Paediatric Respiratory Reviews 16 (2015) 108–109
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Cochrane Corner
Pancreatic enzyme replacement therapy for people with cystic fibrosis (Review) U.R. Somaraju 1,*, A. Solis-Moya 2 1 2
Department of Biochemistry, Malla Reddy Medical College for Women, Hyderabad, India Servicio de Neumologı´a, Hospital Nacional de Nin˜os, San Jose´, Costa Rica
WHY IT IS IMPORTANT TO DO THE REVIEW Pancreatic enzyme insufficiency is seen in approximately 80% to 90% of people with cystic fibrosis (CF) and results in maldigestion and malnutrition [1]. Malnutrition is associated with poor growth and development in children, poor weight gain in adults, more severe pulmonary disease and shorter life expectancy [2,3]. People with CF have been treated with pancreatic enzyme replacement therapy (PERT) since the 1930s with the aim of improving nutritional status and clinical outcome [4]. Currently there are several PERT preparations available including non-enteric-coated powders, enteric-coated tablets (ECT), enteric-coated microspheres (ECM), enteric-coated minimicrospheres, and enteric coated micro tablets [5]. They differ in composition, formulation, and bioavailability. The required daily dose of PERT is highly variable and depends on the patient’s age, body weight, genotype and degree of pancreatic insufficiency as well as the type and quantity of meals [4]. The efficacy of PERT also depends on the coating and size of enzyme particles in preparations, gastric transit time, gastric and small intestinal pH, and lack of bile acids [6]. Current dosing recommendations for PERT are intended to prevent harm, rather than treat effectively leading to wide variation in clinical practice [7]. Preparations are generally considered safe, but are associated with potential significant side effects. It is therefore very important to establish the evidence for the benefits and risks of PERT; to compare different formulations; to determine the optimum treatment for different age groups; and to clarify the role of tests of pancreatic function in therapy [8]. WHAT COMPARISONS DID WE MAKE IN THE REVIEW? We compared PERT (started at any time after diagnosis) given in any dose or formulation, for at least four weeks to placebo or another PERT preparation. * Corresponding author. http://dx.doi.org/10.1016/j.prrv.2014.11.001 1526-0542/ß 2014 Elsevier Ltd. All rights reserved.
We identified 18 potentially eligible randomized controlled trials and included 12 of these in the review [9–20]. The trials included a total of 426 participants. Two authors independently assessed the trials for inclusion in the review and contacted the trial authors for further information. We reported data by comparison of interventions e.g. ECM to other enteric-coated and non-enteric-coated preparations, and different doses of PERT (Table 1). We planned to perform a subgroup analysis looking at the different formulations and dosages, the presence of symptoms and if possible look at effects at different ages. However, this was not possible due to the small number of included trials. RESULTS Eight trials included children with CF and their ages ranged from 1 to 17 years [9–16]. The participants in the remaining four trials were adults with mean ages varying between 21.4 and 24.8 years [17–20]. The interventions were heterogeneous between the trials; 10 trials compared ECM with other preparations of PERT, including other ECM. Two trials compared PERT in different doses (Table 1). We could only combine data from six trials in the analysis, as the other six trials did not have sufficient information. The risk of bias for the methods of the included studies was classified largely as ‘‘unclear’’ since the description of their methods was inadequate to assess the risk of bias; we judged half of the trials to be at ‘‘high risk’’ of bias with respect to selective reporting of results. Primary outcomes of interest for the review were absolute or relative change in nutritional status (weight, height, BMI). There was a small increase in weight in people taking ECM when compared to non-enteric-coated tablets. Secondary outcomes included bowel symptoms (stool frequency, abdominal pain, flatulence, constipation, distal intestinal obstruction syndrome), days in hospital, quality of life, number
U.R. Somaraju, A. Solis-Moya / Paediatric Respiratory Reviews 16 (2015) 108–109
109
Table 1 Number of studies included in the review using different kinds and doses of PERT preparations. Comparisons ECM vs non-enteric coated preparations ECM vs other enteric coated preparations
Different doses of PERT
Lyophilized Total Pancreatic Extracts Non-enteric coated tablets ECT Enteric coated granules ECM Enteric coated minimicrospheres High dose vs low dose Three doses
No.of studies
Reference
1 2 2 1 3 1 1 1
Vidailhit 1987 [14] Henker 1987 [10], Stead 1987 [20] Stead 1986 [19], Vyas 1990 [15] Peterson 1984 [13] Elliott 1992 [9], Williams 1990 [16], Lacy 1992 [11] Patchell 1999 [12] Assoufi 1994 [17] Borowitz 2005 [18]
Figure 1. Forest plot of comparison: ECM versus ECT, outcome: FFE [g/day].
