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Can Rectal NSAIDs Replace Prophylactic Pancreatic Stent Placement for the Prevention of Post-ERCP Pancreatitis?
January 2014
(113/147; 77%) were diagnosed owing to symptoms, the true prevalence of interval cancers may be underestimated owing to the possibility of nondiagnosed asymptomatic lesions. These asymptomatic cancers might have been detected in protocol driven studies (Gut 2013). On the other hand, inclusion of CRCs occurring within a few months following colonoscopy might have led to overestimation by including diagnostic colonoscopies that were appropriately performed owing to worrisome findings on a previous examination. Previous population-based studies have reported a much higher percentage of CRCs deemed to be PCCRCS compared with the 2.9% rate in the current study (Gastroenterology 2011;140:65–72; Am J Gastroenterol 2010;105:2588–2596; Cancer 2012;118:3044–3052). The magnitude of risk for CRC after a colonoscopy varies in different studies and might be explained by variation in study population, time period, and methods. Furthermore, many studies have used a 3-year interval to define PCCRCs. To their credit, the current study investigators extended this interval to 5 years to optimize the correct identification of all PCCRCs. Finally, the algorithm for classifying these tumors, although logical and consistent, may not be correct. As pointed out by one expert, the classifying algorithm is based on assumptions (Gut 2013; Am J Gastroenterol 2013;108:1341–1343). The specific example provided is that a lesion that is diagnosed within 36 months may not be missed but possibly a new lesion that has developed from normal mucosa. In addition, underestimating the adenoma dwell time (time for adenoma to carcinoma) may also falsely lower the number of cases classified as missed and inflate those deemed to be new cases (Gut 2013). In summary, these findings suggest that endoscopists are missing a large percentage of cancers that are diagnosed interval lesions. The exact percentage of missed tumors that could have been prevented may be subject to debate, but the study’s message is a reminder for endoscopists to be cognizant of quality. In addition, the study points out the need for studies that examine the efficacy of current quality benchmarks for reducing the incidence of interval cancers. TARUN RUSTAGI Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut JOSEPH C. ANDERSON Department of Veterans Affairs Medical Center White River Junction, Vermont and The Geisel School of Medicine at Dartmouth Medical Hanover, New Hampshire
Reply. We thank Rustagi and Anderson for their interest in our paper and thorough comment. Indeed, identification of postcolonoscopy colorectal cancers (PCCRCs)—defined as invasive cancers diagnosed after a colorectal examination in which no cancer was detected—and especially elucidation of their etiology are key to improving the effectiveness and quality of colonoscopic cancer prevention. In our study,
Selected Summaries
313
conducted in a community-based environment, 86% of the PCCRCs identified were attributable to procedural factors (Gut 2013 Jun 6 [Epub ahead of print]). Missed lesions (57.8% of the PCCRCs) and incomplete polypectomy (8.8% of the PCCRCs) were major contributors, highlighting the need for educational improvements. With regard to phenotype, PCCRCs were predominantly proximal tumors and more likely to have a nonpolypoid macroscopic appearance than prevalent cancers. It is possible that nonpolypoid neoplasms, such as lateral spreading tumors of nongranular type and depressed neoplasms, as well as sessile serrated adenomas/polyps have contributed to the occurrence of PCCRCs. Such lesions are also preferentially located proximal in the colon, more challenging to recognize and resect, and a subset of them harbor biologic features leading to a more rapid progression to cancer (Am J Gastroenterol 2013;108:1042–1056; Cancer Res 2013;73: 2863–2872). Because this study was retrospective in nature, caution is needed in interpretation of etiology, and further prospective investigation is required. A first step in such an endeavor would be to establish a standardized definition for PCCRCs, in which the time interval to cancer diagnosis is derived from the currently recommended surveillance intervals. Second, a comprehensive data set would be needed, including age, gender of patients diagnosed with PCCRCs, overall risk profiles (family history, comorbidity, smoking habits, body mass index, etc), tumor characteristics (location, stage at diagnosis, histopathology, etc), and a rigorous characterization of lesions identified at colonoscopy (location, size, shape and histology). Ideally, such information would be linked to the endoscopist’s performance indicators to identify modifiable factors. Last, we agree that principles for disentangling procedural from biologic factors, as described in the study by Pabby et al (Gastrointest Endosc 2005;61:385–391) will need to be revisited. While awaiting further prospective studies, our data already indicate the vast majority of PCCRCs are avoidable, emphasizing the importance of training in detection of precursors, including the recognition of subtle appearing lesions, and their complete endoscopic resection. SILVIA SANDULEANU AD. A. M. MASCLEE Department of Internal Medicine Division of Gastroenterology & Hepatology Maastricht University Medical Center Maastricht, the Netherlands
