Surgical Endoscopy (2023) 37:3701–3709 and Other Interventional Techniques

https://doi.org/10.1007/s00464-023-09880-4

Transoral incisionless fundoplication for recurrent symptoms

after laparoscopic fundoplication
Gaurav Ghosh1   · Alyssa Y. Choi2 · Mohamad Dbouk3 · Jacques Greenberg4 · Rasa Zarnegar4 · Michael Murray5 ·
Peter Janu6 · Nirav Thosani7 · Barham K. Abu Dayyeh8 · David Diehl9 · Ninh T. Nguyen10 · Kenneth J. Chang2 ·
Marcia Irene Canto3 · Reem Sharaiha1 on behalf of the TIF Research Consortium

Received: 22 October 2022 / Accepted: 8 January 2023 / Published online: 17 January 2023
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023

Abstract
Background  Revision of a failed laparoscopic fundoplication carries higher risk of complication and lower chance of success
compared to the original surgery. Transoral incisionless fundoplication (TIF) may be an endoscopic alternative for select
GERD patients without need of a moderate/large hiatal hernia repair. The aim of this study was to assess feasibility, efficacy,
and safety of TIF 2.0 after failed laparoscopic Nissen or Toupet fundoplication (TIFFF).
Methods  This is a multicenter retrospective cohort study of patients who underwent TIFFF between September 2017 and
December 2020 using TIF 2.0 technique (EsophyX Z/Z+) performed by gastroenterologists and surgeons. Patients were
included if they had (1) recurrent GERD symptoms, (2) pathologic reflux based upon pH testing or Grade C/D esophagitis or
Barrett’s esophagus, and (3) hiatal hernia ≤ 2 cm. The primary outcome was improvement in GERD Health-Related Quality
of Life (GERD-HRQL) post-TIFFF. The TIFFF cohort was also compared to a similar surgical re-operative cohort using
propensity score matching.
Results  Twenty patients underwent TIFFF (median 4.1 years after prior fundoplication) and mean GERD-HRQL score
improved from 24.3 ± 22.9 to 14.75 ± 21.6 (p = 0.014); mean Reflux Severity Index (RSI) score improved from 14.1 ± 14.6
to 9.1 ± 8.0 (p = 0.046) with 8/10 (80%) of patients with normal RSI (< 13) post-TIF. Esophagitis healed in 78% of patients.
PPI use decreased from 85 to 55% with 8/20 (45%) patients off of PPI. Importantly, mean acid exposure time decreased from
12% ± 17.8 to 0.8% ± 1.1 (p = 0.028) with 9/9 (100%) of patients with normalized pH post-TIF. There were no statistically
significant differences in clinical efficacy outcomes between TIFFF and surgical revision, but TIFFF had significantly fewer
late adverse events.
Conclusion  Endoscopic rescue with TIF is a safe and efficacious alternative to redo laparoscopic surgery in symptomatic
patients with appropriate anatomy and objective evidence of persistent or recurrent reflux.

Keywords  Gastroesophageal reflux disease · GERD · Hiatal hernia · Proton pump inhibitor · Transoral incisionless
fundoplication · Nissen fundoplication

Abbreviations PPI Proton pump inhibitor

BMI Body mass index RSI Reflux Symptom Index
GERD Gastroesophageal reflux disease TIF Transoral incisionless fundoplication
GERD-HRQL GERD Health-Related Quality of Life TIFF Transoral incisionless fundoplication
LNF Laparoscopic Nissen fundoplication after failed fundoplication

Gaurav Ghosh and Alyssa Y. Choi are co-first authors.

Gastroesophageal reflux disease (GERD) affects 20–40% of
The members of TIF Research Consortium have been listed in Americans and 4 in 1000 GERD patients develop compli-
acknowledgements. cations, including ulceration, stricture, or dysplasia [1, 2].
GERD is typically treated first with lifestyle modifications
* Gaurav Ghosh
gghosh010@gmail.com and medical therapy. For patients with symptoms refrac-
tory to these measures or for those seeking more definitive
Extended author information available on the last page of the article

