Am Fam Physician. 2008;77(9):1214-1216
Author disclosure: Nothing to disclose.
Purpose
Each month, three presenters will review an interesting journal article in a conversational manner. These articles will involve “hot topics” that affect family physicians or will “bust” commonly held medical myths. The presenters will give their opinions about the clinical value of the studies discussed. The opinions reflect the views of the presenters, not those of AFP or the AAFP.
This Month's Article
Qureshi F, Zaritsky A, Welch C, Meadows T, Burke BL. Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med. 2005;46(1):29–36.
For children with acute asthma exacerbations, does levalbuterol work better or have fewer side effects than albuterol?
Bob: If you have not seen a big marketing push from your local drug reps on levalbuterol (Xopenex), you will very likely be targeted in the future (more about that later). But is levalbuterol really better than the traditional beta agonist, albuterol (Proventil), in children with acute exacerbations of asthma?
What does this article say?
Bob: This study is a prospective randomized trial of 129 children two to 14 years of age who presented to the emergency department with an acute exacerbation of asthma. One half of the children received nebulized albuterol, and the other half received levalbuterol. The doses chosen were weight based, and participants were eligible to receive up to five nebulization treatments.
What was the outcome? There was no difference between these agents in any effectiveness outcomes, including asthma scores, FEV1 measures, number of nebulizations required, respiratory rates, pulse oximetry readings, length of emergency department care, or hospitalization rates (Table 1).
Levalbuterol has been promoted to have fewer side effects than albuterol. But were fewer side effects noted with this agent? Absolutely not (Table 1).
| Outcomes/side effects | Albuterol (n = 64) | Levalbuterol (n = 65) |
|---|---|---|
| Median change in pulse rate* | ||
| After first nebulization | +8 bpm | +9 bpm |
| After third nebulization† | +21 bpm | +22 bpm |
| After fifth nebulization‡ | +18 bpm | +18 bpm |
| Median change in respiratory rate* | ||
| After first nebulization | –2 | –2 |
| After third nebulization† | –4 | –4 |
| After fifth nebulization‡ | –4 | –5 |
| Median change in pulse oximetry* | ||
| After first nebulization | +1 | +1 |
| After third nebulization† | +1 | +1 |
| After fifth nebulization‡ | –1 | +1 |
| Side effects | ||
| Tremulousness | 21 (33%) | 24 (37%) |
| Nausea and vomiting | 11 (17%) | 5 (8%) |
| Headache | 4 (6%) | 8 (12%) |
| Lightheadedness | 3 (5%) | 9 (14%) |
| Decreased potassium levels (< 3.0 mEq per L [< 3.0 mmol per L]) | 3 (5%) | 3 (5%) |
| Other§ | 1 (2%) | 1 (2%) |
Should we believe this study?
Bob: While there are a couple of minor limitations to this study, I believe it does get to the right answer. Why? Albuterol is composed of equal parts of a racemic mixture of R- and S-enantiomers; levalbuterol is composed of only the active R-enantiomer. Both agents contain an active ingredient, so there is no good reason why one should outperform the other. Some have postulated that the inactive S-enantiomer in albuterol may result in unwanted effects; however, this study debunks that theory.
Andrea: One limitation of this study is that most of the participants had moderate asthma, raising the question about whether the results would be similar in children with severe asthma. And because of the low hospitalization rate (13 percent), firm conclusions regarding this end point cannot be drawn. Another limitation is the relatively small sample size, making it possible that, if there was a clinically meaningful difference, there were too few study participants for it to be statistically significant.
But I agree with Bob; these are similar drugs and there is no reason why one would outperform the other. Many previous studies suggest that this is the case.1–3 The only discernible difference appears to be cost. Xopenex is more expensive than generic albuterol; it accounted for more than $500 million in sales in 2006.4,5
Mark: The “spin” that can be created to promote a drug is amazing. Part of this spin is a result of which studies actually get published. Companies are not knocking down doors to have negative studies published about their drugs. This is called publication bias. Studies are more likely to get submitted for publication if they show a company's drug in a good light. However, if you look at all of the studies submitted to the FDA (which I did), levalbuterol turns out to be no better than albuterol (e.g., no difference in effectiveness, side effects). In fact, plain old albuterol had a superior side effect profile in a number of the studies.
This trend of developing drugs that are simply an isomer of an existing drug is likely to boom as manufacturers attempt to replace drugs with expiring patents; it's all about market share. Just look at esomeprazole (Nexium) and omeprazole (Prilosec).
Bob: With regard to market share, the makers of Xopenex (Sepracor Inc.) are hoping to get out in front of the curve regarding the big change coming in metered-dose inhalers.
Currently, most of the 52 million annual prescriptions for albuterol are for metered-dose inhalers that contain chlorofluorocarbon (CFC) propellants. Because of the detrimental effects that CFC has on ozone levels, metered-dose inhalers containing CFC will be not be sold in the United States after 2008.6 An alternative propellant (hydrofluoroalkane [HFA]) that does not cause ozone depletion has been developed and incorporated into commercially available inhalers. Sepracor recently hired 500 additional drug representatives (for a total of 2,000 sales reps) and is planning a “relatively extensive sampling product recognition program” for Xopenex HFA.7 So physicians should expect to see many samples arriving at their offices in the near future as part of an expanded marketing campaign.
Mark: Samples are given to physicians for one reason—marketing. It has been clearly shown that samples will lead physicians to dispense and later prescribe brand name medications, even if these drugs were not the physician's preferred first-line choice.8 And while the physician may believe that distributing samples lowers costs for the patient, in reality, the long-term costs of using a brand name drug over a generic exceed any initial cost savings.
Andrea: If samples were not good business for the drug companies, the sample cabinet would be empty.
Bob: To read more about the detrimental effects of samples and other drug company freebies that ultimately drive up health care costs, I would recommend the Web site http://nofreelunch.org.
What should the family physician do?
Bob: For me, it's straightforward—since there is no difference in effectiveness or side effects between albuterol and levalbuterol, there is no good reason to choose the more expensive drug, Xopenex, when treating children with moderate asthma. Further, a recent study in adults with severe asthma came to the same conclusion: good old fashioned albuterol works just as well as the new drug, Xopenex, at a fraction of the cost.3
Andrea: I agree; when switching to new metered-dose inhalers with HFA, go with the most cost-effective drug.
Mark: And do your best to avoid accepting samples—it ultimately costs patients more in the long run.
Main Points
There is no difference between albuterol and levalbuterol in effectiveness or side effects in children with moderate asthma exacerbations.
Be prepared for the mandatory switch in metered-dose inhalers to products containing hydrofluoroalkane (HFA) in place of chlorofluorocarbon (CFC) by the end of 2008.
Drug samples can increase health care costs and lead to inappropriate prescribing patterns.
EBM Points
Be aware of publication bias. Studies that show drugs in a positive light are more likely to be submitted for publication. For this reason, the published studies on levalbuterol look good. But if you look at all of the studies submitted to the FDA, levalbuterol and albuterol are equivalent, with albuterol costing less.
Watch for “spins” promoted by pharmaceutical salespersons. Testimonials, isolated experiences, small company-sponsored studies with surrogate markers or “fuzzy” end points, and endless reprints are often used to try to convince physicians to use a certain drug or intervention.