Meta-Analysis of Randomized and Nonrandomized Clinical Trials
Two remaining pediatric studies, although nonrandomized, were reviewed to increase the power of this analysis. Although the study participants were not randomized, there was no evidence of selection bias. The analysis was stratified to acknowledge this difference. In the study by Breese et al. (41), 10 consecutive patients had been treated with corticosteroids, and the next 18 patients were randomized to receive cyclosporin A or enteral nutrition. The study of Chafai et al. (42) was a retrospective analysis of patients treated with corticosteroids and enteral nutrition.
Papadopoulou et al. (31) completed a retrospective analysis of very similar treatment groups, yet their study included more than one treatment episode per patient. Repeated entry of the same patient could compound any selection bias, and thus we omitted this study from our analysis (despite its having the highest RR of 1.30 [nonsignificant CI] and favoring enteral nutrition). Nicholls et al. (30) randomized patients to receive either conventional treatment (steroids or enteral nutrition) or cyclosporin A. However, they then selected patients in the conventional treatment group with small bowel disease for treatment with enteral nutrition (n = 10) and those with colonic involvement for steroid therapy (n = 4). Although a 100% remission rate was achieved in both groups, we did not include this study in our final analysis.
Although treatment was clearly allocated in a nonrandom manner by Chafai et al., (42) the allocation was made in the best interests of the patient—that is, selection of the most effective and appropriate treatment for each patient. Although the comparison of outcome is less valid than if treatment allocation is randomized, the similarity of treatment groups in some way minimizes any selection bias.
The pooled relative risk for all seven studies was 0.982 (95% CI 0.73–1.33; values identical in fixed and random effects models). Heterogeneity Q statistic was 0.82 with 6 df (P = 0.991;Fig. 2, Table 3).
The inclusion of semirandomized studies assessed the sensitivity of our inclusion criteria. There was no significant change in RR or CI ranges and homogeneity was maintained (Table 3), confirming the two additional studies to be very similar to the truly randomized series. This calculation was extended to assess how many further studies would be required to reach a statistically significant treatment effect (Table 3). Only after the inclusion of 10 further studies (data not shown) that were identical in size and outcome to the largest reported pediatric study (n = 68) was a significant RR achieved in favor of steroid therapy (RR = 0.86 [95% CI 0.74–0.99]; Q = 0.83, 14 df;P = 1.0).
In view of the relatively limited number of children randomized, quantitative analysis of other factors had limited statistical value. We reviewed the available data with particular reference to speed of remission induction, duration of remission, nutritional endpoints, and height velocities. The only significant difference between the two treatment groups was in height velocities achieved at short-term follow-up. Thomas et al. (37) showed the children randomized to enteral nutrition to have a significantly higher mean height velocity standard deviation score (SDS) 6 months after treatment (+0.32 vs. −3.1). This was despite a significantly higher calorie intake in the steroid-treated group, indicating the growth suppressant effects of steroids are not overcome by simply increasing calorie intake.
An identical finding was reported by Sanderson et al. (13), who showed a significantly higher mean height velocity SDS at 3 months in the group randomized to enteral nutrition (+0.2 vs. −2.85). Chafai et al. (42) also confirmed a significantly higher growth velocity in the group receiving elemental diet.
In this analysis of 194 children with acute Crohn's disease, enteral nutrition was as effective as steroids at inducing a clinical remission (RR = 0.98, 95% CI 0.73–1.33).
Meta-analyses published in the adult literature (1–3) suggest a clear benefit of steroid therapy over enteral nutrition. These studies in adults with acute Crohn's disease all report an OR of 0.35 (95% CI 0.23–-0.53) for achieving a remission with enteral nutrition. The RR we calculated from data presented by Griffiths et al. (1) is 0.71. The 95% CI (0.56–0.90) remains below equivalence (RR = 1.0), yet closer to the range we present.
