Re: Minimal access surgery compared with medical management for gastro-oesophageal reflux disease: five year follow-up of a randomised controlled trial (REFLUX)
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Minimal access surgery compared with medical management for gastro-oesophageal reflux disease: five year follow-up of a randomised controlled trial (REFLUX)
Re: Minimal access surgery compared with medical management for gastro-oesophageal reflux disease: five year follow-up of a randomised controlled trial (REFLUX)
Dear Editor
Thank you for the opportunity to respond to Professor Lundell and colleagues from the LOTUS trial group. Your readers may wish to refer to a newly published full report of the REFLUX trial five-year follow-up (Grant AM et al Health Technology Assessment 2013; vol 17; issue 22); this includes a detailed discussion of the findings in the context of the other three comparable randomised trials, the largest of which is the LOTUS trial.
The issues raised by Professor Lundell and colleagues reflect design and related differences between the two trials. The LOTUS trial had an ‘explanatory’ design aiming to “estimate the efficacy of laparoscopic anti-reflux surgery and PPI treatment”; entry criteria (‘PPI responders’) were tightly defined, surgical and medical treatments strictly standardised, primary outcome was a clinical judgement of success or failure, and analysis based on those who received their allocated treatment (the 40 participants who were randomly allocated surgery who did not receive it were excluded). In contrast, the REFLUX trial design was pragmatic, aiming to compare two management policies as used in everyday practice, acknowledging that some participants would inevitably not have their allocated treatments. Eligibility was based on current practice, experienced surgeons chose their favoured approach to fundoplication and specialist gastroenterologists optimised medical management with most subsequent care being in general practice, and the primary outcome was a patient-reported disease-specific quality of life measure. Non-design differences were that the REFLUX trial was coordinated by an accredited trials unit, local recruitment was led by gastroenterologist/gastrointestinal surgeon partnerships, rather than gastrointestinal surgeons alone, and the trial was publically funded rather than by a pharmaceutical company.
REFLUX trial analyses were based on the intention to treat principle (mirroring the comparison of the two policies). These are not biased as Lundell and colleagues seem to imply. However, the percentage of those randomly allocated surgery who actually had surgery was lower than would occur in normal practice, as judged by the parallel, non-randomised preference for surgery group, and secondary analyses adjusting for this showed larger differences favouring surgery. Secondary analyses also showed that those allocated medical management who later had surgery had relatively low REFLUX scores (more severe symptoms) at trial entry, whereas those allocated surgery who did not receive it had relatively high scores (less severe symptoms). This at least partially explains why the differences between the randomised groups, though still statistically significant, narrowed over time. To put this another way, analyses closer to an explanatory approach suggest greater symptomatic relief than were observed in REFLUX’s primary intention to treat analyses.
The LOTUS trial and other studies have demonstrated that some patients do experience post-fundoplication problems, such as dysphagia, flatulence and bloating. In the first year of follow-up in the REFLUX trial, 3 (1%) of those who had surgery subsequently had a dilatation of the wrap. This applied to only one patient in the subsequent four years and based on patients’ reports there were no differences between the trial groups in symptoms related to these problems. Possible explanations for the differences between REFLUX and LOTUS in these respects are that around 50% of those who had surgery in the REFLUX randomised comparison had partial fundoplication (compared with a total procedure for all in the LOTUS trial), and details of the actual procedure were left to the discretion of the surgeon, in contrast to the prescribed approach used in LOTUS.
One of our principal concerns about the LOTUS trial is that its primary outcome, ‘treatment failure’, was likely biased: it was not based on a common definition across the trial but was defined differently for each trial group; for example, it was permissible to double the PPI dose in the medical group without the patient being classified as a treatment failure whereas a ‘need’ for regular medication in the surgical group constituted a treatment failure. In contrast to the LOTUS trial, both these situations were treated as parts of the management policies being compared in the REFLUX trial. Using medication after surgery was considered to be a way of enhancing the benefits of surgery rather than equating to surgical failure. As Lundell and colleagues point out has been shown in the REFLUX and other studies, using medication after surgery is common. However, this inevitably leads to a high ‘failure rate’ after surgery, according to the definition used in LOTUS. From a pragmatic clinical perspective, it seems anomalous to categorise patients whose symptoms are suppressed by medication and who feel well as ‘treatment failures’.
The principal outcomes in the REFLUX trial were all validated disease-specific (REFLUX score – see Macran S et al Qual Life Res2007; 16: 331-43) or generic (SF-36 and EQ-5D) patient reported health–related quality of life measures that could be applied uniformly across the study groups and time points to provide a common currency. All were consistent in suggesting greater benefit from the surgery policy. The LOTUS trial did include a disease-specific quality of life measure (the QOLRAD) as a secondary measure. The five-year results are only reported in an e-table without formal statistical analysis (Galmiche et al JAMA2011; 305(19): 1969-1977 eTable 2). Our reading is that at all time points (1, 3 and 5 years) and for all four dimensions (vitality, food and drink, sleep, and physical/social) scores are statistically significantly higher (indicating greater improvement) in the surgical group. These results are not commented on in the LOTUS report. Yet, if we have interpreted the table correctly, they indicate that analysing LOTUS from more of a patient-centred pragmatic perspective gives results favouring surgery similar to the REFLUX trial.
