Pharmacological Prophylaxis Against Post-ERCP Pancreatitis
Pharmacological Prophylaxis Against Post-ERCP Pancreatitis
Despite the numerous agents evaluated in prior RCTs and in clinical use for the prevention of PEP, the majority of agents have not been compared in head-to-head RCTs. We conducted a NMA of 16 pharmacological agents evaluated in 99 RCTs involving 25 313 patients as well as several sensitivity analyses and found that topical epinephrine and rectal NSAIDs are the most efficacious agents for the prevention of PEP.
The top six agents, from most to least efficacious for preventing PEP, were topical epinephrine, rectal NSAIDs, nafamostat, antibiotics, secretin and somatostatin (Figure 4). The sharp demarcation in the probability of ranks, between topical epinephrine and the other agents, indicates that topical epinephrine should be further evaluated in future studies. Similarly, the difference between the sixth ranking agent, somatostatin, and the seventh ranking agent, gabexate, highlights the limited efficacy of those agents ranking from seventh to 16th and suggests that future clinical trials should exclude these agents from further study.
(Enlarge Image)
Figure 4.
Sensitivity analysis: after exclusion of trials evaluating oral, intramuscular NSAIDs and inclusion of only rectal NSAIDs; rankograms comparing pharmacological agents to prevent post-ERCP pancreatitis. The vertical axis lists the agents evaluated. The horizontal axis lists the probability of achieving the best, second best or the third best rank based on repeated draws of the algorithm. The agent with the longest bar indicates the most efficacious agent. The total probability for top three ranks together is 300%.
There were agents that share a similar mechanism of action, but had widely discrepant ranks. For example, nafamostat, gabexate and ulinastatin are all protease inhibitors, but nafamostat ranked higher than gabexate and ulinastatin. This is probably because of the higher potency and longer duration of action of nafamostat. Somatostatin and octreotide are also similar for their anti-secretory properties, but somatostatin ranked higher, potentially because octreotide causes constriction, while somatostatin causes relaxation of the sphincter of Oddi.
There were two RCTs comparing topical epinephrine with placebo and these were conducted at different centres in Asia. The primary limitations of these studies were that they included only patients undergoing diagnostic ERCP and both utilised an ERCP protocol that mandates that a more experienced endoscopist complete difficult procedures. While patients undergoing diagnostic ERCP are typically considered to be at low risk for PEP, it should be noted that, in the epinephrine trial conducted by Xu et al., 9% of the patients had acinarisation and the mean number of pancreatic duct contrast injections was 4.6. This suggests that many patients became high risk due to procedural interventions. However, these particular limitations and other methodological limitations can be similarly found in all of the trials evaluating the other top-ranking agents in the present NMA. It should be highlighted that we conducted several sensitivity analyses and found that the rank order of the top six agents did not change after excluding each individual agent from the analysis. Interestingly, when we excluded only the epinephrine trials and re-evaluated the rank order, nafamostat ranked in the top position followed by antibiotics and then NSAIDs.
There are several possible explanations for why topical epinephrine was found to be the most efficacious agent for the prevention of PEP. Although the pathophysiology of PEP is not well understood, several human and animal studies support the important role that pancreatic ductal outflow obstruction due to papillary oedema plays in the development of PEP. Topical application of epinephrine induces arteriolar vasoconstriction in the papillary vasculature that reduces oedema and subsequent pancreatic ductal outflow obstruction. Topical epinephrine has also been shown to relax duodenal musculature and the sphincter of Oddi, both of which also reduce pancreatic outflow obstruction. The concept of pancreatic ductal outflow obstruction as an early step in the pathogenesis of PEP has been espoused in prior reviews. By reducing pancreatic ductal outflow obstruction, topical epinephrine acts at an early point in the pathogenesis of PEP. In addition, the local application of epinephrine increases the likelihood of it acting within this early therapeutic window and represents a clear advantage over other agents, which act on a more downstream point in the pathogenesis of PEP when the inflammatory cascade may no longer be attenuated. A topical agent also carries certain advantages over agents that are administered through different routes. For example, rectally administered agents may be expelled due to endoscopic air insufflation of the bowel or incomplete absorption. Rectal agents can also be difficult for endoscopy staff to administer when patients undergo ERCP in the supine position.