13
Vol.:(0123456789)

3702
therapy, laparoscopic anti-reflux surgery is a generally safe
and effective treatment option. Laparoscopic Nissen fun-
doplication (LNF) is the current “gold standard” for surgi-
cal treatment of GERD, with an efficacy of up to 96% after
5 years and 80% up to 15 years, while the laparoscopic 270°
partial (Toupet) fundoplication is similarly effective and has
also become a common anti-reflux operation [3, 4].
However, recurrent GERD symptoms are reported in
10–30% of patients after LNF [5, 6]. Fundoplication fail-
ures can occur for various reasons, including recurrent
hiatal hernias, wrap disruption, or wrap slippage [7, 8].
These issues can lead to persistent or recurrent symptoms
of reflux or significant new symptoms (i.e., postopera-
tive dysphagia) and ultimately 3–10% of these patients
will undergo revisional anti-reflux surgery [9]. Redo
LNFs are feasible but technically challenging and carry a
higher risk of complication than initial LNF with success
rate of 79–86% and complication rates up to 44% [5, 10].
Redo partial (Toupet) fundoplications are another option,
but likewise have reduced success rates compared to the
original anti-reflux procedure [11]. The risks can be even
higher for other re-operative procedures (e.g., Roux-en-Y
gastric bypass), and complication rates increase, while
patient-reported outcomes worsen with each subsequent
attempt at fundoplication revision [12–14].
Transoral incisionless fundoplication (TIF) is an endo-
scopic anti-reflux procedure that has been used as a primary
GERD intervention in selected patients with hiatal hernias
length ≤ 2 cm and Hill grade 1 to 2 [15, 16]. The most recent
systematic review and meta-analysis of published clinical
trials showed that TIF may offer a long-term, safe therapeu-
tic alternative for selected patients with GERD [17]. Cur-
rently, there are limited data on the use of TIF to address
GERD after a prior failed fundoplication. Therefore, the aim
of this study was to assess the feasibility, efficacy, and safety
of TIF 2.0 with the EsophyX Z/Z+ devices (EndoGastric
Solutions, Inc., Redmond, WA, USA) after failed laparo-
scopic Nissen or Toupet fundoplication (TIFFF).
Materials and methods
Study population and study sites
We conducted a retrospective cohort study of adult patients
who had previously undergone a laparoscopic primary or
revisional fundoplication surgery and presented with recur-
rent symptoms. We identified all patients who underwent
TIF after previous fundoplication between September 2017
and December 2020 using TIF 2.0 technique and EsophyX
Z/Z+ device. The multicenter cohort registered in the Heart-
burn Center TIF Registry (REDCap electronic data collec-
tion tool) were treated at 7 academic and community centers
13
Surgical Endoscopy (2023) 37:3701–3709
and the TIF procedures were performed by gastroenterolo-
gists and surgeons.
All patients underwent pre-procedural endoscopy, with
ambulatory pH reflux testing off of PPI, if necessary, to
confirm recurrent GERD. Patients were included in the
study if they had (1) recurrent GERD symptoms, (2) path-
ologic reflux based upon pH testing (mean acid exposure
time > 4%) or endoscopic evidence of Grade C/D esophagitis
or Barrett’s esophagus, and (3) small ≤ 2 cm or no hiatal
hernia on pre-TIF endoscopy. Patients with dysphagia as
the only symptom were excluded (i.e., no other symptoms of
recurrent GERD). All TIF procedures were performed with
TIF 2.0 technique, as previously described, using EsophyX
Z/Z+ devices (Fig. 1) [16].
To assess the efficacy of TIFFF, the primary outcome
was improvement in the GERD Health-Related Quality of
Life (GERD-HRQL) score post-TIF [18]. All patients were
encouraged to participate in objective postoperative evalu-
ation off of PPI. The secondary clinical efficacy outcomes
were improvement in GERD-HRQL subscores, Reflux
Symptom Index (RSI) < 13, healing of esophagitis using
LA classification, change in esophageal acid exposure time
(AET) by wireless pH monitoring, and reduction or dis-
continuation of proton pump inhibitor (PPI) use post-TIF
[19]. TIF procedural details, including valve characteris-
tics, number of fasteners, time of procedure, and technical
success, were also recorded. Adverse event rates were used
to determine the safety of TIFFF and reported based upon
previously described definitions for grading severity by the
American Society for Gastrointestinal Endoscopy (ASGE)
[20]. Authors had complete access to all data used in this
study and coauthors reviewed and approved the final manu-
script. Approval for this study was granted at each center’s
respective Institutional Review Boards (IRBs).
Statistical methods
For statistical analysis of paired data, Wilcoxon signed-
rank test or McNemar’s test was used to compare pre- and
post-TIF clinical outcomes, as these variables did not show
a normal distribution by the Shapiro–Wilk normality test.
To further evaluate the efficacy and safety of TIF after
previous fundoplication, the TIF cohort was compared to
a surgical re-operative cohort. The control surgical group
was a retrospective cohort of all patients who underwent
surgical fundoplication after previous fundoplication from
one surgical center (New York-Presbyterian Hospital/
Weill Cornell Medicine). Propensity score matching
was performed to reduce the effect of selection bias and
logistic regression of the following predictors was used for
propensity score calculation: age, PPI use, hiatal hernia
presence, and presence of moderate/large or > 2-cm hernia.
These were deemed to be clinically significant variables
Surgical Endoscopy (2023) 37:3701–3709 3703
Fig. 1  TIF 2.0 technique for reconstruction of the flap valve. A The
length of the neo-valve is reconstructed with traction of tissue into the
Esophyx Z+ device. B The tissue mold is closed and rotated counter-
clockwise toward the lesser curve and full-thickness serosa-to-serosa
plications are deployed. C The circumference of the neo-valve is
restored with additional fasteners placed along the anterior aspect.
for fundoplication outcomes; some variables were baseline
characteristics that were statistically significantly different
between the surgical re-operative cohort and TIF cohort.
The 1:1 matching between the TIF and surgical re-operative
cohorts was performed using the nearest-neighbor method
without replacement and with a caliper width of 0.2. To
assess balance of covariate distribution between the
treatment groups, standardized mean differences were
calculated and all were < 0.10. After propensity score
matching, differences between the two groups were
calculated. Continuous variables were compared with a
Wilcoxon rank sum test. Categorical variables were analyzed
using the χ2 test or Fisher exact test, as appropriate, with
two-sided p values < 0.05 considered to be significant. All
analyses were performed using IBM SPSS Statistics for
Windows, v26.0 (IBM Corp., Armonk, N.Y., USA) and
R Core team software version 3.5.0 (R Foundation for
Statistical Computing, Vienna, Austria).
Results
A total of 20 patients (60% female, mean age 59.8 years)
underwent TIF after recurrent symptoms and met inclusion
criteria (Table 1). TIF was performed a median of 4.1 years
[IQR 1.9-16.5] after prior fundoplication with the primary
symptoms most often being heartburn (65%) or regurgitation
A mirror image procedure is then performed with fasteners placed
on the posterior corner. D After the TIF, endoscopy shows a recon-
structed valve that is 270–300 degrees in circumference and 3–4 cm
in length. (Courtesy of EndoGastric Solutions, Redmond, WA; with
permission)
(20%). The previous fundoplication was most often a
laparoscopic Nissen (95%). Ninety percent of patients had
a Hinder type 1 failure of previous fundoplication (partial
or complete breakdown of wrap, often recurrence of
hiatal hernia) and the remaining 10% were noted to have
fundoplication failure due to patulous hiatal repair. Prior to
TIF, 85% of patients were using PPIs, 47.4% had evidence of
esophagitis on endoscopy (Los Angeles Grade A/B: 26.3%,
Grade C: 21.1%), and 30% had Barrett’s esophagus. Half
of the patients had pre-TIF pH testing, of which 7/10 (70%)
were abnormal. For the 3 patients who underwent TIF with
AET < 4%, 2 had grade C esophagitis and 1 had Barrett’s
esophagus on pathology. The mean AET was 12.0% ± 17.8
(n = 10).
The pre-TIF median Hill grade and hiatal hernia (axial
length) were 2 (IQR 1-2) and 2 cm (IQR 1-2), respectively.
As assessed on immediate post-TIF endoscopy, a median
TIF valve circumference of 270 degrees (IQR 270-205) was
created with 3.25-cm (IQR 3-4) valve length. A median of
30 (IQR 20-36) fasteners were used to create the new TIF
valves. The mean procedure length was 70.7 ± 28.1 min
(including pre- and post-TIF EGDs). TIF was technically
completed as planned in 100% of patients.
There was one minor intra-procedural adverse event
involving a superficial mucosal tear distal to the gastroe-
sophageal junction successfully treated with endoscopic
clip placement. This patient had the longest length of stay
13

