- Email: [email protected]
An evaluation of current GERD therapy:
Best Practice & Research Clinical Gastroenterology Vol. 18, No. S, pp. 39–45, 2004 doi:10.1016/j.bpg.2004.06.011 available online at http://www.sciencedirect.com
An evaluation of current GERD therapy: A summary and comparison of effectiveness, adverse effects and costs of drugs, surgery and endoscopic therapy Peter H. Katelaris* MD, FRACP, FRCP Gastroenterology Department, Concord Hospital, University of Sydney, Sydney, NSW 2139, Australia
Gastroesophageal reflux disease (GERD) is among the commonest of gastro-intestinal disorders and the costs of management worldwide are considerable. GERD symptoms impair quality of life and in a minority of subjects, there is a risk of significant morbidity due to complications including strictures and extra-esophageal manifestations. There is also a significant mortality related to the risk of esophageal adenocarcinoma. Although the absolute risk is low in any individual, the incidence of this cancer is rising in Western populations, particularly among Caucasian males over 50 years of age. Therefore, the goals of GERD therapy are to relieve symptoms, restore quality of life, heal esophagitis if present and reduce complications in the most cost-effective manner. Medical therapy is the mainstay of treatment for most patients with surgery appropriate for a well selected minority. Newer endoscopic techniques are currently under evaluation. A direct comparison of the benefits and drawbacks of all modalities of treatment is limited by the lack of quality comparative data, the different interests of the providers of therapy and also by the complementary rather than competing nature of these alternatives.
MEDICAL THERAPY OF GERD A substantial body of clinical trial data has established that proton pump inhibitors (PPIs) are the most effective pharmacotherapy for gastroesophageal reflux disease. * Tel.: C61-2-9767-5548; Fax: C61-2-9767-7907. E-mail address: [email protected] 1521-6918/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
40 P. H. Katelaris
While less potent acid suppression with H2-receptor antagonists (H2-RAs) is effective for some patients, symptom resolution and healing of esophagitis is more rapidly and reliably achieved with PPI therapy across all grades of severity of disease. This is reflected in the results of a large meta-analysis and proves the widespread recommendation for first line therapy with PPIs.1,2 However, despite the effectiveness of PPIs, control of symptoms is not universal and represents an area of unmet need. The management of GERD has two distinct phases.2 The first phase involves an accurate diagnosis, assessment of severity and an appropriate initial plan of management. After initial treatment, usually with a PPI, the second phase of management involves individually tailoring a long-term plan for each patient. Such a plan is based on the initial assessment and response to therapy. The aims of maintenance therapy are to control symptoms, minimize risks and avoid unnecessary costs. The latter is particularly relevant as therapy is often long-term. For the majority of patients symptom control is the overriding issue. However, in patients with esophagitis, long-term therapy aims to maintain mucosal healing as this is likely to reduce the risk of complications. Medical therapy aims at achieving these goals with the lowest dose and frequency of drug use possible. In general terms, patients who have had longstanding, frequent and severe symptoms, particularly if associated with moderate or severe esophagitis, will need higher level therapy with continuous PPI use, as relapse is almost inevitable with treatment withdrawal.2 In some of these patients twice daily or double dose PPI therapy is required. Patients with milder disease, including many without endoscopic esophagitis, can be treated with less intense therapy. In these patients, a trial of treatment cessation after initial control of symptoms is appropriate because not all patients will relapse or continue to have frequent or chronic symptoms. If symptoms do relapse on cessation of therapy, repeat treatment is required. With PPI therapy, an attempt can be made to ‘step down’ the dosage, usually to half the standard dose, as long as symptom control is maintained satisfactorily. An alternative strategy is to heal and control symptoms with a PPI and then step down to therapy with H2-RAs, although this method may be clumsy and has not been rigorously tested against a PPI-only strategy. Currently, a step down approach is generally preferred to a ‘step-up’ strategy but the merits of each approach continue to be debated. In some patients, intermittent, self-directed (‘on demand’) therapy may be an effective way of controlling symptoms and has been shown to be cost-effective as it reduces drug usage.3 However, in patients who have frequent symptoms, therapy will become daily. Prokinetics have little role except as an occasional adjunctive therapy, particular in patients who also have evidence of hypomotility of the esophagus or stomach. Lifestyle modification including weight reduction, dietary fat reduction, avoidance of late large meals in those with predominant nocturnal reflux, moderation of excessive alcohol intake and smoking cessation are adjunctive measures. There has been relatively little clinical trial evaluation of the effectiveness of many of these time honoured lifestyle changes and available evidence suggests they are of relatively low efficacy for symptom relief and ineffective for healing esophagitis.2 However, they should be considered as part of an overall health care plan.
