Review of antireflux procedures for proton pump inhibitor nonresponsive gastroesophageal reflux disease

Summary

Up to 40% of patients with gastroesophageal reflux disease (GERD) report persistent symptoms despite proton pump inhibitor (PPI) therapy. This review outlines the evidence for surgical and endoscopic therapies for the treatment of PPI nonresponsive GERD. A literature search for GERD therapies from 2005 to 2015 in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews identified 2928 unique citations. Of those, 45 unique articles specific to surgical and endoscopic therapies for PPI nonresponsive GERD were reviewed. Laparoscopic fundoplication (n = 19) provides symptomatic and physiologic relief out to 10 years, though efficacy wanes with time. Magnetic sphincter augmentation (n = 6) and transoral incisionless fundoplication (n = 9) improve symptoms in PPI nonresponders and may offer fewer side effects than fundoplication, though long-term follow-up is lacking. Radiofrequency energy delivery (n = 8) has insufficient evidence for routine use in treating PPI nonresponsive GERD. Electrical stimulator implantation (n = 1) and endoscopic mucosal surgery (n = 2) are newer therapies under evaluation for the treatment of GERD. Laparoscopic fundoplication remains the most proven therapeutic approach. Newer antireflux procedures such as magnetic sphincter augmentation and transoral incisionless fundoplication offer alternatives with varying degrees of success, durability, and side effect profiles that may better suit individual patients. Larger head-to-head comparison trials are needed to better characterize the difference in symptom response and side effect profiles.

ABBREVIATIONS

AF:

anterior fundoplication

EAE:

esophageal acid exposure

EE:

erosive esophagitis

GERD:

gastroesophageal reflux disease

GERD-HRQL GERD:

Health Related Quality of Life Questionnaire

LES:

lower esophageal sphincter

LF:

laparoscopic fundoplication

LNF:

laparoscopic Nissen fundoplication

MSA:

magnetic sphincter augmentation

NERD:

nonerosive reflux disease

PF:

posterior fundoplication

PPI:

proton pump inhibitor

PPINR PPI:

nonresponder

RCT:

randomized controlled trial

RDQ:

reflux disease questionnaire

RFED:

radiofrequency energy delivery

TIF:

transoral incisionless fundoplication

INTRODUCTION

Management of gastroesophageal reflux disease (GERD) is challenging as up to 40% of patients report persistent symptoms despite proton pump inhibitor (PPI) therapy.¹ Procedures to structurally restore the antireflux barrier and reduce reflux events serve as approaches to eliminate GERD and control symptoms that are refractory to acid suppression. Fundoplication, first developed in 1955 by Dr. Rudolph Nissen, and subsequently modified to laparoscopic fundoplication (LF) in 1991, has historically been the gold-standard intervention for PPI nonresponsive GERD.^2,3 While PPI nonresponse is typically considered a predictor of unfavorable outcomes for antireflux surgery, it remains the most common indication for LF.^4,5 Clinicians are often weary of fundoplication due to significant side effects including dysphagia (3%–24%), gas-bloat syndrome, and an inability to vomit.⁶ Despite modifications to the degree of wrap that have lowered the incidence of troublesome complications, minimally invasive alternatives with fewer side effects are desired.^6–8

Magnetic sphincter augmentation (MSA), transoral incisionless fundoplication (TIF), and radiofrequency energy delivery (RFED) are emerging antireflux alternatives for PPI nonresponders (PPINR). The LINX Reflux Management System (Torax Medical, St. Paul, MN), approved in 2012 by the Food and Drug Administration, is a flexible and expandable MSA device placed laparoscopically around the external gastroesophageal junction.^9,10 The magnetic device augments the lower esophageal sphincter (LES) to prevent reflux into the esophagus but may also allow for normal LES opening during swallowing, belching, and vomiting that is not seen with fundoplication.¹¹

TIF uses an endoscopic approach to correct the anatomical defects of the LES via a gastric fundal wrap and plication, similar to LF. EsophyX (EndoGastric Solutions, Redmond, WA, USA) uses a 270° anterior wrap and is the only TIF device currently marketed in the US and studied in PPINR.¹² Lastly, introduced in 2000, RFED to the LES via the Stretta system (Mederi Therapeutics, Greenwich, CT) offers another minimally invasive endoscopic treatment for PPI nonresponsive GERD. While the exact mechanism of action is unclear, RFED may work by increasing LES pressure secondary to inflammation with subsequent fibrosis, decreasing esophagogastric junction compliance, reducing transient lower esophageal sphincter relaxation by neural modulation of the distal esophagus, or by improving gastric emptying.¹³

Patient selection is critical when pursuing antireflux procedures in PPINR as each procedure has unique technique, side effect, therapeutic benefit, and durability profiles. The paucity of head to head trials comparing these techniques, particularly in PPINR, creates a dilemma for clinicians and patients hoping to make informed and evidence-based decisions when deciding between antireflux interventions. Therefore, the purpose of this review is to outline the evidence for surgical and endoscopic therapies for the treatment of PPI nonresponsive GERD.

MATERIAL AND METHODS

Search strategy

We conducted targeted systematic literature searches of articles published in English from 2005 to 2015 in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews on July 10, 2015 (see Supplementary Material for a detailed description of the search strategy and query results). Of 3,259 records retrieved, we removed 331 duplicate records and uploaded the remaining 2,928 records to Covidence for title and abstract screening. Through manual review of the citations of studies meeting inclusion criteria, we identified 40 additional studies that underwent the same screening process (Fig. 1).

Fig. 1.

Search results for GERD surgical and endoscopic therapies between 2005 and 2015 of PubMed, Cochrane, and EMBASE databases and screening process. RF, radiofrequency.