3704 Surgical Endoscopy (2023) 37:3701–3709

Table 1  Baseline patient characteristics and TIF procedure details The GERD-HRQL score improved significantly post-
Total (n = 20)
TIFFF (24.3 ± 22.9–14.75 ± 21.6; p = 0.014) (Table  2).
Similarly, there was also an improvement in RSI score
Baseline characteristics post-TIF (14.1 vs. 9.1; p = 0.046). The prevalence of reflux
Age (years); mean ± SD 59.8 ± 10.2 esophagitis decreased from 47.4 to 20% (p = 0.625), with
Gender—Female; n (%) 12 (60%) patients having only A or B esophagitis on follow-up endos-
BMI (kg/m2); mean ± SD 28.7 ± 5.7 copy and PPI use decreased from 85 to 55% (p = 0.109) at
Race—White; n (%) 12 (60%) a median follow-up time of 12 months. Importantly, mean
Time since fundoplication (years); median (IQR) 4.1 (1.9–16.5) AET decreased from 12% ± 17.8 to 0.8% ± 1.1 (p = 0.028)
Primary Symptom; n (%) and 9/9 (100%) of patients who had post-TIF pH testing off
    Heartburn 13 (65%) of PPI had complete normalization of acid exposure time
    Regurgitation 4 (20%) (AET < 4%). Of note, 4 of the patients with post-TIF pH
    Dysphagia 1 (5%) testing continued to take PPI despite normal testing.
    Throat or laryngopharyngeal reflux symptoms 2 (10%) Characteristics of the TIF cohort (n = 20) and the sur-
PPI use; n (%) 17 (85%) gical re-operative cohort (n = 49) are shown in Table 3.
Hill Grade; median (IQR) 2 (1–2) Before propensity score matching, some differences were
Hiatal hernia axial length (cm); median (IQR) 2 (1–2) noted between the groups. TIF patients were more likely to
Presence of reflux esophagitis; n (%) 9 (47.4%) have Barrett’s esophagus and surgical patients were more
    LA Grade A 2 (10.5%) likely to have hiatal hernias > 2 cm or classified as “moder-
    LA Grade B 3 (15.8%) ate/large.” After matching, 20 pairs of TIF and surgical re-
    LA Grade C 4 (21.1%) operative patients were selected with characteristics closely
Abnormal pH test prior to TIF; n (%) 7/10 (70%) balanced between the groups. Compared to the TIF cohort,
Average % AET prior to TIF; mean ± SD 12.0 ± 17.8 the surgical control cohort had good clinical outcomes after
Procedural Details re-operative fundoplication with a 66.7% improvement in
Number of fasteners placed; median (IQR) 30 (20–36) symptoms, mean GERD-HRQL score of 7.1 ± 6.0, and only
TIF length (cm); median (IQR) 3.25 (3–4) 6.3% with persistent esophagitis. PPI use decreased from
TIF valve circumference (degrees); median (IQR) 270 (270–305) 73.5 to 35.4% (p < 0.001) and mean AET decreased from
TIF time (minutes); mean ± SD 70.7 ± 28.1 7.5% ± 6.6 to 3.6% ± 5.5 (Supplemental Table 1).
TIF technical success; n (%) 20 (100%) The clinical outcomes of the TIF and redo surgical fun-
Intra-procedural adverse event; n (%) 1 (5%) doplication groups are shown in Table 4. After match-
AET acid exposure time, BMI body mass index, cm centimeters, IQR ing for potential confounders, no statistically significant
interquartile range, LA Los Angeles, PPI proton pump inhibitor, SD differences were identified between the TIF and surgical
standard deviation repeat fundoplication groups in clinical efficacy or safety
profile. Although there were slightly greater improvements
in the surgical cohort for symptom scores, esophagitis, and
(48 h), after which the patient was discharged without fur- PPI use, the TIF cohort had improved pH testing results
ther complications or sequelae due to this event. There were with 100% of patients achieving normalization of AET (vs.
no moderate or serious adverse events. 71.4% in the surgical cohort). Additionally, the TIF cohort