An evaluation of current GERD therapy 41
ADVERSE EFFECTS OF MEDICAL THERAPY PPIs are among the most widely prescribed class of drug worldwide with more than 500 million patient years of experience, over nearly 20 years. In that time, the spectrum of minor and infrequent side effects have been well characterized.4 Headache, nausea and diarrhoea occasionally lead to cessation of therapy or more usually to a switch to an alternative PPI. Very occasional, hypersensitivity reactions are recorded. Rebound acid hypersecretion occurs after cessation of PPI therapy but the clinical consequences of this have been little studied. There has been concern that profound acid suppression may cause micronutrient malabsorption, particularly of vitamin B12 and iron, however the available data does not suggest this is a significant clinical concern as any effect appears marginal. Acid suppression may slightly increase the risk of bacterial gastroenteritis in some circumstances. PPIs are largely free of clinically important drug interactions. There have been concerns that profound acid secretion may increase the risk of gastric malignancy, perhaps related to the known modest increase in serum gastrin levels or exposure to bacterial carcinogens such as nitrosamines. To date, this concern has not been realized but caution is required about the safety of long-term acid suppression as there are no yet data on life long PPI therapy. PPIs per se appear to have little effect on the development of gastric mucosal changes.5 Cystic fundic polyps may occur but appear to be harmless. In the Helicobacter pylori infected stomach however, concomitant long-term PPI therapy worsens gastritis and is associated with a markedly increased risk (above that of H. pylori alone) of gastric mucosal atrophy and metaplasia, which are known premalignant changes.6 This accelerated mucosal change is arrested by eradication of H. pylori.7 Most consensus guidelines therefore advocate eradication of H. pylori prior to long-term PPI therapy.2,8
COSTS OF MEDICAL THERAPY Most information on the cost-effectiveness of varying medical strategies is derived from theoretical modelling rather than real clinical studies or audits. These attempts to model the cost-effectiveness of medical strategies are dependent on the spectrum of severity of GERD modelled, the assumptions made and the location-specific costs of drugs and medical care. As a result, conclusions from modelling are discordant. However, there is agreement that initial PPI-based therapy is best. Traditional step-up therapy has been modelled against step-down therapy preceded by a PPI test using a brief trial of higher dose PPI to confirm diagnosis non-invasively. The cost analysis showed that the initial PPI test followed by step-down therapy resulted in improved symptom relief and quality of life over one year and appropriate utilization of invasive diagnostic testing (reduced endoscopy) at a small marginal increase in cost. These findings await formal testing in a clinical trial.9 However, there is no consensus on the most cost-effective long-term maintenance drug strategy. There are proponents of maintenance with full dose PPI, step-down treatment (PPI or H2RA) and intermittent therapy.9–11 Given the evidence that PPIs are more likely to be clinically effective than H2RAs and that doctors and patients will want to use the most effective therapy, the cost-effectiveness issue depends in part on how much society is willing to pay to achieve health improvements and on opportunity costs in health expenditure.12 Most of the pharmacoeconomic modelling of GERD has been
42 P. H. Katelaris
done in the USA where costs may be markedly different from elsewhere. In a modelling study from Hong Kong for example, standard dose PPI maintenance therapy was suggested to be the most effective and least costly method of maintenance therapy.13 Endoscopy has prognostic value in GERD, as the grade of esophagitis if present, will guide PPI use. Patients with severe esophagitis (for example LA grade D) will have best control of symptoms and maintenance of healing by ongoing PPI therapy, and this is likely to be cost-effective. However, the role of endoscopy and its contribution to the costs of managing GERD overall have not been determined precisely and varies considerably around the world.
