Effectiveness of the pharmacological therapy to prevent post ERCP acute pancreatitis: a network meta-analysis

ABSTRACT

Objective

To determine the effectiveness of the different pharmacological agents in preventing post-ERCP acute pancreatitis

Methods

We included clinical trials of pharmacological interventions for prophylaxis of acute post-ERCP pancreatitis. The event evaluated was acute pancreatitis. We conducted a search strategy in MEDLINE (OVID), EMBASE, and Cochrane Central Register of Controlled Trials from inception to nowadays. We reported the information in terms of relative risks (RR) with a 95% confidence interval. We assessed the heterogeneity using the I² test.

Results

We included 84 studies for analysis (30,463 patients). The mean age was 59.3 years (SD ± 7.01). Heterogeneity between studies was low (I2 = 34.4%) with no inconsistencies (p = 0.2567). Post ERCP pancreatitis was less in prophylaxis with NSAIDs (RR 0.65 95% CI [0.52 to 0.80]), aggressive hydration with Lactate Ringer (RR 0.32 95% CI [0.12–0.86]), NSAIDs + isosorbide dinitrate (RR 0.28 95% CI [0.11–0.71]) and somatostatin and analogues (RR 0.54 [0.43 to 0.68]) compared with placebo.

Conclusions

NSAIDs, the Combination of NSAIDs + isosorbide dinitrate, somatostatin and analogues, and aggressive hydration with lactate ringer are pharmacological strategies that can prevent post-ERCP pancreatitis when compared to placebo. More clinical trials are required to determine the effectiveness of these drugs.

KEYWORDS:

• Cholangiopancreatography
• endoscopic retrograde
• pancreatitis
• prophylaxis
• pharmacological
• therapies

1. Introduction

Post-endoscopic retrograde cholangiography (ERCP) pancreatitis is the most common adverse event derived from the use of the technique [1–3] because of the diagnosis and the management of the multiple conditions affecting the biliary-pancreatic tree. The incidence can vary between 2.1% to 24.4% [4–6]. Mortality from this cause is not negligible either; some works [1] have reported that the associated mortality was 3.08 (95% CI 1.65–4.51). In addition to morbidity, post-ERCP pancreatitis is a costly entity; for 2012, in the United States, the costs of managing post-ERCP pancreatitis amounted to 150 million dollars [7].

The pathophysiology of post-ERCP acute pancreatitis is not well understood. Multiple aggression mechanisms have been described, which classify it as a multifactorial event that includes a combination of events inherent to the patient (chemical, mechanical, hydrostatic, thermal, enzymatic, allergic, and/or microbiological) and surgical intervention (excessive manipulation of the sphincter Oddi, injection of contrast into the pancreatic duct) [8].

In order to prevent acute post-ERCP pancreatitis, multiple pharmacological and non-pharmacological interventions have been studied. Pharmacological interventions include vigorous hydration with crystalloids [9,10], protease inhibitors such as intravenous Nafamostat [11], NSAIDs in different routes of administration [12–14], among others. In each of these studies, the interventions carried out have shown different degrees of effectiveness for preventing pancreatitis. However, prophylactic management remains controversial due to a) the current problem of regular external validity that clinical trials carried out with this objective present and b) the lack of comparisons between treatments (most pharmacological treatments have been compared with placebo). With those mentioned above, the need arises to understand if the effectiveness of the Pharmacological management is comparable among them or if, on the contrary, one intervention may be more effective than another.

Post-ERCP acute pancreatitis affects many patients every year with individual, family, social and economic consequences on a large scale, so it is essential to establish whether the measures used to prevent post ERCP pancreatitis may benefit high-risk patients. This finding would allow the standardization of clinical management guidelines that reduce this event and improve patients’ quality of life. Therefore, this study aimed to determine the effectiveness of the different pharmacological agents in preventing post-ERCP acute pancreatitis in patients at risk.

2. Methods

We performed this review following the Cochrane Collaboration recommendations following the PRISMA statutes. We registered the protocol in PROSPERO (CRD42018114302).

2.1. Inclusion criteria

We included randomized controlled clinical trials that included patients evaluated with pharmacological interventions for the prophylaxis of acute pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). The intervention was any pharmacological therapy for the prophylaxis of post-ERCP pancreatitis. The primary objective was the effectiveness of these different pharmacological agents, defined as the frequency of post-ERCP pancreatitis reported by the authors. The event of acute post-ERCP pancreatitis was defined as pain in the irradiated back band, of the epi-mesogastric location of burning or oppressive colic type that does not yield to the administration of symptomatic management. Also, the increase of serum amylase more than three times the normal value in 24 hours. The presence of radiological changes consistent with the diagnosis of acute pancreatitis. For all objectives, the studies had to have at least 24 hours of follow-up. There were no language restrictions in the search. We excluded animal studies and non-pharmacological surgical or endoscopic interventions.

2.2. Information sources

We carried out the literature search according to the Cochrane recommendations. We searched MEDLINE (OVID), EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to nowadays (Appendix 1). We searched in google scholar, clinical trials, conferences, reference list, thesis database, and asked different authors to saturate the information.

