Transoral incisionless fundoplication for refractory GERD Where...

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Transoral incisionless fundoplication for refractory GERD – Where do we stand?

Running Head:

Endoscopic fundoplication for GERD

Authors:

Deepanshu Jain, MD1, Shashideep Singhal, MD

2

1. Department of Internal Medicine, Albert Einstein medical center, Philadelphia, PA, USA

2. Division of Gastroenterology, Hepatology and Nutrition, University of Texas Health Science Center at Houston, Houston,

Texas, USA

Address for correspondence:

Shashideep Singhal, MD

Division of Gastroenterology, Hepatology and Nutrition, University of Texas Health Science Center at Houston, 6431 Fannin, MSB

4.234, Houston, Texas, USA 77030 Email: [email protected]

mailto:[email protected]

2

Abstract:

Gastro-esophageal reflux disease (GERD) is a chronic, progressive and costly medical condition affecting a substantial proportion of

world population, predominantly the western population. Available treatment options for patients with refractory gastro-esophageal

(GE) reflux disease symptoms are limited to either laparoscopic surgery with significant sequelae or potentially lifelong, high-dose

proton pump inhibitors therapy. Restoration of the anti-reflux competence of the GE junction at the anatomic and physiologic levels is

critical for effective long-term treatment of GERD. Transoral incisionless fundoplication (TIF) surgery is a safe, well-tolerated and

effective treatment that has yielded significant symptomatic improvement in patients with medically refractory gastro-esophageal

reflux disease symptoms. In this review article, we have summarized case series and reports describing the role of TIF for patients

with gastro-esophageal reflux symptoms. Indications, techniques, complications and success rate reported are discussed.

Key words:

Endoscopic fundoplication, gastro-esophageal reflux disease, Proton pump inhibitors

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Introduction:

Gastro-esophageal reflux disease (GERD) is a chronic, progressive and costly medical condition affecting a substantial proportion of

world population, predominantly the western population. The first clinical description of GERD appeared in 1935 as a case report of

severe peptic esophagitis [1]

. GERD symptoms interrupts activities of daily living and have been associated with significantly

increased work absenteeism, reduced productivity at work [2–6]

and increased healthcare resource utilization [6]

.

Over the past years, we have devised many medical and surgical treatment options, but they all are expensive and pose significant side

effects, which paved the way for invent and advancement of effective endoscopic treatment options. Trans-oral incisionless

fundoplication (TIF) is a unique form of Natural Orifice Surgery (NOS), representing a next step in the field of minimally invasive

surgery for the treatment of GERD.

TIF is an endoscopic luminal procedure which restores the anti-reflux competence of gastro-esophageal junction, a critical step for

effective long term treatment of GERD. TIF is based on the principles of conventional anti-reflux surgery. It is done via EsophyX

device, which is inserted transorally under endoscopic visual guidance to reconstruct the gastro-esophageal valve (GEV) by wrapping

the proximal part of stomach (fundus) around the distal end of esophagus, thus reestablishing the reflux barrier. The procedure

involves placement of fasteners at four different positions to create a ≥ 270 degree valve 1-3 cms in length. Due to this endoscopic

incisionless approach, patients undergoing TIF experience less discomfort and faster recovery as compared to traditional anti-reflux

surgery. Clinical studies have shown that TIF is an effective and safe treatment for mild to moderate GERD symptoms in carefully

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selected patients [7]

. The major and minor adverse event experience with TIF compares favourably with that reported for laparoscopic

fundoplication [7]

. TIF has helped patients in getting off the acid suppressive therapy, by maintaining or introducing remission of

GERD symptoms [8]

.

In this review article, we have summarized case series and reports describing the use of TIF for GERD patients. Indications,

techniques, clinical response, endoscopic response, limitations and complications reported are discussed.

Materials and methods:

An extensive English language literature search was done using pubmed, medline, google to identify the peer reviewed original and

review articles using key words endoscopic fundoplication and gastro-esophageal reflux disease. Human only articles were selected.

The references of pertinent studies were manually searched to identify additional relevant studies. The indication, procedural details,

technical and clinical success rates, complications and limitations were considered as part of inclusion criteria. Search results yielded

mostly modest sample sized retrospective and prospective studies including case reports, case series and randomized controlled trials.

None of the authors has any conflicts of interest or financial relationship with the company that produces or distributes the device

described in the review article.

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Results:

10 original articles were considered appropriate to be included in the review article. Out of them 7 were prospective studies from

United States of America[8,9,10]

, Belgium[11]

, Netherlands[12-13]

and Italy[14]

. Others included a retrospective study[15]

, a case report[16]

,

and a prospective sham controlled trial[17]

from U.S.A. All cases have been summarized in Table 1.

Indications:

Initially, TIF was approved by FDA only for chronic GERD patients, who are responsive to PPI but with time we have seen an

expansion in the inclusion criteria for TIF. The most common indication for TIF now, is either refractory chronic GERD symptoms

with only partial response to acid suppressive medications[8-10,12-15,17]

or subjects who don’t want to continue lifelong medications

despite being responsive to acid suppressive medications[11,13,15]

. Kumta et al. described a unique case of TIF use for gastro-esophageal

reflux symptoms which developed post endoscopic myotomy for underlying achalasia[16]

.

