Accepted Manuscript Submission Date:

2019-12-28
Accepted Date: 2020-06-08
Publication Date: 2020-06-08

Endoscopy
Combination of ERCP and EUS-guided Biliary Drainage versus PTBD for Malig-
nant Hilar Biliary Obstruction: A Multicenter Observational Open-Label Study.
Pradermchai Kongkam, Theerapat Orprayoon, Chaloemphon Boonmee, Passakorn Sodarat, Orathai Seabmuangsai, Chatchawan
Wachiramatharuch, Yutthaya Auan-Klin, Khanh C Pham, Abbas A Tasneem, Stephen J Kerr, Rommel Romano, Sureeporn Jangsirikul,
Wiriyaporn Ridtitid, phonthep Angsuwatcharakon, Thawee Ratanachu-ek, Rungsun Rerknimitr.

Affiliations below.

DOI: 10.1055/a-1195-8197

Please cite this article as: Kongkam P, Orprayoon T, Boonmee C et al. Combination of ERCP and EUS-guided Biliary Drainage versus
PTBD for Malignant Hilar Biliary Obstruction: A Multicenter Observational Open-Label Study. Endoscopy 2020. doi: 10.1055/a-1195-
8197

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript
Conflict of Interest: The authors declare that they have no conflict of interest.

This study was supported by HSRI 62-050 , Health Systems Research Institute (HSRI), Thailand, Pancreas research unit, Faculty of
Medicine, Chulalongkorn University

Trial registration: TCTR20180711004, Thai Clinical Trials Registry (http://www.clinicaltrials.in.th), Multicenter Observational Open-La-
bel Study

Abstract:
Background and aim: ERCP may not provide complete biliary drainage (BD) in patients with Bismuth III and IV malignant hilar
biliary obstruction (MHBO). Complete BD is accomplished by adding percutaneous transhepatic biliary drainage (PTBD). We
prospectively compared recurrent biliary obstruction (RBO) rates between combined ERCP and EUS-BD (either EUS-guided
hepaticogastrostomy or EUS-guided hepatico duodenostomy), versus bilateral PTBD, in MHBO.
Patients and methods: Patients presenting to endoscopy services for MHBO management underwent endoscopic procedures
(Group A), and were compared to those presenting to interventional radiology services who underwent bilateral PTBD (Group
B). Primary outcome was the 3-month RBO rate.
Results: 36 patients were recruited into groups A (n=19) and B (n=17). Overall technical success, clinical success, and compli-
cation rates of group A versus B were 84.2% (16/19) vs 100% (17/17) (p=0.23), 78.9% (15/19) vs 76.5% (13/17) (p=1), and 26.3
(5/19) vs 35.3 (6/17) (p=0.56), respectively. Within 3 and 6 months, RBO rates of group A versus B were 26.7% (4/15) versus
88.2% (15/17), p=0.001, and 22.2% (2/9) versus 100% (9/9), p=0.002, respectively. At 3 months, median number of biliary re-in-
tervention procedures in group A was significantly lower than B (0; IQR 0-1 vs 1; IQR 1-2.5) respectively) (p<0.001). Median
time to development of RBO was longer in group A than B [92 (56-217) vs 40 (13.5-57.8) days, respectively; p=0.06].
Conclusions: A combination of ERCP and EUS procedures provided significantly lower RBO rates at 3 and 6 months compared to
bilateral PTBD, with same complication rate and without a significant mortality difference.

Corresponding Author:
Pradermchai Kongkam, Chulalongkorn University, Medicine, 143/52 On-Nut 17 , 10250 Suan-Luang, Thailand, kongkam@hotmail.com,
pkongkam@gmail.com

Affiliations:
Pradermchai Kongkam, Chulalongkorn University, Medicine, Suan-Luang, Thailand

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service
to our customers we are providing this early version of the manuscript. The manuscript will
undergo copyediting, typesetting, and review of the resulting proof before it is published in its
final form. Please note that during the production process errors may be discovered which could
affect the content, and all legal disclaimers that apply to the journal pertain.
 Theerapat Orprayoon, Chulalongkorn University, Gastrointestinal Endoscopy Excellence Center and Division of Gastroenterology,
Department of Medicine,Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross
Society, Bangkok, Thailand
Chaloemphon Boonmee, Thabo Crown Prince Hospital, Surgery, Nongkhai, Thailand
[…]
Rungsun Rerknimitr, Chulalongkorn University, Gastrointestinal Endoscopy Excellence Center and Division of Gastroenterology, Depart-
ment of Medicine,Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society,
Bangkok, Thailand

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service
to our customers we are providing this early version of the manuscript. The manuscript will
undergo copyediting, typesetting, and review of the resulting proof before it is published in its
final form. Please note that during the production process errors may be discovered which could
affect the content, and all legal disclaimers that apply to the journal pertain.
 Combination of ERCP and EUS-guided Biliary Drainage versus PTBD for Malignant Hilar Biliary
Obstruction: A Multicenter Observational Open-Label Study

Pradermchai Kongkam1,2,3, MD, Theerapat Orprayoon1,3, MD, Chaloemphon Boonmee3,4, MD,

Passakorn Sodarat3,5, MD, Orathai Seabmuangsai3,5, MD, Chatchawan Wachiramatharuch3,5, MD,
Yutthaya Auan-Klin1, MD, Khanh Cong Pham1, MD, Abbas Ali Tasneem1,3, MD, Stephen J Kerr6,
PhD, Rommel Romano1,3, MD, Sureeporn Jangsirikul1,3, MD, Wiriyaporn Ridtitid1,3, MD, Phonthep
Angsuwatcharakon1,3, MD, Thawee Ratanachu-ek3,7, MD, Rungsun Rerknimitr1,3, MD.

Authors’ affiliations
1. Gastrointestinal Endoscopy Excellence Center and Division of Gastroenterology, Department
of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial
Hospital, Thai Red Cross Society, Bangkok, Thailand

Downloaded by: Cornell. Copyrighted material.

