Allopurinol to Prevent Pancreatitis After Endoscopic Retrograde Cholangiopancreatography: A Randomized Placebo-Controlled Trial

Published:February 27, 2008DOI:https://doi.org/10.1016/j.cgh.2007.12.032
      Background & Aims: Endoscopic retrograde cholangiopancreatography (ERCP) is associated with a risk of pancreatitis (PEP). Animal studies suggest that (single-dose) allopurinol (xanthine oxidase inhibitor with high oral bioavailability and long-lasting active metabolites) may reduce this risk; human study results are conflicting. The aim of this study was to determine if allopurinol decreases the rate of PEP. Methods: Patients referred for ERCP to 9 endoscopists at 2 tertiary centers were randomized to receive either allopurinol 300 mg or identical placebo orally 60 minutes before ERCP, stratified according to high-risk ERCP (manometry or pancreatic therapy). The primary outcome (PEP) was adjudicated blindly; pancreatitis was defined according to the Cotton consensus, and evaluated at 48 hours and 30 days. Secondary outcomes included severe PEP, length of stay, and mortality (nil). The trial was terminated after the blinded (midpoint) interim analysis, as recommended by the independent data and safety monitoring committee. Results: We randomized 586 subjects, 293 to each arm. The crude PEP rates were 5.5% (allopurinol) and 4.1% (placebo), (P = .44; difference = 1.4%; 95% confidence interval, −2.1% to 4.8%). The Mantel–Haenszel combined risk ratio for PEP with allopurinol, considering stratification, was 1.37 (95% confidence interval, 0.65–2.86). Subgroup analyses suggested nonsignificant trends toward possible benefit in the high-risk group, and possible harm for the remaining subjects. Logistic regression found pancreatic therapy, pancreatic injection, and prior PEP to be the only independent predictors of PEP. Conclusions: Allopurinol does not appear to reduce the overall risk of PEP; however, its potential benefit in the high-risk group (but potential harm for non–high-risk patients) means further study is required.

      Abbreviations used in this paper:

      CI (confidence interval), DSM (data and safety monitoring), ERCP (endoscopic retrograde cholangiopancreatography), OR (odds ratio), PEP (post–endoscopic retrograde cholangiopancreatography pancreatitis), SOD (sphincter of Oddi dysfunction)
      See CME exam on page 371.
      See Editorial on page 374.
      Biliopancreatic diseases are extremely common in North America and Europe and endoscopic retrograde cholangiopancreatography (ERCP) plays a pivotal role in their diagnosis confirmation and treatment. Pancreatitis is the most common complication of ERCP, with an overall incidence of 2% to 15%, and a related mortality rate of 0.1% to 0.5%.
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      In addition, there are 3 other barriers to routine prophylactic pancreatic stenting: (1) not all ERCP endoscopists are comfortable placing pancreatic stents; (2) placing a stent is not always possible; and (3) pancreatic stents can cause damage to the duct wall.
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      Oxygen radicals can mediate capillary endothelial injury, which may be an early step in the pathogenesis of acute pancreatitis.
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      Other anti-inflammatory drugs such as steroids have not been shown to provide significant reductions in PEP.
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      • Catanzano C.
      Use of corticosteriods in the prevention of post-ERCP pancreatitis: results of a controlled prospective study.
      Interleukin-10 infusion has shown some promise; however, it is expensive and not widely available.
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      Interleukin 10 reduces the incidence of pancreatitis after therapeutic endoscopic retrograde cholangiopancreatography.
      Several animal studies have suggested that allopurinol (a xanthine oxidase inhibitor and an effective anti-oxidant with anti-apoptotic effects, that historically has been effective in preventing attacks of acute gouty arthritis) might prevent the initial oxidative insult that can trigger the onset of PEP.
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      Pretreatment with allopurinol diminishes pancreatography-induced pancreatitis in a canine model.
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      Allopurinol has high oral bioavailability (80%–90%), a rapid onset (peak, 0.5–2 h), and a 70% hepatic transformation to a long-lasting active metabolite (oxypurinol half-life, 15 h).
      These pharmacokinetic attributes mean a single oral dose of allopurinol before ERCP conceivably might prevent PEP because the drug targets those changes that contribute to the initial triggering of pancreatitis.
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      • Cameron J.L.
      Increased capillary permeability: an early lesion in acute pancreatitis.
      • Sanfey H.
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      • Cameron J.L.
      The pathogenesis of acute pancreatitis The source and role of oxygen-derived free radicals in three different experimental models.
      Allopurinol is also an inexpensive generic drug with an excellent safety record related to its use for prevention of acute gout. A pilot study of allopurinol treatment in 30 randomized human subjects, with the same dosing regimen used in the current study, showed very promising results with a 21% absolute risk difference in PEP and a significant reduction in 3-hour lipase levels.
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      In addition to this, 1 other positive-outcome randomized trial and 2 negative-outcome randomized trials of allopurinol for PEP prevention have been published.
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      • Marek T.
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      Oral allopurinol does not prevent the frequency or the severity of post-ERCP pancreatitis.
      Given the promising pilot study data, the compelling animal data, and the practical benefits of allopurinol’s potential use for PEP prevention, we designed a randomized blinded multicenter trial to compare the rates of PEP seen with treatment with either allopurinol or placebo.

