Journal of Parenteral and Enteral Nutrition http://pen.sagepub.com/
JPEN Journal Club 6. Meta-Analysis Ronald L. Koretz JPEN J Parenter Enteral Nutr 2014 38: 761 DOI: 10.1177/0148607114522648 The online version of this article can be found at: http://pen.sagepub.com/content/38/6/761
Published by: http://www.sagepublications.com
On behalf of:
The American Society for Parenteral & Enteral Nutrition
Additional services and information for Journal of Parenteral and Enteral Nutrition can be found at: Email Alerts: http://pen.sagepub.com/cgi/alerts Subscriptions: http://pen.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
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Downloaded from pen.sagepub.com at UNIV TORONTO on August 10, 2014
522648
research-article2014
PENXXX10.1177/0148607114522648Journal of Parenteral and Enteral NutritionKoretz
Journal Club Journal of Parenteral and Enteral Nutrition Volume 38 Number 6 August 2014 761–763 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0148607114522648 jpen.sagepub.com hosted at online.sagepub.com
JPEN Journal Club 6. Meta-Analysis Ronald L. Koretz, MD1
The article to be discussed1 is a systematic review that assesses the efficacy of artificial nutrition (parenteral nutrition [PN] or enteral nutrition [EN]) in patients with acute pancreatitis. The authors specifically state that they want to assess the absolute effect of PN on major clinical outcomes (mortality and infectious complications) using randomized clinical trials (RCTs) comparing PN with no nutrition intervention, the absolute effect of EN on those same outcomes using RCTs comparing EN with no nutrition intervention, and the relative efficacy of PN compared with EN on those outcomes using RCTs comparing those 2 interventions. To get a numerical estimate of the actual effect sizes and differences, they planned to combine the identified trials in each of the study categories using a process called meta-analysis. Meta-analysis is not the same thing as systematic reviewing. Systematic reviewing is a process whereby a specific question is asked, a protocol is written to use the published literature to answer that question, and pertinent papers are obtained and the data are assessed, from which assessment conclusions are made. Meta-analysis may or may not be employed in a systematic review. Meta-analysis is simply a mathematical method of pooling the data from multiple trials. While this mathematical method can be applied to any set of data, for our purposes, we will focus on systematic reviews of RCTs in the following discussion. There are 2 advantages of data pooling; one is to increase the power to see smaller differences, and the other is to get a more precise estimate of the actual effect. Simple data pooling can be done just by adding the numerators and denominators from each RCT. Meta-analysis differs from simple data pooling in that each RCT is weighted by the “variance,” a number that is calculated from the standard deviation. Any single RCT produces only an approximation of the true answer. However, in RCTs, the data are usually normally distributed, so 2 standard deviations on either side of the mean (the observed value) will encompass 95% of the possible results. Hence, it is highly probable that the true answer will be contained within these limits. Observed values with small standard deviations (and variances) are thought to be more precise estimates of the true answer and are given more weight. In meta-analysis, the observed values from each trial are weighted by a formula using the reciprocals of the variances, and these weighted values are then added together.
