The effect of steroid inhalers containing the drug beclometasone for patients with COPD

Background

Chronic obstructive pulmonary disease (COPD; i.e. chronic bronchitis or emphysema or both, also called "smoker's lung disease") is a disease in which patients (predominantly smokers) experience breathlessness and produce a lot of phlegm or sputum. COPD is diagnosed by using international guidelines provided by the Global Initiative for Obstructive Lung Disease (GOLD).

One of the treatments that may be used to slow down worsening of this disease consists of steroid inhalers. These inhalers are known as preventer inhalers because they are taken daily to prevent symptoms. GOLD recommends that steroid inhalers are now to be used only in combination with inhaled LABA drugs (long-acting beta2-agonists, e.g. formoterol). They are recommended for patients who have COPD with high risk of flare-ups ("exacerbations").

Why do this review?

It is still unsure whether these steroid preventer inhalers, such as beclometasone inhalers, make a difference to patients with COPD.

Therefore we decided to do a systematic review of existing studies to look into the effects and side effects of beclometasone inhalers for people with COPD.

Which questions does this review try to answer?

Our study consisted of two parts: (A) Are beclometasone inhalers better than placebo? and (B) Is beclometasone in combination with LABA drugs in one inhaler (a beclometasone/formoterol combination inhaler) better than a LABA (formoterol) inhaler?

How did this review do this?

We searched all research papers of clinical trials on this topic and made a special effort to find unpublished trials.

We compared effects on breathing ability, death rates, how often pneumonias and flare-ups happened, how often rescue inhalers had to be used, quality of life and side effects.

The evidence obtained is up to date to February 2013.

What were the results?

For (A) we found two studies, with a total of 298 study participants. For (B) we found one study, with 474 study participants, all with severe (stage 3) COPD.

For (A) we found no differences that could not be due to chance (not "statistically significant"). Therefore we found no evidence that beclometasone is better or worse than placebo for COPD. It is possible that this conclusion is not fully informed, however, as we were able to use only one trial. We await further statistics from another trial, and we suspect that many trials addressing (A) have gone unpublished in the past.

For (B) we found real differences in breathing capacity and rescue inhalers ("statistically significant"), but as the differences were small, they are unlikely to be noticeable for patients (not "clinically significant"). We also found a real increase in the average rate of severe flare-ups of COPD requiring hospital admission when study participants were using steroid-containing inhalers. However, the trial authors showed that these differences could have been caused by different hospital policies in the many countries that participated. For the other aspects that we compared, we found no differences in benefits or harms; any differences found were so small that they could have been due to chance. Further research is being done in this area, and findings of these studies may change our conclusions in the future.

Are there any criticisms of this review's results?

Our conclusions are limited by the small number of studies that were useful (only three), the poor/average quality of the evidence and the fact that most of these studies apply only to patients with severe but very stable COPD.

Authors' conclusions: 

We found little evidence to suggest that beclometasone is a safer or more effective treatment option for people with COPD when compared with placebo or when used in combination with LABA; when statistically significant differences were found, they mostly were not clinically meaningful or were based on data from only one study. The review was limited by an inability to obtain data from one study and likely publication bias for BDP versus placebo, and by the inclusion of one study only for BDP/LABA versus LABA. An ongoing study of BDP/LABA versus LABA may have a further impact on these conclusions.

Read the full abstract...
Background: 

Chronic obstructive pulmonary disease (COPD) is a chronic obstructive lung condition, diagnosed in patients with dyspnoea, chronic cough or sputum production and/or a history of risk factor exposure, if their postbronchodilator forced expiratory lung volume in 1 second (FEV1)/forced vital lung capacity (FVC) ratio is less than 0.70, according to the international GOLD (Global Initiative for Obstructive Lung Disease) criteria.

Inhaled corticosteroid (ICS) medications are now recommended for COPD only in combination treatment with long-acting beta2-agonists (LABAs), and only for patients of GOLD stage 3 and stage 4 severity, for both GOLD groups C and D.

ICS are expensive and how effective they are is a topic of controversy, particularly in relation to their adverse effects (pneumonia), which may be linked to more potent ICS. It is unclear whether beclometasone dipropionate (BDP), an unlicensed but widely used inhaled steroid, is a safe and effective alternative to other ICS.

Objectives: 

To determine the effectiveness and safety in COPD of inhaled beclometasone alone compared with placebo, and of inhaled beclometasone in combination with LABAs compared with LABAs alone.

Search strategy: 

We searched the Cochrane Airways Group Specialised Register of trials (CAGR) (includes Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and handsearching of respiratory journals and meeting abstracts) (February 2013), conference abstracts, ongoing studies and reference lists of articles. We contacted pharmaceutical companies and drug marketing authorisation bodies/ethics committees in 49 countries and obtained licensing information.

Selection criteria: 

Randomised controlled trials of BDP compared with placebo, or BDP/LABA compared with LABA, in stable COPD. Minimum trial duration is 12 weeks.

Data collection and analysis: 

Inclusion, bias assessment and data extraction were conducted by two review authors independently. The analysis was performed by one review author. Study authors were contacted to obtain missing information.

Main results: 

For BDP versus placebo, two studies were included, of which one trial (participants n = 194) was included in the quantitative analysis. This study was a very high-dose trial with stable stage 2 and 3 COPD participants. No statistically significant results in change in lung function, mortality, exacerbations, dyspnoea scores or withdrawal were obtained. The quality of the evidence of all these outcomes was graded low to very low. Data on risk of pneumonia were lacking.

The main focus of the review was the more clinically relevant BDP/LABA versus LABA arm. Therefore the findings are reported more fully.

For BDP/LABA versus LABA, one study (n = 474) was included, with a further ongoing study identified for future inclusion. The included trial was a high-dose study of stable stage 3 COPD participants. Compared with LABA, people receiving BDP/LABA showed a statistically significant improvement in FEV1 lung function measurements of 0.051 L (95% confidence Interval (CI) 0.001 to 0.102, P = 0.046) (high quality of evidence) and in (self-reported) days without rescue bronchodilators (mean difference 7.05, 95% CI 0.84 to 13.26, P = 0.03) (low quality), both of which are unlikely to be clinically significant. Participants receiving BDP/LABA also had a statistically significant increased rate of exacerbations leading to hospitalisation (risk ratio (RR) 1.84, 95% CI 1.17 to 2.90, P = 0.008) (moderate quality), although this finding is debatable as this study's post hoc analysis showed no statistically significant difference when accounting for country-specific differences in hospitalisation policies. We did not find statistically significant differences for mortality (very low quality), pneumonia (low quality), exacerbations, exercise capacity, quality of life and dyspnoea scores, adverse events and withdrawal (all moderate quality).

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