of diagnoses of vitamin deficiency, adverse events attributed to PERT, fecal fat excretion (FFE) or co-efficient of fat absorption (Figure 1) and lung disease. The people with CF taking ECM experienced decreases in stool frequency, in abdominal pain and in FFE, when compared to non-enteric coated preparations and ECT. There was no significant difference in any of the outcomes from the different preparations of ECM or enteric-coated minimicrospheres. IMPLICATIONS FOR PRACTICE The available evidence suggests that ECM are better at improving clinical symptoms in patients with CF compared to non-enteric-coated enzyme preparations. This evidence is, however, limited and is from a few small trials that are prone to bias. Further research is needed to study the different forms of PERT, their efficacy, safety, and role in improving nutritional status, quality of life and their long-term effects. In addition it is also necessary to investigate if the same amount of PERT is applicable to all ranges of pancreatic insufficiencies in CF. In collaboration with the Cochrane CF and Genetic Disorders Group’ http://cfgd.cochrane.org/. References [1] Dodge JA, Turck D. Cystic fibrosis: nutritional consequences and management. Best practice & research. Clinical Gastroenterology 2006;20(3):531–46. [2] Corey M, McLaughlin FJ, Williams M, Levinson H. A comparison of the survival, growth and pulmonary function in patients with cystic fibrosis. Journal of Clinical Epidemiology 1988;41:583–91. [3] Stallings V, Stark L, Robinson K, Feranchak A, Quinton H. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. Journal of the American Dietetic Association 2008;108(5): 832–9. [4] Imrie CW, Connett G, Hall RJ, Charnley RM. Review article: enzyme supplementation in cystic fibrosis, chronic pancreatitis, pancreatic and periampullary cancer. Alimentary Pharmacology & Therapeutics 2010;32(Suppl. 1):1–25. [5] Fieker A, Philpott J, Armand M. Enzyme replacement therapy for pancreatic insufficiency: present and future. Clinical and Experimental Gastroenterology 2011;4:55–73. http://dx.doi.org/10.2147/CEG.S17634.
[6] Li Li, Somerset S. Digestive system dysfunction in cystic fibrosis: Challenges for nutrition therapy. Digestive and Liver Disease 46 (2014) 865–874. [7] Haupt ME, Kwasny MJ, Scheschter MS, McColley SA. Pancreatic Enzyme Replacement Therapy Dosing and Nutritional Outcomes in Children with Cystic Fibrosis. J Pediatr 2014;164:1110–5. [8] Somaraju UR, Solis-Moya A. Pancreatic enzyme replacement therapy for people with cystic fibrosis. Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No.: CD008227. DOI:10.1002/14651858.CD008227.pub2. [9] Elliott RB, Escobar LC, Lees HR, Akroyd RM, Reilly HC. A comparison of two pancreatin microsphere preparations in cystic fibrosis. New Zealand Medical Journal 1992;105(930):107–8. [10] Henker J, Jutta Hein L, Vogt E. Comparison of effectiveness of Pankreon ForteR and KreonR in children with cystic fibrosis [abstract]. 15th Annual Meeting of the European Working Group for Cystic Fibrosis; 1987. 1987.p. 72. [11] Lacy D, West J, Venkataraman M, Vyas J, MacDonald A, Weller PH, et al. A comparison of Nutrizym GR and Creon in children with CF [abstract]. 11th International Cystic Fibrosis Congress; 1992. 1992. TP76. [12] Patchell CJ, Desai M, Weller PH, MacDonald A, Smyth RL, Bush A, et al. Creon1 10000 minimicrospheresTM vs. Creon1 8000 microspheres - an open randomized crossover preference study. Journal of Cystic Fibrosis 2002;1(4): 287–91. [13] Petersen W, Heilmann C, Garne S. Pancreatic enzyme supplementation as acidresistant microspheres versus enteric-coated granules in cystic fibrosis. A double placebo- controlled crossover study. Acta Paediatrica Scandinavica 1987;76(1):66–9. [14] Vidailhet M, Derelle J, Morali A, De Gasperi JP. Comparison of effectiveness and tolerance of enteric coated versus unprotected pancreatic extracts in CF patients [abstract]. 