2. Pancreas Research Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn
Accepted Manuscript

Accepted Manuscript
University
3. Thai Association for Gastrointestinal Endoscopy (TAGE)
4. ThaBo Crown Prince Hospital, Ministry of Public Health, Thailand
5. Roi-Et Hospital, Ministry of Public Health, Thailand
6. Biostatistics Excellence Centre, Faculty of Medicine, Chulalongkorn University
7. Rajavithi Hospital, Ministry of Public Health, Thailand

Email address:
Pradermchai Kongkam: Kongkam@hotmail.com
Theerapat Orprayoon: platy_pt1301@hotmail.com
Chaloemphon Boonmee: c22boonmee@gmail.com
Passakorn Sodarat: cocosodarat@gmail.com
Orathai Seabmuangsai: sakurako.md29@gmail.com
Chatchawan Wachiramatharuch: chsurgery@gmail.com
Yutthaya Auan-Klin: dr.yutthaya@gmail.com
Khanh Cong Pham: khanh.pc@umc.edu.vn

1
 Abbas Ali Tasneem: draayt@yahoo.com
Stephen J Kerr: stephen.k@hivnat.org
Rommel Romano: ome.romano@gmail.com
Sureeporn Jangsirikul: aomzz23@gmail.com
Wiriyaporn Ridtitid: wiriyaporn_r@yahoo.com
Phonthep Angsuwatcharakon: borndeb@gmail.com
Thawee Ratanachu-ek: thawee1958@gmail.com
Rungsun Rerknimitr: ercp@live.com

Study Funding
Pancreas research unit, Faculty of Medicine, Chulalongkorn University

Downloaded by: Cornell. Copyrighted material.

Health Systems Research Institute (HSRI), grant number HSRI 62-050
Accepted Manuscript

Accepted Manuscript
Corresponding Author
Pradermchai Kongkam, M.D.
Gastrointestinal Endoscopy Excellence Center and Pancreas Research Unit, Department of
Medicine, Faculty of Medicine,
Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
1873 Rama 4 Road, Pathumwan, Bangkok, Thailand 10330
Email address: kongkam@hotmail.com Tel: +66-2-256-4356, Fax: +66-2-652-4219

Keywords
Malignant hilar biliary obstruction, Hilar Cholangiocarcinoma, Klatskin's Tumor, Perihilar
Cholangiocarcinoma, Endosonography, Endoscopic Ultrasonography, ERCP, EUS, EUS-guided
biliary drainage (EUS-BD)

2
 Abbreviations
Malignant hilar biliary obstruction (MHBO), biliary drainage (BD), percutaneous transhepatic
biliary drainage (PTBD), EUS-guided biliary drainage (EUS-BD), distal bile duct obstruction
(DBO), self-expandable metal stent (SEMS), EUS-guided hepaticogastrostomy (EUS-HGS) , EUS-
guided hepaticoduodenostomy (EUS-HDS), technical success rate (TSR), clinical success rate
(CSR), recurrent biliary obstruction (RBO), not significant (NS), randomized controlled trials
(RCTs)

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript

3
 Abstract

Background and aim: ERCP may not provide complete biliary drainage (BD) in patients with

Bismuth III and IV malignant hilar biliary obstruction (MHBO). Complete BD is accomplished by

adding percutaneous transhepatic biliary drainage (PTBD). We prospectively compared

recurrent biliary obstruction (RBO) rates between combined ERCP and EUS-BD (either EUS-

guided hepaticogastrostomy or EUS-guided hepatico duodenostomy), versus bilateral PTBD, in

MHBO.

Patients and methods: Patients presenting to endoscopy services for MHBO management

underwent endoscopic procedures (Group A), and were compared to those presenting to

Downloaded by: Cornell. Copyrighted material.

interventional radiology services who underwent bilateral PTBD (Group B). Primary outcome
Accepted Manuscript

Accepted Manuscript
was the 3-month RBO rate.

Results: 36 patients were recruited into groups A (n=19) and B (n=17). Overall technical success,

clinical success, and complication rates of group A versus B were 84.2% (16/19) vs 100% (17/17)

(p=0.23), 78.9% (15/19) vs 76.5% (13/17) (p=1), and 26.3 (5/19) vs 35.3 (6/17) (p=0.56),

respectively. Within 3 and 6 months, RBO rates of group A versus B were 26.7% (4/15) versus

88.2% (15/17), p=0.001, and 22.2% (2/9) versus 100% (9/9), p=0.002, respectively. At 3 months,

median number of biliary re-intervention procedures in group A was significantly lower than B

(0; IQR 0-1 vs 1; IQR 1-2.5) respectively) (p<0.001). Median time to development of RBO was

longer in group A than B [92 (56-217) vs 40 (13.5-57.8) days, respectively; p=0.06].

Conclusions: A combination of ERCP and EUS procedures provided significantly lower RBO rates

at 3 and 6 months compared to bilateral PTBD, with same complication rate and without a

significant mortality difference.

4
 INTRODUCTION

Current palliative biliary drainage methods for patients with Bismuth Corlette class III, IV or

more advanced malignant hilar biliary obstruction (MHBO) are not perfect. An ideal procedure

would be minimally invasive with internal placement, and offer adequate biliary drainage (BD),

defined as draining >50% of liver volume [1]. Unfortunately, currently available procedures

cannot meet these needs. Surgical bypass is relatively invasive for patients such as these, who

typically have short survival times. ERCP with multi-segmental drainage is technically difficult

Downloaded by: Cornell. Copyrighted material.

due to the tightness of stricture and selective intrahepatic duct cannulation is also challenging
Accepted Manuscript

Accepted Manuscript
[2]. A recent guideline from European Society of Gastrointestinal Endoscopy (ESGE)

recommended percutaneous transhepatic biliary drainage (PTBD) or a combination of PTBD and

ERCP as palliative BD procedures for Bismuth types III and IV MHBO [3]. However, PTBD is

inconvenient for most patients because of the associated external lines and bags.

EUS-guided biliary drainage (EUS-BD) has been increasingly used worldwide as an alternative

when ERCP is not possible, or fails. Most studies have focused on utilizing EUS-BD in patients

with distal bile duct obstruction (DBO), and information about EUS-BD for patients with MHBO

is limited. Nakai et al recently reported that among 88 patients with MHBO treated with EUS-

BD, the technical success rate (TSR) was 98%, the clinical success rate (CSR) was 77%, and the

complication rate was 8% [4]. EUS-BD was performed as either a primary BD method, or a

rescue method for failed ERCP. Given the lower CSR and higher complication rate of EUS-BD in

5
 MHBO compared to ERCP, it still should not be considered as the first choice for palliative

endoscopic BD.[5]

Since ERCP with stent placement is simpler for drainage of single rather than multiple

segments, we hypothesized that combining ERCP and EUS-BD procedures as a primary BD

procedure in patients with MHBO would ensure more complete emptying of the undrained

segments. Transmural EUS-BD including EUS-guided hepaticogastrostomy and EUS-guided

hepaticoduodenostomy can be performed following ERCP with biliary stenting in right and left

intrahepatic bile duct, respectively, in order to accomplish adequate internal BD for MHBO.[5]

Downloaded by: Cornell. Copyrighted material.