SURGICAL THERAPY OF GERD With the availability of laparoscopic fundoplication, surgery for GERD has become more common. Laparoscopic fundoplication may provide effective long-term control of reflux symptoms. However, the evaluation of the effectiveness and the morbidity and mortality associated with the procedure is difficult for a number of reasons. Firstly, there has yet to be a large prospective multicenter trial comparing surgery with PPI therapy. Secondly, the existing literature is mostly comprised of outcomes from tertiary centres of excellence and these may not be reproducible by less experienced generalists. It has been suggested that outcomes of laparoscopic fundoplication may be optimized if the procedure is confined to centers with particular expertise and interest in anti-reflux surgery. Thirdly, results are operator-dependent and affected by the learning curve, which may not feature in reported series. Fourthly, results are often single center experience without independent analysis of outcomes. Lastly, the methodology for assessing outcomes is not standardized, often not comparable and sometimes disputed. When considering the rigour with which drug therapy has been evaluated, there is much less high-level evidence on which to assess the risks and benefits of laparoscopic surgery for GERD. There has been considerable controversy about the effectiveness of fundoplication. Some surgical series report excellent control of heartburn, high levels of patient satisfaction, low peri-operative morbidity, restored quality of life and few ongoing adverse effects.14,15 However, other assessments have been less uniform. One well cited report revealed that 62% of patients were using anti-reflux medication after fundoplication and had a higher 11 year mortality than medically treated patients16 and another reported lower satisfaction scores.17 Fundoplication has not been shown to cause regression of Barrett’s epithelium or to reduce the risk of esophageal cancer. Patient selection is crucial to the outcome of fundoplication. Patients who have good control of reflux symptoms with PPIs may do well with fundoplication. In these patients, the decision for ongoing medical therapy or surgery is based largely on informed choice, in the context of an understanding of the risks and benefits of both approaches. Patients with atypical symptoms, who are endoscopy negative and respond poorly to acid suppression may fare poorly with fundoplication. Surgery should be considered in the few patients with medically refractory reflux, with or without esophagitis and in the rare patient who is intolerant of PPI therapy (and has evidence of reflux). In patients with problematical ‘volume reflux’ or symptoms derived from large and particularly para-esophageal herniae, laparoscopic hernia reduction and fundoplication is often appropriate.
An evaluation of current GERD therapy 43
ADVERSE EFFECTS OF SURGICAL THERAPY There is a risk of death or serious morbidity from fundoplication although the absolute risk is relatively small. A mortality rate of 0.2% has been reported from expert centers18 and this exceeds the estimated annual risk of esophageal cancer (of about 0.02%) and far exceeds potential risk from PPI therapy. This risk issue is of the most importance as GERD is a disease with a very low mortality. Peri-operative complications including surgical mishap, infection and the need to convert to open fundoplication occur in a minority. In one large series, significant early surgical morbidity occurred in 11% of patients.18 The most common adverse effects following surgery are inadequate control of heartburn (leading to a re-operation rate of 3–7%), dysphagia and the ‘gas bloat’ syndrome with an inability to belch or vomit. Disturbed bowel function, particularly troublesome flatulence and diarrhoea, is also well described. These adverse effects are common (two-thirds of patients may report new symptoms after fundoplication) and severe in a subset. These symptoms may be more difficult to treat than the reflux for which the surgery was done. This may impair quality of life.17 Indeed, it has been observed that if the frequency of adverse effects that occur after fundoplication were to occur with drug therapy for reflux, such a drug may not pass regulatory scrutiny nor find favor among prescribers.