15th Annual Meeting of the European Working Group for Cystic Fibrosis; 1987. 1987.p. 69. [15] Vyas H, Matthew DJ, Milla PJ. A comparison of enteric coated microspheres with enteric-coated tablet pancreatic enzyme preparations in cystic fibrosis. A controlled study. European Journal of Pediatrics 1990;149(4): 241–3. [16] Williams J, MacDonald A, Weller PH, Fields J, Pandov H. Two enteric coated microspheres in cystic fibrosis. Archives of Disease in Childhood 1990;65(6): 594–7. [17] Assoufi BK, Doig C, Hodson ME. High dose Nutrizym 22 in adults with cystic fibrosis [abstract]. Pediatric Pulmonology 1994;18(Suppl 10):337. [18] Borowitz D, Goss CH, Limauro S, Konstan MW, Blake K, Casey S, et al. Study of a novel pancreatic enzyme replacement therapy in pancreatic insufficient subjects with cystic fibrosis. Journal of Pediatrics 2006;149(5): 658–62. [19] Stead RJ, Skypala I, Hodson ME, Batten JC. Enteric coated microspheres of pancreatin in the treatment of cystic fibrosis: comparison with a standard enteric coated preparation. Thorax 1987;42(7):533–7. [20] Stead RJ, Skypala I, Hodson ME. Treatment of steatorrhoea in cystic fibrosis: a comparison of enteric-coated microspheres of pancreatin versus non-entericcoated pancreatin and adjuvant cimetidine. Alimentary Pharmacology & Therapeutics 1988;2(6):471–82.
In collaboration with the Cochrane CF and Genetic Disorders Group’ http://cfgd.cochrane.org/.
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Cochrane Corner
Pancreatic enzyme replacement therapy for people with cystic fibrosis (Review) U.R. Somaraju 1,*, A. Solis-Moya 2 1 2
Department of Biochemistry, Malla Reddy Medical College for Women, Hyderabad, India Servicio de Neumologı´a, Hospital Nacional de Nin˜os, San Jose´, Costa Rica
WHY IT IS IMPORTANT TO DO THE REVIEW Pancreatic enzyme insufficiency is seen in approximately 80% to 90% of people with cystic fibrosis (CF) and results in maldigestion and malnutrition [1]. Malnutrition is associated with poor growth and development in children, poor weight gain in adults, more severe pulmonary disease and shorter life expectancy [2,3]. People with CF have been treated with pancreatic enzyme replacement therapy (PERT) since the 1930s with the aim of improving nutritional status and clinical outcome [4]. Currently there are several PERT preparations available including non-enteric-coated powders, enteric-coated tablets (ECT), enteric-coated microspheres (ECM), enteric-coated minimicrospheres, and enteric coated micro tablets [5]. They differ in composition, formulation, and bioavailability. The required daily dose of PERT is highly variable and depends on the patient’s age, body weight, genotype and degree of pancreatic insufficiency as well as the type and quantity of meals [4]. The efficacy of PERT also depends on the coating and size of enzyme particles in preparations, gastric transit time, gastric and small intestinal pH, and lack of bile acids [6]. Current dosing recommendations for PERT are intended to prevent harm, rather than treat effectively leading to wide variation in clinical practice [7]. Preparations are generally considered safe, but are associated with potential significant side effects. It is therefore very important to establish the evidence for the benefits and risks of PERT; to compare different formulations; to determine the optimum treatment for different age groups; and to clarify the role of tests of pancreatic function in therapy [8]. WHAT COMPARISONS DID WE MAKE IN THE REVIEW? We compared PERT (started at any time after diagnosis) given in any dose or formulation, for at least four weeks to placebo or another PERT preparation. * Corresponding author. http://dx.doi.org/10.1016/j.prrv.2014.11.001 1526-0542/ß 2014 Elsevier Ltd. All rights reserved.
