a cost-effectiveness analysis of prescribing strategies in the management of gastroesophageal reflux...

A Cost-Effectiveness Analysisof Prescribing Strategies in theManagement of Gastroesophageal Reflux DiseaseLauren B. Gerson, M.D., M.Sc., Anthony S. Robbins, M.D., Alan Garber, M.D., Ph.D.,John Hornberger, M.D., M.Sc., and George Triadafilopoulos, M.D.Division of Gastroenterology and Departments of Medicine and Health Research and Policy, StanfordUniversity School of Medicine, Stanford, California; VA Palo Alto Health Care System, Palo Alto,California; and Division of Medical Economics, Roche Pharmaceuticals, Palo Alto, California

OBJECTIVE: Patients who have uncomplicated gastroesoph-ageal-reflux disease (GERD) typically present with heart-burn and acid regurgitation. We sought to determine thecost-effectiveness of H2-receptor antagonists (H2RAs) andproton-pump inhibitors (PPIs) as first-line empiric therapyfor patients with typical symptoms of GERD.

METHODS: Decision analysis comparing costs and benefitsof empirical treatment with H2RAs and PPIs for patientspresenting with typical GERD was employed. The six treat-ment arms in the model were: 1) Lifestyle therapy, includingantacids; 2) H2RA therapy, with endoscopy performed if noresponse to H2RAs; 3) Step up (H2RA-PPI) Arm: H2RAfollowed by PPI therapy in the case of symptomatic failure;4) Step down arm: PPI therapy followed by H2RA if symp-tomatic response to PPI, and antacid therapy if response toH2RA therapy; 5) PPI-on-demand therapy: 8 wk of treat-ment for symptomatic recurrence, with no more than threecourses per year; and 6) PPI-continuous therapy. Measure-ments were lifetime costs, quality-adjusted life years(QALYs) gained, and incremental cost effectiveness.

RESULTS: Initial therapy with PPIs followed by on-demandtherapy was the most cost-effective approach, with a cost-effectiveness ratio of $20,934 per QALY gained for patientswith moderate to severe GERD symptoms, and $37,923 forpatients with mild GERD symptoms. This therapy was alsoassociated with the greatest gain in discounted QALYs. ThePPI-on-demand strategy was more effective and less costlythan the H2RA followed by PPI strategy or the other treat-ment arms. The results were not highly sensitive to cost oftherapy, QALY adjustment from GERD symptoms, or thesuccess rate of the lifestyle arm. However, when the successrate of the PPI-on-demand arm was#59%, the H2RA-PPIarm was the preferred strategy.

CONCLUSION: For patients with moderate to severe symp-toms of GERD, initial treatment with PPIs followed byon-demand therapy is a cost-effective approach. (Am JGastroenterol 2000;95:395–407. © 2000 by Am. Coll. ofGastroenterology)

INTRODUCTION

Symptoms of gastroesophageal-reflux disease (GERD),such as heartburn and acid regurgitation, are common. Sur-veys have found that 44% of all Americans suffer fromheartburn at least once per month (1), 30% at least once perweek (2), and up to 7% daily. Heartburn is often chronic (3),and may diminish quality of life (4). In addition, lifetimedrug therapy is costly.

Management of heartburn commences with lifestyle mod-ification and prescription of antacids or H2-receptor antag-onists (H2RAs). After an 8-wk trial of H2RA therapy forrelief of heartburn, patients may be managed in severalways. If improved, they may remain on H2RAs either in-definitely or intermittently, with therapy resumed uponsymptom recurrence. If not improved, patients may betreated with proton-pump inhibitors (PPIs, so-called “stepup” therapy) or be referred for an endoscopic examination.If they fail empirical PPI therapy, most patients will undergoendoscopic examination. The term “step down” therapyrefers to starting with a PPI for 8 wk, followed by H2RAs ifthe patient responds to a PPI, and then stepping down toantacids if the patient is asymptomatic on H2RAs; this is anadditional approach. Another therapeutic option, used lessfrequently, is to perform initial endoscopy to define diseaseseverity and to screen for Barrett’s esophagus. AlthoughPPIs cost more than H2RAs at usual dosages, they may bemore cost-effective because they are more effective in heal-ing both erosive (5–14) and nonerosive disease (15), thusdecreasing the number of office visits and diagnostic tests.

