Minimal access surgery compared with medical management for gastro-oesophageal reflux disease: five year follow-up of a randomised controlled trial (REFLUX)

Dear sir

It was with great interest that we read the recent article in BMJ (Grant et al ,2013; 346: april), from the REFLUX trial consortium, about the 5-year follow up results of the pragmatic trial on the long-term management of GORD. As representatives of the LOTUS trial group, we would like to raise a number of issues relevant to the scientific evaluation of these different therapeutic strategies in GORD patients. It might be useful to BMJ readers for us to recap briefly on the main results of the LOTUS trial, which was a strictly controlled comparison of laparoscopic antireflux surgery and optimized PPI therapy. In summary, we found no clinically relevant difference between the two strategies (Galmiche et al, JAMA 2011;305(19):1969-1977).

Firstly, we would like to focus on trial design. We understand that the pragmatic design of the REFLUX trial aimed to be more representative of the general practice situation than more controlled scientific trials conducted in secondary or tertiary referral centers. However, the pragmatic design introduces some potential uncontrolled bias which needs to be fully acknowledged before accepting generalization of the reported findings. For example, in the LOTUS study, the GORD patients were PPI responders with chronic well documented GORD, whilst in the REFLUX trial they were probably a mix of PPI responders and partial or non responders. Was antisecretory drug therapy stopped for a run-in period in the REFLUX study and if so, for how long, before the baseline symptoms were assessed, endoscopic severity was scored and the amount of acid reflux into the oesophagus was measured? This is necessary to confirm the fact that these so called “typical GORD patients” do in fact need potent antisecretory drugs, as data are accumulating that show many do not require such drugs at all or only require them intermittently. This question can to some extent be addressed using a structured and well designed long run-in period before randomization.

When offering medical and surgical therapies for GORD, both therapies have to be realistic and ethically defendable alternatives for all candidate patients. The question then arises as to what to do with those GORD patients who were randomized to surgery but never had surgery. A somewhat (but scientifically most valid) fundamentalist analytical approach in the ITT analysis is to score them as failures for that particular strategy. This can be particularly relevant if the patient actually refused to have the allocated therapy (the specific reasons are not relevant for this kind of analysis). Such an analysis would radically change the outcome profile and open up for a modified conclusion. Since the ultimate goal is to compare treatment strategies, if one therapeutic strategy cannot, for a variety of reasons, be accepted even among those initially opting for it, this is of critical importance to the analysis and needs to be comprehensively discussed.

In the paper you have presented very rough estimates concerning the background characteristics and differences between those who initially preferred surgery or medical therapy, and those who ultimately accepted that treatment at randomization. It is possible that there are substantial differences in personalities and psychological characteristics between these different patient groups that may have a major impact on the clinical and quality of life related outcome variables.

Secondly, we would like to focus on details of the treatments received in the LOTUS and REFLUX trials and how treatment outcomes were measured. In the LOTUS trial the issue of standardization was further strengthened by the acceptance of only one type of fundoplication. This was not a preemptive opinion that a total fundoplication is superior to the posterior partial wrap, but rather an attempt to control as many factors as possible in a complex trial. In some countries and institutions, the partial fundoplication is not considered to offer as good and durable reflux control as the Nissen. How was the quality of surgery documented in your trial? Did you also collect information about the exact procedures and outcome of antireflux surgery from the respective participating centres?

Another important point pertaining to your treatment methodology relates to standardization of medical therapy. Did you set up strict rules for dosing and timing of PPI:s in order to optimize this therapeutic concept and if not, how should this be interpreted with regard to its inferiority, as compared to surgery, detected in the REFLUX trial? As was shown in the REFLUX trial (and previously demonstrated in the SOPRAN study by Lundell et al, Clin Gastroenterol Hepatol 2009;7(12):1292-1298), there is a cumulative increase in the number of surgical cases who, over time, require antisecretory drugs to control reflux symptoms. How were these patients scored in the trial (failures? quality of life?)? The most scientifically correct way is to score them according to the situation at the time of relapse (symptoms, QoL etc) and then allow these values to be carried forward and incorporated in the 5-year follow up data.

Concerning assessment of treatment outcomes, quality of life is now well tested and validated, but for postfundoplication complaints, no single instrument is available that has been scientifically validated. Do you really believe that there is no difference between medical and surgical therapy concerning postfundoplication-related problems? Is this lack of difference just a reflection of the fact that blunt instruments have been used and/or data acquisition was suboptimal? Of course any sort of blinding is impossible to apply in trials like these, but one possibility to avoid bias, is to involve both surgeons and gastroenterologists in the pre- as well as postoperative assessments (e.g. surgeons following medical patients and vice versa). How did you tackle this problem to avoid unbiased assessments?

We are indebted to the REFLUX trial group for their considerable achievement in conducting this study and for having published a paper which will be read with great interest by a large clinical audience. Our plea is that the many methodological difficulties and challenges harboured in the design and conduct of trials like these need to be carefully and critically discussed to facilitate a comprehensive and meaningful interpretation of the results.

On behalf of the LOTUS trial steering committee