Study and participant selection

Initial study screening of title and abstract was assessed by a single author (LH). All trials evaluating the efficacy of surgical or endoscopic therapies for the management of GERD in adults were eligible for full-text review. After the initial screen, 287 studies underwent independent full-text screening by two authors (LH, AJT). Only full-text articles available in English were included. Studies were limited to PPI nonresponsive populations as defined as persistent typical reflux symptoms (heartburn and regurgitation) despite at least daily PPI. Studies with unclear or complete response to PPIs were excluded, with the exception of systematic reviews and meta-analyses that grouped all responder types. Study populations with primarily or persistent atypical GERD symptoms were excluded. Studies including the following were excluded: subjects <18 years old, specific subsets of patients (i.e. postsurgical reflux), and evaluation of open Nissen fundoplication as LF is now standard of care (with the exception of outcomes following LF from two randomized controlled trials (RCTs) comparing LF with open fundoplication). Devices no longer marketed in the United States were excluded. For studies with multiple publications, we used the publication with the longest follow-up evaluation. Any disagreements during study selection were resolved by a third author (RY).

Outcomes

The primary outcomes of interest were: (1) Improvement in GERD symptoms as assessed by a validated symptom questionnaire or patient report and (2) Physiologic parameters including distal esophageal acid exposure (EAE; % time pH < 4), DeMeester score, reflux events, and erosive esophagitis (EE) healing. Secondary outcomes included ability to stop PPIs and postprocedural side effects. Results of secondary outcomes are reported in the figures.

Data extraction and reporting

Two authors (LH, AJT) independently extracted data using a standardized data extraction form which contained the items: (1) general information: study title, authors, date; (2) study characteristics: design, intervention, and duration of follow-up; (3) patient characteristics: number of patients enrolled, diagnosis of GERD, history and response to PPI therapy; (4) primary outcome measurements: symptomatic and objective response as defined above; (5) secondary outcomes: PPI usage and side effects.

RESULTS

The query returned 287 unique citations on antireflux procedures: 242 were excluded with 45 articles meeting inclusion criteria: LF (n = 19), MSA (n = 6), TIF (n = 9), RFED (n = 8). We identified one study using EndoStim, a laparoscopically implanted LES stimulator and two studies evaluating endoscopic mucosal surgery for PPINR, however, due to the limited evaluation of these therapies for our targeted population, we present the results of those studies in Supplementary Table 1.^14–16

Table 1.

Laparoscopic fundoplication studies—comparison of techniques and cohort studies

References	Study design	PPINR definition	Symptom/QoL improvement	Esoph acid exposure	DeMeester score	No. reflux events	Esophagitis rates	PPI use	Side effects
Comparison of fundoplication techniques
Cao et al.18	RCT•LNF (n = 47) vs. AF (n = 49)•f/u 5 years	Sx uncontrolled for ≥6 months on medical therapy NOS	HB/regurg VAS:•LNFHB: Pre: 7.7 Post: 1.4R: Pre: 6.2 Post: 1.3•AFHB: Pre: 7.8 Post: 1.5R: Pre: 6.3 Post: 1.4	Not reported	•LNFPre: 109.5Post: 9.5•AFPre: 106.9Post: 10.2	Not reported	SM grade >2•LNFPre: 26 Post: 4•AFPre: 24 Post: 9	•LNF: 8.5% (4/47)•AF: 8.2% (4/49)	Dysphagia VAS:•LNFPre: 5.3 Post: 7.2•AFPre: 5.1 Post: 5.3
Pessaux et al.19	Retrospective CoS•LNF (n = 711) vs. PF (n = 559) vs. AF (n = 70)•f/u 7.1 years	Sx uncontrolled on ≥3 months of PPI NOS	Visick grade 1–2•LNF: 661 (93.0%)•PF: 519 (92.8%)•AF: 66 (94.3%)	Not reported	Not reported	Not reported	Not reported	•9.1% (122/1340) resumed anti-secretory medications	Dysphagia•LNF: 7.6% (54/711)•PF: 2.0% (11/559)•AF: 4.3% (3/70)Overall AE•LNF: 8.7% (62/711)•PF: 4.8% (27/559)•AF: 2.8% (2/70)
Lal et al.20	Prospective nonrandomized trial•LNF (n = 25) vs. LTF (n = 25)•f/u 6 weeks	Sx + EE despite OME 20–80 mg daily for ≥8 weeks	DMSS•LNFPre: 4.1 Post: 0.0•LTFPre: 4.1 Post: 0.2	% time pH < 4•LNFPre: 10.2 Post: 0.9•TNFPre: 12.3 Post:1.9	Not reported	Not reported	Not reported	Not reported	Dysphagia:LNF: 20% (5/25)LTF: 0% (0/25)Dysphagia resolved in all by week 4
PPI nonresponsive cohorts
Kelly et al.29	Prospective CoS•LNF (n = 226)•f/u 10 years	Sx uncontrolled on acid-suppressive therapy NOS	Patient satisfaction:•83%HB VAS:•84% good/excellent	Not reported	Not reported	Not reported	Not reported	•21% (47/226) using antacid medication	•no change in VAS dysphagia scores for liquids or solids
Antoniou et al.21	Prospective CoS•LNF (n = 32)•f/u 1 year	Sx uncontrolled on OME 20mg for ≥4 months → Sx despite OME 40 mg for 8–10 weeks	•87% pt satisfaction% w/ HB•Pre: 60% Post: 0%% w/ Regurgitation•Pre: 93% Post: 13%	Not reported	Not reported	Not reported	Not reported	•17% (5/30) using PPI	Not reported
Broeders et al.26	RCT•LNF (n = 79)•f/u 10 years	Sx + persistent EE or EAE despite OME ≥40 mg	Visick grade I–II•92.4% (73/79)	Not reported	Not reported	Not reported	Not reported	27% (21/79) using PPI	Not reported
Brillantino et al.25	Prospective CoS•LNF (n = 35)•f/u 1 year	Sx + EAE despite OME 40 mg or LAN 30 mg for ≥3 months	GERD-HQRL•Pre: 20.1 Post: 3.5	% time pH < 4•Pre: 4.9 Post: 2.1	Not reported	Not reported	•Pre: 72% (25/35)•Post: 3.5% (1/28)	Not reported	•Transient dysphagia: 7.1% (2/28)
Broeders et al.22	Prospective CoS•LNF (n = 31)•f/u 1 year	Sx uncontrolled on PPI NOS	GERD HRQL•Pre:18.6 Post: 1.6	Total EAE (%)•Pre: 13.8 Post: 1.1	Not reported	Acidic Reflux•Pre: 76.0 Post 1.6Weak acidic reflux•Pre: 13.6 Post: 5.7	•Pre:48% (15/31)•Post:17% (5/30)	Not reported	•6.6% (2/31) developed air swallowing, gastric belching
Tosato et al.24	Prospective CoS•LNF (n = 36)•f/u 1 year	Sx uncontrolled on PPI NOS	GERD HQRL•Pre: 25 Post: 5	Not reported	•Pre: 30.7•Post: 7.6	Not reported	‘…complete healing of esophagitis in all patients’	•5.5% (2/36) using PPI	•Dysphagia at 3 months: 19.4%(7/36)•0% dysphagia @ 12 months
Frazzoni et al.27	Prospective CoS•LNF (n = 44)•f/u 3 years	Sx + EAE despite 4 weeks high-dose PPI NOS	Cure rate: 89% (34/38)	% time pH <4:•Pre: 1 Post: 0.1	Not reported	Total Reflux•Pre: 68 Post: 8Acid Reflux•Pre: 10 Post: 3Weak acid reflux•Pre: 50 Post: 4	Not reported	•89% (34/38) discontinued PPI	•5.3% (2/38) w/ severe dysphagia treated successfully w/ dilatation
Kellokumpu et al.23	Prospective CoS•LNF (n = 139)•f/u 10.2 years	Sx uncontrolled on medication NOS or EE despite ≥3 months of PPI NOS	Cure rate: 72.9%	% time pH<4•Pre: 11.5•Post: 0.6	Not reported	Not reported	EE rates @ 3 months•Pre:73% (181/249)•Post: 1.6% (245/249)	•12% (16/139) using PPI on daily/weekly basis	•↓ belching ability: 61.2%•↑ rectal flatulance: 91.4%•↑ bloating: 71.9%•Inability to vomit: 30.9%
Nomura et al.28	Prospective CoS•LNF (n = 4) and LTF (n = 4)•f/u 1 year	Sx + SI+ despite RBZ 10 mg twice daily for ≥8 weeks	Patient satisfaction:•Good: 87.5% (6/8)•Excellent: 12.5% (2/8)	Not reported	Not reported	Total Reflux events (n = 4)•Pre: 342 Post: 106	Not reported	Not reported	‘dysphagia which resolved within 2 months w/o treatment’