The downside to meta-analysis is heterogeneity—namely, how different the RCTs are from each other. Obviously, if they are too different, it does not even make sense to try to combine them. In the study we are about to discuss,1 the meta-analyses were limited to specific nutrition interventions in a common disease, so it would seem reasonable to do the pooling for the RCTs in each nutrition intervention scenario. However, as can be seen in Table 1 of the article,1 there were still differences between the RCTs with regard to when the trial was published (ranging from 1984–2007), the setting (where the RCT was conducted), the severity of disease, and the methodologic details (and the last 3 columns represent the components of the Jadad score). If one wanted to explore the possibility of heterogeneity, one could look at subsets of these RCTs (eg, we could perform a subgroup analysis of the RCTs that only enrolled severely ill patients). The results of a meta-analysis are typically presented as a forest plot (Figures 2–5 of the article1). In the forest plots in the systematic review by Petrov et al,1 the results from each of the trials that reported the outcome of interest are listed in the first 5 columns. The calculated weight of each trial is numerically presented in the sixth column and, as will be noted shortly, is also reflected by the size of the box in the last column. In general, data from RCTs can be either dichotomous (the event happened or did not happen) or continuous (the outcome is measured on a continuous scale, as done for such parameters as length of stay in the hospital); for our purposes, all data were dichotomous (presence or absence of either death or infection). 1
From the Olive View–UCLA Medical Center, David Geffen–UCLA School of Medicine, Sylmar and Los Angeles, California. Financial disclosure: Dr Koretz receives ongoing support from GIIssues, Inc, a 401(c)(3) nonprofit organization that promotes the use and dissemination of evidence-based medicine. While no particular funds were used for this particular project, GIIssues, Inc, will support Dr Koretz’s academic travel, society memberships, and other academic activities that have some relationship to the mission of the promulgation of evidence-based medicine. GIIssues, Inc, does not provide any salary support for Dr Koretz. No research materials related to this article can be accessed other than the stated references. Corresponding Author: Ronald L. Koretz, MD, Emeritus Professor of Clinical Medicine, Olive View–UCLA Medical Center, 14445 Olive View Dr, Sylmar, CA 91342, USA. Email: [email protected]
Downloaded from pen.sagepub.com at UNIV TORONTO on August 10, 2014
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Journal of Parenteral and Enteral Nutrition 38(6)
Dichotomous data can be presented in several ways; in this case, the risk ratio is calculated. The risk ratio represents the incidence of the outcome in the treated group divided by the incidence in the control group; for the RCTs comparing PN and EN, the PN group was used as the comparator (since there was no true control group). The risk ratios for each of the individual trials, along with the 95% confidence intervals, are in the seventh column, and the last column pictorially represents columns 6 and 7, with the box representing the estimated risk ratio and the horizontal line the confidence interval. To be noted, the size of the box corresponds to the weight of each trial. The last line of data in the forest plot represents the result of the meta-analysis. The total weight is 100% (since all trials were considered), and the estimated risk ratio is presented numerically as well as pictorially in the last 2 columns. However, the pictorial representation is no longer a box and horizontal line but a diamond; the peak of the diamond is the estimated effect, and the left and right extremes of the diamond represent the confidence interval. Significance is defined as a 95% confidence interval that does not cross the line of equivalence. If the incidence of the outcome is the same in both groups, the risk ratio is precisely 1.00; this is the vertical line of equivalence depicted in the last column. Let us now consider the conclusions of the systematic review by Petrov et al.1 As we noted earlier, these authors systematically sought all of the RCTs addressing the use of artificial nutrition (PN or EN) in patients with acute pancreatitis. The authors were only able to perform meta-analysis if there were at least 2 trials in the category of interest. (It makes no sense to consider combining data if only 1 trial is available.) They found 3 trials that compared PN with no nutrition intervention and 11 trials that compared PN with EN. However, only 1 trial compared EN with no nutrition intervention.2 As a result, they did not report on that trial but instead did what is known as an indirect meta-analysis—that is, they attempted to calculate the effect of EN alone by comparing the trials comparing EN with PN and PN with