Glyceryl trinitrate for prevention of pancreatitis after endoscopic retrograde cholangiopancreatography: meta-analysis of randomized, controlled trials

Samir H Kohla; Ashraf A Zein El-Dein; Fawzy A Mahmoud; Haith A Mukhtar

doi:10.4103/1110-2098.173584

ORIGINAL ARTICLE

Year : 2015 | Volume : 28 | Issue : 4 | Page : 793-799

Glyceryl trinitrate for prevention of pancreatitis after endoscopic retrograde cholangiopancreatography: meta-analysis of randomized, controlled trials

Samir H Kohla, Ashraf A Zein El-Dein, Fawzy A Mahmoud, Haith A Mukhtar MBBCh
Department of General Surgery, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission	07-Nov-2014
Date of Acceptance	18-Dec-2014
Date of Web Publication	12-Jan-2016

Correspondence Address:
Haith A Mukhtar
Al Mahalla El Kobra, 317811
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/1110-2098.173584

Abstract

Objective
The aim of the study was to conduct a meta-analysis of published, full-length, randomized controlled trials (RCTs) evaluating the effect of prophylactic glyceryl trinitrate (GTN) on the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography (PEP) and the prevention of hyperamylasemia.
Data sources
Literature searches were conducted using PubMed, EMBASE, The Cochrane Library, and Web of Knowledge databases (up to May 2014) using keywords 'post-ERCP', 'pancreatitis', 'ERCP', 'post endoscopic retrograde cholangiopancreatography pancreatitis', 'GTN', 'glyceryl trinitrate', and 'nitroglycerin', and were limited to RCTs. No language restriction was imposed.
Study selection
The following selection criteria were applied: (i) study design - RCTs; (ii) study population - patients undergoing endoscopic retrograde cholangiopancreatography (ERCP); (iii) intervention - prophylactic administration of GTN; (iv) comparison intervention - control or no treatment; and (v) outcome measures - the overall incidence of PEP, the incidence of moderate to severe PEP, the incidence of hyperamylasemia, and the incidence of adverse effect with prophylactic use of GTN.
Data extraction
Data from eligible studies were extracted independently by using standard forms. Details of the studies included name of the first author, year of publication, country, setting, sample size, interventions, dosage, follow-up, routes of drug administration, inclusion and exclusion criteria of each study, definition, incidence of PEP (including overall and moderate to severe pancreatitis, respectively) and hyperamylasemia.
Data synthesis
All statistical analyses were performed using Comprehensive Meta-analysis Version 2. All outcomes were expressed as odds ratio (OR) with 95% confidence interval (CI).
Findings
Eleven randomized controlled trials (RCTs) involving 2395 patients were included. Eleven RCTs compared GTN with placebo for PEP prevention. Meta-analysis showed that the overall incidence of PEP was significantly reduced by GTN treatment (OR 0.65, 95% CI 0.483-0.784). Nevertheless, GTN administration did not decrease the incidence of moderate to severe PEP (OR 0.687, 95% CI 0.407-1.16). Subgroup analyses revealed that GTN administered sublingually was more effective than transdermal and topical administration in reducing the incidence of PEP. In addition, the incidence of hyperamylasemia was significantly reduced by GTN treatment (OR 0.483, 95% CI 0.289-0.809).

Keywords: Prophylactic use of GTN reduced the overall incidence of PEP and hyperamylasemia. However, GTN was not helpful in reducing the severity of PEP

How to cite this article:
Kohla SH, Zein El-Dein AA, Mahmoud FA, Mukhtar HA. Glyceryl trinitrate for prevention of pancreatitis after endoscopic retrograde cholangiopancreatography: meta-analysis of randomized, controlled trials. Menoufia Med J 2015;28:793-9

How to cite this URL:
Kohla SH, Zein El-Dein AA, Mahmoud FA, Mukhtar HA. Glyceryl trinitrate for prevention of pancreatitis after endoscopic retrograde cholangiopancreatography: meta-analysis of randomized, controlled trials. Menoufia Med J [serial online] 2015 [cited 2023 Mar 31];28:793-9. Available from: http://www.mmj.eg.net/text.asp?2015/28/4/793/173584

Introduction

Pancreatitis remains the most common, severe complication of endoscopic retrograde cholangiopancreatography (ERCP) ^[1] . The incidence of post-ERCP pancreatitis has been increasing rapidly for 30 years, varying from less than 2 to 40% ^[2] . Although most cases of PEP are mild, severe pancreatitis can also occur. Despite attempting to address this problem, effective strategies to prevent this serious complication remain elusive.