AF, anterior fundoplication, CoS, cohort study, DMSS, DeMeester symptom score, EAE, esophageal acid exposure, EE, erosive esophagitis, Esoph, Esophageal, f/u, follow-up, GERD-HRQL, gastroesophageal reflux disease Health Related Quality of Life, HB, heartburn, LAN, lansoprazole, LNF, laparoscopic Nissen fundoplication, LTF, laparoscopic Toupet fundoplication, mo, months, NOS, not otherwise specified, OME, omeprazole, PF, posterior fundoplication, PPI, proton pump inhibitor, QoL, quality of life, RBZ, rabeprazole, RCT, randomized controlled trial, SI, symptom index, SM, Savary-Miller esophagitis score, Sx, symptoms, VAS, visual analog scale.

Laparoscopic fundoplication

A systematic review of 17 studies published between 1966 and 2011 describing outcomes specific to PPINR following LF found a one-year reduction in EAE from 8.5%-17.8% (off PPI) to 0.3%–1.8% and from 0.5%-4.9% (on PPI) to 0.5%–2.0%, improvement in GERD Health Related Quality of Life Questionnaire (GERD-HRQL) (12–20.1 to 1–3.5), and reduction in incidence of EE from 63.6% to 8%.¹⁷ However, 10 years post-LF, nearly 35% of patients experienced recurrent heartburn, 30% reported regurgitation, and PPI use increased from 8.8% at 1 year to 18.2%. Additionally, 9.6% of patients required surgical reintervention within 10 years.

Three studies compared fundoplication techniques in PPINR (Table 1). In an RCT of 100 patients randomized to anterior fundoplication (AF) or conventional laparoscopic Nissen fundoplication (LNF), heartburn and regurgitation as measured by a visual analog scale significantly improved with both AF and LNF at 5 years.¹⁸ Similar reductions in DeMeester scores were also observed between groups. There was no statistically significant difference in PPI usage after 5 years. Similarly, in a retrospective cohort study of 1340 patients undergoing LNF, partial posterior fundoplication (PF), or AF, satisfaction rates were comparable across all surgical techniques.¹⁹ Likewise, in a cohort study comparing LNF versus Toupet fundoplication, similar reductions in DeMeester symptom scores and EAE were reported at 6 weeks.²⁰

Nine other studies (one RCT, seven prospective cohorts, and one retrospective cohort) reported outcomes of varying LF techniques in PPINR with follow-up ranging from 1 to 10.2 years.^21–29 In three studies, symptoms improved as measured by GERD-HRQL score from 18.6–25 to 1.6–5.^22,24,25 At 10 years, Broeders et al. reported resolution or improvement of symptoms in 92.4% of patients.²⁶ Kelly et al. also reported improvement in symptoms at 10 years using a visual analog scale.²⁹ The other four studies report satisfaction/cure rates from 84.9%-100%.^21,23,27,28 Objectively, four studies reported significant reductions in EAE from 11.5%-13.8% off PPI to 0.6%–1.1% and 1.0%–4.9% on PPI to 0.1%–2.0%.^22,23,25,27 Tosato et al. also found a reduction in DeMeester score from 30.7 to 7.6 at 1 year.²⁴ In two studies, LF also significantly reduced total reflux events from 68–76 to 1.6–8, as well as weakly acidic refluxes from 13.6–50 to 4–5.7.^22,27 Across four studies, EE healing rates ranged from 66%-100%.^22–25 PPI use at 1–3 years ranged from 5.5%–16.7% and rose to 15%–26.6% at 10 years.^{21,23,24,26,27,29} Three prospective cohort studies compared the effectiveness of LF between PPI responsive and nonresponsive populations (Table 2).^30–32 All studies found symptom improvement in PPINR, though when compared to responders, symptom control was slightly lower. Additionally, post-LF outcomes in PPINR were similar in cases of nonerosive reflux disease (NERD) and EE, as well as in those with positive and negative symptom indices.^33–35

Table 2.