CAN RECTAL NSAIDS REPLACE PROPHYLACTIC PANCREATIC STENT PLACEMENT FOR THE PREVENTION OF POST-ERCP PANCREATITIS? Akbar A, Abu Dayyeh BK, Baron TH, et al. Rectal nonsteroidal anti-inflammatory drugs are superior to pancreatic duct stents in preventing pancreatitis after endoscopic
314
Selected Summaries
retrograde cholangiopancreatography: a network metaanalysis. Clin Gastroenterol Hepatol 2013;11:778–783. Network meta-analysis (NMA) is a novel statistical method for comparing the effectiveness of multiple competing interventions based on both direct (head-tohead) and indirect (effect relative to a common comparator) evidence. As opposed to traditional (pairwise) metaanalysis, which can only pool head-to-head data pertaining to 2 treatments (eg, drug A vs placebo), NMA can simultaneously evaluate 3 interventions (eg, fecal occult blood testing vs flexible sigmoidoscopy vs colonoscopy vs no intervention) by creating a network of direct and indirect evidence from which comparative summary effects and rankings can be derived. In addition to thoughtful patient selection and sound procedural techniques, 2 specific prophylactic interventions have now been proven to be effective in the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), namely, pancreatic stent placement (PSP; Gastrointest Endosc 2011;73:275–282) and administration of periprocedural rectal nonsteroidal antiinflammatory drugs (NSAIDs; Gut 2008;57:1262–1267). A recent, large-scale, randomized, controlled trial (RCT) demonstrated that rectal indomethacin confers protection in addition to PSP (N Engl J Med 2012;366:1414–1422); however, there are no comparative effectiveness studies examining which of the 2 interventions is more effective. Moreover, it remains unclear whether rectal NSAIDs can replace PSP in clinical practice. Because PSP is technically challenging, time consuming, costly, and potentially dangerous (if attempted but unsuccessful), the need to compare PSP and NSAIDs has been proposed (N Engl J Med 2012;367:277–278). To further evaluate this issue, in a recent study in Clinical Gastroenterology and Hepatology, Akbar et al utilize NMA to pool and compare the available published data on the relative effectiveness of PSP and rectal NSAIDs. The authors systematically searched the world’s literature to identify 29 RCTs or observational studies addressing this topic. Of these, 22 compared stent placement with no intervention, 6 studies compared rectal NSAIDs with placebo, and 1 study provided direct comparisons of indomethacin alone, stent placement alone, the combination of both, and no intervention at all (N Engl J Med 2012;366:1414–1422). Pooling data from these 29 studies, the authors used traditional meta-analysis and NMA to calculate summary comparisons of the following prophylactic strategies: (1) PSP versus no intervention, (2) NSAIDs versus placebo, (3) PSP versus NSAIDs, (4) PSPþNSAIDs versus no treatment, (5) PSPþNSAIDs versus NSAIDs alone, and (6) PSPþNSAIDs versus PSP alone. The results of the traditional metaanalysis confirm that both PSP and rectal NSAIDs are more effective than no intervention (or placebo). NMA results suggest that rectal NSAIDs are superior to PSP (odds ratio [OR], 0.48; 95% credible interval [CrI], 0.26–0.87) and perhaps more importantly, the combination of NSAIDs and
Gastroenterology Vol. 146, No. 1
PSP is not better than rectal NSAIDs alone (OR, 1.46; 95% CrI, 0.79–2.69). The authors conclude that randomized trials are necessary, but rectal NSAIDs may be an acceptable firstline alternative to PSP in selected high-risk scenarios, such as early difficulty in PSP or biliary sphincter of Oddi dysfunction patients in whom pancreatic access is not attempted or achieved. Comment. Now that we have >1 effective prophylactic intervention for post-ERCP pancreatitis, we can welcome the era of comparative effectiveness research in this field. The first natural question in this line of investigation is: Which is more effective, rectal NSAIDs or PSP? However, the more salient question may be whether NSAIDs can replace PSP in clinical practice. This distinction is important because the first question does not account for the possibility that the combination of both is more effective than either intervention alone; this is mechanistically plausible given that these interventions may complement one another by working in completely different ways. The results of this NMA are congruent with those from a recent post hoc analysis of the 2012 NEJM indomethacin RCT which demonstrated that, after adjusting for