Gatekeeper reflux repair system; a mechanistic hypothesis

Although there can clearly be an argument regarding the threshold at which it becomes a disease, gastro-oesophageal reflux disease (GORD) is ultimately the result of excessive gastro-oesophageal reflux and the associated consequences of that. It then seems rather straightforward that therapeutic interventions should seek to reduce or eliminate gastro-oesophageal reflux. The paradox is that the dominant medical interventions do not; rather, they alter the content of the refluxate (by inhibiting gastric acid secretion) so as to make it less noxious to the oesophageal epithelium. This, in a nutshell, summarises the decades old argument regarding the relative merits of medical verses surgical therapy for GORD. Or so it was, until the dawn of the era of endoluminal therapies for GORD a few short years ago. Now it seems that physicians have assumed some attributes of their surgical colleagues as they experiment with therapies that target the reflux itself.

The Gatekeeper reflux repair system is the fifth endoluminal therapy for GORD to gain regulatory approval either in the European Union or in the USA (Stretta, Endocinch, Enteryx, and NDO Plicator). As detailed by Cicala and colleagues¹ in this issue of Gut(see page 183) and by Fockens et al in a recent summary report of a multicentre study,² the concept behind Gatekeeper is to restrict the luminal dimensions of the distal oesophagus by the submucosal implantation of a relatively bioinert hydrogel material. The intended consequence of this is not necessarily to alter lower oesophageal sphincter (LOS) pressure, length, or relaxation characteristics, but to restrict the aperture through which gastro-oesophageal refluxate must flow. Flow through a tube, be it round or elliptical, is highly dependent on both the cross sectional area of the tube and the viscosity of the fluid flowing through it.^3,4 Thus to use the example of transient LOS relaxation, the effect of the Gatekeeper procedure would not be to alter the frequency with which these occur but to change the consequences of their occurrence. Whereas prior to implantation the opening dimensions during transient LOS relaxations allow for voluminous reflux of gas or gastric juice, afterwards reflux is relatively restricted to gas (owing to its viscosity being 55-fold less than water). In essence, the effect of the Gatekeeper implantation is to reverse the oesophagogastric junction opening anomalies recently described in GORD patients compared with normals.⁴

So, are the data presented herein consistent with the above mechanistic hypothesis? Cicala and colleagues¹ investigated the effect of the Gatekeeper treatment in nine patients on pH data, oesophageal manometry, and GORD-health related quality of life scores. pH data were obtained at 5 cm above the manometrically identified LOS and both 3 and 10 cm below the upper oesophageal sphincter prior to treatment and six months afterwards. They found that the distal acid exposure time was unchanged (quite possibly due to a type 2 error given the small number of subjects studied). However, reflux detected by both more proximally positioned sensors decreased substantially. Conceptually, reflux was still occurring but at a slower flow rate and, hence, with less proximal migration. Given that existing physiological data support the notion that an important determinant of reflux symptom generation is the proximal extent of mucosal acidification,^5,6 this observation offers a mechanistic explanation for the observed therapeutic effect of Gatekeeper. Similarly, in the Fockens study² of 68 patients (49 of whom were followed for six months), the treatment resulted in less oesophageal acid exposure and less regurgitation. In both studies, these effects were associated with substantial symptom reduction, albeit with an uncontrolled study design. So, yes, these data do argue for a relevant therapeutic effect.

Given the above data, does this now mean that the Gatekeeper treatment is ready for widespread application? Clearly, not yet. There are many aspects to a treatment modality that define its optimal utilisation. With respect to an endoluminal therapy for GORD, one must consider: (1) safety, (2) efficacy, (3) cost, (4) durability, and (5) reversibility. In terms of safety and reversibility, the data on Gatekeeper are encouraging. The few complications reported in the multicentre study were easily remedied by removing the implants.² Cost has yet to be determined but, as with other endoscopic therapies, will likely be somewhere between that of chronic proton pump inhibitor use and surgical fundoplication. Thus the dominant unresolved questions are of efficacy and durability, and much remains to be learned in these domains. Fockens et al reported that 70.4% of prostheses were retained at six months.² These authors also found a statistical correlation between the number of retained prostheses and the quality of the clinical response. However, major issues remain to be addressed. Who are the ideal patients to treat? Is oesophagitis or hiatus hernia a relative contraindication? Where is the optimal implant location? What is the optimal number of implants per treatment? Is this number the same for every patient or is it dependent on other variables? How long will the implants remain in place? Is retreatment feasible? How much of the observed treatment effect is a placebo response? These and a myriad of other questions can only be answered by further studies and it is imperative that such studies utilise appropriate controls in their design. Encouragingly, one such study has recently been initiated. Hopefully, that ongoing, multicentred, randomised, sham controlled study of GORD patients with mild or absent oesophagitis will shed light on the most fundamental question of all: the magnitude of the Gatekeeper treatment effect.