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Communications to the Editor |

Levalbuterol Is Not More Cost-Effective Than Albuterol for COPD FREE TO VIEW

Leslie Hendeles; Abraham Hartzema
Author and Funding Information

Affiliations: University of Florida Gainesville, FL,  Halifax Regional Hospital Halifax, NS, Canada Exponent Alexandria, VA

Correspondence to: Leslie Hendeles, PharmD, Professor, Pharmacy and Pediatrics, University of Florida, Gainesville, FL 32610-0486



Chest. 2003;124(3):1176. doi:10.1378/chest.124.3.1176
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Published online

To the Editor:

In a recent issue of CHEST, Truitt et al (January 2003)1 claimed that their retrospective chart review demonstrated that “levalbuterol afforded clinical and pharmacoeconomic advantages over racemic albuterol” in the treatment of hospitalized patients with COPD and asthma. The primary end point of the study was the total number of nebulizer treatments required. However, the target care path that was in operation during the historical cohort required albuterol to be administered every 4 h (six treatments per day), while in the current cohort levalbuterol was administered every 8 h (three treatments per day). Thus, the statistically significant difference in the primary end point was a result of differences in the care plans. There were no statistically significant differences in the number of extra treatments required by either cohort. Surprisingly, the reviewers missed this fatal flaw in the study design.

The combination of more treatments, by design, and an artificially higher cost basis for albuterol resulted in a spurious statistical difference for the total cost of nebulizer therapy. They used the “average wholesale price” (AWP), but no hospital pharmacy ever pays the AWP. For many hospitals, the acquisition cost of racemic albuterol is around $0.32 per 2.5-mg dose compared to $1.82 per 1.25 mg for an equivalent dose of levalbuterol (ie, a 5.7-fold difference). In contrast, the AWP for the two products are $1.21 and $2.08, respectively (a 1.7-fold difference).2

No conclusions can be drawn about clinical advantages since the treatments were not administered in a double-blind randomized manner. Moreover, in patients with COPD (about 80% of the patients), FEV1 did not significantly increase from hospital admission to hospital discharge in either cohort. In such patients, it is possible that dosing every 8 h with albuterol would be as effective as dosing every 4 h since these patients show little response to bronchodilators. Also, we are incredulous about the statement that levalbuterol “appeared to have a more prolonged therapeutic effect.” The basis for this statement was a difference in the hospital readmission rate, but since this was a retrospective chart review, other factors such as differences in hospital discharge medication (data not presented) may have affected this end point.

Last, “not significant” was designated as p > 0.1 when the convention is p > 0.05. As a consequence, the authors inferred that important pharmacoeconomic end points were different when they were not statistically different. For example, the authors state that those treated with levalbuterol “had shorter lengths of hospital stay” and “decreased costs for hospitalization,” but the p values for these end points for patients with COPD were 0.07 and 0.11, respectively.

We conclude that the differences between albuterol and levalbuterol in this study were a result of differences in the number of treatments required by the care plan, invalid cost calculations, and the emphasizing of numerical differences that were not statistically significant by conventional criteria.

Neither author has received money in the last 3 years from a competitor of Sepracor, the manufacturer of Xopenex.

The authors of this letter have been paid consultants to Sepracor, Inc.

Truitt, T, Witko, J, Halpern, M (2003) Levalbuterol compared to racemic albuterol; efficacy and outcomes in patients hospitalized with COPD and asthma.Chest123,128-135. [PubMed] [CrossRef]
 
Medical Economics Inc.. 2001 drug topics red book2001,170 Medical Economics Inc. Montvale, NJ: 571
 
To the Editor:

We welcome the opportunity to respond to the letters to the editor in CHEST regarding our recent article (January 2003).1 We agree with Dr. Crater that in retrospective studies, care must be taken to ensure that treatment groups are fully comparable. This is why we compared treatment with racemic albuterol and levalbuterol among patients with the same diagnosis codes, who had been treated at the same hospital, by the same pulmonologists, and during the same months of two sequential years. Furthermore, as indicated in the footnote to Table 1 of our article, there were no significant differences in age, gender distribution, racial distribution, percentage of patients hospitalized in the past year, steroid use, or hospital admission and discharge FEV1 and FVC levels between the levalbuterol and racemic albuterol groups. We also acknowledged and addressed the limitations of the study in the “Discussion” section of our article, including the limitations associated with a retrospective study performed at a single institution.

Dr. Crater expressed concern that one of the references cited in the manuscript (Reference 6) is a letter that was published in Lancet. However, research letters published in Lancet undergo peer review prior to publication. Furthermore, multiple other references cited in this article (References 7 to 14) present evidence from in vitro and animal studies of the detrimental effects of (S)-albuterol.