imbalances in risk factors for PEP between study groups, subjects who received rectal indomethacin alone had the lowest risk of PEP—even lower than those who received the combination of indomethacin and stent (Am J Gastroenterol 2013;108:410–415). This hypothesis is biologically plausible because a strategy of indomethacin alone avoids manipulation of the pancreatic orifice and instrumentation of the pancreatic duct—interventions necessary to place a stent but also known to contribute to the risk of PEP. Through their forward-thinking application of NMA methodology, Akbar et al provide additional support to the hypothesis that rectal NSAIDs may eliminate the need for PSP by showing that subjects who received NSAIDs alone had lower odds of developing PEP than those who received PSP, and that this strategy was not inferior to combination therapy. Beyond the potential reduction in PEP, replacing prophylactic stent placement with indomethacin monoprevention in clinical practice has several additional potential advantages. First, indomethacin alone avoids the phenomenon of attempted but failed PSP, which is associated with a high rate of PEP by causing pancreatic orifice injury but providing no ductal decompression (Gastrointest Endosc 2004;5:8–14). Presumably, this phenomenon actually occurs more frequently in real-world practice than observed in clinical trials conducted at expert centers with highly experienced pancreatic endoscopists. Second, avoiding PSP would also eliminate the 4% of cases that result in significant nonpancreatitis complications, such as stent migration and duct perforation (Endoscopy 2010;42:842–845). Further, a strategy of indomethacin alone would substantially reduce healthcare expenditures by eliminating the cost of stent placement in most cases, as well as eliminating the need for follow-up abdominal radiography (to ensure spontaneous passage of the stent) and follow-up
January 2014
upper endoscopies to remove retained stents. A recent cost–benefit analysis revealed that a prevention strategy employing rectal indomethacin alone could save approximately $150 million annually in the United States compared with a strategy of PSP alone, and $85 million compared with a strategy of indomethacin and PSP (Am J Gastroenterol 2013;108:410–415). Despite the provocative nature of this NMA and the major potential implications of its results, there are several important issues worth considering. First, the estimates of effect are based on the results of randomized trials and observational studies. In general, observational studies, particularly retrospective ones, have a tendency to overestimate effect sizes and could contribute to incorrect conclusions. However, for the purpose of this summary, we performed a repeat Bayesian-driven NMA restricted to RCTs (using data provided in the manuscript), which did not change the overall findings of the study. For example, the comparative odds ratio for PEP associated with NSAIDs alone versus combination therapy was 0.74 (95% CrI, 0.25–2.13) in the RCT-restricted model versus 0.73 (95% CrI, 0.26–2.11) in the full analysis comprising all studies. In addition, this NMA was based predominantly on indirect comparisons (28 of 29 included studies). The only direct comparisons were derived from one RCT that was not specifically designed to compare the 4 strategies of indomethacin alone, PSP alone, combination therapy, and no prophylaxis. In this RCT, the decision to place a prophylactic stent was left to the discretion of the endoscopist who was unaware of study group assignment. As such, study results were biased against PSP, since subjects who received a stent were at greater risk for PEP because they induced more concern on the part of the endoscopist. This phenomenon was not adjusted for in the NMA and may have inflated the relative effectiveness of rectal NSAIDs compared with PSP. Another important consideration is that although it seems rectal NSAIDs are superior to PSP at reducing overall PEP, we do not have RCT confirmation of this phenomenon, nor do we understand the impact of withholding PSP (giving NSAIDs alone) on the risk of severe PEP, the prevention of which is arguably the most important benefit of stent placement. Therefore this meta-analysis and the aforementioned post hoc analysis should be considered hypothesisgenerating as their results do not produce RCT-level evidence, which currently supports the use of indomethacin in addition to PSP in high-risk cases (N Engl J Med 2012;366:1414–1422). A multicenter, randomized, noninferiority trial comparing rectal indomethacin alone versus the combination of indomethacin and prophylactic stent placement is in its final planning phases, should begin enrolling subjects in 2014, and will hopefully provide concrete guidance for this critical management issue. Awaiting the results of this study, our current clinical practice is to place prophylactic stents and administer rectal indomethacin during ERCP to all high-risk patients. Moreover, based