COMPARING COSTS OF SURGICAL AND MEDICAL THERAPY There has been a number of attempts to compare the cost-effectiveness of medical versus surgical therapy of GERD. There are many difficulties in making meaningful comparisons based on cost. To use cost as the basis of comparison assumes equal effectiveness. Such comparisons are also highly dependant on the assumptions made and the breadth of the modelling used (not all surgical reports cost complications or failures) as well as local health costs, which may vary enormously. As has been stated, ‘medical economic models are not necessarily portable across geographic or political boundaries’.19 Modelling does not account for variation in surgical skill nor provide long-term information and efficacy of fundoplication which may decline with time.19 Moreover, it is difficult to attach monetary value to gains in health status. It is not surprising that attempts to model costs yield varying results. European studies report conflicting results while another more detailed study reported rough parity of costs.20 Perhaps most importantly, modelling does not take into account patient choice. The ethics of choice should not be based on modelled costs. For patients with GERD that is well controlled with PPI therapy, surgery is an alternative mode of treatment that most will choose not to have, irrespective of the theoretical possibility of cost-effectiveness. Patients cannot be compelled in this way but have the right to be aware of the risks and benefits of alternative modes of GERD treatment.
ENDOSCOPIC ANTI-REFLUX THERAPY There has been a rapid development of endoscopic methods for treating GERD and in some areas, rapid regulatory approval and adoption into clinical practice. A common observation has been that if these devices were considered as drugs they would require far more stringent evaluation before gaining regulatory approval for use outside
44 P. H. Katelaris
the context of clinical trials in major centres. Techniques include endoscopic plication, application of radiofrequency energy or injection of polymer around the lower esophageal sphincter. Data at present is from short-term studies. These describe improvement in heartburn scores but not normalization of esophageal acid exposure or healing of esophagitis. Long-term data are lacking and safety issues are unresolved. Complications including deaths have been reported. The first randomized controlled data are just emerging21 and is not convincing and there are no prospective comparative data with PPIs. At present, the place of such techniques remains to be established22 and it is far too early to consider cost-effectiveness issues for these techniques. Patients need to be aware of the current uncertainty about the status of such techniques relative to conventional medical or surgical therapy for GERD.
REFERENCES *1. Chiba N, De Gara CJ, Wilkinson JM & Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997; 112: 1798–1810. 2. Katelaris P, Holloway R, Talley N et al. Digestive Health Foundation of the Gastroenterological Society of Australia. Gastro-oesophageal reflux disease in adults: guidelines for clinicians. J Gastroenterol Hepatol 2002; 17: 825–833. *3. Talley NJ, Lauritsen K, Tunturi-Hihnala H et al. Esomeprazole 20 mg maintains symptom control in endoscopy-negative gastro-oesophageal reflux disease: a controlled trial of ‘on-demand’ therapy for 6 months. Aliment Pharmacol Ther 2001; 15: 347–354. *4. Moessner J, Koop H, Porst H et al. One-year prophylactic efficacy and safety of pantoprazole in controlling gastro-oesophageal reflux symptoms in patients with healed reflux oesophagitis. Aliment Pharmacol Ther 1997; 11: 1087–1092. 5. Klinkenberg-Knol EC, Nelis F, Dent J et al. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology 2000; 118: 661–669. 6. Kuipers EJ, Lundell L, Klinkenberg-Knol EC et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med 1996; 334: 1018–1022. 7. Moayyedi P, Wason C, Peacock R et al. Changing patterns of Helicobacter pylori gastritis in long-standing acid suppression. Helicobacter 2000; 5: 206–214. 8. Malfertheiner P, Megraud F, O’Morain C et al. European Helicobacter pylori Study Group (EHPSG). Current concepts in the management of Helicobacter pylori infection—the Maastricht 2-2000 Consensus Report. Aliment Pharmacol Ther 2002; 16: 167–180. *9. Ofman JJ, Dorn GH, Fennerty MB & Fass R. The clinical and economic impact of competing management strategies for gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2002; 16: 261–273. 10. Gerson LB, Robbins AS, Garber A et al. A cost-effectiveness analysis of prescribing strategies in the management of gastroesophageal reflux disease. Am J Gastroenterol 2000; 95: 395–407. 11. Harris RA, Kuppermann M & Richter JE. Proton pump inhibitors or histamine-2 receptor antagonists for the prevention of recurrences of erosive reflux esophagitis: a cost-effectiveness analysis. Am J Gastroenterol 1997; 92: 2179–2187. 12. Goeree R, O’Brien BJ, Blackhouse G et al. Cost-effectiveness and cost-utility of long-term management strategies for heartburn. Value Health 2002; 5: 312–328. 13. You JH, Lee AC, Wong SC & Chan FK. Low-dose or standard-dose proton pump inhibitors for maintenance therapy of gastro-oesophageal reflux disease: a cost-effectiveness analysis. Aliment Pharmacol Ther 2003; 17: 785–792. 14. Gotley DC, Smithers BM, Rhodes M et al. Laparoscopic Nissen fundoplication—200 consecutive cases. Gut 1996; 38: 487–491.