As ESGE has recommended PTBD or a combination of PTBD with ERCP as the procedure of
Accepted Manuscript

Accepted Manuscript
choice for BD in patients with MHBO, our team aimed to compare the benefits and harms of BD

using a combination of ERCP and EUS-guided biliary drainage procedures against a historical

control group treated with PTBD, as a primary BD method in this prospective cohort study.

METHODS

Patients

Patients included in the study were those with native high grade-MHBO defined as Bismuth

Corlette class III, IV or more advanced MHBO, small or trivial malignant hilar liver mass causing

MHBO with radiological image showing viable liver parenchyma > 80% of liver volume, ECOG

score ≤2 (capable of all self-care but unable to carry out any work activities, up and about >50%

of waking hours) [6], expected survival of more than 3 months, aged between 18-80 years with

6
 unresectable tumor. Exclusion criteria were patients with uncorrectable coagulopathy,

pregnant women, patients with large volume ascites [7], known benign hilar biliary obstruction,

IgG4-mediated cholangiopathy, and inability or unwillingness to follow the study protocol.

Patients meeting the inclusion criteria and presenting in any of the three tertiary care hospitals

of Thailand (King Chulalongkorn Memorial Hospital, Bangkok, Tha-Bo Crown Prince Hospital,

Nong Khai and Roi-Et Hospital, Roi-Et) were identified and enrolled into the study between

March 2016 and October 2019. The study was conducted under the administration of the Thai

Association for Gastrointestinal Endoscopy (TAGE). These patients presenting to endoscopy

Downloaded by: Cornell. Copyrighted material.

services for primary BD management who received endoscopic BD were classified as group A .
Accepted Manuscript

Accepted Manuscript
We retrospectively reviewed the database of patients with Bismuth Corlette class III, IV or more

advanced MHBO who underwent bilateral PTBD in interventional radiology service from 2015

to 2019 at King Chulalongkorn Memorial Hospital, Bangkok and enrolled these patients

consecutively as historical PTBD controls with no exclusions (Group B)). Since all group A

patients were Bismuth Corlette stage IV, we selected controls who matched the staging of the

group A, namely those with Bismuth Corlette stage IV MHBO who underwent bilateral PTBD for

biliary drainage; Bismuth Corlette stage IV MHBO patients who underwent unilateral PTBD only,

were not eligible.

The protocol was approved by the Institutional Review Board of Faculty of Medicine,

Chulalongkorn University, Bangkok, Thailand. Funding was obtained from the Pancreas

Research Unit, Chulalongkorn University and Health Systems Research Institute (HSRI), grant

number HSRI 62-050. The study was registered at Thai Clinical Trials Registry

(http://www.clinicaltrials.in.th) with clinical trial number TCTR20180711004.

7
 Selection of drainage methods

In group A patients; CT or MRI was reviewed before endoscopic biliary drainage. Details about

the choice of the procedure performed are as follows.

For MHBO caused by biliary stricture alone or a small mass in the bile hilum with both lobes of

the liver functioning (Figure 1A), ERCP with a single self-expandable metal stent (SEMS) placed

into right intrahepatic bile duct (IHD) was done. EUS-guided hepaticogastrostomy (EUS-HGS)

was subsequently performed to achieve adequate BD, either in the same session or within 2

weeks after the initial ERCP procedure (Figure 1B).

Downloaded by: Cornell. Copyrighted material.

However, if the SEMS of ERCP was placed into left IHD, EUS- guided hepaticoduodenostomy
Accepted Manuscript

Accepted Manuscript
(EUS-HDS) was then performed (Figure 1C). If ERCP plus single EUS-BD (EUS-HGS or EUS-HDS

procedure) still could not drain bile fluid sufficiently, (i.e.; persistent bile duct dilation of

intrahepatic bile duct of posterior segment of right lobe of liver with clinical symptoms of

localized cholangitis), then an additional EUS-BD procedure was added to accomplish adequate

BD (Figure 1D).

Endoscopic techniques

ERCP and biliary stenting

The duodenoscope was passed into the second part of duodenum. The bile duct was

cannulated and opacification over hilar biliary stricture area was achieved using retrograde

contrast injection. The guidewire was passed across and beyond the stricture. A non-covered

8
 biliary SEMS (10-12 cm in length, 10 mm in diameter) was placed into either the right or left

biliary system.

EUS-guided Hepaticogastrostomy (EUS-HGS)

A linear echoendoscope was introduced into the stomach, and the dilated intrahepatic bile

ducts in the left lobe were endosonographically identified. A 19-gauge needle for EUS-guided

fine needle aspiration was inserted into either a biliary segment 3 or 2 duct, taking care to avoid

puncturing blood vessels. The segment without liver mass was the first choice, however, if

there is no tumor involvement in both segment 2 and 3, segment 3 is preferable to avoid

Downloaded by: Cornell. Copyrighted material.

unnecessary transesophageal puncture. Aspiration of bile and injection of contrast was then
Accepted Manuscript

Accepted Manuscript
performed to confirm that the needle was in the bile duct. Thereafter, dilatation of the

punctured tract was achieved by passing a guidewire into the bile duct and dilating a 6-Fr

cystotome followed by a bougie dilator (Soehendra dilator, Wilson-Cook), or a 4-8mm balloon

dilator (Hurricane; Boston Scientific Japan). A hybrid metal stent, 100-120 mm in length

(partially covered with the Anti-migration flared end on gastric site: Taewoong, Korea) was

deployed at the punctured tract, bridging the intrahepatic bile duct and the stomach. The

hybrid stent has a long-covered portion (70%) to prevent bile leakage between the left

intrahepatic duct and the stomach, and a bare portion (30%) at the other end to avoid blockage

of the side branch in the hepatic duct, and prevent migration into the hepatic duct. The anti-

migration flared end was placed out of the stomach wall to prevent migration into the left

intrahepatic duct.

EUS-guided Hepaticoduodenostomy

9
 A linear echoendoscope was introduced into the duodenal bulb and the dilated intrahepatic

bile ducts in the right lobe were identified. A 19-gauge needle for EUS-guided fine needle

aspiration was inserted into the dilated right intrahepatic duct taking care to avoid puncturing

blood vessels. The same procedure was then followed as in cases of hepaticogastrostomy.

Finally, a fully covered SEMS of 6-8 cm in length was deployed at the punctured tract, bridging

the intrahepatic bile duct and the duodenum.