Selected Summaries
315
on highly favorable risk and cost–benefit ratios, it seems to be reasonable to administer rectal indomethacin (without stent) to average-risk patients as well. B. JOSEPH ELMUNZER AKBAR K. WALJEE Division of Gastroenterology University of Michigan Medical Center Ann Arbor, Michigan
Reply. We thank Elmunzer and Waljee for their excellent synopsis of our article, critical review of its methodology, and interpretation of the results. Of course our study was inspired by the randomized, controlled trial of nonsteroidal anti-inflammatory drugs (NSAIDs) versus placebo for prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP; N Engl J Med 2012;366:1414–1422). However, in that study >80% of patients in each arm underwent prophylactic stent placement (PSP) and thus it was not an NSAID alone versus placebo alone trial. Since the publication of a post hoc analysis of the NEJM data (Am J Gastroenterol 2013;108:410–415) and indirect network meta-analysis (Clin Gastroenterol Hepatol 2013;11:778–783), the approach to use of NSAIDs to prevent PEP has varied within our own practice at Mayo Clinic, Rochester. Our ERCP practice employs the services of 6 ERCPists, all of whom now administer rectal NSAIDs but without a uniform approach. Some believe in using NSAIDs alone, whereas others are uncomfortable withholding PSP. Among our group’s practice, the approach to use of NSAIDs alone or PSP combined with NSAIDs varies not only between endoscopists, but within endoscopists, depending on the individual patient. Although we have not adopted the approach to administer NSAIDs to low-risk patients, one could argue that if ERCPists have a “zero tolerance policy” with regard to PEP, NSAIDs should be administered to all patients undergoing ERCP. In addition, one-time administration of rectal NSAIDs is low cost and low risk for adverse events, further supporting its potential for uniform administration. We eagerly await the results of the randomized trial of NSAIDs alone and stents alone, understanding that participating centers may find it difficult to enroll patients who may be randomized to not receive PSP. Not only do we encourage centers to participate in the randomized controlled trial, but also encourage centers to collect data prospectively during clinical practice that could also provide useful additional information on NSAIDS and PEP. TODD H. BARON Division of Gastroenterology & Hepatology Mayo Clinic Rochester, Minnesota Acknowledgments Dr Baron is currently affiliated with the Division of Gastroenterology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina.
(113/147; 77%) were diagnosed owing to symptoms, the true prevalence of interval cancers may be underestimated owing to the possibility of nondiagnosed asymptomatic lesions. These asymptomatic cancers might have been detected in protocol driven studies (Gut 2013). On the other hand, inclusion of CRCs occurring within a few months following colonoscopy might have led to overestimation by including diagnostic colonoscopies that were appropriately performed owing to worrisome findings on a previous examination. Previous population-based studies have reported a much higher percentage of CRCs deemed to be PCCRCS compared with the 2.9% rate in the current study (Gastroenterology 2011;140:65–72; Am J Gastroenterol 2010;105:2588–2596; Cancer 2012;118:3044–3052). The magnitude of risk for CRC after a colonoscopy varies in different studies and might be explained by variation in study population, time period, and methods. Furthermore, many studies have used a 3-year interval to define PCCRCs. To their credit, the current study investigators extended this interval to 5 years to optimize the correct identification of all PCCRCs. Finally, the algorithm for classifying these tumors, although logical and consistent, may not be correct. As pointed out by one expert, the classifying algorithm is based on assumptions (Gut 2013; Am J Gastroenterol 2013;108:1341–1343). The specific example provided is that a lesion that is diagnosed within 36 months may not be missed but possibly a new lesion that has developed from normal mucosa. In addition, underestimating the adenoma dwell time (time for adenoma to carcinoma) may also falsely lower the number of cases classified as missed and inflate those deemed to be new cases (Gut 2013). In summary, these findings suggest that endoscopists are missing a large percentage of cancers that are diagnosed interval lesions. The exact percentage of missed tumors that could have been prevented may be subject to debate, but the study’s message is a reminder for endoscopists to be cognizant of quality. In addition, the study points out the need for studies that examine the efficacy of current quality benchmarks for reducing the incidence of interval cancers. TARUN RUSTAGI Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut JOSEPH C. ANDERSON Department of Veterans Affairs Medical Center White River Junction, Vermont and The Geisel School of Medicine at Dartmouth Medical Hanover, New Hampshire