Exclusion criteria:

The experience with TIF has grown in past few years but only to specific segment of GERD patients. In nine out of ten studies

included in our review, subjects with BMI >35 Kg/m2, Hiatal hernia > 2cm, Grade D esophagitis as per Los Angeles classification,

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esophageal motility disorder and Barretts esophagus were excluded from the study[8-15]

. History of previous failed anti-reflux surgery

was also one of the exclusion criteria in few studies[11-13]

.

Technique:

EsophyX device has been designed by Endogastric solutions (EGS) for the treatment of GERD. EsophyX-2 device via flexible

endoscope has been the method of choice for most physicians performing transoral incisionless fundoplication.

The procedure is performed under general anesthesia and involves the assistance of two physicians (surgeons and or

gastroenterologists). First physician controls the esophyX device thus monitoring appropriate application of fasteners to secure the

newly created GE valve and the second physician ensures continuous direct visualization via endoscope. The device creates a GEV by

retracting full thickness plications and tailored placement of multiple fasteners circumferentially around the gastro-esophageal

junction[18]

.

There have been different versions of TIF protocol with major difference being in the degree of circumference of reestablished valve

i.e. 220 degree in 1.0 protocol versus 240 degree in 2.0 protocol and the location of valve i.e. at the level of gastro-esophageal junction

(GEJ) in 1.0 protocol in contrast to 2.0 protocol where valve is created at a distance of 3-5 cm from the GEJ (Figure 1). Cadiere et al.

described the use of TIF 1.0 protocol in his study of 86 subjects undergoing TIF[11]

with a mean wrap of 230 (160-300) degree

whereas TIF 2.0 protocol was used in the majority of other studies[8,10,13-15,17]

with minimum reported wrap of 240 degree[10,15]

, but as

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high as of 300 degree[15]

. Also, the length of reconstructed valve has been reported to vary from as low as 2 cm[10,11,15]

to as high as 6

cm[11]

.

Clinical response:

Authors have used a wide variety of objective scales to quantify the GERD symptoms pre and post TIF like GERD-HRQL (Health

related quality of life)[8,10-15]

, GERSS score (GERD symptom score)[10,15]

, RSI (Reflux symptom index)[8,10,15]

, RDQ (Reflux disease

questionnaire)[8,17]

and GERD-QUAL (GERD quality of life)[14]

. Each of these scores, GERD-HRQL[19]

, GERSS[20]

, RSI[21]

, RDQ[22]

and GERD-QUAL[23]

have been validated for assessing the GERD symptom severity and the response to the treatment.

Trad et al. study described a significant decrease in mean GERD-HRQL (26.25 to 5.41), mean RDQ (2.91 to 0.50) and mean RSI

scores (22.0 to 4.79), post TIF at 12 month follow up[8]

. The study also showed the TIF group {mean GERD-HRQL (26.25 to 5.23),

mean RDQ (2.91 to 0.35) and mean RSI scores (22.0 to 4.64)} did better than the high dose PPI group {mean GERD-HRQL (26.43 to

18.86), mean RDQ (3.04 to 2.14) and mean RSI scores (22.62 to 19.62)} at 6 month follow up[8]

. The high dose PPI group showed

further decrease in mean GERD-HRQL (18.86 to 10.05), mean RDQ (2.14 to 1.33) and mean RSI scores (19.62 to 8.76) after TIF at 6

months[8]

. Tooney et al. study described the patient satisfaction score (67%, 92% & 86%) and the fraction of subjects with frequency

of symptoms (<1/month) (83%, 92% & 80%) post intervention at follow up across three sub-groups (TIF, Toupet fundoplication &

Nissen fundoplication) respectively[9]

. Wilson et al. study revealed a drop in median GERD-HRQL (24 to 2), median GRESS (26 to 4)

and median RSI score (20 to 4) post TIF at 12 month follow up[10]

. Cadiere et al. showed a decrease in median GERD-HRQL scores

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from 12 to 7 post TIF at 12 months[11]

. Rinsma et al. described a drop in mean GERD-HRQL score from 23.7 to 8.5 post TIF in

contrast to almost similar results in mean GERD-HRQL scores (26.0 to 23.6) in the PPI study arm at 6 month follow up[12]

. In another

study Rinsma et al. showed a similar trend in mean GERD-HRQL score (27.5 to 13.2) post TIF at 6 month follow up[13]

. Testoni et al.

study did not showed a significant difference in GERD-HRQL (20 to 17) and GERD-QUAL (84 to 80) post TIF at 2 year follow up[14]

.

Trad et al. results in another study showed a decremental trend in median GERD-HRQL (26.0 to 4), median RDQ (24 to 3) and

median RSI scores (17 to 4) post TIF at 14 months follow up[15]

. Hunter et al. in the recent study reported elimination of troublesome

regurgitation symptoms in 54/81 (67%) of subjects who underwent TIF and placebo treatment in contrast to 17/38 (45%) subjects who

underwent sham procedure and PPI therapy at 6 month follow up[17]

. The trend in the median regurgitation RDQ score (3.5 to 0.5),

median heartburn RDQ score (2.6 to 0.5) and composite median regurgitation and heartburn RDQ score (3.1 to 0.6) among subjects

who underwent TIF and placebo medication was similar to that of subjects who underwent sham procedure and PPI treatment {median

regurgitation RDQ score (3.8 to 0.8), median heartburn RDQ score (3.0 to 0.8) and composite median regurgitation and heartburn

RDQ score (3.3 to 0.9)} at 6 month follow up[17]

.

Overall, the author’s report from their respective studies seems to be reflective of improvement in quality of life of GERD patients

post TIF.

