Introduction
Transoral incisionless fundoplication (TIF) currently is used to restore the continence
of the gastroesophageal junction in selected patients suffering from gastroesophageal
reflux disease (GERD), with either a competent gastroesophageal valve or hiatal hernia
< 2.5 cm, who refuse or are intolerant or unresponsive to proton pump inhibitor (PPI)
maintenance therapy.
TIF reconfigures the tissue to establish a full-thickness gastroesophageal valve from
inside the stomach and has been performed by using either the EsophyX device (EndoGastric
Solutions, Redmond, Washington, United States) or Medigus ultrasonic surgical endostapler
(MUSE, Medigus, Omer, Israel). The technique mimicks a 180° up to 270° surgical fundoplication,
depending upon the device used, but is less invasive and is not associated with persistent
surgery-related side effects.
Several studies have shown the efficacy of TIF in obtaining a significant improvement
in both typical and atypical GERD-related symptoms, and reduction in the acid exposure
time with 2-year follow-up [1]
[2]; however, few studies have assessed long-term outcomes of TIF, raising concerns
about the long-term performance of the procedure, compared with surgical outcomes
[3].
The aim of this meta-analysis was to assess long-term outcomes of TIF in terms of
patient satisfaction, quality of life, and use of PPIs.
Methods
Registration
This review was registered on the PROSPERO international database (from University
of York Centre for Reviews and dissemination) (registration ID 169382).
Search strategy and study selection
A computerized search of PubMed, Scopus, Embase/Medline, and Cochrane Library databases
was executed to identify publications from inception to May 2020 that included patients
treated with endoscopic TIF procedures, with either EsophyX 1.0 /2.0 or the MUSE technique.
The following search terms were used: transoral incisionless fundoplication, transoral
fundoplication, TIF, EsophyX, MUSE, Medigus, endoscopic treatment of gastroesophageal
reflux/GERD, gastroesophageal reflux. Titles of all the identified articles were screened
to exclude studies not related to study topic or meeting one of the exclusion criteria.
The remaining potentially relevant studies were screened for eligibility by analysis
of the abstract and the full text. Studies reporting data on TIF fundoplication with
long term outcomes (≥ 3 years) were included in the quantitative synthesis through
meta-analysis (see below for inclusion criteria). An analysis of references for each
included article was made to retrieve additional eligible studies. The methodology
was developed from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) checklist [4].
Inclusion and exclusion criteria
The analysis included all studies published in English reporting long-term outcomes
of patients undergoing TIF fundoplication with either MUSE or EsophyX. We adopted
as cut-off between short- and long-term outcomes a period of 3 years. Thus, all studies
reporting only short-term (< 3 years) outcomes were excluded. Excluded from the analysis
were also all studies published in languages other than English, as well as conference
abstracts, book chapters, reviews, and commentaries, retrospective and unpublished
studies. In case of patient overlap between studies, the largest or most recent study
was included. Excluded studies and reasons for exclusion were recorded ([Fig. 1]).
Fig. 1 Excluded studies and reasons for their exclusion.
Data extraction
Two reviewers (S.T. and G.M.) independently performed the electronic search, comparing
results for congruence, in consultation with other investigators when the evaluators’
opinions differed. Data extraction was performed independently by the two reviewers
and crosschecked by the investigators. From each included study, the following data
were extracted: study design, sample size, patient characteristics, duration of follow-up,
TIF technique, device for TIF (EsophyX or MUSE), patient inclusion and exclusion criteria,
subjective outcomes (symptomatic relief after TIF), severe adverse events (AEs), and
publication year. No restrictions with respect to patient age, ethnic group, or sex
were adopted. The overall quality of the included studies was judged on the basis
of the IHE (Institute of Health Economics) quality appraisal tool for case series
studies [5]. The quality assessment checklist includes seven domains with a total of 18 item
as follows: study objective (1 item), study population (5 items), interventions and
co-interventions (2 items), outcomes measures (3 items), statistical analysis (1 item),
results and conclusions (5 items), competing interests and sources of support (1 item).
Studies complying with 14 or more items (C70 %) were considered to be of acceptable
quality. The overall quality of the randomized clinical trials as determined by Jadad
et al. [6] was judged.
Statistical analysis
Outcomes of the meta-analysis were: overall patient satisfaction, PPI daily consumption
(stopped or at least halved), mean GERD-health related quality of life (GERD-HRQL)
score, normalization of heartburn score, normalization of regurgitation score, before
and after TIF. PPI consumption was considered “continued” when the daily drug dose
was the same as before the procedure; “reduced” when any daily dose was taken for
less than half the total number of days during follow-up; and “completely stopped”
when not one dose of PPI was taken during the follow-up. Heartburn and regurgitation
scores were extrapolated from the GERD-HRQL questionnaire and assessed separately.