Table 2  Clinical outcomes of Outcome Pre-TIF Post-TIF p-value

TIF patients
GERD-HRQL total score; mean ± SD 24.3 ± 22.9 14.8 ± 21.6 0.014
    Heartburn subscore 12.6 ± 11.6 5.1 ± 8.8 0.008
    Regurgitation subscore 8.7 ± 9.8 6 ± 9.8 0.068
RSI score; mean ± SD 14.1 ± 14.6 9.1 ± 8.0 0.046
Reflux esophagitis; n (%) 9/19 (47.4%) 2/10 (20%) 0.625
PPI use; n (%) 17/20 (85%) 11/20 (55%) 0.109
Average % AET; mean ± SD 12.0 ± 17.8 0.8 ± 1.1 0.028
    AET upright 8.4 ± 13.5 0.7 ± 1.0 0.093
    AET supine 11.7 ± 20.9 1.1 ± 2.7 0.161

AET acid exposure time, GERD-HRQL Gastroesophageal Reflux Disease Health-Related Quality of Life,
PPI proton pump inhibitor, RSI Reflux Symptom Index, SD standard deviation

13
Surgical Endoscopy (2023) 37:3701–3709 3705

Table 3  TIF vs. Surgical Re-operative cohort baseline characteristics

Variable Before matching After ­matchinga
TIF (n = 20) Surgical Re-op (n = 49) p-value TIF (n = 20) Surgical Re-op (n = 20) p-value

Age (years); mean ± SD 59.8 ± 10.2 58.5 ± 15.2 0.634 59.8 ± 10.2 59.4 ± 14.4 0.725

Gender—Female; n (%) 12 (60%) 29 (59%) 0.950 12 (60%) 11 (55%) 1.000
BMI (kg/m2); mean ± SD 28.7 ± 5.7 27.9 ± 6.5 0.639 28.7 ± 5.7 28.4 ± 7.2 0.931
Race—White; n (%) 12 (60%) 41 (84%) 0.057 12 (60%) 15 (75%) 0.501
Barrett’s esophagus; n (%) 7 (30%) 6 (12%) 0.028 7 (30%) 3 (15%) 0.273
Time since fundoplication (years); median 4.1 (1.9–16.5) 4.7 (1.7–12.4) 0.843 4.1 (1.9–16.5) 4.5 (1.8–8.7) 0.700
(IQR)
Last follow-up for clinical assessment 12 (9–12) 12.2 (4.1–40.0) 0.901 12 (9–12) 14.5 (4.5–51.2) 0.680
(months); median (IQR)
Symptoms; n (%)
    Heartburn 15 (75%) 33 (67.3%) 0.531 15 (75%) 12 (60%) 0.501
    Regurgitation 7 (35%) 25 (51%) 0.406 7 (35%) 11 (55%) 0.527
PPI use; n (%) 17 (85%) 36 (73.5%) 0.364 17 (85%) 17 (85%) 1.00
Presence of hiatal hernia 12 (60%) 32 (65.3%) 0.677 12 (60%) 10 (50%) 0.751
Hiatal hernia > 2 cm or moderate/large 1 (5%) 14 (28.6%) 0.031 1 (5%) 1 (5%) 1.00
Presence of reflux esophagitis; n (%) 9 (47.4%) 16 (32.7%) 0.259 9 (47.4%) 5 (25%) 0.191
Abnormal pH test prior to TIF; n (%) 7/10 (70%) 18/31 (58.1%) 0.712 7/10 (70%) 8/12 (66.7%) 1.00
Average % AET prior to TIF; mean ± SD 12.0 ± 17.8 7.5 ± 6.6 0.699 12.0 ± 17.8 10.2 ± 13.0 0.356

AET acid exposure time, BMI body mass index, cm centimeters, IQR interquartile range, PPI proton pump inhibitor, SD standard deviation
a
 Matched on age, PPI use, hiatal hernia presence, and presence of moderate/large or > 2-cm hernia

Table 4  Comparison of TIF vs. surgical re-operative fundoplication post-procedure

Variable Before matching After ­matchinga
TIF Surgical Re-op p-value TIF Surgical Re-op p-value

GERD-HRQL ≤ 12 post-op 9/12 (75%) 17/20 (85%) 0.647 9/12 (75%) 6/7 (85.7%) 1.000
Esophagitis 2/10 (20%) 1/16 (6.3%) 0.538 2/10 (20%) 0/8 (0%) 0.477
PPI use 11/20 (55%) 17/48 (35.4) 0.135 11/20 (55%) 8/20 (40%) 0.527
AET < 4% 9/9 (100%) 5/7 (71.4%) 0.175 9/9 (100%) 3/4 (75%) 0.308
Any adverse event 3/20 (15%) 16/49 (32.7%) 0.136 3/20 (15%) 7/20 (35%) 0.273
   Intra-procedural adverse event; n (%) 1/20 (5%) 3/49 (6.1%) 1.00 1/20 (5%) 1/20 (5%) 1.00
   Immediate (within 24 h) 1/20 (5%) 1/49 (2%) 0.499 1/20 (5%) 0/20 (0%) 1.00
   Early adverse events (< 14 days) 0/20 (0) 6/49 (12.2%) 0.171 0/20 (0%) 1/20 (5%) 1.00
   Late adverse events 1/20 (5%) 11/49 (22.4%) 0.158 1/20 (5%) 6/20 (30%) 0.091

AET acid exposure time, GERD-HRQL Gastroesophageal Reflux Disease Health-Related Quality of Life, PPI proton pump inhibitor, SD stand-
ard deviation
a
 Matched on age, PPI use, hiatal hernia presence, and presence of moderate/large or > 2-cm hernia

had fewer late adverse events compared to the surgical Discussion

patient group (5% vs. 30%; p = 0.091), which included
patients developing incisional hernias or postoperative
dysphagia, which required surgical repair or endoscopic
dilation, respectively. Overall, the TIF adverse events were
of a less severe ASGE grade as well.
In a multicenter retrospective study of 20 patients, TIF for
recurrent symptoms after traditional fundoplication was
found to be feasible, safe, and efficacious. Although many
parameters are used for measuring reflux, such as symptom