Due to its ability to reduce pancreatic ductal outflow obstruction, topical epinephrine essentially acts as the 'pharmacological equivalent' of a pancreatic stent. Numerous RCTs have shown the superiority of pancreatic stents over no stent for preventing PEP in high-risk patients. The key difference between topical epinephrine and pancreatic stents is the short duration of action of epinephrine. However, one RCT reported that 60% of prophylactic pancreatic stents spontaneously migrate within 24 h with no difference noted in the incidence of PEP between this group and those in whom the pancreatic stents remained in situ. Another study reported that the mean time for spontaneous pancreatic stent dislodgement can be as little as 2.1 days. These studies suggest that pancreatic stents may also act within a narrow therapeutic window. In addition, pancreatic stents have many drawbacks, including technical difficulty with placement as well as the cost of stents and follow-up endoscopy commonly required for stent removal.
When only RCTs evaluating rectal NSAIDs were included in the model, rectal NSAIDs ranked second after topical epinephrine. Rectal NSAIDs are the only pharmacological agents currently recommended in clinical guidelines based on their efficacy, low cost, favourable safety profile and widespread availability. While nafamostat and antibiotics ranked in the third and fourth positions, there are several reasons limiting their use in clinical practice. Nafamostat is intravenously administered over an extended time period before, during and after ERCP. One study administered nafamostat for as long as 24 h. The primary limitation of antibiotics is microbial resistance, which is already a significant global health problem.
A closer examination of route of administration, dose, cost, advantages and disadvantages of each of the six top-ranking agents from the present NMA suggests that topical epinephrine and rectal NSAIDs are both inexpensive, widely available, easy to administer and associated with few side effects. The costs of rectal NSAIDs and topical epinephrine, $1.12 and $0.24, respectively, are much lower than the cost of prophylactic pancreatic duct stent placement, which can range from $160 to $508. Given that topical epinephrine and rectal NSAIDs act to counter different steps in the pathogenesis of PEP, i.e. pancreatic ductal outflow obstruction and the inflammatory cascade, respectively, they can potentially be used in combination for a synergistic effect. A recent meta-analysis concluded that NSAIDs are only able to reduce the incidence of PEP from 13.9% to 8%. It is possible that the concomitant use of topical epinephrine and rectal NSAIDs could further reduce the incidence of PEP.
There are several limitations to the present NMA. The first is the inclusion of RCTs that enrolled patients with wide discrepancies of risk for developing PEP, as this results in statistical heterogeneity. However, when we excluded trials of only high-risk patients from our NMA, there was less heterogeneity and the rank order of agents did not change. A separate analysis of the trials that included only high-risk patients showed a similar ranking of agents, although topical epinephrine was not evaluated in high-risk patients. It is also important to emphasise that there is currently no method to quantify the risk of developing PEP based on known demographic, clinical and procedural risk factors. This limitation essentially affects not only our NMA but also all RCTs conducted in this field. The second limitation is the use of pancreatic duct stents, in addition to drugs, for PEP prophylaxis in some of the trials. While we were not able to control for the effect of pancreatic stenting in our NMA, pancreatic stenting was performed in only a small percentage of patients, equally distributed in the intervention and placebo arms, and in more recent trials and, therefore, did not significantly impact the performance of the drugs in the NMA.
It must be emphasised that the objectives of NMA differ from conventional meta-analyses. While conventional meta-analyses summarise evidence from RCTs for a particular agent(s) and provide evidence for framing management guidelines, NMA summarises evidence from multiple competing interventions simultaneously and provides direction for future research and clinical practice. Our study identified potential sources of heterogeneity across trials and recommends exclusion of relatively poor performing agents and further evaluation of better performing agents.
In conclusion, the present network meta-analysis found that topical epinephrine and rectal NSAIDs are the best performing agents to prevent PEP. Future trials are needed to determine whether topical epinephrine, alone or in combination with rectal NSAIDs, can effectively reduce or further reduce the incidence of PEP.
