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Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis

  1. Larry C Lands1,*,
  2. Sanja Stanojevic2

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 13 JUN 2013

Assessed as up-to-date: 23 MAY 2013

DOI: 10.1002/14651858.CD001505.pub3


How to Cite

Lands LC, Stanojevic S. Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD001505. DOI: 10.1002/14651858.CD001505.pub3.

Author Information

  1. 1

    Montreal Children's Hospital, Department of Pediatrics, Montreal, Quebec, Canada

  2. 2

    The Hospital for Sick Children, Child Health Evaluative Sciences & Respiratory Medicine, Toronto, Ontario, Canada

*Larry C Lands, Department of Pediatrics, Montreal Children's Hospital, 2300 Tupper Street, Montreal, Quebec, H3H-1PA, Canada. larry.lands@muhc.mcgill.ca.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 13 JUN 2013

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This is not the most recent version of the article. View current version (07 APR 2016)

 
Characteristics of included studies [ordered by study ID]
Konstan 1991

MethodsRandomized, double-blinded, placebo-controlled, 3-month dose escalation study in children with CF.
Randomized to ibuprofen or placebo in a ratio of 2:1.
Computer-generated random code.


Participants19 children with CF aged 6-12 years.
Inclusion criteria - diagnosed clinically and by sweat test, aged 6-12 years. Eligible if FEV1 > 30% predicted for age, height and gender; judged to be clinically stable; no history of adverse effects with aspirin, ibuprofen or other NSAID; not taking 'interfering medication' (not defined).
13 (7 male) in treatment group and 6 (3 male) in placebo group. 1 female in placebo group dropped out on day 1 because of difficulty with venous access.


Interventions3-month dose escalation study. Participants received 300 mg of drug orally and twice daily during the first month, and, depending on pharmacokinetic studies, 400 mg in the second month, and 600 mg in the third month. Control - placebo.


OutcomesCompliance.
Number to complete.
Dropout rates.
Number hospital admissions for exacerbations.
Number hospital days for exacerbations.
Percentage predicted FEV1.
Adverse events e.g. abdominal pain, occult blood, change in number of stools and epistaxis.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdequate, randomisation was based upon a computer-generated randomisation sequence.

Allocation concealment (selection bias)Low riskAdequate, the randomisation sequence was provided by the pharmaceutical company (Upjohn).

Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as double blinded. The pharmaceutical company provided the clinics with identical-appearing placebo tablets.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 15% of participants excluded (three participants) due to poor venous access, behavioural problems and difficulty in transport to follow up trial visits.

Selective reporting (reporting bias)High riskOutcomes listed were reported, but the trial investigators monitored a large number of potential adverse effects of ibuprofen: reporting was confined to those considered to be most important and findings which were not statistically significant were not reported

Other biasUnclear riskReported adverse events.

Konstan 1995

MethodsRandomized double-blinded, placebo-controlled study.
Permuted blocks of 4 participants stratified by age.
Randomization code was known only by the pharmacologist and the pharmacist.


Participants85 people with CF aged 5-39 years.
Inclusion criteria - people with CF, diagnosed clinically and by sweat test, not treated with intravenous antibiotics in preceding 2 months and with FEV1 at least 60% predicted.
42 (26 male) were in the treatment group and 43 (15 male) in placebo group; age range 5-39 years.
Exclusion criteria: systemic or inhaled corticosteroids used within two years of recruitment or inhaled sodium cromoglycate used within 6 months of recruitment.

A total of 28 participants withdrew from study, with similar numbers in both groups (15 in treatment group, 13 in placebo group).


InterventionsParticipants randomly assigned to receive high-dose oral ibuprofen twice daily for 4 years or placebo twice daily for 4 years. Dose 20-30 mg per kg of body weight, to a maximum of 1600 mg, determined by pharmacokinetic analyses.


OutcomesCompliance (pill counts and blood monitoring)
Number to complete
Dropout rates
Number hospital admissions for exacerbations
Number hospital days for exacerbations
Annual rate of change in FEV1, FVC, FEF25-75%
Percentage predicted FEV1, FVC, FEF25-75
Annual rate of change in percentage ideal body weight
Change in Brasfield chest X-ray score over 4-year period
Intravenous antibiotics administered at home
Adverse events e.g. abdominal pain, conjunctivitis, epistaxis
Concomitant therapy


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdequate, randomisation was carried out with permuted blocks of four participants each stratified by age (under 13 years, 13 to 18 years and 19 years or over).

Allocation concealment (selection bias)Low riskAdequate, paper states that only the pharmacologist and pharmacist were privy to the allocation.

Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as double blinded. The placebo tablets were identical in appearance to the ibuprofen tablets.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAnalysis was based on intention-to-treat.

A total of 28 participants withdrew from study, with similar numbers in both groups (15 in treatment group, 13 in placebo group).