We identified 18 potentially eligible randomized controlled trials and included 12 of these in the review [9–20]. The trials included a total of 426 participants. Two authors independently assessed the trials for inclusion in the review and contacted the trial authors for further information. We reported data by comparison of interventions e.g. ECM to other enteric-coated and non-enteric-coated preparations, and different doses of PERT (Table 1). We planned to perform a subgroup analysis looking at the different formulations and dosages, the presence of symptoms and if possible look at effects at different ages. However, this was not possible due to the small number of included trials. RESULTS Eight trials included children with CF and their ages ranged from 1 to 17 years [9–16]. The participants in the remaining four trials were adults with mean ages varying between 21.4 and 24.8 years [17–20]. The interventions were heterogeneous between the trials; 10 trials compared ECM with other preparations of PERT, including other ECM. Two trials compared PERT in different doses (Table 1). We could only combine data from six trials in the analysis, as the other six trials did not have sufficient information. The risk of bias for the methods of the included studies was classified largely as ‘‘unclear’’ since the description of their methods was inadequate to assess the risk of bias; we judged half of the trials to be at ‘‘high risk’’ of bias with respect to selective reporting of results. Primary outcomes of interest for the review were absolute or relative change in nutritional status (weight, height, BMI). There was a small increase in weight in people taking ECM when compared to non-enteric-coated tablets. Secondary outcomes included bowel symptoms (stool frequency, abdominal pain, flatulence, constipation, distal intestinal obstruction syndrome), days in hospital, quality of life, number
U.R. Somaraju, A. Solis-Moya / Paediatric Respiratory Reviews 16 (2015) 108–109
109
Table 1 Number of studies included in the review using different kinds and doses of PERT preparations. Comparisons ECM vs non-enteric coated preparations ECM vs other enteric coated preparations
Different doses of PERT
Lyophilized Total Pancreatic Extracts Non-enteric coated tablets ECT Enteric coated granules ECM Enteric coated minimicrospheres High dose vs low dose Three doses
No.of studies
Reference
1 2 2 1 3 1 1 1
Vidailhit 1987 [14] Henker 1987 [10], Stead 1987 [20] Stead 1986 [19], Vyas 1990 [15] Peterson 1984 [13] Elliott 1992 [9], Williams 1990 [16], Lacy 1992 [11] Patchell 1999 [12] Assoufi 1994 [17] Borowitz 2005 [18]
Figure 1. Forest plot of comparison: ECM versus ECT, outcome: FFE [g/day].
of diagnoses of vitamin deficiency, adverse events attributed to PERT, fecal fat excretion (FFE) or co-efficient of fat absorption (Figure 1) and lung disease. The people with CF taking ECM experienced decreases in stool frequency, in abdominal pain and in FFE, when compared to non-enteric coated preparations and ECT. There was no significant difference in any of the outcomes from the different preparations of ECM or enteric-coated minimicrospheres. IMPLICATIONS FOR PRACTICE The available evidence suggests that ECM are better at improving clinical symptoms in patients with CF compared to non-enteric-coated enzyme preparations. This evidence is, however, limited and is from a few small trials that are prone to bias. Further research is needed to study the different forms of PERT, their efficacy, safety, and role in improving nutritional status, quality of life and their long-term effects. In addition it is also necessary to investigate if the same amount of PERT is applicable to all ranges of pancreatic insufficiencies in CF. In collaboration with the Cochrane CF and Genetic Disorders Group’ http://cfgd.cochrane.org/. References [1] Dodge JA, Turck D. Cystic fibrosis: nutritional consequences and management. Best practice & research. Clinical Gastroenterology 2006;20(3):531–46. [2] Corey M, McLaughlin FJ, Williams M, Levinson H. A comparison of the survival, growth and pulmonary function in patients with cystic fibrosis. Journal of Clinical Epidemiology 1988;41:583–91. [3] Stallings V, Stark L, Robinson K, Feranchak A, Quinton H. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. Journal of the American Dietetic Association 2008;108(5): 832–9. [4] Imrie CW, Connett G, Hall RJ, Charnley RM. Review article: enzyme supplementation in cystic fibrosis, chronic pancreatitis, pancreatic and periampullary cancer. Alimentary Pharmacology & Therapeutics 2010;32(Suppl. 1):1–25. [5] Fieker A, Philpott J, Armand M. Enzyme replacement therapy for pancreatic insufficiency: present and future. Clinical and Experimental Gastroenterology 2011;4:55–73. http://dx.doi.org/10.2147/CEG.S17634.
