Transoral fundoplication offers durable symptom control for chronic GERD: 3-year report from the TEMPO randomized trial with a crossover arm

This 3-year report represents the longest follow-up on the TF procedure performed with the EsophyX^® device in the USA to date. In addition to quality of life assessments, it included analyses of variations over time in physiologic parameters, endoscopic evaluation of healing esophagitis, as well as rates of complete PPI discontinuation following the procedure. Perhaps most importantly, it addresses concerns about the durability of the outcomes after the TF procedure, which is relevant given the historical context of the poor long-term results of first-generation endoscopic plication devices such as the Endo-Cinch and the NDO Plicator [13]. Our study demonstrated that the TF procedure results in sustained, significant, and clinically meaningful elimination of troublesome GERD symptoms, healing of reflux esophagitis, and improvements in all pH parameters. The authors of this study believe that the quality of the data offers reassurance as to the prolonged benefits of TF up to 3 years post-procedure.

In addition to durable elimination of troublesome regurgitation and atypical symptoms, our primary outcome measure, this study provides evidence that the TF procedure is effective in the sustained elimination of troublesome heartburn, as evaluated by the GERD-HRQL (Fig. 4). Furthermore, prolonged healing of reflux esophagitis (86 % at 3 years) in this study and significant improvements in all pH parameters recorded over 48-h (Table 4) provide additional proof of the durability of the TF procedure. A disconnect (by a factor of 2:1) between the high rates of elimination of troublesome symptoms and the normalization rates of EAE achieved in this study may be viewed as problematic by some. It is important to note that several studies evaluating TF [15, 19], PPI therapy [20], and traditional laparoscopic fundoplication [21, 22] have demonstrated poor correlation between post-treatment pH parameters and symptom control as evaluated with various disease-specific symptom scores [13].

While elimination of troublesome symptoms and healing of reflux esophagitis are well-established and clinically relevant goals of GERD treatment [1], our studies [14, 15] and a report by Hunter et al. [13] suggest that symptom control may not require pH normalization. In fact, PPI therapy may be less effective in controlling abnormal EAE in certain patients than previously thought [15]. The rate of pH normalization off PPIs noted in our study 3 years post-TF (40 %) is comparable to rates of pH normalization reported in patients on double-dose PPI therapy (approximately 50 %) [20, 23]. These observations raise two important questions for future research. First, how much of pH improvement is necessary to achieve adequate symptom control and acceptable patient satisfaction? Second, does pH normalization have complementary effects on overall control of GERD? Uncontrolled GERD symptoms are a major reason for patients to visit their physicians and to utilize healthcare resources. We believe that the GERD therapies that are safe and able to provide control of GERD symptoms and prevent complications may reduce total medical and societal costs associated with the treatment of symptomatic GERD by reducing the frequency of outpatient visits and improving work productivity.

The published literature suggests that achievement of higher normalization rates of EAE after traditional anti-reflux surgery may be attributed to the creation of a supra-competent valve in such procedures; this may contribute to troublesome and sometimes debilitating dysphagia and bloating [13]. This is not the case in patients who receive the TF procedure, as de novo occurrence of post-procedure dysphagia and bloating is virtually nonexistent [14, 15, 24].

The results of the 6- and 12-month follow-ups of the TEMPO trial comparing TF with high-dose PPIs had established the superiority of TF in controlling regurgitation, heartburn, and atypical symptoms in a subgroup of chronic GERD patients with small (<2 cm) or absent hiatal hernias and with incomplete responses to PPIs [14, 15]. Similar results were reported in two other double-blinded randomized trials, one of which compared TF and placebo pills versus sham procedure and high-dose PPIs [13] and another comparing TF versus sham procedure in a European population [12].

The cohort of patients considered for our report consisted of the totality of patients enrolled in the TEMPO trial, merging the group originally randomized to TF with the initial high-dose PPI control group (of which all patients elected to undergo crossover TF). Both groups were statistically similar in every respect, allowing for this design [15].

All TF procedures in this study were completed without perioperative or long-term SAE reported, underscoring the safety of the procedure. There have been more than 17,000 procedures performed worldwide to date, without mortality and with an estimated SAE rate of 3.4 % in the published literature [24]. In this study, there were two reoperations (3 %); these patients were considered as failures of TF and included as such in our statistical analysis. Both revisional operations were performed without difficulty, confirming previous reports on the safety and feasibility of laparoscopic anti-reflux surgery after TF [25]. Recently, a study discussing another more invasive anti-reflux procedure purported that the rate of reoperation following TF could range from 11.5 to 52.6 % [26], citing reports from Europe where earlier iterations of the device and technique had been used [27‐30] in a suboptimally selected patient population which included large hiatal hernias and Hill grade III and IV. In contrast, in the TEMPO trial and other recent randomized controlled TF trials [12‐15], all patients received a standardized TF 2.0 procedure with a rotational component, as described by Bell and Cadière [11]. Further, TEMPO participants deployed 21 fasteners on average, in accordance with previous reports indicating a direct correlation between the number of fasteners and the durability of favorable outcomes [31]. Lastly, the quality of our results can be attributed to the adherence to strict selection criteria, particularly by excluding patients with hiatal hernias larger than 2 cm in either axial height or greatest transverse dimension, patients with Hill grade III or IV ratings of the GEJ, and patients with more severe erosive esophagitis (Los Angeles grade C or D).