Endoscopic response:

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Trad et al. study described a significant decrease in mean Demeester score (35.28 to 25.32) with normalization of esophageal pH in 45%

(17/38) of subjects and healing of esophagitis in 100% of subjects (19/19) post TIF at 12 month follow up[8]

. The study also showed

the TIF group {mean Demeester score (35.28 to 23.64) with normalization of esophageal pH in 54% of subjects (21/39) and healed

esophagitis in 90% of subjects (18/20)} did better than the high dose PPI group {mean Demeester score (35.79 to 19.29) with

normalization of esophageal pH in 52% of subjects (11/21) and healed esophagitis in only 38% (5/13) of subjects} at 6 month follow

up[8]

. The high dose PPI group showed further improvement in fraction of subjects with healed esophagitis (85%- 11/13) but a poor

response in mean Demeester score (19.29 to 28.60) with normalization of esophageal pH in only 33% of subjects (7/21) after TIF at 6

months[8]

. Wilson et al. reported normalization of esophageal acid exposure in 52% (14/27) of subjects with healed esophagitis in 76%

of subjects post TIF at 12 month follow up[10]

. Cadiere et al. study showed a decrease in median Demeester score (34 to 28) post TIF

at 12 month follow[11]

. Rinsma et al. described an improvement in distal baseline impedance (1769Ω to 2294Ω) with decrease in acid

exposure time (9.7% to 6.9%) and mean acid reflux episodes (63.2 to 39.3) in post TIF group which was comparable to the PPI group

{improvement in distal baseline impedance (1088Ω to 2470Ω), decrease in acid exposure time (12.4% to 5.9%) and mean acid reflux

episodes (65.6 to 33.9)} at 6 month follow up[12]

. In another study Rinsma et al. showed improvement in multiple endoscopic

measured parameters like mean EGJ distensibility (2.4 to 1.6 mm2/ mm Hg), Upright acid exposure time (11.7 to 6.6%), Liquid reflux

episodes (30.4 to 16.7%) and mean number of transient lower esophageal sphincter relaxation episodes (16.8 to 9.2) post TIF at 6

month follow up[13]

. Testoni et al. study also reported mild improvement in Demeester score (22 to 19) with decrease in total number

of reflux episodes (66 to 43) and increase in LES pressure (8 to 12 mm Hg) post TIF at 2 year follow up[14]

. Trad et al. reported only 2

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subjects at 14 month follow up, with one showing normalization of esophageal pH and other subject showed a decrement in

Demeester score from 29 to 24.5[15]

. Hunter et al. reported a statistically significant (p value < .001) improvement in the Demeester

score (33.6 to 23.9), percent time with pH < 4 (9.3 to 6.4) and number of reflux episodes (135 to 94) in the subjects who underwent

TIF and placebo treatment in contrast to the subjects who underwent sham procedure and PPI therapy {Demeester score (30.9 to 32.7),

percent time with pH < 4 (8.6 to 8.9) and number of reflux episodes (125 to 122)} at 6 month follow up[17]

.

Overall, the author’s report from their respective studies seems to be reflective of effective esophageal mucosal healing in majority of

GERD patients post TIF, thus indirectly decreasing the risk of chronic GERD complications.

PPI Requirement:

Proportion of subjects requiring PPIs to control their GERD symptoms is one of the indirect measure of efficacy of the underlying

intervention for the GERD.

Trad et al. study reported a significant decline in proportion of daily PPI users (100 to 3%) with a concomitant increase in fraction of

occasional PPI users (0 to 15%) and those who remain off PPIs (0 to 82%) post TIF at 12 month follow up[8]

. The high dose PPI group

also showed similar trend in proportion of daily PPI users (100 to 10%) with a concomitant increase in fraction of occasional PPI users

(0 to 9%) and those who remain off PPIs (0 to 71%) after TIF at 6 months follow up[8]

. Wilson et al. study reported a decline in

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proportion of daily PPI users (92 to 23%) and occasional PPI users (8 to 3%) with concomitant increase in subjects who remain off

PPIs (0 to 74%) post TIF at 12 month follow up[10]

. Cadiere et al. also showed a decline in proportion of daily PPI users (100 to 15%)

with a concomitant increase in fraction of occasional PPI users (0 to 16%) and those who remain off PPIs (0 to 68%) post TIF at 12

months follow up[11]

. Rinsma et al. showed a similar trend, with 11/15 (73.3%) subjects stopping their PPI use all together and the rest

4/15 (26.7%) users reported daily use but 3/4 daily users had been able to decrease the dose of daily PPI, post TIF at 6 month follow

up[13]

. Testoni et al. study was unique in comparison to the rest of the studies because of long follow up of 6 years[14]

. The results

showed that post TIF, the fraction of daily PPI users decreased at 6 month (100 to 16.3%) and 6 year (16.3 to 14.3%) follow up. There

was a concomitant increase in subjects using half the PPI dose at 6 month (0 to 22.5%) and 6 year (22.5 to 50.0%) follow up[14]

. Also,

the proportion of subjects who have been off PPI, initially increased (0 to 61.2%) and then decreased (61.2 to35.7%) at 6 year follow

up[14]

. Trad et al. results in another study reported trend of decline in proportion of daily PPI users (89 to 18%) with a concomitant

increase in fraction of occasional PPI users (11 to 18%) and those who remain off PPIs (0 to 64%) post TIF at 14 months follow up[15]

.