no intervention. The common arm of these latter 2 comparisons was the delivery of PN, and they looked at the relative differences to infer how EN would compare with no intervention. Indirect meta-analysis is less commonly done in systematic reviews, and we will consider it shortly. With regard to PN vs no intervention, the data are summarized in Figures 4 and 5; while no significant difference was seen when the 2 trials that reported infections were combined (Figure 4), the PN did appear to have a dramatic effect on mortality (Figure 5). To be noted, this beneficial effect was largely a consequence of the data from the 1 trial by Xian-li et al,3 which accounted for 75% of the weight in the analysis. (In statistical terms, we would say that the Xian-li trial “drove” the analysis.) When PN was compared with EN, the latter resulted in fewer infections (Figure 2), although there was no significant difference in mortality (Figure 3). In the meta-analysis addressing infectious complications, the trial contributing the
greatest weight was the one by Petrov et al4 (41%); while that was the only trial to find a significant difference favoring EN, it should be noted that the infectious complications were less frequent in the EN arm of 8 of the remaining 9 RCTs. Thus, this significant difference was not a result of data from 1 trial driving the analysis. Since only 1 RCT was identified that compared EN with no nutrition intervention, Petrov et al1 chose to address the absolute efficacy of EN using indirect meta-analysis. The risk ratio for an outcome in the EN vs PN trials was the incidence in the EN group divided by the incidence in the PN group. The calculated risk ratio for the outcomes in the PN vs no nutrition intervention was the incidence of the outcome in the PN group divided by the incidence in the no-treatment group. The indirect meta-analysis assesses the ratio of these 2 risk ratios, assuming that the incidences of the outcomes in the PN groups were comparable. To do this, the authors reexpressed the risk ratio in the PN vs no-intervention study so the PN group was the comparator (ie, the risk ratio was the incidence in the nointervention group divided by the incidence in the PN group). Since it is assumed that the incidences of the outcomes in the PN groups were the same regardless of to what intervention the PN was being compared, dividing the risk ratio of EN compared with PN by the risk ratio of no intervention compared with PN resulted in the ratio of EN compared with no intervention. The data for the indirect meta-analysis are seen in Table 2 of the article.1 The risk ratios of the EN vs PN RCTs are the same as what was calculated. The risk ratios for the no-nutrition intervention vs PN RCTs are the reciprocals of the risk ratios that were calculated for the PN vs no-intervention RCTs. (For example, the risk ratio for the infectious complications is 1/1.36, or 0.73.) The ratio of these 2 ratios is 0.56 (0.41/0.73) for the infectious complications; since the confidence interval overlapped 1.00, this was not significant, and Petrov et al1 concluded that EN had no effect on infectious complications. On the other hand, the ratio of ratios for mortality was 0.22 (0.60/2.77), and that confidence interval did not cross the line of equivalence, resulting in the conclusion that EN would improve mortality. Inherent in indirect meta-analysis is the assumption that the groups receiving the treatment in common (PN in this case) are truly comparable. However, the trial that drove the PN vs nointervention mortality calculation3 would appear to represent a true outlier in the PN literature because the difference in mortality between the PN recipients and those not receiving any nutrition interventions is far more dramatic than has been seen in any other of over 100 such RCTs of PN.5 The article was published in a supplement, and it is not clear how much peerreviewing it received. (I did contact the editors of the journal shortly after this trial was published and asked for contact information for the author, but the editors could only provide the mailing address that was available in the paper; a subsequent letter that I wrote to Dr Xian-li went unanswered.) The
Downloaded from pen.sagepub.com at UNIV TORONTO on August 10, 2014
Koretz
763
