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Communications to the Editor |

Apples and OrangesApples and Oranges: Flaws and Guffaws FREE TO VIEW

Thomas L. Petty, MD, Master FCCP
Author and Funding Information

University of Colorado Health Sciences Center, Denver, CO. Dr. Petty is Professor of Medicine at the University of Colorado Health Sciences Center and Chairman of the National Health Lung Education Program.

Correspondence to: Thomas L. Petty, MD, Master FCCP, University of Colorado Health Sciences Center, Chairman, National Health Lung Education Program, 1850 High St, Denver, CO 80218



Chest. 1999;116(4):1137-1138. doi:10.1378/chest.116.4.1137
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A recent article by Mahler et al (April 1999)1 that compared the effectiveness of a highly potent inhaled β-agonist with an established and effective inhaled anticholinergic prompts this letter. Since I have been, and currently remain, on the respective speakers’ bureaus of the pharmaceutical industries for both salmeterol and ipratropium, I can give an unbiased opinion (or at least it can be equally biased).

The apples and oranges, of course, refer to the fact that the authors compared salmeterol in its full dosage form (ie, 42μ g/d)2 with ipratropium in a very low dose, at least by European standards. In a study using salmeterol in the treatment of COPD,2a dose of 50 μg twice a day gave the same clinical improvement as 100 μg twice daily. By contrast, a dose-ranging study of the anticholinergics strongly suggests that 500μ g is the peak effective dose.3 The apple vs orange metaphor looms larger when one considers comparing a drug with a 12-h duration of action with a drug having a 6-h duration. The study becomes more like a comparison of grapefruit to grapes when, as the authors admit, the patients who were randomized to salmeterol had statistically significant, milder disease and greater bronchodilator responsiveness than those randomized to ipratropium. Thus, this study is badly flawed to the point of humor since there are so many unequal comparisons. Nonetheless, my interpretation of the data is that the global outcomes were essentially equal.

Without question, this study was designed for marketing purposes. It is probably significant that a modification of Figure 1 from the article appears on the back cover of the abstracts volume for the annual meeting of the American Thoracic Society (ATS) held in exactly the same month that this article appeared. However, this does not particularly trouble me, because studies that I have done have also appeared in promotional literature.4

It is great that pulmonologists and industry are working together to find better, more cost-effective methods of treating patients who have various stages of COPD. An often-quoted review suggests initiating therapy with an anticholinergic.5This is reasonable, since patients with COPD are often more responsive to anticholergics than to β-agonists in equivalent dosage.6 The article by Ferguson and Cherniack,5 as well as the ATS guidelines, considered β-agonists as a second or alternative strategy. But why put anticholinergics and β-agonists in a competitive posture? They work through different mechanisms. Their effects are additive. Indeed, the article that follows the article on efficacy of salmeterol makes exactly this point.7 Maximum reversibility of airflow obstruction is achieved by the addition of ipratropium to aβ -agonist.7

Finally, why not include cost comparisons in an analysis of management strategies? Failure to do this is interesting, since the authors’ conclusion in the article is that salmeterol should be considered a first choice in the bronchodilator management of COPD.

It has been wisely stated that, “what the results giveth, the methods taketh away.” This is the fault of many studies, but it does make amusing, and sometimes entertaining, reading. It is not who is right, but what is right that interests me most as we pursue better methods of treatment for patients with both advanced as well as early stages of COPD.

Mahler, DA, Donahue, JF, Barbee, RA, et al (1999) Efficacy of salmeterol xinafoate in the treatment of COPD.Chest115,957-965. [PubMed] [CrossRef]
 
Boyd, G, Morice, AH, Pounsford, JC, et al An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD).Eur Respir J1997;10,815-821. [PubMed]
 
Gross, NJ, Petty, TL, Friedman, M, et al Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease: a three-center study.Am Rev Respir Dis1989;139,1188-1191. [PubMed]
 
Petty, TL In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial.Chest1994;105,1411-1419. [PubMed]
 
Ferguson, GT, Cherniack, RM Management of chronic obstructive pulmonary disease.N Engl J Med1993;328,1017-1022. [PubMed]
 
Braun, SR, McKenzie, WN, Copeland, C, et al A comparison of the effect of ipratropium and albuterol in the treatment of chronic obstructive airway disease.Arch Intern Med1989;149,544-547. [PubMed]
 
Dorinsky, PM, Reisner, C, Ferguson, GT, et al The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with COPD.Chest1999;115,966-971. [PubMed]
 
To the Editor:

The purpose of our study (April 1999)1 was to compare the efficacy and safety of salmeterol, ipratropium bromide, and placebo in the treatment for COPD. Contrary to Dr. Petty’s statement, this study was not designed for marketing purposes but was conducted for registration of salmeterol for the indication of COPD. Thus, the study design was developed with the Food and Drug Administration to meet their requirements and regulations.