An evaluation of current GERD therapy 45 15. Bloomston M, Nields W & Rosemurgy AS. Symptoms and antireflux medication use following laparoscopic Nissen fundoplication: outcome at 1 and 4 years. JSLS 2003; 7: 211–218. * 16. Spechler SJ, Lee E, Ahnen D et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial. JAMA 2001; 285: 2331–2338. * 17. Vakil N, Shaw M & Kirby R. Clinical effectiveness of laparoscopic fundoplication in a U.S. community. Am J Med 2003; 114: 1–5. 18. Perdikis G, Hinder RA, Lund RJ et al. Laparoscopic Nissen fundoplication: where do we stand? Surg Laparosc Endosc 1997; 7: 17–21. 19. Koelz HR, Blum AL & Modlin IM. Costs of GERD: facts and fiction. Gastroenterology 2003; 125: 981–982. 20. Sonnenberg A. Motion—Laparoscopic Nissen fundoplication is more cost-effective than oral PPI administration: arguments against the motion. Can J Gastroenterol 2002; 16: 627–631. 21. Kahrilas PJ. Radiofrequency energy treatment of GERD. Gastroenterology 2003; 125: 970–973. * 22. Hogan WJ & Shaker R. A critical review of endoscopic therapy for gastroesophageal reflux disease. Am J Med 2003; 115(Suppl 3A): 201S–210S.
An evaluation of current GERD therapy: A summary and comparison of effectiveness, adverse effects and costs of drugs, surgery and endoscopic therapy Peter H. Katelaris* MD, FRACP, FRCP Gastroenterology Department, Concord Hospital, University of Sydney, Sydney, NSW 2139, Australia
Gastroesophageal reflux disease (GERD) is among the commonest of gastro-intestinal disorders and the costs of management worldwide are considerable. GERD symptoms impair quality of life and in a minority of subjects, there is a risk of significant morbidity due to complications including strictures and extra-esophageal manifestations. There is also a significant mortality related to the risk of esophageal adenocarcinoma. Although the absolute risk is low in any individual, the incidence of this cancer is rising in Western populations, particularly among Caucasian males over 50 years of age. Therefore, the goals of GERD therapy are to relieve symptoms, restore quality of life, heal esophagitis if present and reduce complications in the most cost-effective manner. Medical therapy is the mainstay of treatment for most patients with surgery appropriate for a well selected minority. Newer endoscopic techniques are currently under evaluation. A direct comparison of the benefits and drawbacks of all modalities of treatment is limited by the lack of quality comparative data, the different interests of the providers of therapy and also by the complementary rather than competing nature of these alternatives.