trial was conducted in China, and there have been suggestions that trials labeled as randomized, at least in the complementary and alternative medicine literature, are not truly randomized.6,7 This problem with indirect meta-analysis is not limited to this systematic review. Others have questioned the reliability of such comparisons.8,9 The indirect meta-analysis resulted in the authors not even considering the single trial that was identified.2 In that RCT, 27 patients with predicted severe pancreatitis were randomized to EN (n = 13) or conventional treatment (n = 14). No data were reported regarding mortality or infections, but no differences were seen with regard to organ failure scores or duration of hospitalization; the nausea scores were higher in the EN group. Contrary to what Petrov et al1 predicted about the utility of EN in acute pancreatitis, a large RCT was presented at the 2012 United European Gastroenterology Week; more than 200 patients with moderate to severe pancreatitis were randomized into 2 groups, one receiving EN that was begun within 24 hours and the other no nutrition intervention.10 No significant differences in mortality, organ failure, local complications, infected pancreatic necrosis, or duration of hospitalization were observed. The other issue that did not seem to be considered very strongly by Petrov et al1 related to the risks of bias in the RCTs that were considered. These authors used the Jadad scale to assess this problem and, even though this scale is somewhat insensitive in identifying risks of bias, only 2 of the 15 RCTs that had been identified even met the lowest criterion for better methodology—namely, a score of 3. (These scores can be calculated11 from the information in Table 1.1) In general, RCTs at higher risks of bias tend to overestimate benefit.11,12 Thus, the conclusions made about the efficacy of either EN or PN in patients with acute pancreatitis are overstated, given the totality of the evidence we have to date. Perhaps the conclusion that was best supported by the evidence was that the provision of EN results in fewer infectious complications compared with the provision of PN. However, if PN causes excess infections,5 we have no evidence to assure us that providing EN is better than doing nothing. For the next installment, please read the following article: Sandstrom R, Drott C, Hyltander A, et al. The effect of postoperative intravenous feeding (TPN) on outcome following major surgery evaluated in a randomized study. Ann Surg. 1993;217:185-195. This is a still-cited randomized trial
comparing PN with hypertonic dextrose in patients after major surgery; it includes curious subgroup analyses. I encourage you to engage in discussion on ASPENConnect’s Journal Club discussion board. A.S.P.E.N. has created an information kit with guidelines for how chapters, hospitals, and universities can develop their own journal clubs (www.nutritioncare.org/ journalclub).
References 1. Petrov MS, Pylypchuk RD, Emelyanov NV. Systematic review: nutritional support in acute pancreatitis. Aliment Pharm Ther. 2008;28: 704-712. 2. Powell JJ, Murchison JT, Fearon KCH, Ross JA, Siriwardena AK. Randomized controlled trial of the effect of early enteral nutrition on markers of the inflammatory response in predicted severe acute pancreatitis. Br J Surg. 2000;87:1375-1381. 3. Xian-li H, Qing-jiu M, Jian-guo L, Yan-kui C, Xi-lin D. Effect of total parenteral nutrition (TPN) with and without glutamine dipeptide supplementation on outcome in severe acute pancreatitis (SAP). Clin Nutr Suppl. 2004;1:43-47. 4. Petrov MS, Kukosh MV, Emelyanov NV. A randomized controlled trial of enteral versus parenteral feeding in patients with predicted severe acute pancreatitis shows a significant reduction in mortality and in infected pancreatic complications with total enteral nutrition. Dig Surg. 2006;23: 336-345. 5. Koretz RL, Lipman TO, Klein S. AGA technical review on parenteral nutrition. Gastroenterology. 2001;121:970-1001. 6. Taixiang W, Xunzhe Y, Xiaoxi Z, et al. How many false ‘RCTs’ were included in Cochrane systematic reviews of traditional Chinese medicine [abstract]? Z Evid Fortbild Qual Gesundh Wesen. 2008;102:26. 7. Liu J, Kjaergard LL, Gluud C. Misuse of randomization: a review of Chinese randomized trials of herbal medicines for chronic hepatitis B. Am J Chin Med. 2002;30:173-176. 8. Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis or randomized controlled trials. J Clin Epidemiol. 1997;50:683-691. 9. Song F, Xiong T, Parekh-Bhurke S, et al. Inconsistency between direct and indirect comparisons of competing interventions: meta-epidemiological study. BMJ. 2011;343:d4909. 10. Poropat G, Franjic N, Stimac D. Enteral nutrition for patients with acute pancreatitis [abstract]. Gut. 2012;61(suppl 3):A61. 11. Jadad AR, Moor RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clin Trials. 1996;17:1-12. 12. Higgins JPT, Altman DG, and Sterne JAC, eds. Assessing risk of bias in included studies. In: Higgins, JPT and Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. www. cochrane-handbook.org
Downloaded from pen.sagepub.com at UNIV TORONTO on August 10, 2014
JPEN Journal Club 6. Meta-Analysis Ronald L. Koretz JPEN J Parenter Enteral Nutr 2014 38: 761 DOI: 10.1177/0148607114522648 The online version of this article can be found at: http://pen.sagepub.com/content/38/6/761
Published by: http://www.sagepublications.com
On behalf of:
The American Society for Parenteral & Enteral Nutrition
Additional services and information for Journal of Parenteral and Enteral Nutrition can be found at: Email Alerts: http://pen.sagepub.com/cgi/alerts Subscriptions: http://pen.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Jul 16, 2014 What is This?
