A safety and effectiveness evaluation of RefluxStop in the treatment of acid reflux comparing large and small hiatal hernia groups: results from 99 patients in Switzerland with up to 4-years follow-up

Gastroesophageal reflux disease (GERD) is a serious ailment due to the associated progressive complications, including significant mortality due to subsequent esophageal adenocarcinoma via Barrett’s esophagus. For instance, in the United States (US) and European Union (EU) alone, about 48,000 persons die from esophageal adenocarcinoma with most of them attributable to acid reflux [1‐6]. Repeated acid exposure leads to tissue damage (i.e., esophagitis) and precancerous changes (i.e., Barrett’s esophagus) that fulminate to carcinoma. Barrett’s esophagus occurs in up to 20% of GERD patients [4‐6], with subsequent progression to esophageal carcinoma at an average incidence rate of 0.6% [7]. Unfortunately, about 85% of those suffering from esophageal cancer succumb to the illness [3, 7]. These considerations merit significant attention when bearing in mind that GERD affects nearly 20% of the US population on a weekly basis [8].

Currently, first-line management of reflux disease is proton pump inhibitor (PPI)-based therapy. However, PPIs do not directly address the cause of reflux itself, but instead only reduce the acidity of gastric contents flowing back into the esophagus, without reducing the frequency of reflux episodes, increasing lower esophageal sphincter (LES) tone, or reducing transient LES relaxations [9‐12]. Moreover, up to 59% of patients continue to experience intermittent heartburn while on PPI therapy [13] and 30–40% have complete irresponsiveness to drug therapy, as evidenced by persistent GERD symptoms with pH-measurable reflux episodes [11]. More specifically, it has been reported that almost 40% of daily PPI users continue to have a pathologic result on 24-hour pH monitoring [14]. Furthermore, many studies report long-term risks of PPI use, such as a study by Yan Xie et al. on excess mortality [2].

Several surgical options currently exist as an alternative to PPI-based medical therapy in the management of GERD. However, these antireflux surgeries, such as Nissen fundoplication (i.e., gold-standard) and magnetic sphincter augmentation (MSA) via the LINX system, use mechanisms of action that encircle or augment the lower esophagus, part of the food passageway [15, 16]. The challenge with this approach is effectively treating acid reflux without incurring serious swallowing difficulties and related side effects.

In cases of large hiatal hernia (HH) ≥3 cm size, there is a unique challenge in the management of reflux patients. More recently developed antireflux procedures are not approved, recommended, or evaluated as an effective treatment [17‐19]. These include MSA, endoscopic transoral incisionless fundoplication, and the Medigus Ultrasonic Surgical Endostapler (MUSE), thus providing a limited repertoire of options to manage disease. For such patients, the currently available surgical treatments often do not provide favorable outcomes with a high rate of reherniation independent of the use of mesh, with up to 55% reccurrence at 5 years as per a randomized clinical trial by Watson et al. from 2020 [20]. A shorter study assessing hernia recurrence after antireflux surgery, for temporal comparison, reports a 15% reherniation rate with 20-month follow-up [21]. Since large HH is associated with a high rate of recurrence after antireflux management, it is clear that innovative surgical strategies are necessary to mitigate this substantial unmet need that is rapidly growing around the world.

A novel method, the RefluxStop™ (Implantica, Zug, Switzerland) procedure, addresses this crucial treatment gap through its distinctive therapeutic principle that aims to prevent reherniation in large HH cases, by not encircling the food conduit and applying circumferential pressure. The approach of RefluxStop is intended to prevent gastroesophageal junction mobility superiorly into the chest cavity while maintaining dynamic flexibility during respiration and alimentation, acting as a mechanical anchor in the abdomen. Implantation of the RefluxStop device ensures an appropriate distance between the LES and diaphragm, thereby preventing acid reflux. Furthermore, the procedure aims to correct all aspects of the antireflux barrier through realignment of the angle of His, treating reflux disease by restoring the normal anatomy and physiology of the gastroesophageal junction without incurring complications associated with augmentation of the food passageway.

The purpose of this study is to assess the safety results of the RefluxStop device in treating patients with reflux disease and concomitant HH comparing two groups, small and large HH, to better understand the role of this novel treatment option in the reflux treatment landscape. We present the safety and effectiveness outcomes of RefluxStop surgery in Swiss GERD patients with severe disease and concomitant small or large HH for up to 4 years. The combined cohorts presented herein are, from a clinical perspective, well-suited for comparison of results in small and large HH subgroups since patients were operated on by a solitary, surgeon at each center.

