Abstract

Graphical abstract

Introduction

Endoscopic retrograde cholangiopancreatography has long been considered the gold standard for palliation in patients with malignant biliary obstruction (MBO), with over 500,000 procedures performed annually in the U.S. alone. ¹ The technical failure of the Endoscopic Retrograde Cholangiopancreatography (ERCP) procedure varies between 5% and 15%. ² Failure is exceptionally high in a subset of patients, such as those with surgically altered anatomy and duodenal obstruction. ³ In case of ERCP failure, percutaneous biliary drainage (PTBD) can be an alternative procedure of choice.

Since first described by Giovannini et al.^4,5 in 2001 and 2003, endoscopic ultrasound-guided (EUS) biliary drainage has been gaining traction over the last decade. A recent meta-analysis suggests that compared to PTBD, EUS-biliary drainage offers better clinical success and fewer adverse events. ⁶ Combined with its higher cost-effectiveness, it is predictable that soon, EUS-biliary drainage can replace PTBD in case of primary ERCP failure or even become an alternative to primary ERCP. ⁷ The umbrella term EUS-biliary drainage consists of different procedures with different bilio-enteric anastomoses such as choledochoduodenostomy, hepaticogastrostomy (HGS), gallbladder drainage, or lack of anastomoses such as the rendezvous and antegrade stenting (AGS) techniques. ⁸ A consensus on when each procedure should be performed has emerged, individual patient anatomy and malignancy play an important role. ⁹

In 2011, Imai et al. ¹⁰ were the first to combine the HGS procedure with AGS (HGAS). The rationale is that the combination can minimize bile leakage that could be caused by each procedure separately while increasing stent patency. The existence of two drainage routes allows the bile to keep draining in the event the HGS is occluded by sludge or debris, as well as in stent dysfunction due to migration. Therefore, the aim of our study was to compare the combined procedure of HGAS versus HGS alone in terms of early outcomes such as clinical and technical success, overall adverse events, re-intervention rates, and explore outcomes such as time to stent dysfunction and overall survival.

Methods

We report our systematic review and meta-analysis based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines (see Supplemental Table S1), while we followed the Cochrane Handbook. The protocol of the study was registered on PROSPERO (CRD42022371848).^11–13

Results

Pooled ORs

Four studies were included for technical success, clinical success, and overall adverse events, and three for re-intervention. Results are summarized in Figure 1.

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Figure 1.

Summary figure for direct comparisons of HGS and HGAS. (a) Technical success. (b) Clinical success. (c) Overall adverse events rates. (d) Re-intervention rates.

CI, confidence interval; HGAS, hepaticogastrostomy with antegrade stent; HGS, hepaticogastrostomy; OR, odds ratio.

Overall, technical success between HGS and HGAS showed an OR=0.38 (CI: 0.07–2.00), p=0.179 (Figure 1(a)). Clinical success showed an OR=1.02 (CI: 0.50–2.06), p=0.944 (Figure 1(b)). The overall adverse events showed an OR=1.09 (CI: 0.30–3.94), p=0.867 (Figure 1(c)). For the re-intervention, comparison of HGS and HGAS showed an OR=0.37 (CI: 0.27–0.52), p=0.006 (Figure 1(d)).

Pooled rates

Pooled technical and clinical success

All 26 studies included information on technical success and a total of 22 studies included information on clinical success. The pooled technical success was 94% (CI: 92%–96%) for HGS and 89% (CI: 83%–93%) for HGAS, p=0.00273 (Figure 2). The pooled clinical success was 88% (CI: 84%–91%) for HGS and 94% (CI: 89%–97%) for HGAS, p=0.0367 (Figure 3).

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Figure 2.

Pooled technical success with (HGAS) and without (HGS) antegrade stenting.

CI, confidence interval; HGS, hepaticogastrostomy; HGAS, hepaticogastrostomy with antegrade stent.

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Figure 3.

Pooled clinical success with (HGAS) and without (HGS) antegrade stenting.