Discussion
Despite the numerous agents evaluated in prior RCTs and in clinical use for the prevention of PEP, the majority of agents have not been compared in head-to-head RCTs. We conducted a NMA of 16 pharmacological agents evaluated in 99 RCTs involving 25 313 patients as well as several sensitivity analyses and found that topical epinephrine and rectal NSAIDs are the most efficacious agents for the prevention of PEP.
The top six agents, from most to least efficacious for preventing PEP, were topical epinephrine, rectal NSAIDs, nafamostat, antibiotics, secretin and somatostatin (Figure 4). The sharp demarcation in the probability of ranks, between topical epinephrine and the other agents, indicates that topical epinephrine should be further evaluated in future studies. Similarly, the difference between the sixth ranking agent, somatostatin, and the seventh ranking agent, gabexate, highlights the limited efficacy of those agents ranking from seventh to 16th and suggests that future clinical trials should exclude these agents from further study.
(Enlarge Image)
Figure 4.
Sensitivity analysis: after exclusion of trials evaluating oral, intramuscular NSAIDs and inclusion of only rectal NSAIDs; rankograms comparing pharmacological agents to prevent post-ERCP pancreatitis. The vertical axis lists the agents evaluated. The horizontal axis lists the probability of achieving the best, second best or the third best rank based on repeated draws of the algorithm. The agent with the longest bar indicates the most efficacious agent. The total probability for top three ranks together is 300%.
There were agents that share a similar mechanism of action, but had widely discrepant ranks. For example, nafamostat, gabexate and ulinastatin are all protease inhibitors, but nafamostat ranked higher than gabexate and ulinastatin. This is probably because of the higher potency and longer duration of action of nafamostat. Somatostatin and octreotide are also similar for their anti-secretory properties, but somatostatin ranked higher, potentially because octreotide causes constriction, while somatostatin causes relaxation of the sphincter of Oddi.
There were two RCTs comparing topical epinephrine with placebo and these were conducted at different centres in Asia. The primary limitations of these studies were that they included only patients undergoing diagnostic ERCP and both utilised an ERCP protocol that mandates that a more experienced endoscopist complete difficult procedures. While patients undergoing diagnostic ERCP are typically considered to be at low risk for PEP, it should be noted that, in the epinephrine trial conducted by Xu et al., 9% of the patients had acinarisation and the mean number of pancreatic duct contrast injections was 4.6. This suggests that many patients became high risk due to procedural interventions. However, these particular limitations and other methodological limitations can be similarly found in all of the trials evaluating the other top-ranking agents in the present NMA. It should be highlighted that we conducted several sensitivity analyses and found that the rank order of the top six agents did not change after excluding each individual agent from the analysis. Interestingly, when we excluded only the epinephrine trials and re-evaluated the rank order, nafamostat ranked in the top position followed by antibiotics and then NSAIDs.
There are several possible explanations for why topical epinephrine was found to be the most efficacious agent for the prevention of PEP. Although the pathophysiology of PEP is not well understood, several human and animal studies support the important role that pancreatic ductal outflow obstruction due to papillary oedema plays in the development of PEP. Topical application of epinephrine induces arteriolar vasoconstriction in the papillary vasculature that reduces oedema and subsequent pancreatic ductal outflow obstruction. Topical epinephrine has also been shown to relax duodenal musculature and the sphincter of Oddi, both of which also reduce pancreatic outflow obstruction. The concept of pancreatic ductal outflow obstruction as an early step in the pathogenesis of PEP has been espoused in prior reviews. By reducing pancreatic ductal outflow obstruction, topical epinephrine acts at an early point in the pathogenesis of PEP. In addition, the local application of epinephrine increases the likelihood of it acting within this early therapeutic window and represents a clear advantage over other agents, which act on a more downstream point in the pathogenesis of PEP when the inflammatory cascade may no longer be attenuated. A topical agent also carries certain advantages over agents that are administered through different routes. For example, rectally administered agents may be expelled due to endoscopic air insufflation of the bowel or incomplete absorption. Rectal agents can also be difficult for endoscopy staff to administer when patients undergo ERCP in the supine position.