It is also of note that in almost all pediatric and adult studies a clinical disease activity index was used (44–47) to define a clinical remission. These indices, by including measures of a patient's clinical well-being, are likely to favor remission in the steroid-treated groups, given the effect steroids have on improvement of overall well-being.
A significant difference between the adult and pediatric studies is the degree of compliance. Up to 40% of adults were withdrawn from nutritional therapy because of intolerance of the diet (1). Not surprisingly this was highest in those taking an elemental or semielemental diet by mouth (18–41%). However, of 98 children included in this meta-analysis, only 8% did not complete the course of enteral nutrition, despite requiring a semielemental diet administered by nasogastric tube. Griffiths et al. report results excluding patients who withdrew from their study because of intolerance to the diet, yet the OR remains significantly in favor of steroid therapy, 0.57 (95% CI 0.35–0.94). Calculation of the pooled RR for the same data, however, fails to reach significance (RR = 0.86, 95% CI 0.68–1.09). This implies that adults who are able to tolerate nutritional therapy are as likely to go into remission as those treated with steroids, a fact also reported in large adult studies (48).
Compliance in excess of 90% is often reported when using enteral nutrition in children (13,30,31,38). Compliance with a prolonged course of exclusive enteral diet is clearly more difficult for an adult. In addition to the inconvenience, the possible benefits for growth and development do not apply.
Recent observational studies with more palatable polymeric diets are confirming excellent compliance in children who take the diet by mouth (49,50). Successful use of enteral nutrition also requires motivated nursing, dietetic, and medical staff to support children and families during therapy. This may well explain some of the better results obtained in pediatric units in which dietary therapy has become more commonplace (31,37,40,49).
A further difference from published adult data is that in most trials of adults, prevalent rather than incident cases are recruited. In our meta-analysis of pediatric trials a large proportion of randomized patients had newly diagnosed disease. Inclusion of patients with more long-standing or intractable disease may introduce a systematic bias into adult studies. Although not proven, patients with more recently diagnosed disease may respond better to nutritional therapy than those with more long-standing disease. This would make enteral nutrition more effective and better tolerated in the pediatric population.
A qualitative review of treatment effects on growth was also performed. Despite the well-described adverse effects that corticosteroids can have on development, growth, and pubertal maturation (51), only two of the randomized studies document the short-term effects of treatment on growth velocities. The randomized studies by Sanderson et al. (13) and Thomas et al. (37) documented significantly improved height velocity in the enterally fed groups at 3 and 6 months, respectively, although pubertal staging was not controlled for specifically.
It was also impossible to quantify the impact of enteral nutrition on different disease sites. In contrast to the widely held belief that enteral feeding is less effective in large bowel disease (13,52), available data from pediatric studies (38,40) suggests large and small bowel disease respond equally well to nutritional therapy. This is confirmed by the larger adult studies (33,53). As in the meta-analyses of about 400 adults with active Crohn's disease, it was also impossible to detect valid differences in speed of remission induction and time to first relapse.
The efficacy of polymeric diets is also still debated. There are insufficient randomized pediatric or adult data comparing elemental with whole protein, polymeric diets. Although the latter are the ideal clinical choice in palatability and cost, there are no comparative studies to confirm this.
Only 32 patients in the world literature have received polymeric diets in randomized trials comparing those diets with elemental diets; however, meta-analyses including studies of semielemental diets have been unable to document significant differences in efficacy between any one of the three types of diet (1,2). Even these analyses are only able to detect large differences in treatment effects. However, along with findings in multiple observational studies in children documenting the efficacy and palatability of polymeric diets (38,49,50), these findings provide some indication of their potential. Further randomized studies comparing polymeric and elemental diets may be justified to contribute to a statistically conclusive answer.