Percutaneous transhepatic biliary drainage (PTBD)

In this current study, PTBD meant only external catheter drainage. The usual size of catheter

Downloaded by: Cornell. Copyrighted material.

was 8 French in diameter. Catheters were exchanged when patients developed RBO symptoms.
Accepted Manuscript

Accepted Manuscript
Sedation

Patients were in supine position for ERCP and EUS procedures. At King Chulalongkorn Memorial

hospital, conscious sedation with propofol was used; in other hospitals sedated patients with

general anesthesia, according to their usual protocols.

Definition of events and outcomes

Malignant hilar biliary obstruction (MHBO) was classified according to the Bismuth Corlette

classification. Adequate BD was defined as drainage of >50% of liver volume according to a

recent consensus [1]. Our primary study outcome was the 3-month biliary reintervention rate

after adequate biliary drainage was achieved by BD procedure. Secondary outcomes were time

to recurrent biliary obstruction (RBO), TSR, CSR, and complication rates.

10
 Procedure related terminology for this current study modified the definitions set by the Tokyo

Criteria for transpapillary stenting by ERCP [8]. Technical success rate (TSR) was defined as the

rate of successful deployment of stent in the desired position. EUS-HGS technical success was

defined as transgastric and transhepatic deployment of the metal stent into the left IHD. EUS-

HDS technical success was defined as transduodenal and transhepatic deployment of the metal

stent into the right IHD. ERCP technical success was transpapillary deployment of the metal

stent into either the right or left IHD. Clinical success (CSR) was defined as a 50% reduction in

bilirubin level within 2 weeks of the intervention without additional biliary drainage.[9] RBO

was development of jaundice, cholangitis and increased bilirubin secondary to obstruction or

Downloaded by: Cornell. Copyrighted material.

stent migration. Biliary re-intervention was any endoscopic, percutaneous or surgical procedure
Accepted Manuscript

Accepted Manuscript
performed to improve biliary drainage after EUS/ERCP completion. Biliary re-intervention was

an on-demand: stents and catheters were exchanged only when patients developed RBO

symptoms. Time to RBO was the time successful BD to biliary re-intervention. Follow-up time

was the date of drainage procedure to last follow-up.

Sample size and statistical methods

Sample size calculations were based on the primary study outcome. We assumed 3 month re-

intervention rates of 16% versus 60% in our EUS-BD versus PTBD groups [10,11]. Based on

these percentages, 16 patients per group would provide 75% power to detect these differences

at a 2-sided significance level of 5%. This was inflated this to 19 per group to compensate for

possible losses to follow-up.

11
 Demographic characteristics were summarized by group. TSR and CRS were formally compared

between groups using Fisher’s exact test. The Kaplan-Meier method was used to calculate

survival probabilities in patients who achieved technical success: the survival function was

formally compared with using a log-rank test. Statistical analysis was conducted using Stata

15.1 (Statacorp, College Station, TX, USA). No adjustments were made for potential prognostic

confounders, because disease staging and severity were comparable between groups.

Adverse events

Downloaded by: Cornell. Copyrighted material.

Adverse event severity was classified according to the American Society for Gastrointestinal
Accepted Manuscript

Accepted Manuscript
Endoscopy lexicon to grade and describe adverse events [12].

Follow-up period

All patients were admitted overnight after the procedure for close observation of possible post-

procedure complications, and researchers were notified of any adverse events. Serum total

bilirubin was tested 2-4 weeks after the BD procedure to assess clinical success. If any clinical

symptoms, signs or blood tests indicated inadequate BD, procedure related adverse events, or

RBO, patients were fully evaluated for management of such events. All recruited patients were

followed up with physicians who provided subsequent health care to them. Group A patients

were followed up by the endoscopist and interventionist who performed the biliary

intervention, respectively, up to 6 months

12
 RESULTS

Thirty-eight patients were eligible in both groups, however, 2 from group A were excluded due

to large volume of ascites (n=1) and an ECOG score too poor to allow endoscopic treatment

(n=1). Study flow is shown in Figure 2. Thirty-six patients (24 males, 12 females) were recruited

into our study. Group A, n=19, enrolled patients from March 2016 to August 2019. Controls

(Group B, n=17) had PTBD performed between July 2015 and March 2019. Mean (SD) age of

group A and B patients were 62 (10) versus 58.8 (12.8) years, respectively. Male to female ratio

Downloaded by: Cornell. Copyrighted material.

was 13:6 versus 11:6 in group A and B, respectively. Baseline characteristics including total
Accepted Manuscript

Accepted Manuscript
serum bilirubin were comparable between groups (Table 1).

In group A, the following endoscopic procedures were provided to patients: EUS-HGS plus ERCP

(n=17), EUS-HDS plus ERCP (n=1) and EUS-HGS plus EUS-HDS plus ERCP (n=1). TSR and CSR in

this group were 84.2% (16/19) and 78.9% (15/19), respectively. ERCP and EUS-BD were

performed during the same session in 7 cases (36.8%) and performed separately in 12 cases

(63.2%). For the 12 cases with different sessions, all cases started with ERCP and EUS-BD was

subsequently performed within 2 weeks. Median ERCP and EUS-BD procedure time in group A

were 62.5 minutes (range 23-98), and 33.5 min (range 29-60), respectively. Operators

performing endoscopic procedures had performed > 500 ERCP and/or EUS procedures.

In group B (PTBD group), all the patients had bilateral PTBD tubes. TSR, CSR, and complication

rates (CR) of group A versus B were 84.2% (16/19) vs 100% (17/17) (p=0.23), 78.9% (15/19) vs

76.5% (13/17) (p=1.0), and 26.3 (5/19) vs 35.5 (6/17) (p= 0.56), respectively (Table 2).

13
 In technical success patients who were alive up to 3 months, and from 3 - 6 months, the RBO

rates of group A versus B were 26.7% (4/15) versus 88.2% (15/17), p=0.001, and 22.2% (2/9)

versus 100% (9/9), p=0.002, respectively. At 3 months, the median number of biliary re-

intervention procedures in group A was significantly lower than group B (0; IQR 0-1 vs 1; IQR 1-

2.5) respectively) (p = 0.001). After 6 months the median number of biliary re-intervention

procedures in group A was the same as observed at 3 months, and the median number in group

B was 2; IQR 1-3.5 (p<0.001). Group A had a significantly longer median time to development of

RBO than group B [92 (56-217) vs 40 (13.5-57.8) days, respectively; p=0.06]; (Table 2).