Downloaded from pen.sagepub.com at UNIV TORONTO on August 10, 2014
522648
research-article2014
PENXXX10.1177/0148607114522648Journal of Parenteral and Enteral NutritionKoretz
Journal Club Journal of Parenteral and Enteral Nutrition Volume 38 Number 6 August 2014 761–763 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0148607114522648 jpen.sagepub.com hosted at online.sagepub.com
JPEN Journal Club 6. Meta-Analysis Ronald L. Koretz, MD1
The article to be discussed1 is a systematic review that assesses the efficacy of artificial nutrition (parenteral nutrition [PN] or enteral nutrition [EN]) in patients with acute pancreatitis. The authors specifically state that they want to assess the absolute effect of PN on major clinical outcomes (mortality and infectious complications) using randomized clinical trials (RCTs) comparing PN with no nutrition intervention, the absolute effect of EN on those same outcomes using RCTs comparing EN with no nutrition intervention, and the relative efficacy of PN compared with EN on those outcomes using RCTs comparing those 2 interventions. To get a numerical estimate of the actual effect sizes and differences, they planned to combine the identified trials in each of the study categories using a process called meta-analysis. Meta-analysis is not the same thing as systematic reviewing. Systematic reviewing is a process whereby a specific question is asked, a protocol is written to use the published literature to answer that question, and pertinent papers are obtained and the data are assessed, from which assessment conclusions are made. Meta-analysis may or may not be employed in a systematic review. Meta-analysis is simply a mathematical method of pooling the data from multiple trials. While this mathematical method can be applied to any set of data, for our purposes, we will focus on systematic reviews of RCTs in the following discussion. There are 2 advantages of data pooling; one is to increase the power to see smaller differences, and the other is to get a more precise estimate of the actual effect. Simple data pooling can be done just by adding the numerators and denominators from each RCT. Meta-analysis differs from simple data pooling in that each RCT is weighted by the “variance,” a number that is calculated from the standard deviation. Any single RCT produces only an approximation of the true answer. However, in RCTs, the data are usually normally distributed, so 2 standard deviations on either side of the mean (the observed value) will encompass 95% of the possible results. Hence, it is highly probable that the true answer will be contained within these limits. Observed values with small standard deviations (and variances) are thought to be more precise estimates of the true answer and are given more weight. In meta-analysis, the observed values from each trial are weighted by a formula using the reciprocals of the variances, and these weighted values are then added together.