      Methods

       Patients and Randomization

      After institutional review board approval at each site, the study screened for eligible adult patients presenting for an ERCP at 2 institutions (the University of Calgary, Peter Lougheed Center in Calgary, Alberta, Canada; and the University of Alberta Hospital in Edmonton, Alberta, Canada) between 2002 and 2006. At registration, eligible patients were randomized, after giving informed consent, to receive either allopurinol or an identical placebo. After the oral administration of the treatment drug or placebo, ERCP was performed by 1 of 9 ERCP endoscopists with comparable baseline complication rates (data not shown). An independent data and safety monitoring (DSM) committee oversaw the trial and was chaired from McMaster University in Hamilton, Canada. The study followed Consolidate Standards of Reporting Trials (CONSORT) guidelines.
      • Moher D.
      • Schulz K.F.
      • Altman D.G.
      The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials.
      Randomization was performed centrally at the University of Calgary by using computer-generated random numbers and allocation was concealed from subjects, coordinators, and investigators with coded packets of study drug delivered by the investigational pharmacy to the endoscopy unit after the patient was recruited and informed consent was obtained. Thus, the randomization assignments were known only to the investigational pharmacy. Patients were randomized in blocks of 4, stratified according to site and according to risk, so that the 2 arms of the trial contained equal numbers of high-risk ERCP cases (defined as planned pancreatic therapy or planned sphincter of Oddi manometry).
      Exclusion criteria included a hemoglobin level of less than 8 g/dL; a platelet count of less than 60 × 109/L; relative neutropenia (absolute neutrophil count <2.0 × 109/L); significant renal dysfunction (serum creatinine level, >200 μmol/L); decompensated cirrhosis; a known allergy to allopurinol; a known or suspected pregnancy or lactation; current or recent (within 48 hours) use of allopurinol; current use of drugs with a known interaction with allopurinol, including cyclophosphamide, chlorpropamide, azathioprine/mercaptopurines, or probenecid; an inability to swallow or absorb oral medication; and recent (onset within 5 days of the ERCP) acute pancreatitis. The latter exclusion was mandated by the difficulty in diagnosing PEP when acute pancreatitis already is present (lipase often still is increased, pain often still is present) and imaging findings of pancreatic inflammation persist.
      After randomization, patients were given either allopurinol (300 mg) or the identical placebo orally with a sip of water at 60 minutes (±20 min) before the start of ERCP. Baseline demographics, indication, and laboratory results were recorded. Procedural details were recorded, along with the final diagnosis. Follow-up evaluation, still blinded for both patients and research personnel, was performed either in the hospital (if the patient was admitted or remained an inpatient), or by telephone, at 48 hours and at 30 days. During this time, additional records and/or laboratory results were obtained when needed to clarify potential complications. PEP, unlike bleeding, perforation, or infection (all of which may be delayed in presentation), occurs within 24 hours of ERCP. Therefore, if no PEP was documented at either follow-up evaluation, the patients were considered not to have had PEP.