Cumulative biliary re-intervention rate until patients’ death or last follow-up in group A versus B

Downloaded by: Cornell. Copyrighted material.

were 6/16 (37.5%) versus 15/17 (88.2%) (p=0.004), respectively. Number of biliary re-
Accepted Manuscript

Accepted Manuscript
intervention procedures per person until a patients’ death or last follow-up in group A versus B

were 0.5 (0-1) versus 4 (2-5) (p=0.003), respectively (Table 2).

Details of group A patients with RBO within 3 months were tumor ingrowth in the first ERCP

stent corrected with a second stent insertion (n=2); tumor ingrowth in an ERCP stent treated

with PTBD (n=1); localized cholangitis from bile duct obstruction in segment 3 corrected with

PTBD (n=1: preexisting HGS stent was in segment 2); and food debris in the HGS stent treated

with balloon extraction through the HGS stent (n=1). Another group A patient with RBO after 3

and before 6 months had tumor outgrowth in the HGS stent and was treated with PTBD (n=1).

In technical success patients, overall survival between arms was not significantly different (log

rank P = 0.19, figure S1). The 25th percentile and median survival were 2.2 and 5 months in the

group A versus 4.4 and 7.8 months in the PTBD group. Mortality rates for patients who had

reached two years of follow-up were 16/16 (100%) in group A, and 16/17 (94.1%) in group B.

14
 Table 3 describes procedure related adverse events. In group A, there were 4 patients with mild

and one patient with a moderate grade adverse event; in group B, there were 2 severe and one

moderate grade complications. All responded to treatment; no statistically significant

differences in procedure related complications between groups were noted.

In 3 cases where endoscopic procedures failed, details were as follows. In the first case, we

failed to pass a mechanical dilator (Soehenda dilator, 8.5 Fr) across the gastric wall into the

liver. PTBD with external drainage was consequently used and total bilirubin level decreased

back to within normal range. In the second case, we failed to place a self-expandable metal

Downloaded by: Cornell. Copyrighted material.

stent into right intrahepatic bile duct. PTBD with antegrade metal stent placement was
Accepted Manuscript

Accepted Manuscript
consequently successfully performed. In the third case, we failed to dilate the punctured tract

of EUS-HGS with cystotome 6Fr, so aborted the procedure. PTBD with external drainage was

used to salvage the procedure. No procedure related complications were observed in these 3

cases.

DISCUSSION

Our current study found a highly significantly lower risk of biliary reintervention procedures

with consequent lower morbidity, in patients treated with combining ERCP and EUS-BD

procedures versus those treated with PTBD. In the first 3 months when the majority of patient

were still alive, the cumulative rate of biliary re-intervention in the endoscopy group was

significantly lower than in the PTBD group. Moreover, endoscopic procedures had a lower

median number of biliary re-intervention procedures at both 3 and 6 months, plus a longer

time to RBO despite no survival difference. This information favors endoscopy over PTBD for

15
 long-term care of MHBO, predominantly because endoscopy provides larger diameter of

drainage tube than PTBD. For ERCP, 2 RCTs have shown SEMS have longer patency time than

plastic stents [13,14]; confirmed by our group for BD in MHBO in 2 other clinical trials [15,16].

ESGE guidelines now recommend PTBD, or a combination of PTBD and ERCP should be

considered as palliative BD procedures for Bismuth types III and IV MHBO [3], to achieve

adequate liver volume drainage, since ERCP alone with multi-segmental BD is technically

challenging due to stricture tightness [1,2]. Nevertheless, external drainage by PTBD adversely

affects quality of life, because of external lines and bags, and pain, particularly in the days

Downloaded by: Cornell. Copyrighted material.

following the procedure. ERCP with SEMS is, therefore, practically preferred over PTBD [17]. In
Accepted Manuscript

Accepted Manuscript
a systematic review, ERCP with multi-segmental drainage in MHBO had lower rate of successful

BD than PTBD [17]. However, the latter was inconvenient in terms of maintenance, making

EUS-BD an interesting alternative in achieving adequate and complete BD for patients with

MHBO. Despite this, there are limited data supporting the use of EUS-BD in MHBO. A recent

review reported that only 88 patients from 11 published studies underwent EUS-BD in MHBO,

and only 4 studies had ≥10 patients. These 4 studies employed EUS-BD alone for MHBO as an

initial or rescue BD procedure. Moreover, some patients in these studies were Bismuth I and II

MHBO, conditions which do not require multiple stents for adequate and complete BD. In our

opinion, ERCP with multi-segmental drainage should still be the first choice as the SEMS

placement involves passage through a natural orifice, not a transmural route as in EUS. EUS-BD

should be used as a rescue method, or combined to achieve adequate and complete BD in

MHBO. We, therefore, decided to initiate the current study to evaluate results of a combination

of ERCP and EUS-BD procedures in patients with Bismuth III and IV MHBO (Figure 3).

16
 EUS-BD is an emerging endoscopic BD procedure predominantly used for DBO drainage.

Current indications for EUS-BD include failed ERCP in experienced hands, inaccessible major

papilla, surgically altered anatomy, conversion of PTBD to EUS-BD, and as a primary BD method

as recently reported [18]. A recent systematic review and meta-analysis of 9 studies with 483

patients comparing EUS-BD versus PTBD in DBO, concluded there was no difference in TSR

between these procedures, but EUS-BD was associated with better clinical success, fewer post-

procedure adverse events, and lower re-intervention rates [19]. Regarding biliary drainage in

MHBO, a systematic review of nine studies (N = 546) compared ERCP versus PTBD for BD in

MHBO, and found the pooled odds ratio for successful BD in PTBD versus EBD was 2.53 (95% CI

Downloaded by: Cornell. Copyrighted material.

= 1.57 to 4.08) whereas PTBD was comparable to ERCP in regard to overall adverse effects and
Accepted Manuscript

Accepted Manuscript
30-day mortality [17]. To the best of our knowledge, no study thus far, has compared EUS-BD

versus PTBD in MHBO. Results from our current study show that a combination of ERCP and

EUS-BD in MHBO had comparable TSR, CSR, and complication rates compared to PTBD. This

point is very interesting, as when ERCP was combined with EUS and used for MHBO BD, the

success rate was comparable with PTBD. Given these improvements in providing internal

drainage, longer RBO time and lower RBO rate, the combination of ERCP and EUS-BD

procedures may become the BD method of choice, in patients with Bismuth III and IV MHBO in

the future.