2.3. Data collection

Each reference was inspected by title and abstract. Subsequently, the studies’ full-text were reviewed, applying the inclusion and exclusion criteria, and we extracted the data. Disagreements were resolved by consensus. Relevant data were collected using a standardized data extraction tool that included the following variables: Name of the authors, year of publication, title, study design, geographic location, objectives, age, gender, number of participants, conflicts of interest, intervention, clinical and paraclinical variables of follow-up and outcome (pancreatitis).

2.4. Data analysis/results synthesis

The statistical analysis was carried out in R with the frequentist model of the netmeta library together with the netmeta command. We reported the information on relative risks (RR) with a 95% confidence interval for categorical outcomes according to the type of variables studied. Subsequently, we pooled the information through a random effect meta-analysis according to the expected heterogeneity. Heterogeneity was assessed using the I² test. The transitivity assumptions were taken into account and evaluated according to the type of comparisons. Similarities and possible effect modifications were considered during the different comparisons paired or not.

2.5. Risk of bias

We assessed the risk of bias for each study using Cochrane’s risk of bias tool by REVMAN 5.3. Two independent investigators judged the possible risk with the extracted information that is classified as ‘high risk,’ ‘low risk,’ or ‘unclear risk.’ A graphical representation of the risk of bias was constructed using the Cochrane REVMAN 5.3 collaboration tool

2.6. The geometry of the network

For each treatment, we estimated the probability of appearing in a position to infer a classification of treatments. Through the network geometry, we compared all treatments versus placebo. The resulting significant pharmacological options were compared with the rest of the treatments. We designed network diagrams to show the amount of evidence available for each outcome and the most frequent comparisons. The nodes’ size was proportional to the total number of patients assigned to each intervention in the clinical trials, and the width of the lines was proportional to the number of studies evaluated in each comparison.

2.7. Inconsistency assessment

We evaluated the state of consistency through direct and indirect comparisons in pharmacological therapies. Statistical inconsistency was also evaluated. We considered the model inconsistent if the p-value was less than 0.05.

3. Results

3.1. Study selection

We found 2683 studies using the search strategy. We removed 25 duplicates. After review by title/abstract and full text, 84 records that met the inclusion criteria were included (Figure 1).

Figure 1. Clinical study selection flow diagram.

3.2. Characteristics of included studies

Thirty thousand four hundred sixty-three patients were included, with a median of 293 patients per study (Interquartile range [IQR] 157 to 456). The mean age of the patients was 59.3 years (SD ±7.01). The male: female ratio was 1: 1.2. Seventy-one studies compared some type of intervention with placebo (Table 1).

Table 1. Clinical trials included in the network meta-analysis.