Accumulating data reveal that risk factors associated with PEP development include both patient-related factors (female, Sphincter of Oddi ^{More Details} dysfunction, previous pancreatitis, and age <60 years) and procedure-related factors (precut sphincterotomy, pancreatic duct injection, balloon dilation of intact sphincter, pancreatic sphincterotomy, difficult cannulation, minor papilla sphincterotomy, pain during ERCP, and ampullectomy). At present, the pathogenesis of ERCP-induced pancreatitis is not completely clear. During diagnostic and therapeutic ERCP, the pancreas is exposed to multiple potentially damaging factors, including mechanical, hydrostatic, chemical, and enzymatic etiologies. The exact mechanisms by which these factors trigger pancreatitis are unknown ^[3] .

Materials and methods

Study identification and selection

Literature searches were conducted of the electronic databases PubMed, EMBASE, The Cochrane Library, and Web of Knowledge databases (up to May 2014) using keywords 'post-ERCP', 'pancreatitis', 'ERCP', 'post endoscopic retrograde cholangiopancreatography pancreatitis', 'GTN', 'glyceryl trinitrate', and 'nitroglycerin'; the selection was limited to randomized controlled trials (RCTs). No language restriction was imposed. The following selection criteria were applied:

Study design - RCTs;
Study population - patients undergoing ERCP;
Intervention - prophylactic administration of GTN;
Comparison intervention - placebo or no treatment; and
Outcome measures - the overall incidence of PEP, incidence of moderate to severe PEP, incidence of hyperamylasemia, and incidence of adverse effect with prophylactic use of GTN.

Study quality analysis and data extraction

The quality score of primary trials was assessed according to the Jadad scale ([Table 1]) ^[13] , which ranges from 0 to 5. Higher scores indicate better reporting. We defined studies with a Jadad score of 3 points or higher as being of high quality in this meta-analysis. Data from eligible studies were extracted independently by using standard forms. Details of the studies included name of the first author, year of publication, country, setting, sample size, interventions, dosage, follow-up, routes of drug administration, inclusion and exclusion criteria of each study, definition, incidence of PEP (including overall and moderate to severe pancreatitis, respectively), and hyperamylasemia ([Table 2] and [Table 3]).

Table 1 Jadad quality scores of randomized controlled trials included in the meta-analysis

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Table 2 Principal characteristics of the published randomized studies included in the meta-analysis

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Table 3 Principal characteristics of the published randomized studies included in the meta-analysis

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Statistical analysis

All statistical analyses were performed using Comprehensive Meta-analysis Version 2. All outcomes were expressed as odds ratio (OR) with 95% confidence interval (CI). Heterogeneity was assessed by visual inspection of a forest plot and the I² statistic. Heterogeneity was considered significant at P less than 0.05 or by I² greater than 50% ^[14] . A fixed-effects model or random-effects model was used, depending on the absence or presence of heterogeneity. We performed a subgroup analysis according to the route of GTN administration (topical vs. transdermal vs. intravenous vs. sublingual). We also assessed the potential for publication bias, shown as a funnel plot. A P value less than 0.05 was judged as being statistically significant.

Results

Eleven RCTs involving 2395 patients were included. Eleven RCTs compared GTN with placebo for PEP prevention. Meta-analysis showed that the overall incidence of PEP was significantly reduced by GTN treatment (OR 0.65, 95% CI 0.483-0.874) ([Figure 1]). Nevertheless, GTN administration did not decrease the incidence of moderate to severe PEP (OR 0.687, 95% CI 0.407-1.16) ([Figure 2]). Subgroup analyses revealed that GTN administered sublingually was more effective than transdermal and topical administration in reducing the incidence of PEP. In addition, the incidence of hyperamylasemia was significantly reduced by GTN treatment (OR 0.483, 95% CI 0.289-0.809) ([Figure 3]).

Figure 1 Forest plot for the analysis of overall incidence after endoscopic retrograde cholangiopancreatography pancreatitis. CI, confidence interval; GTN, glyceryl trinitrate.

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Figure 2 Forest plot for the meta-analysis of the incidence of moderate to severe pancreatitis. CI, confidence interval; GTN, glyceryl trinitrate.

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Figure 3 Forest plot for the meta-analysis of the incidence of hyperamylasemia. CI, confidence interval; GTN, glyceryl trinitrate.

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Discussion

Meta-analysis of the 11 included RCTs demonstrates that the OR of PEP developing after prophylactic GTN use was 0.65 (95% CI 0.483-0.874). In other words, patients who received GTN in the periprocedural period were 35% less likely to have pancreatitis. However, GTN-treated patients did not show a reduction in the development of moderate to severe PEP.