One important limitation of our study comes from its observational nature. Patients recruited

to group B were historical controls, so the possibility of bias exists. In future studies,

randomizing patients to receive either a combination of ERCP and EUS-BD procedures or PTBD,

will allow evaluation of clinical outcomes with less bias.

17
 In patients whose liver function is well preserved, 33% of liver volume should be drained for

adequate BD, however, 50% should be drained if the liver function is impaired [20,21]. To

accomplish adequate BD in MHBO, multi-segmental BD is required. A recent RCT showed

superiority of bilateral over unilateral SEMS in MHBO. The former had longer stent patency

time than the latter (252 days vs. 139 days, p<0.01) [22]. However, conventional ERCP with

bilateral SEMS is technically challenging with reported TSR ranging from 71% to 95.5% [22,23].

Results of this current study show the combination of ERCP and EUS-BD procedures has a high

TSR and satisfactory biliary re-intervention rate. Therefore, a combination of ERCP and EUS-BD

procedures is another potential alternative for BD in MHBO, not only PTBD or PTBD plus ERCP

Downloaded by: Cornell. Copyrighted material.

as previously recommended. A study on ERCP with multi-segmental drainage versus a
Accepted Manuscript

Accepted Manuscript
combination of ERCP and EUS-BD procedures is warranted.

18
 References

1. Rerknimitr R, Angsuwatcharakon P, Ratanachu-ek T et al. Asia-Pacific consensus

recommendations for endoscopic and interventional management of hilar
cholangiocarcinoma. J Gastroenterol Hepatol 2013; 28: 593-607
2. Puli SR, Kalva N, Pamulaparthy SR et al. Bilateral and unilateral stenting for malignant
hilar obstruction: a systematic review and meta-analysis. Indian J Gastroenterol 2013;
32: 355-362
3. Dumonceau JM, Tringali A, Papanikolaou IS et al. Endoscopic biliary stenting:
indications, choice of stents, and results: European Society of Gastrointestinal
Endoscopy (ESGE) Clinical Guideline - Updated October 2017. Endoscopy 2018; 50:
910-930
4. Nakai Y, Kogure H, Isayama H et al. Endoscopic Ultrasound-Guided Biliary Drainage for
Unresectable Hilar Malignant Biliary Obstruction. Clin Endosc 2019; 52: 220-225
5. Kongkam P, Tasneem AA, Rerknimitr R. Combination of endoscopic retrograde
cholangiopancreatography and endoscopic ultrasonography-guided biliary drainage in
malignant hilar biliary obstruction. Dig Endosc 2019; 31 Suppl 1: 50-54
6. Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the Eastern
Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655

Downloaded by: Cornell. Copyrighted material.

7. Moore KP, Wong F, Gines P et al. The management of ascites in cirrhosis: report on the
consensus conference of the International Ascites Club. Hepatology 2003; 38: 258-266
Accepted Manuscript

Accepted Manuscript
8. Isayama H, Hamada T, Yasuda I et al. TOKYO criteria 2014 for transpapillary biliary
stenting. Dig Endosc 2015; 27: 259-264
9. Khashab MA, Van der Merwe S, Kunda R et al. Prospective international multicenter
study on endoscopic ultrasound-guided biliary drainage for patients with malignant distal
biliary obstruction after failed endoscopic retrograde cholangiopancreatography. Endosc
Int Open 2016; 4: E487-496
10. Bill JG, Darcy M, Fujii-Lau LL et al. A comparison between endoscopic ultrasound-
guided rendezvous and percutaneous biliary drainage after failed ERCP for malignant
distal biliary obstruction. Endosc Int Open 2016; 4: E980-985
11. Sharaiha RZ, Kumta NA, Desai AP et al. Endoscopic ultrasound-guided biliary drainage
versus percutaneous transhepatic biliary drainage: predictors of successful outcome in
patients who fail endoscopic retrograde cholangiopancreatography. Surg Endosc 2016;
30: 5500-5505
12. Cotton PB, Eisen GM, Aabakken L et al. A lexicon for endoscopic adverse events: report
of an ASGE workshop. Gastrointest Endosc 2010; 71: 446-454
13. Mukai T, Yasuda I, Nakashima M et al. Metallic stents are more efficacious than plastic
stents in unresectable malignant hilar biliary strictures: a randomized controlled trial. J
Hepatobiliary Pancreat Sci 2013; 20: 214-222
14. Sangchan A, Kongkasame W, Pugkhem A et al. Efficacy of metal and plastic stents in
unresectable complex hilar cholangiocarcinoma: a randomized controlled trial.
Gastrointest Endosc 2012; 76: 93-99
15. Rerknimitr R, Kladcharoen N, Mahachai V et al. Result of endoscopic biliary drainage in
hilar cholangiocarcinoma. J Clin Gastroenterol 2004; 38: 518-523
16. Rerknimitr R, Kongkam P, Kullavanijaya P. Outcome of self-expandable metallic stents
in low-grade versus advanced hilar obstruction. J Gastroenterol Hepatol 2008; 23: 1695-
1701
17. Moole H, Dharmapuri S, Duvvuri A et al. Endoscopic versus Percutaneous Biliary
Drainage in Palliation of Advanced Malignant Hilar Obstruction: A Meta-Analysis and
Systematic Review. Can J Gastroenterol Hepatol 2016; 2016: 4726078

19
 18. Baars JE, Kaffes AJ, Saxena P. EUS-guided biliary drainage: A comprehensive review
of the literature. Endosc Ultrasound 2018; 7: 4-9
19. Sharaiha RZ, Khan MA, Kamal F et al. Efficacy and safety of EUS-guided biliary
drainage in comparison with percutaneous biliary drainage when ERCP fails: a
systematic review and meta-analysis. Gastrointest Endosc 2017; 85: 904-914
20. Takahashi E, Fukasawa M, Sato T et al. Biliary drainage strategy of unresectable
malignant hilar strictures by computed tomography volumetry. World J Gastroenterol
2015; 21: 4946-4953
21. Vienne A, Hobeika E, Gouya H et al. Prediction of drainage effectiveness during
endoscopic stenting of malignant hilar strictures: the role of liver volume assessment.
Gastrointest Endosc 2010; 72: 728-735
22. Lee TH, Kim TH, Moon JH et al. Bilateral versus unilateral placement of metal stents for
inoperable high-grade malignant hilar biliary strictures: a multicenter, prospective,
randomized study (with video). Gastrointest Endosc 2017; 86: 817-827
23. Inoue T, Ishii N, Kobayashi Y et al. Simultaneous Versus Sequential Side-by-Side
Bilateral Metal Stent Placement for Malignant Hilar Biliary Obstructions. Dig Dis Sci
2017; 62: 2542-2549

