Pancreatic enzyme replacement therapy for people with cystic fibrosis
Abstract
Background
Most people with cystic fibrosis (80% to 90%) need pancreatic enzyme replacement therapy to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed. A systematic review on the efficacy and safety of pancreatic enzyme replacement therapy is needed to guide clinical practice, as there is variability between centres with respect to assessment of pancreatic function, time of commencing treatment, dose and choice of supplements.
Objectives
To evaluate the efficacy and safety of pancreatic enzyme replacement therapy in children and adults with cystic fibrosis and to compare the efficacy and safety of different formulations of this therapy and their appropriateness in different age groups. Also, to compare the effects of pancreatic enzyme replacement therapy in cystic fibrosis according to different diagnostic subgroups (e.g. different ages at introduction of therapy and different categories of pancreatic function).
Search methods
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 14 August 2014.
We also searched an ongoing trials website and the websites of the pharmaceutical companies who manufacture pancreatic enzyme replacements for any additional trials. Most recent search: 12 May 2014.
Selection criteria
Randomised and quasi‐randomised controlled trials in people of any age, with cystic fibrosis and receiving pancreatic enzyme replacement therapy, at any dosage and in any formulation, for a period of not less than four weeks, compared to placebo or other pancreatic enzyme replacement therapy preparations.
Data collection and analysis
Two authors independently assessed trials and extracted outcome data. They also assessed the risk of bias of the trials included in the review.
Main results
One parallel trial and 11 cross‐over trials of children and adults with cystic fibrosis were included in the review. The number of participants in each trial varied between 14 and 129 with a total of 426 participants included in the review. All the included trials were for a duration of four weeks. The included trials had mostly an unclear risk of bias from the randomisation process as the details of this were not given; they also mostly had a high risk of attrition bias and reporting bias.
We could not combine data from all the trials as they compared different formulations. Findings from individual studies provided insufficient evidence to determine the size and precision of the effects of different formulations. Ten studies reported information on the review's primary outcome (nutritional status); however, we were only able to combine data from two small cross‐over studies (n = 41). The estimated gain in body weight was imprecise, 0.32 kg (95% confidence interval ‐0.03 to 0.67, P = 0.07). Combined data from the same studies gave statistically significant results favouring enteric‐coated microspheres over enteric‐coated tablets for our secondary outcomes stool frequency, abdominal pain and fecal fat excretion. Data from another single small cross‐over study also favoured enteric‐coated microspheres over non‐enteric‐coated tablets with adjuvant cimetidine in terms of stool frequency.
Authors' conclusions
There is limited evidence of benefit from enteric‐coated microspheres when compared to non‐enteric coated pancreatic enzyme preparations up to one month. In the only comparison where we could combine any data, the fact that these were cross‐over studies is likely to underestimate the level of inconsistency between the results of the studies due to over‐inflation of confidence intervals from the individual studies.There is no evidence on the long‐term effectiveness and risks associated with pancreatic enzyme replacement therapy. There is also no evidence on the relative dosages of enzymes needed for people with different levels of severity of pancreatic insufficiency, optimum time to start treatment and variations based on differences in meals and meal sizes. There is a need for a properly designed trial that can answer these questions.
PICOs
Plain language summary
Pancreatic enzyme supplements for people with cystic fibrosis
Review question
We reviewed the evidence about how good pancreatic enzyme supplements are in overcoming the enzyme deficiency in people with cystic fibrosis and if these supplements have any side effects.
Background
Between 80% and 90% of people with cystic fibrosis take pancreatic enzyme supplements. In these people, the pancreas is often not able to make the enzymes needed to digest food, which in children can result in a failure to gain weight and to thrive. In adults, it can lead to a loss in body weight and in malnutrition because the body does not absorb vitamins properly. In both children and adults with CF, malnutrition is linked to poorer general health, more severe lung disease and shorter life expectancy. If the pancreas is not making enough enzymes, people with CF can also experience unpleasant symptoms such as painful, frequent, bulky, offensive bowel movements. Pancreatic enzyme supplements are therefore needed to help gain weight, to prevent malnutrition and to avoid some vitamin deficiencies, as well as to control bowel symptoms.
Search date
We last searched for evidence: 14 August 2014.
Study characteristics
The review included 12 studies with 426 adults and children with cystic fibrosis; in all of them treatment lasted for four weeks. Studies compared different formulations of pancreatic enzyme supplements, so we could not combine many of the results. Also the design of 11 of the studies meant that volunteers received both types of supplement for four weeks each, although the order in which they received them was chosen at random. This also made it difficult to analyse the results. Most of the studies were old; the most recent was from 2005, but the oldest was from 1986.
Key results
We could only combine data from two small studies where volunteers took miniature drug capsules (microspheres), which were treated so that the release of the medication is delayed until they have passed from the stomach into the intestine and normal size tablets which were treated in the same way. The results did not clearly favour one or the other treatment for any of our most important outcomes (weight, height or body mass index). However, those taking the delayed‐release microspheres had less fat in their faeces than those taking delayed release tablets (normal size) as well as having less abdominal pain and not needing to go to the toilet as often. In a different study, the volunteers taking the delayed‐release microspheres also had less fat in their faeces than those taking supplements that weren't treated so the release of medication was delayed. We didn't find any evidence that one type of these enteric‐coated microspheres was better than another; or that enteric‐coated microspheres were better than enteric‐coated mini‐microspheres (which are smaller).
We didn't find any evidence on different doses of enzymes needed for people who produce different levels of pancreatic enzymes, on the best time for patients to start treatment and different amounts of supplements based on differences in type of food eaten and meal sizes. A properly designed trial to answer these questions is needed.
Quality of the evidence
We could not be sure that the patients in the included trials had equal chances of being put into the different treatment groups as no details were published about how the decisions were made. Several trials also had large numbers of participants who dropped out and often reasons for this were not given. In most trials, volunteers took one treatment and then after a while swapped to the alternative treatment; we could only combine results from two trials which were designed in this way, and that design means that the results may seem to be more consistent than they really are when we analyse them. Finally, several trials did not completely report their findings in a way we could analyse in this review. We are not sure how these factors affect our confidence in the results we found.