Patients found to have erosive disease on endoscopy areusually treated with maintenance PPI therapy. However,recent studies suggest that patients who have nonerosivedisease do not differ from those with erosive disease interms of symptom severity, duration, or response to antise-cretory therapy (16, 17). Therefore, regardless of endo-scopic findings, patients with nonerosive disease may betreated with PPIs. Traditionally, to receive PPIs, patientswith nonerosive disease must fail H2RA therapy and dem-

THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 95, No. 2, 2000© 2000 by Am. Coll. of Gastroenterology ISSN 0002-9270/00/$20.00Published by Elsevier Science Inc. PII S0002-9270(99)00818-7

onstrate pathological reflux on 24-h ambulatory esophagealpH testing.

Even after healing of erosive esophagitis with either PPIsor H2RAs, multiple studies have shown that nearly all pa-tients will relapse by 6 months if they do not receivemaintenance therapy (18). Daily PPI maintenance therapyreduces the 6-month and 12-month relapse rates to 15–30%(19–21). After initial treatment with a PPI, approximatelyone-half of the patients who are stepped down to an H2RAwill relapse (22, 23). Intermittent therapy with PPI giventhree times per week, or on the weekends, is not as effectiveand is associated with relapse rates roughly equivalent tothose for daily H2RAs (24, 25). Patients who require chronicmedical therapy for symptom relief may also consider sur-gery with a laparoscopic Nissen fundoplication. However,postoperative complications, which can include dysphagiaand the gas-bloat syndrome, can occur in 10–30% of pa-tients postfundoplication (26, 27).

Patients with nonerosive disease also may require chronicmaintenance therapy. Two randomized double-blind pla-cebo studies in such patients showed the superiority of PPIover placebo (28, 16). Intermittent or on-demand treatment(defined as an 8-wk course of treatment given as needed forsymptom recurrence) for patients with GERD is a promisingapproach that has not been well studied. Natural historystudies of GERD demonstrate that often patients take theirmedication intermittently (3). Recently, the first clinical trialof intermittent therapy for GERD comparing omeprazoleand ranitidine was published (29). This double-blind mul-ticenter European study randomized patients with nonero-sive or mild-moderate erosive disease to 2–4 wk of ome-prazole or ranitidine therapy for symptomatic recurrence ofheartburn symptoms over the course of a year. Although PPItherapy was significantly superior to H2RA in terms ofsymptomatic relief by the second week, the percent ofpatients who were able to tolerate intermittent therapy wasnot affected by initial treatment at randomization. Fiftypercent of patients from both PPI and H2RA groups com-pleted intermittent treatment, whereas approximately one-quarter of patients from each group required maintenancetherapy. Although an 8-wk course of therapy is usuallyrequired for healing of erosive esophagitis, the study pro-vides evidence that intermittent therapy is an effective clin-ical strategy for the majority of GERD patients.

In the current era of cost consciousness, there is a grow-ing need to demonstrate that available treatments not onlyimprove quality of life, but also are cost-effective. Severalcost-effectiveness studies regarding the chronic manage-ment of GERD have been published (30–38). The majordrawbacks to these studies have been they study exclusivelypatients who have erosive esophagitis, and thus disregardthe remaining 50% of patients who have nonerosive symp-tomatic disease; they require endoscopy to determine dis-ease severity before treatment; they omit quality-of-life as-sessments; they include surgery only for patients who havefailed medical therapy, not accounting for patients who

choose surgery to stop taking medications; they do notconsider prokinetic therapy; 24-h ambulatory esophagealpH studies and/or manometry are not included as part of theGERD evaluation; they calculate costs over 1 yr, rather thanover the patient’s lifetime; and none of the prior modelsinclude the options of step-up or step-down therapy. Inaddition, some of the studies used a modified Delphi tech-nique to obtain probabilities and costs. Finally, the option oftreatment on demand (treatment for symptomatic recur-rence) has not been considered.

To determine the most cost-effective therapy for the em-pirical management of patients with GERD, we constructeda decision model using a 40-yr-old patient with heartburn asour base case, and modeled total costs and QALYs over thecourse of that individual’s lifetime.

