Oral non‐steroidal anti‐inflammatory drug therapy for lung disease in cystic fibrosis New search for studies and content updated (no change to conclusions)
Progressive lung damage causes most deaths in cystic fibrosis. Non‐steroidal anti‐inflammatory drugs (such as ibuprofen) may prevent progressive pulmonary deterioration and morbidity in cystic fibrosis. This is an update of a previously published review.Objectives
To assess the effectiveness of treatment with oral non‐steroidal anti‐inflammatory drugs in cystic fibrosis.Search methods
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, hand searches of relevant journals and abstract books of conference proceedings. We contacted manufacturers of non‐steroidal anti‐inflammatory drugs and searched online trials registries.
Latest search of the Group's Trials Register: 21 November 2018.Selection criteria
Randomized controlled trials comparing oral non‐steroidal anti‐inflammatory drugs, at any dose for at least two months, to placebo in people with cystic fibrosis.Data collection and analysis
Two authors independently assessed trials for inclusion the review and their potential risk of bias. Two authors independently rated the quality of the evidence for each outcome using the GRADE guidelines.Main results
The searches identified 17 trials; four are included (287 participants aged five to 39 years; maximum follow‐up of four years) and one is currently awaiting classification pending publication of the full trial report and two are ongoing. Three trials compared ibuprofen to placebo (two from the same center with some of the same participants); one trial assessed piroxicam versus placebo.
The three ibuprofen trials were deemed to have good or adequate methodological quality, but used various outcomes and summary measures. Reviewers considered measures of lung function, nutritional status, radiological assessment of pulmonary involvement, intravenous antibiotic usage, hospital admissions, survival and adverse effects. Combined data from the two largest ibuprofen trials showed a lower annual rate of decline for lung function, % predicted forced expiratory volume in one second (FEV1), mean difference (MD) 1.32 (95% confidence interval (CI) 0.21 to 2.42) (moderate‐quality evidence); forced vital capacity (FVC), MD 1.27 (95% CI 0.26 to 2.28) (moderate‐quality evidence); forced expiratory flow (FEF25%‐75%), MD 1.80 (95% CI 0.15 to 3.45). The post hoc analysis of data from two trials split by age showed a slower rate of annual decline of FEV1 % predicted and FVC in the ibuprofen group in younger children, MD 1.41% (95% CI 0.03 to 2.80) (moderate‐quality evidence) and MD 1.32% (95% CI 0.04 to 2.60) (moderate‐quality evidence) respectively. Data from four trials demonstrated the proportion of participants with at least one hospitalization may be slightly lower in the ibuprofen group compared to placebo, Peto odds ratio 0.61 (95% CI 0.37 to 1.01) (moderate‐quality evidence). In one trial, long‐term use of high‐dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. No major adverse effects were reported, but the power of the trials to identify clinically important differences in the incidence of adverse effects was low.
We did not have any concerns with regards to risk of bias for the trial comparing piroxicam to placebo. However, the trial did not report many data in a form that we could analyze in this review. No data were available for the review's primary outcome of lung function; available data for hospital admissions showed no difference between the groups. No analyzable data were available for any other review outcome.Authors' conclusions
High‐dose ibuprofen can slow the progression of lung disease in people with cystic fibrosis, especially in children, which suggests that strategies to modulate lung inflammation can be beneficial for people with cystic fibrosis.
Larry C Lands, Sanja Stanojevic
Plain language summary
Treatment with oral drugs other than steroids to reduce lung inflammation and deterioration in lung function in people with cystic fibrosis
We reviewed evidence to see if drugs that were not steroids could reduce inflammation in the lungs and stop lung function getting worse in people with cystic fibrosis.
Inflammation in the lungs increases the damage done to them and is the most common reason for early death in people with cystic fibrosis. In high doses, non‐steroidal anti‐inflammatory drugs, particularly ibuprofen, may work against inflammation, but in low doses there is some evidence that they may cause the inflammation. The use of high doses has also raised concerns about the potential for unwanted effects, which has limited the use of these drugs in cystic fibrosis.
The evidence is current to: 21 November 2018.
We looked for trials comparing oral non‐steroidal anti‐inflammatory drugs to a a placebo (a tablet that contained no active medicine). We looked for any dose level. but the trial had to run for at least two months in people with cystic fibrosis. We found 17 trials and included four of these with a total of 287 people aged five to 39 years; one further trial has not yet been published in full and two are still ongoing; we will assess these when we have more information. Three of the four included trials compared ibuprofen to a placebo; two of these trials were run in the same center and used some of the same people. One trial compared a drug called piroxicam to placebo. The longest trial lasted four years.
We aimed to report on lung function, nutritional status, lung x‐rays, how often intravenous antibiotics were needed, details about hospital admissions, survival and side effects.