The four routes of GTN used in the trials were topical, sublingual, transdermal, and intravenous. Whether the route of GTN administration affects the clinical efficacy was uncertain. From a clinical perspective, three studies ^{[4],[10],[15]} assessing sublingually administered GTN in the prevention of PEP revealed positive results or demonstrated a trend toward positivity. In contrast, among five studies ^{[6],[7],[9],[11],[12]} assessing transdermal GTN administration, only one trial revealed positive results and the other four trails revealed negative results or demonstrated a trend toward negativity. Further, two trials ^[5],[6] assessed topical administration and only one trial ^[8] assessed intravenous GTN administration, but all had negative results or demonstrated a trend toward negativity. By summarizing the available evidence, the sublingual route of GTN administration seemed to be the best way for PEP prevention. Although the sublingual route seemed to be more effective than the transdermal route, the results were not convincing for a few patients administered sublingually (407 patients) compared with the transdermal route (1596 patients).

The present meta-analysis suggests a significant benefit of GTN in PEP prevention (P = 0.004).

There are several hypotheses for ERCP-induced pancreatitis but none are completely understood ^[16] . The papillary instrumentation during ERCP may cause a spasm of the sphincter of odi dysfunction (SOD) and result in transient pancreatic duct obstruction and subsequent development of PEP ^[17] . It was demonstrated that GTN, a nitric oxide donor, lowered basal pressure and contraction amplitude in the SO ^[18] . Luman et al. ^[19] reported that local application of GTN inhibited SO motility and concluded that this may imply the application of GTN for diagnostic and therapeutic biliary endoscopy ^[19] . Three trials ^{[10],[11],[15]} reported the incidence of hyperamylasemia with prophylactic administration of GTN through transdermal and sublingual routes. Prophylactic GTN administration significantly reduced the incidence of hyperamylasemia.

PEP is commonly prevented through two methods: pharmacological intervention and procedural intervention. ERCP should be avoided in unnecessary or low-yield cases, especially when multiple patient-related risk factors for pancreatitis development are found. A number of pharmacological drugs, in particular rectal NSAIDs, have also shown potential but none are being used consistently ^[20] . The procedural interventions that have demonstrated reduction in PEP incidence include guidewire cannulation ^[21] and pancreatic stent placement ^[22] in high-risk cases.

Ideal pharmacological drugs should have the following properties: they should be highly effective in reducing post-ERCP pancreatitis; they should have a short administration time; they should be well tolerated with a low side-effect profile; and they should be cost-effective. Several drugs have shown potential. However, the vast majority have fallen short of these goals. Therefore, the adverse effects of GTN should be weighed against its potential clinical benefit. The main adverse effects were transient hypotension and headache, which were more frequent in intravenous administration of GTN, but they were not severe and responded well to conventional treatment. The side effects were significantly more frequent in the GTN group and led to dose reduction or cessation of infusion ^[8] . Therefore, compared with intravenous administration, sublingual or transdermal delivery of GTN may be much safer, well tolerated, and easier to administer. Although we acknowledge that GTN can prevent PEP incidence, we should pay attention to its adverse events. More importantly, the present meta-analysis did not have any publication bias.

By summarizing all relevant RCTs published to date, the present meta-analysis confirmed the efficacy and relative safety of GTN. For patients undergoing ERCP, the sublingual route of administration of GTN is recommended, although careful attention should be paid to its adverse effects.

Summary

Acute pancreatitis is the most common complication of diagnostic and therapeutic ERCP. Several clinical trials used glyceryl trinitrate (GTN) to prevent the incidence of post-ERCP pancreatitis (PEP). However, the results are still controversial.

This study aimed to conduct a meta-analysis of published, full-length, RCTs evaluating the effect of prophylactic GTN on the prevention of PEP and the prevention of hyperamylasemia.

Literature searches, limited to RCTs, were conducted using PubMed, EMBASE, The Cochrane Library, and Web of Knowledge databases, using keywords 'post-ERCP' and 'pancreatitis'.

Eleven RCTs involving 2395 patients were included. The meta-analysis showed that the overall incidence of PEP was significantly reduced by GTN treatment (OR 0.65, 95% CI 0.483-0.874). Nevertheless, GTN administration did not decrease the incidence of moderate to severe PEP (OR 0.687, 95% CI 0.407-1.16). Subgroup analyses revealed that GTN administered sublingually was more effective than transdermal and topical administration in reducing the incidence of PEP. In addition, the incidence of hyperamylasemia was significantly reduced by GTN treatment (OR 0.483, 95% CI 0.289-0.809).

Conclusion

In conclusion, this meta-analysis shows that the prophylactic use of GTN is an effective and relatively safe intervention for preventing PEP and hyperamylasemia, but has no effect on the severity of PEP.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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