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Do inhaled steriods in COPD do more harm than good?

New research suggests combination therapy has little benefit and significant risks. So where does that leave GPs?

By Nigel Praities

New research suggests combination therapy has little benefit and significant risks. So where does that leave GPs?

It is one of the holy grails of drug company research – that elusive proof that adding inhaled steroids to long-acting ß-agonists really does save lives.

Companies have spent millions on trials aiming to convince GPs that steroids are an essential part of their armoury.

But although steroids can reduce exacerbation rates and improve quality of life, overall mortality improvements have proven harder to demonstrate. Smoking cessation and oxygen supplementation are still the only treatments shown to reduce mortality rates.

And concerns that adding in a steroid can actually cause harm, by increasing the risk of pneumonia, have further muddied the waters.



Now the rollercoaster of changing evidence has taken a steep plunge downwards with a new analysis concluding combined therapy should not be used. Researchers analysed data from 12,446 patients with moderate to severe COPD and concluded the benefits of combined therapy were ‘borderline' and the drawbacks clear-cut.

‘Combination therapy offers no significant survival benefit and increased risk of serious adverse effects. It is likely that most COPD patients with these levels of severity should only be treated with LABA monotherapy,' concluded the study, published in Chest last week.

For now, regulatory authorities are urging GPs to keep following national guidance. NICE discourages the use of inhaled steroids as monotherapy, but does encourage their use with bronchodilators if patients have moderate or severe COPD and are still symptomatic, or are experiencing two or more exacerbations requiring treatment per year.

This recommendation is based on good evidence. Combinations of an inhaled steroid and LABA have been shown to reduce exacerbations and improve quality of life in a number of trials in this patient group.

The TORCH study results – released in 2007 – first showed combined inhalers could slow lung function decline, with a 16ml-a-year improvement in FEV1 compared with placebo.

The study narrowly missed statistical significance in reducing mortality with combination therapy, but was also the first to surprise GPs by revealing a significant increased risk of pneumonia. Nearly a fifth of patients (19.6%) receiving LABA-inhaled steroid combination therapy had a reported episode of pneumonia, compared with only 12% in the placebo group.

This result has been criticised, as the pneumonia diagnosis was not confirmed by X-ray and COPD patients are inevitably more prone to chest infections. Yet subsequent anal-yses have confirmed the link and suggested inhaled steroids may achieve locally high concentrations in the lung, raising the risk of pneumonia because of their immunosuppression.

A meta-analysis of 11 studies – including TORCH – published in JAMA detailed a 34% increase in the risk of pneumonia in patients taking inhaled steroids, compared with controls.

Authors of that study recommended the ‘lowest effective dose' should be used to minimise potential adverse effects.

Dr Bradley Drummond, lead author of the study and a research fellow at Johns Hopkins University School of Medicine in the US, says: ‘Because of the increased pneumonia risk, these medications may not be suitable for all patients with COPD. We identified several factors which may increase the risk of pneumonia in certain people, including poor lung function, higher doses of inhaled steroids, and using inhaled steroids along with other inhaled medicines to treat COPD.'

A 2007 gold-standard review from the Cochrane Collaboration reported favourable effects on exacerbations with combination treatment, but also showed a concurrent 58% increase in pneumonia risk compared with LABA alone.

Specialists have been divided on what GPs should do to minimise the risks of steroids.

The National Prescribing Centre issued advice on it earlier this year, urging GPs to talk with patients about the risks of introducing steroid therapy and to treat the use of combined inhalers as a ‘therapeutic trial', with monitoring of symptoms and side-effects.

Dr Neal Maskrey, director of evidence-based therapeutics at the centre, says inhaled steroids have only ‘limited benefits' in COPD and so treatment options should depend on discussions with the patient.

‘It's not clear what is the best option and there almost certainly isn't much to choose between the options.

‘If a patient is significantly symptomatic on salbutamol and tiotropium, wants to do more, and their FEV1 is less than 50%, the data says add in a LABA or steroid. Both have pros and cons. I'd do a therapeutic trial of one and see how the symptoms and side-effects went.'

But Professor Peter Calverley, lead investigator for the TORCH study and professor of respiratory medicine at the University of Liverpool, says he is concerned patients are becoming overly fearful of the risk of pneumonia – which he describes as a ‘rare event'.