The RefluxStop procedure uses a novel treatment principle that is intended to treat reflux disease by restoring the antireflux barrier and maintaining regional anatomical and physiological stability, even during dynamic processes like respiration. The device is composed of medical-grade silicone that is considered to be inactive. The thesis behind its mechanism of action includes one important function that is designed to reduce reherniation in large HH subjects: Fundus reinforcement with RefluxStop is thought to act like a mechanical stop, maintaining the LES inferiorly in the abdomen. Esophageal dissection high up in the mediastinum, esophagogastroplication (90–110°), and placement of the RefluxStop implant in an invagination on the outside of the gastric fundus using a dedicated deployment tool, provides anchoring and stability of the newly restored antireflux physiology and anatomy. Ultimately, the result of RefluxStop surgery resembles the depiction in Fig. 1.

Large HH is thought to be an insurmountable risk factor for antireflux surgery with a reherniation frequency of up to 55% in the long term [16, 21, 23]. Moreover, patients with large HH have not been evaluated for many antireflux procedures, such as MSA with the LINX system [24], Stretta radiofrequency therapy [19], endoscopic transoral incisionless fundoplication [17], and MUSE [18], the latter two of which have a contraindication for HH larger than 3 cm in size. Thus, surgical treatment options for GERD patients with concomitant large HH are limited and outcomes are discouraging with the current standard of care, predominantly contingent on failure of hernia repair. For instance, a randomized trial by Watson et al. [20] from 2020 compared large hernia repair in three groups (i.e., without mesh, with non-resorbable mesh, and with resorbable mesh) with 5-year follow-up and found the highest recurrence rate (56%) in the group managed by resorbable mesh. Considering that this type of mesh repair is likely what surgeons utilize most in the current paradigm of antireflux surgery, the implications on long-term treatment success are concerning. The 20-month study by Armijo et al. [21] in 2019 reported follow-up more comparable to our study (i.e., up to 4 years ranging from 3 to 47 months in our study), in which a 15% hernia recurrence rate after standard-of-care antireflux surgery was appreciated.

Surgeons may have been reluctant to operate on large HH patients in the past due to high complication and treatment failure rates [25]. The RefluxStop device, on the other hand, has a design premise intended for treatment of this aruduously-managed patient group. For instance, as compared to the double-wall thickness of the cuff created during Nissen fundoplication, the RefluxStop device invaginated as part of a large fundic package that is adjacent to the diaphragmatic hiatus (as opposed to being in-line with it) seems to minimize the risk of gastroesophageal junction protrusion into the the chest cavity, logically speaking. According to Linnaus and colleauges [26], the recurrence of hiatal hernia has a high frequency on the ventral-left/upper-left aspect of the diaphragmatic hiatus. With RefluxStop surgery, a dorsal row of plication sutures results in reinforcement of the fundic package (presumably acting as a mechanical stop) located on the left-dorsal side, a region affected very little by recurrence according to Linnaus et al. [26]. Thus, one may argue that RefluxStop may reduce the reherniation rate in cases of large HH by interacting with a consistently preserved aspect of the diaphragmatic boundary. Moreover, there are other factors in the RefluxStop procedure that may reduce the likelihood of reherniation: dissection is performed extensively into the mediastinum; mobilization achieves a long intraabdominal esophagus; and reduced tension on the esophagus minimizes muscular contraction that may lead to reherniation. Taking this rationale to its logical conclusion, the only factor that may potentially lead to reherniation after RefluxStop surgery is total (or circumferential) collapse of hiatal repair, where the fundic package with the device invaginated in the center thereof (i.e., the device on its own is about 2.5 cm in size) is not large enough to prevent passage through the hiatal opening. In the study by Linnaus et al. [26], analysis of the position and extension of failed hiatus repair with median 5-year follow-up found a circumferential recurrence of 29%, the presupposed risk factor for reherniation after RefluxStop surgery. In such an instance, repositioning of the fundus followed by a new hiatus repair is possible, while leaving the RefluxStop implant untouched in its enclosed invagination pouch. As such, due to the design of RefluxStop as a mechanical stop intended to reduce hernia recurrence, it may have the potential to substantially reduce the recurrence rate of large HH in reflux surgical management, as indicated by these results.