MEDICAL THERAPY OF GERD A substantial body of clinical trial data has established that proton pump inhibitors (PPIs) are the most effective pharmacotherapy for gastroesophageal reflux disease. * Tel.: C61-2-9767-5548; Fax: C61-2-9767-7907. E-mail address: [email protected] 1521-6918/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
40 P. H. Katelaris
While less potent acid suppression with H2-receptor antagonists (H2-RAs) is effective for some patients, symptom resolution and healing of esophagitis is more rapidly and reliably achieved with PPI therapy across all grades of severity of disease. This is reflected in the results of a large meta-analysis and proves the widespread recommendation for first line therapy with PPIs.1,2 However, despite the effectiveness of PPIs, control of symptoms is not universal and represents an area of unmet need. The management of GERD has two distinct phases.2 The first phase involves an accurate diagnosis, assessment of severity and an appropriate initial plan of management. After initial treatment, usually with a PPI, the second phase of management involves individually tailoring a long-term plan for each patient. Such a plan is based on the initial assessment and response to therapy. The aims of maintenance therapy are to control symptoms, minimize risks and avoid unnecessary costs. The latter is particularly relevant as therapy is often long-term. For the majority of patients symptom control is the overriding issue. However, in patients with esophagitis, long-term therapy aims to maintain mucosal healing as this is likely to reduce the risk of complications. Medical therapy aims at achieving these goals with the lowest dose and frequency of drug use possible. In general terms, patients who have had longstanding, frequent and severe symptoms, particularly if associated with moderate or severe esophagitis, will need higher level therapy with continuous PPI use, as relapse is almost inevitable with treatment withdrawal.2 In some of these patients twice daily or double dose PPI therapy is required. Patients with milder disease, including many without endoscopic esophagitis, can be treated with less intense therapy. In these patients, a trial of treatment cessation after initial control of symptoms is appropriate because not all patients will relapse or continue to have frequent or chronic symptoms. If symptoms do relapse on cessation of therapy, repeat treatment is required. With PPI therapy, an attempt can be made to ‘step down’ the dosage, usually to half the standard dose, as long as symptom control is maintained satisfactorily. An alternative strategy is to heal and control symptoms with a PPI and then step down to therapy with H2-RAs, although this method may be clumsy and has not been rigorously tested against a PPI-only strategy. Currently, a step down approach is generally preferred to a ‘step-up’ strategy but the merits of each approach continue to be debated. In some patients, intermittent, self-directed (‘on demand’) therapy may be an effective way of controlling symptoms and has been shown to be cost-effective as it reduces drug usage.3 However, in patients who have frequent symptoms, therapy will become daily. Prokinetics have little role except as an occasional adjunctive therapy, particular in patients who also have evidence of hypomotility of the esophagus or stomach. Lifestyle modification including weight reduction, dietary fat reduction, avoidance of late large meals in those with predominant nocturnal reflux, moderation of excessive alcohol intake and smoking cessation are adjunctive measures. There has been relatively little clinical trial evaluation of the effectiveness of many of these time honoured lifestyle changes and available evidence suggests they are of relatively low efficacy for symptom relief and ineffective for healing esophagitis.2 However, they should be considered as part of an overall health care plan.
An evaluation of current GERD therapy 41
ADVERSE EFFECTS OF MEDICAL THERAPY PPIs are among the most widely prescribed class of drug worldwide with more than 500 million patient years of experience, over nearly 20 years. In that time, the spectrum of minor and infrequent side effects have been well characterized.4 Headache, nausea and diarrhoea occasionally lead to cessation of therapy or more usually to a switch to an alternative PPI. Very occasional, hypersensitivity reactions are recorded. Rebound acid hypersecretion occurs after cessation of PPI therapy but the clinical consequences of this have been little studied. There has been concern that profound acid suppression may cause micronutrient malabsorption, particularly of vitamin B12 and iron, however the available data does not suggest this is a significant clinical concern as any effect appears marginal. Acid suppression may slightly increase the risk of bacterial gastroenteritis in some circumstances. PPIs are largely free of clinically important drug interactions. There have been concerns that profound acid secretion may increase the risk of gastric malignancy, perhaps related to the known modest increase in serum gastrin levels or exposure to bacterial carcinogens such as nitrosamines. To date, this concern has not been realized but caution is required about the safety of long-term acid suppression as there are no yet data on life long PPI therapy. PPIs per se appear to have little effect on the development of gastric mucosal changes.5 Cystic fundic polyps may occur but appear to be harmless. In the Helicobacter pylori infected stomach however, concomitant long-term PPI therapy worsens gastritis and is associated with a markedly increased risk (above that of H. pylori alone) of gastric mucosal atrophy and metaplasia, which are known premalignant changes.6 This accelerated mucosal change is arrested by eradication of H. pylori.7 Most consensus guidelines therefore advocate eradication of H. pylori prior to long-term PPI therapy.2,8
COSTS OF MEDICAL THERAPY Most information on the cost-effectiveness of varying medical strategies is derived from theoretical modelling rather than real clinical studies or audits. These attempts to model the cost-effectiveness of medical strategies are dependent on the spectrum of severity of GERD modelled, the assumptions made and the location-specific costs of drugs and medical care. As a result, conclusions from modelling are discordant. However, there is agreement that initial PPI-based therapy is best. Traditional step-up therapy has been modelled against step-down therapy preceded by a PPI test using a brief trial of higher dose PPI to confirm diagnosis non-invasively. The cost analysis showed that the initial PPI test followed by step-down therapy resulted in improved symptom relief and quality of life over one year and appropriate utilization of invasive diagnostic testing (reduced endoscopy) at a small marginal increase in cost. These findings await formal testing in a clinical trial.9 However, there is no consensus on the most cost-effective long-term maintenance drug strategy. There are proponents of maintenance with full dose PPI, step-down treatment (PPI or H2RA) and intermittent therapy.9–11 Given the evidence that PPIs are more likely to be clinically effective than H2RAs and that doctors and patients will want to use the most effective therapy, the cost-effectiveness issue depends in part on how much society is willing to pay to achieve health improvements and on opportunity costs in health expenditure.12 Most of the pharmacoeconomic modelling of GERD has been
42 P. H. Katelaris
done in the USA where costs may be markedly different from elsewhere. In a modelling study from Hong Kong for example, standard dose PPI maintenance therapy was suggested to be the most effective and least costly method of maintenance therapy.13 Endoscopy has prognostic value in GERD, as the grade of esophagitis if present, will guide PPI use. Patients with severe esophagitis (for example LA grade D) will have best control of symptoms and maintenance of healing by ongoing PPI therapy, and this is likely to be cost-effective. However, the role of endoscopy and its contribution to the costs of managing GERD overall have not been determined precisely and varies considerably around the world.
SURGICAL THERAPY OF GERD With the availability of laparoscopic fundoplication, surgery for GERD has become more common. Laparoscopic fundoplication may provide effective long-term control of reflux symptoms. However, the evaluation of the effectiveness and the morbidity and mortality associated with the procedure is difficult for a number of reasons. Firstly, there has yet to be a large prospective multicenter trial comparing surgery with PPI therapy. Secondly, the existing literature is mostly comprised of outcomes from tertiary centres of excellence and these may not be reproducible by less experienced generalists. It has been suggested that outcomes of laparoscopic fundoplication may be optimized if the procedure is confined to centers with particular expertise and interest in anti-reflux surgery. Thirdly, results are operator-dependent and affected by the learning curve, which may not feature in reported series. Fourthly, results are often single center experience without independent analysis of outcomes. Lastly, the methodology for assessing outcomes is not standardized, often not comparable and sometimes disputed. When considering the rigour with which drug therapy has been evaluated, there is much less high-level evidence on which to assess the risks and benefits of laparoscopic surgery for GERD. There has been considerable controversy about the effectiveness of fundoplication. Some surgical series report excellent control of heartburn, high levels of patient satisfaction, low peri-operative morbidity, restored quality of life and few ongoing adverse effects.14,15 However, other assessments have been less uniform. One well cited report revealed that 62% of patients were using anti-reflux medication after fundoplication and had a higher 11 year mortality than medically treated patients16 and another reported lower satisfaction scores.17 Fundoplication has not been shown to cause regression of Barrett’s epithelium or to reduce the risk of esophageal cancer. Patient selection is crucial to the outcome of fundoplication. Patients who have good control of reflux symptoms with PPIs may do well with fundoplication. In these patients, the decision for ongoing medical therapy or surgery is based largely on informed choice, in the context of an understanding of the risks and benefits of both approaches. Patients with atypical symptoms, who are endoscopy negative and respond poorly to acid suppression may fare poorly with fundoplication. Surgery should be considered in the few patients with medically refractory reflux, with or without esophagitis and in the rare patient who is intolerant of PPI therapy (and has evidence of reflux). In patients with problematical ‘volume reflux’ or symptoms derived from large and particularly para-esophageal herniae, laparoscopic hernia reduction and fundoplication is often appropriate.
An evaluation of current GERD therapy 43
ADVERSE EFFECTS OF SURGICAL THERAPY There is a risk of death or serious morbidity from fundoplication although the absolute risk is relatively small. A mortality rate of 0.2% has been reported from expert centers18 and this exceeds the estimated annual risk of esophageal cancer (of about 0.02%) and far exceeds potential risk from PPI therapy. This risk issue is of the most importance as GERD is a disease with a very low mortality. Peri-operative complications including surgical mishap, infection and the need to convert to open fundoplication occur in a minority. In one large series, significant early surgical morbidity occurred in 11% of patients.18 The most common adverse effects following surgery are inadequate control of heartburn (leading to a re-operation rate of 3–7%), dysphagia and the ‘gas bloat’ syndrome with an inability to belch or vomit. Disturbed bowel function, particularly troublesome flatulence and diarrhoea, is also well described. These adverse effects are common (two-thirds of patients may report new symptoms after fundoplication) and severe in a subset. These symptoms may be more difficult to treat than the reflux for which the surgery was done. This may impair quality of life.17 Indeed, it has been observed that if the frequency of adverse effects that occur after fundoplication were to occur with drug therapy for reflux, such a drug may not pass regulatory scrutiny nor find favor among prescribers.
COMPARING COSTS OF SURGICAL AND MEDICAL THERAPY There has been a number of attempts to compare the cost-effectiveness of medical versus surgical therapy of GERD. There are many difficulties in making meaningful comparisons based on cost. To use cost as the basis of comparison assumes equal effectiveness. Such comparisons are also highly dependant on the assumptions made and the breadth of the modelling used (not all surgical reports cost complications or failures) as well as local health costs, which may vary enormously. As has been stated, ‘medical economic models are not necessarily portable across geographic or political boundaries’.19 Modelling does not account for variation in surgical skill nor provide long-term information and efficacy of fundoplication which may decline with time.19 Moreover, it is difficult to attach monetary value to gains in health status. It is not surprising that attempts to model costs yield varying results. European studies report conflicting results while another more detailed study reported rough parity of costs.20 Perhaps most importantly, modelling does not take into account patient choice. The ethics of choice should not be based on modelled costs. For patients with GERD that is well controlled with PPI therapy, surgery is an alternative mode of treatment that most will choose not to have, irrespective of the theoretical possibility of cost-effectiveness. Patients cannot be compelled in this way but have the right to be aware of the risks and benefits of alternative modes of GERD treatment.
ENDOSCOPIC ANTI-REFLUX THERAPY There has been a rapid development of endoscopic methods for treating GERD and in some areas, rapid regulatory approval and adoption into clinical practice. A common observation has been that if these devices were considered as drugs they would require far more stringent evaluation before gaining regulatory approval for use outside
44 P. H. Katelaris
the context of clinical trials in major centres. Techniques include endoscopic plication, application of radiofrequency energy or injection of polymer around the lower esophageal sphincter. Data at present is from short-term studies. These describe improvement in heartburn scores but not normalization of esophageal acid exposure or healing of esophagitis. Long-term data are lacking and safety issues are unresolved. Complications including deaths have been reported. The first randomized controlled data are just emerging21 and is not convincing and there are no prospective comparative data with PPIs. At present, the place of such techniques remains to be established22 and it is far too early to consider cost-effectiveness issues for these techniques. Patients need to be aware of the current uncertainty about the status of such techniques relative to conventional medical or surgical therapy for GERD.
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