Author-year	Country	Age	N	M	F	Placebo group	AP (%)	Intervention group	AP (%)	Intervention 1	Intervention 2	Intervention 3	lost of follow-up %.
Abu-Safieh 2014 [22]	Palestine	54	182	71	111	93	10.4	89	4.7	Diclofenac 75 mg IM	Placebo	No	8.5
Alizadeh 2016) [92]	Iran	56.4	372	175	197	95	12.4	102	3.6	Diclofenac 100 mg Rectal	Indometacin 100 mg rectal	Naproxen 500 Mg rectal	17.3
Andrade-Dávila 2015 [23]	Mexico	52.7	166	56	110	84	20.23	82	4.8	Indometacin 100 mg Rectal	Placebo	No	0
Bai 2015 [63]	China	60	900	434	466	445	12.3	445	4.5	Somatostatin 250UI Hr IV	Placebo	No	0.9
Barkay 2008 [60]	Israel	64.6	105	43	62	54	7.8	51	7.4	Heparin 5000UI SC	Placebo	No	0.9
Beauchant 2008 [54]	France	52	208	58	150	103	17	105	17	Nitroglicerin 0.1 mg bolus − 35 UI/Kg/min IV	Placebo	No	5
Bhatia 2011 [24]	India	41	371	123	248	123	15	245	16	Valdecoxib 20 mg IV	Gliceril trinitrato 10 mg twice a day	Control	2.4
Bordas 1988 [64]	Spain	65	33	15	18	16	94	17	8	Somatostatin 4 UI/Kg IV	Placebo	No	0
Bordas 1998 [65]	Spain	59	160	96	64	80	10	80	2.5	Somatostatin 4 UI/Kg IV	Placebo	No	16.7
Budzyńska 2001 [49]	Poland	58.5	300	87	213	101	7.9	199	12	Prednisone 40 mg Oral	Allopurinol 200 mg Oral	Placebo	0
Buxbaum 2014 [89]	EEUU	44	62	30	32	39	17	23	-	Lactato ringer 3 lm/kg 8 hr + bolus 20 ml/kg IV	Lactato ringer (3 ml Kg Iv 8 hours)	no	12.7
Cavallini 1996 [66]	Italy	60.4	435	199	236	210	14	208	6	Gabexate 1gr IV	Placebo	No	0
Chan 2008 [72]	China	62.6	133	72	61	49	40.8	84	13	Somatostatin 250 mcg IV pre y post	Somatostatin 250 mg	Placebo	0
Cheon 2007 [25]	EE. UU.	45.8	207	69	138	112	16.7	111	16.2	Diclofenac 50 Mg VO	Placebo	No	7.2
Chik 2018 [26]	Malaysia	52.5	122	61	61	61	14	61	3.8	Diclofenac 75 Mg IV	Placebo	No	4.7
Choi 2009 [68]	Corea	65.1	704	365	339	350	7.4	354	3.3	Nafamostat 20 mg IV	Placebo	No	2.6
Choi 2017 [15]	Corea	57.6	510	278	232	250	9.8	205	4.3	Lactato ringer IV (10 ml/kg pre +3 ml/kg during y 8 hr +10 ml/kg post)	Lactato ringer (1.5 ml/kg during the procedure and during 8 hr)	No	0
Concepción-Martín 2013 [69]	SPAIN	73	510	241	269	255	6.7	255	7.5	Somatostatin IV 250Ui h total 1250 Ui	Placebo	No	58.9
De Quadros Onófrio 2016 [27]	Brazil	57	477	141	336	253	7.1	244	6.5	Ketoprofen 100 Mg IV	Placebo	No	4.6
De Palma 1999 [52]	Italy	58.6	529	279	250	266	9.1	263	4.6	Hidrocortisone 100 Mg IV	Placebo	No	1.1
Devie’re 2001 [93]	Belgica	60.6	137	59	78	68	5.4	69	3.8	interleukin 10 4Ui/kg	interleukin 10 20 UI/Kg	Placebo	4.9
Döbrönte 2014 [28]	Hungary	66.6	665	239	426	318	6.3	347	5.1	Indometacin 100 Mg rectal	Placebo	No	3.1
Dumot 1998 [50]	EEUU	52	255	107	148	176	8.7	129	6.7	Metilprednisolona 125 Mg IV	Placebo	No	10.8
Elmunzer 2012 [9]	EEUU	45	602	126	476	307	16.1	295	9.7	Indometacin 100 Mg Rectal	Placebo	No	24.7
Fujishiro 2006 [94]	Japan	64.8	139	75	64	69	4.5	70	2.3	Gabexate 900 mg	Unilastatin 450mil UI	Unilastatin 150mil UI	7.3
Fujita 2016 [29]	Japan	63.6	100	72	28	53	17	47	4.3	Flurbiprofeno 50 Mg IV	Placebo	No	30.6
Hauser 2016 [86]	Croatia	71.9	272	144	128	129	14.5	143	8.7	Diclofenac Rectal 100 mg	Ceftazidime 1 gr IV	No	4.9
Hosseini 2016 [95]	Iran	49	406	202	204	203	18	203	5.6	Indometacin 100 mg Rectal	Ssn 0.9% 1lt Iv single dose	Indometacin 100 rectal + 1lt ssn	32.3
Ishiwatari 2016 [18]	Japan	69	407	227	180	214	20.3	216	21.3	Diclofenac 100 Mg oral	Placebo	No	5.3
Jowell 2011 [70]	EEUU	55	869	372*	494*	443	15.1	426	8.7	Secretine 16 UI IV	Placebo	No	4.6
Kaffes 2006 [55]	Australia	53.2	318	124	194	163	7.4	155	7.7	glyceryl trinitrate 5 mg Transdérmic patch	Placebo	No	9.4
Kapetanos 2007 [56]	Grecia	65.8	320	169	151	162	3	158	5.6	Pentoxifiline 400 mg vo	Control	No	0
kato 2017 [30]	Japon	70.5	170	101	69	85	5.6	85	5	Celecoxib oral 400 mg	Placebo	No	6.1
Katsinelos 2005 [43]	Greece	66	243	117	126	118	17.8	125	3.2	Allopurinol 600 mg Vo	Placebo	No	2.8
Katsinelos 2011 [47]	Greece	68.5	515	232	283	260	23	255	4.5	Diclofenac 100 mg Rectal + Somatostatin 0.25 mg/h IV	Placebo	No	4.6
Khoshbaten 2008 [31]	Iran	58.5	100	47	53	50	13	50	2	Diclofenac 100 mg Rectal	Placebo	No	44.4
Kim 2016 [100]	Korea	66.7	371	195	176	186	25	185	23	Nafamostat 20 mg IV	Nafamostat 20 mg IV	No	2.9
Lavy 2004 [48]	Israel	66	321	122	199	180	9.4	141	10	Beta carotene 2 g Oral	Placebo	No	5.6
Lee 2008 [71]	Korea	62.5	391	200	191	196	9.6	197	3.6	Somatostatin 3 mg IV +500 ml Ssn	Placebo	No	2.3
Lee 2015 [62]	Korea	54.8	216	122	94	109	15.8	107	16.5	Udenafil 200 mg + aceclofenac 100 mg	Placebo	No	0
Levenick 2016 [32]	EEUU	54.7	449	213	236	226	4.9	223	7.2	100 mg Indometacin rectal	Placebo	No	0
Li 20075 [70]	China	54.8	832	432	400	418	20.7	414	12.3	Octreotide 0.3 mg IV	Placebo	No	13.4
Lua 2015 [33]	Malaysia	50	144	59	85	75	7	69	4	Diclofenac 100 mg rectal	Control	No	10.6