RefluxStop treats the cause of acid reflux without encircling the food conduit and compounding swallowing difficulties, as is common in standard-of-care procedures [27‐29]. The RefluxStop procedure aims to restore the angle of His, repair all three components of the antireflux barrier (i.e., the gastroesophageal flap valve, LES and its sling fibers, and the crural diaphragm) [30], re-institute optimal physiology and anatomy of the gastroesophageal junction, and maintain regional dynamic stability without invoking food passageway limitations. When the RefluxStop device was first implemented for use in real-world practice, large hiatal hernia patients were not specifically kept in mind and several surgeons used the implant based on clinical judgement and patient willingness, notably in severe cases (as shown in one of our centers particularly). The experience at our clinics prompted this investigation, to determine the relative treatment performance of this novel treatment between small and large hiatal hernia cases. This study showed comparable and excellent quality-of-life improvements in both small (median 85.7% improvement) and large (median 93.8% improvement) hernia groups, aligning well with the design rationale of RefluxStop in prevention of LES protrusion into the chest cavity. The relatively higher improvement in quality of life with large hernia patients is particularly notable since a larger proportion of large HH patients achieved long-term follow-up with better results as compared to the small hernia group. In total, nine patients reached 3-year follow-up, of which six had large hiatal hernia at baseline.

The patients operated on in this study belong to the most difficult-to-treat group pertaining to GERD, not only with 50% having large hernia (size 4–10 cm), but also a great number suffering from severe acid reflux. Approximately 44% (of the 70 patients tested) had Barrett’s esophagus, many with Los Angeles esophagitis grade C and D, and 35% had severe dysphagia prior to surgery. Moreover, most of these patients had gas-bloating preoperatively. The combination of large HH and dysphagia would be expected to result in suboptimal outcomes with high rates of reherniation and swallowing difficulties, affiliated with unfavorable quality-of-life (i.e., GERD-HRQL) scores. In view of the patient selection for this study, this report indicates that RefluxStop has a low risk profile and robustly treats acid reflux even in large HH patients, resulting in similar safety and effectiveness outcomes in those with small (≤3 cm) or large (4–10 cm) HH preoperatively.

This report provides important safety observations clinically relevant for implementation of this novel treatment option, particularly when considering the troublesome late side effects associated with fundoplication as a standard-of-care surgical option. In a recently published systematic literature review on Nissen fundoplication, results of nine studies found considerable rates of gas-bloating (52.7%), inability to vomit/belch (39.8%), dysphagia (28.9%), and heartburn or epigastric/sternal pain (27.0%) at 5 years after surgery [31]. These may be particularly accentuated in difficult-to-treat patients considering, inter alia, that those with large HH currently have unsatisfactory treatment options. Although not from the perspective of hiatal hernia patients, head-to-head study comparing RefluxStop to the standard of care, Nissen fundoplication, is currently underway and is expected to provide better resolution as to the role of this novel treatment option.

According to this analysis, RefluxStop implantation is well-tolerated even in these difficult-to-treat patients while also substantially improving patient quality of life, as documented by GERD-HRQL score. The GERD-HRQL score improved slightly more in the large HH group, albeit insignificantly as compared to the small HH group (i.e., median 94% improvement from baseline at 1 year in the large HH group compared to 86% in the small HH group), which may be attributed to more severe symptoms at baseline. Although surgical outcomes were basically equivalent between the large and small hernia groups of this study, one could not exclude the risk of a higher recurrence rate for large HH patients in the long term. However, as this study has indicated, the RefluxStop procedure is designed to, and has the potential to, substantially reduce such recurrence rates based on the logic described above. Thus, RefluxStop’s design and mechanism of action posit it as a promising treatment option in reflux patients with small and large HH alike. Longer follow-up and further randomized studies are in the pipeline.

This study shows that the RefluxStop procedure is a promising treatment to manage reflux disease in both small (≤3 cm) or large (4–10 cm) HH patients. Despite patient selection including severe sufferers at baseline, with Barrett’s esophagus in 44% and severe dysphagia in approximately 35%, excellent safety results were reported for up to 4 years, with no significant difference in either safety or efficacy between the large (n = 49) and small hernia (n = 50) groups. Moreover, 93% of the patients had > 50% improvement of the GERD-HRQL score, demonstrating robust and successful treatment outcomes.

In the large hernia group, the total GERD-HRQL score improved by median 93.8% from baseline, and in the small hernia group, the total GERD-HRQL score improved by a median of 85.7% from baseline. Additional studies are underway and will continue to provide ancillary evidence on the safety and effectiveness outcomes of this unique and promising treatment option.