Reply. We thank Rustagi and Anderson for their interest in our paper and thorough comment. Indeed, identification of postcolonoscopy colorectal cancers (PCCRCs)—defined as invasive cancers diagnosed after a colorectal examination in which no cancer was detected—and especially elucidation of their etiology are key to improving the effectiveness and quality of colonoscopic cancer prevention. In our study,
Selected Summaries
313
conducted in a community-based environment, 86% of the PCCRCs identified were attributable to procedural factors (Gut 2013 Jun 6 [Epub ahead of print]). Missed lesions (57.8% of the PCCRCs) and incomplete polypectomy (8.8% of the PCCRCs) were major contributors, highlighting the need for educational improvements. With regard to phenotype, PCCRCs were predominantly proximal tumors and more likely to have a nonpolypoid macroscopic appearance than prevalent cancers. It is possible that nonpolypoid neoplasms, such as lateral spreading tumors of nongranular type and depressed neoplasms, as well as sessile serrated adenomas/polyps have contributed to the occurrence of PCCRCs. Such lesions are also preferentially located proximal in the colon, more challenging to recognize and resect, and a subset of them harbor biologic features leading to a more rapid progression to cancer (Am J Gastroenterol 2013;108:1042–1056; Cancer Res 2013;73: 2863–2872). Because this study was retrospective in nature, caution is needed in interpretation of etiology, and further prospective investigation is required. A first step in such an endeavor would be to establish a standardized definition for PCCRCs, in which the time interval to cancer diagnosis is derived from the currently recommended surveillance intervals. Second, a comprehensive data set would be needed, including age, gender of patients diagnosed with PCCRCs, overall risk profiles (family history, comorbidity, smoking habits, body mass index, etc), tumor characteristics (location, stage at diagnosis, histopathology, etc), and a rigorous characterization of lesions identified at colonoscopy (location, size, shape and histology). Ideally, such information would be linked to the endoscopist’s performance indicators to identify modifiable factors. Last, we agree that principles for disentangling procedural from biologic factors, as described in the study by Pabby et al (Gastrointest Endosc 2005;61:385–391) will need to be revisited. While awaiting further prospective studies, our data already indicate the vast majority of PCCRCs are avoidable, emphasizing the importance of training in detection of precursors, including the recognition of subtle appearing lesions, and their complete endoscopic resection. SILVIA SANDULEANU AD. A. M. MASCLEE Department of Internal Medicine Division of Gastroenterology & Hepatology Maastricht University Medical Center Maastricht, the Netherlands
CAN RECTAL NSAIDS REPLACE PROPHYLACTIC PANCREATIC STENT PLACEMENT FOR THE PREVENTION OF POST-ERCP PANCREATITIS? Akbar A, Abu Dayyeh BK, Baron TH, et al. Rectal nonsteroidal anti-inflammatory drugs are superior to pancreatic duct stents in preventing pancreatitis after endoscopic
314
Selected Summaries
retrograde cholangiopancreatography: a network metaanalysis. Clin Gastroenterol Hepatol 2013;11:778–783. Network meta-analysis (NMA) is a novel statistical method for comparing the effectiveness of multiple competing interventions based on both direct (head-tohead) and indirect (effect relative to a common comparator) evidence. As opposed to traditional (pairwise) metaanalysis, which can only pool head-to-head data pertaining to 2 treatments (eg, drug A vs placebo), NMA can simultaneously evaluate 3 interventions (eg, fecal occult blood testing vs flexible sigmoidoscopy vs colonoscopy vs no intervention) by creating a network of direct and indirect evidence from which comparative summary effects and rankings can be derived. In addition to thoughtful patient selection and sound procedural techniques, 2 specific prophylactic interventions have now been proven to be effective in the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), namely, pancreatic stent placement (PSP; Gastrointest Endosc 2011;73:275–282) and administration of periprocedural rectal nonsteroidal antiinflammatory drugs (NSAIDs; Gut 2008;57:1262–1267). A recent, large-scale, randomized, controlled trial (RCT) demonstrated that rectal indomethacin confers protection in addition to PSP (N Engl J Med 2012;366:1414–1422); however, there are no comparative effectiveness studies examining which of the 2 interventions is more effective. Moreover, it remains unclear whether rectal NSAIDs can replace PSP in clinical practice. Because PSP is technically challenging, time consuming, costly, and potentially dangerous (if attempted but unsuccessful), the need to compare PSP and NSAIDs has been proposed (N Engl J Med 2012;367:277–278). To further evaluate this issue, in a recent study in Clinical Gastroenterology and Hepatology, Akbar et al utilize NMA to