New evidence on antibiotics for exacerbations of chronic obstructive pulmonary disease – with some bits missing

Key message: Giving antibiotics to people admitted to the Intensive Care Unit (ICU) with severe exacerbations of COPD showed large and consistent benefits. Evidence relating to the use of antibiotics for people with moderate or mild exacerbations is inconsistent and there is continued uncertainty about whether antibiotics benefit those who can be treated as outpatients. 

Recently I blogged about new Cochrane evidence on the role of nutritional supplementation for people living with chronic obstructive pulmonary disease (COPD), something which seems to have a beneficial effect on weight, respiratory muscle strength and quality of life in those people with COPD who are also malnourished – about a third of this patient population. Another aspect of living with COPD is dealing with flare-ups or ‘exacerbations’, when symptoms such as cough and the amount of phlegm or sputum produced, and shortness of breath, get worse. These exacerbations can range from mild to very severe. It’s not always possible to say what causes them, but some may be triggered by air pollution and about half by infection in the lungs or airways, caused by a virus or bacteria. Treatment with antibiotics may be considered.

With concerns about the overuse of antibiotics, including possible interactions with other medicines and side effects (though these are usually mild), costs, and the global problem of multi-resistance (bacteria developing resistance to antibiotics) it is important to gather the best evidence in a systematic way to help inform decisions about when to use them. The authors of this new review from The Cochrane Airways Group, like so many, found they couldn’t get all the data they needed. The reviewers found 16 randomised controlled trials (RCTs) suitable for inclusion, which compared antibiotics with placebo in 2068 COPD patients with a wide range of severities of exacerbations.

What did they find and how good is the evidence?

  • The only trial with patients admitted to the ICU showed a large and statistically significant beneficial effect on treatment failure and on mortality (high-quality evidence)
  • High quality evidence that antibiotics reduced the risk of treatment failure (no improvement) in inpatients with severe exacerbations (excluding ICU)
  • Low quality evidence (more of that below…) that for people with mild or moderate exacerbations treated as outpatients antibiotics reduced the risk of treatment failure between seven days and one month after treatment initiation but this effect was not significant when only currently available drugs were considered (trials range from 1957 to 2012)
  • In ICU patients, antibiotics reduced the length of stay in hospital. Length of stay was similar for all other patient groups
  • Moderate quality evidence showed that more people taking antibiotics had side effects than those taking placebo (sugar pill). Twice as many people taking antibiotics had diarrhoea compared to people taking a placebo
  • Most trials were at low risk of bias
  • There is a lack of data on patient-reported outcomes or health-related quality of life
  • The trials included only small numbers of people, ranging from 19 to 310 people
  • The severity of underlying COPD could not be compared because the relevant data were not reported consistently

Crucially, some of the results were missing….

The problem of missing results and how we can change that

The reviewers commented that the quality of the evidence for people treated as outpatients was partly brought down because the results from one trial were not made available by the study authors (and the results of another are not yet in the public domain). Failure to have all the relevant data seriously weakens our ability to draw sound conclusions about the benefits and harms of treatments and this problem is at the heart of the All Trials campaign which the Cochrane Collaboration, along with other key organizations and many individuals, is backing. It calls for all clinical trials to be registered and all results reported. Cochrane reviews are internationally recognised as the highest standard in evidence based health care and are based on the best available evidence – but the scandal is that not all the evidence is made available.  If you want to help change that, do visit the All Trials site and sign the petition at www.alltrials.net.

Another problem – not asking about the things that most matter to patients

I frequently read in systematic reviews, as I did in this one, that there is little or no data on patient- reported outcomes or health-related quality of life. That’s not to say that patients don’t care about how long they stay in hospital or whether their cough improves; I imagine they do. But time off work during exacerbations, for example, is a big issue for many people with COPD and keeping this to a minimum is likely to be an important aspect of helping them manage their condition. Yet most trials did not look at this outcome. If you’re someone living with COPD, I wonder what sorts of outcomes you would like to see researchers explore in future trials?