       Outcomes

      The primary outcome was the proportion of patients developing pancreatitis within 24 hours after ERCP (PEP). PEP was defined based on the Cotton consensus criteria.
      • Cotton P.B.
      • Lehman G.
      • Vennes J.
      • et al.
      Endoscopic sphincterotomy complications and their management: an attempt at consensus.
      Thus, PEP diagnosis required the presence of typical pancreatic pain (epigastric pain often radiating into the back and associated with nausea and/or vomiting) requiring medical attention, in association with a serum lipase or amylase level greater than 2 times the upper limit of normal. The pain had to have begun within 24 hours of ERCP and must have lasted longer than 24 hours (defined as residual pain >5 of 10 on an analogue scale). Pancreatic pain requiring hospitalization for more than 24 hours was considered sufficient to diagnose PEP in the case of patients with chronic pancreatitis because enzyme level increases may not occur (because of the potential lack of enzyme reserve in those patients).
      The main secondary outcomes were the proportion of patients with local complications of pancreatitis (necrotizing pancreatitis, pseudocyst, or abscess) or the need for surgery. The definition and grading of other post-ERCP complications (bleeding, sepsis, perforation, other infection) was performed according to published guidelines.
      • Cotton P.B.
      • Lehman G.
      • Vennes J.
      • et al.
      Endoscopic sphincterotomy complications and their management: an attempt at consensus.
      Cardiorespiratory events also were recorded, as were other unusual unplanned events (such as basket impaction, aspiration pneumonia, and medication reactions). Thirty-day mortality rates attributable to complications also were recorded. The study used an intention-to-treat analysis strategy.

       Statistical Analysis

      Blinded statistical analysis was completed with Stata (v. 7.0, StataCorp, College Station, TX). The analysis was stratified (Mantel–Haenszel weights) in accordance with the stratified randomization approach. Logistic regression also was used to control for the possible confounding effects of chance imbalances in randomization. Model building was performed using likelihood ratio tests of nested models of clinically plausible factors. Proportions were compared using the chi-square or the Fisher exact test where applicable, and t tests were used for continuous variables. Nonparametric tests were used for nonnormal continuous variable comparisons. Ninety-five percent confidence intervals (CIs) were calculated for ratios and differences. Planned subgroup analyses of interactions (differential effect of allopurinol therapy among subgroups) included high-risk versus non–high-risk ERCP and prophylactic pancreatic stent insertion versus no stent.
      The sample size calculation was based on an estimated baseline pancreatitis rate of 7%, a relative risk reduction of 0.5, a power of 80%, and a 2-sided α of .05, yielding a target sample size of 1266 patients. A blinded interim analysis according to the primary outcome was planned at 2 years, using O’Brien-Fleming α spending function thresholds.
      • Piantadosi S.
      Data-dependent stopping.
      After this blinded review, the independent DSM committee recommended a second interim analysis at the patient recruitment midpoint (533 of 1266 patients). This second blinded analysis, along with conditional power and stochastic curtailment analyses with realistic and optimistic scenarios, then was presented to the DSM; in the meantime, additional patients were recruited. On the basis of these data, however, the DSM decided the trial should cease recruitment, primarily owing to futility in achieving significance with respect to the overall primary outcome. Thereafter, the previously recruited patients (n = 586) completed their follow-up evaluations, and the formal blinded statistical analysis was completed.