The inclusion of seven pediatric trials in the current analysis ensured sufficient power to detect a clinically significant difference between the two therapies. Further sensitivity analyses demonstrate that for steroids to achieve a statistically significant benefit over enteral nutrition, approximately 700 more children with acute Crohn's disease would require randomization. Results obtained from these children would also have to equal the most favorable outcome for steroid therapy reported so far (RR = 0.84) (40), if our current results were to be overruled. The volume of data necessary to overturn the evidence we report here greatly strengthens these findings (RR = 0.98, CI 0.23–0.53). The entire adult literature includes only approximately 400 randomized patients. With an incidence of less than 10 per 100,000 children (54), larger studies are unlikely to be feasible in children.
Besides reaching a statistically significant conclusion, a meta-analysis must assess and quantify interstudy variability for a conclusion to be valid. A best estimate that encompasses this heterogeneity may be much more robust than a result from a large, tightly controlled, one-center study. The seven studies included in this meta-analysis were found to be substantially homogeneous in their outcomes, making the pooled estimate less uncertain and more generalizeable. Although studies tend to become more diverse as researchers try to avoid duplication of work, this field of study has remained limited in its variability in view of the well-defined population and treatment strategies.
An inherent limitation of meta-analysis is the availability of good quality studies. A key factor in this is often the quality of randomization. Lack of allocation concealment and double-blinding can lead to substantially inflated results of evaluations of treatment effects (55).
Double-blinding in studies with enteral nutrition has never been possible, and although five studies stated that patients were randomized, none reported details of their randomization methods. Because most studies have reported no difference between the treatment effect of steroids and enteral nutrition, a publication bias is most unlikely. Studies demonstrating a clear benefit for either therapy are unlikely to have been overlooked. In addition, we selected studies in abstract form to ensure inclusion of all available data. Although this prevented a quality assessment of included trials as performed by some investigators (1,2), a quality score has not always been useful in a final analysis (1,3).
This systematic review provides both a quantitative and qualitative analysis of the data available on the use of enteral nutrition in children with active Crohn's disease.
If new research in this field is to contribute significantly to our practice and not merely support the current evidence, this analysis also provides an idea of the quality and volume of data required to achieve this. Allocation of funds and enrollment of patients, even if randomized, to studies merely supporting current good-quality evidence is inappropriate. In the absence of large, multicenter studies, however, this analysis demonstrates the benefit of small, well-designed randomized trials if the accumulation of quality evidence is to continue.
Corticosteroids clearly remain essential in the management of patients with Crohn's disease. However, despite their proven efficacy and ease of use, this should not preclude the use of an equally efficacious, but less-convenient therapy. The effect of steroids on growth and puberty make their repeated use particularly unsuitable for children approaching their major period of growth. Steroids also remain poor at healing bowel mucosa (56), whereas there are initial observational studies documenting improved mucosal cytokine profiles after enteral nutrition (28,50). Concerns about the long-term risks of malignancy in the face of active bowel inflammation continue (57–59). With more years of Crohn's disease ahead of them than adults, children may benefit more from achieving a better mucosal remission.
We therefore conclude that enteral nutrition is as effective as steroids in achieving a remission in children with active Crohn's disease. It is likely that a palatable, whole-protein polymeric diet is no less efficacious than an elemental, amino acid–based formula. This should make nutritional therapy a much more practical choice for both patient and clinician.
In view of the benefits of dietary therapy on growth, development, and probably the gut mucosa, an enteral diet should be recommended as first-line therapy in all children with active Crohn's disease.
The authors thanks Michael A. Stoto, Ph.D., Professor and Chair, Department of Epidemiology and Biostatistics, School of Public Health and Health Services, The George Washington University, Washington, DC, for his help with the statistical analysis.
Supported by grant T32-DK07477-16 from the the National Institutes of Health Training Grant in Pediatric Gastroenterology and Nutrition for training in clinical effectiveness (R.H.).
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Keywords:© 2000 Lippincott Williams & Wilkins, Inc.
Child; Crohn's disease; Enteral nutrition; Meta-analysis of publications; Steroids