Laparoscopic fundoplication studies—comparison of population subsets

Reference	Study design	PPINR definition	Symptom/QoL improvement	Esoph acid exposure	DeMeester score	No. reflux events	Esophagitis rates	PPI use	Side effects
Comparison of PPI responders and nonresponders
Wilkerson et al.32	Prospective CoS	Sx uncontrolled on OME 40 mg or LAN 60 mg	Visick grade I-II	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
	•LNF•PPIR (n = 233) vs. PPINR (n = 91)•f/u 1 year		•PPIR: 94% (218/223)•PPINR: 87% (79/91)
			DMSS
			•PPIR: Pre: 5 Post: 0
			•PPINR: Pre: 5 Post: 1
Borie et al.30	Prospective CoS	Sx uncontrolled on PPI NOS	GIQLI	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
	•LNF		•PPIR:
	PPIR (n = 16) vs. PPINR (n = 19)•f/u 72 months		Pre: 99.3 Post: 111.2•PPINR:Pre: 94.6 Post: 107.4
Hamdy et al.31	Prospective CoS	Sx uncontrolled on 20–40 mg PPI NOS for ≥2 months	% w/o HB	% total reflux time:•PPIR:	•PPIR	Not reported	•PPIR	Not reported	Not reported
	•LNF•PPIR (n = 296) vs. PPINR (n = 74)•f/u 1 year		•PPIR: 93%•PPINR: 73%% w/o Regurg•PPIR: 96%•PPINR: 84%		Pre: 35.3 Post: 5.1		Pre: 87% (256/296)
				Pre: 11.3 Post: 0.9	•PPINRPre: 39.9 Post: 5.0		Post: 6% (14/234)•PPINRPre: 80% (59/74)Post: 13% (8/62)
				•PPINRPre: 9.7 Post: 0.7
Comparison of PPINR subgroups
Kamolz et al.34	Prospective CoS•LNF•EE (n = 89) vs. NERD (n = 89)•f/u 5 years	Sx uncontrolled on 20–80 mg PPI NOS	GIQLI•EE:Pre: 93.8 Post: 120.9•NERD: Pre: 81.7 Post: 121.2	Not reported	•EE:	Not reported	No patients with evidence of EE in either group	•1 patient in NERD group using on-demand PPI, 0 in EE group	•No long-term side effects at 5 years
					Pre: 59.7 Post:5.9•NERD:Pre: 41.4 Post:6.3
Broeders et al.33	Prospective CoS	Sx uncontrolled on OME 40 mg	Visick I–II	% time pH < 4	Not reported	Not reported	3 months post-LNF:•EE: 13% (12/94)•NERD: 7.1% (5/70)	•EE	Not reported
	•LNF		•EE: 96% (66/69)	•EE				Pre: 81% (79/97)
	•EE (n = 117) vs. NERD (n = 96)•f/u 5 years		•NERD: 89% (68/76)	Pre: 13.8 Post: 2.9•NERDPre: 12.7 Post: 2.0				Post: 15% (10/66)•NERDPre: 82% (68/83)Post: 21% (15/71)
Broeders et al.35	Prospective CoS	Sx uncontrolled on OME 40mg	Visick grade I-II	% time pH < 4	Not reported	Not reported	•SI+	Antisecretory Med	Post-LNF Dysphagia
	•LNF		•SI+: 87% (60/69)	•SI+			Pre: 61% (54/89)	•SI+	•SI+: 44% (29/66)
	•SI+ (n = 109) vs. SI− (n = 29)•f/u 5 years		•SI−: 95% (20/21)	Pre: 11.1 Post: 0.2			Post: 12% (13/89)	Pre: 85% (81/95)	•SI-: 53% (10/19)
				•SI-			•SI-	Post: 14% (9/63)
				Pre: 13.4 Post: 1.6			Pre: 44% (8/18)	•SI-
							Post: 6% (1/18)	Pre: 80% (20/25)
								Post: 25% (5/63)

CoS, cohort study, DMSS, DeMeester symptom score, EAE, esophageal acid exposure, EE, erosive esophagitis, Esoph, Esophageal, f/u: follow-up, GIQLI, Gastrointestinal Quality of Life Index, HB, heartburn, LAN, lansoprazole, LNF, laparoscopic Nissen fundoplication, mo, months, NERD, nonerosive reflux disease, NOS, not otherwise specified, OME, omeprazole, PPI, proton pump inhibitor, PPIR, PPI responder, PPINR, PPI nonresponder, QoL, quality of life, SI, symptom index, Sx, symptoms.

Laparoscopic magnetic sphincter augmentation

Five cohort studies prospectively enrolled PPINR who received MSA with follow-up ranging from 4 weeks to 5 years (Table 3).^36–40 Symptom response as measured by median GERD-HRQL significantly improved in all studies decreasing from 24–29 at baseline off PPI to 3.3–6 post-treatment.^36–40 Bonavina et al. found MSA significantly reduced EAE, normalized or reduced acid exposure by >50% in 80% of patients, reduced baseline DeMeester Score, and decreased total reflux episodes at median follow-up time of 4.2 years.³⁷ Lipham et al. likewise found a reduction in EAE, normalization of pH in 80% of patients, and a reduction in DeMeester score at median follow-up time 3.7 years; though the reduction in reflux episodes was nonsignificant.³⁶ In the only study that reported healing of esophagitis, Ganz et al. found healing of esophagitis in 76.5% of patients at 5 years.⁴⁰ Complete cessation of all PPI use was achieved in 71.4%–85.3%, with 75.3% of patients reporting complete cessation and 9.4% reporting on demand PPI use at longest follow-up of 5 years.^36–40

Table 3.

Summary of magnetic sphincter augmentation studies

References	Study design	PPINR definition	Symptom/QoL improvement	Esoph acid exposure	DeMeester score	No. reflux events	Esophagitis rates	PPI use	Side effects
Lipham et al.36	Prospective CoS	Sx uncontrolled on PPI NOS	GERD-HRQL	% time pH < 4	Pre: 42.3	Pre: 112.5	Not reported	•80% (16/20) discontinued PPI	•43% (20/44) experienced mild dysphagia,•4.5% (2/44) unable to belch or vomit
	•n = 44		•Pre: 25.7 Post: 3.3	•Pre: 11.9%	Post: 14.7	Post: 70.2
	•f/u 3.7 years			•Post: 3.8%
Bonavina et al.37	Prospective	Sx uncontrolled on PPI NOS	GERD-HRQL	% time pH < 4	Pre: 30.1	Pre: 51.7	Not reported	•85% (81/95) discontinued PPI	•Dysphagia: 8% → 0%
	Case series		•Pre: 24 Post: 2	•Pre: 8.0%	Post: 11.2	Post: 31.5			•Inability to belch: 1% (1/100)
	•n = 100			•Post: 3.2%
	•f/u 3 years
Schwameis et al.38	Prospective CoS	Partial Sx response on PPI NOS	GERD-HRQL	Not reported	Not reported	Not reported	Not reported	•71% (15/21) discontinued PPI	•Dysphagia: 70% (n/a)
	•n = 23		•Pre: 29 Post: 4						•Regurgitation: 50% (n/a)
	•f/u 4 weeks								Resolved within first 4 weeks
Smith et al.39	Prospective CoS•n = 66•f/u 5.8 months	Sx uncontrolled on PPI NOS (nine patients with normal EAE on PPI but abnormal nonacid reflux)	GERD-HRQL•Pre: 26 Post: 6	Not reported	Not reported	Not reported	Not reported	•83% (54/65) discontinued PPI	•No peri-operative complications
Ganz et al.40	Prospective CoS•n = 85•f/u 5 years	Partial response to PPI NOS defined as GERD-HRQL <10 on PPI, >15 off PPI, or >6-point improvement on PPI	GERD-HRQL•Pre: 27 Post: 4	Not reported	Not reported	Not reported	EE Healing Rate•76.5% (26/34)	•75% (64/85) discontinued PPI	•Dysphagia: 5% → 6%•Bloating: 52% → 9.3%•100% reported ability to belch and vomit
Riegler et al.41	Prospective	Sx uncontrolled on PPI NOS	GERD-HRQL	Not reported	Not reported	Not reported	Not reported	PPI Discontinuation:	Dysphagia:
	Observational study		•MSA: Pre: 20 Post: 3					•MSA: 82% (n/a)	•MSA: 7.0% LF: 10.6%
	•MSA (n = 249) vs.		•LF: Pre: 23 Post: 3.5					•LF: 63% (n/a)	Bloating:
	•LF (n = 47)								•MSA: 10.0.0% LF: 31.9%
	•f/u 1 year

CoS, cohort study; EAE, esophageal acid exposure; EE, erosive esophagitis; Esoph, Esophageal, f/u, follow-up, GERD-HRQL, Gastroesophageal reflux disease Health Related Quality of Life, LF, laparoscopic fundoplication, MSA, magnetic sphincter augmentation, n/a, not available, NOS, not otherwise specified, PPI, proton pump inhibitor, QoL, quality of life.

Comparing MSA to LF in a prospective observational study, Riegler et al. reported similar improvements in median GERD-HRQL scores at 1 year; however, discontinuation of PPI use was significantly greater for MSA patients compared to the LF patients.⁴¹

Transoral incisionless fundoplication

We identified one systematic review evaluating TIF and eight studies specific to PPINR (Table 4). A systematic review of 15 observational studies published between 2006 and 2012 reported the impact of TIF on both symptomatic and physiologic GERD indices, but studies were not exclusive to PPINR.⁴² Across 10 studies, TIF reduced mean GERD-HRQL from 21.9 to 5.9 and resulted in a PPI discontinuation of 67% at mean follow-up of 9.8 months.

Table 4.

Summary of transoral incisionless fundoplication studies

References	Study design	PPINR definition	Symptom/QoL improvement	Esoph acid exposure	DeMeester score	No. reflux events	Esophagitis rates	PPI use	Side effects
Trad et al.43	RCT	Sx uncontrolled on PPI NOS	GERD-HRQL	MD time pH < 4	MD:	MD:	•TIF: 90% (18/20)•PPI: 38% (5/13)	•TIF: 90% (35/39) discontinued PPI	•No serious adverse events, de novo dysphagia or bloating in either group
	•TIF (n = 40) vs. PPI (n = 23)•f/u 6 months		•TIF: Pre: 27 Post: 4	•TIF: -3.4	•TIF: -11.6	•TIF: -55.9
			•PPI: Pre: 26 Post: 19	•PPI: -5.5	•PPI: -16.5	•PPI: -99.1
Hunter et al.44	Sham controlled trial	Sx uncontrolled on ≥ 40 mg PPI NOS	RDQ	% time pH < 4	•TIF	•TIF	EE Healing Rate	•28% (24/87) resumed PPI post-TIF at 18 months	•No difference in complications or adverse events between groups
	•TIF → placebo (n = 87) vs sham → PPI (n = 42)		•TIFPre: 3.1 Post: 0.6	•TIFPre: 9.3 Post: 6.4	Pre: 33.6 Post:23.9•Sham	Pre: 135 Post: 94•Sham	•TIF: 77% (10/13)•Sham: 50% (1/2)
	•f/u 6 months		•Sham	•Sham:	Pre: 30.9 Post: 32.7	Pre: 125 Post: 122
			Pre: 3.3 Post: 0.9	Pre: 8.6 Post: 8.9
Barnes et al.45	Retrospective CoS	Sx uncontrolled on double-dose PPI NOS	GERD-HRQL	Not reported	Not reported	Not reported	Not reported	•93% (102/110) discontinued PPI	•No post-operative dysphagia or odynophagia
	•n = 123		•Pre: 28 Post: 2
	•f/u 7 months		RSI
			•Pre: 29 Post: 4
Ihde et al.47	Retrospective CoS	Sx uncontrolled on PPI NOS	GERD-HRQL	Not reported	Not reported	Not reported	Not reported	•67% (28/42) discontinued PPI	•1 esophageal perforation
	•n = 42		•Pre: 29 Post: 3						•No reports of dysphagia or inability to vomit/belch
	•f/u 6 months		RSI
			•Pre: 19 Post: 4
Petersen et al.48	Prospective CoS	Sx + EAE despite PPI NOS for >3 months	Likert Scale (0-4)	% time pH < 4.5	Pre: 32.5	Pre: 81	Not reported	•42% (8/19) discontinued PPI	•Dysphagia:16% (3/19)
	•n = 22		HB frequency	•Pre: 8.9%	Post: 19.3	Post: 48			•Bloating: 21% (4/19)
	•f/u 6.7 months		•Pre: 4 Post: 2	•Post: 3.8%
			RG Frequency
			•Pre: 3 Post: 2
Trad et al.46	Retrospective CoS	Sx uncontrolled on PPI NOS	GERD-HRQL	Reported for 1 patient	Reported for 1 patient	Not reported	Not reported	•64% (18/28) discontinued PPI	•No peri-operative complications
	•n = 28		•Pre: 26 Post: 4
	•f/u 14 months		RSI
			•Pre: 17 Post: 4
Bell et al.49	Prospective CoS	Sx uncontrolled on PPI NOS	GERD-HRQL	Not reported	Not reported	Not reported	Not reported	•70% (110/158) discontinued PPI	•2 procedures aborted due to small esophageal tear
	•n = 158		•Pre: 28 Post: 5
	•f/u 22 months		RSI
			•Pre: 26 Post: 5.5
Frazzoni et al.50	Prospective open-label trial•TIF (n = 10) vs. LF (n = 10)•f/u 3 months	Sx + EAE or SI+ despite high-dose PPI NOS ≥4 weeks	•30% (3/10) Sx remission with TIF•100% (10/10) Sx remission with LF	% time pH < 4•TIF: Pre: 0 Post: 3•LF: Pre: 0.5 Post: 0	Not reported	TIF•Pre: 96 Post: 101LF•Pre: 122 Post: 34	EE rates @ 3 months•TIF:20% (2/10)•LF: 0% (0/10)	Not reported	•20% (2/10) de novo dysphagia after LF and 10% (1/10) after TIF•20% (2/10) de novo bloating after LF

CoS, cohort study, EAE, esophageal acid exposure, EE, erosive esophagitis, Esoph, Esophageal, f/u, follow-up, GERD-HRQL, Gastroesophageal reflux disease Health Related Quality of Life; HB, heartburn; LF, laparoscopic fundoplication; MD, mean difference; NOS, not otherwise specified; PPI, proton pump inhibitor; QoL, quality of life; RCT, randomized controlled trial; RDQ, Reflux Disease Questionnaire; RG, regurgitation; RSI, Reflux Symptom Index, Sx, symptoms, TIF, transoral incisionless fundoplication.

In a multicenter RCT comparing TIF to PPI therapy in partial responders, 62% of patients reported complete resolution of daily symptoms 6 months post-TIF compared to 5% of patients on PPI.⁴³ In both groups, median total GERD-HRQL and Reflux Disease Questionnaire (RDQ) scores significantly improved, but for patients with abnormal distal EAE off PPI at baseline, the change in mean GERD-HRQL and RDQ scores was only significantly improved with TIF. Rates of EAE normalization were comparable between groups and both groups experienced significant improvements in DeMeester score. TIF achieved greater rates of esophagitis healing compared to PPI therapy. In a sham controlled trial of patients treated with TIF/placebo or sham/omeprazole, patients reported a greater elimination of troublesome regurgitation symptoms in the TIF/placebo arm versus the sham/PPI arm at 6 months; however, symptom improvement measured by RDQ was comparable.⁴⁴ TIF was associated with a significant decrease in EAE, improvement in DeMeester score and reduction in reflux episodes (135 to 94) while these parameters remained unchanged in the sham arm. At 18 months, 28% of patients in the TIF group had resumed PPI.

Two prospective and three retrospective cohort studies, follow-up ranging from 6 to 22 months, enrolled PPINR to receive TIF.^45–49 Four studies found significant improvement in symptoms measured by reductions in pretreatment median GERD-HRQL scores on PPI from 26–29 to 2–5.^45–47,49 Using a Likert scale, Petersen et al. reported an improvement in the frequency and severity of heartburn symptoms but no change in baseline of regurgitation symptoms.⁴⁸ Petersen et al. was the only cohort study to report physiologic parameters finding a significant reduction in total EAE and DeMeester scores with a nonsignificant reduction in reflux episodes at 6 months.⁴⁸ In five studies, complete PPI therapy discontinuation was achieved in 42%–93%.^45–49

In a small open-label trial of 20 patients with persistent symptoms despite twice daily PPI choosing to undergo either TIF or LF, Frazzoni et al. reported 100% symptom remission in the LF group at 3 months compared to only 30% in the TIF group.⁵⁰ The EAE time was normal in 100% of cases after LF and 50% after TIF with significantly fewer distal and proximal reflux events in the LF group.

Radiofrequency energy delivery

Our search retrieved two systematic reviews evaluating RFED and six cohort studies specific to PPINR (Table 5). Perry et al. performed a systematic review of 20 publications (two RCTs and 18 cohort studies) with mean follow-up of 17 months reporting significant improvement in symptoms (GERD-HRQL 26.11 vs. 9.25), EAE (10.39 vs. 6.51), and DeMeester score (44.37 vs. 28.53).⁵¹ In 2013, based off these results, the Society of American Gastrointestinal and Endoscopic Surgeons recommended RFED with a high level of evidence for PPINR.⁵² In 2015, Lipka et al. subsequently published a meta-analysis limited to RCTs after raising concerns about the methodology and quality of the prior systematic review.⁵³ Their meta-analysis of four RCTs, two of which were published after Perry et al., found no significant benefit of RFED over sham therapy for EAE, mean LES pressure, ability to stop PPI use, or GERD-HRQL and concluded that the overall quality of evidence on the efficacy of RFED is low.⁵³

Table 5.

Summary of radiofrequency energy delivery studies

References	Study design	PPINR definition	Symptom/QoL improvement	Esoph acid exposure	DeMeester score	No. reflux events	Esophagitis rates	PPI use	Side effects
Arts et al.54	Prospective CoS	Partial Sx response to ESO or LAN dose NOS	14 Question Sx Score	% time pH<4	•Pre: 46.8	Not reported	•Pre: 54% (7/13)	•38% (5/13) discontinued PPI•62% (8/13) discontinued or reduced PPI use	•7.7% (1/13) developed post-RFED ulceration
	•n = 13		•Pre: 12.5 Post: 7.5	•Pre: 11.6%	•Post: 7.3		•Post: 31% (4/13)
	•f/u 6 months			•Post: 8.5%
Liang et al.55	Prospective CoS	Sx uncontrolled on PPI NOS	Likert Scale (0–6)	Not reported	Not reported	Not reported	Not reported	•43% (59/138) discontinued PPI	•No perforations, mucosal lacerations, bleeding episodes
	•n = 138		HB Score
	•f/u 5 years		•Pre: 5.9 Post: 2.5
			RG Score
			•Pre: 5.6 Post: 2.2
Liu et al.56	Prospective CoS	Sx uncontrolled on PPI NOS	GERD-HRQL	Not reported	Not reported	Not reported	•Pre: 46% (n/a)	•77% (n/a) discontinued or reduced PPI use	•No serious complications
	•n = 90		•Pre: 25.6 Post: 8.1				•Post: 20% (n/a)		•5.6% (5/90) dyspepsia
	•f/u 1 year								•5.6% (5/90) mucosal injury
									•All resolved <1 week
Mavrelis et al.57	Prospective CoS	Sx uncontrolled (GERD-HRQL >15) on at least double-dose PPI NOS	GERD-HRQL	Not reported	Not reported	Not reported	Not reported	•6.3% (2/32) discontinued PPI•63% (20/32) discontinued or reduced PPI use	•No perforations or bleeding episodes
	•n = 32•f/u 2.5 years		•Pre: 24.3 Post: 14.2						•3.1% (1/32) prolonged gastroparesis
Noar et al.58	Prospective CoS•n = 99•f/u 10 years	Sx uncontrolled on twice daily PPI NOS	GERD-HRQL•Pre: 27.8 Post: 8.6	Not reported	Not reported	Not reported	Not reported	•41% (41/99) discontinued PPI	•50% experienced minor transient Sx lasting <2 weeks (i.e. dyspepsia, chest discomfort)
								•75% (74/99) discontinued or reduced PPI use
Reymunde et al.59	Prospective	Partial Sx response to PPI NOS	QOLRAD	Not reported	Not reported	Not reported	•Pre: 83% (69/72)	•86% (69/80) discontinued PPI•89% (71/90) discontinued or reduced PPI use	•No serious complications
	Case series		•Pre: 2.4 Post: 4.3				•Post: 51% (37/72)
	•n = 83		GERD Symptom Score
	•f/u 4 years		•Pre: 2.7 Post: 0.6

CoS, cohort study; EE, erosive esophagitis, Esoph, Esophageal, ESO, esomeprazole, f/u, follow-up; GERD, gastroesophageal reflux disease, GERD-HRQL, Gastroesophageal reflux disease Health Related Quality of Life; HB, heartburn; LAN, lansoprazole; n/a, not available; NOS, not otherwise specified; PPI, proton pump inhibitor; QoL; quality of life; QOLRAD; Quality of Life in Reflux and Dyspepsia; RG, regurgitation; Sx, symptoms.

Specific to PPINR, we identified six cohort studies with follow-up time ranging from 6 months to 10 years.^54–59 Three studies using GERD-HRQL to measure symptom response reported a significant reduction from a baseline scores off PPI of 25.6–27.8 to post-treatment scores of 8.1–17.1.^56–58 Reymunde et al. found a significant reduction in symptoms and an improvement of their Quality of Life in Reflux and Dyspepsia scale at 4 years.^59,60 Arts et al. measured symptom response using a 14-question symptom score reporting a significant reduction from pretreatment scores off PPI of 12.5 to 7.5 at 6 months; however, post-treatment scores were not significantly different from baseline scores on PPI (7.2).^54,61 Liang et al., utilizing a six-point Likert scale to measure the frequency and severity of symptoms, found a significant improvement in heartburn scores and regurgitation scores 5 years after RFED therapy.⁵⁵ Studies reported a wide range for patients with complete PPI cessation (6.3%–86%), though overall PPI use was reduced in 43%–89% of patients.^54–59

Arts et al., the only study to report physiologic parameters, found a significant, though modest, reduction in baseline EAE from 11.6% to 8.5% and a corresponding improvement in DeMeester score from 46.8 to 35.6.⁵⁴ There was no significant change in resting LES pressure (17.3 vs. 18.2 mm Hg). Healing of EE at 1 year was reported in 80.5% of patients at by Liu et al. and 38.3% by Reymunde et al.^56,59

DISCUSSION

In this systematic search strategy, we present a narrative review of 45 studies from 2005 to 2015 regarding surgical and endoscopic therapies for PPI nonresponsive GERD; variability in study design and poor quality of outcome reporting did not allow for head-to-head comparisons.

LF remains the most well-studied therapy for PPI nonresponsive GERD with the longest follow-up out to 10 years. LF provides both symptomatic and physiologic relief of acid reflux, including patients with NERD and those with negative symptom indexes.^{23,26,29,33,35} Efficacy does wane with time as roughly one in three patients experience recurrence of symptoms, and one in five patients require antisecretory medication; however, no other therapy has follow-up past 5 years.¹⁷ Newer techniques using partial fundoplication have also been reported to have fewer postoperative complications. According to a recent meta-analysis, AF is associated with lower rates of post-operative dysphagia than PF; however at the expense of a higher recurrence rate.⁶²

MSA appears to be an effective alternative to LF for the treatment of PPINR. In five cohort studies, MSA improved symptoms out to 5 years in PPINR. Approximately 25% restarted acid suppressive medication 5 years post-MSA, comparable to rates seen with LF.⁴⁰ In the only small observation comparison study between MSA and LF, GERD-HRQL scores were comparable though patients treated with MSA had greater discontinuation of PPIs.⁴¹ Additionally, rates of dysphagia were comparable between MSA and LF, but, MSA was associated with lower rates of bloating, inability to belch and vomit suggesting a more favorable side effect profile for MSA.⁴¹ This study and two retrospective case-control studies, albeit not in PPINR, were included in a meta-analysis comparing MSA to LF that found MSA was superior in preserving the ability to belch and vomit without significant differences in gas-bloat, dysphagia, or PPI discontinuation.^63–65 Other characteristics favoring MSA over LF include a less extensive surgery, removal via minimally invasive techniques, and less intersurgeon variability due to the standardized device. Use of MSA, however, is less versatile than LF as it is not indicated for patients with severe EE or large hiatal hernia. Additionally, MSA has never been evaluated in an RCT, neither in PPI responders or nonresponders, though the CALIBER trial is currently enrolling patients in an RCT comparing omeprazole 20 mg twice daily to MSA. Also of note, the MSA is magnetic resonance imaging (MRI) compatible.⁶⁶

TIF offers a nonsurgical treatment for PPINR that has shown an ability to improve symptoms and reduce EAE. PPI usage is slightly higher in TIF than that seen with LF or MSA, and symptom remission was found to be lower than LF in a small comparison trial.⁵⁰ Though the longest follow-up time is 22 months in PPINR, TIF has been shown to be effective in PPI responsive patients at 6 years.⁶⁷ Wendling et al. reports a dysphagia rate of 0.5% with TIF, which is dramatically lower than rates typically reported with LF or MSA; however, these data are all from observation studies rather than head-to-head comparisons.⁴² Some investigators have argued TIF may be a valuable treatment for patients at higher risk of developing dysphagia due to esophageal dysmotility, though ineffective esophageal motility is an independent risk factor for TIF failure.⁶⁷

All six cohort studies evaluating RFED reported improvement in symptoms but with less impressive PPI discontinuation rates seen with LF, MSA, or TIF. Additionally, while the one study reporting physiologic parameters found a reduction in EAE, it failed to demonstrate normalization of EAE.⁵⁴ Given the uncertain mechanism of action of RFED, the symptomatic improvement without concurrent physiologic changes may suggest a placebo effect of the procedure. The recent meta-analysis by Lipka et al. has called into question the routine use of RFED for the treatment of GERD as pooled analysis of four RCTs failed to show any benefit over sham or PPI therapy.⁵³ All-in-all, there is limited evidence to support the use of RFED for the treatment of PPINR. While there are no head-to-head comparisons, MSA and TIF appear to be better minimally invasive alternatives to LF than RFED.

A major limitation to this review is the critical deficiency of high quality of studies in regards to participant enrollment defined as ‘PPI non-response.’ Patients treated with PPIs for possible GERD represent a heterogeneous group. Rigorous inclusion criteria are necessary to assess treatment efficacy in subgroups. Patients must demonstrate incomplete or no response to double-dose PPI therapy trialed for at least 8 weeks to be included as a PPI nonresponder. Unfortunately, only two studies included in this review defined their population as PPI nonresponsive after failing twice daily PPI.^28,58 While some may argue incomplete response to daily PPI is sufficient to define PPI failure, twice daily dosing may help achieve adequate symptom control in 20%–30% of patients on daily PPI and eliminate residual acid reflux.⁶⁸ The PPI refractory GERD subgroup must additionally manifest pathologic acid exposure despite double-dose PPI therapy. While all studies in this review required pathologic acid exposure on endoscopy or pH testing for participant enrollment, only eight studies defined PPI nonresponse as objective evidence of persistent pathologic reflux despite PPI therapy.^{20,23,25–28,48,50} This number may be an underestimate as many studies failed to document whether physiologic testing was performed on or off of therapy. Nevertheless, documentation of persistent pathologic esophageal reflux on PPI therapy is of critical importance to exclude nonreflux causes of reflux symptoms. An additional limitation is the uncertainty of whether populations were partial or complete PPI nonresponders. These distinct populations may have heterogeneous physiologic profiles and response to treatments; thus, specification of degree of response is essential. Only six studies in this review defined their population as partial responders, two included both partial and nonresponders, while the remaining studies were ambiguous as to the degree of PPI response.^{21,30,38-40,43,54,59} Conditions such as functional dyspepsia, functional heartburn, rumination, or belching disorder, and irritable bowel syndrome overlap in symptom presentation with GERD, and are thus often misdiagnosed as GERD.^69,70 Exclusion of patients with functional disorders from future studies is important not only to establish the true efficacy of antireflux procedures in PPINR, but also to avoid unnecessary procedures in patients unlikely to respond to these interventions.

Another concern raised by this review is inconsistent reporting measurements particularly in regards to subjective outcomes. Symptom response was reported in 14 different measures, with six validated questionnaires, GERD-HRQL being most frequently used. While questionnaires provide a standardized assessment of symptoms, they can differ significantly in characteristic, design and therapeutic response (i.e. symptom reduction or quality of life) that make comparisons between studies difficult. We are subsequently left using surrogate measurements such as postprocedural PPI usage to compare techniques. Ideally, larger head-to-head comparison trials would better characterize the difference in symptom response and side effect profiles.

In conclusion, management of PPINRs is a common challenge faced by gastroenterologists and there is uncertainty surrounding newer antireflux procedures. LF remains the most proven therapeutic approach for PPINR. Newer antireflux procedures such as MSA and TIF offer alternatives with varying degrees of success, durability, and side effect profiles that may better suit individual patients. This review also highlights the heterogeneity of defining PPI nonresponse and reporting measures that makes comparison between techniques difficult. In the future, development of a consensus PPI nonresponse definition and more uniform reporting measures should be adopted.

Supplementary Material

Supplemental material

Supplementary data are available at DOTESO online.

SUPPLEMENTARY DATA

Supplementary data are available at DOTESO online.