pool and compare the available published data on the relative effectiveness of PSP and rectal NSAIDs. The authors systematically searched the world’s literature to identify 29 RCTs or observational studies addressing this topic. Of these, 22 compared stent placement with no intervention, 6 studies compared rectal NSAIDs with placebo, and 1 study provided direct comparisons of indomethacin alone, stent placement alone, the combination of both, and no intervention at all (N Engl J Med 2012;366:1414–1422). Pooling data from these 29 studies, the authors used traditional meta-analysis and NMA to calculate summary comparisons of the following prophylactic strategies: (1) PSP versus no intervention, (2) NSAIDs versus placebo, (3) PSP versus NSAIDs, (4) PSPþNSAIDs versus no treatment, (5) PSPþNSAIDs versus NSAIDs alone, and (6) PSPþNSAIDs versus PSP alone. The results of the traditional metaanalysis confirm that both PSP and rectal NSAIDs are more effective than no intervention (or placebo). NMA results suggest that rectal NSAIDs are superior to PSP (odds ratio [OR], 0.48; 95% credible interval [CrI], 0.26–0.87) and perhaps more importantly, the combination of NSAIDs and
Gastroenterology Vol. 146, No. 1
PSP is not better than rectal NSAIDs alone (OR, 1.46; 95% CrI, 0.79–2.69). The authors conclude that randomized trials are necessary, but rectal NSAIDs may be an acceptable firstline alternative to PSP in selected high-risk scenarios, such as early difficulty in PSP or biliary sphincter of Oddi dysfunction patients in whom pancreatic access is not attempted or achieved. Comment. Now that we have >1 effective prophylactic intervention for post-ERCP pancreatitis, we can welcome the era of comparative effectiveness research in this field. The first natural question in this line of investigation is: Which is more effective, rectal NSAIDs or PSP? However, the more salient question may be whether NSAIDs can replace PSP in clinical practice. This distinction is important because the first question does not account for the possibility that the combination of both is more effective than either intervention alone; this is mechanistically plausible given that these interventions may complement one another by working in completely different ways. The results of this NMA are congruent with those from a recent post hoc analysis of the 2012 NEJM indomethacin RCT which demonstrated that, after adjusting for imbalances in risk factors for PEP between study groups, subjects who received rectal indomethacin alone had the lowest risk of PEP—even lower than those who received the combination of indomethacin and stent (Am J Gastroenterol 2013;108:410–415). This hypothesis is biologically plausible because a strategy of indomethacin alone avoids manipulation of the pancreatic orifice and instrumentation of the pancreatic duct—interventions necessary to place a stent but also known to contribute to the risk of PEP. Through their forward-thinking application of NMA methodology, Akbar et al provide additional support to the hypothesis that rectal NSAIDs may eliminate the need for PSP by showing that subjects who received NSAIDs alone had lower odds of developing PEP than those who received PSP, and that this strategy was not inferior to combination therapy. Beyond the potential reduction in PEP, replacing prophylactic stent placement with indomethacin monoprevention in clinical practice has several additional potential advantages. First, indomethacin alone avoids the phenomenon of attempted but failed PSP, which is associated with a high rate of PEP by causing pancreatic orifice injury but providing no ductal decompression (Gastrointest Endosc 2004;5:8–14). Presumably, this phenomenon actually occurs more frequently in real-world practice than observed in clinical trials conducted at expert centers with highly experienced pancreatic endoscopists. Second, avoiding PSP would also eliminate the 4% of cases that result in significant nonpancreatitis complications, such as stent migration and duct perforation (Endoscopy 2010;42:842–845). Further, a strategy of indomethacin alone would substantially reduce healthcare expenditures by eliminating the cost of stent placement in most cases, as well as eliminating the need for follow-up abdominal radiography (to ensure spontaneous passage of the stent) and follow-up
January 2014