CI, confidence interval; HGS, hepaticogastrostomy; HGAS, hepaticogastrostomy with antegrade stent.

Pooled overall adverse events

Seventeen studies included information on pooled overall adverse events. The pooled adverse events were 20% (CI: 16%–25%) for HGS and 14% (CI: 9%–20%) for HGAS, p=0.0728 (Figure 4).

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Figure 4.

Pooled overall adverse events with (HGAS) and without (HGS) antegrade stenting.

CI, confidence interval; HGAS, hepaticogastrostomy with antegrade stent; HGS, hepaticogastrostomy.

Bile leakage and overall adverse events without pancreatitis prevalence

In the case of HGS, 28 events were observed among 477 patients, while the addition of AGS resulted in the observation of a single event among 212 patients. Thus, bile leakage in the HGS group had a 4% prevalence (CI: 2%–9%), whereas the prevalence in the HGAS group was calculated at 0% (CI: 0%–5%) (Figure 5(a)).

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Figure 5.

(a) Bile leakage prevalence with (HGAS) and without (HGS) antegrade stenting. (b) Overall adverse events prevalence without pancreatitis for HGAS.

CI, confidence interval; HGAS, hepaticogastrostomy with antegrade stent; HGS, hepaticogastrostomy.

For the prevalence of overall adverse events for HGAS, excluding pancreatitis, the rate was 8% (CI: 4%–14%) (Figure 5(b)).

Time to stent dysfunction and overall survival

Four articles, 2 two-arm and 2 one-arm with a total of 208 patients for HGAS and 5 articles, 2 two-arm and 2 one-arm with a total of 193 for HGS were used to generate survival curves for time to stent dysfunction. For HGS, 5 articles with 248 patients for HGAS and 9 articles with 361 patients for HGS were used to compare survival plots for overall survival outcomes.

The time to stent dysfunction was 217 (CI: 120–308)days for HGS and 333 (CI: 280–not reached)days for HGAS (Figure 6(a)). The overall survival for HGS and HGAS was 117 (CI: 94–147) and 140 (CI: 105–170)days, respectively (Figure 6(b)).

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Figure 6.

Summary figure of survival curves. (a) Time to stent dysfunction. (b) Overall survival.

Risk of bias and assessment and quality of evidence

According to the GRADE system, the certainty of evidence regarding technical success was high. The certainty of evidence was considered low for clinical success and overall adverse events (Supplemental Table S5). Overall, no significant bias was observed, results of the risk of bias assessment are summarized in Supplemental Table S6 and Supplemental Figure S2.

Publication bias and heterogeneity

No significant small-study publication bias was observed in the funnel plots for all outcomes (Supplemental Figures S3–S9). For direct comparisons, heterogeneity was I²=18% for technical success. For clinical success and overall adverse event rates, heterogeneity was calculated as I²=0% and I²=64%, respectively. Re-intervention showed I²=0%. The between- and within-study heterogeneity was I²=0% for pooled technical success. For clinical success, between-study heterogeneity was I²=0% and the within-study was calculated at I²=7%. The between-study heterogeneity for the overall adverse event rates was I²=0% and within-study heterogeneity was calculated at I²=23%. Bile leakage showed a heterogeneity of I²=0%.

Discussion

This meta-analysis suggests that although more technically challenging, the addition of AGS is more successful in relieving biliary obstruction as well as increasing stent patency than HGS alone, together with its lower re-intervention rates and reduced bile leakage prevalence, the technical difficulties associated with HGAS could be justified for the patients’ benefits. The lower re-intervention rates may be attributed to a decrease in sludge and debris formation. In our exploratory analysis, median time to stent dysfunction appears to increase with no change in overall survival. Further research must be conducted to conclusively prove the increased time to stent dysfunction.