      Results

      We enrolled 586 subjects, randomizing 293 patients each to the allopurinol and the placebo arms. The baseline characteristics and procedural details are summarized in Table 1. The average subject age was 54.7 years (±SD 17 y) and 42.8% of the subjects were male. Overall, 29.1% of patients were randomized, based on screen-fail data from the first 1000 patients screened. Based on detailed data from 100 consecutive screening failures, the average age was slightly older at 61.9 years (±SD 20.6 y) and 41.4% were male. The most common reasons for exclusion were as follows: an inability to obtain consent (dementia, inability to speak English) or a refusal to consent (48%); issues related to current allopurinol use or contraindication (9%); onset of acute pancreatitis within 5 days (15%); insufficient time window (to allow the minimum time between drug and procedure) (11%); and pregnancy or lactation (6%). The frequencies of all other exclusion criteria were less than 5%. The most common indications for ERCP among screen-fails were similar to those of the study population. The most common indication among amon patients failing screening still was suspected bile duct stone (51.4%). The next two most common were bile leaks and suspected malignant obstruction (9.7% and 8.3%, respectively); the former was significantly more common than it was in the study population, perhaps because patients with bile leaks are generally in the immediate postoperative state, in considerable pain, and are less likely to elect to participate in a clinical trial.
      Table 1Demographics, Indications, and Procedure Details for Allopurinol and Placebo Arms
      VariableAllopurinol (n = 293)Placebo (n = 293)P value
      Demographics/baseline data
       Age, y53.9 (17.6)55.5 (16.7)
       Male sex127 (43.3%)115 (39.2%)
       Body mass index26.9 (5.3)27.2 (5.8)
       Aspartate aminotransferase level, U/L159.4 (198.0)144.2 (173.1)
       Bilirubin level, μmol/L61.3 (89.0)54.2 (70.8)
       Malignancy clinically suspected32 (10.9%)35 (11.9%)
       Biliary dilation suspected84 (28.7%)89 (30.4%)
       History of chronic pancreatitis8 (2.7%)11 (3.8%)
       Pre-ERCP abdominal pain68 (23.2%)67 (22.9%)
       Previous PEP17 (5.8%)11 (3.8%)
       University of Calgary site
      Peter Lougheed Center, Calgary, Alberta.
      263 (89.8%)264 (90.1%)
      Indications
       Acute pancreatitis8 (2.7%)7 (2.4%)
       Chronic pancreatitis9 (3.1%)8 (2.7%)
       Recurrent pancreatitis13 (4.4%)18 (6.1%)
       Suspected malignant obstruction25 (8.5%)25 (8.5%)
       Suspected bile duct stone174 (59.4%)169 (57.7%)
       Suspected sphincter dysfunction (SOD)10 (3.4%)5 (1.7%)
       Suspected bile leak11 (3.8%)8 (2.7%)
       Suspected postoperative biliary stricture5 (1.7%)12 (4.1%)
       Suspected primary sclerosing cholangitis5 (1.7%)6 (2.0%)
       Other28 (9.6%)31 (10.6%)
      Procedure details
       Time delay from study drug to endoscope insertion, min
      Median (interquartile range).
      60.0 (45.0–75.0)55.0 (42.0–69.5).01
       Pre-ERCP antibiotics81 (27.6%)77 (26.3%).71
       Total procedure time, min
      Median (interquartile range).
      25.0 (16.0–40.0)25.0 (16.0–39.0).52
       Cannulation time, min
      Median (interquartile range).
      4.0 (2.0–14.0)3.5 (1–11.0)
       Pancreatic duct injection129 (44.0%)102 (34.8%).02
        Number of pancreatic injections
      Median (interquartile range).
      2.0 (1.0–2.0)1.0 (1.0–2.0).01
        Acinarization with injection3 (1.0%)2 (0.68%).65
      Invasive diagnostics
       Cytology25 (8.5%)16 (5.5%).15
       Bile sample2 (0.68%)3 (1.0%).65
       Intrabiliary biopsy13 (4.4%)11 (3.8%).68
       Sphincter manometry (biliary)6 (2.0%)7 (2.4%).78
       Sphincter manometry (pancreatic)3 (1.0%)8 (2.7%).13
      Therapeutics (selected)
       Any therapeutics252 (86.0%)252 (86.0%)1.00
       Biliary stent insertion54 (18.4%)50 (17.1%).67
       Stone extraction68 (23.2%)73 (24.9%).63
       Mechanical lithotripsy8 (2.7%)14 (4.8%).19
       Biliary sphincterotomy (EBS)220 (75.1%)213 (72.7%).51
        Needle-knife/precut EBS31 (10.6%)30 (10.2%).89
       Pancreatic stent11 (3.8%)17 (5.8%).25
      ERCP cancelled1 (0.34%)4 (1.4%).18
      High-risk ERCP (see text for definition)32 (10.9%)34 (11.6%).79
      NOTE. Categoric/dichotomous variables are summarized as number (%), and continuous variables as mean (SD). P values were calculated only for postrandomization factors.
      EBS, Endoscopic biliary sphincterotomy.
      a Peter Lougheed Center, Calgary, Alberta.
      b Median (interquartile range).
      The majority of the ERCPs performed in randomized subjects were therapeutic (86.0%), and just over half were performed for a suspected bile duct stone. A small proportion (n = 66) of the participants was classified as being in a high-risk category, as defined earlier. Most patients (n = 527) were recruited at the University of Calgary, and the remaining were recruited at the University of Alberta. There were no clinically significant chance imbalances in baseline or procedural characteristics. Five patients (0.85%; 4 in the placebo group and 1 in the allopurinol group) had their ERCP cancelled after randomization (while the study still was blinded), but they were included in their original group assignment in the primary (intention-to-treat) analysis.