13

3706
scores (i.e., GERD-HRQL, RSI), PPI use, or presence of
esophagitis, normalization of esophageal acid exposure is
still considered the gold standard of response to anti-reflux
therapy. In our study, the patients who followed up for
post-TIF pH monitoring achieved normalization of AET.
Additionally, in comparison to a matched re-operative sur-
gical cohort, our TIF cohort had similar success in clinical
outcomes with an improved safety profile. Therefore, TIF
post-failed fundoplication may be a promising alternative
to a redo surgical fundoplication.
While laparoscopic fundoplication is an established,
effective, and durable anti-reflux treatments for GERD, with
approximately 15,000 laparoscopic anti-reflux operations
performed annually in the USA [21], up to 10% of these
patients will undergo a revisional procedure due to recur-
rence of symptoms [5]. Recurrent or persistent symptoms
of reflux and postoperative dysphagia are the most common
symptoms of fundoplication failure, but the specific symp-
tom profile may depend on type of anatomic fundoplica-
tion failure. Fundoplication failure can be classified into six
types: tight Nissen, patulous or incompetent repair, disrup-
tion of the wrap, stomach slippage above the diaphragm,
slipped Nissen, and transdiaphragmatic wrap herniation
[22]. A tight Nissen fundoplication may present with dys-
phagia or bloating, while a patulous/incompetent fundopli-
cation repair may have persistent regurgitation secondary to
an ineffective barrier to reflux.
All fundoplication failure types are potential candidates
for repair, but revisions are often more complicated than
the primary anti-reflux procedure. Reoperation for failed
fundoplication can be performed via laparotomy, thoracic
approach, minimally invasive robotic-assisted surgery, or
most commonly, a laparoscopic approach [11]. Regard-
less of approach, re-operative surgery adds complexity and
increased risk, mainly due to the presence of adhesions from
the primary procedure, leading to increased morbidity and
mortality. Conversion from laparoscopic to open operations
has been reported in up to 8.7% of re-operative cases, while
complications occur more frequently than primary surger-
ies (14% vs. 6%) [23, 24]. A systematic review found that
while intraoperative complications occurred in 21.4% of
cases, the postoperative complication rate was also high at
15.6%, often leading to longer hospital stays (mean hospital
stay 5.5 days) [5].
Since surgical re-operative fundoplication can be difficult
and is associated with higher risk, we examined TIF 2.0
technique with the EsophyX Z/Z+ devices as an alternative
to redo surgical fundoplication. The most appropriate can-
didate for a TIF revision of a prior surgical fundoplication is
a patient with proven pathologic GERD on a pH monitoring
study with loosening of the wrap, with a small or no hiatal
hernia recurrence. With the TIF 2.0 procedure, a prior loose
fundoplication does not need to be taken down before it is
13
Surgical Endoscopy (2023) 37:3701–3709
revised. This avoids the need to dissect surgical scar tissue,
as one would do in a redo fundoplication. Working from
within the stomach, the flap valve can be augmented and
reinforced internally.
Outcomes of TIF after failed traditional anti-reflux sur-
gery have been reported once before, with Bell et al. follow-
ing 11 such patients over a median follow-up of 14 months
[25]. Our study builds upon this earlier work in several ways.
The Bell et al. study focused primarily on patients with
recurrent symptoms due to loosening of the wrap without
evidence of recurrent hiatal hernia, an important cause of
fundoplication failure. Our study was able to include these
patients with small, recurrent hiatal hernia as well, due
to use of the more modern iterations of the TIF EsophyX
device (Z classes introduced in 2015). Additionally, to assess
efficacy of TIF for post-fundoplication patients, we included
a matched surgical cohort for comparison.
The clinical outcomes of our study were encouraging and
similar to results seen with primary TIF. Patients had an
improvement in GERD-HRQL and RSI symptom scores,
with improvement of symptoms in 75% of patients who had
post-TIF GERD-HRQL scores. This symptomatic improve-
ment is comparable to 2-year primary TIF outcomes from
the TIF US registry (66% with improvement in GERD-
HRQL) and our post-TIF median GERD-HRQL was 8.5
(vs. 6) [26]. Regurgitation was only a primary symptom in
20% of our cohort with a mean RSI of 14 (abnormal > 13),
which may explain why a statistically significant improve-
ment was not seen for regurgitation post-TIF. Healing of
reflux esophagitis was achieved in 78%, similar to what is
seen across various studies, including the TIF US registry
(75%), RESPECT trial (77%), and TEMPO trial (100% at
1 year) [27, 28]. In the remaining 20% of those with persis-
tent esophagitis, the LA classification was from grade C to
grade A/B.
PPI use was higher (55%) in our cohort post-TIF com-
pared to the larger primary TIF studies, with the TEMPO
trial having only 17% of patients on PPI 1 year after TIF.
However, PPI use in the TEMPO trial rose to 34% at 5 years,
a similar rate to a recent Yadlapati et al. study in which 33%
of patients were unable to stop PPI even with 0 days of posi-
tive acid exposure on ambulatory pH monitoring study [29].
These data suggest a more realistic goal for PPI use after
treatment, as subjective measures, such as symptoms and
PPI use, have not been shown to consistently correlate with
rates of esophageal pH normalization [30]. The discrepancy
in PPI usage and normalization of AET reinforce how dif-
ficult it can be to discontinue PPIs in some patients who may
no longer have pathologic GERD but may have superim-
posed functional heartburn or reflux hypersensitivity.
In contrast to persistent use of PPI, the improvement in
mean percentage time with pH < 4 in our cohort was more
notable (12–0.8) than for primary TIF trials, such as the
