Clinical Outcome Measures

The Big Asthma Lie

New Treatment of Asthma

Get Instant Access

The first major meta-analysis of this kind was based on placebo-controlled dose-response studies of the ICS FP in adults and adolescents with asthma (34). This demonstrated that for different outcome measures, including lung function, symptoms, p-agonist use, and exacerbations, at least 90% of the maximum efficacy can be achieved with a dose of FP of around 200 mg/day (Fig. 3). In moderate to severe adult asthmatic patients the maximum effect was achieved with a dose of FP of around 500 mg/day. This meta-analysis challenged the dogma that existed at the time that higher doses were required to achieve the maximal obtainable effect and that there were marked differences in the dose-response relationship for different clinical outcome measures. In particular, the dose of FP required to reduce exacerbations was similar to that required to reduce symptoms and improve lung function.

Fluticasone dose (pig/day)

0 100 200 300 400 500

Fluticasone dose (pig/day)

0 100 200 300 400 500

0 200 400 600 800 1000

Budesonide (fig/day)

Figure 3 Dose-response curve of fluticasone and budesonide in adult asthma for the major clinical outcomes. Source: From Refs. 34, 37.

0 200 400 600 800 1000

Budesonide (fig/day)

Figure 3 Dose-response curve of fluticasone and budesonide in adult asthma for the major clinical outcomes. Source: From Refs. 34, 37.

The major limitation of this meta-analysis was the small number of studies that included FP doses of 1000 mg/day or greater, due to the requirement for the studies to be placebo controlled. This led to a subsequent meta-analysis that specifically focused on comparisons between the dose of 200 mg/day and higher doses to determine whether the 200 mg/day dose regime provided most of the therapeutic benefit as suggested in the original study (35). It was confirmed that most of the therapeutic benefit was achieved with a dose of 200 mg/day, and that the mean further improvement for FEV1 and morning peak flow resulting from an increase in dose from 200 to >500mg/day was 0.07L (95% CI -0.01 to 0.14) and 5.9L/min (95% CI —3.0 to 15.3), respectively. The odds ratio for withdrawals with 200 mg/day compared with >500 mg/day was 1.27 (0.78-2.07).

Similarly in a meta-analysis of eight placebo-controlled trials of FP, no significant differences were noted in magnitude of change in morning peak flow in patients receiving high (500 or 1000 mg/day) or low (<200 mg/day) doses of FP (36). The time taken to reach either 50% or 100% of the best observed effect was not any longer in the low-dose group, once again demonstrating no reduction in different parameters of efficacy.

A similar meta-analysis with inhaled budesonide has shown that most of the clinical efficacy for the same outcome measures is achieved with a dose of around 400 mg/day (Fig. 3) (37). These findings are comparable with those of FP when their relative potencies are considered [FP vs. budesonide, BDP or triamcinolone (TAA) 2:1]. Consistent findings have also been observed with studies of BDP and TAA in which a plateau in response is observed between 400 and 800 mg/day, depending on the clinical outcome variable (39,40). With regard to mometasone, which has a similar potency to FP (41), the top of the dose-response curve for the major clinical outcome variables is around 400 mg/day (42).

The clinical significance of these dose-response studies is that the therapeutic range for the majority of adult asthmatics lies between 100 and 1000 mg/day of BDP, budesonide, or TAA and 50-500 mg/day of FP or mometasone. As a result, there should be few patients who require doses above this range, as minimal further improvement and clinically significant adverse effects can be expected at higher doses.

This recommendation should be qualified by the recognition that there is considerable interindividual variability in response to ICS in asthma, which means that some patients may obtain a greater clinical benefit at higher doses, just as some patients may obtain the maximum efficacy at lower doses (43). Furthermore, there are some circumstances in which higher doses of ICS may be indicated. These include oral steroid—dependent subjects in whom there is evidence for increasing efficacy up to doses of 2000 mg of FP or equivalent (44-47). There is also preliminary data to suggest that high doses of ICS (e.g., FP 2000 mg/day and budesonide 3200 mg/day) may be as effective as oral steroids in the treatment of moderate to severe exacerbations of asthma (48,49). However, currently there is insufficient evidence to date to recommend the use of such high doses in this situation (50).

Was this article helpful?

0 0
Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

Get My Free Ebook


Post a comment