One requirement was to use the dose of medication as listed in the package insert for ipratropium bromide. The package insert for ipratropium bromide states that, “The usual starting dose of Atrovent (ipratropium bromide) is two inhalations (36 μg) four times a day. Patients may take additional inhalations as required; however, the total number of inhalations should not exceed 12 inhalations in 24 hours.” It should be noted that the 500 μg suggested as a single dose by Dr. Petty is substantially higher than the total daily dose of 12 inhalations (432 μg) recommended over the period of 24 h by the package insert. It should also be noted that the dose cited by Dr. Petty was demonstrated in a study using the nebulizer solution.2 It would be both impractical and costly to deliver this dose (10 to 14 puffs) by metered-dose inhaler four times per day. Despite this, we have acknowledged on page 964 of the article that “…higher doses (four to six puffs) of ipratropium have been used in clinical practice.”1 However, clinicians do not routinely start treatment with 10 to 14 inhalations four times a day.

Related to the baseline differences, this study was a randomized, double-blind, placebo-controlled trial, and any differences noted would have occurred purely by chance. Furthermore, we have controlled for these baseline differences in the analyses, and the results that have been reported incorporate this control. Approximately 65% of patients in each treatment group responded to albuterol, and the magnitude of the response did not differ among the three treatment groups.

The results of the study demonstrated improvements in all outcomes with both agents including improvement in pulmonary function, symptoms, functional ability, and quality of life. Thus, as stated by Dr. Petty, we demonstrated that the “global outcomes were essentially equal.” We note that although outcomes were equal, salmeterol was delivered only twice a day while ipratropium was given four times a day. Thus, salmeterol provided a more convenient dosing regimen for the patient. The collective data support the use of salmeterol as a first-line therapy for the long-term treatment of airflow obstruction in patients with COPD. This indication is now included in the package insert for salmeterol. We agree that both agents in combination may be useful in many patients with moderate or severe disease to achieve maximal benefit.

We agree with Dr. Petty that comparative cost-effectiveness data would be interesting. However, such data were too extensive to be included in the present publication. We anticipate presentation of this information in the future.

Correspondence to: Donald A. Mahler, MD, FCCP, Section of Pulmonary and Critical Care Medicine, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756

References
Mahler, DA, Donohue, JF, Barbee, RA, et al Efficacy of salmeterol xinafoate in the treatment of COPD.Chest1999;115,957-965. [PubMed] [CrossRef]
 
Gross, NJ, Petty, TL, Friedman, M, et al Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease: a three-center study.Am Rev Respir Dis1989;139,1188-1191. [PubMed]
 

Figures

Tables

References

Mahler, DA, Donahue, JF, Barbee, RA, et al (1999) Efficacy of salmeterol xinafoate in the treatment of COPD.Chest115,957-965. [PubMed] [CrossRef]
 
Boyd, G, Morice, AH, Pounsford, JC, et al An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD).Eur Respir J1997;10,815-821. [PubMed]
 
Gross, NJ, Petty, TL, Friedman, M, et al Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease: a three-center study.Am Rev Respir Dis1989;139,1188-1191. [PubMed]
 
Petty, TL In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial.Chest1994;105,1411-1419. [PubMed]
 
Ferguson, GT, Cherniack, RM Management of chronic obstructive pulmonary disease.N Engl J Med1993;328,1017-1022. [PubMed]
 
Braun, SR, McKenzie, WN, Copeland, C, et al A comparison of the effect of ipratropium and albuterol in the treatment of chronic obstructive airway disease.Arch Intern Med1989;149,544-547. [PubMed]
 
Dorinsky, PM, Reisner, C, Ferguson, GT, et al The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with COPD.Chest1999;115,966-971. [PubMed]
 
Mahler, DA, Donohue, JF, Barbee, RA, et al Efficacy of salmeterol xinafoate in the treatment of COPD.Chest1999;115,957-965. [PubMed] [CrossRef]
 
Gross, NJ, Petty, TL, Friedman, M, et al Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease: a three-center study.Am Rev Respir Dis1989;139,1188-1191. [PubMed]
 
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