Efficacy of anti-inflammatory or antibiotic treatment in patients with non-complicated acute bronchitis and discoloured sputum: randomised placebo controlled trial facilitated by Prof Chris Del Mar

20 November 2013                                                                                

Background

Acute bronchitis is a common reason for visits in primary care: patients present with a persistent cough without pneumonia that is usually self-limiting but can last for four weeks or more. Although usually of viral origin, antibiotics are prescribed in more than 50% of cases, especially if purulent sputum is present. The role of bacteria in acute bronchitis is however very controversial. A Cochrane review including four randomised controlled trials (RCTs) with 275 patients and another large trial with over 2000 patients concluded that treatment of acute bronchitis with antimicrobials in primary care has only a marginal effect on coughing and recovery time1,2. Over-prescription of antibiotics contributes to the global rise of antibiotic resistance and it is therefore vital to limit their use for conditions where they are proven beneficial for the patient. 

Evidence from basic research suggests that acute bronchitis may be driven by an inflammatory rather than an infectious process. Non-steroidal anti-inflammatory drugs (NSAIDs) are often prescribed in patients with lower respiratory infections to alleviate symptoms such as cough but their efficacy in the management of acute bronchitis has not been adequately assessed in RCTs.

Paper presented

Llor et al. conducted a multicentre, parallel, single-blinded placebo controlled randomised clinical trial across nine primary care centres in Spain to evaluate the efficacy of oral anti-inflammatory or antibiotic therapy in the resolution of cough in patients with acute bronchitis with discoloured sputum.

390 patients aged 18 to 70 who have had a cough, discoloured sputum and at least one other symptom of lower respiratory tract infection for less than one week were randomised to receive either ibuprofen (600 mg three times daily), amoxicillin-clavulanic acid (500 mg/125 mg three times daily) or placebo (three times daily) for 10 days. The main outcome measure – number of days with frequent cough after the randomisation visit – was analysed through reporting of symptom diaries.

The author’s main conclusions were:

  • Patients on ibuprofen coughed for slightly fewer days (9 days, 95% confidence interval 8 to 10 days) than those on antibiotics (11 days, 10 to 12 days) or placebo (11 days, 8 to 14 days). This difference is not statistically significant and therefore the authors conclude that anti-inflammatory or antibiotic treatment is not more effective than placebo in shortening cough time.
  • The percentage of adverse side effects was low (27 out of 390 patients, 12% in the antibiotic arm, 5% in the ibuprofen arm, and 3% in the placebo arm) but this was statistically significant.

Discussion

We critically appraised the study using the RAMbo mnemonic:

‘R’andomisation was good: equal distribution of characteristics between groups and external block randomisation of patients.

‘A’ttrition was not significant: few patients were lost in follow-up and the drop-out rate was similar for all groups.

‘M’easurement was deemed appropriate, although not ideal as the trial was only single-blinded and the tablets given were not identical.

The subsequent discussion was mainly focussed around the interpretation of the Kaplan-Meyer survival analysis of days with frequent cough. At two weeks post-randomisation, about 45% of patients on the placebo arm were still coughing compared with around 30% on the ibuprofen arm. It was suggested that the author’s may have underestimated the effect of ibuprofen. Although not statistically significant, the effect could be deemed clinically significant because ibuprofen treatment does not cause much harm and for a patient who is coughing, getting relief 1-2 days earlier may actually be beneficial. Moreover, if this result would convince a few GPs to prescribe ibuprofen instead of antibiotics, then that could be a step forward in the fight of antibiotic resistance.

The results were also compared to those of the Little study2. Their Kaplan-Meyer curve follows a similar separation, although it occurs earlier (45% of patients on antibiotics report symptom improvement by day 7 vs 55% on the placebo arm). However, this study had a different outcome measure (symptoms rated “moderately bad” or worse) and recruited patients later (mean duration of cough 9.3-9.5 days) than the Llor study (mean duration of cough 3.8-4.1 days).

We finished by discussing what would be an appropriate outcome measure for a similar study. Symptom severity was considered a good candidate, but it could be useful to first conduct a community survey to determine the most frequent symptoms of bronchitis and which are the most bothersome. Perhaps the number of different concurrent symptoms could be an indication of disease severity and provide a more objective and quantitative outcome measure.

What should we do next?

We wondered whether ‘area under the curve’ (cough duration x time) might give us a significant benefit (in units of ‘days of cough time’). To be discussed with statisticians…

References

  1. Smith SM, Fahey T, Smucny J, Becker LA. Antibiotics for acute bronchitis. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD000245.
  2. Little P, Stuart B, Moore M, Coenen S, Butler CC, Godycki-Cwirko M, Mierzecki A, Chlabicz S, Torres A, Almirall J, Davies M, Schaberg T, Mölstad S, Blasi F, De Sutter A, Kersnik J, Hupkova H, Touboul P, Hood K, Mullee M, O’Reilly G, Brugman C, Goossens H, Verheij T; GRACE consortium. Amoxicillin for acute lower-respiratory-tract infection in primary care when pneumonia is not suspected: a 12-country, randomised, placebo-controlled trial. Lancet Infect Dis. 2013 Feb; 13(2):123-9.
  3. Llor C, Moragas A, Bayona C, Morros R, Pera H, Plana-Ripoll O, et al. Efficacy of anti-inflammatory or antibiotic treatment in patients with non-complicated acute bronchitis and discoloured sputum: randomised placebo controlled trial. BMJ 2013;347

 (Summary by Michele Weber)

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