Comparison of the effects of salmeterol/fluticasone propionate with fluticasone propionate on airway physiology in adults with mild persistent asthma

Clinical trials of drug treatments for asthma commonly use the spirometric assessment of FEV₁ to assess improvements in lung function. FEV₁ is a relatively simple and reproducible measurement that is required by regulatory authorities. However, in patients with mild asthma, FEV₁ may be close to normal and is not as sensitive as body plethysmography and impulse oscillometry (IOS) for measuring small changes in lung function in response to broncodilators [1‐3]. Furthermore, body plethysmography assesses airway resistance while IOS measures pulmonary resistance and reactance, properties not assessed by spirometry [3‐6].

Combination therapies of inhaled corticosteroids (ICS) with a long acting beta agonist (LABA) are effective in the treatment of asthma. The combination of salmeterol and fluticasone propionate (SFC, Seretide GSK™) improves symptoms, lung function and exacerbation rates when compared to the same or double the dose of fluticasone propionate (FP) in symptomatic patients with asthma who have moderately impaired lung function (FEV₁ <80% predicted) [7‐9]. However, there are less data regarding the effects of SFC in symptomatic patients with mild asthma who may have almost normal FEV₁ values. The advantages of SFC over ICS alone in this subgroup is difficult to evaluate using FEV₁, as this measurement is near normal. In the absence of studies using more sensitive pulmonary function measurements than FEV₁, guidelines have favoured the use of ICS alone for mild asthma patients [10]. However, the benefits of combination therapy with SFC in patients with mild asthma may be more apparent if sensitive pulmonary function measurements, such as body plethysmography and IOS are used.

We report a comparison of the effects of SFC 50/100 μg twice daily compared to FP 100 μg bd in patients with mild asthma already being treated with ICS. Our primary aim was to compare the changes in lung function, assessed by plethysmography, IOS and spirometry.

Fifty six patients were enrolled into the run in period, of which 13 did not meet the daily symptom score requirement, 3 did not complete the diary card correctly and 1 was non compliant with run in medication. The demography and lung function at screening (before run in) of the remaining 39 subjects who were eligible for randomisation is shown in Table 1. Baseline measurements of pulmonary function after the run in are shown in Table 2. There were 2 withdrawals following randomisation, one in each treatment group due to loss of study medication in he SFC group and medication running out in the FP group.

We have studied patients with mild persistent asthma who are symptomatic despite being treated with ICS. Asthma guidelines advocate a step wise approach to pharmacological therapy in such patients, with the aim of optimizing asthma control defined by a range of clinical endpoints, including symptoms, exacerbation rates and pulmonary function. One possible step wise approach is the use of combined LABA and ICS in these patients. This is the first study to investigate the benefits on airway patency of combination therapy with SFC (50/100 μg bd) compared with ICS (FP 100 μg bd) alone in a group of mild asthma patients.

Our primary endpoint was the sensitive measurement of sRaw using body plethysmography. The key findings were that SFC caused significant improvements in sRaw, sGaw and IOS resistance and reactance parameters at 12 hours post dose after 2 and 4 weeks treatment. At 2 weeks, a small but statistically significant difference was observed using FEV₁, but not at 4 weeks. In this population of mild asthma patients, selected for reversibility using criteria based on sRaw, we have therefore shown that SFC 50/100 μg has greater benefits on pulmonary function compared with FP 100 μg, which are most apparent when using more sensitive methods than spirometry. Further studies are needed to determine if these pulmonary function findings are true in other asthma populations, and whether overall asthma control is improved by such a strategy.

In order to optimise asthma control in symptomatic mild asthma patients being treated with low dose ICS, it is possible to increase the ICS dose or add in a LABA. Using the SFC combination, we have proved that the addition of LABA has pulmonary function benefits compared to the same dose of ICS alone in this particular population. It would now be important to compare SFC to an increased dose of ICS alone in this population, as these are the 2 treatment options available in clinical practice.

The bronchodilator profile of salmeterol in asthma is well established, with maximal effects observed within 1–2 hrs [13, 14]. In this study using SFC, it was therefore relevant to study both the maximal effects (at 2 hrs post dose) as well as the effects at 12 hrs post dose, immediately prior to the next scheduled dose. We chose 12 hrs for the primary endpoint (sRaw) measurement, as this is the time point when the effects of SFC are most likely to be similar to FP. Thus, any superiority of SFC over FP at 12 hrs would indicate that the benefits of SFC are sustained over the full 12 hrs, and not just confined to the first 2 hrs post dose.