      There were no significant differences in the overall rates of PEP in the 2 groups (Table 2). The raw PEP rates were 5.5% (allopurinol) and 4.1% (placebo), (P = .44; difference, 1.4%; 95% CI, −2.1% to 4.8%). The Mantel–Haenszel combined risk ratio, considering stratification on center and high-risk status, for PEP with allopurinol was 1.37 (95% CI, 0.65–2.86). The stochastic curtailment analysis showed that despite recruiting the additional planned patients, using an optimistic view of assuming that the relative risk ratio of 0.5 (the risk ratio used in the sample size calculation) would be seen in the subsequent recruits, using the baseline PEP rate observed in the trial so far (lower PEP rate of the 2 groups), the rates at the end of the trial would be 5.5% (group with higher event rate) and 3.4% (group with lower event rate) (difference 95% CI, −1.7% to 4.4%, P = .07). The DSM believed further recruitment was futile.
      Table 2Outcomes for Allopurinol and Placebo Arms
      VariableAllopurinol (n = 293)Placebo (n = 293)P value
      Procedure-related complications
       Overall complications25 (8.5%)18 (6.1%).34
        Overall fatal complications0 (0%)0 (0%)1.0
       Pancreatitis (PEP)16 (5.5%)12 (4.1%).44
        Mild
      All patients admitted except 1.
      8 (2.7%)4 (1.4%).24
        Moderate6 (2.0%)6 (2.0%)1.0
        Severe2 (0.7%)2 (0.7%)1.0
        Fatal0 (0%)0 (0%)1.0
       Bleeding0 (0%)0 (0%)1.0
       Perforation0 (0%)0 (0%)1.0
       Infection (cholecystitis/cholangitis)6 (2.0%)1 (0.3%).12
       Other (including unexplained pain)4 (1.4%)
      One patient also had pancreatitis.
      5 (1.7%)1.0
      Disease-related adverse events
       Pancreatitis0 (0%)0 (0%)1.0
       Bleeding0 (0%)0 (0%)1.0
       Infection4 (1.4%)0 (0%)1.0
       Other2 (0.7%)3 (1.0%)1.0
      Resource use
       Critical care unit length of stay, d0.02
      One patient had a 5-day critical care admission.
      0.32
       Hospital length of stay for complication or adverse event, d
      Median (interquartile range) shown.
      6.0 (2.0–15.0)5.0 (2.0–7.0).40
       Hospital length of stay for post-ERCP pancreatitis, d
      Median (interquartile range) shown.
      3.5 (2.5–7.5)5.5 (3.0–8.0).50
      NOTE. Categoric/dichotomous variables are summarized as number (%), and continuous variables as mean (SD).
      a All patients admitted except 1.
      b One patient also had pancreatitis.
      c One patient had a 5-day critical care admission.
      d Median (interquartile range) shown.
      There were, however, differences between the treatment effects seen for the high-risk and non–high-risk subgroups; the corresponding interaction term (P = .01) was significant. In the non–high-risk group (n = 520), the crude PEP rates were 5.4% (allopurinol) and 1.5% (placebo) (P = .017, favoring placebo, indicating harm associated with allopurinol), whereas in the high-risk group (n = 66), the PEP rates were 6.3% (allopurinol) and 23.5% (placebo) (P = .050, favoring allopurinol).
      By using logistic regression, correcting for the blocked strata (center and high-risk group), age, and sex, the only independent predictors of PEP were found to be previous PEP (odds ratio [OR], 15.8; 95% CI, 4.6–54.7; P < .001), pancreatic injection (OR, 4.8; 95% CI, 1.3–16.9), and pancreatic therapy (OR, 5.9; 95% CI, 1.4–24.7; P = .02). Correcting for these factors, the adjusted OR for PEP with allopurinol was 1.0 (95% CI, 0.35–2.8; P = .99). An older age also showed a trend toward a lower PEP rate (OR, 0.8; 95% CI, 0.6–1.1 per decade; P = .13). Other factors, including sex, body mass index, time from drug ingestion to procedure, indication (pancreatitis, stone/malignancy, suspected SOD, other), procedure, cannulation success and/or duration of cannulation attempt, number of pancreatic injections, biliary sphincterotomy (regular or precut), and pancreatic stent placement were not significant predictors. As stated earlier, there was an interaction between the allocation (treatment vs placebo) and the risk group (P = .01), but not between the allocation and pancreatic stent insertion, or between the allocation and prior PEP history, age, sex, or recruitment site. Although pancreatic injection was performed, by chance, more frequently in the allopurinol arm, there was no significant confounding in the model in the non–high-risk group. Furthermore, correcting for this factor, in a logistic model stratified by high-risk group, allopurinol still had a nonsignificant trend toward harm in the non–high-risk group (OR, 3.1; 95% CI, 0.62–15.4; P = .17), albeit with a wide CI.
      Only 14 patients had confirmed SOD, with manometry followed by pancreatic and/or biliary sphincterotomy. There was a trend toward a higher rate of PEP in this group (P = .09). Fifty-seven percent of these persons received a pancreatic stent. In the confirmed SOD subgroup, no differences were seen with respect to pancreatic stenting and treatment allocation arm; however, the statistical power of this subgroup analysis was very limited.
      In terms of the secondary outcomes, there were no differences in length of stay or critical care stay attributed to PEP (Table 2). There were also no differences in the spectrums of PEP severity; severe PEP was rare in both groups and there were no fatal complications.