We combined results from the two largest ibuprofen trials and showed that those taking ibuprofen had a lower annual rate of decline in lung function which was consistent across three lung function measurements. We then looked at these results split by age (even though we did not originally plan to do this) and found that two of the measurements showed a slower rate of annual decline in lung function in younger children. Results from four trials showed that fewer participants in the ibuprofen group were admitted to hospital at least once compared to placebo, although it was not clear if the difference was just chance or not. In one trial, people taking a long‐term high dose of ibuprofen were less likely to need intravenous antibiotics, had better nutritional status and healthier lungs as seen by X‐ray. No major side effects were reported in the trials, but they had not been designed to show differences in the rates of side effects.
To summarize, we found evidence showing that a high dose of a non‐steroidal anti‐inflammatory drug, most notably ibuprofen, may slow the progression of lung damage in people with cystic fibrosis, especially in younger people. The long‐term safety results are limited but we feel that there is enough evidence to suggest that non‐steroidal anti‐inflammatory drugs be temporarily stopped when people with cystic fibrosis are receiving intravenous aminoglycosides or other drugs that may badly damage the kidneys.
The trial of the drug piroxicam did not report many results in a form that we could analyse in the review. We did not have any results for our main outcome of lung function. The only results we had reported no difference between the piroxicam group and the placebo group for the number of hospital admissions.
Quality of the evidence
We judged the evidence to be of moderate quality overall. We thought the three ibuprofen trials had a good or adequate level of methodological quality with little risk of bias to the results, but used a range of different outcomes and summary measures. We did not have any concerns with regards to risks of bias for the trial comparing piroxicam to placebo.
Larry C Lands, Sanja Stanojevic
Implications for practice
The results of this review suggest that high‐dose ibuprofen probably slows the progression of lung disease in children with cystic fibrosis (CF). There may also be a beneficial effect on the number of days spent in hospital and ibuprofen appears to be relatively well‐tolerated. However, the long‐term effects of prolonged use of high doses of oral non‐steroidal anti‐inflammatory drugs (NSAIDs) have yet to be determined. Furthermore, gastrointestinal protection is required as are regular pharmacokinetic trials and safety profiles.
The need to repeat pharmacokinetic analyses in people taking ibuprofen is important to note. The current programs using ibuprofen suggest repeating these assays at least every two years, but more frequent follow‐up is necessary if there is a weight change of more than 25%. It is suggested that hematologic, renal, and hepatic status are monitored annually.
Given the findings on adverse events from non‐randomised studies as outlined above and the evidence on adverse effects from this review, the use of NSAIDs should be temporarily discontinued during intravenous administration of aminoglycosides and possibly colymycin (colistin) (Bertenshaw 2007). Furthermore, individuals with esophagitis or peptic ulcer disease should not use high‐dose ibuprofen. Individuals with recurrent significant hemoptysis should also not be placed on this treatment.
Implications for research
The clinical variability of CF suggests that it may be helpful for future updates of this systematic review to be based on individual patient data rather than on the published trial reports, as this will allow appropriate meta‐analysis of within‐participant changes from baseline. All trials should be designed to be of adequate power to reliably identify important adverse events such as, for example, major gastrointestinal haemorrhage. Multicenter trials will add to the validity of findings by enhancing their generalisability.
While this review suggests that NSAID therapies probably slow down the rate of lung function decline in people with CF, further work is required to understand the mechanism of action so that therapies with enhanced safety profiles can be developed. Trials examining the effectiveness and safety of long‐term use of NSAIDs and other anti‐inflammatory therapies are required in young symptomatic children as well as very young pre‐symptomatic children.
Monitoring the effects of therapeutic treatment relies on appropriate detection of important clinical changes in lung function. Since a biological marker for identifying lung function changes has yet to be identified, follow‐up studies require recruitment of a sufficiently large sample, followed repeatedly over a period deemed adequate to detect important clinical changes which are a direct result of the therapeutic intervention.
Future trials need to address the age at which therapy is most effective. While pulmonary function and nutritional status are the primary outcomes of interest, evidence for a reduction in concomitant therapy, specifically intravenous antibiotic use, as well as in hospital admissions for respiratory exacerbations, should be sought. Evidence from this review suggests that there may be important reductions in days spent in hospital for all causes, but these findings require confirmation in other studies, which ideally should identify hospital admissions for respiratory exacerbations separately. These secondary outcome measures may have important implications for cost‐effectiveness of treatment as well as quality of life. Although there are methodological problems in measuring quality of life for very young children, it is feasible to measure quality of life in older children and in their parents or carers. Future trials should begin to assess these outcomes as, given the current median survival for CF, quality of life assumes greater relevance.
Finally, the effectiveness of NSAIDs may need to be re‐investigated in the era of CF modulator therapy.Get full text at The Cochrane Library
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