The downside to meta-analysis is heterogeneity—namely, how different the RCTs are from each other. Obviously, if they are too different, it does not even make sense to try to combine them. In the study we are about to discuss,1 the meta-analyses were limited to specific nutrition interventions in a common disease, so it would seem reasonable to do the pooling for the RCTs in each nutrition intervention scenario. However, as can be seen in Table 1 of the article,1 there were still differences between the RCTs with regard to when the trial was published (ranging from 1984–2007), the setting (where the RCT was conducted), the severity of disease, and the methodologic details (and the last 3 columns represent the components of the Jadad score). If one wanted to explore the possibility of heterogeneity, one could look at subsets of these RCTs (eg, we could perform a subgroup analysis of the RCTs that only enrolled severely ill patients). The results of a meta-analysis are typically presented as a forest plot (Figures 2–5 of the article1). In the forest plots in the systematic review by Petrov et al,1 the results from each of the trials that reported the outcome of interest are listed in the first 5 columns. The calculated weight of each trial is numerically presented in the sixth column and, as will be noted shortly, is also reflected by the size of the box in the last column. In general, data from RCTs can be either dichotomous (the event happened or did not happen) or continuous (the outcome is measured on a continuous scale, as done for such parameters as length of stay in the hospital); for our purposes, all data were dichotomous (presence or absence of either death or infection). 1
From the Olive View–UCLA Medical Center, David Geffen–UCLA School of Medicine, Sylmar and Los Angeles, California. Financial disclosure: Dr Koretz receives ongoing support from GIIssues, Inc, a 401(c)(3) nonprofit organization that promotes the use and dissemination of evidence-based medicine. While no particular funds were used for this particular project, GIIssues, Inc, will support Dr Koretz’s academic travel, society memberships, and other academic activities that have some relationship to the mission of the promulgation of evidence-based medicine. GIIssues, Inc, does not provide any salary support for Dr Koretz. No research materials related to this article can be accessed other than the stated references. Corresponding Author: Ronald L. Koretz, MD, Emeritus Professor of Clinical Medicine, Olive View–UCLA Medical Center, 14445 Olive View Dr, Sylmar, CA 91342, USA. Email: [email protected]
Downloaded from pen.sagepub.com at UNIV TORONTO on August 10, 2014
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Journal of Parenteral and Enteral Nutrition 38(6)
Dichotomous data can be presented in several ways; in this case, the risk ratio is calculated. The risk ratio represents the incidence of the outcome in the treated group divided by the incidence in the control group; for the RCTs comparing PN and EN, the PN group was used as the comparator (since there was no true control group). The risk ratios for each of the individual trials, along with the 95% confidence intervals, are in the seventh column, and the last column pictorially represents columns 6 and 7, with the box representing the estimated risk ratio and the horizontal line the confidence interval. To be noted, the size of the box corresponds to the weight of each trial. The last line of data in the forest plot represents the result of the meta-analysis. The total weight is 100% (since all trials were considered), and the estimated risk ratio is presented numerically as well as pictorially in the last 2 columns. However, the pictorial representation is no longer a box and horizontal line but a diamond; the peak of the diamond is the estimated effect, and the left and right extremes of the diamond represent the confidence interval. Significance is defined as a 95% confidence interval that does not cross the line of equivalence. If the incidence of the outcome is the same in both groups, the risk ratio is precisely 1.00; this is the vertical line of equivalence depicted in the last column. Let us now consider the conclusions of the systematic review by Petrov et al.1 As we noted earlier, these authors systematically sought all of the RCTs addressing the use of artificial nutrition (PN or EN) in patients with acute pancreatitis. The authors were only able to perform meta-analysis if there were at least 2 trials in the category of interest. (It makes no sense to consider combining data if only 1 trial is available.) They found 3 trials that compared PN with no nutrition intervention and 11 trials that compared PN with EN. However, only 1 trial compared EN with no nutrition intervention.2 As a result, they did not report on that