‘The benefits outweigh the risks. The pneumonia risk is not a function of age or lung function and there are no known additional risk factors, although patients with a background of bronchiectasis might warrant more caution.' He insists: ‘Patients shouldn't be frightened about the potential for problems with steroids. They are very well tolerated in the great majority of patients.'

Dr Kevin Gruffydd-Jones, a GP in Wiltshire and a member of the General Practice Airways Group, agrees there is a danger of ramping up patient fears and says the risk of pneumonia has to be ‘put in inverted commas'.

‘The pneumonia risk is definitely a signal, but in the trials it was physician-determined and not proven on X-ray. So it could have been called pneumonia, but could just have been a chest infection.

‘What's important is that patients have self-management plans and can recognise at an early stage if they do have a problem with a chest infection.'

So what does the ultimate arbiter of drug safety, the MHRA, say? In an attempt to clear up confusion, it conducted a review of published and unpublished data, which reported back last month.

It tried to allay concerns by reporting a positive risk-benefit association for combination therapy in COPD, but admitted the risk of pneumonia with steroids was still a ‘key issue'.

It will continue to monitor the safety of steroid therapy– and also raised concerns over evidence that the treatment is being prescribed earlier than guidelines advise and as monotherapy in some cases.

Clarity over when to use steroids in COPD may come in the form of updated guidance from NICE. The institute is currently revising its guideline on COPD and is due to report back in June 2010.

Dr Gruffydd-Jones, a member of the guideline development group, is concerned NICE guidance is unclear and hints there may be changes. ‘Combination therapy should be reserved for more severe patients. Unfortunately there is a small clause in the guidelines that says if a bronchodilator does not seem to be working and the patient is still symptomatic, then you should add in the combination at that point.

‘I am not 100% convinced of the evidence of that. In some cases this leads to them being inappropriately used too early.'

With the Government's long-awaited clinical strategy – due for publication later this year – likely to recommend better case-finding of COPD patients, it is even more crucial there is clarity about the risks and benefits of steroid treatment.

Unfortunately, the only thing experts currently agree on is that more evidence on the safety of steroids in COPD is needed. Until then, the rollercoaster looks set to continue.

Twists and turns in evidence

Feb 2007 - TORCH study falls short of any mortality benefit, but shows LABA/ICS combination therapy can reduce exacerbations and improve quality of life. Also records surprise increase in the risk of pneumonia

May 2007 - Cost-effectiveness study shows LABA/ICS combination therapy in COPD is ‘as cost-effective as statins'

Jul 2007 - Case-control analysis shows 70% increase in hospitalizations for pneumonia in elderly patients with COPD

Oct 2007 - Cochrane review reports a 58% increase in pneumonia risk with LABA/ICS combination treatment compared with LABA alone

Feb 2008 - TORCH study demonstrates LABA/ICS combination therapy can reduce the progression of disease in COPD

Nov 2008 - JAMA meta-analysis of 11 trials shows increased risk of pneumonia in COPD patients taking ICS and LABA and those with worse lung function

Feb 2009 - Meta-analysis of 18 PCTs shows ICS is associated with 68% increased risk of pneumonia with LABA/ICS treatment compared with LABA alone

May 2009 - Post-hoc analysis of TORCH study confirms increased risk of pneumonia with ICS, but finds no link with pneumonia-related mortality

Jul 2009 - MHRA says the increased risk of pneumonia is a ‘key issue' and warns ICS is being added to LABA too early

Jul 2009 - Analysis of 18 RCTs find ‘limited extra efficacy' when ICS are added to LABA therapy in patients with moderate to severe COPD and an increased risk of adverse events

Sources: 1: N Engl J Med 2007; 356; 775-89; 2: American Thoracic Society Meeting 2007, San Francisco, US; 3: Am J. Respir Crit Care Med 2007; 176:162-66; 4: Cochrane Database of Systematic Reviews 2007; 17: CD006829; 5: Am J Respir Crit Care Med 2008; 178: 332-8; 6: JAMA 2008; 300: 2407-2416; 7: Arch Intern Med. 2009;169: 219-229; 8: Eur Respir J 2009; published early online 14 May 2009; 9: MHRA Drug Safety Update, July 2009; 10: Chest 2009; published early online 24 July 2009

A new study suggests risk of pneumonia with inhaled steroids may outweigh their benefits A new study suggests risk of pneumonia with inhaled steroids may outweigh their benefits Pneumonia risk Pneumonia risk

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