Hunter et al. reported that out of 87 subjects who underwent TIF with placebo treatment, 10 subjects (11%) at 3 month follow up and

24 subjects (28%) at 18 month follow up resumed the PPI therapy because of lack of resolution of GERD symptoms[17]

.

Overall, the author’s report from their respective studies are reflective of significant decrease in the proportion of GERD patients

requiring PPI, post TIF, which indirectly has a major impact in decreasing the incidence of PPI related complication among these

subjects.

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Follow up:

Most authors report a follow up of the subjects ranging from a minimum of 6 months[12,13,17]

to a maximum of 6 years[14]

. A total of

575 subjects were studied by virtue of 10 studies, included in our review, out of which 22 subjects were lost to follow up. Despite a

good follow up, many subjects with successful control of symptoms post fundoplication might still be compliant with clinical

questionnaire on return visits but are nearly universally noncompliant about follow-up pH monitoring, thus leaving behind fewer

subjects to compare the endoscopic outcomes.

TIF failure:

Out of 575 total cases, 492 subjects underwent TIF and 14 subjects (2.84%) required a repeat intervention. One subject underwent

repeat TIF procedure[10]

and other thirteen required laparoscopic fundoplication[10-11, 14-15]

. Of these 13 cases, four were secondary to

persistent GERD symptoms[14]

, two were secondary to esophageal perforation post TIF[11]

, three were secondary to non-compliance

with post TIF dietary recommendations[10,15]

, one was secondary to severe post TIF vomiting[10]

and the other three had unknown

etiology[10-11]

. Hunter et al. reported TIF failure in 10/87 (11%) subjects at 3 month and 24/87 (28%) at 18 month follow up,

necessitating the resumption of PPI use but none of the subjects underwent a repeat TIF or laparoscopic surgery[17]

. In the same study,

Hunter et al. reported that among the group who underwent sham surgery with placebo medication, 15/42 (35.7%) subjects at 3 month

and 30/42 (71.4%) subjects at 18 month follow up underwent TIF for persistent GERD symptoms[17]

.

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Peri-procedural Complications (Requiring extended hospital stay):

Out of 575 total cases, 492 subjects underwent TIF and 5 subjects (1.01%) required an extension of hospital stay secondary to the

procedure related complication. Of these 5 subjects, two had esophageal perforation which required surgical treatment[11]

, two had

pneumothorax which was treated with transthoracic drainage[14]

and the other one had gastrointestinal bleeding which was treated with

endoscopic clips, fibrin glue and supportive blood transfusion[11]

.

Long term procedure related side effects (persistent/de-novo >1m post TIF):

Out of 575 total cases, 492 subjects underwent TIF and only 8 subjects (1.62%) were reported to have symptom which persisted

beyond 1 month post TIF or was all together new and appeared 1 month post TIF, but was attributed to the procedure. Three subjects

had worsening flatulence at 12 month follow up[8,10]

, two had de-novo dysphagia at 12 month follow up[10]

, one had de-novo bloating

at 12 month follow up[10]

, one had persistent abdominal pain at one month follow up[11]

and other one had persistent nausea at one

month follow up[11]

.

Summary and future directions:

Transoral incisionless fundoplication for chronic GERD patients can be a safe, minimally invasive and equally efficacious alternative

approach to surgery in selected patients who have refractory symptoms or are reluctant to take lifelong acid suppressive medications

or have contraindications to surgery. With evolving technique and increasing experience, TIF seems to be reasonable first line

approach for management of specific subgroup of chronic GERD patients. Preliminary reports appear promising but larger multi-

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centric prospective randomized sham controlled trials with longer follow up and head to head comparison against PPI and other

modalities for treatment of GERD are needed in future to ascertain its benefits before we adopt it as a standard alternative therapy for

chronic GERD patients.

Disclosure:

Dr. Deepanshu Jain and Shashideep Singhal have no conflict of interest or financial ties to disclose.

Acknowledgement:

Jain D contributed to literature search, data collection, compilation of results and writing up the manuscript.

Singhal S contributed to literature search and editing of the manuscript.

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15) KARIM S. TRAD, DANIEL G. TURGEON, EMIR DELJKICH. LONG-TERM OUTCOMES AFTER TRANSORAL INCISIONLESS

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MY. GASTROINTEST ENDOSC. 2015 JAN;81(1):224-5. DOI: 10.1016/J.GIE.2014.05.321. EPUB 2014 JUL 10. PMID: 25016405

17) JOHN G. HUNTER, PETER J. KAHRILAS, REGINALD C. W. BELL, ERIK B. WILSON, KARIM S. TRAD, JAMES P. DOLAN, KYLE A.

PERRY, BRANT K. OELSCHLAGER, NATHANIEL J. SOPER, BRAD E. SNYDER, MIGUEL A. BURCH, WILLIAM SCOTT MELVIN, KEVIN

M. REAVIS, DANIEL G. TURGEON, ERIC S. HUNGNESS AND BRIAN S. DIGGS. EFFICACY OF TRANSORAL FUNDOPLICATION VS

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18) CADIÈRE GB, RAJAN A, GERMAY O, HIMPENS J. ENDOLUMINAL FUNDOPLICATION BY A TRANSORAL DEVICE FOR THE

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19) VELANOVICH V.

THE DEVELOPMENT OF THE GERD-HRQL SYMPTOM SEVERITY INSTRUMENT

DIS ESOPHAGUS. 2007;20(2):130-4. DOI: 10.1111/J.1442-2050.2007.00658.X

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20) ALLEN CJ, PARAMESWARAN K, BELDA J, ANVARI M.

