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Ninewells Hospital and Medical School University of Dundee Dundee, Scotland
Correspondence to: Brian J. Lipworth, MD, Professor of Allergy and Respiratory Medicine, Asthma and Allergy Research Group, Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland UK DD19SY
To the Editor:
I read with interest the recent study of Baraniuk et al (September 1999),1 which reported significantly superior asthma control with fluticasone propionate, 440 µg/d, or the combination of fluticasone propionate, 176 µg, plus salmeterol, 84 µg/d, vs monotherapy with triamcinolone acetonide 1,200 µg/d. There were, however, some potential flaws in the study design that made it difficult to draw valid conclusions from these data.
In terms of the active treatment moieties, fluticasone given as monotherapy or as cotherapy comprised taking a total of 4 puffs/d of fluticasone, in contrast to a total of 12 puffs/d of triamcinolone acetonide, with salmeterol being a total of 4 puffs/d. Although the study was double-blind and triple-dummy, there is no mention in the description of the study design as to whether the various active or placebo inhalers within each treatment arm were randomized according to the sequence in which they were taken, either in the morning or the evening. Thus, there was a likelihood for patients to begin their dosing sequence with the treatment that involved the least number of puffs (ie, either fluticasone propionate or salmeterol or their matching placebos), rather than the treatment that involved a greater number of puffs (ie, triamcinolone acetonide or its matching placebo). The likelihood of such a sequence bias was increased as a consequence of (1) the high total number of puffs of active treatment and placebo for each treatment arm (a total of 20 puffs/d); (2) the 12-week duration of the trial; and (3) the patients’ poor asthma control while already taking a high number of puffs of inhaled corticosteroid therapy prior to entering the study (6 to 16 puffs/d). This would result in patients being less inclined to comply with taking the higher number of puffs with triamcinolone acetonide as compared to salmeterol or fluticasone.
As well as potential problems with compliance, there was no mention made as to whether any formal checks were made on inhaler technique at each of the assessments over the 12-week treatment period. As pressurized metered-dose inhalers (pMDI) are notoriously difficult to use without reinforced instruction, one cannot exclude the possibility that suboptimal inhaler technique might be an explanation for the apparently poorer response to the treatment regimen that contained the highest number of puffs of active treatment (ie, triamcinolone acetonide). Again, looking at the inclusion criteria for required treatment with a high number of puffs of inhaled corticosteroid, one has to question whether poor inhaler technique was a cause for their suboptimal asthma control.
A further potential problem with the patient inclusion criteria was that there were no patients enrolled who were already receiving fluticasone propionate as their usual maintenance inhaled corticosteroid therapy. This would again tend to bias the results towards a better response to the treatment regimens containing fluticasone as opposed to those containing triamcinolone acetonide (which comprised 42% to 46% of the enrolled patients).
The likelihood of compliance and adequate inhaler technique being a confounding factor in the apparently suboptimal response to triamcinolone acetonide 1200 µg/d is supported by data from a previous dose-ranging study (triamcinolone acetonide 200 µg/d to 1600 µg/d) in similar type of patients, where a plateau in the dose-response curve for asthma control parameters occurred between 400 µg/d and 800 µg/d.2
In terms of the safety profiles, no comment was made by the authors on the finding of hoarseness or dysphonia in 4% of patients receiving fluticasone 440 µg/d as compared to <1% in patients receiving triamcinolone acetonide 1,200 µg/d. Presumably, this reflects the effects of the integrated spacer attachment with the triamcinolone acetonide pMDI compared to the pMDI alone with fluticasone propionate. Alternatively, this finding could be interpreted as being due to better compliance with the fluticasone-containing regimes that involved taking a fewer number of puffs. However, the higher incidence of hoarseness with fluticasone may also have been related to its increased glucocorticoid potency, and, in this respect, there has been a recent case report of laryngeal aspergillosis in association with fluticasone propionate.3
Aside from compliance issues, the findings of Baraniuk et al1 suggest superior overall asthma control with the addition of salmeterol to a lower dose of fluticasone propionate as compared to monotherapy with a higher dose of fluticasone propionate. This finding would be consistent with the long-acting bronchodilator properties of salmeterol when given alone during twice-daily treatment. However, this does not take into account what may be happening to the underlying asthmatic inflammatory process, which may not be adequately suppressed by lower doses of inhaled corticosteroid.4 5 Indeed, it has been shown that, in patients taking regular twice-daily salmeterol, apparently good control of symptoms and lung function occurs in the presence of increased airway inflammation, prior to an exacerbation during tapering of inhaled corticosteroid therapy.6 This emphasizes the importance of following accepted asthma management guidelines by optimally titrating the dose of inhaled corticosteroid before considering adding in regular long-acting ß2-agonist therapy, as the latter may inadvertently mask uncontrolled airway inflammation.7