Surgical Endoscopy (2023) 37:3701–3709 3707
RESPECT trial (9.3–6.4) and TEMPO (10.5–7.9) [27, 28].
The TIFFF cohort also had 100% of patients with post-TIF
pH monitoring achieve normalization of acid exposure time,
in comparison to the TIF US registry, in which esophageal
acid exposure normalized in 57% of patients [26]. The only
other TIF study with this degree of improvement in esopha-
geal acid exposure time is the original Bell et al. study which
studied TIF post-surgical fundoplication [25]. In that study,
abnormal acid exposure time decreased from 8.1 to 0.6%
(p = 0.008) and AET normalized in 5/6 patients. This may
be explained by the fact that the prior fundoplication had
created length before eventually loosening, thereby provid-
ing more length to work with in a TIF post-fundoplication
to re-create a flap valve than in a primary TIF. Furthermore,
a previous study of hiatal hernia repair prior to TIF showed
that if the hiatal repair and fundoplication were intact that
there was significant control of acid exposure (improvement
of DeMeester score from 35.3 to 10.9) [31]. In our post-
surgical TIF cohort, patients may have had some continued
benefit of previous repair of their hiatus (if hernia was pre-
sent), as only 10% had recurrence of symptoms in the setting
of apparent patulous hernia repair.
In addition to subjective and objective measures of reflux,
we assessed feasibility and safety of TIF 2.0 after a prior sur-
gical fundoplication. We confirmed the feasibility of TIF in
this patient population with the new EsophyX Z/Z+ devices
with technical success of 100% in our cohort. In our study,
the mean procedure length was similar to the Bell et al. study
(70.7 vs. 64.5 min). These procedure times are still signifi-
cantly less than the average time for laparoscopic revision
(164–177 min) [5, 24]. As a result, the average length of
hospital stay after TIF for our patient cohort was 22.7 h, an
overnight stay for observation (only 4 patients stayed longer
than 24 h), compared to 5.5 days in systematic reviews of
laparoscopic revision after surgical fundoplication. In our
study, there were a higher median number of fasteners
placed compared to the standard primary TIF (30 vs. 20), as
the redo TIF requires rotating fibrotic tissue from the prior
fundoplication and may require more fasteners to hold the
wrap. Although concerns have been raised about the higher
number of fasteners if a laparoscopic fundoplication were to
be needed after TIF, studies of post-TIF laparoscopic revi-
sion have not shown prolonged operative times or increased
morbidity [32, 33].
An important addition of our study to the literature is a
comparison of our outcomes to a matched surgical cohort
and we found no statistically significant differences in clini-
cal efficacy outcomes between TIF after fundoplication
and surgical revision. Although our improvement in AET
is similar to what has been documented in the surgical re-
fundoplication literature, it is helpful to be able to meas-
ure the efficacy of TIF against a matched surgical cohort
with a similar presence and/or size of hiatal hernia. The
comparison of safety for TIF vs. laparoscopic revision found
that our TIF cohort had a clinically significantly lower num-
ber of late adverse events when compared to the matched
surgical cohort (5 vs. 30%). This finding is consistent with
published data on the increased morbidity of surgical redo
fundoplications [5].
The limitations of this study are the small number of
patients and retrospective nature of the analysis. However,
data are currently being collected prospectively to assess
the reproducibility and durability of these results and this is
the largest case series investigating TIF in failed fundopli-
cations, to date. Another limitation is that all TIF patients
were only from 2 fundoplication failure types so the results
of this study cannot be generalizable to all patients with
symptoms after surgical fundoplication. For many patients,
including those with tight Nissen or wrap migration, a surgi-
cal revision may still be the approach with the best evidence.
Concomitant hiatal hernia with TIF may be able to expand
the utility of TIF in this post-surgical fundoplication popula-
tion but prospective and head-to-head trials are necessary.
In our study, TIF after laparoscopic fundoplication led
to improvement in patient symptoms, as well as a decrease
in esophagitis and mean acid exposure time. Compared to
a matched surgical cohort, the TIF procedure had an out-
standing safety profile in this post-surgical population.
These findings suggest TIF is a reasonable consideration
for endoscopic rescue in patients with recurrent symptoms
after laparoscopic fundoplication who have evidence of sur-
gical failure.
Supplementary Information  The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00464-0​ 23-0​ 9880-4.
Acknowledgements  TIF Research Consortium: Cheguevara Afaneh,
Daniella Assis, Christy Dunst, Jon Gabrielsen, Olaya Brewer Gutier-
rez, Glen Ihde, Harshit Khara, Jennifer Kolb, Michael Marohn, Jason
Samarasena, and Erik Wilson.
Author contributions  GG and AC participated in the study conception
and design; JG, RZ, MM, PJ, NT, BKA, DD, NTN, and KC participated
in the acquisition of data; GG participated in the analysis of data; GG
and MD participated in the interpretation of data; GG and AC partici-
pated in the drafting of manuscript; DD, MD, and RZ participated in
the revision of manuscript; MC and RS participated in the final revision
and approval of manuscript.
Funding  This investigator-initiated study was supported in part by the
Johns Hopkins Heartburn Center (TIF Registry) and Endogastric Solu-
tions. Endogastric Solutions was not involved in the design, conduct,
or analysis of the data and preparation of the manuscript.
Declarations 
Disclosures  Michael Murray is a Consultant for Endogastric solu-
tions. Peter Janu is a Consultant and speaker in Endogastric Solutions,
Ethicon, J&J, and Olympus. Barham K. Abu-Dayyeh is a Consult-
13

