NSAIDs as treatment for uncomplicated urinary tract infections

Journal reference: Gagyor I, Bleidorn J, Kochen MM, Schmiemann G, Wegscheider K, Hummers-Pradier E. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial. Bmj 2015 Dec 23;351:h6544.

Link: http://doi.org/10.1136/bmj.h6544

Published: December 2015

Evidence cookie says…

NSAIDs should not be recommended as a first line treatment for uncomplicated UTIs in women compared with women who received empirical antibiotics, those who received regular ibuprofen as treatment experienced more UTI symptoms however, most of the women who received NSAIDs did recovery from the UTI and used less antibiotics

Clinical scenario

Evangeline, a 21-year-old female university student, recently presented with typical symptoms of uncomplicated cystitis.  I recalled a discussion on the GPs Down Under forum that discussed the surprising (to me) concept that NSAIDs (non-steroidal anti-inflammatory drugs) could be used rather than antibiotics.  What is the evidence for this therapy?

Clinical question

What is the effect of oral NSAIDs on symptoms and cure of uncomplicated UTIs, as compared to antibiotics?

What does the research evidence say?

Step 1: The Cochrane Library

There are several systematic reviews of antibiotics as treatment for urinary tract infections (UTIs) [1], but not on the use of NSAIDs.

Step 2: TripDatabase

I conducted a search using the TripDatabase PICO search tool (Participant: “UTI”, Intervention: “NSAID”, Comparator: “antibiotics”, Outcomes: blank).  The first and only relevant result was an evidence synopsis in BestBETs on this topic that, that found only one small pilot study published in 2010 [2].

Step 3:

I further conducted a search in PubMed to identify any newer and larger studies.  I identified one randomised trial by the authors of the 2010 study, published in the BMJ in 2015.  Let’s look at this study by Gágyor and colleagues in more detail [3].

Critical appraisal

I will use the randomised controlled trial appraisal sheet from the Centre for Evidence Based Medicine [4].

PICO

Participants: who was studied?

Women aged 18-65 attending general practice clinics in northern Germany with symptoms suggestive of a UTI (dysuria ± frequency/urgency ± lower abdominal pain) were approached for inclusion in the study.    Exclusions included: signs of upper urinary tract infection (fever, loin tenderness), pregnancy, renal disease, UTI within the last two weeks, urinary catheterisation, current NSAID use, and current antibiotic use.

Out of 1,184 assessed for eligibility, 494 were randomised, and 446 competed the study.  The mean age of the participants was 37 years.  Almost all the participants had dysuria and frequency/urgency as symptoms, and just over half had had symptoms for up to 2 days.  Around 75% had a positive urine culture, with E. coli the most common isolate.

Intervention: what was the exposure?

3 × ibuprofen 400 mg daily, for three days, with 1 × sachet placebo granules

Comparator: what was the control/alternative?

1 × fosfomycin 3 g sachet, with 3 × placebo tablets for three days

Women in both groups were advised to consult their GP again if symptoms persisted or worsened, and antibiotic treatment could be initiated on the GP’s discretion.

Outcomes: what was measured?

Primary outcome:

• total number of courses of antibiotics on days 0-28
• burden of symptoms on days 0-7 (measured as area under the curve of the sums of daily symptom scores)

Internal validity: are the trial results valid?

Randomised patient assignment?

Yes.  The randomisation process was computer generated.

Groups similar at the start?

Yes.  The groups were largely similar (see Table 1, p. 4) [3].

Groups treated equally apart from assigned treatment?

Yes.  The protocol was well designed.

All patients accounted for?

Yes.  There were a small number (< 10%) of participants who did not complete the study, and the analysis was conducted on an intention-to-treat basis (see Stat Facts).

Measures objective?  Or patients and clinicians kept blinded?

Yes/Probably.  Self-reported symptom measures of UTI are somewhat subjective, but there is no evidence that the participants or clinicians not kept blinded.

What were the results?

Primary outcomes:

• The ibuprofen group used less antibiotics compared to the fosfomycin group:
  • incidence rate reduction: 66.5% (95% CI 58.8% to 74.4%, p < 0.001)
• The ibuprofen as compared to the fosfomycin group experienced more symptoms:
  • area under the curve ratio: 140.5% (95% CI 125.4% to 157.3%)

Other outcomes:

• all secondary outcomes related to symptoms favoured the fosfomycin group
• there were more cases of pyelonephritis in the ibuprofen group (4 vs 1) though this was not statistically significant

Discussion and conclusion

The earlier pilot study suggested that ibuprofen might be non-inferior to antibiotics for uncomplicated UTIs [2] – an interesting finding that challenged the assumption that antibiotics are necessary, and perhaps a reminder that in the pre-antibiotic era, UTIs were ultimately self-limiting.

This well conducted and better powered study demonstrates that most women who received ibuprofen had resolution of their UTI.  However, this was at the cost of worse symptoms for a longer duration.  There is furthermore, a suggestion that there is an increased risk for severe outcomes, such as pyelonephritis.

If we take the position that the patient meaningful outcome is symptom burden and cure, rather than necessarily antibiotic avoidance, then ibuprofen most likely inferior to antibiotics.  NSAIDs should not be recommended as a first line treatment for uncomplicated UTIs, though it may have a role in individuals who refuse antibiotic therapy.

Evangeline received an empirical course of trimethoprim and recovered without issue.

Stat Facts

Intention-to-treat analysis

In randomised trials, noncompliance (to the study protocol) and missing outcomes (e.g., participant drop outs) can lead to exaggerated estimates of treatment effects.  One way to address this is for the data to be analysed according to the “intention-to-treat” principle – to include all participants who were randomised in the study [5].

References

1. Zalmanovici Trestioreanu A, Green H, Paul M, Yaphe J, Leibovici L. Antimicrobial agents for treating uncomplicated urinary tract infection in women. Cochrane database of systematic reviews 2010 Oct 06(10):CD007182.
2. Bleidorn J, Gagyor I, Kochen MM, Wegscheider K, Hummers-Pradier E. Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection?–results of a randomized controlled pilot trial. BMC Med 2010 May 26;8:30.
3. Gagyor I, Bleidorn J, Kochen MM, Schmiemann G, Wegscheider K, Hummers-Pradier E. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial. Bmj 2015 Dec 23;351:h6544.
4. Centre for Evidence-Based Medicine. Critical Appraisal tools.  2014  [cited 2017 Apr 10]; Available from: http://www.cebm.net/critical-appraisal/
5. Gupta SK. Intention-to-treat concept: A review. Perspect Clin Res 2011 Jul;2(3):109-12.