Links:

Vollenweider DJ, Jarrett H, Steurer-Stey CA, Garcia-Aymerich J, Puhan MA. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: CD010257. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010257/abstract

Cochrane summaries http://summaries.cochrane.org/CD010257/antibiotics-for-exacerbations-of-chronic-obstructive-pulmonary-disease

Cochrane summaries of reviews about COPD http://summaries.cochrane.org/search/site/COPD

Evidently Cochrane blog: Nutritional support may be useful for people with stable COPD https://evidentlycochrane.wordpress.com/2012/12/17/nutritional-support-may-be-useful-for-people-with-stable-chronic-obstructive-pulmonary-disease/#more-229 December 17th 2012

7 thoughts on “New evidence on antibiotics for exacerbations of chronic obstructive pulmonary disease – with some bits missing

  1. This is brilliant. I don’t have COPD but I do have Cystic Fibrosis. Are you doing something similar for CF exacerbations? I imagine COPD and CF have a good deal in common in terms of patient-relevant outcomes and designing better trials that help patients and provide NICE with the kind of data that would enable them to quantify and include quality of life (and actually adherence) factors as part of their QALY calculations. I think Colobreathe should be recommended for use even for patients who do tolerate the nebulised version because of the quality of life (40-60 mins per day saved, portability, no need for sterilising neb mouthpiece parts after each treatment, hygiene, no need to constitute/prepare drugs, no need for sharps) and obvious adherence gains. Adherence for nebs is probably 50-60% but much higher for inhalers. Until somebody does a trial to demonstrate that inhalers beat nebs on adherence and that this reduces hospitalisation (and therefore save NHS money), it seems these factors have no currency in QALY terms. That said, Bronchitol was approved and some weight was given to quality of life although not much and not in a way that seems rational. I don’t know why there was an ERG report and they took a lot of evidence from an expert patient advisor as part of the NICE guidance in that case but not for Colobreathe. For Bronchitol, no work seems to have been done on the effect of this sugar-based treatment on glucose levels in the airways which, as someone with CF-related diabetes who knows that bugs love sugar, would worry me. And it only has a very marginal effect on FEV1. I think perhaps NICE want to move people from expensive Pulmozyme onto Bronchitol over time but there is no evidence to say patients can switch. The evidence submitted seems so arbitrary and variable. I hate to see patients denied good drugs for bad reasons! Sorry to rant. Keep up the great work.

    • We are indeed doing something similar in CF – check out the reviews from the Cystic Fibrosis & Genetic Disorders Group via The Cochrane Library (www.thecochranelibrary) or our own website (www.cfgd.cochrane.org). We also have problems with data not being available – in our recent review of inhaled antibiotics for exacerbations the most of the trials were run in the 1980s and data have simply been lost because no one knows who has the records. We also still have problems with the more recent trials where data are not made available even though we know the investigators have access to them – this can be for multitude of reasons and I won’t get into a rant about that one just now! You might also be interested in another review of oral anti-pseudomonal antibiotics for CF which couldn’t show if oral antibiotics were better than alternatives or not. We have more antibiotic reviews in the pipeline – one of which is looking at IV antibiotics for exacerbations. It has been held up somewhat because the authors have been … guess what … oh yes, trying to get data from trial investigators! But we hope to be able to move this on soon. Another interesting angle which might interest you is our review on antibiotic adjuvant therapies, in other words treatments you can use to try and make bacteria more sensitive to either antibiotics or to the body’s own immune system. These treatments are simple things like garlic and zinc supplements – although unfortunately at the moment there are only trials of long-term use and not for exacerbations.

      Oli, picking up on your interest on nebs and inhalers, we have another review which will hopefully be online by the end of March comparing different nebuliser systems for different drugs. We’re always looking at getting patient input on our reviews, so if you’re interested drop me a line and next time I want a patient perspective I’ll be in touch.

      • Thanks for flagging this up Oli. For those who don’t know, Prof Alan Smyth is the Co-ordinating Editor of the Cochrane Cystic Fibrosis and Genetic Disorders Group. Love the new CF Unite website and there’s some really useful stuff about the research process. Great to see a place which aims to bring health researchers together with people who have CF and get them talking!

  2. Thanks Oli for your positive feedback on the blog – we’re hoping to feature some CF reviews in future posts – and for your interesting comments. Thanks too to Nikki for the info on activity from the Cochrane Cystic Fibrosis and Genetic Disorders Group. It’s interesting to hear yet another instance of trial data being withheld… Cochrane reviews use the best available evidence, but sometimes the evidence isn’t made available! We really hope this blog will become a space where people discuss what Cochrane reviews might mean for them, and what future trials (and reviews!) should consider. We find lots of conversations are taking place on twitter (where I try to add the hashtag #CochraneEvidence to my tweets) and we’re hoping to generate some conversation on Facebook. We have a UK Cochrane Centre page but you might also be interested in the Cochrane Cystic Fibrosis and Genetic Disorders Group’s page and the Cochrane Consumer Network page.
    Keep the comments coming!
    Sarah Chapman UK Cochrane Centre

  3. Pingback: Newer nebulisers cut treatment times for people with cystic fibrosis | Evidently Cochrane

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s