Selective reporting (reporting bias)High riskOutcomes listed were reported, but the trial investigators monitored a large number of potential adverse effects of ibuprofen: reporting was confined to those considered to be most important and findings which were not statistically significant were not reported

Other biasUnclear riskIntention-to-treat and completed treatment analysis are presented, intention-to-treat analysis was only used in the meta-analysis.

Reported adverse events.

Funded by the Cystic Fibrosis Foundation and the National Institutes of Health.

Lands 2007

MethodsMulticenter double-blind placebo-controlled trial.
Allocated treatment by a centralized pharmacy using a pre-defined block randomization schedule.


Participants142 children with CF aged 6-18 years.
Inclusion criteria: FEV1 >60% predicted at time of entry into the trial, with no hospitalizations in the previous 2 months.
Exclusion criteria: people who had taken systemic corticosteroids or non-steroidal anti-inflammatory agents for more than 1 month in the past year, had abnormal hepatic, renal, hematoologic disorders or coagulopathy, documented evidence of peptic ulcer disease(endoscopy) or allergic bronchopulmonary aspergillosis, or a history of hypersensitivity reactions to non-steroidal anti-inflammatory agents.

18 participants (9 in each group) did not complete full 2 years of follow up, 11 due to adverse events (4 in treatment group, 7 in placebo group).


InterventionsAll participants underwent a baseline pharmoacokinetic study (baseline every hour for 3 hours), employing 200 mg tablets (Upjohn-Pharmacia) at a dose of 20 to 30 mg/kg to a maximum of 1600 mg. The number of assigned pills were then adjusted by the coordinating pharmacologist to provide a peak plasma concentration of 50 to 100 microg/ml for each participant in the study. Participants then were asked to take the prescribed number of pills (ibuprofen or placebo) twice daily.


OutcomesAnnual rate of change in FEV1 % predicted, FVC % predicted, anthropometric data, chest radiograph score, number of hospitalizations (and length of stay), adverse effects, compliance, concomitant therapy(antibiotics, inhaled anti-inflammatory agents).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdequate, participants were allocated using a predefined block-randomisation schedule.

Allocation concealment (selection bias)Low riskAdequate, a central pharmacy coded and shipped the tablets to the participating centers; the code was broken by the central pharmacy only on request from the Safety and Monitoring Committee.

Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as double blinded. Paper states that participants, care-givers and study personnel were all blinded to treatment assignment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAnalysis was based on intention-to-treat.

18 participants (9 in each group) did not complete full 2 years of follow up, 11 due to adverse events (4 in treatment group, 7 in placebo group); details of these events in paper.

Selective reporting (reporting bias)Low riskOutcomes listed were reported.

Other biasUnclear riskReported adverse events.

Funders did not have a role in the analysis or publication of results.

Shmarina 2004

MethodsParallel trial, authors confirmed randomised but not blinded.


Participants47 participants enrolled; 20 in Group A and 27 in Group B


InterventionsGroup A: nimesulide (an NSAID with analgesic and antipyretic properties; it is a sulphonanilide analogue, not related to conventional NSAIDs) daily 3 mg per kg of body weight

Group B: clarithromycin 250 mg every other day orally


OutcomesInflammatory markers in sputa (neutrophil elastase activity, IL-8 and TNF-α levels and protein concentration) and peripheral blood (lymphocyte response to PHA and cell sensitivity to steroid suppression). Also, FEV1 and FVC % change.

Measured at baseline, 3, 6 and 12 months of treatment


NotesFirst abstract states 6 months of treatment, second abstract states up to 12 months of treatment.

First abstract states 42 participants (15 in nimesulide group and 27 in clarithromycin group) but second abstract states 47 participants (20 in nimesulide group and 27 in clarithromycin group).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAuthors confirmed randomised, but no details available regarding method yet.

Allocation concealment (selection bias)Unclear riskNo details given.

Blinding (performance bias and detection bias)
All outcomes
High riskAuthors confirmed not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information available to make judgement.

Selective reporting (reporting bias)Unclear riskInsufficient information available to make judgement.

Other biasUnclear riskInsufficient information available to make judgement.

Sordelli 1994

MethodsRandomized, double-blinded, placebo-controlled study of piroxicam or placebo.
Participants distributed into 2 balanced groups according to sex, age and Shwachman score.
Allocation concealment and generation of the allocation sequence unclear.


Participants41 people with CF aged 5 - 37 years.
Inclusion criteria: people with CF, diagnosed by sweat test and clinically, and regularly attending the CF clinic at the Children's Hospital in Buenos Aires.
Participants were aged 5 - 37 years and 20 (10 male) were randomized to active treatment with piroxicam and 21 (11 male) to treatment with placebo.


InterventionsDoses were according to participants' body weight: <15 kg: 5 mg/day; 16-25 kg: 10 mg/day; 26-45 kg: 15 mg/day and >46 kg: 20 mg/day. Piroxicam and placebo were taken by the participants in a single morning dose. Treatment was suspended during periods of hospitalization and reinstated after discharge. Participants for whom treatment was suspended for more than 30 days were removed from the trial.