Due to its ability to reduce pancreatic ductal outflow obstruction, topical epinephrine essentially acts as the 'pharmacological equivalent' of a pancreatic stent. Numerous RCTs have shown the superiority of pancreatic stents over no stent for preventing PEP in high-risk patients. The key difference between topical epinephrine and pancreatic stents is the short duration of action of epinephrine. However, one RCT reported that 60% of prophylactic pancreatic stents spontaneously migrate within 24 h with no difference noted in the incidence of PEP between this group and those in whom the pancreatic stents remained in situ. Another study reported that the mean time for spontaneous pancreatic stent dislodgement can be as little as 2.1 days. These studies suggest that pancreatic stents may also act within a narrow therapeutic window. In addition, pancreatic stents have many drawbacks, including technical difficulty with placement as well as the cost of stents and follow-up endoscopy commonly required for stent removal.
When only RCTs evaluating rectal NSAIDs were included in the model, rectal NSAIDs ranked second after topical epinephrine. Rectal NSAIDs are the only pharmacological agents currently recommended in clinical guidelines based on their efficacy, low cost, favourable safety profile and widespread availability. While nafamostat and antibiotics ranked in the third and fourth positions, there are several reasons limiting their use in clinical practice. Nafamostat is intravenously administered over an extended time period before, during and after ERCP. One study administered nafamostat for as long as 24 h. The primary limitation of antibiotics is microbial resistance, which is already a significant global health problem.
A closer examination of route of administration, dose, cost, advantages and disadvantages of each of the six top-ranking agents from the present NMA suggests that topical epinephrine and rectal NSAIDs are both inexpensive, widely available, easy to administer and associated with few side effects. The costs of rectal NSAIDs and topical epinephrine, $1.12 and $0.24, respectively, are much lower than the cost of prophylactic pancreatic duct stent placement, which can range from $160 to $508. Given that topical epinephrine and rectal NSAIDs act to counter different steps in the pathogenesis of PEP, i.e. pancreatic ductal outflow obstruction and the inflammatory cascade, respectively, they can potentially be used in combination for a synergistic effect. A recent meta-analysis concluded that NSAIDs are only able to reduce the incidence of PEP from 13.9% to 8%. It is possible that the concomitant use of topical epinephrine and rectal NSAIDs could further reduce the incidence of PEP.
There are several limitations to the present NMA. The first is the inclusion of RCTs that enrolled patients with wide discrepancies of risk for developing PEP, as this results in statistical heterogeneity. However, when we excluded trials of only high-risk patients from our NMA, there was less heterogeneity and the rank order of agents did not change. A separate analysis of the trials that included only high-risk patients showed a similar ranking of agents, although topical epinephrine was not evaluated in high-risk patients. It is also important to emphasise that there is currently no method to quantify the risk of developing PEP based on known demographic, clinical and procedural risk factors. This limitation essentially affects not only our NMA but also all RCTs conducted in this field. The second limitation is the use of pancreatic duct stents, in addition to drugs, for PEP prophylaxis in some of the trials. While we were not able to control for the effect of pancreatic stenting in our NMA, pancreatic stenting was performed in only a small percentage of patients, equally distributed in the intervention and placebo arms, and in more recent trials and, therefore, did not significantly impact the performance of the drugs in the NMA.
It must be emphasised that the objectives of NMA differ from conventional meta-analyses. While conventional meta-analyses summarise evidence from RCTs for a particular agent(s) and provide evidence for framing management guidelines, NMA summarises evidence from multiple competing interventions simultaneously and provides direction for future research and clinical practice. Our study identified potential sources of heterogeneity across trials and recommends exclusion of relatively poor performing agents and further evaluation of better performing agents.
In conclusion, the present network meta-analysis found that topical epinephrine and rectal NSAIDs are the best performing agents to prevent PEP. Future trials are needed to determine whether topical epinephrine, alone or in combination with rectal NSAIDs, can effectively reduce or further reduce the incidence of PEP.
