Correspondence regarding, "The Cost Effectiveness of Levalbuterol Versus Racemic Albuterol"

TO THE EDITOR

In a July 2004 supplement, Dr. Quinn concludes that levalbuterol (LEV) represents a clinically important and cost-effective advance over racemic albuterol (RA) in the management of asthma.¹ I believe that these conclusions are premature and are not supported by the 4 primary studies discussed by the author.

The study by Milgrom et al is offered as evidence that LEV is clinically superior to RA in the treatment of chronic stable asthma.² In fact, this study compared LEV to placebo and RA to placebo; there was no direct comparison of LEV and RA. The conclusion by these authors that LEV was superior to RA is not possible given their study design. Even if this conclusion was true, there is no evidence that the improved forced expiratory volume after 1 second (FEV¹) seen with LEV led to a decrease in emergency department (ED) visits or hospital admissions. In addition, other studies comparing LEV to RA in adults with chronic stable asthma have found no difference in peak FEV¹ after 4 weeks use of the respective drug.³

The study by Nowak et al is cited as evidence that LEV (more than RA) decreases the need for hospital admission among adult patients presenting to the ED with acute asthma.⁴ While it is true that the patients treated with LEV had a more dramatic improvement in FEV¹ compared with patients treated with RA, patient outcome was not improved in a similar manner. Dr Quinn states in the table on page S155 that the Nowak study showed a decrease in the need for hospital admission among the subset of patients treated with LEV. In fact the opposite was true. Only 1/27 (4%) of patients treated with RA required hospital admission compared with 7/64 (11%) of patients treated with LEV.

The study by Carl et al is presented as further evidence that LEV results in fewer admissions for acute asthma compared with RA.⁵ The admission rates for asthmatic children in this study treated with LEV and RA were 37% and 45%, respectively. These admission rates are 5-10 times higher than what is normally encountered in most clinical settings. This is because at the institution at which the study was done, a disposition decision had to be made no more than 2 hours after arrival to the ED. This is dramatically different than the treatment of asthma at most EDs. Had treatment been allowed to continue in the ED beyond 2 hours, it is likely that the admission rates would have been lower. How LEV and RA would have affected admission rates beyond 2 hours is unclear. It is impossible to extrapolate the results of this study to the vast majority of US hospitals, in which ED care frequently extends beyond 2 hours.

Finally, the study by Truitt et al is cited as evidence that patients hospitalized with chronic obstructive pulmonary disease (COPD) or asthma have a shorter length of stay and fewer readmissions to the hospital if they are treated with LEV compared with RA.⁶ On the surface, it is difficult to believe these conclusions. Beta agonists provide only symptomatic relief to patients hospitalized with asthma or COPD, not a "cure." Corticosteroids, not beta agonists, are the cornerstone of therapy for such patients. In the Truitt study, almost no information is given on when patients got steroids, how much was given and for how long. Likewise, the notion that any beta agonist given in the hospital (all of which have a short duration of action) will impact the 30-day readmission rate makes little sense. These points aside, the study suffers from numerous design flaws, which make it impossible to claim the superiority of one beta agonist over another. This was a retrospective, non-blinded study, funded by the manufacturer of LEV. No information is given on how many patients were excluded from the study or for what reasons. The number of asthmatic patients included is so small as to invalidate any conclusion about this disease. Finally, vital information about the primary confounder, the use of corticosteroids, is not provided.

In conclusion, there is no convincing evidence that LEV is clinically superior to or more cost effective than RA. Documented improvements in pulmonary function with LEV have not been accompanied by similar improvements in clinical outcomes or decreased utilization of resources. Until larger, better-designed studies can prove clinical benefits to justify the higher cost of LEV (5-10 times the cost of RA), the use of this drug is not warranted. For now, RA remains the drug of choice for managing asthma.

Alan L. Weiner, MDDepartment of Emergency Medicine

Meriden, Conn

1. Quinn C. The cost effectiveness of levalbuterol versus racemic albuterol. Am J Manag Care. 2004;10:S153-S157.

2. Milgrom H, Skoner DP, Bensch G, et al for the Levalbuterol Pediatric Study Group. Low dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol. J Allergy Clin Immunol. 2001;109:938-945.