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Re: Minimal access surgery compared with medical management for gastro-oesophageal reflux disease: five year follow-up of a randomised controlled trial (REFLUX)
Dear Editor
Thank you for the opportunity to respond to Professor Lundell and colleagues from the LOTUS trial group. Your readers may wish to refer to a newly published full report of the REFLUX trial five-year follow-up (Grant AM et al Health Technology Assessment 2013; vol 17; issue 22); this includes a detailed discussion of the findings in the context of the other three comparable randomised trials, the largest of which is the LOTUS trial.
The issues raised by Professor Lundell and colleagues reflect design and related differences between the two trials. The LOTUS trial had an ‘explanatory’ design aiming to “estimate the efficacy of laparoscopic anti-reflux surgery and PPI treatment”; entry criteria (‘PPI responders’) were tightly defined, surgical and medical treatments strictly standardised, primary outcome was a clinical judgement of success or failure, and analysis based on those who received their allocated treatment (the 40 participants who were randomly allocated surgery who did not receive it were excluded). In contrast, the REFLUX trial design was pragmatic, aiming to compare two management policies as used in everyday practice, acknowledging that some participants would inevitably not have their allocated treatments. Eligibility was based on current practice, experienced surgeons chose their favoured approach to fundoplication and specialist gastroenterologists optimised medical management with most subsequent care being in general practice, and the primary outcome was a patient-reported disease-specific quality of life measure. Non-design differences were that the REFLUX trial was coordinated by an accredited trials unit, local recruitment was led by gastroenterologist/gastrointestinal surgeon partnerships, rather than gastrointestinal surgeons alone, and the trial was publically funded rather than by a pharmaceutical company.
REFLUX trial analyses were based on the intention to treat principle (mirroring the comparison of the two policies). These are not biased as Lundell and colleagues seem to imply. However, the percentage of those randomly allocated surgery who actually had surgery was lower than would occur in normal practice, as judged by the parallel, non-randomised preference for surgery group, and secondary analyses adjusting for this showed larger differences favouring surgery. Secondary analyses also showed that those allocated medical management who later had surgery had relatively low REFLUX scores (more severe symptoms) at trial entry, whereas those allocated surgery who did not receive it had relatively high scores (less severe symptoms). This at least partially explains why the differences between the randomised groups, though still statistically significant, narrowed over time. To put this another way, analyses closer to an explanatory approach suggest greater symptomatic relief than were observed in REFLUX’s primary intention to treat analyses.
The LOTUS trial and other studies have demonstrated that some patients do experience post-fundoplication problems, such as dysphagia, flatulence and bloating. In the first year of follow-up in the REFLUX trial, 3 (1%) of those who had surgery subsequently had a dilatation of the wrap. This applied to only one patient in the subsequent four years and based on patients’ reports there were no differences between the trial groups in symptoms related to these problems. Possible explanations for the differences between REFLUX and LOTUS in these respects are that around 50% of those who had surgery in the REFLUX randomised comparison had partial fundoplication (compared with a total procedure for all in the LOTUS trial), and details of the actual procedure were left to the discretion of the surgeon, in contrast to the prescribed approach used in LOTUS.
One of our principal concerns about the LOTUS trial is that its primary outcome, ‘treatment failure’, was likely biased: it was not based on a common definition across the trial but was defined differently for each trial group; for example, it was permissible to double the PPI dose in the medical group without the patient being classified as a treatment failure whereas a ‘need’ for regular medication in the surgical group constituted a treatment failure. In contrast to the LOTUS trial, both these situations were treated as parts of the management policies being compared in the REFLUX trial. Using medication after surgery was considered to be a way of enhancing the benefits of surgery rather than equating to surgical failure. As Lundell and colleagues point out has been shown in the REFLUX and other studies, using medication after surgery is common. However, this inevitably leads to a high ‘failure rate’ after surgery, according to the definition used in LOTUS. From a pragmatic clinical perspective, it seems anomalous to categorise patients whose symptoms are suppressed by medication and who feel well as ‘treatment failures’.
The principal outcomes in the REFLUX trial were all validated disease-specific (REFLUX score – see Macran S et al Qual Life Res2007; 16: 331-43) or generic (SF-36 and EQ-5D) patient reported health–related quality of life measures that could be applied uniformly across the study groups and time points to provide a common currency. All were consistent in suggesting greater benefit from the surgery policy. The LOTUS trial did include a disease-specific quality of life measure (the QOLRAD) as a secondary measure. The five-year results are only reported in an e-table without formal statistical analysis (Galmiche et al JAMA2011; 305(19): 1969-1977 eTable 2). Our reading is that at all time points (1, 3 and 5 years) and for all four dimensions (vitality, food and drink, sleep, and physical/social) scores are statistically significantly higher (indicating greater improvement) in the surgical group. These results are not commented on in the LOTUS report. Yet, if we have interpreted the table correctly, they indicate that analysing LOTUS from more of a patient-centred pragmatic perspective gives results favouring surgery similar to the REFLUX trial.
Yours etc.
Adrian Grant (a.grant@abdn.ac.uk) on behalf of the REFLUX trial group.
Competing interests: No competing interests