The technical success between HGS and HGAS were 94% (CI: 92%–96%) and 89% (CI: 83%–93%), respectively. This is not surprising as combined procedures are always more challenging than single ones. The results of the clinical success, which is measured as a reduction in bilirubin levels of at least 40% within a month of the procedure, suggests that the addition of AGS was better than HGS alone, 94% (CI: 89%–97%) to 88% (CI: 84%–91%), respectively. In terms of overall adverse events, HGAS performed similarly to HGS, 14% (CI: 9%–20%) and 20% (CI: 16%–25%), respectively. The deployment of AGS can lead to pancreatitis which does not occur during HGS, this might eventually balance the overall adverse event rates as shown in our analysis where the prevalence of adverse events without pancreatitis for HGAS was 8% (CI: 4%–14%). Moreover, the hypothesis of reduced bile leakage which can lead to serious complications such as bile peritonitis appears to be true with 1 event in 212 patients for HGAS compared to 28 events in 477 patients for HGS.

The need for re-intervention after HGAS compared to HGS was significantly decreased OR=0.37 (CI: 0.27–0.52), this can be attributed to a decrease in sludge and debris formation in the HGS stent thus decreasing the need for endoscopic removal. Thus, although the addition of AGS comes with increased hospital costs and fluoroscopic radiation dosage, at the same time it can end up decreasing future costs and radiation that are associated with re-interventions. ²⁵ Although an exploratory analysis, median time to stent dysfunction appears to increase, with HGAS median 333 (CI: 280–not reached) and HGS median 217 (CI: 120–308), since the existence of two drainage routes alleviates the intraductal pressure by said malignancies thus relieving the stress in the HGS stent. Since the stomach is a movable organ, with the addition of the AGS the bile can continue flowing in the physiological direction, thus the burden on the HGS stent is reduced which allows it to remain in place longer and not migrate into the abdominal cavity. No difference in overall survival was observed HGS median 117 CI: (94–147) and HGAS median 140 CI: (105–170). For this reason, to re-affirm the justification for the use of HGAS, we suggest that more long-term follow-up studies should be conducted examining the time to stent dysfunction. Lastly, during data collection, it was noted that many studies would report patient death as the time to stent dysfunction outcome. Our results only used those studies that didn’t confound the two outcomes. Future studies should always treat them separately.

Conclusion

Our findings guide endoscopists in the decision to use HGAS EUS-biliary drainage. Although technically more challenging, the increased time to stent dysfunction, higher rate of clinical success, and reduction in re-interventions together with the decrease in bile leakage prevalence with no change in the rate of overall adverse events argue in favor of the benefits associated with HGAS.

Supplemental Material

Acknowledgments

Footnotes

Contributor Information

Panagiotis Paraskevopoulos, Centre for Translational Medicine, Semmelweis University, Budapest, Hungary.

Mahmoud Obeidat, Centre for Translational Medicine, Semmelweis University, Budapest, Hungary.

Dániel Bednárik, Centre for Translational Medicine, Semmelweis University, Budapest, Hungary. Heim Pál National Pediatric Institute, Budapest, Hungary.

Petrana Martinekova, Centre for Translational Medicine, Semmelweis University, Budapest, Hungary.

Dániel Sándor Veres, Centre for Translational Medicine, Semmelweis University, Budapest, Hungary. Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.

Nándor Faluhelyi, Centre for Translational Medicine, Semmelweis University, Budapest, Hungary. Department of Medical Imaging, Medical School, University of Pécs, Pécs, Hungary.

Alexandra Mikó, Centre for Translational Medicine, Semmelweis University, Budapest, Hungary. Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary. Institute of Medical Genetics, Medical School, University of Pécs, Pécs, Hungary.

Péter Mátrai, Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.

Péter Hegyi, Centre for Translational Medicine, Semmelweis University, Budapest, Hungary. Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary. Translational Pancreatology Research Group, Interdisciplinary Centre of Excellence for Research Development and Innovation, University of Szeged, Szeged, Hungary. Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary.

Bálint Erőss, Centre for Translational Medicine, Semmelweis University, Üllői út 26, Budapest H-1085, Hungary. Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary. Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary.

References