3. Nelson HS, Bensch G, Pleskow WW, et al. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol. 1998;102:943-952.

4. Nowak RM, Emerman CL, Schaefer K, Disantostefano RL, Vaickus L, Roach JM. Levalbuterol compared with racemic albuterol in the treatment of acute asthma: results of a pilot study. Am J Emerg Med. 2004;22:29-36.

5. Carl JC, Myers TR, Kirshner HL, Kercsmar CM. Comparison of racemic albuterol and levalbuterol in the treatment of acute asthma. J Pediatr. 2003;143:731-736.

6. Truitt T, Witko J, Halpern M. Levalbuterol compare to racemic albuterol: efficacy and outcomes in patients hospitalized with COPD or asthma. Chest. 2003;123;128-135.

IN REPLY

I thank Dr. Weiner for his comments. To address the issues he raised, the study by Milgrom et al did compare all 5 regimens (levalbuterol [LEV] 0.31 and 0.63 mg, racemic albuterol [RAC] 1.25 and 2.5 mg, and placebo), and reported that the improvement in FEV¹ was significantly better with LEV at either dose than with RAC 1.25 mg.¹ Dr. Weiner is correct in pointing out that this measure does not necessarily translate into decreased need for emergency treatment or hospital admission; the study did not address that topic.

Similarly, the study by Nowak et al did not specifically address patient disposition.² However, the rate of hospitalization as presented by Dr. Weiner requires some clarification. As my article noted, the outcome with the 3.75-mg dose of LEV was inexplicably poorer than at higher and lower dose levels. In the other LEV groups, the combined rate of hospitalization was 3/50 (6%), which is consistent with the low rate seen in the patients who received RAC. Moreover, even if we include the 3.75-mg LEV group, the proportion of patients discharged after 3 treatments was higher with LEV than with RAC (71.9% vs 55.6%) while the proportion requiring additional therapy during the poststudy observation period was lower (17.2% vs 37.0%). Dr. Weiner is correct about the wording in the table in my article; the entry for the Nowak study should have indicated a potential reduction in the need for hospitalization, which is what the investigators concluded.

With respect to the study by Carl et al,³ my article simply reported his findings of the theoretical savings that would accrue from reduced hospitalization with LEV versus RAC based on responses within the 2-hour window specified. Although that timeframe may, as Dr. Weiner indicates, be shorter than the typical emergency department stay for patients with asthma, it is not inconsistent with the general recommendations of the NIH Expert Panel Report 2, Guidelines for the Diagnosis and Management of Asthma.⁴

The asthma and COPD patients in the study by Truitt et al⁵ all received corticosteroids in addition to LEV or RAC; as it was a retrospective chart review, the dosage regimens of corticosteroids were not specified, but there is no reason to assume that usage varied from accepted standards of care. The study included 54 patients with asthma, which does not seem remarkably small. The major criticism relates to the retrospective design, which was noted in my article. Despite its corporate funding and retrospective design, this study was accepted for publication by a highly respected journal in the field of pulmonary medicine.

Finally, Dr. Weiner says that it would be premature to recommend routine substitution of LEV for RAC, and I agree. My article made no such recommendation, but rather pointed out that LEV offers a theoretical advantage as the R eniantiomer of albuterol; that short-term studies suggest some clinical advantage and potential cost savings; and that longer follow-up studies are still needed.

Campion Quinn, MDRockville Centre, New York

J Allergy Clin Immunol.

1. Milgrom H, Skoner DP, Bensch G, et al for the Levalbuterol Pediatric Study Group. Low dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol. 2001;109:938-945.

Am J Emerg Med.

2. Nowak RM, Emerman CL, Schaefer K, Disantostefano RL, Vaickus L, Roach JM. Levalbuterol compared with racemic albuterol in the treatment of acute asthma: results of a pilot study. 2004;22:29-36.

J Pediatr.

3. Carl JC, Myers TR, Kirshner HL, Kercsmar CM. Comparison of racemic albuterol and levalbuterol in the treatment of acute asthma. 2003;143:731-736.

National Asthma Education and Prevention Program Expert Panel Report 2:

Guidelines for the Diagnosis and Management of Asthma.

4. NIH Publication No. 97-4051; July 1997:110-116.

Chest.

5. Truitt T, Witko J, Halpern M. Levalbuterol compare to racemic albuterol: efficacy and outcomes in patients hospitalized with COPD or asthma. 2003;123;128-135.

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