OutcomesDropout rates.
Deaths.
Number of hospital admissions.
Number of hospital days.
Number of participants admitted.
Increase in abdominal pain.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskProcess was described as random in the paper, but the randomisation method was not described.

Allocation concealment (selection bias)Unclear riskUnclear, concealment of allocation was not discussed.

Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as double blinded. Paper describes the placebo tablets as being "indistinguishable" from the piroxicam tablets.

Incomplete outcome data (attrition bias)
All outcomes
Low riskMore than 15% of participants were excluded from the intention-to-treat analysis (n = 8) (Sordelli 1994). Four participants from the treatment group and four from the control group did not complete the study. Reasons for exclusion included abdominal pain, hematemesis, hepatic dysfunction and acute respiratory exacerbation.

Selective reporting (reporting bias)Low riskOutcomes listed were reported.

Other biasUnclear riskReported adverse events.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Chmiel 2007Follow-up period did not meet inclusion criteria

Kovaleva 2000Not a study of NSAIDs. Study reported a mucolytic combined with nebulizer therapy compared to nebulizer therapy alone.

Noritake 1982Study reported effect of single dose of aspirin only.

 
Comparison 1. Oral nonsteroidal anti-inflammatory drug versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Annual rate of change in % predicted FEV12226Mean Difference (IV, Fixed, 95% CI)1.32 [0.21, 2.42]

 2 Annual rate of change in % predicted FEV1 (split by age)2226Mean Difference (IV, Fixed, 95% CI)1.16 [0.07, 2.25]

    2.1 Under 13 years at randomisation
2147Mean Difference (IV, Fixed, 95% CI)1.41 [0.03, 2.80]

    2.2 13 years or over at randomisation
279Mean Difference (IV, Fixed, 95% CI)0.75 [-1.02, 2.52]

 3 Annual rate of change in % predicted FVC2226Mean Difference (IV, Fixed, 95% CI)1.27 [0.26, 2.28]

 4 Annual rate of change in % predicted FVC (split by age)2226Mean Difference (IV, Fixed, 95% CI)1.09 [0.12, 2.06]

    4.1 Under 13 years at randomisation
2147Mean Difference (IV, Fixed, 95% CI)1.32 [0.04, 2.60]

    4.2 13 years and over at randomisation
279Mean Difference (IV, Fixed, 95% CI)0.78 [-0.71, 2.27]

 5 Annual rate of change in % predicted FEF25-75%2218Mean Difference (IV, Fixed, 95% CI)1.80 [0.15, 3.45]

 6 Annual rate of change in % predicted FEF25-75% (split by age)2214Mean Difference (IV, Fixed, 95% CI)1.72 [0.10, 3.34]

    6.1 Under 13 years at randomisation
2138Mean Difference (IV, Fixed, 95% CI)2.03 [-0.09, 4.16]

    6.2 13 years or older at randomisation
276Mean Difference (IV, Fixed, 95% CI)1.28 [-1.22, 3.79]

 7 Proportion with at least one respiratory hospitalisation1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 8 Proportion with at least one hospital admission4286Peto Odds Ratio (Peto, Fixed, 95% CI)0.61 [0.37, 1.01]

 9 Number of deaths3245Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Annual rate of change in % ideal body weight1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 11 Annual rate of change in % ideal body weight (split by age)184Mean Difference (IV, Fixed, 95% CI)0.81 [0.08, 1.53]

    11.1 Under 13 years at randomisation
149Mean Difference (IV, Fixed, 95% CI)1.45 [0.33, 2.57]

    11.2 13 years or older at randomisation
135Mean Difference (IV, Fixed, 95% CI)0.34 [-0.61, 1.29]

 12 Chest X-ray score2226Mean Difference (IV, Fixed, 95% CI)0.37 [-0.08, 0.81]

 13 Chest X-ray score (split by age)184Mean Difference (IV, Fixed, 95% CI)0.51 [-0.04, 1.07]

    13.1 Under 13 years at randomisation
149Mean Difference (IV, Fixed, 95% CI)0.45 [-0.24, 1.14]

    13.2 13 years or older at randomisation
135Mean Difference (IV, Fixed, 95% CI)0.63 [-0.30, 1.56]

 14 Increase in abdominal pain2226Peto Odds Ratio (Peto, Fixed, 95% CI)0.54 [0.20, 1.48]

 15 Decrease in abdominal pain1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 16 Proportion with at least one gastrointestinal hospitalisation1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 17 Stool frequency1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 18 Occult blood1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 19 Increase in epistaxis1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 20 Decrease in epistaxis1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 21 Increase in conjunctivitis2226Peto Odds Ratio (Peto, Fixed, 95% CI)0.72 [0.22, 2.40]

 22 Decrease in conjunctivitis1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 23 Increase in nausea1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 24 Increase in diarrhoea1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected