Letters

Treatment of gastro-oesophageal reflux disease in adults

Efficacy of surgery needs to be compared with that of proton pump inhibitors

"Step down" strategy of treatment would be expensive

Authors' reply

Efficacy of surgery needs to be compared with that of proton pump inhibitors

EDITORGalmiche et al reviewed the treatment of gastro-oesophageal reflux disease in adults and claimed that surgery is an efficient treatment with a success rate of up to 90%.¹ Among the few available controlled trials comparing surgery with medical treatment they cited the study of Spechler et al, which showed that surgery is more effective than medical treatment in improving symptoms and oesophagitis for up to two years.² Unfortunately, this trial is flawed. At the time of the study the most efficient drugs (proton pump inhibitors) were not available, and the medical arm used ranitidine, metoclopramide, and antacids. Altogether 247 patients were included, but after randomisation 40 of them refused to participate, 32 of them being allocated to the surgery group. Follow up data were available at two years for only 106 patients, which invalidates all the results. The grade of oesophagitis (range 1-4) on endoscopy in the surgery group and in the continuous medical treatment group was better at two years (1.5 (SD 0.2) and 1.9 (0.1) respectively) than at baseline (2.9 (0.1) for both groups). But no direct statistical comparison was made between the two groups. The patients' satisfaction was also assessed; this was in favour of surgery. This result tells us little, since it was evaluated by a technician aware of the treatment received by the patients. Lastly, an activity index score (range 74-122) was better in the surgery group (78 (2)) than in the continuous medical treatment group (88 (2)). This evaluation was also not blinded, and the authors did not discuss the clinical relevance of a 10 point difference. This trial cannot be taken into consideration.³

Another controlled trial, which Galmiche et al did not cite, compared ranitidine 150 mg twice daily with fundoplication and concluded that surgical treatment was superior.⁴ This trial also gives rise to major criticisms: only 31 patients were included, no randomisation or blinded evaluation was carried out, and the ranitidine and surgical groups were not compared.

With the availability of powerful proton pump inhibitors, the notion of refractory oesophagitis tends to disappear.⁵ Indications for surgery are now mostly limited to recurrent oesophagitis in young patients refusing continuous treatment. But the efficacy of surgery still needs to be proved in comparison with that of proton pump inhibitors.

O Chassany, Senior lecturer in therapeutics. 
J F Bergmann, Professor of therapeutics. 
C Caulin, Professor of therapeutics.  .
Service de Médecine Interne, Hôpital Lariboisière, 75010 Paris, France

1. Galmiche JP, Letessier E, Scarpignato C. Treatment of gastro-oesophageal reflux disease in adults. BMJ 1998; 316: 1720-1723[Free Full Text]. (6 June.)
2. Spechler SJ and the Department of Veterans Affairs Gastroesophageal Reflux Disease Study Group. Comparison of medical and surgical therapy for complicated gastroesophageal reflux disease in veterans. N Engl J Med 1992; 326: 786-792[Abstract].
3. Checklist for authors submitting reports of randomized controlled trials (CONSORT). JAMA 1996; 276: 637-639[Medline].
4. Johansson KE, Tibbling L. Maintenance treatment with ranitidine compared with fundoplication in gastro-oesophageal reflux disease. Scand J Gastroenterol 1986; 21: 779-788[Medline].
5. Bardhan KD, Morris P, Thompson M, Dhande DS, Hinchliffe RF, Jones RB, et al. Omeprazole in the treatment of erosive oesophagitis refractory to high-dose cimetidine and ranitidine. Gut 1990; 31: 745-749[Abstract/Free Full Text].

"Step down" strategy of treatment would be expensive

EDITORWe are concerned by Galmiche et al's assertion that, for patients with mild to moderate gastro-oesophageal reflux disease, the "step down" strategy (starting treatment with proton pump inhibitors) may be more cost effective than the traditional "step up" strategy (starting treatment with less powerful interventions).¹ The evidence quoted in support of the step down approach was a modelling analysis undertaken in the context of the American healthcare system that specifically excluded patients with mild disease. A more recent empirical analysis of prescribing in mild to moderate gastro-oesophageal reflux disease in the United Kingdom emphasised the comparative cost effectiveness of the step up approach.²

The cost effectiveness of the step down approach would be even more uncertain were it to be applied routinely in primary care. Most patients presenting with heartburn and associated symptoms are managed by primary care doctors without recourse to specialist advice. Treatments are normally started empirically, and only when these are unsuccessful will an endoscopy or specialist advice be sought. Thus the step up approach is particularly relevant for such patients. In contrast, gastroenterologists treat a highly selected cohort who bear little resemblance to most patients presenting in primary care, and they need to bear this in mind when making recommendations.

