The Second Canadian Gastroesophageal Reflux Disease Consensus: Moving forward to new concepts

Gastroesophageal reflux disease (GERD) is a disease with serious consequences that may result in significant impairment in quality of life and disease morbidity. Across all grades of severity of symptoms and severity of underlying esophageal disease, proton pump inhibitors (PPIs) provide therapeutic gains over prokinetics (PKs) or H2 receptor antagonists (H2RAs). The potential cost effectiveness of using medications with higher acquisition costs that may lower health care costs overall is often disregarded when conducting cost comparisons with medications having lower ‘up-front’ costs. Limiting therapy to less effective agents condemns many patients to protracted suffering, repeated physician visits and needless reinvestigation of symptoms that could have been resolved by appropriate initial therapy. Based on current data, use of any classification of symptom severity as a basis for selecting one class of therapeutic agents over another for first line therapy (ie PKs, H2RAs for ‘mild’ GERD, versus a PPI for ‘severe’ disease) is unwarranted.

T he publication of the Second Canadian Gastroesophag- eal Reflux Disease Consensus Conference on the management of patients with gastroesophageal reflux disease (GERD) (1) was awaited with considerable interest and expectation.Publication of the document took place 15 months after the conference in June 1996, reflecting the time needed to write and revise the manuscript to incorporate revisions requested by the 38 participants who attended the conference.The many controversies involved, particularly regarding the step-up versus the step-down approach to therapy, lengthened the publication process.Moreover, because of the lack of previously approved rules of revision, revisions in the cognitive aspects of the document were necessary in order to incorporate more recently available literature.Consensus signifies agreement, and the nature of the controversy surrounding the development of a treatment algorithm, and the immense commercial implications involved, implied the need to reduce the protocol to the lowest common denominator of physician comfort rather than aspiring to the heights of idealism for the best approach based on evidence and common sense.
This paper examines new evidence, reassesses old data and interprets possible choices for treatment of patients with GERD, all of which form the basis for the proposal that stepdown therapy is the only treatment for patients with GERD that can be supported by the evidence.Step-down therapy denotes a short two-to four-week course of therapy with a proton pump inhibitor (PPI), after which the patient is reassessed.At the time of reassessment the physician may initiate a step-down to a lower dose or intermittent PPI therapy, 'less potent' H 2 receptor antagonist (H 2 RA) therapy or prokinetic (PK) therapy.Endoscopy is not necessary to diagnose GERD and is indicated only if the patient has alarm symptoms, or if reflux symptoms persist or recur despite adequate therapy.Patients who require long term maintenance therapy should undergo an elective, 'once-in-a-lifetime' endoscopy to screen for Barrett's esophagus, provided that they are eligible for, and desirous of, appropriate therapy if Barrett's esophagus is diagnosed.