Although FEV₁ is the "gold standard" of clinical trials, we observed that substantial improvements in airway resistance occurred in mild asthmatics without a statistically significant change in FEV₁ after 4 weeks treatment. We have previously shown that body plethysmography is a sensitive measurement of bronchodilation in mild asthmatics i.e. although body plethysmography has increased variability compared to FEV₁, it is also more sensitive to changes in airway tone, and so was able to detect changes caused by 10 μg salbutamol while there was no change in FEV₁[1]. The current study provides further evidence that changes in pulmonary function in patients with mild asthma are detected more sensitively by plethysmography compared to spirometry [1, 2].

We did not measure FEV1 reversibility at screening. In the SFC group, there was an improvement in pulmonary function of 260 mls after the first dose, equivalent to 8% reversibility. A higher degree of FEV1 reversibility would not be expected, as the baseline FEV1 was approximately 94% predicted.

Body plethysmography is more time consuming compared to spirometry, and is a more complex technique that requires a greater degree of operator training. However, it is clear that body plethysmography offers advantages in terms of sensitivity and we encourage its use in clinical trials of mild asthmatics [1‐3, 15]. The demonstration of improvements in airway resistance in patients with mild asthma is important, because it suggests that even in the context of minimal evidence of lung function impairment using spirometry, there is significant reversible disease activity that can be detected by measures of lung function that are more sensitive than those routinely used in clinical practice.

Involvement of the small airways, even in patients with mild asthma is increasingly recognised [16]. Improved deposition of inhaled corticosteroid in the small airways may lead to a clinical benefit by reducing the persistent inflammation seen in these airways [16]. It has been suggested that combination therapy may result in enhanced delivery of inhaled corticosteroid to the peripheral airways [17]. Furthermore LABA's may have a direct bronchodilator effect in the small airways [17]. Frequency dependant changes in resistance and compliance have been demonstrated in small airway disease [18, 19]. It has been suggested that oscillometry is a sensitive measure of small airway dysfunction as a range of frequencies are employed and changes in R5, X5 and RF may reflect small airway physiology [20‐22]. Thus, the changes in IOS demonstrated in this study may indicate beneficial small airway effects of SFC. There was no improvement in the spirometric measurement of MMEF, which has also been suggested to be an indicator of small airway function. This is likely to be due to the increased variability of MMEF compared to IOS causing reduced sensitivity [1]. The use of IOS is increasing in clinical practice, and the current study shows a valuable application of this method for detecting subtle but important effects of drugs that cannot be measured by standard spirometry.

This study produced some additional findings concerning the use of combination therapy. We found that post dose pulmonary function measurements were stable for 4 weeks in both groups. There have been some concerns about desensitisation to the effects of long-acting beta₂ agonists after prolonged treatment [23]. However, long-term studies up to 12 months duration have shown no evidence of tachyphylaxis or tolerance to the bronchodilator effects of salmeterol [24, 25]. The current study also did not observe desensitisation, as 2 hr post dose lung function measurements in mild asthmatics treated with SFC were stable over a 4 week period.

There was a trend to an improvement in airway hyper reactivity (AHR) from baseline in the SFC treatment group but this was not significant. The current study did not enrol patients based on an inclusion criterion of AHR, and was not statistically powered to evaluate changes in AHR, as AHR was a secondary endpoint. Further studies powered to assess AHR as a primary endpoint are required to assess any potential benefit of SFC compared to FP alone on AHR in this patient population. However, a recent study has shown in mild to moderate patients that SFC improved AHR to a significantly greater extent than FP or salmeterol alone [26].

It is recognised that a substantial number of patients have mild persistent asthma associated with significant morbidity [27, 28]. We have clearly shown that SFC has beneficial effects on lung function in patients with mild asthma that are not observed with ICS alone. These benefits of SFC therapy were sensitively demonstrated by body plethysmography and IOS. Further long term studies in mild asthma are required to ascertain the relationship between the improvements in lung function observed in the current study using SFC and clinical parameters such as symptoms and exacerbation rates.