trial but instead did what is known as an indirect meta-analysis—that is, they attempted to calculate the effect of EN alone by comparing the trials comparing EN with PN and PN with no intervention. The common arm of these latter 2 comparisons was the delivery of PN, and they looked at the relative differences to infer how EN would compare with no intervention. Indirect meta-analysis is less commonly done in systematic reviews, and we will consider it shortly. With regard to PN vs no intervention, the data are summarized in Figures 4 and 5; while no significant difference was seen when the 2 trials that reported infections were combined (Figure 4), the PN did appear to have a dramatic effect on mortality (Figure 5). To be noted, this beneficial effect was largely a consequence of the data from the 1 trial by Xian-li et al,3 which accounted for 75% of the weight in the analysis. (In statistical terms, we would say that the Xian-li trial “drove” the analysis.) When PN was compared with EN, the latter resulted in fewer infections (Figure 2), although there was no significant difference in mortality (Figure 3). In the meta-analysis addressing infectious complications, the trial contributing the
greatest weight was the one by Petrov et al4 (41%); while that was the only trial to find a significant difference favoring EN, it should be noted that the infectious complications were less frequent in the EN arm of 8 of the remaining 9 RCTs. Thus, this significant difference was not a result of data from 1 trial driving the analysis. Since only 1 RCT was identified that compared EN with no nutrition intervention, Petrov et al1 chose to address the absolute efficacy of EN using indirect meta-analysis. The risk ratio for an outcome in the EN vs PN trials was the incidence in the EN group divided by the incidence in the PN group. The calculated risk ratio for the outcomes in the PN vs no nutrition intervention was the incidence of the outcome in the PN group divided by the incidence in the no-treatment group. The indirect meta-analysis assesses the ratio of these 2 risk ratios, assuming that the incidences of the outcomes in the PN groups were comparable. To do this, the authors reexpressed the risk ratio in the PN vs no-intervention study so the PN group was the comparator (ie, the risk ratio was the incidence in the nointervention group divided by the incidence in the PN group). Since it is assumed that the incidences of the outcomes in the PN groups were the same regardless of to what intervention the PN was being compared, dividing the risk ratio of EN compared with PN by the risk ratio of no intervention compared with PN resulted in the ratio of EN compared with no intervention. The data for the indirect meta-analysis are seen in Table 2 of the article.1 The risk ratios of the EN vs PN RCTs are the same as what was calculated. The risk ratios for the no-nutrition intervention vs PN RCTs are the reciprocals of the risk ratios that were calculated for the PN vs no-intervention RCTs. (For example, the risk ratio for the infectious complications is 1/1.36, or 0.73.) The ratio of these 2 ratios is 0.56 (0.41/0.73) for the infectious complications; since the confidence interval overlapped 1.00, this was not significant, and Petrov et al1 concluded that EN had no effect on infectious complications. On the other hand, the ratio of ratios for mortality was 0.22 (0.60/2.77), and that confidence interval did not cross the line of equivalence, resulting in the conclusion that EN would improve mortality. Inherent in indirect meta-analysis is the assumption that the groups receiving the treatment in common (PN in this case) are truly comparable. However, the trial that drove the PN vs nointervention mortality calculation3 would appear to represent a true outlier in the PN literature because the difference in mortality between the PN recipients and those not receiving any nutrition interventions is far more dramatic than has been seen in any other of over 100 such RCTs of PN.5 The article was published in a supplement, and it is not clear how much peerreviewing it received. (I did contact the editors of the journal shortly after this trial was published and asked for contact information for the author, but the editors could only provide the mailing address that was available in the paper; a subsequent letter that I wrote to Dr Xian-li went unanswered.) The
Downloaded from pen.sagepub.com at UNIV TORONTO on August 10, 2014
Koretz