LIMITED USE OF A SYMPTOM SEVERITY SCALE
Table 4 in the introductory article of the consensus document outlines an arbitrary clinical scale estimating the symptom severity of GERD (1).Although it is a plausible scale, no data exist to substantiate the classification of symptoms as 'mild' if they have been present for less than six months, if they occur less than three times per week or if the patient rates symptom intensity as 'three or less' on an undefined scale of 10.It is well documented that the symptoms of acid reflux disease are not reliable predictors of the presence or severity of underlying esophagitis.Mild symptoms may mask the presence of severe esophagitis (2)(3)(4)(5).For example, approximately 80% of patients classified as having mild symptoms of acid reflux disease had underlying esophagitis grades two to four, and nearly 40% had esophagitis grades three and four (Figure 1).Furthermore, a recent meta-analysis of pooled data from 16 independent clinical trials that studied a total of 3478 patients with acid reflux disease demonstrated that approximately 70% of patients experienced moderate to severe heartburn, irrespective of the severity of the underlying esophagitis (6).Thus, patients with mild symptoms may have severe erosive esophagitis, and patients who do not have erosive esophagitis may experience severe symptoms.Furthermore, 'mild' symptoms, or a diagnosis of 'mild' esophagitis, are not a guarantee of a good response to 'mild' or less potent therapy.Even for patients with grade II erosive esophagitis, the group that comprises approximately 62% of patients studied in clinical trials (7), there is a major therapeutic gain using PPIs over H 2 RAs; the rate of healing and symptom relief is approximately twice as fast (7).
The symptom severity scale was introduced partly because it was recognized that primary care physicians base patient management largely on symptoms.However, to be useful in practice a symptom scale should first be validated to ensure that it can provide a predictable basis for determining appropriate investigation and treatment strategies.Because the symptom scale proposed by the consensus guidelines has not been validated, a number of practical management problems are created: • Very mild symptoms may require little, if any, therapy, but there are no data to indicate an appropriate threshold for initiating therapy.
• The presence of 'mild' symptoms may mask severe mucosal damage that will not respond to treatment with lifestyle modifications or H 2 RAs.
• There are no data to indicate that PPI therapy is medically inappropriate for some patients with 'mild' symptoms.
• The duration of symptoms for more than six months has no bearing on symptom severity; it is simply indicative of chronicity.
• Limiting the initial use of PPIs deprives physicians of a potentially cost effective diagnostic tool.In the patient who has typical symptoms, a good symptomatic response to a short course of PPI therapy is virtually diagnostic of reflux disease.Provided that the patient's response to therapy is assessed within two weeks, a step-down approach need not be more costly.In conclusion, current data do not warrant use of any classification of symptom severity as a basis for selecting one class of therapeutic agents over another for first line therapy (ie, PK or H 2 RA for 'mild' GERD, versus PPI for 'severe disease').

MILD THERAPY IS LIMITED FOR MILD SYMPTOMS OR MILD ESOPHAGITIS
Some physicians are uncomfortable prescribing 'potent' PPI therapy to relieve symptoms arising from a condition that they consider to be relatively trivial; however, GERD is not a trivial condition.Using either the Psychological General Well-Being (PGWB) index or the Gastrointestinal Symptomatic Rating Scale (GSRS), it is clear that reflux symptoms, with or without associated esophagitis, significantly impair quality of life (8)(9)(10)(11).Accepting that there is a dissociation between the severity of symptoms and the severity of underlying esophageal disease, employing a step-up approach to therapy withholds effective PPI therapy from patients who require effective acid inhibition.Furthermore, PPIs are superior to PKs and H 2 RAs for treating mild symptoms arising in patients with endoscopy-negative reflux disease (ENRD) and across all grades of erosive esophagitis.In five large, double-blind trials including over 2500 patients with GERD, with or without associated esophagitis, omeprazole provided better symptom relief than ranitidine 150 mg bid or cisapride 10 mg qid (12)(13)(14)(15)(16).The therapeutic gains at four weeks with omeprazole 20 mg administered once daily were 21% over ranitidine (P<0.0001) and 26% over cisapride (P<0.01);omeprazole 10 mg daily produced therapeutic gains of 9% and 13%, respectively (Figure 2).Differences were also noted between PPI and PK (16).Omeprazole also produced therapeutic gains of 28% to 30% over placebo in the four-week resolution of heartburn (12,13,15).Rapid symptom relief was achieved in primary care patients who had heartburn, with or without esophagitis (16).Regurgitation was also decreased, and quality of life (PGWB scale) was normalized (9,11).PPIs consistently produced higher healing rates than H 2 RAs in patients with erosive esophagitis, irrespective of the severity of the esophagitis (2), and without the development of tolerance that occurs with H 2 RA (17-20).
It is noteworthy that much of the controversy about choice of therapy is related to the 'up-front' (acquisition) cost of therapy.PPIs are used less often not because they are too 'potent', but because they are relatively costly.If PPIs and H 2 RAs were equal in price, little, if any, controversy regarding step-up versus step-down therapy would exist; however, most cost comparisons consider only 'up-front' drug acquisition costs.The Canadian Coordinating Office for Health Technology Assessment health economic analysis indicates that using more costly medications may reduce overall health care costs provided that they are more effective.Thus, because of the rapid and high rate of symptom resolution achieved with PPIs and the higher probability of complete healing of associated esophagitis, the patient with GERD can be managed more effectively, whether the endpoint is resolution of symptoms, improved quality of life or healing of esophagitis.Limiting therapy to less effective agents condemns many patients to protracted suffering, repeated physician visits and needless reinvestigation of symptoms that could have been relieved by appropriate initial therapy.