The advantage of proton pump inhibitors is only that they can be used in more severe disease. The evidence quoted by Galmiche et al in support of their use in mild disease is a short term placebo controlled trial, but substantial evidence exists in favour of first line use of less powerful acid suppressants. One meta-analysis identified more rapid healing with a proton pump inhibitor than with histamine receptor antagonists in patients with gastro-oesophageal reflux disease but included patients with more severe disease³; the more detailed analysis of the literature undertaken by Kahrilas indicates that mild disease is equally well managed by proton pump inhibitors or the alternative drug treatments available.⁴

Proton pump inhibitors are already the most costly drugs for the NHS. There is substantial evidence of their overuse when less expensive drugs might be equally effective.⁵ Stepped down treatment depends on careful clinical review and patient education, and the deficiencies of repeat prescribing in this regard are well recognised. The danger of a recommendation to use high dose proton pump inhibitors more generally as first line treatment is that many patients will receive drugs that they do not require, in either the short or the long term. The wasted costs to the NHS would be substantial.

Alan Haycox, Senior research fellow. 
Stuart Barton, Reader in primary care. 
T Walley, Professor of clinical pharmacology. 
Prescribing Research Group, Department of Pharmacology and Therapeutics, The Infirmary, Liverpool L69 3GF

1. Galmiche JP, Letessier E, Scarpignato C. Treatment of gastro-oesophageal reflux disease in adults. BMJ 1998; 316: 1720-1723. (6 June.)
2. Eggleston A, Wigerinck A, Huijghebaert S, Dubois D, Haycox A. Cost effectiveness of treatment for gastrointestinal reflux disease in clinical practice: a clinical database analysis. Gut 1998; 42: 13-16[Abstract/Free Full Text].
3. Chiba N, De Cara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastro-oesophageal reflux disease: a meta-analysis. Gastroenterology 1997; 112: 1798-1810[Medline].
4. Kahrilas PJ. Gastro-oesophageal reflux disease. JAMA 1996; 276: 983-988[Abstract].
5. Bashford JNR, Norwood J, Chapman SR. Why are patients prescribed proton pump inhibitors? Retrospective analysis of link between morbidity and prescribing in the General Practice Research Database. BMJ 1998; 317: 452-456[Abstract/Free Full Text]. (15 August.)

Authors' reply

EDITORThe results of a large randomised trial comparing open antireflux surgery with maintenance treatment with omeprazole are now available.¹ They confirmed that both treatments were effective, allowing patients' quality of life to return to normal within two months. Analysis of time to failure of treatment, however, showed a significant superiority of surgery after three years of follow up. Therefore, despite the methodological biases emphasised by Chassany et al, all controlled trials have concluded that open antireflux surgery is more effective than traditional treatment with H₂ receptor antagonists and at least as effective as maintenance treatment with proton pump inhibitors. A blind evaluation, as suggested by Chassany et al, is difficult because a sham operation is not feasible ethically. Now seems an appropriate time to compare laparoscopic surgery and proton pump inhibitors and to include costs and quality of life as important end points.

Haycox et al dispute the merits of a step down approach. In our opinion, severity is the most important determinant of whether a step up or a step down strategy is appropriate. Severity applies to the entire range of the disease. A study in primary care clearly showed that quality of life is impaired in patients with gastro-oesophageal reflux disease with no abnormality at endoscopy as well as in reflux oesophagitis.² From a cost effectiveness standpoint there is no evidence to recommend either the top down or the stepwise approach.

We agree that a modelling analysis does not provide sufficient evidence in support of the top down strategy. However, Eggleston et al's study is also flawed as it is a retrospective analysis of data from a database of patients treated in the United Kingdom.³ The reasons for choosing ranitidine, cisapride, or omeprazole for treatment were not specified. The efficacy of the different treatments and of their impact on quality of life were not evaluated. It is also difficult to extrapolate the results of cost effectiveness analysis to countries with different healthcare systems. Finally, the cost of drugs may change dramatically when, for instance, drugs such as omeprazole lose their patent or additional competitors become available.

We agree that empirical treatment without referral to a specialist is the preferred approach in primary care. Bytzer et al showed, however, that this approach was associated with higher costs than management of dyspepsia guided by results of endoscopy and that patients treated empirically were more frequently dissatisfied.⁴

In conclusion, proton pump inhibitors are probably more cost effective in moderate or severe gastro-oesophageal reflux disease. The issue in mild disease needs further investigation.

Jean Paul Galmiche, Professor of gastroenterology. 
University of Nantes, France

Carmelo Scarpignato, Professor of pharmacology. 
University of Parma, Italy

1. Lundell L, Dalenbäck J, Hattlebakk J, Janatuinen E, Lewander K, Miettinen P, et al. Omeprazole (OME) or antireflux surgery (ARS) in the long term management of gastroesophageal reflux disease (GERD): results of a multicentre, randomised clinical trial. Gastroenterology 1998; 114: A207. (Abstract.)
2. Carlsson R, Dent J, Watts R, Riley S, Sheikh R, Hatlebakk J, et al. Gastro-oesophageal reflux disease in primary care: an international study of different treatment strategies with omeprazole. Eur J Gastroenterol Hepatol 1998; 10: 119-124[Medline].
3. Eggleston A, Wigerinck A, Huijghebaert S, Dubois D, Haycox A. Cost effectiveness of treatment for gastro-oesophageal reflux disease in clinical practice: a clinical database analysis. Gut 1998; 42: 13-16.
4. Bytzer P, Moller-Hansen J, Schaffalitzky de Muckadell OB. Empirical H₂-blocker therapy or prompt endoscopy in management of dyspepsia. Lancet 1994; 343: 811-816[Medline].