Statin use does not decrease the incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis

KEYWORDS:

• Biliary
• ERCP
• inflammation
• pancreas
• statin

1. Introduction

Three-Hydroxy-3-methyl-glutaryl-coenzyme A (HMG co-A) reductase inhibitors (statins) represent an effective therapeutic tool used worldwide in the treatment of dyslipidemia, and a growing body of evidence supports also their pleiotropic anti-inflammatory properties [1,2]. In spite of preliminary discording results, several recent studies demonstrated that the chronic use of statins may appear as a protective factor against acute pancreatitis (AP) [3–6].

Based on these premises, statin use was found to be associated with lower rates of iatrogenic pancreatitis after interventional endoscopic procedures, such as endoscopic ultrasound (EUS) tissue sampling [7] or endoscopic retrograde cholangio-pancreatography (ERCP) [8].

However, these promising findings have been recently debunked in larger studies which did not find a significant benefit with statin chronic use in decreasing post-ERCP pancreatitis (PEP) [9,10].

In order to shed further light on this controversial topic, we reviewed our series of patients treated with ERCP at our tertiary center from 2006 to 2019. Local ethic committee approved this retrospective series.

2. Body

Baseline characteristics and treatment outcomes are reported in Table 1. Out of 1543 patients treated with ERCP, 395 were on statin therapy for at least 6 months before ERCP and 1148 represented the control group. Baseline demographic and clinical characteristics were well-balanced between the two groups.

Table 1. Baseline parameters and outcomes stratified according to the study group.

Variable	Statin users (n = 395)	Control group (n = 1148)	P value
Gender male	241 (61%)	665 (57.9%)	0.28
Age (years)	73.1 ± 11.4	69 ± 13.1	0.31
Body mass index	23.4 ± 4.1	21.8 ± 3.5	0.42
Indications to ERCP			0.52
Biliary	355 (89.8%)	1044 (90.9%)
Pancreatic	40 (10.2%)	104 (9.1%)
History of acute pancreatitis	34 (8.6%)	95 (8.2%)	0.83
Papilla			0.88
Without previous EST or EPBD	325 (82.2%)	941 (81.9%)
Biliary cannulation			0.35
Easy	287 (72.6%)	861 (75%)
Difficult	108 (27.4%)	287 (25%)
Wirsung cannulation	95 (24%)	252 (21.9%)	0.38
Pancreatitis	26 (6.5%)	98 (8.5%)	0.21
Severe pancreatitis	8 (2%)	17 (1.4%)	0.45
Statin users subgroup	Pancreatitis	Severe pancreatitis
Pancreatitis according to statin class
Hydrophilic	10 (2.5%)	3 (0.7%)	0.34
Lipophilic	16 (4%)	5 (1.3%)
Pancreatitis according to statin dose
Low	16 (4%)	5 (1.3%)	0.21
High	10 (2.5%)	3 (0.7%)

Variables were expressed as mean (± standard deviation) in the case of continuous variables and absolute number (percentage) in the case of categorical variables.

Comparisons were performed through chi square test for categorical variables and Kruskal-Wallis test for continuous ones.

Abbreviations: EPBD, endoscopic papillary balloon dilation; ERCP, Endoscopic retrograde cholangio-pancreatography; EST, endoscopic sphincterotomy.

Indication to ERCP was mainly due to biliary disease in both the cohorts and history of previous AP was registered in less than 10% of total patients. Biliary cannulation was defined as difficult (i.e., >5 minutes/>5 contacts) [11] in nearly 25% of patients. All patients underwent pre-procedural administration of rectal indomethacin.

AP was experienced in 26 patients (6.5%) in the statin group and 98 patients (8.5%) in the control group (p = 0.21), whereas severe pancreatitis was observed in 8 (2%) and 17 (1.4%) patients in the two groups, respectively (p = 0.45). Logistic regression analysis confirmed the non-significant difference between the two groups both in the univariate (odds ratio 0.75, 95% confidence interval 0.48–1.18) and the multivariate setting (odds ratio 0.81, 0.57–1.43). Other significant predictors of PEP in multivariate analysis were alcohol intake and procedure time (>20 minutes).

Subgroup analysis conducted according to statin class (lipophilic versus hydrophilic; p = 0.34) and dose (low versus high; p = 0.21) confirmed the ‘class effect’ of statins regardless of the singular molecule used (Table 1).

The consumption of statins the night before the procedure (175 patients) was not associated with a decreased risk of PEP (11/175 [6.2%] versus 15/220 [6.8%]; p = 0.83).

Therefore, our results seem to suggest that statin chronic use is not associated to a significant decrease in the rates of PEP, as already found in the study by Hakuta et al [9]. Furthermore, a large multicentre prospective study has recently terminated the enrollment of patients and the results have been published as conference abstracts, confirming our findings [10].

These results are in contrast with the series published by Mahamid et al [8], where a striking beneficial effect of statins was showed both in univariate and multivariate analysis. However, this study did not take into account important factors associated with the incidence of PEP including the use of non-steroidal anti-inflammatory drugs (NSAIDs) and only included patients undergoing biliary interventions.

However, the potential beneficial effects of statins in this setting still have a robust biological background and they deserve to be further explored in randomized trials. Given the marginal effect of statins in this study, a very large sample size (5442 patients) would be needed in a randomized trial to confirm these findings.

Statins are well known to improve endothelial function by inducing endothelial nitric oxide synthase (eNOS) accumulation within endothelial cells and decreasing exocytosis of Weibel–Palade bodies, granules whose contents promote vascular thrombosis and inflammation [12]. Furthermore, statin use impairs leukocytes recruitment in the sub-endothelial space through down-regulation of several chemokines such as monocyte chemoattractant protein (MCP)-1, interleukin (IL)-8, and regulated upon activation, normal T cell expressed and presumably secreted (RANTES) and inhibition of β₂-integrins [2].

In attendance of prospective trials, no definitive assumptions could be drawn on the effects of statins in preventing PEP and further studies are warranted in order to clarify this important issue.

3. Expert opinion

Statins represent an effective therapeutic tool used worldwide in the treatment of dyslipidemia, and a growing body of evidence supports also the evidence that the chronic use of statins may appear as a protective factor against acute pancreatitis.

Retrospectively reviewing our series of patients undergoing ERCP, we found that there was no statistically different incidence of acute pancreatitis and severe pancreatitis between the group of patients treated with statins as compared to the control group.

Logistic regression analysis confirmed the non-significant difference between the two groups both in the univariate and the multivariate setting. Subgroup analysis conducted according to statin class (lipophilic versus hydrophilic) and dose (low versus high) confirmed the “class effect” of statins regardless of the singular molecule used.

Therefore, our results seem to suggest that statin chronic use is not associated to a significant decrease in the rates of post-ERCP pancreatitis. In attendance of prospective trials, no definitive assumptions could be drawn on the effects of statins in this setting and further studies are warranted in order to clarify this important issue.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.