3708
ant for Endogenex, Endo-TAGSS, Metamodix, and BFKW; receives
Consulting and grant/research support from USGI, Cairn Diagnostics,
Aspire Bariatrics, and Boston Scientific; speaker in Olympus and
Johnson and Johnson; and receives Speaker and rant/research support
from Medtronic and Endogastric solutions and research support from
Apollo Endosurgery, and Spatz Medical. David Diehl is a Consultant
and speaker for Olympus, Boston Scientific, Cook Medical, Cernostics,
GI Supply, Lumendi, Microtek, Actuated Medical, and Pentax. Rasa
Zarnegar is a Consultant for Bard. Ninh T. Nguyen is a Speaker for
Endogastric Solutions and Olympus. Kenneth J. Chang is a Consult-
ant for Apollo, Boston Scientific, Cook Medical, Erbe, Endogastric
Solutions, Mauna Kea, Medtronic, Olympus, Ovesco Endoscopy, and
Pentax. Marcia Irene Canto receives research grant from Endogastric
Solutions. Reem Sharaiha is a Consultant for Boston scientific, Olym-
pus, and Cook Medical. Drs. Gaurav Ghosh, Alyssa Choi, Mohamad
Dbouk, Jacques Greenberg, and Nirav Thosani have no conflicts of
interest or financial ties to disclose.
Ethical approval  Granted for this study by each center’s respective
Institutional Review Board.
References
1. Richter JE, Rubenstein JH (2018) Presentation and epidemi-
ology of gastroesophageal reflux disease. Gastroenterology
154:267–276
2. Waring JP, Hunter JG, Oddsdottir M, Wo J, Katz E (1995) The
preoperative evaluation of patients considered for laparoscopic
antireflux surgery. Am J Gastroenterol 90:35–38
3. Csendes A, Orellana O, Cuneo N, Martinez G, Figueroa M (2019)
Long-term (15-year) objective evaluation of 150 patients after
laparoscopic Nissen fundoplication. Surgery 166:886–894
4. Mickevičius A, Endzinas Z, Kiudelis M, Jonaitis L, Kupčinskas
L, Pundzius J, Maleckas A (2013) Influence of wrap length on the
effectiveness of Nissen and Toupet fundoplications: 5-year results
of prospective, randomized study. Surg Endosc 27:986–991
5. Furnee EJ, Draaisma WA, Broeders IAM, Gooszen HG (2009)
Surgical reintervention after failed antireflux surgery: a systematic
review of the literature. J Gastrointest Surg 13:1539–1549
6. Del Campo SEM, Mansfield SA, Suzo AJ, Hazey JW, Perry KA
(2017) Laparoscopic redo fundoplication improves disease-spe-
cific and global quality of life following failed laparoscopic or
open fundoplication. Surg Endosc 31:4649–4655
7. Grover BT, Kothari SN (2015) Reoperative antireflux surgery.
Surg Clin North Am 95:629–640
8. Frantzides CT, Carlson MA (1997) Laparoscopic redo nissen fun-
doplication. J Laparoendosc Adv Surg Tech A 7:235–239
9. Munie S, Nasser H, Gould JC (2019) Salvage options for fundopli-
cation failure. Curr Gastroenterol Rep 21:41
10. Van Beek DB, Auyang ED, Soper NJ (2011) A comprehen-
sive review of laparoscopic redo fundoplication. Surg Endosc
25:706–712
11. Al Hashmi AW, de Chambrun GP, Souche R, Bertrand M, Blasi
VD, Jacques E, Azagra S, Fabre JM, Borie F, Prudhomme M,
Nagot N, Navarro F, Panaro F (2019) A retrospective multicenter
analysis on redo-laparoscopic anti-reflux surgery: conservative or
conversion fundoplication? Surg Endosc 33:243–251
12. Yadlapati R, Hungness ES, Pandolfino JE (2018) Complications
of antireflux surgery. Am J Gastroenterol 113:1137–1147
13. Stefanidis D, Navarro F, Augenstein VA, Gersin KS, Heniford
BT (2012) Laparoscopic fundoplication takedown with conver-
sion to Roux-en-Y gastric bypass leads to excellent reflux control
13
Surgical Endoscopy (2023) 37:3701–3709
and quality of life after fundoplication failure. Surg Endosc
26:3521–3527
14. Singhal S, Kirkpatrick DR, Masuda T, Gerhardt J, Mittal SK
(2018) Primary and redo antireflux surgery: outcomes and les-
sons learned. J Gastrointest Surg 22:177–186
15. Ihde GM (2020) The evolution of TIF: transoral incisionless fun-
doplication. Therap Adv Gastroenterol 13:1–16
16. Bell RCW, Cadiere GB (2011) Transoral rotation esophagogastric
fundoplication: technical, anatomical, and safety considerations.
Surg Endosc 25:2387–2399
17. Testoni S, Hassan C, Mazzoleni G, Antonelli G, Fanti L, Passaretti
S, Correale L, Cavestro GM, Testoni PA (2021) Long-term out-
comes of transoral incisionless fundoplication for gastro-esopha-
geal reflux disease: systematic review and meta-analysis. Endosc
Int Open. https://​doi.​org/​10.​1055/a-​1322-​2209
18. Velanovich V (2007) The development of the GERD-HRQL
symptom severity instrument. Dis Esophagus 20:130–134
19. Belafsky PC, Postma GN, Koufman JA (2002) Validity and reli-
ability of the reflux symptom index (RSI). J Voice 16:274–277
20. Cotton PB, Eisen GM, Aabakken L, Baron TH, Hutter MM,
Jacobson BC, Mergener K, Nemcek A Jr, Petersen BT, Petrini
JL, Pike IM, Rabeneck L, Romagnuolo J, Vargo JJ (2010) A lexi-
con for endoscopic adverse events: report of an ASGE workshop.
Gastrointest Endosc 71:446–454
21. Funk LM, Kanji A, Melvin WS, Perry KA (2014) Elective antire-
flux surgery in the US: an analysis of national trends in utili-
zation and inpatient outcomes from 2005 to 2010. Surg Endosc
28:1712–1719
22. Patti MG, Allaix ME, Fisichella PM (2015) Analysis of the
causes of failed antireflux surgery and the principles of treatment
a review. JAMA Surg 150:585–590
23. Carlson MA, Frantzides CT (2001) Complications and results of
primary minimally invasive antireflux procedures: a review of
10,735 reported cases. J Am Coll Surg 193:428–439
24. Symons NR, Purkayastha S, Dillemans B, Athanasiou T, Hanna
GB, Darzi A, Zacharakis E (2011) Laparoscopic revision of failed
antireflux surgery: a systematic review. Am J Surg 202:336–343
25. Bell RCW, Hufford RJ, Fearon J, Freeman KD (2013) Revi-
sion of failed traditional fundoplication using EsophyX tran-
soral fundoplication. Surg Endosc. https://​d oi.​o rg/​1 0.​1 007/​
s00464-​012-​2542-7
26. Bell RCW, Barnes WE, Carter B, Sewell RW, Mavrelis PG, Ihde
GM, Hoddinott KM, Fox MA, Freeman KD, Gunsberger T, Haus-
mann MG, Dargis D, Gill BD, Wilson E, Trad KS (2014) Tran-
soral incisionless fundoplication: 2-year results from the prospec-
tive multicenter US Study. Am Surg 80:1093–1105
27. Hunter JG, Kahrilas PJ, Bell RCW, Wilson EB, Trad KS, Dolan
JP, Perry KA, Oelschlager BK, Soper NJ, Snyder BE, Burch MA,
Melvin WS, Reavis KM, Turgeon DG, Hungness ES, Diggs BS
(2015) Efficacy of transoral fundoplication vs omeprazole for
treatment of regurgitation in a randomized controlled trial. Gas-
troenterology 148:324–333
28. Trad KS, Simoni G, Barnes WE, Shughoury AB, Raza M, Heise
JA, Turgeon DG, Fox A, Mavrelis PG (2014) Efficacy of transoral
fundoplication for treatment of chronic gastroesophageal reflux
disease incompletely controlled with high-dose proton-pump
inhibitors therapy: a randomized, multicenter, open label, crosso-
ver study. BMC Gastroenterol 14:174
29. Yadlapati R, Masihi M, Gyawali CP, Carlson DA, Kahrilas PJ,
Nix BD, Jain A, Triggs JR, Vaezi MF, Kia L, Kaizer A, Pandol-
fino JE (2021) Ambulatory reflux monitoring guides proton pump
inhibitor discontinuation in patients with gastroesophageal reflux
symptoms: a clinical trial. Gastroenterology 160:174–182
30. Lord RVN, Kaminski A, Oberg S, Bowrey DJ, Hagen JA,
DeMeester SR, Sillin LF, Peters JH, Crookes PF, DeMeester TR
(2002) Absence of gastroesophageal reflux disease in a majority
Surgical Endoscopy (2023) 37:3701–3709 3709