It is also correct that individuals with asthma comprised a greater proportion of those who received racemic albuterol compared with those who received levalbuterol (28% vs 17.9%, respectively). However, separate analyses were performed comparing patients with asthma to those with COPD in the two study populations. Length of hospitalization was 1 day less among patients with COPD and 1.2 days less among patients with asthma when treated with levalbuterol, although these differences were not significant (p = 0.097 and p = 0.07, respectively). The reduction in the need for nebulizer treatments among patients treated with levalbuterol vs those treated with racemic albuterol was greater for patients with asthma than for patients with COPD. Furthermore, as presented in Table 4, multivariate regressions controlling for diagnosis (ie, asthma vs COPD) indicated statistically significant impacts of levalbuterol treatment compared with racemic albuterol treatment on the length of hospitalization and the total costs. Finally, while the percent predicted FEV1 on hospital admission among patients with asthma was lower during the racemic albuterol treatment period compared with the levalbuterol treatment period (44.6% vs 48.6%, respectively), this difference was not statistically significant, as noted in the footnote of Table 2. Thus, the differences between the racemic albuterol and levalbuterol treatments presented in our study were not due to differences in the relative proportion of patients with asthma to those with COPD in each group.

We also reported that patients in the levalbuterol group had a reduction in the 30-day hospital readmission rate. As this was a finding present in the data, we thought that it would be inappropriate not to report it. However, we were careful not to attribute this finding to the in-hospital use of levalbuterol. While levalbuterol treatment may have been partially responsible for the reduction in 30-day hospital readmissions, we indicated that multiple post-hospital discharge factors that were not included in the medical charts, and therefore could not be evaluated, also might have affected hospital readmission.

Dr. Crater’s letter questioned the effectiveness of dosing every 8 h with racemic albuterol. While this is certainly a reasonable question, it is not the question our study addressed. We note that the Food and Drug Administration-approved prescribing information states that the usual starting dose of levalbuterol for patients ≥ 12 years of age is 0.63 mg administered three times per day (ie, every 6 or 8 h). Patients with more severe disease or those who do not respond adequately may benefit from a dosage of 1.25 mg tid. Although the label for racemic albuterol states that it should be administered three or four times a day by nebulization, in our clinical experience hospitalized patients require more frequent use (ie, every 3 to 4 h). In a pilot study that we conducted prior to our retrospective review,2 we found that despite treatment with racemic albuterol, 2.5 mg every 4 h, 25% of patients had breakthrough symptoms that required as-needed therapy. Thus, our results clearly indicated the advantages of treatment with levalbuterol compared with racemic albuterol for hospitalized patients with asthma and COPD.12

With respect to Dr. Crater’s comment on the introduction of levalbuterol therapy in a “real-world” context, patients were not asked whether they would accept this change of therapy. The use of levalbuterol every 8 h was instituted as the standard practice for the treatment of patients with asthma and COPD at Halifax Regional Hospital. By July 1, 1999, this regimen was the standard practice and was used on a routine basis. Thus, there was no patient discussion regarding a switch from therapy every 4 h to every 8 h, which could potentially bias their responses.

The comment of Drs. Hendeles and Hartzema that the statistically significant difference in the total number of nebulizer treatments was due to differences in care plans misses the point of our study. We clearly stated in our article that the purpose of our study was to evaluate the impact of levalbuterol therapy on clinical effectiveness, patient outcomes, and direct medical costs. We wanted to confirm that levalbuterol could be used in hospitalized patients at the labeled dosage of 1.25 mg tid without increasing the frequency of breakthrough symptoms. The fact that the use of levalbuterol resulted in significantly fewer total nebulizer treatments was the basis for our statement that “levalbuterol appeared to have a more prolonged therapeutic effect,” not the lower hospital readmission rates, as Dr. Hendeles claims. Parenthetically, we also suspect that the reviewers of our article would take exception to the notion that they missed a “fatal flaw” in the study design. Rather, we believe that these reviewers understood the study for what it was, and we thank them for their valuable comments and input. We are confident in the peer-review process as well as in the quality of the reviewers at CHEST.

Dr. Hendeles also criticized the use of average wholesale price (AWP) for medication costs in the analysis. We would first like to point out that, while savings in medications costs were noted, the greatest cost savings came from the reduction in hospital costs. Considering only medication acquisition costs fails to appreciate the total cost benefit one can achieve with appropriate therapy. In economic analyses, it is crucial to use a consistent standard for costs. This allows the comparison of results between studies. While we agree that AWP does not correspond to the cost paid for medications by many hospitals, in the United States it is a cost that often is used in analyses and is a well-accepted standard. For example, in the Format for Formulary Submissions, the Academy of Managed Care Pharmacy specifies the inclusion of AWP as part of the product information.3 The book by Gold et al,4 a standard reference for cost-effectiveness analysis, also specifies AWP as a source of information for pharmaceutical transaction prices. Dr. Hendeles provides acquisition costs of $0.32 and $1.82, respectively, for racemic albuterol and levalbuterol. However, there is no information on where these costs come from, what hospitals or populations they apply to, and whether they would be appropriate and relevant for our analysis or other analyses. Without additional information and the standardization of costs, an analysis using the values suggested by Dr. Hendeles would not be comparable to any other analysis and would have limited usefulness.