Continuous data were reported as the median (interquartile range [IQR]) or mean (standard
deviation [SD]), whereas categorical data were reported as the count and percentage.
Event rates for binary outcomes (e. g., % of patients off-PPI) were defined as the
proportion of events among the number of patients who were available for follow-up. Standard
errors (SEs) and 95 % confidence intervals (CIs) for a single proportion were derived.
Heterogeneity among studies was assessed by using the I2 statistic, which describes the percentage of total variation attributable to between-study
heterogeneity as opposed to random error or chance. Percentages of 25 % (I2 = 25), 50 % (I2 = 50), and 75 % (I2 = 75) were considered as low, moderate, and high degree of heterogeneity, respectively.
In the presence of substantial heterogeneity (I2 > 50 %), a random effects model was used as the pooling method; otherwise, a fixed
effects model was adopted as the pooling method. Prediction intervals for size effects
of a new study were also calculated according to Higgins et al. [7]. Sensitivity analysis was performed by sequentially omitting each study to test
the influence of each individual study on pooled data [8]. The Egger’s test and the trim and fill method of Duval and Tweedie were used to
test and adjust for publication bias [9]. All statistical analyses were conducted in R. In particular, we used the metafor
libraries in R to carry out the meta-analysis and meta-regression [10].
Results
Study description
The PRISMA flowchart and reasons for exclusion are shown in [Fig. 1]. The initial electronic search retrieved 356 references. Of the 99 studies screened
for eligibility, eight (418 enrolled patients; males: 55.5 %) were included in the
meta-analysis [11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]. One study was an open label, crossover, multicenter, randomized controlled trial
[15]; three were multicenter, prospective studies [11]
[13]
[14]; and four were single-center, prospective studies [12]
[16]
[17]
[18]. Mean follow-up time was 5.3 years (range: 3–10 years). In detail, two studies had
a follow up of 3 years (73 patients) [11]
[12], four studies up to 4 to 5 years (137 patients) [13]
[14]
[15]
[16], and two studies up to 8 to 10 years (35 patients) [17]
[18]. Follow-up of patients was carried out annually in six studies, at 1 and 8 years
after TIF in one study [18], and at 1, 2, 3, 5, 7, and 10 years in another study [17].
Patient characteristics
Median/mean age, body mass index, GERD duration were 44.6 (range 19–79, 4 studies)
and 47.1 ± 13.2 (3 studies), 25.9 kg/m2 (range 17.1–36.0) and 25.9 kg/m2 ± 4.1, and 4.8 years (range 0.5–25 years) and 11.2 ± 9.8 years, respectively. In
addition, GERD duration was reported as longer than 3 and 6 months in two studies
[14]
[17], while it was not reported in the remaining study [18]. Daily PPI dependence was 100 % in five studies [14]
[15]
[16]
[17]
[18] and 97 % in one study [12], while it was not provided in two studies. The presence of hiatal hernia and esophagitis
was reported in six of eight studies [11]
[12]
[15]
[16]
[17]
[18], and it was 65.8 % and 49.9 %, respectively. Studies and patient characteristics
for each study are reported in [Table 1].
Table 1
Studies and patient characteristics.
|
Author, publication year
|
Study design
|
No. patients
|
Age, yr[1]
|
BMI,
kg/m2
[1]
|
Duration of symptoms (yr)[1]
|
Hiatal hernia %
|
Esophagitis %
|
PPI consumption prior to TIF %
|
|
Witteman, 2012 [12]
|
Retrospective
|
38
|
46
(22–79)
|
26.3
(20.1–36.0)
|
6 (1–25)
|
94.8
|
58.0
|
97
|
|
Muls, 2013 [11]
|
Prospective
|
86
|
49
(19–73)
|
25.1
(17.1–35.3)
|
6 (1–16)
|
58.0
|
82.0
|
NR
|
|
Roy-Shapira, 2015 [13]
|
Prospective
|
15
|
46
(26–64)
|
18–31
|
2.5 (0.5–20)
|
NR
|
NR
|
NR
|
|
Kim HJ, 2016 [14]
|
Prospective
|
64
|
44.7 ± 3.3
|
26.2 ± 4.9
|
> 6 months
|
NR
|
NR
|
100
|
|
Stefanidis, 2017 [16]
|
Retrospective
|
45
|
36
(23–55)
|
26.2
(18.3–34.9)
|
5 (1–24)
|
71.1
|
73.3
|
NR
|
|
Trad KS, 2018 [15]
|
Prospective
|
63
|
51.5 ± 10.3
|
28.5 ± 3.7
|
11.2 ± 9.8
|
87.3
|
52.4
|
100
|
|
Chimukangara M, 2019 [18]
|
Prospective
|
57
|
46
(37–59)
|
28.8 ± 4.9
|
NR
|
45.6
|
21.1
|
100
|
|
Testoni PA, 2019 [17]
|
Prospective
|
50
|
45 ± 16
|
22 ± 3
|
> 3 months
|
56.0
|
22.0
|
100
|
PPI, proton pump inhibitor; TIF, transoral incisionless fundoplication; NR, not reported.