of patients taking acid suppression medications after Nissen fun-
doplication. J Gastrointest Surg 6:3–9
31. Ihde G, Pena C, Scitern C, Brewer S (2019) pH Scores in
hiatal repair with transoral incisionless fundoplication. JSLS
23(e2018):00087
3 2. Ashfaq A, Rhee HK, Harold KL (2014) Revision of failed tran-
soral incisionless fundoplication by subsequent laparoscopic Nis-
sen fundoplication. World J Gastroenterol 20:17115–17119
33. Bell RC, Kurian AA, Freeman KD (2015) Laparoscopic anti-
reflux revision surgery after transoral incisionless fundoplication
is safe and effective. Surg Endosc 29:1746–1752
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Springer Nature or its licensor (e.g. a society or other partner) holds
exclusive rights to this article under a publishing agreement with the
author(s) or other rightsholder(s); author self-archiving of the accepted
manuscript version of this article is solely governed by the terms of
such publishing agreement and applicable law.

Authors and Affiliations

Gaurav Ghosh1   · Alyssa Y. Choi2 · Mohamad Dbouk3 · Jacques Greenberg4 · Rasa Zarnegar4 · Michael Murray5 ·

Peter Janu6 · Nirav Thosani7 · Barham K. Abu Dayyeh8 · David Diehl9 · Ninh T. Nguyen10 · Kenneth J. Chang2 ·
Marcia Irene Canto3 · Reem Sharaiha1 on behalf of the TIF Research Consortium

1 6
Division of Gastroenterology and Hepatology, New York- Fox Valley Surgical Associates, Affinity Health Systems,
Presbyterian Hospital/Weill Cornell Medicine, 1283 York Appleton, WI, USA
Ave, 9th Floor, New York, NY 10065, USA 7
Center for Interventional Gastroenterology at UTHealth,
2
HH Chao Comprehensive Digestive Disease Center, McGovern Medical School, UTHealth, Houston, TX, USA
University of California Irvine Medical Center, Orange, CA, 8
Division of Gastroenterology and Hepatology, Mayo Clinic,
USA
Rochester, MN, USA
3
Division of Gastroenterology and Hepatology, Johns Hopkins 9
Department of Gastroenterology and Nutrition, Geisinger
Medical Institutions, Baltimore, MD, USA
Medical Center, Danville, PA, USA
4
Department of Surgery, New York-Presbyterian 10
Department of Surgery, University of California Irvine
Hospital/Weill Cornell Medicine, New York, NY, USA
Medical Center, Orange, CA, USA
5
Northern Nevada Medical Group, Fallon, NV, USA

13