      Discussion

      Despite a great deal of scientific interest in the area, endoscopists and their patients are still in great need of a simple, widely available, and inexpensive intervention that can reduce the rate of PEP. This complication is the main driving force in algorithms that lead toward noninvasive imaging of patients with suspected biliopancreatic disease for whom therapy or invasive diagnostics likely are not needed. However, a large proportion of patients still need ERCP, for both diagnostic and therapeutic reasons, and pancreatitis remains an important limitation of this procedure.
      Three randomized trials have been published in full to date: a negative study from Poland
      • Budzynska A.
      • Marek T.
      • Nowak A.
      • et al.
      A prospective, randomized, placebo-controlled trial of prednisone and allopurinol in the prevention of ERCP-induced pancreatitis.
      (n = 300), a positive study from Greece
      • Katsinelos P.
      • Kountouras J.
      • Chatzis J.
      • et al.
      High-dose allopurinol for prevention of post-ERCP pancreatitis: a prospective randomized double-blind controlled trial.
      (n = 243), and a negative study from the United States
      • Mosler P.
      • Sherman S.
      • Marks J.
      • et al.
      Oral allopurinol does not prevent the frequency or the severity of post-ERCP pancreatitis.
      (n = 701) (Table 3). There was variability in the doses used in the studies, and in the baseline rates of PEP in the control (placebo) groups (some of which are out of the usual range reported), but these differences do not appear to completely explain the heterogeneity in the results. There remains a possibility for a threshold effect or a minimally effective dose for allopurinol, given that the positive study
      • Katsinelos P.
      • Kountouras J.
      • Chatzis J.
      • et al.
      High-dose allopurinol for prevention of post-ERCP pancreatitis: a prospective randomized double-blind controlled trial.
      used the highest dose (1200 mg); however, there does not seem to be a clear dose-response relationship with a larger negative study
      • Mosler P.
      • Sherman S.
      • Marks J.
      • et al.
      Oral allopurinol does not prevent the frequency or the severity of post-ERCP pancreatitis.
      having used a fairly high dose (900 mg) (Table 3).
      Table 3Summary of Randomized Trials of Allopurinol in PEP Prevention
      Study (y), SC vs MC, countrynDose, mgAllopurinol vs placebo PEP ratesPercentage high risk
      As defined in this protocol, namely sphincter manometry and/or pancreatic therapy. Other higher-risk cases (eg, precut sphincterotomy, suspected SOD) were not considered.
      Comment
      Romagnuolo 2007, MC, Canada (current study)586300
      • 5.5% vs 4.1%
      • 16 vs 12
      11.3%Harm in average risk; benefit in high risk
      Mosler et al,
      • Mosler P.
      • Sherman S.
      • Marks J.
      • et al.
      Oral allopurinol does not prevent the frequency or the severity of post-ERCP pancreatitis.
      (2005) MC, USA
      701900
      600 mg 4 hours before, 300 mg 1 hour before.
      • 13.0% vs 12.1%
      • 46 vs 42
      70.2%4% absolute benefit in high risk; 4% absolute harm in average risk
      Katsinelos et al,
      • Katsinelos P.
      • Kountouras J.
      • Chatzis J.
      • et al.
      High-dose allopurinol for prevention of post-ERCP pancreatitis: a prospective randomized double-blind controlled trial.
      (2005) SC, Greece
      2501200
      600 mg 15 hours before, 600 mg 3 hours before.
      • 3.2% vs 17.8%
      • 4 vs 21
      0%2 patients with suspected SOD
      Budzynska et al,
      • Budzynska A.
      • Marek T.
      • Nowak A.
      • et al.
      A prospective, randomized, placebo-controlled trial of prednisone and allopurinol in the prevention of ERCP-induced pancreatitis.
      (2001) SC, Poland
      300400
      200 mg 15 hours before, 200 mg 3 hours before.
      • 12.1% vs 7.9%
      • 12 vs 8
      0%3-arm study, with third arm (n = 100) given prednisone
      Raw pooled1837 (923 vs 914)
      • 8.5% vs 9.1%
      • 78 vs 83
      −0.6% difference (95% CI, −3.2% to 2.0%)
      MC, multicenter; SC, single center.
      a As defined in this protocol, namely sphincter manometry and/or pancreatic therapy. Other higher-risk cases (eg, precut sphincterotomy, suspected SOD) were not considered.
      b 600 mg 4 hours before, 300 mg 1 hour before.
      c 600 mg 15 hours before, 600 mg 3 hours before.
      d 200 mg 15 hours before, 200 mg 3 hours before.
      In fact, our study found significant differences in treatment effects for different subgroups (ie, significant interactions). The 3 prior studies all formally or informally checked for interactions, presenting the active treatment and placebo PEP rates in different subgroups. None found significant interactions between diagnostic and therapeutic procedures. The most detailed analysis of this type in the 3 studies was found in the study by Mosler et al.