1 Median (range)/mean ± SD.
Procedure details
EsophyX and MUSE were used in six studies (196 patients) [11]
[12]
[15]
[16]
[17]
[18] and two studies (49 patients) [13]
[14], respectively. Among studies using EsophyX, two reported outcomes with TIF 1.0 [11]
[12] and four with the TIF 2.0 technique [15]
[16]
[17]
[18]. TIF was technically feasible in 414 of 418 patients (99.0 %). Severe AEs occurred
in seven of 418 procedures (1.7 %). Pneumothorax was reported in three patients after
Esophyx and was the commonest complication of this intervention; pneumomediastinum
was reported in one patient after MUSE; 24-hour delayed bleeding occurred in two cases
with Esophyx; esophageal mucosal lesion without full-thickness perforation occurred
in one case with the introduction of Esophyx. All these AEs resolved spontaneously
within 48 hours.
Procedures and follow-up details for each study are reported in [Table 2].
Table 2
Procedures and follow-up details.
|
Author, publication year
|
Procedure device
|
Technical success %
|
Procedure time (minute)[1]
|
Major adverse events, No. (%)
|
Duration of follow-up (years)
|
No. patients with long-term follow-up
|
Timing of follow-up evaluation
|
Revisions Repeated TIF/Surgery No. (%)
|
|
Witteman, 2012 [12]
|
EsophyX TIF 1.0
|
100
|
65
(35–142)
|
2 (5.3)
|
3
|
19
|
Every year
|
14 (37)
|
|
Muls, 2013 [11]
|
EsophyX TIF 1.0
|
100
|
NR
|
0
|
3
|
54
|
Every year
|
12 (13.9)
|
|
Roy-Shapira, 2015 [13]
|
MUSE
|
86.7
|
NR
|
0
|
4
|
13
|
Every year
|
0
|
|
Kim HJ, 2016 [14]
|
MUSE
|
100
|
NR
|
1 (1.6)
|
4
|
64
|
Every year
|
0
|
|
Stefanidis, 2017 [16]
|
EsophyX TIF 2.0
|
97.8
|
60
(45–100)
|
2 (4.4 %)
|
5
|
44
|
Every year
|
0
|
|
Trad KS, 2018 [15]
|
EsophyX TIF 2.0
|
100
|
49
(21–119)
|
0
|
5
|
44
|
Every year
|
3 (4.8)
|
|
Chimukangara M, 2019 [18]
|
Esophy X TIF 2.0
|
100
|
NR
|
NR
|
8
|
57
|
1- and 8-year
|
12 (21.1)
|
|
Testoni PA, 2019 [17]
|
EsophyX TIF 2.0
|
98
|
69 ± 19
|
2 (4.0)
|
10
|
12
|
1-, 2-, 3-, 5-, 7- and 10-year
|
7 (14)
|
TIF, transoral incisionless fundoplication; NR, not reported.
1 Median (range)/mean ± SD.
Patient satisfaction at baseline and after TIF
Before and after TIF, the pooled rate (random-effect) of patient satisfaction was
12.3 % (95 % CI:12.3–35.1 %, I2 = 87.4 %) and 70.6 % (95 % CI:51.2–84.6, I2 = 80 %), respectively (6 studies, 197 patients) [11]
[12]
[13]
[15]
[16]
[18], with no publication bias (Egger test: z =–0.1578, P = 0.8746), corresponding to an odds ratio of 21.4 (95 % CI:3.27–140.5) ([Fig. 2]). At sensitivity analysis, heterogeneity improved after the exclusion of one study
[18] (pooled rate estimate, 76.0 % (95 % CI:65.0–84.0 %); I2 = 44,5 %, Egger test: z = 1.26, P = 0.200). The median rates of patients who were satisfied with TIF after 3 years
[11]
[12], 4 to 5 years [13]
[15]
[16]), and 8 years [18] were 74.0 %, 86.2 %, and 78 %, respectively.