Dr. Hendeles criticizes our presentation of values for the statistical significance of results. Contrary to the statement of Dr. Hendeles that “‘not significant’ was designated at p > 0.1 when the convention is p > 0.05,” we did define statistical significance “based on an α value of 0.05 (two-tailed test)” (page 129), which is the standard definition used. As is common practice, and at the request of the reviewers, we did present p values that approached 0.05 to allow readers to interpret these results as they deemed appropriate, but we did not indicate that any of these results were “statistically significant.”

We understand that the question of improved efficacy of levalbuterol compared with racemic albuterol has been controversial,58 in part due to previous opinion pieces,56 in which Dr. Hendeles has expressed his view. While we welcome the letters to the editor as an opportunity to clarify issues of study design and results, we find the overall tone of the letters from Hendeles and Crater, particularly their titles, to be needlessly offensive.

We take responsibility for our results and note that Sepracor Inc did provide funding for data abstraction from medical charts (the actual abstraction was performed by hospital personnel) and for data analysis (which was conducted by Michael Halpern). We look forward to further discussion of this important topic.

References
Truitt, T, Witko, J, Halpern, M Levalbuterol compared to racemic albuterol: efficacy and outcomes in patients hospitalized with COPD or asthma.Chest2003;123,128-135. [PubMed] [CrossRef]
 
Truitt, TJ, Witko, J, Kotter, S, et al Levalbuterol reduces total and breakthrough treatments in hospitalized patients [abstract]. Am J Respir Crit Care Med. 2000;;161 ,.:A553
 
Academy of Managed Care Pharmacy. Format for formulary submissions, version 2.0. Available at: http://www.fmcpnet.org/data/resource/formatv20.pdf. Accessed July 28, 2003.
 
Gold, MR Siegel, JE Russell, LB Weinstein, MC eds. Cost-effectiveness in health and medicine. 1996; Oxford University Press. New York, NY:.
 
Asmus, MJ, Hendeles, L Levalbuterol nebulizer solution: is it worth five times the cost of albuterol?Pharmacotherapy2000;20,123-129. [PubMed]
 
Asmus, MJ, Hendeles, L, Weinberger, M, et al Levalbuterol has not been established to have therapeutic advantage over racemic albuterol [letter]. J Allergy Clin Immunol. 2002;;110 ,.:325. [PubMed]
 
Chowdhury, BA Comparative efficacy of levalbuterol and racemic albuterol in the treatment of asthma [letter]. J Allergy Clin Immunol. 2002;;110 ,.:324. [PubMed]
 
Milgrom, H, Skoner, D, Bensch, G, et al Author reply [letter].J Allergy Clin Immunol2002;110,325-328. [PubMed]
 

Figures

Tables

References

Truitt, T, Witko, J, Halpern, M (2003) Levalbuterol compared to racemic albuterol; efficacy and outcomes in patients hospitalized with COPD and asthma.Chest123,128-135. [PubMed] [CrossRef]
 
Medical Economics Inc.. 2001 drug topics red book2001,170 Medical Economics Inc. Montvale, NJ: 571
 
Truitt, T, Witko, J, Halpern, M Levalbuterol compared to racemic albuterol: efficacy and outcomes in patients hospitalized with COPD or asthma.Chest2003;123,128-135. [PubMed] [CrossRef]
 
Truitt, TJ, Witko, J, Kotter, S, et al Levalbuterol reduces total and breakthrough treatments in hospitalized patients [abstract]. Am J Respir Crit Care Med. 2000;;161 ,.:A553
 
Academy of Managed Care Pharmacy. Format for formulary submissions, version 2.0. Available at: http://www.fmcpnet.org/data/resource/formatv20.pdf. Accessed July 28, 2003.
 
Gold, MR Siegel, JE Russell, LB Weinstein, MC eds. Cost-effectiveness in health and medicine. 1996; Oxford University Press. New York, NY:.
 
Asmus, MJ, Hendeles, L Levalbuterol nebulizer solution: is it worth five times the cost of albuterol?Pharmacotherapy2000;20,123-129. [PubMed]
 
Asmus, MJ, Hendeles, L, Weinberger, M, et al Levalbuterol has not been established to have therapeutic advantage over racemic albuterol [letter]. J Allergy Clin Immunol. 2002;;110 ,.:325. [PubMed]
 
Chowdhury, BA Comparative efficacy of levalbuterol and racemic albuterol in the treatment of asthma [letter]. J Allergy Clin Immunol. 2002;;110 ,.:324. [PubMed]
 
Milgrom, H, Skoner, D, Bensch, G, et al Author reply [letter].J Allergy Clin Immunol2002;110,325-328. [PubMed]
 
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