Luo 2016 [96]	China	62.5	2600	1237	1363	1300	12.3	1300	4.5	100 mg Indometacin Rectal Pre-procedure	100 mg Indometacine Rectal Post-procedure	No	0
Manes 2007 [97]	Italy	63.5	608	328	280	304	12.3	304	10.2	Gabexate 500 mg IV pre-procedimiento	Gabexate 500 mg Iv post procedimiento	Placebo	2.3
Manolakopoulos 2002 [72]	Greece	64	340	138	202	115	13.8	225	9.1	Octreotid 100 mcg Sc	Hidrocortisone 100 mg Iv	Placebo	4
Mansour-ghanaei 2016 [34]	Iran	45.5	324	173	151	162	28	162	12	Naproxen 500 mg Rectal	Placebo	No	0
Martinez-Torres 2009 [44]	Mexico	53.1	170	70	100	85	9.4	85	2.3	Allopurinol 600 mg Vo	Placebo	No	43.3
Masci 2003 [98]	Italia	63.9	434	201	233	217	10.2	217	4.5	Gabexate 500 mg IV *6.5 h + Gabexate 500 mg *6.5 h	Gabexate 500 mg IV *6.5 h + placebo	No	7.4
Masjedizadeh 2017 [87]	Iran	56.1	186	84	102	62	43.7	124	21	Ringer lactate 20 ml/kg pre +3 ml/kg durante 8 hr	Indometacin 50 mg rectal pre + 50 Indometacina 50 mg rectal 12 hrs post	No	0
Montano 2016 [42]	Mexico	54.2	117	38	79	58	11.3	59	4.6	Indometacin 100 mg Rectal	Placebo	No	0
Montaño Loza 2007 [35]	Mexico	55.3	150	50	100	75	37.3	75	28.3	Indometacin 100 mg Rectal	Placebo	No	0
Moreto 2003 [57]	Spain	65.9	144	87	57	70	23.5	74	24.5	Glyceryl trinitrate Transdermal Patch	Placebo	No	26.9
Mosler 2005 [45]	EEUU	51.7	701	194	507	346	12.14	355	12.96	Allopurinol 600 mg 4 h pre + Allopurinol 300 mg 1 h pre Vo	Placebo	No	0
Murray 2003 [36]	Scotland	56.5	220	77	143	110	37.4	110	15.4	Diclofenac 100 mg Rectal	Placebo	No	0
Nøjgaard 2009 [59]	International	66	806	332	474	401	7.1	405	4.5	glyceryl trinitrate parche 15 Mg.Td	Placebo	No	1.7
Ohuchida 2014 [73]	Japan	68.8	809	502	307	404	6.7	405	3.5	Nafamostat 20 mg en 500 ml de DAD5%	Placebo	No	7.6
Otsuka 2012 [37]	Japan	73.5	104	53	51	53	18.9	51	3.9	Diclofenac 50 mg rectal	Control	No	32.9
Park 2011 [74]	Korea	63	595	319	276	220	14	475	5.1	Nafamostat 50 mg IV + DAD 5% 500cc	Nafamostat 20 mg IV + DAD 5% 500cc	Placebo	2.1
Park 2014 [41]	Korea	64.5	343	204	139	180	11.8	163	12.7	Diclofenaco 90 mg IM	Placebo	No	9.7
Park 2017 [99]	Korea	59	395	179	216	129	6.7	134	3	Lactato Ringer IV (3 ml/kg/h pre +20 ml/kg post +3 ml/kg/h *8 h)	Solucón Salina IV (3 ml/kg/h pre +20 ml/kg post +3 ml/kg/h)	Lactato R (1.5 ml/kg/h y post procedimiento 8 horas)	2.7
Poon 1999 [75]	China	62.8	220	102	118	109	16	111	8	Somatostatina 3 mg IV +500 ml Ssn	Placebo	No	4.3
Poon 2003 [76]	China	68	270	137	133	135	14.4	135	3	Somatostatina 250Ui IV	Placebo	No	4.3
Rabenstein 2004 [61]	Germany	58	448	135	313	227	8.8	221	8.1	HBPM 3000 ui IV	Placebo	No	0
Romagnuolo 2008 [46]	Canada	54.7	586	242	344	293	4.4	293	5.3	allopurinol 300 mg V	Placebo	No	0
Sand 1993 [53]	Finland	61.5	166	68	98	84	4	82	4	Nifedipine 20 mg * 3 dosis Vo	Placebo	No	0
Senol 2009 [38]	Turkey	60	80	43	37	40	17.5	4	7.5	Diclofenac 75 Mg Im	Placebo	No	12.1
Shaygan 2015 [83]	Iran	50.8	150	51	99	75	5.6	75	3.4	ringer Lactato 20 ml/kg pre +3 ml/kg/h *8 h	ringer Lactato (1.5 ml/kg/8*h)	No	0
Sherman 2003 [51]	EEUU	51.2	1115	396	719	555	13.6	560	16.6	prednisone Oral 40 mg	Placebo	No	0
Sherman 2009 (101)	International	51	305	74	231	153	12.5	152	10.5	IL10 (8Ui/kg)	IL10 (20 Ui/kg)	Placebo	10
Sotoudehmanesh 2007 [39]	Iran	58.2	490	226	264	245	15	245	7	Indometacin 100 mg rectal	Placebo	No	9.8
Sotoudehmanesh 2014 [88]	Iran	58	300	146	154	150	15.3	150	6.7	Indometacine 100 mg rectal + Isosorbide dinitrate 5 mg Sl	Indometacin 100 mg Rectal + placebo	No	0
Testoni 2001 [77]	Italy	51.8	120	49	71	58	14.3	56	12	Octreotid 200 Ug Sc/4 dosis	Control	No	0
Thomopoulos 2006 [78]	Grecce	69.8	201	99	102	101	8.9	101	2	Octreotid 500 Ug Sc * 3 dosis	Placebo	No	0.5
Tsujino 2005 [79]	Japan	65	406	244	162	204	7.4	202	2.9	Ulinastatin 150 mil Ui IV	Placebo	No	2.4
Tsujino 2012 [91]	Japan	60	226	148	78	113	8.8	113	5.3	Ulinastatin 150 mil Ui IV + risperidone 2 mg Vo	Ulinastatin 150 mil Ui Iv	No	0
UÇAR 2015 (102)	Turkey	60.2	150	50	100	75	12.5	75	11.8	Diclofenac 75 mg IM	Diclofenaco 100 mg rectal	Control	0
Uchino 2013 [85]	Japan	65	483	295	188	250	8.8	250	10	Risperidona 2 mg Vo	Placebo	No	3.4
Upendra Shah 2012 [80]	EEUU	48	73	18	55	37	12.5	36	13.2	Aprepitant 125 mg Vo	Placebo	No	20.7
Xiong 2006 [81]	China	62	193	90	103	95	10	98	3.1	Gabexato 300 mg IV	Placebo	No	3.5
Yoo 2008 [83]	Korea	63.5	227	123	104	108	5.6	119	6.7	Unilastatina 100.000 Ui IV + 500 cc ssn	Placebo	No	0
Yoo 2011 [82]	Korea	62.5	286	143	143	143	21	143	16.1	Nafamostat 50 mg IV + DAD 5% 500cc	Placebo	No	2.1
Yu Hao 2009 [58]	China	64	74	31	43	37	17	37	12	glyceryl trinitrate 5 mg SL	Placebo	No	0
Zhao 2014 [40]	China	59	120	52	68	60	20	60	13	Dilofenac 75 mg Im	Control	No	0