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GASTROESOPHAGEAL REFLUX DISEASE. DIS ESOPHAGUS. 2000;13(4):265-70.

DOI: 10.1111/J.1442-2050.2000.00129.X

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21) BELAFSKY PC, POSTMA GN, KOUFMAN JA.

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J VOICE. 2002 JUN;16(2):274-7.

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22) SHAW M, DENT J, BEEBE T, JUNGHARD O, WIKLUND I, LIND T, JOHNSSON F. THE REFLUX DISEASE QUESTIONNAIRE: A

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HEALTH QUAL LIFE OUTCOMES. 2008 APR 30;6:31. DOI: 10.1186/1477-7525-6-31.

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23) CHAN Y, CHING JY, CHEUNG CM, TSOI KK, POLDER-VERKIEL S, PANG SH, QUAN WL, KEE KM, CHAN FK, SUNG JJ, WU JC.

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19

DEVELOPMENT AND VALIDATION OF A DISEASE-SPECIFIC QUALITY OF LIFE QUESTIONNAIRE FOR GASTRO-OESOPHAGEAL

REFLUX DISEASE: THE GERD-QOL QUESTIONNAIRE.

ALIMENT PHARMACOL THER. 2010 FEB 1;31(3):452-60. DOI: 10.1111/J.1365-2036.2009.04187.X. EPUB 2009 OCT 31.

PMID: 19878152

Figure legend:

Figure 1: TIF technique creates an esophagogastric fundoplication proximal to the Z-line. (Bell & Cadiere. Transoral rotational esophagogastric

fundoplication: technical, anatomical and safety considerations. Surgical Endoscopy. 2010. No permission needed as per journal open access

policy)

Footnote for Table 1: Comparative description of different studies evaluating the role of transoral incisionless fundoplication

a. BMI Body mass index

b. PPI Proton Pump Inhibitors

c. RDQ Reflux disease questionnaire

d. RSI Reflux symptom index

e. GERD-HRQL Health related quality of life

f. DNA Data not available

g. OT Operation time

h. HSL Hospital stay length



20

i. LESS Laparo-endoscopic single site

j. LNF Laparoscopic Nissen Fundoplication

k. TLESR Transient Lower Esophageal sphincter relaxation

l. GERSS GERD symptom score

m. ITT Intention to Treat analysis

Table 1: Comparative description of different studies evaluating the role of transoral incisionless fundoplication

S.No

Author/ Year/ Location

Type of study

Intervention

Indication Exclusion Criteria

Total Subjects/ Subjects lost to follow up

Instrument

Technique/ Extent of wrap around the esophagus/ length of reconstructed valve)

Clinical response

Endoscopic response

PPIb

requirement

Follow up period

Peri-procedure complications (requiring extended hospital stay)

TIF failure requiring second endoscopic/ surgical intervention

Other complications (persistent > 1m, post TIF)

Miscellaneous facts

1

Trad et al. 2014, U.S.A [8]

Prospective Randomized Multicenter Crossover study

Transoral incisionless fundoplication (TIF)

1. Daily regurgitation or atypical symptoms (montreal criteria) on PPI

b

2. Abnormal 48 hr ambulatory pH test 3. H/O daily PPI

b

use for at least 6 months

1. BMIa >35

2. Barrett's esophagus > 2cm 3. Hill grade valve III or IV 4. Hiatal hernia >2 cm in either dimension 5. Los Angeles grade C or D classification

40/1

EsophyX-2 device via flexible endoscope

TIF 2.0 protocol

1. Resolution of regurgitation and atypical symptoms- a.) 6m- 13/20 (65%) b). 12m-30/39 (77%) 2. Mean GERD-HRQL

e-

a.) Baseline- 26.25 b.) 6m- 5.23 c.) 12m- 5.41 3. Mean RDQ

c-

a.) Baseline- 2.91 b.) 6m- 0.35 c.) 12m- 0.50

1. Healed esophagitis- a.) 6m- 18/20 (90%) b.) 12m- 19/19 (100%) 2. Normalized esophageal pH- a.) 6m- 21/39 (54%) b.) 12m- 17/38 (45%) 3. Mean Demeester Score (48 hr pH study)- a.) Baseline- 35.28 b.) 6m- 23.64 c.) 12m- 25.32

1. Baseline- a. Daily- 100% b. Occasional- 0% c. None- 0% 2. 6m- a.) Daily- 2% b.) Occasionally- 8% c.) None- 90% 3. 12m- a.) Daily-3% b.) Occasionally- 15% c.) None- 82%

12 months

None None Flatulence- 1/39

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

4. Mean RSI

d-

a.) Baseline- 22.00 b.) 6m- 4.64 c.) 12m- 4.79

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

High dose PPI

b

for first 6 months, followed by TIF

twenty three/ two

maximal labelled dose of PPI

b,

split into twice daily regimen for 6 m followed by esophyX-2 device via flexible endoscope

TIF 2.0 protocol

1. Resolution of regurgitation and atypical symptoms - a.) 6m- 1/21 (.05%) b.) 12m-6/9 (67%) 2. Mean GERD-HRQL

e-

a.) Baseline- 26.43 b.) 6m- 18.86 c.) 12m- 10.05 3. Mean RDQ

c-

a.) baseline- 3.04 b.) 6m- 2.14 c.) 12m- 1.33 4. Mean RSI

d-

a.)