      • Mosler P.
      • Sherman S.
      • Marks J.
      • et al.
      Oral allopurinol does not prevent the frequency or the severity of post-ERCP pancreatitis.
      If one were to group that study’s manometry and pancreatic therapy subjects together into a high-risk group as we did in this study, one would see the same (although in this case, nonsignificant) trends: reduction of PEP by allopurinol from 27% to 23% in the high-risk group, and harm by allopurinol (8% vs 12% PEP) in the non–high-risk group. Budzynska et al
      • Budzynska A.
      • Marek T.
      • Nowak A.
      • et al.
      A prospective, randomized, placebo-controlled trial of prednisone and allopurinol in the prevention of ERCP-induced pancreatitis.
      also included primarily non–high-risk patients and showed a higher rate of PEP with allopurinol. In contrast, the patients in the study by Katsinelos et al
      • Katsinelos P.
      • Kountouras J.
      • Chatzis J.
      • et al.
      High-dose allopurinol for prevention of post-ERCP pancreatitis: a prospective randomized double-blind controlled trial.
      also primarily were non–high-risk patients, and yet the study showed a significant benefit for allopurinol.
      If allopurinol is truly harmful for non–high-risk patients undergoing ERCP (the adjusted subgroup OR was not significant), the mechanism responsible for this harm is unclear. It could be the result of an idiosyncratic reaction to the medicine itself; one study does suggest that medications with a history of inducing pancreatitis could increase the risk of PEP.
      • Perney P.
      • Berthier E.
      • Pageaux G.P.
      • et al.
      Are drugs a risk factor of post-ERCP pancreatitis?.
      However, allopurinol is not particularly known to cause drug-induced pancreatitis. Other anti-inflammatory medicines (ie, steroids) appear to either have no effect or increase the risk of pancreatitis in randomized trials.
      • Sherman S.
      • Urszula B.
      • Watkins J.L.
      • et al.
      Does prophylactic administration of corticosteroid reduce the risk and severity of post-ERCP pancreatitis: a randomized, prospective, multicenter study.
      • Budzynska A.
      • Marek T.
      • Nowak A.
      • et al.
      A prospective, randomized, placebo-controlled trial of prednisone and allopurinol in the prevention of ERCP-induced pancreatitis.
      • De Palma G.D.
      • Catanzano C.
      Use of corticosteriods in the prevention of post-ERCP pancreatitis: results of a controlled prospective study.
      • Dumot J.A.
      • Conwell D.L.
      • O’Connor J.B.
      • et al.
      Pretreatment with methylprednisolone to prevent ERCP-induced pancreatitis: a randomized, multicenter, placebo-controlled clinical trial.
      • Manolakopoulos S.
      • Avgerinos A.
      • Vlachogiannakos J.
      • et al.
      Octreotide versus hydrocortisone versus placebo in the prevention of post-ERCP pancreatitis: a multicenter randomized controlled trial.
      Again, the mechanism responsible for this increase also is unknown, although for hydrocortisone, drug-related pancreatitis is a well-recognized phenomenon. Nonsteroidal anti-inflammatory drugs might have a more consistent benefit.
      • Murray B.
      • Carter R.
      • Imrie C.
      • et al.
      Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography.
      • Sotoudehmanesh R.
      • Khatibian M.
      • Kolahdoozan S.
      • et al.
      Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP.
      We considered that the association between allopurinol and PEP could be owing to the fact that the percentage of patients with pancreatic injections was significantly higher in the allopurinol group (P = .02), as was the median number of injections; this could have confounded that subgroup analysis. However, confounding was not confirmed statistically, and correcting for pancreatic injection in a stratified model still showed a nonsignificant trend toward harm for allopurinol in the non–high-risk subgroup (OR, 3.1; P = .17).
      Pancreatic therapy, pancreatic injection, and a history of prior PEP were the only significant independent predictors of PEP in our study, with a trend being seen toward higher PEP rates in younger patients. Several other studies have commented on PEP predictors.
      • Cheng C.L.
      • Sherman S.
      • Watkins J.L.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective multicenter study.
      Multivariate analyses have shown suspected SOD,
      • Cheng C.L.
      • Sherman S.
      • Watkins J.L.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective multicenter study.
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.
      female sex,
      • Williams E.J.
      • Taylor S.
      • Fairclough P.