LIMITED USE OF PKS AND H 2 RAs FOR MAINTENANCE THERAPY
The healing of erosive esophagitis and resolution of reflux symptoms are a temporary respite for nearly two-thirds of patients with GERD.Despite effective acute therapy, symp-Can J Gastroenterol Vol 12 No 8 November/December 1998 553 The Figure 4) Omeprazole is superior to ranitidine and cisapride in maintaining pateints with healed reflux esopagitis in long term endoscopic remission toms and esophageal erosion recur in the majority of patients with reflux esophagitis and, in studies of patients with erosive esophagitis, relapse rates of 80% to 90% have been documented within six to 12 months of stopping therapy (21).Thus, maintenance therapy is indicated for a substantial proportion of patients who initially require acute medical therapy.The Second GERD Consensus Conference, therefore, recommended that these patients be maintained on the agent that had been successfully used to treat their reflux symptoms and/or erosive esophagitis.However, regardless of which therapeutic agent was used initially and of the severity of the reflux esophagitis, PPIs produce higher symptomatic and endoscopic remission rates than do H 2 RAs or PKs (Figures 3,4).Although H 2 RAs are effective for some patients with mild GERD, they are of questionable efficacy in patients with more severe erosive esophagitis (Savary-Miller grades two to four) (21).
For patients with erosive esophagitis, PPIs clearly provide a superior outcome in terms of symptom relief and freedom from recurrent esophageal injury.However, particularly in the primary care setting, it is impractical to arrange for endoscopy in all patients with reflux symptoms, either at initial presentation or after therapy.Thus, in most instances physicians must rely on symptoms to gauge disease severity and treatment success.The relevance of studies conducted in patients with erosive esophagitis in primary care practice remains controversial, but recent studies suggest that 29% to 51% of reflux patients have erosive esophagitis (14,(22)(23)(24).Patients with endoscopy-positive reflux disease are indistinguishable, with respect to symptom severity, from patients with ENRD (6).These observations, combined with studies showing that PPIs provide better symptom relief than PKS or H 2 RAs in patients with ENRD (14,16), strongly suggest that PPIs are superior for maintenance therapy over the full 554 Can J Gastroenterol Vol 12 No 8 November/December 1998

Thomson et al
Figure 5) Suggested approach to patients with typical gastroesophageal reflux disease (GERD) symptoms.OTC-H 2 RA Over-the-counter histamine H 2 receptor antagonists; pH Ambulatory esophageal pH monitoring; PPI Proton pumb inhibitor; Rx Reaction spectrum of GERD.It is also irrelevant whether some GERD patients develop recurrent symptoms in the absence of erosive esophagitis.Symptomatic ENRD is a chronic condition (10,25); about half of these patients experience recurrent symptoms within six months of stopping prescription therapy, despite the use of antacids.Using short courses of PPIs to treat symptomatic recurrences is sensible, given their superior pain relief compared with PKs or H 2 RAs (7,14,16).Is there any risk that intermittent use of PPIs for recurrent symptoms increases the risk of the patient developing a complication?Follow-up of patients who initially had mild esophagitis showed that more severe esophagitis later occurred in 20% of these patients (26).There is no evidence that intermittent PPI therapy reduces this risk, but there is also no evidence that it increases the risk of progression.Furthermore, because PPIs provide a greater likelihood of healing recurrent esophagitis, independent of an overall increase in the propensity for severe esophagitis, it is more likely that the risk of esophageal ulceration or stricture will be decreased (27).