1. Healed esophagitis- a.) 6m- 5/13 (38%) b.) 12m- 11/13 (85%) 2. Normalized esophageal pH- a.) 6m- 11/21 (52%) b.) 12m- 7/21 (33%) 3. Mean Demeester Score (48 hr pH study)- a.) Baseline- 35.79 b.) 6m- 19.29 c.) 12m- 28.60

1. Baseline- a.) Daily- 100% b.) Occasionally- 0% C.) None- 0% 2. 6m- a.) Daily- 100% b.) Occasionally- 0% c.) None- 0% 3. 12m- a.) Daily-10% b.) Occasionally- 9% c.) None- 71%

None None None

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

Baseline- 22.62 b.) 6m-19.62 c.) 12m-8.76

2

Toomey et al. 2014, U.S.A [9]

Case- control study with prospective follow up

TIF

GERD refractory to or requiring open ended medical therapy

1. Hital hernia > 2 cm 2. Esophageal dysmotility

20


DNAf

1. Patient satisfaction at follow up - 67% 2. Patients with

DNAf DNA

f

DNAf

None None None

Operating time (OT)- 71 min HSL

h- 1

day

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

symptom frequecy (< 1/month) - 83%

Toupet fundoplication

GERD refractory to or requiring open ended medical therapy with abnormal esophageal motility

1. Failed surgical fundoplication in past

20 DNAf LESS

i

1. Patient satisfaction at follow up - 92% 2. Patients with symptom frequecy (< 1/month) - 92%

DNAf DNA

f

DNAf

DNAf NA DNA

f

OTg- 85

min HSL

h- 1

day 10%- operation related complication (severity not reported)

Nissen fundoplication

GERD refractory to or requiring open ended medical therapy with normal esophageal motility

1. Failed surgical fundoplication in past 2. Esophageal dysmotility

20 DNAf LESS

i

1. Patient satisfaction at follow up - 86% 2. Patients with symptom frequecy (< 1/month

DNAf DNA

f

DNAf

DNAf NA DNA

f

OTg- 119

min HSL

h- 2

days 5%- procedure related complication (severity not reported)

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

) - 80%

3

Wilson et al. 2013, U.S.A [10]

Prospective multicenter trial

TIF

Chronic GERD (>1 year), daily PPI

b

use > 6 months, with unsatisfactory response

1. Hiatal hernia > 2 cm (axial), >3 cm (transverse) 2. BMI

a >35

3. Esophageal achalasia 4. Barretts esophagus > 2cm 5. Reflux esophagitis- grade D Los Angeles classification 6. Miscellaneous- gastroparesis, zenker diverticulum, gastroparesis, scleroderma

100/4


TIF 2.0 protocol 240-330 2-5 cm

1. Median GERD-HRQL

e-

a.) Baseline- 24 b.) 6m- 4 c.) 12m- 2 2. Median GERSS

l-

a.) baseline- 26 b.) 6m- 4 c.) 12m- 4 3. Median RSI

d-

a.) Baseline- 20

1. Esophagitis- a.) Healed (12m)- 13/17 (76%) b.) Improved (12m)- 2/17 (12%) 2. Esophageal acid exposure- a.) Normalization (12m)- 14/27 (52%)

1. Baseline- a.) Daily- 92% b.) Occasionally- 8% C.) None- 0% 2. 6m- a.) Daily- 11% b.) Occasionally- 9% c.) None- 80% 3. 12m- a.) Daily-23% b.) Occasionally- 3% c.) None- 74%

12 months

None

1. 5/96- underwent LNF

j

(one had severe vomiting post procedure, two were non compliant with dietary instructions, other two- unspecified reason) 2. 1/96- underwent repeat TIF

At 12 months- a.) De-novo dysphagia- 2 b.) De-novo bloating- 1 c.) Worsening flatulence- 2

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

b.) 6m- 5 c.) 12m- 4

4

Cadiere et al. 2008, Belgium [11]

Prospective Multicenter

TIF

18-80 years , chronic GERD (> 6m) responsive to PPI

b

therapy, with symptom recurrence on discontinuation of PPI

b for

14 days

1. Irreducible hiatal hernia > 2cm 2. Previous failed anti-reflux surgery 3. BMI

a =>35

4. Delayed gastric emptying 5. Esophageal disease- motility disorder, ulcer, biopsy proven

86/7


TIF 1.0 protocol 230 (160-300) 4 cm (2-6)

1. Median GERD-HRQL

e-

a.) Baseline- 24 b.) 6m- 5 c.) 12m- 7

1. Median Demeester Score- a.) Baseline- 34 b.) 6m- 24 c.) 12m- 28

1. Baseline- a. Daily- 100% b. Occasional- 0% c. None- 0% 2. 6m- a.) Daily- 14/86 (17%) b.) Occasionally- 14% c.) None- 69%

12 months

1. Esophageal perforation- 2/86 - successfully repaired surgically 2. Post TIF intraluminal bleeding- treated with endoscopic clips,

3/86- LNF

j

(two were post perforation during TIF , and the third one-reason not specified)

1. Abdominal pain- 1/86 2. Nausea- 1/86

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

Barretts, stricture 6. Reflux esophagitis- grade D Los Angeles classification

3. 12m- a.) Daily- 12/86 (15%) b.) Occasionally- 16% c.) None- 68%

fibrin glue and blood transfusion

5

Rinsma et al. 2014, Netherlands [12]