Fig. 2 Meta-analysis of patient-reported satisfaction after TIF.
Patients off PPI or occasionally on PPI after TIF
The overall pooled rate of patients completely off PPI was 53.8 % (95 % CI: 42.0 %-65.1 %,
I2 = 66.2 %) with no publication bias (Egger test: z =–0.1578, P = 0.8746). The heterogeneity improved after the exclusion of one study [12] (pooled rate estimate: 59.0 %; 95 % CI: 52.2–65.5; I2 = 52.6 %) ([Fig. 3]). The pooled percentage of patients who were either completely off or took PPIs
occasionally was 75.8 % (95 % CI: 67.6–82.6; I2 = 22.1 %; P = 0.267, [Fig. 4]). Such rates at 3, 4 to 5, and 8 to 10 years were 53.5 %/73.8 %, 57.5 %/76.4 %,
and 34.4 %/91.7 %, respectively.
Fig. 3 Meta-analysis of patients who were completely free of PPIs.
Fig. 4 Meta-analysis of patients who were completely free of PPIs or took them occasionally.
The pooled rates of patients completely off PPI and who were either completely off
or only took PPIs occasionally were 65.3 % and 54 %, after Esophyx and MUSE, respectively,
and this difference was not statistically significant (P = 0.2)
GERD-HRQL score at baseline and after TIF
The pooled estimated mean GERD-HRQL scores off PPI before TIF and after TIF at a mean
follow-up of 5.3 years were 26.1 (95 % CI: 21.5–30.7) and 5.9 (95 % CI: 0.35.1–11.4),
indicating that post TIF mean-HRQL scores significantly improved (P < 0.001). However, based on the Q-statistic (P < 0.05), there appeared to be statistically significant heterogeneity between score
estimates reported by the studies. [Table 3] summarizes GERD-HRQL scores at 3-, 4- to 5-, and 8- to 10-year follow-up.
Table 3
Patient satisfaction, GERD-HRQL scores, and PPI consumption at 3-, 4- to 5-, and 8-
to 10-year follow-up.
|
Author, publication year
|
Long-term follow-up, years
|
Patient satisfaction, no. (%)
|
GERD-HRQL score, median (range) or mean ± SD
|
Patients off-PPI no. (%)
|
Patients off-PPI/occasionally on PPI, N. (%)
|
|
|
Pre-TIF
|
Post-TIF
|
Pre-TIF
|
Post-TIF
|
Pre-TIF
|
Post-TIF
|
Pre-TIF
|
Post-TIF
|
|
Witteman, 2012 [12]
|
3
|
0
|
27 (70)
|
33 (7–69)
|
5 (0–29)
|
3 (15.8)
|
8 (42.1)
|
NR
|
11 (57.9)
|
|
Muls, 2013 [11]
|
3
|
3 (6)
|
38 (70)
|
25 (13–38)
|
4 (0–32)
|
NR
|
NR
|
NR
|
NR
|
|
Roy-Shapira, 2015 [13]
|
4
|
0
|
13 (100)
|
24.2 ± 6.9
|
5 (1–15)
|
0
|
10 (76.9)
|
0
|
13 (100)
|
|
Kim HJ, 2016 [14]
|
4
|
NR
|
NR
|
66.1 ± 33.2
|
12.8 ± 19.4
|
NR
|
25 (69.4)
|
NR
|
NR
|
|
Stefanidis, 2017 [16]
|
5
|
0
|
32 (72.7)
|
27 (2–45)
|
4 (0–26)
|
0
|
32 (72.7)
|
0
|
38 (86.4)
|
|
Trad KS, 2018 [15]
|
5
|
1 (2.3)
|
33 (75)
|
26.4
|
6.8
|
0
|
20 (45.5)
|
0
|
29
|
|
Chimukangara M, 2019 [18]
|
8
|
0
|
18 (78.3)
|
24 (15–28)
|
10 (6–14)
|
0
|
6 (26.1)
|
NR
|
NR
|
|
Testoni PA, 2019 [17]
|
10
|
NR
|
NR
|
46 ± 19
|
9.5 ± 6.1
|
0
|
5 (41.7)
|
0
|
11 (91.7)
|
GERD-HRQL, gastroesophageal reflux disease health care-related quality of life; PPI,
proton pump inhibitor; TIF, transoral incisionless fundoplication; NR, not reported.