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript

20
 Listing of Tables
Table 1: Baseline characteristics of group of patients whom underwent combination of ERCP
and EUS-guided biliary drainage versus CERES and PTBD patients for malignant hilar biliary
obstruction (Abbreviation: CERES=combination of ERCP and EUS-guided biliary drainage,
PTBD=percutaneous biliary drainage)
Table 2: Comparison of results of the combination of ERCP and EUS-guided biliary drainage
procedures versus PTBD in patients with malignant hilar biliary obstruction (Abbreviation:
CERES=combination of ERCP and EUS-guided biliary drainage, PTBD=percutaneous biliary
drainage, RBO=recurrent biliary obstruction)
Table 3: This table demonstrated types, grading, length of stay, and management of
complications of endoscopic and PTBD treatment in patients with malignant hilar biliary
obstruction. (Abbreviation: CERES=combination of ERCP and EUS-guided biliary drainage,
PTBD=percutaneous biliary drainage)

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript

21
 Listing of Figures
Figure 1: These illustrations demonstrate the methods used for applying a combination of
endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound-guided
biliary drainage (EUS-BD), in patients with malignant hilar biliary obstruction (MHBO). Figure 1A
shows a hilar tumor causing MHBO, with an upstream dilated intrahepatic bile duct (IHD).
Figure 1B shows ERCP with stent placement into the right IHD system plus EUS-guided
hepaticogastrostomy. Figure 1C shows ERCP with stent placement into left IHD system plus
EUS-guided hepaticoduodenostomy. Figure 1D shows ERCP with failed stent placement across
the obstructed area; both EUS-guided hepaticogastrostomy and EUS-guided
hepaticoduodenostomy are then performed to accomplish BD.
Figure 2: Study flow diagram for patients undergoing combination of ERCP and EUS-guided
biliary drainage (Group A) and PTBD (Group B) procedures for management of MBHO.
(Abbreviations: CERES = combination of endoscopic retrograde cholangiopancreatography
(ERCP) and endoscopic ultrasound-guided biliary drainage (EUS-BD), PTBD = percutaneous
biliary drainage, MHBO=malignant hilar biliary obstruction, HGS = hepaticogastrostomy, HDS =

Downloaded by: Cornell. Copyrighted material.

hepaticoduodenostomy).
Accepted Manuscript

Accepted Manuscript
Figure 3: Figure 3A shows CT abdomen of a patient with malignant hilar biliary obstruction.
Figure 3B demonstrates 2 percutaneous transhepatic biliary drainage catheters from right and
left lobes of the liver. Figure 3C demonstrates a hybrid metal stent (partially covered with the
Anti-migration flared end on gastric site: GIOBORTM Biliary stent, Taewoong, Korea) connecting
left intrahepatic bile duct (segment 3) to the gastric lumen. Figure 3D shows an uncovered self-
expandable biliary metal stent draining bile fluid from the right intrahepatic bile duct to the
duodenum.
Figure 4: Figure 4A demonstrates a linear echoendoscope deploying an 80-mm covered self-
expandable metal stent (10 mm in diameter) during an EUS-guided Hepatico-duodenostomy
procedure (EUS-HDS). Figure 4B shows the stent successfully connected the right intrahepatic
bile duct to the duodenum.
Figure S1: Kaplan-Meier curve showing survival probabilities, between group A (combination of
ERCP and EUS-guided biliary drainage) and B (PTBD) patients who achieved technical success.

22
 Table 1: Baseline characteristics of group of patients whom underwent combination of ERCP
and EUS-guided biliary drainage versus PTBD for malignant hilar biliary obstruction
(Abbreviation: CERES=combination of ERCP and EUS-guided biliary drainage,
PTBD=percutaneous biliary drainage)

Characteristic CERES PTBD

group group
(n=19) (n=17)

Age; years (mean+SD) 62 + 10 58.8 +

12.8

Gender

Downloaded by: Cornell. Copyrighted material.

Male, n (%) 13 (68) 11 (65)
Accepted Manuscript

Accepted Manuscript
Female, n (%) 6 (32) 6 (35)

Total bilirubin; mg/dL (mean + SD) 17.1 + 9.7 19.3 + 8.3

Direct bilirubin; mg/dL (mean + SD) 15.4+ 7.7 9.8 + 6.2

Alkaline phosphatase; IU/L (mean + SD) 437.2 + 484.1 +

228.3 334.8

Diagnosis, n (%)

 Cholangiocarcinoma 16 (84.2) 17 (100)

 Gallbladder cancer 2 (10.5) 0

 Metastasis from colon cancer 1 (5.3) 0

23
 Table 2: Comparison of results of the combination of ERCP and EUS-guided biliary drainage
procedures versus PTBD in patients with malignant hilar biliary obstruction (Abbreviation:
CERES=combination of ERCP and EUS-guided biliary drainage, PTBD=percutaneous biliary
drainage, RBO=recurrent biliary obstruction)

Parameter CERES group PTBD group p value

(n=19) (n=17)

Technical success rate; n (%) 16 (84.2) 17 (100) 0.23

Clinical success rate; n (%) 15 (78.9) 13 (76.5) 1.00

Biliary re-intervention

RBO within 3 months; n (%) 4/15 (26.7)* 15/17 (88.2) 0.001

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript
RBO within 6 months; n (%) 2/9 (22.2)# 9/9 (100) 0.002

Cumulative biliary reintervention 6/16 (37.5)** 15/17 (88.2) 0.002

rate in technical success
patients, until death or last
follow-up, n (%)

Number of biliary re- 0 (0-1) 1 (1-2.5) <0.001

intervention procedures per
person at 3 months; median
(IQR)

Number of biliary re- 0 (0-1) 2.5 (1-4) 0.001

intervention procedures per
person at 6 months; median
(IQR)

Cumulative number of biliary re- 0.5 (0-1) 4 (2-5) 0.003

intervention procedures per
person until death or last follow-
up; median (IQR)

Time to recurrent biliary 92 (56-217) 40 (13.5-57.8) 0.06

24
 obstruction; days; median (IQR)

Other outcomes

Complication; n (%) 5 (26.3) 6 (35.3) 0.56

2-year death in technical success 16/16 (100) 16/17 (94.1) 1.00

patients; n (%)