N = Number; M = Men; F = Women; mg = milligram; IM = Intramuscular; UI = International Units; Hr = Hour; IV = Intravenous; SC = Subcutaneous; min = minute; Kg = Kilogram; ml = milliliter; g = gram; mcg = microgram; pre = Pre-intervention; post = Post-intervention; VO = Oral route; SSN = Normal Saline Solution; DAD = Dextrose in Distilled Water; IL = Interleukin; SL = Sublingual; L = Liter; AP: acute pancreatitis.

*Incomplete data for the sex variable.

3.3. Excluded studies

We excluded 307 studies due to the following reasons: a) they did not assess the presence of post ERCP pancreatitis, b) the design did not correspond to a randomized clinical trial, c) the type of publication did not correspond to a scientific article, and/or d) they used prophylactic methods other than pharmacological ones.

3.4. Geometric network abstract

Seventy-one studies compared some type of pharmacological intervention with placebo. Of these, 23 studies used non-steroidal anti-inflammatory drugs (NSAIDs) [7,12,15–35]; four studies compared placebo with allopurinol [36–39], one evaluated somatostatin in conjunction with NSAIDs [40], one evaluated beta carotenes [41], four evaluated corticosteroids [42–45], one evaluated the use of nifedipine [46], six studies compared placebo with glyceryl trinitrate [47–52], two estimated the effect of heparin [53,54], one study compared the effect of udenafil aceclofenac [55] and placebo, 22 studies evaluated the use of somatostatin and analogues [56–77], one compared risperidone to placebo [78], Moreover, one evaluated the aggressive hydration regimen with lactate ringer [9].

Three studies compared NSAIDs versus another pharmacological intervention. In one study, the intervention was the Combination of antibiotics and NSAIDs [79],

another study evaluated aggressive hydration with lactate ringer [80] Moreover, the third compared them with Isosorbide Dinitrate [81]. Two studies compared aggressive hydration regimen with lactate ringer vs. aggressive hydration regimen with normal lactate [82,83].

Finally, a study compared somatostatin vs. somatostatin and risperidone [84] (Figure 2).