In the four studies in which GERD-HLQR before TIF was calculated also for patients
on PPI therapy, the scores off PPIs after TIF were significantly better compared with
those on PPIs before TIF, at 3, 5, and 10 years. Overall, GERD-HLQR scores after TIF
improved by four-fifths and remained stable up to 4 to 5 years, while at 10-year follow-up,
they appeared improved by two-thirds with a 57.1 % worsening of GERD-related symptoms.
Normalization of heartburn and regurgitation score after TIF
Data for heartburn normalization were available for 133 patients from four studies
[11]
[12]
[15]
[16]. Meta-analysis of these trials yielded an overall pooled rate of heartburn normalization
of 73.0 % (95 % CI: 0.62–0.82). Only three trials (80 patients) reported data on regurgitation
score after TIF [12]
[15]
[16]. Combining data from these three trials, the pooled rate of resolution of regurgitation
was 86 % (95 % CI: 75.0–91.0 %). One study reported heartburn and regurgitation scores
pre- and post-TIF, instead of normalization, with significant improvement for both
(heartburn score: 4.2 ± 3 vs 18 ± 9 pre-TIF; regurgitation score 3.2 ± 4.4 vs 17 ± 9
pre-TIF; P < 0.01) [17].
The median pooled rates of patients with normalized heartburn and regurgitation scores
after TIF 3 and 4 to 5 years were r68.6 %/79 % and 86.2 %/87.1 %, respectively.
Discussion
According to our meta-analysis, TIF resulted in long-term patient satisfaction rates
of 74 % to 86 %, with interruption/reduction of PPI in about 75 % of cases at 3 and
4 to 5 years, and with a significant and persistent improvement in GERD-related symptoms
and quality of life in four-fifths and two-thirds of patients at 4 to 5 and 10 years,
respectively.
These results are clinically relevant because they show that the satisfactory outcomes
reported after TIF in the short term are maintained even in the long term, arguing
in favor of TIF as an effective alternative to surgery in selected patients. Our data
confirm and strengthen over the long term the results of two previous pooled analyses
of short-term [1]
[2] reporting a short-term success rate of 99 % and a low rate (2 %) of serious AEs.Overall,
up to 10 years after TIF, about two-thirds of patients were satisfied, compared with
before TIF, and the satisfaction rate appeared to be maintained over time.
These long-term TIF outcomes can be compared with those reported after laparoscopic
surgical fundoplication. In detail, after TIF, pooled PPI interruption or reduction
was observed in 53.8 % and 75.8 % of patients, respectively, versus a 5-year post
anti-reflux-surgery use of PPI nationwide survey showing that 57.5 % and 29.5 % of
patients still took PPIs or were daily PPI-dependent [19]. The symptom normalization found by our study of 73 % is higher than reported by
a Cochrane meta-analysis on long-term results of Nissen fundoplication, showing recurrence
or persistence of heartburn and reflux symptoms in 41.2 % and 24.6 % of cases, respectively,
with persistent side effects in 14 % up to 23 % of cases [20].
There are very few reports on 10-year outcomes after surgical fundoplication, but
again, results are substantially comparable with our TIF findings [20]
[21]
[22]
[23].
This analysis has limitations, partly due to the nature of included studies. First,
the long-term follow-up in most included studies (3 to 10 years) was rarely carried
out with a complete clinical assessment (i. e. endoscopic and/or functional evaluations)
in a small number of patients; however, studies evaluating long-term outcomes (5 to
10 years) after surgical fundoplication also harbor the same limitations (usually
assessing only clinical outcomes) permitting nonetheless a trustworthy comparison.
Furthermore, the symptomatic curve over a such long period suggests that the results
would not change much even with a larger number of fully-assessed patients. Second,
a high heterogeneity across studies for patient reported overall satisfaction after
TIF was found. However, this result must be analyzed next to the substantial reduction
in overall PPI use, which yielded a much lower heterogeneity, as well as the solid
reduction in GERD QoL scores that was maintained over time, which are both more objective
parameters for evaluating procedure outcomes.
Conclusion
In conclusion, this meta-analysis showed that pooled long-term post-TIF data seem
sufficient to confirm that TIF appears to offer a therapeutic option as effective
as surgery in the long term and safe for selected symptomatic patients with GERD,
with a Hill grade I or II gastroesophageal valve or a hiatal hernia no longer than
2.5 cm, who refuse life-long medical therapy or surgery, are intolerant to PPIs, or
are at risk of persistent postsurgical side effects.