* In the CERES group, 4 patients were excluded from denominator due to technical failure
(n=3), and death within 3 months (n=1).
** In CERES group 3 patients were excluded from denominator due to technical failure
# In CERES group, 10 patients were excluded from denominator due to technical failure (n=3),
and death within 6 months (n=7). In PTBD group, 8 patients were excluded from denominator

Downloaded by: Cornell. Copyrighted material.

due to death within 6 months
Accepted Manuscript

Accepted Manuscript

25
 Table 3: This table demonstrated types, grading, length of stay, and management of
complications of endoscopic and PTBD treatment in patients with malignant hilar biliary
obstruction. (Abbreviation: CERES=combination of ERCP and EUS-guided biliary drainage,
PTBD=percutaneous biliary drainage)

Parameters Group A (CERES) Group B (PTBD)

Rate of complications 26.3% (5/19) 35.3% (6/17)
Type of complications (n) -Symptomatic bile leak (n=1) -Abdominal pain (n=4)
-Bleeding in the liver from -Fever (n=1)
left hepatic artery (n=1) -Liver abscess (n=1)
-Cholangitis (n=2)
-Pancreatitis (n=1)
Gradings and length of stay -Bile leak; mild; 3 days -Abdominal pain; moderate;
-Bleeding; moderate; 4 days 7, 7, 13, and 20 days
-Cholangitis: mild; 2 days -Fever (n=1); severe; 14 days
-Pancreatitis; mild; 2 days -Liver abscess (n=1); severe;
21 day

Downloaded by: Cornell. Copyrighted material.

Management -Angiogram plus -Abdominal pain;
embolization in 1 patient conservative management
Accepted Manuscript

Accepted Manuscript
with bleeding (n=3), revise PTBD 2 times
-Conservative management (n=1)
for the rests -Fever; antibiotics
-Liver abscess; antibiotic and
aspiration x 2 times
Outcomes -Success in all cases -Success in all cases

26
 CERES PROCEDURE (Group A) PTBD PROCEDURE (Group B)

Patients with MBHO presenting Patients with MBHO presenting

to endoscopy service for CERES to interventional radiology
(n=21) service for PTBD (n = 17)

2 cases were excluded: poor ECOG

status (n=1), large volume ascites
(n=1)

CERES PROCEDURES

 HGS+ERCP (n=17)
 HDS+ERCP (n=1)
 HGS+HDS+ERCP (n=1)

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript
Lost to follow-up (n=0) Lost to follow-up (n=0)
Follow-up and
Analysed (n=16) analysis Analysed (n=17)

N=3 excluded from analysis due

to technical failure
 Graphical abstract

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript

Parameters Combination of PTBD (n=17) P value

ERCP and EUS-
 guided biliary
drainage (CERES)
(n=19)

Technical success 84.2% (16/19) 100% (17/17) 0.23

rate

Clinical success rate 78.9% (15/19) 76.5% (13/17) 1.0

Complication rate 26.3% (5/19) 35.3% (6/17) 0.56

Recurrent biliary 26.7% (4/15) 88.2% (15/17) 0.001

obstruction rate within
3 months

Recurrent biliary 22.2% (2/9) 100% (9/9) 0.002

obstruction rate within
6 months

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript
 Supplementary material

Endoscopy

Pradermchai Kongkam et al.

Combination of ERCP and EUS-guided Biliary Drainage versus PTBD for Malignant Hilar
Biliary Obstruction: A Multicenter Observational Open-Label Study.

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript

1
 STROBE Statement—Checklist of items that should be included in reports of cohort studies

Item Page
No Recommendation No
Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the 1
abstract
(b) Provide in the abstract an informative and balanced summary of what was 3,4
done and what was found
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being 4,5,6
reported
Objectives 3 State specific objectives, including any prespecified hypotheses 6
Methods
Study design 4 Present key elements of study design early in the paper 6-13
Setting 5 Describe the setting, locations, and relevant dates, including periods of 13
recruitment, exposure, follow-up, and data collection
Participants 6 (a) Give the eligibility criteria, and the sources and methods of selection of 6, 7,
participants. Describe methods of follow-up 10
(b) For matched studies, give matching criteria and number of exposed and
unexposed

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and 10
effect modifiers. Give diagnostic criteria, if applicable
Data sources/ 8* For each variable of interest, give sources of data and details of methods of 7-11
measurement assessment (measurement). Describe comparability of assessment methods if
there is more than one group
Bias 9 Describe any efforts to address potential sources of bias 7
Study size 10 Explain how the study size was arrived at 11,12
Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, N
describe which groupings were chosen and why
Statistical methods 12 (a) Describe all statistical methods, including those used to control for 11,12
confounding
(b) Describe any methods used to examine subgroups and interactions
(c) Explain how missing data were addressed
(d) If applicable, explain how loss to follow-up was addressed
(e) Describe any sensitivity analyses
Results
Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers 13, 30
potentially eligible, examined for eligibility, confirmed eligible, included in the
study, completing follow-up, and analysed
(b) Give reasons for non-participation at each stage
(c) Consider use of a flow diagram
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) 13,14,
and information on exposures and potential confounders 24,25
(b) Indicate number of participants with missing data for each variable of
interest
(c) Summarise follow-up time (eg, average and total amount)
Outcome data 15* Report numbers of outcome events or summary measures over time 14-
16,
26-28

Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their 13,14,
precision (eg, 95% confidence interval). Make clear which confounders were adjusted for 26,
and why they were included 28, 31

2
 (b) Report category boundaries when continuous variables were categorized
(c) If relevant, consider translating estimates of relative risk into absolute risk for a
meaningful time period
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity N/A
analyses
Discussion
Key results 18 Summarise key results with reference to study objectives 16, 17
Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or
imprecision. Discuss both direction and magnitude of any potential bias
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, 18
multiplicity of analyses, results from similar studies, and other relevant evidence
Generalisabilit 21 Discuss the generalisability (external validity) of the study results 19
y
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if 2
applicable, for the original study on which the present article is based

*Give information separately for exposed and unexposed groups.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological

Downloaded by: Cornell. Copyrighted material.

Accepted Manuscript

Accepted Manuscript
background and published examples of transparent reporting. The STROBE checklist is best used in conjunction
with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of
Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the
STROBE Initiative is available at http://www.strobe-statement.org.

3
 Accepted Manuscript

Accepted Manuscript
Downloaded by: Cornell. Copyrighted material.
 Accepted Manuscript

Accepted Manuscript
Downloaded by: Cornell. Copyrighted material.
 Accepted Manuscript

Accepted Manuscript
Downloaded by: Cornell. Copyrighted material.