Figure 2. Post-ERCP acute pancreatitis network. A: non-steroidal analgesics (NSAIDs); AB: NSAIDs and Antibiotics; AD: NSAIDs and Isosorbide Dinitrate; AL: Allopurinol; AS: NSAIDs and somatostatin; B: beta carotenes; C: Corticosteroids; CB: Nifedipine; D: glyceryl trinitrate; H: Heparin; N: hydration with normal lactate; PDA: udenafil aceclofenac; S: somatostatin and analogs; SI: Risperidone; SSI: unilastatin-Risperidone; V: aggressive hydration with lactate ringer.

3.5. Risk of bias in included studies

All but six studies were considered low risk. One study due to the random sequence generation, two studies due to group allocation concealment, two due to non-masking of the study personnel, and two due to the non-masking of the assessor. Montaño’s 2006 study [28] it was classified as high risk due to the generation of the random sequence and due to the evaluator’s non-masking. The risk of reporting bias was measured as low as well (Figures 3 and 4).

Figure 3. Assessment of risk of bias within studies.

Figure 4. Assessment of risk of bias across studies.

3.6. Post-ERCP acute pancreatitis

Post-ERCP pancreatitis was 35% lower in patients who received NSAID prophylaxis than patients who received placebo (RR 0.65 95% CI [0.52 to 0.80]).

Aggressive hydration with Lactate Ringer was also significantly protective compared to placebo (RR 0.32 95% CI [0.12 to 0.86]). NSAID therapy in Combination with Isosorbide dinitrate was also protective when compared to placebo (RR 0.28 95% CI [0.11 to 0.71]), and somatostatin analogs were equally effective (RR 0.54 95% CI [0.43 to 0.68]).

There were no significant associations between antibiotics, allopurinol, somatostatin, beta-carotenes, corticosteroids, nifedipine, glyceryl trinitrate, heparin, aggressive hydration with lactate versus placebo concerning the outcome of post-ERCP acute pancreatitis.

NSAIDs, aggressive hydration with ringer lactate, NSAIDs + isosorbide dinitrate, and somatostatin analogues were independently compared with the rest of the pharmacological therapies to determine whether there were inconsistencies with previously estimated associations with placebo. We did not find significant differences between the effectiveness of the four treatments (see Figure 5). However, these four pharmacological modalities were significantly superior to the others.

Figure 5. Forrest plot for post-ERCP acute pancreatitis A: non-steroidal analgesics (NSAIDs); AB: NSAIDs and Antibiotics; AD: NSAIDs and Isosorbide Dinitrate; AL: Allopurinol; AS: NSAIDs and somatostatin; B: beta carotenes; C: Corticosteroids; CB: Nifedipine; D: glyceryl trinitrate; H: Heparin; N: hydration with normal lactate; PDA: udenafil aceclofenac; S: somatostatin and analogs; SI: Risperidone; SSI: unilastatin-Risperidone; V: aggressive hydration with lactate ringer.

3.7. Inconsistency exploration

However, these four pharmacological modalities were significantly superior to the others. For the post ERCP pancreatitis event, heterogeneity between studies was low (I2 = 34.4%) with no inconsistencies (p = 0.2567). The p-value was higher for studies comparing placebo with allopurinol (0.8127), risperidone (0.7361), and corticosteroids (0.7203) (See annex).

The comparisons that made it possible to evaluate the consistency of the model were: NSAIDs versus Glyceryl trinitrate (p = 0.7746), NSAIDs versus placebo (p = 0.8263), Allopurinol versus corticosteroids (p = 0.7391) and Allopurinol versus placebo (p = 0.5539). We concluded that there were no inconsistencies in the model.

4. Discussion

4.1. Summary of main results

In the present study, NSAIDs, NSAIDs + isosorbide dinitrate, somatostatin analogues, and aggressive hydration with lactate ringer were the pharmacological strategies that prevented post-ERCP pancreatitis when compared to placebo. None of these methods were superior to each other. There were no significant associations for antibiotics, allopurinol, the combined use of somatostatin and NSAIDs, beta-carotenes, corticosteroids, nifedipine, heparin, regular hydration with lactate ringer, udenafil aceclofenac, glyceryl trinitrate, risperidone, and unilastatin-risperidone.

4.2. Comparison with the literature

Previous systematic reviews evaluated endoscopic interventions in addition to pharmacological ones. Akshintala et al. [85] evaluated 16 pharmacological interventions. They concluded that topical epinephrine administered endoscopically and NSAIDs administered rectally were effective agents in preventing post-ERCP pancreatitis. In our study, we decided to exclude topically administered epinephrine as a pharmacological strategy, as well as any endoscopic or procedural measure. We considered the above mentioned due to the difficulty of finding the pancreatic papilla and the probability of generating adverse events such as bleeding, pancreatitis, and perforations that could complicate the patient’s clinical status [86].

Furthermore, Akshintala et al. [85] concluded that NSAIDs, regardless of administration route, turned out to be an effective prevention measure for post-ERCP pancreatitis. Like the Akshintala group, Kubillium et al. [87]

In 2015 confirmed that NSAIDs, in general, are appropriate for the prevention of post-ERCP pancreatitis, especially for high-risk cases.

Lyu et al. [88] concluded that gabexate, as a somatostatin analog, is the most effective drug for preventing post-ERCP pancreatitis in a previously published meta-analysis. In this study, NSAIDs, glyceryl trinitrate, and unilastatin also presented protective factors. In our study, glyceryl trinitrate did not confirm its effectiveness.

This meta-analysis confirms what is described by Akshintala et al. [85] and Kubillium et al. [87] on the protective effect conferred by NSAIDs administered before ERCP. NSAIDs have inhibitory properties on phospholipase A2, the cyclooxygenase cascade, and the neutrophil-endothelium interactions and different pathways to reduce the activation of the inflammatory phenomenon, which could justify the positive results found by this study and previous ones [12,89].

Unlike previous studies, this study found that somatostatin inhibitors and other peptides also have a comparable protective effect with NSAIDs and aggressive hydration with lactate ringer. By inhibiting pancreatic enzymes’ secretion, it reduces the risk of increased hydrostatic pressure that, added to that already provided by contrast liquid, generates post-ERCP pancreatitis [77]. Therapy with NSAIDs + isosorbide dinitrate reduces the risk of post-ERCP pancreatitis for a multimodal mechanism.

4.3. Implications for practice

The causes of post-ERCP pancreatitis are not well understood. Multiple theories have been developed in order to explain the cause and the pathophysiological mechanisms by which acute post-ERCP pancreatitis develops, the most important of which consist of the presence of a transient ischemic or inflammatory event caused by various mechanisms, among these, decrease in the mean arterial pressures of patients during the procedure or the presence of mild local insult or increased intraductal pressure by cannulation or injection of contrast into the pancreatic duct [90]. With these premises, various pharmacological and non-pharmacological interventions have been proposed. In this study, the use of isotonic solutions turned out to be a prevention strategy for post-ERCP pancreatitis. Increasing the mean arterial pressure using hydration schemes allows the perfusion of organs and tissues to be improved, reducing the described ischemic event.

From the findings found in this meta-analysis and previously published studies, the need arises to establish pre-surgical preventive protocols, especially in high-risk patients, to reduce the incidence of post-ERCP pancreatitis. The European Society for Gastrointestinal Endoscopy Guide [91] suggests using 100 mg of diclofenac transrectal or indomethacin as first-line preventive management, aggressive hydration with lactate ringer in case of intolerance of NSAIDs, or 5 mg of glyceryl trinitrate in case of contraindication of the previous measures.

4.4. Strengths and limitations

This meta-analysis showed that NSAIDs, aggressive hydration with ringer lactate, therapy with NSAIDs + isosorbide dinitrate, and somatostatin inhibitors and analogs are effective pharmacological strategies to prevent post-ERCP pancreatitis. Since there was no heterogeneity or inconsistency, a network analysis was possible.

This study has some limitations. The first is related to the sample size; not including observational studies could have some impact. On the other hand, unlike controlled clinical trials, observational studies allow information on more variables to be obtained, thus approaching the reality of clinical practice. Although we clarify that randomized clinical trials are the ideal method to evaluate an intervention, but they are difficult to reproduce in clinical practice. Regarding the non-evaluation of non-pharmacological measures, it could influence the sample size, but also, but these are the cause of other adverse events that could alter the outcomes and, therefore, the result of our study. Further prospective studies are required to confirm the effectiveness of these groups of drugs against each other.

5. Conclusion

NSAIDs, the combination of NSAIDs + isosorbide dinitrate, somatostatin analogues, and aggressive hydration with lactate ringer are pharmacological strategies that can prevent post-ERCP pancreatitis when compared to placebo. More clinical trials are required to compare the effectiveness of these groups of drugs with each other.

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.

Appendix 1.

Search strategy

Medline (Ovid):

Choledocholithiasis.mp or Exp Choledocholithiasis or Exp common bile duct neoplasms or exp Cholangiocarcinoma or Cholangiocarcinoma.mp or (Cholangiocellular adj2 Carcinoma).mp or (Cholangiocarcinoma* adj2 Extrahepatic).mp or Exp common bile duct disease or (biliar adj2 stricture*).mp or (biliar adj2 injur*).mp or Exp cholangiopancreatography, endoscopic retrograde or (cholangiopancreatograph* adj2 endoscopic).mp or Cholangiopancreatograph*.mp or ercp.mp or Exp ercp

and/

Exp antibiotic prophylaxis or (prophylaxis adj2 antibiotic*).mp or Exp drug therapy or (drug adj2 therap*).mp or Exp pharmacotherapy or Pharmacotherap*.mp or Exp Anti-Inflammatory Agents, Non-Steroidal or (Anti-Inflammatory adj2 Agent*).mp or Exp nsaids or Nsaids.mp or Exp isotonic solutions or (isotonic adj2 solution*).mp or Exp fluid therapy or (fluid adj2 therap*).mp or Exp hyperhydration status, organism or (Nafamostat adj2 administration).mp or (ketoprofen adj2 administration).mp or exp diclofenac or diclofenac.mp or exp indomethacin or indomethacin.mp or exp naproxen or naproxen.mp

and/

randomized controlled trial.pt or controlled clinical trial.pt or randomized.ab or placebo.ab or randomly.ab or trial.ab or (clinical adj2 trial).mp or (randomi*ed adj2 controlled adj2 trial).mp or exp double-blind method or exp cohort studies or (cohort adj2 stud*).mp or Non-randomized controlled trials as topic or (non-randomized adj2 stud*).mp or (quasi*experiment adj2 stud*).mp