FOR CONSIDERATION
Optimal therapy for patients with GERD eliminates reflux symptoms and prevents the development of complications.The symptom pattern correctly predicts the diagnosis of GERD in at least two out of three patients (28), and self administered questionnaires may also facilitate the diagnosis of GERD (6,31).Many patients with GERD experience symptoms that are sufficiently severe to impair their quality of life (29,30).The endoscopic severity of esophagitis correlates poorly with GERD symptom severity (31).In the absence of alarm symptoms, upper gastrointestinal series or endoscopy are not indicated (32).It is controversial whether endoscopy is indicated for patients with nonresponsive reflux symptoms, and 24 h esophageal pH monitoring may be required in patients with reflux symptoms that persist after administration of standard doses of a PPI to determine whether higher or more frequent doses are needed.If neither erosive disease nor Barrett's esophagus is found on initial endoscopy, further endoscopies are not indicated, even in the presence of continued symptoms.
Treatment with a PPI may be used effectively as a diagnostic therapeutic trial in patients with troublesome, but not alarm, symptoms of GERD (33)(34)(35).Health-related quality of life in patients with GERD is more likely to be restored by initial treatment with a PPI than with an H 2 RA (9,10,15,36,37).The debate continues as to whether step-up therapy is the preferred strategy or whether PPIs should be considered the only appropriate therapy for symptoms of GERD.Antacids, alginates, over-the-counter H 2 RAs and lifestyle changes are appropriate therapy for trivial or infrequent heartburn or regurgitation.However, most patients have self-medicated by the time they consult a physician.Recommending step-up therapy is not warranted when the consequences of ineffective or less effective treatment include persistent symptoms, impaired quality of life, time lost from work and repeated physician visits.Thus, the step-up approach is difficult to support because it delays the institution of adequate therapy.Inadequate therapy ultimately leads to more health care dollars being spent on repeated physician visits, specialist consultations and investigations, only to culminate in prescribing a PPI that could have initiated therapy in a step-down approach.
Thus, step-up therapy is impractical and inadequate for many patients.Step-down therapy is only limited in that some patients may be adequately managed with less potent, or initially less costly, therapy; however, three-quarters of patients treated by the step-up approach suffer the consequences of suboptimal therapy.The cost of PPIs is greater than that of generic H 2 RAs.The economic argument, which is based on drug acquisition costs, is often used to support the step-up approach: use cheaper therapy in all patients with the hope that endoscopy, complications, poor quality of life and the later need for a PPI can be avoided.However, less potent therapy is not necessarily less costly.Acquisition costs for PKs are almost comparable with those for PPIs, and, there is, therefore, little support for endorsing the recommendation of the Second GERD Consensus Conference that PKs be considered as first-line therapy.PK therapy should be considered not because it is less potent, but because there are accompanying indicators of altered gastrointestinal motility that may respond appropriately to this class of medication.
The cost of caring for patients with GERD goes far beyond the cost of the initial physician consultation and the initial prescription cost.Failure of therapy may lead to follow-up visits, referral and investigations, all of which are costly.Most patients, if they were properly and honestly informed, would not tolerate enduring unpleasant, suboptimal symptom relief because funding agencies only support the use of less effective therapies based on lower initial, up-front drug acquisition costs.Properly designed clinical trials with prospective evaluation of the downstream health care costs are urgently required to settle these important issues.
More debate about better strategies of management, more studies and more patient-oriented discussions are required.A simple approach to the patient with GERD symptoms is proposed to initiate the process of further discussion (Figure 5).Let's hear from you -what is your viewpoint?

Figure 1 )
Figure 1) Esophagitis by endoscopic grade in patients with mild symptoms of acid reflux disease.Data from references 3,4

Figure 3 ) 2 )
Figure 3) Predictable maintenance treatment with omeprazole in reflux esophagitis, irrespective of pre-entry grade Figure 2) Resolution of heartburn in patients with symptomatic acid reflux disease.Data from references 12-16