MATERIALS AND METHODS

General ApproachWe constructed decision trees of five alternative treatmentsfor GERD and performed all calculations using Excel (39)(Microsoft Excel, Microsoft Corporation, Redmond, WA)spreadsheets. The reference treatment was lifestyle modifi-cation, against which we compared pharmacological treat-ments to compute incremental cost and effectiveness. Thesix treatments thus were (1) Lifestyle Arm: lifestyle modi-fication, which served as the reference treatment; (2) H2RAArm: the current standard practice for patients who haveheartburn, which starts with empirical H2RAs, followed byan endoscopic examination if symptoms are not controlled,and prescribes PPI therapy only if erosive disease is con-firmed; (3) H2RA-PPI (Step Up) Arm: Empirical H2RAtherapy followed by an 8-wk course of PPI therapy ifsymptoms are not controlled on H2RA therapy, and endos-copy if there is symptomatic failure on the PPI (Fig. 1); (4)Step-Down Arm: 8-wk course of PPI followed by 8-wkcourse of H2RA if symptomatic relief obtained on the PPI.Patients who respond to H2RAs are stepped down to antacidtherapy. Endoscopy is performed if patients fail to respondto PPI therapy (Fig. 2); (5) PPI-On Demand Arm: empiricaltreatment with an 8-wk course of PPI therapy administeredon demand when GERD symptoms recur. Patients in thisgroup require at most three 8-wk courses (24 wk) of med-ication per year. Patients failing on demand therapy (recur-rence of symptoms earlier than 2 months without medica-tion) receive continuous PPI therapy, and endoscopy isperformed only if symptoms recur on daily PPI therapy; (6)PPI-Continuous Arm: empirical treatment with continuousdaily maintenance PPI therapy, without performance ofendoscopy unless there is symptomatic failure.

Patients failing PPI therapy in any treatment arm wererequired to undergo endoscopy. If erosive disease was dem-onstrated, or if nonerosive disease was found and followedby a confirmatory 24-h ambulatory esophageal pH test,patients could progress to more complex therapy to remain

396 Gerson et al. AJG – Vol. 95, No. 2, 2000

symptom-free (e.g., higher doses of PPI, addition of proki-netic agents, or surgery).

The lifestyle and H2RA arms were based on currentstandards of practice. The step-up and step-down arms arealternative approaches that would theoretically decreasecosts because they use the response to medical therapy as anindicator of GERD, and therefore decrease the need forendoscopy and other diagnostic tests. The two PPI treatmentmodels were hypothetical, in that few GERD patients aretreated empirically with PPIs, mainly because of their rel-atively high cost (Table 1). For each treatment, we modeledcosts and effectiveness separately for the first year afterdiagnosis and for all subsequent years. Costs related todiagnosis, surgery, and unsuccessful pharmacological treat-ments were incurred only during the first year after diagno-sis. By the end of that first year, patients would have

received any necessary diagnostic tests and/or treatmentinterventions.

Model AssumptionsWe assumed that patients who failed a particular regimendid so within 4 wk of finishing that course of therapy.Although patients could fail a regimen as early as 8 wk afterthe start of the study, we used 1-yr relapse rates from theliterature regardless of when a patient failed therapy.

Patients diagnosed with nonulcer dyspepsia (normal up-per endoscopy followed by a normal 24-h ambulatoryesophageal pH test) did not receive any further medicationafter this diagnosis was made. Although these patients oftenreceive H2RAs or PPIs, there is no established standard forchronic medical therapy for this subset of patients.

We assumed that patients remained in a steady state after

Figure 1. Decision tree for the H2RA-PPI (step-up) arm. Circles represent chance nodes. Squares represent decision nodes. The percentageof patients responding to each intervention is listed below each arm of the tree. Patients who fail a PPI agent at any point are referred forendoscopy. Patients who fail to respond to once-daily PPI therapy progress to a higher PPI dose. Prokinetic therapy is given if a patientremains symptomatic on twice-daily PPI therapy. Motility studies and/or surgery are performed if patients elect to undergo surgery or failmedical management. Triangles represent end nodes, where patients remain for the duration of the study.

397AJG – February, 2000 Cost-Effectiveness of GERD Management

the first year, so that patients who did not respond to anytherapy were assumed to stay in their symptomatic state onhigh-dose PPIs and prokinetic agents indefinitely. If pa-tients’ symptoms were well controlled on medication, theyremained on that therapy indefinitely. Patients who werewell after surgery were assumed to remain symptom freewithout medications indefinitely. Although the duration ofsymptomatic relief from a laparoscopic Nissen fundoplica-tion is not known, recent studies suggest that patients mayremain symptom free up to 20 yr after an open fundoplica-tion (40, 41). Patients with a poor surgical outcome in ourmodel were assumed to have an impaired quality of lifeindefinitely and were assumed to remain on high-dose PPItherapy and prokinetic agents indefinitely.