Embase:

‘common bile duct stone’/exp or (common next/2 bile next/2 duct* Stone):ti,ab or ‘bile duct carcinoma’/exp or (bile next/2 duct next/2 carcinoma*):ti,ab or ‘bile duct cancer’/exp or (bile next/2 duct* next/2 cancer):ti,ab or (bile next/2 duct next/2 cancer next/2 Extrahepatic):ti,ab or ‘common bile duct disease’/exp or (common next/2 bile next/2 duct* next/2 disease*):ti,ab (biliar next/2 stricture*):ti,ab or (biliar next/2 injur*):ti,ab or ‘extrahepatic bile duct obstruction’/exp or (extrahepatic next/2 bile next/2 duct* next/2 obstruct*):ti,ab or ‘endoscopic retrograde cholangiopancreatography’/exp or (endoscopic next/2 retrograde next/2 cholangiopancreatograph*):ti,ab or cholangiopancreatography:ti,ab or ercp:ti,ab

and/

‘antibiotic prophylaxis’/exp or (prophylaxis next/2 antibiotic*):ti,ab or ‘drug therapy’/exp or (drug next/2 therap*):ti,ab or ‘prophylaxis’/exp or ‘antiinflammatory agent’/exp or ‘nonsteroid antiinflammatory agent’/exp or (Anti-Inflammatory next/2 Agent*):ti,ab or (nonsteroid next/2 antiinflammatory agent):ti,ab or ‘isotonic solution’/exp or (isotonic Next/2 solution*):ti,ab or ‘fluid therapy’/exp or (fluid next/2 therap*):ti,ab or ‘fluid resuscitation’/exp or ‘nafamstat mesilate’/exp or (nafamstat next/2 administration):ti,ab or (ketoprofen next/2 administration):ti,ab or ‘diclofenac’/exp or diclofenac:ti,ab or ‘indomethacin’/exp or indomethacin:ti,ab or ‘naproxen’/exp or naproxen:ti,ab or ‘Ringer lactate solution’/exp or (infusion fluid next/2 administration):ti,ab or ‘infusion fluid’/exp or ‘sodium chloride’/exp or (sodium chloride next/2 administration):ti,ab

and/

‘randomized controlled trial’/exp or (randomi*ed NEXT/2 controlled NEXT/2 trial):ti,ab or ‘clinical trial’/exp or (clinical NEXT/2 trial):ti,ab or ‘double blind procedure’/exp or ‘cohort analysis’/exp or (cohort next/2 stud*):ti,ab or (quasi*experimental next/2 stud*):ti,ab

Central (through ovid)

Choledocholithiasis.mp or Exp Choledocholithiasis or Exp common bile duct neoplasms or exp Cholangiocarcinoma or Cholangiocarcinoma.mp or (Cholangiocellular adj2 Carcinoma).mp or (Cholangiocarcinoma* adj2 Extrahepatic).mp or Exp common bile duct disease or (biliar adj2 stricture*).mp or (biliar adj2 injur*).mp or Exp cholangiopancreatography, endoscopic retrograde or (cholangiopancreatograph* adj2 endoscopic).mp or Cholangiopancreatograph*.mp or ercp.mp or Exp ercp

and/

Exp antibiotic prophylaxis or (prophylaxis adj2 antibiotic*).mp or Exp drug therapy or (drug adj2 therap*).mp or Exp pharmacotherapy or Pharmacotherap*.mp or Exp Anti-Inflammatory Agents, Non-Steroidal or (Anti-Inflammatory adj2 Agent*).mp or Exp nsaids or Nsaids.mp or Exp isotonic solutions or (isotonic adj2 solution*).mp or Exp fluid therapy or (fluid adj2 therap*).mp or Exp hyperhydration status, organism or (Nafamostat adj2 administration).mp or (ketoprofen adj2 administration).mp or exp diclofenac or diclofenac.mp or exp indomethacin or indomethacin.mp or exp naproxen or naproxen.mp

LILACS

(tw:(mh:” Cholangiopancreatography, Endoscopic Retrograde“)) AND (tw:((mh:Pancreatitis”) NOT (mh:”Pancreatitis, Chronic”))) AND (tw:(tw:”Prophylaxis”)) AND (mh:(ensayo clinico)) OR (tw:(doble ciego)) OR (tw:(experimento clinico)) AND (instance “Regional”)