We report in this study complete discontinuation of PPI use in 71 % of patients 3 years after TF, without statistically significant change compared to PPI cessation rates at 1- and 2-year follow-ups in the same group of patients. Testoni et al. [32] had reported that the percentage of patients who either stopped or halved their PPI therapy at 3-year follow-up was unchanged at 6 years (84 %), which portends positively for maintaining even longer-term PPI cessation rates in the same range. Interestingly, in the same study, complete discontinuation of PPIs dropped from 61 % of patients at 6 months to 30 % at 6 years, with the sharpest drop observed between 6 and 12 months post-TF, indicating that resumption of PPIs was most common within the first year after the procedure. In our view, this underscores the importance of patient selection and good technique. Furthermore, various factors make PPI use after any anti-reflux procedure an unreliable measure of success or failure, including easy access to over-the-counter medications and patients’ tendencies to resume PPI use without objective documentation of GERD. In fact, PPIs may be viewed an acceptable adjunct to TF procedures in patients whose GERD symptoms were uncontrolled on high-dose PPIs preoperatively [14, 15].

Limitations of the current study include its open-label, crossover design that may introduce a potential bias. While a comparison at 3 years of the medical (PPI) group and the TF group might have offered valuable additional data, there are several reasons for using a crossover design. Following enrollment, patients in the PPI group were required to take the maximum standard dose of currently used PPI in an attempt to optimize control of their GERD symptoms [14]. Patients experiencing ongoing symptoms despite medical therapy are routinely stepped up to maximum dosage in an attempt to control troublesome symptoms. Furthermore, the recommended treatment for patients with predominant extraesophageal symptomatology (our study population) is aggressive acid reduction using PPIs twice daily short term over a duration of 3–4 months [33]. A 3-year comparison between two groups would have likely made enrollment of patients and perhaps IRB approval very difficult. Furthermore, we elected to utilize a crossover design rather than analyzing two parallel groups to eliminate any potential confounding factors that may influence clinical outcomes [14]. Primarily, the TEMPO study was designed to evaluate efficacy of TF versus high-dose PPI therapy at 6- and 12-month follow-ups and secondarily to assess a durability of TF in all patients who underwent the TF procedure. Therefore, for the long-term outcomes each patient served as his/her own control. While we recognize that 11 patients were lost to follow-up for the 3-year evaluation, we believe that an attrition rate of 17 % is acceptable for any 3-year follow-up study. Additionally, as commonly seen in studies evaluating GERD therapies, not all patients were willing to undergo objective evaluation at the study intervals (Table 4); however, the consistent results between 1-, 2-, and 3-year follow-ups from this study, combined with the evidence from double-blind randomized studies [12, 13] and from the long-term European study [32], further support the safety, efficacy, and durability of TF. We conclude that TF offers chronic GERD patients with incomplete symptom control on PPI therapy an effective therapeutic alternative with lasting effect.

A study designed to provide a direct randomized comparison of the traditional anti-reflux surgery and the TF would be very difficult to enroll. Traditional anti-reflux surgery is often reserved for the patients with the most severe GERD, including patients with large hiatal hernias. In such patients, a diaphragmatic crural closure is routinely performed. In contrast, the use of the EsophyX device to perform the endoscopic TF procedure is restricted to a well-selected subset of GERD patients with small (≤2 cm) or absent hiatal hernia. This is reflected in the selection criteria of the TEMPO trial. Such patients are not typically referred for a surgical fundoplication; these patients receive a dose escalation of PPIs and addition of H2 blockers for breakthrough symptoms. In the case–control study of patients undergoing TF, Nissen, or Toupet fundoplication, TF achieved similar dramatic symptom resolution, when compared to Nissen or Toupet fundoplication; a shorter operative times and lengths of stay were observed after TF [34]. The TEMPO trial offered a randomized comparison of the two options for a common clinical scenario which presents significant challenges; it was conducted to find out whether TF is a viable alternative to patients with incomplete symptom control on optimized PPI therapy and who are fearful of the potential side effects of fundoplication. Furthermore, the level of scientific proof of its efficacy and therapeutic gain surpasses anything currently available outside the area of traditional laparoscopic anti-reflux surgery [12]. Based on currently available evidence, the authors believe that the TF procedure performed with the EsophyX device should not be considered experimental and should be offered to well-selected chronic GERD patients.