Estimation of ProbabilitiesEstimates of responses to empirical treatment and to sur-gery, and of the outcomes of diagnostic tests, were based onpublished articles, on the esophageal motility database atStanford University Hospital, and on expert opinion (Table2). Our estimate of the success rate of on-demand PPItherapy (the percentage of patients who could remain symp-tom free without medication for 8 wk) was based on pub-lished cumulative relapse rates at 2 months for erosive andnonerosive disease. For patients with erosive disease whoare taken off of PPI therapy, approximately 15% will relapseat 30 days, and 40% by 60 days (18). In nonerosive diseasepatients, the relapse rate is 20% at 2 months for patients onplacebo, compared with,5% for patients on omeprazole 20mg taken on demand (mean number of capsules, 0.43 perday) (50, 51). In addition, a randomized trial (29) comparingintermittent omeprazole with intermittent ranitidine therapyin patients with nonerosive or mild erosive disease demon-strated that approximately 25% of patients taking omepra-

zole or ranitidine intermittently would relapse by 60 days offof therapy. Assuming a case mix of patients with 50%nonerosive and 50% erosive disease, we therefore estimatedthat 20% of the patients would require PPI therapy earlierthan 8 wk after the initial course of medication.

Our estimate of the average annual success rate for life-style modification (5%) was based mainly on our clinicalobservations. The only published prospective trial (58) com-paring 15 patients treated with surgical therapy with 36patients who received lifestyle therapy (consisting of ant-acid use, elevation of the head of the bed, weight loss, andbland diet) showed that 17% of the medically treated pa-tients were asymptomatic or had mild GERD symptomsduring the first year of follow-up. However, this responserate fell to 11% by 3 yr. The total number of patients in thestudy was small, and only patients with nonerosive diseaseresponded to conservative treatment. Therefore, we derivedour estimate of 5% from the low probability of long-termsymptom relief from interventions designed to change be-havior, such as those that encourage cessation of smoking(59), reduction in alcohol use, loss of weight (60), andelevation of the head of the bed (61) (which has beenquestioned as a strategy, because most reflux occurs duringthe daytime hours (62). We estimated that, in any givenyear, 5% of patients treated with lifestyle modificationwould be symptom free; this 5% is a steady-state rate, ratherthan a cumulative one, as many patients who have madebehavior changes will relapse in any given year, and otherswho have previously been unsuccessful will make thechanges.

Estimation of Utilities for Each Health StateScores on general health surveys have demonstrated thatpatients with esophagitis have a decreased quality of life (4,

Figure 2. Decision tree for the step-down therapy arm. Circles represent chance nodes. Squares represent decision nodes. The percentageof patients responding to each intervention is listed below each arm of the tree. Patients who have a response to 8 wk of PPI therapy arestepped down to H2RA therapy for 8 wk. If they remain asymptomatic, patients are then placed on antacids. In the case of symptomaticrelapse, a patient can receive the therapy that was successful in the previous arm of the tree. Patients who fail PPI are referred for anendoscopic examination. The endoscopy subtree refers to all of the decisions and treatments that follow endoscopy and is showncompletely in the H2RA-PPI arm tree (Fig. 1).


63). Symptoms of unhealed erosive esophagitis have beenshown to reduce general well-being to levels lower thanthose reported by patients who have angina or mild heartfailure (64). Using the standard-gamble utility assessmentmethod, where perfect health has a utility of 1.0 and death0, prior studies in patients with angina pectoris demon-strated utility scores of 0.97 for patients with Class I disease,compared with 0.88 for patients with Class III/IV disease(65). Measurements of utilities in patients with differingseverities of GERD found that after 1 wk of symptoms, allpatients had lower scores on the SF-36 compared withage-matched population, with mean standard gamble scoresof 0.90 compared with a mean score of 0.97 using the timetrade-off method (66). Because the disutilities associatedwith gastroesophageal reflux disease are not well estab-lished, we elected to test a range of 0.90–0.99, with 0.98 setas the utility for mild GERD symptoms (meaning that pa-

tients would be willing to face a 2% risk of death in agamble with a probability of 98% that perfect health is theoutcome) and 0.95 set as the utility for moderate to severeGERD symptoms. These utilities reflect previously pub-lished findings in patients with mild and moderate symp-toms and endoscopy-negative reflux disease using Psycho-logical General Well-Being (PGWB) index scores (67).Because patients with a poor surgical outcome suffer fromdysphagia, gas-bloat syndrome, and recurrent GERD symp-toms, we estimated the utility of that state to be 0.95, thesame utility as for moderate to severe GERD symptoms.

Estimation of Time Spent in Various Health StatesFor the pharmacological treatments, we estimated (based onpublished articles) that the symptoms of most patients re-sponding successfully to therapy with H2RA or PPI wouldremit after 2 wk of therapy (6, 7). Based on average waitingtimes at Stanford University Hospital, we estimated thatpatients would wait 2 wk for either upper endoscopy, 24-hambulatory pH monitoring, or a test for esophageal motility,and 4 wk for laparoscopic Nissen fundoplication.

On-demand therapy was given as a possible maintenancetherapy for patients who initially responded to H2RAs in theH2RA or H2RA-PPI arm, and for patients who failed H2RAsand responded to PPIs in the H2RA or H2RA-PPI arm.However, on-demand therapy was not prescribed in thestep-down arm because this arm of therapy has traditionallyfocused on changing patients to the less expensive drug,rather than decreasing the usage of the effective medication.Patients in the PPI on-demand arm received this therapy asthe first line of treatment. In all of these arms, the treatmentgiven was 8 wk of medication followed by 8 wk withoutmedication. If a patient’s symptoms recurred earlier than 8wk, then the patient was advanced to the next level in thedecision tree.

Estimation of CostsWe used standard doses of ranitidine (150 mgp.o. b.i.d.)and omeprazole (20 mgp.o. q.d.) to calculate the costs ofmedical therapy. Drug costs were based on the averagewholesale price (AWP) listed in the 1999 Drug Topics RedBook (68) (Table 1). The generic cost for ranitidine wasused throughout the model. We calculated the cost forcisapride therapy by averaging the costs between doses of10 mg b.i.d. and 20 mgq.i.d., because many patients areunable to tolerate 20 mg four times a day, or require lowerdoses to control their symptoms. We estimated costs fordiagnostic and therapeutic procedures using current proce-dural terminology (CPT) codes and the 1999 Medicare FeeSchedule (69) for Area 16. The facility (technical) fee for anupper endoscopy was obtained from the Endoscopy Suite atStanford University Hospital. The cost for a 2-day inpatienthospital stay for a laparoscopic Nissen fundoplication wasestimated based on average charges billed by Stanford Uni-versity Hospital at approximately $5000 per day. We esti-mated that the cost of the extra physician visits associated

Table 1. Costs Used in GERD Model*

Diagnostic or Therapeutic ManeuverCost

(1999 Dollars)

H2RA (generic ranitidine 150 mg, $1.48 per pill)empiric 8-wk course

$ 165.76

H2RA (ranitidine 150 mgb.i.d.) 1-yr continuousmaintenance

$ 1080.40

H2RA (ranitidine 150 mgb.i.d.) 1-yr demandmaintenance†

$ 497.28

PPI (omeprazole 20 mgq.d., $3.87 per pill)empiric 8-wk course

$ 216.70

PPI (omeprazole 20 mgq.d.) 1-yr continuousmaintenance

$ 1412.55

PPI (omeprazole 20 mgq.d.) 1-yr demandmaintenance†

$ 650.10

PPI (omeprazole 20 mgb.i.d.) 8-wk course $ 433.44PPI (omeprazole 20 mgb.i.d.) 1-yr continuous

maintenance$ 2825.10

PPI (omeprazole 20 mgb.i.d.) plus prokineticagent (propulsid average of 10 mgb.i.d. and20 mgq.i.d., $0.75 for 10 mg propulsid and$1.50 for 20 mg propulsid) 8-wk course

$ 643.44

PPI (20 mgb.i.d.) plus prokinetic agent(propulsid average of 10 mgb.i.d. and 20 mgq.i.d) 1-yr continuous maintenance

$ 4193.85

Upper endoscopy with biopsy (includes facilityfee and pathology)‡

$ 1444.86

Prolonged acid reflux test‡ $ 144.48Esophageal motility test‡ $ 144.83Laparoscopic Nissen fundoplication (includes

2-day hospital stay)‡$11,064.87

* Costs obtained from 1999 Drug Topics Red Book (68).† Defined as three courses of medication per year with 8 wk of medication per

course.‡ Data sources for costs are the 1999 Medicare RBRVS: The Physicians’ Guide,

the 1999 Medicare fee schedule for area 16, and Billing Department, StanfordUniversity Hospital. For upper endoscopy, the professional fee is obtained using thefollowing Current Procedural Terminology (CPT) Codes: 43239 (endoscopy withbiopsy, $238.61), 99141 (conscious sedation, $65.30), and 88305 (pathology, $64.95).The 1999 facility fee at Stanford University Hospital for an upper endoscopy is $1076.The CPT codes for the other tests include 91033 (24-h ambulatory esophageal pH test,$144.48), 91011 (esophageal manometry, $144.83), and 43324 (laparoscopic Nissen,$1064.87). Each day in the hospital after the fundoplication costs $5000. GERD5gastroesophageal reflux disease; H2RA 5 histamine2-receptor antagonist; PPI, protonpump inhibitor.


with each of the H2RA and PPI arms was equivalent to thecosts associated with the lifestyle treatment. The lifestyletreatment would actually require a substantial outlay ofresources, such as for referrals to pharmacologically basedsmoking-cessation programs or for medical treatments forweight loss. Because the costs for the extra physician visitsin the H2RA and PPI arms cancel out the costs of thelifestyle treatment, neither value is included in the model.

ModelingFor each treatment, we computed the expected number ofQALYs accumulated during the first year after diagnosisand in each subsequent year. We obtained this quantity bycomputing (for each distinct pathway of diagnostic andtherapeutic procedures) the product of the utility for eachhealth state (qi), the fraction of a year spent in that state (ti),the probability of being in that health state (pi), and thensumming these products (qi p ti p pi) over all health states foreach treatment. After computing the expected QALYs foreach treatment arm for year 1 and for each subsequent year,

we computed the incremental cost-effectiveness (C/E) ratiousing the following formula. We assumed that all patientswere 40 yr of age at diagnosis and were under medical carefor their GERD until they died:

Incremental CE ratio5

Oi51

n c2i

~1 1 r ! i 2 Oi51

n c1i

~1 1 r ! i

Oi51

n p2iq2i

~1 1 r ! i 2 Oi51

n p1iq1i

~1 1 r ! i

,

(1)

wherep2i is the probability that the individual is alive at yeari, q2i is the expected utility,c2 is the expected cost during theith interval for the intervention, andr is the real (inflation-adjusted) discount rate of 3% applied to both costs andhealth outcomes. The quantities with a “1” subscript are theanalogous quantities for the lifestyle treatment. The inter-vals in this model are single years of the patient’s life,

Table 2. Probabilities Used in GERD Model

Health Outcome, Diagnostic/Therapeutic Maneuver, orDecision Outcome/Decision 1 (%)

LowValue

HighValue References

8-wk empiric course of H2RA Symptom-free on H2RA(0.50)

0.34 0.70 (5–14)

Patients symptom-free on demand* H2RA therapy On-demand maintenance(0.50)

(29, 42)

Patients initially controlled on H2RA or PPI who relapse†on maintenance H2RA therapy

Relapse on H2RA(0.50)

0.55 0.87 (20–22, 24, 43)

Endoscopy Shows erosive GERD(0.50

0.30 0.65 (44–46, 17)

24-h ambulatory pH monitoring Positive(0.80)

0.61 1.0 (47–49)

8-wk course of PPI Symptom-free on PPI(0.85)

0.64 0.92 (5–14)

Success rate of on-demand PPI therapy Symptom-free at 2 months(0.80)

0.58 0.98 (18, 29, 50, 51)

Patients initially controlled on PPI who relapse‡ onmaintenance and require high-dose PPI

Relapse on PPI(0.20)

0.11 0.30 (19–21)

Patients controlled on high-dose PPI who relapse† andrequire addition of prokinetic agent

Relapse high-dose PPI(0.15)

0.71 0.96 (6, 10, 11, 52)

Patients not controlled on high-dose PPI who arecontrolled after addition of prokinetic agent

Symptom-free(0.10)

(22, 53)

Patients controlled on high-dose PPI and prokinetic agentwilling to take medication indefinitely

Willing to takeindefinitely(0.90)

(53)

Esophageal motility study Supportive(0.70)

(54)

Patients who choose to undergo surgery Choose surgery (54)who have failed all medications (0.80)who are asymptomatic on medication (0.10)

Patients maintained on medication who develop “coldfeet” and cancel surgery

Develop “cold feet”(0.30)

(54)

Surgery successful Good-quality outcome(0.90)

0.70 0.97 (19, 26, 27,55–57, 84)

* On-demand therapy defined as an 8-wk course of medication taken no more than three times per year.† Defined as symptomatic relapse within 12 months.‡ Presence of heartburn at least three times a week or more despite daily PPI therapy.The low and high values for the probabilities tested in the model were determined from the cited references.Abbreviations as in Table 1.


beginning when the patient is 40 yr old and extending untildeath. We estimated the probabilities of death during eachinterval using the most recent available (1992) life tables forthe U.S. population (both genders, all ethnic groups) (70).

RESULTS

The results of the cost-effectiveness analysis are shown inTable 3. The PPI-on-demand strategy is the most cost-effective approach, with a discounted incremental cost-ef-fectiveness ratio of $20,934 per QALY gained for patientswith moderate to severe GERD symptoms (QALY level of#0.95, Fig. 3) and $37,923 per QALY gained for patientswith mild GERD symptoms (QALY level of$0.98). Thisstrategy dominated the H2RA arm, step-up and step-downarms, and the PPI-continuous arm. The alternative armsproduced fewer or equal QALYs at a higher cost. ThePPI-on-demand strategy remained dominant regardless ofthe QALY level.

The reasons for the effectiveness of the PPI-on-demandstrategy are partially demonstrated in Table 4. Applying a

hypothetical cohort of 1000 patients to each treatment arm,the number of patients in treatment-related endpoints wascalculated for the three least expensive treatment strategies.The H2RA category refers to patients who are successfullytreated with H2RAs for GERD. The PPI category refers toall patients who receive PPI therapy, regardless of whetherthey ultimately receive a Nissen fundoplication or combi-nation therapy with a prokinetic agent. The largest compo-nent of the costs is procedural related. The PPI-on-demandand step-up therapy arms have the lowest costs becausesignificantly fewer endoscopies are performed comparedwith the H2RA arm. Though the costs for the first year oftherapy are slightly less in the H2RA-PPI arm, the subse-quent years of therapy cost less in the PPI-on-demand armand are associated with a greater number of QALYs, thusyielding the more favorable cost-effectiveness ratio for thePPI-on-demand arm.

Sensitivity analyses were performed on the cost of med-ication, the efficacy of H2RA and PPI therapies, the efficacyof PPI-on-demand therapy, the length of on-demand ther-apy, the annual success rate of the lifestyle arm, the effec-tiveness of Nissen fundoplication, and the costs of officevisits.

Costs of MedicationWe compared results varying the price difference of the twomedications from a scenario where the prices of the twomedications ranged from $0.33 each (i.e., equal cost) to atenfold higher cost for PPI ($0.33 for the H2RA vs$3.63 forthe PPI). In the first scenario, the PPI-on-demand was dom-inant with an incremental cost-effectiveness ratio (compar-ing PPI-on-demand to lifestyle therapy) of $2197/QALYgained. Once the price difference was fourfold or greater(when the H2RA cost $0.33 and the PPI $1.20 per pill) theH2RA-PPI strategy cost the least but was associated with

Table 3. Incremental Cost-Effectiveness Analysis*

Strategy

Discounted IncrementalCost (From Age 40 Yr

Until Death)

Discounted QALYs(From Age 40 Yr

Until Death)

Discounted IncrementalCost Effectiveness(From Age 40 Yr

Until Death)

QALY 5 0.95, Base case, severe GERDLifestyle $ 0 23.66 Reference treatmentPPI-on-demand $26,167 24.91 $20,934H2RA-PPI $27,846 24.37 Dominated by PPI-on-demandH2RA $29,965 24.42 Dominated by PPI-on-demandStep down $37,641 24.43 Dominated by PPI-on-demandPPI, continuous $41,112 24.65 Dominated by PPI-on-demand

QALY 5 0.98, Base case, mild GERDLifestyle $ 0 24.38 Reference treatmentPPI-on-demand $26,167 25.07 $37,923H2RA-PPI $27,846 24.55 Dominated by PPI-on-demandH2RA $29,965 24.66 Dominated by PPI-on-demandStep down $37,641 24.66 Dominated by PPI-on-demandPPI, continuous $41,112 24.76 Dominated by PPI-on-demand

* Incremental cost-effectiveness ratios were obtained by comparing treatments in a stepwise fashion by order of cost and effectiveness. The ratio for PPI-on-demand comparesthat strategy to the lifestyle arm, the H2RA-PPI strategy is compared to the PPI-on-demand arm, and so on. Because the PPI-on-demand arm costs less and is equal or greaterin effectiveness compared to the other arms, it is the dominant strategy.

Abbreviations as in Table 1.

Figure 3. Cost-effectiveness ratio for PPI-on-demand therapy as afunction of QALY level. The PPI-on-demand strategy remainsdominant regardless of the QALY decrement from GERD symp-toms. However, at a level of#0.99, the cost-effectiveness ratiofalls within the acceptable range of#$50,000/QALY.


fewer QALYs than the PPI-on-demand arm. The cost-ef-fectiveness ratio of H2RA-PPI compared with lifestyle was$11,949. However, because the PPI-on-demand strategywas more effective than the H2RA-PPI despite a slightlyhigher cost, the PPI-on-demand is preferred over the H2RA-PPI arm by extended dominance. The incremental cost-effectiveness ratio for the PPI-on-demand compared withthe H2RA-PPI in this scenario was $724. So at a pricedifference of fourfold or greater between the two drugs, theH2RA-PPI strategy is no longer dominated by the PPI-on-demand strategy, but the PPI-on-demand arm is still asso-ciated with the most favorable cost-effectiveness ratio (Fig.4).