      • et al.
      Risk factors for complication following ERCP; results of a large-scale, prospective multicenter study.
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.
      history of post-ERCP pancreatitis,
      • Ho K.Y.
      • Montes H.
      • Sossenheimer M.J.
      • et al.
      Features that may predict hospital admission following outpatient therapeutic ERCP.
      • Cheng C.L.
      • Sherman S.
      • Watkins J.L.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective multicenter study.
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.
      younger age,
      • Loperfido S.
      • Angelini G.
      • Benedetti G.
      • et al.
      Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study.
      • Cheng C.L.
      • Sherman S.
      • Watkins J.L.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective multicenter study.
      • Williams E.J.
      • Taylor S.
      • Fairclough P.
      • et al.
      Risk factors for complication following ERCP; results of a large-scale, prospective multicenter study.
      normal bilirubin level,
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.
      normal bile duct size,
      • Loperfido S.
      • Angelini G.
      • Benedetti G.
      • et al.
      Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study.
      absence of chronic pancreatitis,
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.
      difficult cannulation,
      • Williams E.J.
      • Taylor S.
      • Fairclough P.
      • et al.
      Risk factors for complication following ERCP; results of a large-scale, prospective multicenter study.
      pancreatic sphincterotomy,
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.
      and (multiple) pancreatic injection
      • Loperfido S.
      • Angelini G.
      • Benedetti G.
      • et al.
      Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study.
      • Cheng C.L.
      • Sherman S.
      • Watkins J.L.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective multicenter study.
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.
      to be independent risk factors, but the factors are not consistently predictive among the studies. For example, female sex, difficult cannulation, and pancreatic sphincterotomy were not confirmed by Cheng et al
      • Cheng C.L.
      • Sherman S.
      • Watkins J.L.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective multicenter study.
      and lower case volume was not confirmed by Freeman et al.
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.
      Biliary sphincterotomy does not appear to be an independent predictor of PEP.
      • Loperfido S.
      • Angelini G.
      • Benedetti G.
      • et al.
      Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study.
      • Cheng C.L.
      • Sherman S.
      • Watkins J.L.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective multicenter study.
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.
      The factors found in our study are among those often cited and reproduced.
      In summary, it appears that allopurinol does not decrease the overall rate of post-ERCP pancreatitis; it potentially could be harmful for non–high-risk patients (we were underpowered for that specific question, and the CI is wide). Its effect on the highest-risk subgroup remains unclear, and although there is some indication of benefit, the drug-procedure interaction needs to be tested specifically in a randomized trial that enrolls only that subgroup. Unfortunately, interventions that are effective in high-risk subgroups, such as prophylactic pancreatic stenting, although helpful for referral ERCP centers, are not especially useful for community ERCP centers. Allopurinol potentially might be used as rescue therapy for high-risk patients in whom pancreatic stent placement has failed, but the protocols studied to date have involved providing the allopurinol before the procedure, rather than afterward. Our analysis does strengthen the suggestion that subgroup analysis by risk category is desirable, and perhaps even necessary, in PEP prevention trials, because results may not be generalizable across risk groups.
      The authors would like to thank the Canadian Association for Gastroenterology (and the Canadian Digestive Health Foundation), the Canadian Institutes for Health Research, and the University of Calgary for joint funding of this trial’s operating budget. In addition, the authors would like to thank the Alberta Heritage Foundation for Medical Research for funding our investigators (J.R., R.H.) with salary support during part of the trial. The authors also are grateful for the help of Scott Miller, MSc (Department of Biostatistics, Epidemiology and Bioinformatics, Medical University of South Carolina) with the interim analysis and conditional power calculation.

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