[6] Li Li, Somerset S. Digestive system dysfunction in cystic fibrosis: Challenges for nutrition therapy. Digestive and Liver Disease 46 (2014) 865–874. [7] Haupt ME, Kwasny MJ, Scheschter MS, McColley SA. Pancreatic Enzyme Replacement Therapy Dosing and Nutritional Outcomes in Children with Cystic Fibrosis. J Pediatr 2014;164:1110–5. [8] Somaraju UR, Solis-Moya A. Pancreatic enzyme replacement therapy for people with cystic fibrosis. Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No.: CD008227. DOI:10.1002/14651858.CD008227.pub2. [9] Elliott RB, Escobar LC, Lees HR, Akroyd RM, Reilly HC. A comparison of two pancreatin microsphere preparations in cystic fibrosis. New Zealand Medical Journal 1992;105(930):107–8. [10] Henker J, Jutta Hein L, Vogt E. Comparison of effectiveness of Pankreon ForteR and KreonR in children with cystic fibrosis [abstract]. 15th Annual Meeting of the European Working Group for Cystic Fibrosis; 1987. 1987.p. 72. [11] Lacy D, West J, Venkataraman M, Vyas J, MacDonald A, Weller PH, et al. A comparison of Nutrizym GR and Creon in children with CF [abstract]. 11th International Cystic Fibrosis Congress; 1992. 1992. TP76. [12] Patchell CJ, Desai M, Weller PH, MacDonald A, Smyth RL, Bush A, et al. Creon1 10000 minimicrospheresTM vs. Creon1 8000 microspheres - an open randomized crossover preference study. Journal of Cystic Fibrosis 2002;1(4): 287–91. [13] Petersen W, Heilmann C, Garne S. Pancreatic enzyme supplementation as acidresistant microspheres versus enteric-coated granules in cystic fibrosis. A double placebo- controlled crossover study. Acta Paediatrica Scandinavica 1987;76(1):66–9. [14] Vidailhet M, Derelle J, Morali A, De Gasperi JP. Comparison of effectiveness and tolerance of enteric coated versus unprotected pancreatic extracts in CF patients [abstract]. 15th Annual Meeting of the European Working Group for Cystic Fibrosis; 1987. 1987.p. 69. [15] Vyas H, Matthew DJ, Milla PJ. A comparison of enteric coated microspheres with enteric-coated tablet pancreatic enzyme preparations in cystic fibrosis. A controlled study. European Journal of Pediatrics 1990;149(4): 241–3. [16] Williams J, MacDonald A, Weller PH, Fields J, Pandov H. Two enteric coated microspheres in cystic fibrosis. Archives of Disease in Childhood 1990;65(6): 594–7. [17] Assoufi BK, Doig C, Hodson ME. High dose Nutrizym 22 in adults with cystic fibrosis [abstract]. Pediatric Pulmonology 1994;18(Suppl 10):337. [18] Borowitz D, Goss CH, Limauro S, Konstan MW, Blake K, Casey S, et al. Study of a novel pancreatic enzyme replacement therapy in pancreatic insufficient subjects with cystic fibrosis. Journal of Pediatrics 2006;149(5): 658–62. [19] Stead RJ, Skypala I, Hodson ME, Batten JC. Enteric coated microspheres of pancreatin in the treatment of cystic fibrosis: comparison with a standard enteric coated preparation. Thorax 1987;42(7):533–7. [20] Stead RJ, Skypala I, Hodson ME. Treatment of steatorrhoea in cystic fibrosis: a comparison of enteric-coated microspheres of pancreatin versus non-entericcoated pancreatin and adjuvant cimetidine. Alimentary Pharmacology & Therapeutics 1988;2(6):471–82.
In collaboration with the Cochrane CF and Genetic Disorders Group’ http://cfgd.cochrane.org/.