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trial was conducted in China, and there have been suggestions that trials labeled as randomized, at least in the complementary and alternative medicine literature, are not truly randomized.6,7 This problem with indirect meta-analysis is not limited to this systematic review. Others have questioned the reliability of such comparisons.8,9 The indirect meta-analysis resulted in the authors not even considering the single trial that was identified.2 In that RCT, 27 patients with predicted severe pancreatitis were randomized to EN (n = 13) or conventional treatment (n = 14). No data were reported regarding mortality or infections, but no differences were seen with regard to organ failure scores or duration of hospitalization; the nausea scores were higher in the EN group. Contrary to what Petrov et al1 predicted about the utility of EN in acute pancreatitis, a large RCT was presented at the 2012 United European Gastroenterology Week; more than 200 patients with moderate to severe pancreatitis were randomized into 2 groups, one receiving EN that was begun within 24 hours and the other no nutrition intervention.10 No significant differences in mortality, organ failure, local complications, infected pancreatic necrosis, or duration of hospitalization were observed. The other issue that did not seem to be considered very strongly by Petrov et al1 related to the risks of bias in the RCTs that were considered. These authors used the Jadad scale to assess this problem and, even though this scale is somewhat insensitive in identifying risks of bias, only 2 of the 15 RCTs that had been identified even met the lowest criterion for better methodology—namely, a score of 3. (These scores can be calculated11 from the information in Table 1.1) In general, RCTs at higher risks of bias tend to overestimate benefit.11,12 Thus, the conclusions made about the efficacy of either EN or PN in patients with acute pancreatitis are overstated, given the totality of the evidence we have to date. Perhaps the conclusion that was best supported by the evidence was that the provision of EN results in fewer infectious complications compared with the provision of PN. However, if PN causes excess infections,5 we have no evidence to assure us that providing EN is better than doing nothing. For the next installment, please read the following article: Sandstrom R, Drott C, Hyltander A, et al. The effect of postoperative intravenous feeding (TPN) on outcome following major surgery evaluated in a randomized study. Ann Surg. 1993;217:185-195. This is a still-cited randomized trial
comparing PN with hypertonic dextrose in patients after major surgery; it includes curious subgroup analyses. I encourage you to engage in discussion on ASPENConnect’s Journal Club discussion board. A.S.P.E.N. has created an information kit with guidelines for how chapters, hospitals, and universities can develop their own journal clubs (www.nutritioncare.org/ journalclub).
References 1. Petrov MS, Pylypchuk RD, Emelyanov NV. Systematic review: nutritional support in acute pancreatitis. Aliment Pharm Ther. 2008;28: 704-712. 2. Powell JJ, Murchison JT, Fearon KCH, Ross JA, Siriwardena AK. Randomized controlled trial of the effect of early enteral nutrition on markers of the inflammatory response in predicted severe acute pancreatitis. Br J Surg. 2000;87:1375-1381. 3. Xian-li H, Qing-jiu M, Jian-guo L, Yan-kui C, Xi-lin D. Effect of total parenteral nutrition (TPN) with and without glutamine dipeptide supplementation on outcome in severe acute pancreatitis (SAP). Clin Nutr Suppl. 2004;1:43-47. 4. Petrov MS, Kukosh MV, Emelyanov NV. A randomized controlled trial of enteral versus parenteral feeding in patients with predicted severe acute pancreatitis shows a significant reduction in mortality and in infected pancreatic complications with total enteral nutrition. Dig Surg. 2006;23: 336-345. 5. Koretz RL, Lipman TO, Klein S. AGA technical review on parenteral nutrition. Gastroenterology. 2001;121:970-1001. 6. Taixiang W, Xunzhe Y, Xiaoxi Z, et al. How many false ‘RCTs’ were included in Cochrane systematic reviews of traditional Chinese medicine [abstract]? Z Evid Fortbild Qual Gesundh Wesen. 2008;102:26. 7. Liu J, Kjaergard LL, Gluud C. Misuse of randomization: a review of Chinese randomized trials of herbal medicines for chronic hepatitis B. Am J Chin Med. 2002;30:173-176. 8. Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis or randomized controlled trials. J Clin Epidemiol. 1997;50:683-691. 9. Song F, Xiong T, Parekh-Bhurke S, et al. Inconsistency between direct and indirect comparisons of competing interventions: meta-epidemiological study. BMJ. 2011;343:d4909. 10. Poropat G, Franjic N, Stimac D. Enteral nutrition for patients with acute pancreatitis [abstract]. Gut. 2012;61(suppl 3):A61. 11. Jadad AR, Moor RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clin Trials. 1996;17:1-12. 12. Higgins JPT, Altman DG, and Sterne JAC, eds. Assessing risk of bias in included studies. In: Higgins, JPT and Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. www. cochrane-handbook.org
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