Prospective Randomized Controlled multicenter trial

Continuation of PPI

b

therapy

Chronic GERD (>6 months), partially responsive to acid suppressive medication

1. Hiatal hernia > 2cm 2. Previous failed anti-reflux surgery 3. BMI

a =>35

4. Esophageal motility disorder on manometry 5. Barretts esophagus 6. Reflux esophagitis- grade D Los Angeles classification

15 NA NA

Mean GERD-HRQL

e-

a.) Baseline- 26.0 b.) 6m- 23.6

1. Distal baseline impedance (Ω) - a.) Baseline- 1088 b.) 6m- 2470 2. Acid exposure time (%)- a.) Baseline- 12.4 b.) 6m- 5.9 3. Mean Acid reflux episodes- a.) Baseline- 65.6 b.) 6m- 33.9

NA 6 months

NA NA NA

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

TIF 32


DNAf

Mean GERD-HRQL

e-

a.) Baseline- 23.7 b.) 6m- 8.5

1. Distal baseline impedance (Ω)- a.) Baseline- 1769 b.) 6m- 2294 2. Acid exposure time (%)- a.) Baseline- 9.7 b.) 6m- 6.9 3. Mean Acid reflux episodes- a.) Baseline- 63.2 b.) 6m- 39.3

DNAf

6 months

DNAf None DNA

f

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

6

Rinsma et al. 2013, Netherlands [13]

Prospective single center study

TIF

Chronic GERD (>6 months), on PPI

b

therapy, dissatisfied or unwilling to continue lifelong PPI

b

therapy

1. Hiatal hernia > 2cm in length 2. Previous failed anti-reflux surgery 3. Esophageal stricture or ulcer 4. Esophageal motility disorder on manometry 5. Barretts esophagus 6. Reflux esophagitis- grade D Los Angeles classification 7. Current pregnancy 8. Severe comorbidity- cardiopulmonary disorder, coagulation disorder, portal hypertension, immunosuppression,

15

EsophyX-TM device via flexible endoscope

TIF 2.0 protocol

1. Mean GERD-HRQL

e-

a.) Baseline- 27.5 b.) 6m- 13.2

1. Mean EGJ distensibility(mm

2/ mm

of Hg)- a.) Baseline- 2.4 b.) 6m- 1.6 2. 24 hr ambulatory impedence pH (upright acid exposure time)(%)- a.) Baseline- 11.7 b.) 6m- 6.6 3. 24 hr ambulatory impedence pH (Liquid reflux episodes)(%)- a.) Baseline- 30.4 b.) 6m- 16.7 4. Total number of TLESR

k-

a.) Baseline- 16.8 b.) 6m- 9.2

1. Baseline- a.) daily - 100% b.) none-0% 2. 6m- a.) daily (same dose)- 1/15 (6.7%) b.) Daily (decreased dose)- 3/15 (20%) c.) None- 11/15 (73.3%), but 1 used non PPI

b

antisecreatory medication

6 months

DNAf None DNA

f

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

morbid obesity

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

7

Testoni et al. 2011, Italy [14]

Prospective single center study

TIF

Symptomatic GERD, on PPI

b

(standard dose twice a day) for a minimum of 3 months

1. Hiatal hernia >3 cm 2. Previous esophageal, gastric or major abdominal surgery 3. Atypical GERD symptoms 4. Biopsy prove Barretts esophagus 5. Esophageal stricture 6. Severe comorbidity- cardio-pulmonary disease and collagen disease

50

EsophyX-TM device via flexible endoscope

TIF 2.0 protocol

1. Mean GERD-HRLQ- a.) Baseline (on PPI

b)- 20

b.) Baseline (off PPI

b)- 46

c.) 12m- 16 d.) 24m- 17 2. Mean GERD-QUAL- a.) Baseline (on PPI

b)- 84

b.) Baseline (off PPI

b)-

114 c.) 12m- 71 d.) 24m- 80

1. pH metry, Johnson demeester score- a.) Baseline- 22 b.) 6m- 18 c.) 24m- 19 2. Impedance, Total refluxes (number)- a.) Baseline- 66 b.) 6m- 38 c.) 24m- 43 3. LES pressure (mm Hg)- a.) Baseline- 8 b.) 6m- 11 c.) 24m- 12

1. 6m- a.) Stopped PPI

b-

61.2% b.) Halved PPI

b-

22.5% C.) On PPI

b-

16.3% 2. 12m- a.) Stopped PPIb- 51.0% b.) Halved PPI

b-

28.6% C.) On PPI

b-

20.4% 3. 6 years- a.) Stopped PPI

b-

35.7% b.) Halved PPI

b-

50.0% C.) On PPI

b-

14.3%

6 years

1. Pneumothorax- 2 subjects- treated successfully with immediate transthoracic drainage

4/50- LNF

j at

12 months secondary to persistent GERD symptoms

DNAf

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

8

Trad et al. 2011, U.S.A [15]

Retrospective

TIF

1. persistent GERD and/ LPR symptoms, not/ partial controlled on antisecreatory medications and 2. Either dissatisfied with current therapy or unwilling to continue taking medications indefinitely

1. Hiatal hernia , axial dimension > 2cm

34/6


TIF 2.0 protocol 270 (240-300) 3 cm (2-4)