upper endoscopies to remove retained stents. A recent cost–benefit analysis revealed that a prevention strategy employing rectal indomethacin alone could save approximately $150 million annually in the United States compared with a strategy of PSP alone, and $85 million compared with a strategy of indomethacin and PSP (Am J Gastroenterol 2013;108:410–415). Despite the provocative nature of this NMA and the major potential implications of its results, there are several important issues worth considering. First, the estimates of effect are based on the results of randomized trials and observational studies. In general, observational studies, particularly retrospective ones, have a tendency to overestimate effect sizes and could contribute to incorrect conclusions. However, for the purpose of this summary, we performed a repeat Bayesian-driven NMA restricted to RCTs (using data provided in the manuscript), which did not change the overall findings of the study. For example, the comparative odds ratio for PEP associated with NSAIDs alone versus combination therapy was 0.74 (95% CrI, 0.25–2.13) in the RCT-restricted model versus 0.73 (95% CrI, 0.26–2.11) in the full analysis comprising all studies. In addition, this NMA was based predominantly on indirect comparisons (28 of 29 included studies). The only direct comparisons were derived from one RCT that was not specifically designed to compare the 4 strategies of indomethacin alone, PSP alone, combination therapy, and no prophylaxis. In this RCT, the decision to place a prophylactic stent was left to the discretion of the endoscopist who was unaware of study group assignment. As such, study results were biased against PSP, since subjects who received a stent were at greater risk for PEP because they induced more concern on the part of the endoscopist. This phenomenon was not adjusted for in the NMA and may have inflated the relative effectiveness of rectal NSAIDs compared with PSP. Another important consideration is that although it seems rectal NSAIDs are superior to PSP at reducing overall PEP, we do not have RCT confirmation of this phenomenon, nor do we understand the impact of withholding PSP (giving NSAIDs alone) on the risk of severe PEP, the prevention of which is arguably the most important benefit of stent placement. Therefore this meta-analysis and the aforementioned post hoc analysis should be considered hypothesisgenerating as their results do not produce RCT-level evidence, which currently supports the use of indomethacin in addition to PSP in high-risk cases (N Engl J Med 2012;366:1414–1422). A multicenter, randomized, noninferiority trial comparing rectal indomethacin alone versus the combination of indomethacin and prophylactic stent placement is in its final planning phases, should begin enrolling subjects in 2014, and will hopefully provide concrete guidance for this critical management issue. Awaiting the results of this study, our current clinical practice is to place prophylactic stents and administer rectal indomethacin during ERCP to all high-risk patients. Moreover, based
Selected Summaries
315
on highly favorable risk and cost–benefit ratios, it seems to be reasonable to administer rectal indomethacin (without stent) to average-risk patients as well. B. JOSEPH ELMUNZER AKBAR K. WALJEE Division of Gastroenterology University of Michigan Medical Center Ann Arbor, Michigan
Reply. We thank Elmunzer and Waljee for their excellent synopsis of our article, critical review of its methodology, and interpretation of the results. Of course our study was inspired by the randomized, controlled trial of nonsteroidal anti-inflammatory drugs (NSAIDs) versus placebo for prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP; N Engl J Med 2012;366:1414–1422). However, in that study >80% of patients in each arm underwent prophylactic stent placement (PSP) and thus it was not an NSAID alone versus placebo alone trial. Since the publication of a post hoc analysis of the NEJM data (Am J Gastroenterol 2013;108:410–415) and indirect network meta-analysis (Clin Gastroenterol Hepatol 2013;11:778–783), the approach to use of NSAIDs to prevent PEP has varied within our own practice at Mayo Clinic, Rochester. Our ERCP practice employs the services of 6 ERCPists, all of whom now administer rectal NSAIDs but without a uniform approach. Some believe in using NSAIDs alone, whereas others are uncomfortable withholding PSP. Among our group’s practice, the approach to use of NSAIDs alone or PSP combined with NSAIDs varies not only between endoscopists, but within endoscopists, depending on the individual patient. Although we have not adopted the approach to administer NSAIDs to low-risk patients, one could argue that if ERCPists have a “zero tolerance policy” with regard to PEP, NSAIDs should be administered to all patients undergoing ERCP. In addition, one-time administration of rectal NSAIDs is low cost and low risk for adverse events, further supporting its potential for uniform administration. We eagerly await the results of the randomized trial of NSAIDs alone and stents alone, understanding that participating centers may find it difficult to enroll patients who may be randomized to not receive PSP. Not only do we encourage centers to participate in the randomized controlled trial, but also encourage centers to collect data prospectively during clinical practice that could also provide useful additional information on NSAIDS and PEP. TODD H. BARON Division of Gastroenterology & Hepatology Mayo Clinic Rochester, Minnesota Acknowledgments Dr Baron is currently affiliated with the Division of Gastroenterology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina.