet al.14 Among patients hospitalized for asthmaor chronic obstructive pulmonary disease(COPD), charts were reviewed from125 patients treated with racemic albuterol0.5 mg at 4-hour intervals (July-December1998) and from 109 patients treated withlevalbuterol 1.25 mg at 8-hour intervals(July-December 1999). Injected corticosteroidswere given to almost all patients; allCOPD patients and asthma patients withinfection also received antibiotics, and ipratropiumwas used as needed. Medication andother hospital costs were calculated usingMedicare reimbursement rates and 1999Red Book listings of wholesale drug costs.The goal was to assess the amount and costof treatment needed to achieve comparabletherapeutic benefit (improvement in FEV1sufficient for discharge) with each drug.
The lower mean number of treatmentswith levalbuterol versus racemic albuterol(19.0 vs 30.8; <.001) was partly due to protocol-mandated differences in the dosingschedules. (A published letter challengedthe study on this basis and also for usingaverage wholesale prices, which may bedifferent from what hospitals actually pay.The study investigators responded that theneed for more frequent dosing with racemicalbuterol than with levalbuterol to achievean adequate clinical response was the verypoint of the study, and that average wholesaleprices are standard in cost analyses.15)However, the protocol did not account forthe fact that the mean duration of β2-agonisttreatment was 29% shorter with levalbuterolthan with racemic albuterol (5.5 vs 3.9days), or that patients receiving levalbuterolversus racemic albuterol required feweradjunctive treatments with ipratropium(mean 9.4 vs 23.2; <.001) and had a lower30-day rehospitalization rate (mean 5.7% vs16.4%; = .01). This difference was notedmainly in the subset of patients with COPD,and other factors may have affected the riskof readmission. Overall costs for deliveringnebulized medications were significantlylower with levalbuterol than with racemicalbuterol (for all patients $61 vs $112, <.001; among asthma patients, $44 vs $99, <.005). Total hospital costs were numericallylower (for all patients $2756 vs$3225, = .11; among asthma patients,$1856 vs $2503). Regression analysis controllingfor baseline FEV1, diagnosis, andipratropium use showed that levalbuterolwas associated with a 0.9-day shorter stay( = .015), a 67% lower rate of rehospitalization( = .056), and total cost savings of$556 per patient ( = .013).
The Economics of Asthma Care
Assessing the costs of asthma and itstreatment, and the cost effectiveness of specifictherapies, is a daunting task. A reviewby Sculpher and Price16 outlines several ofthe difficulties, starting with the fact thatlooking at total direct and indirect costs doesnot address the disproportionate share ofcosts incurred by patients with severe asthmaor the unnecessary costs attributable tosuboptimal management. Moreover, publishedreports employ such a variety of methods,outcome measures, and definitions thattheir findings are difficult to compile andcompare. Finally, most cost-effectivenessdata emerge from short-term studies of clinicalefficacy, safety, and tolerability, and suchfindings are not necessarily predictive oflong-term outcomes.
In an attempt to sort out the numerousvariables that must be considered in allclinical-economic evaluations of drugs,Eisenberg and colleagues17 proposed a 3-dimensional model: (1) type of analysis (costidentification, cost effectiveness, cost benefit);(2) point of view (patient, clinician,insurer, society); and (3) types of outcomemeasures (direct and indirect costs, morbidityand mortality, intangible or unquantifiableresults). For example, quantifiableclinical outcomes are usually of most interestto physicians, less readily quantifiableoutcomes such as quality of life reflect thepatient's point of view, while cost-effectivenessanalyses aimed at obtaining the bestclinical outcome at the lowest cost are ofgreatest concern to managed care, insurers,and government.
Applying this model to asthma, the economiccomparison of levalbuterol versusracemic albuterol involves cost-effectivenessanalysis from the point of view of the clinicianand the insurer, with the focus ondirect medical costs. Yet further definition isnecessary; for example, pharmacy servicesmay focus only on drug acquisition costs,but the overall cost to the medical facilityand insurer may be more strongly affected bysuch clinical outcomes as needed for hospitalization.In the previously cited pediatricstudy,13 the number needed to treat (withlevalbuterol instead of racemic albuterol) toavert a hospitalization was only 10.6patients; the incremental cost of levalbuterolfor such a small number of patientsis minuscule compared with the cost of a singlehospitalization.
Most studies that reflect the interests ofthe clinical audience have focused on objectivemeasures of efficacy, such as FEV1.However, efficacy in the ideal setting of awell-designed clinical trial is not the same aseffectiveness in the real-world setting ofactual clinical practice. For example, howshould a worsening FEV1 be interpreted inclinical practice? Assuming adequate adherenceto treatment, it may be difficult todetermine whether the patient's condition isbecoming more severe or the drug is losingits effectiveness. With the latter possibility,loss of effectiveness may be an intrinsicproblem with the drug or the result of somethingelse happening in that patient, such asa drug interaction that induces increasedmetabolism of the asthma medication.
Just as it is difficult to gauge the overalltherapeutic worth of an asthma drug fromchanges in FEV1 in a short-term controlledclinical trial, it is difficult to assess a drug'scost effectiveness by looking only at directmedical expenditures recorded in that sametrial. A working group from the NationalHeart, Lung, and Blood Institute reviewedthe role of health economics in planningoptimal asthma management strategies,and offered a set of recommendations forfuture research, including adoption of standardizeddefinitions and outcome measures,a focus on long-term effectivenessrather than short-term efficacy, and controlsfor such variables as patients' age andsocioeconomic status, and the duration andseverity of asthma.18
From the evidence currently available, itappears that levalbuterol represents a clinicallyimportant advance over racemicalbuterol. The advantage in clinical efficacy(ie, improved respiratory performance) ismatched by an advantage in cost effectiveness,which leads to a reduction in the needfor hospitalization. Long-term follow-up inthe clinical practice setting may determinethe degree to which these short-term advantagesare maintained.
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