Finally, I was also concerned that the final conclusion, "the largest improvements were evident with the lowest recommended dose of fluticasone propionate (176 µg/d combined with salmeterol," might potentially send the wrong message to asthma caregivers, that patients with more severe asthma (range of percent predicted FEV1 in present study was 40 to 85%) would benefit most from the lowest dose of inhaled corticosteroid therapy combined with long-acting ß2-agonist therapy. The current guidelines clearly advocate the use of long-acting ß2-agonist in combination with a higher dose of inhaled corticosteroid in this category of patients.7
References
Georgetown University Medical Center Washington, DC
Correspondence to: James N. Baraniuk, MD, Georgetown University Medical Center, Department of Medicine, LL Gorman Building, 3800 Reservoir Rd, NW, Washington, DC 20007-2197
To the Editor:
In response to Dr. Lipworth’s questions about compliance and possible "sequence bias," patients in this study were not instructed to use the three study inhalers in any particular sequence. The labeling on the canisters did not suggest the order of administration. In addition, patients were taking up to 16 puffs/d of inhaled corticosteroid prior to entering the study. In this study, patients were using 20 puffs/d of study medication, and improvements in pulmonary function and symptom control were observed in all treatment groups. The mean self-reported compliance rate for each of the delivery devices for salmeterol, fluticasone propionate (FP), and triamcinolone acetonide (TAA) was approximately 97%.
Dr. Lipworth hypothesizes that suboptimal asthma control with TAA compared with FP and the combination regimen occurred as a result of poor inhaler technique. Patients were instructed in proper inhaler technique at screening and at randomization in this study. If inhaler technique was inadequate, suboptimal asthma control would have been observed equally across all treatment groups.
Patients were not entered into this study if they had previously used FP as their maintenance inhaled corticosteroid. FP aerosol had just become commercially available in the United States at the time the protocol for this study was developed. The inhaled corticosteroids used by patients prior to entering the study according to entry criteria reflected the use of these drugs at the time.
The lower incidence of hoarseness or dysphonia observed with TAA compared with FP is likely a result of the spacer built into the TAA metered-dose inhaler as suggested by Dr. Lipworth. It is well known that spacers can reduce the frequency of oropharyngeal side effects that are characteristic of the inhaled corticosteroids.1 Therefore, the difference in frequencies of these effects (4% vs < 1%) is not clinically significant. The clinical relevance of the case report of laryngeal aspergillosis mentioned by Dr. Lipworth is also questionable because the low incidence of this condition makes a causal relationship difficult to establish (reported in the literature in only 12 patients over a period of 30 years).2
Dr. Lipworth mentions that salmeterol may mask symptoms of airway inflammation. The reference that he cites is based on a study that used a steroid-reduction model that tapered inhaled corticosteroid doses on a weekly basis rather than in intervals of a few weeks and completely withdrew patients from inhaled corticosteroids, a practice that is not in accordance with accepted management guidelines.1 3 As suggested by Dr. Lipworth, an exacerbation is a result of poorly controlled asthma and therefore reflects uncontrolled airway inflammation. If salmeterol were masking airway inflammation, one would expect to see higher rates of exacerbations with the use of salmeterol or the combination of salmeterol with FP. However, many studies, including this study, have shown that the opposite is true. In this study, only 13 patients experienced an exacerbation in the FP 88 µg bid/salmeterol combination group compared with 32 patients and 29 patients in the FP 220 µg bid and TAA 600 µg bid treatment groups, respectively. The rate of exacerbations with concomitant use of inhaled corticosteroids with long-acting ß2-agonists has been shown to be similar to or lower than that observed with the use of inhaled corticosteroid alone.4 5 6 7 8 Furthermore, because of data available from clinical trials, treatment guidelines recommend adding salmeterol to an inhaled corticosteroid rather than increasing the dose of inhaled corticosteroid, since this regimen has been shown to be more effective in improving pulmonary function and asthma symptom control.1 4 5 6 7 8 These data suggest that salmeterol does not mask the underlying inflammatory process.
Finally, we agree with Dr. Lipworth that individualizing treatment regimens for the maintenance of asthma stability is important. Clinicians are advised to prescribe the lowest effective dose of inhaled corticosteroid for optimal asthma control and to minimize adverse effects.1
References
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