1. Median GERD-HRQL

e-

a.) Baseline- 26 b.) 14m- 4 2. Median GRESS score- a.) Baseline- 24 b.) 14m- 3 3. Median RSI

d-

a.) Baseline- 17 b.) 14m- 4

24 hr pH (only 2 subjects)- 1. First subject- Demeester score- baseline-29, post TIF at 14m- 24.5 2. Second subject- baseline- abnormal pH, post TIF at 14m- normal pH

1. Baseline- a. Daily- 25/28 (89%) b. Occasional- 3/28 (11%) c. None- 0/28 2. 14m- a.) Daily- 5/28 (18%) b.) Occasionally- 5/28 (18%) c.) None- 18/28 (64%)

14 months

None

1/28- LNF

j

(likely cause failure of dietary restriction post TIF, causing disruption of reconstructed valve)

None

9

Kumta et al. 2014, U.S.A [16]

Case report

TIF

Subject with achalasia, who underwent peroral endoscopic

None 1 DNAf 270 DNA

f DNA

f DNA

f

DNAf

DNAf DNA

f DNA

f

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

myotomy and developed reflux symptoms refractory to PPI

b

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

10

Hunter et al. 2015, U.S.A [17]

Prospective sham controlled mutlicenter study

TIF f/b 6 months of placebo treatment

18-80 year age group with chronic GERD (>6 months) symptoms and troublesome regurgitation despite daily PPI

b

(40 mg) use

1. Systemic disease- not well controlled 2. BMI

a > 35

3. Esophageal ulcer or stricture 4. Current pregnancy or plan of pregnancy in next 12 months 5. Hiatal hernia > 2 cm 6. Barrett's esophagus > 2 cm 7. Esophagitis- Grade C or D Los Angeles classification 8. Esophageal dysmotility 9. Previous esophageal or gastric surgery 10. Peptic ulcer disease 11. Gastric outlet obstruction

81/1


TIF 2.0 protocol 270 (200 - 340) 3 cm (mid-portion); 1 cm (either corner)

1. Elimination of troublesome regurgitation (6m)- 54/81 (67%) 2. Median Regurgitation RDQ

c

score- a.) Baseline (on PPI

b)-

3.5 (3, 4.3) b.) 6m (on placebo)- 0.5 (0, 1.5) 3. Median Heartburn RDQ

c


b)-

2.6 (1.5,

1. Total number of reflux episodes- a.) Baseline- 135 B.) 6m- 94 2. Percent time pH < 4- a.) Baseline- 9.3 B.) 6m- 6.4 3. DeMeester Score- a.) Baseline- 33.6 B.) 6m- 23.9

By ITTm

analysis- a.) 3m- 10/87 (11%) resumed PPI

b

b.) 18m- 24/87 (28%) resumed PPI

b

6 months

None

By ITTm

analysis- 1. Treatment failure a.) 3m- 10/87 (11%), all resumed PPI

b, no

other intervention done b.) 18m- 24/87 (28%), all resumed PPI

b, no

other intervention done

None

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

or Gastroparesis 12. Portal hypertension or coagulapathy 13. Immunosuppression

3.8) b.) 6m (on placebo)- 0.5 (0, 1.6) 4. Composite median heartburn and regurgitation RDQ

c


b)-

3.1 (2.4, 3.8) b.) 6m (on placebo)- 0.6 (0, 1.3)

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

Sham surgery f/b 6 months of PPI

b

therapy

38/1

EGD and 15 F maloney dilator

30 min for EGD and 15 min for Maloney dilator

1. Elimination of troublesome regurgitation (6m)- 17/38 (45%) 2. Median Regurgitation RDQ

c


b)-

3.8 (2.9, 4.5) b.) 6m (on PPI

b)-

0.8 (0, 2) 3. Median Heartburn RDQ

c


b)-

3.0 (2.0, 4.1)

1. Total number of reflux episodes- a.) Baseline- 125 B.) 6m- 122 2. Percent time pH < 4- a.) Baseline- 8.6 B.) 6m- 8.9 3. DeMeester Score- a.) Baseline- 30.9 B.) 6m- 32.7

DNAf

6 months

None

By ITTm

analysis- 1. Treatment failure a.) 3m- 15/42 (35.7%), 12/15 underwent crossover to TIF b.) 18m- 30/42 (71.4%) underwent crossover to TIF

NA

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

b.) 6m (on PPI

b)-

0.8 (0, 2) 4. Composite heartburn and regurgitation RDQ

c


b)-

3.3 (2.5, 4.0) b.) 6m (on PPI

b)-0.9

(0.1, 2.0)

S.No


Type of study

Intervention



Instrument


Clinical response

Endoscopic response

PPIb

requirement

Follow up period




Miscellaneous facts

a. BMI Body mass index b. PPI Proton Pump Inhibitors c. RDQ Reflux disease questionnaire d. RSI Reflux symptom index e. GERD-HRQL Health related quality of life f. DNA Data not available g. OT Operation time h. HSL Hospital stay length i. LESS Laparo-endoscopic single site j. LNF Laparoscopic Nissen Fundoplication k. TLESR Transient Lower Esophageal sphincter relaxation l. GERSS GERD symptom score m. ITT Intention to Treat analysis

Figure 1: TIF technique creates an esophagogastric fundoplication proximal to the Zline. (Bell & Cadiere. Transoral rotational esophagogastric fundoplication: technical, anatomical and safety considerations. Surgical Endoscopy. 2010. No permission needed as per journal open access policy)

Transoral incisionless fundoplication for refractory GERD Where...

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