Success Rate of the PPI-on-Demand TherapyAs explained in the Methods section, we calculated that80% of the patients would be able to tolerate absence of PPIfor 8 wk, assuming that there would be an equal mix ofpatients with erosive and nonerosive disease. We performedsensitivity analysis on this figure, varying the success rate ofon-demand PPI therapy from 30% to 70%. The PPI-on-

demand arm was the most cost-effective strategy when thesuccess rate was 60–70%, with a cost-effectiveness ratioranging from $47,741 for the former to $29,655 for the latter(comparing PPI-on-demand to lifestyle therapy to obtain thecost-effectiveness ratios). At a demand success rate of 59%,the PPI-on-demand arm was the least expensive, but theH2RA-PPI arm was associated with more QALYs and there-fore was the preferred strategy. At a PPI-on-demand successrate of 59%, the cost-effectiveness ratio for PPI-on-demandwas $50,478 (comparing PPI-on-demand to lifestyle), butthe ratio was $14,600 when the H2RA-PPI arm was com-pared to PPI-on-demand. Therefore, at a success rate of#59%, the H2RA-PPI arm would be the preferred regimen.This is the only section of the sensitivity analysis where thePPI-on-demand strategy is no longer favored (Fig. 5).

Success Rate of Nissen FundoplicationWe varied the success rate of a Nissen fundoplication from70% to 90%. There were no changes in the results of ourfindings even if 30% of the patients treated with a Nissenfundoplication had postoperative complications.

Length of On-Demand TherapyThe length of the on-demand therapy was changed from thebase case of 24 wk to 32 wk and 46 wk. At 46 wk, the

Figure 4. The effect of PPI/H2RA cost ratio on the cost-effective-ness ratio. The PPI-on-demand strategy is preferred when the costratio is between 1 and 3 (i.e., the PPI costs three times as much asthe H2RA). When the ratio is$4, the PPI-on-demand is stillpreferred by extended dominance over the H2RA-PPI arm. }PPI-demand; h H2RA-PPI.

Figure 5. Cost-effectiveness ratio variation according to PPI-on-demand success rate. At a success rate of#59%, the PPI-on-demand arm is no longer the preferred strategy. Though the PPI-on-demand costs less than the H2RA-PPI at a success rate of 59%,the latter is more effective and therefore has a more favorablecost-effectiveness ratio. } PPI-demand; h H2RA-PPI.

Table 4. Analysis of 1000 Patients and Treatment-Related Endpoints

Treatment ArmPatients on

H2RA*Patients on

PPI† Endoscopy SurgeryYear 1Cost‡

Year 2Cost‡

H2RA 200 702 780 5 $1877 $1149H2RA-PPI 200 780 216 5 $1244 $1083PPI-on-demand None All 89 2 $1263 $1010

* Patients successfully treated with H2RA therapy.† Patients treated with a PPI either alone, with a prokinetic, before surgery, or after a poor surgical outcome.‡ Discounted marginal costs for a year of therapy. For the PPI-on-demand arm, the Year 1 costs of $1263 included $917 for drug costs, $265 for diagnostictests, and $81

for surgery. For the H2RA arm Year 1 costs, $888 was for drugs, $778 for tests, and $211 for surgery. The costs for Year 2 and subsequent years until death remain constant.Abbreviations as in Table 1.


H2RA-PPI arm was less expensive but also less effectivethan the PPI-on-demand arm. The PPI-on-demand was thepreferred strategy, with a cost-effectiveness ratio of $2930per QALY (comparing H2RA-PPI to PPI-on-demand ther-apy).

Varying Efficacy of the H2RA ArmWe set the efficacy rate of the H2RA at 70% (the high value,Table 2) and then varied the efficacy of on-demand PPItherapy from 50% to 80%. In the first case, where thePPI-on-demand was 50% effective and the H2RA was 70%effective, the PPI-on-demand therapy was less expensivethan the H2RA-PPI arm, but the H2RA-PPI arm was moreeffective, and therefore the preferred strategy. The incre-mental cost-effectiveness ratio was $105,744 for the PPI-on-demand arm (comparing PPI-on-demand to lifestyletherapy) and $1026 for the H2RA-PPI arm (comparing PPI-on-demand to H2RA-PPI therapy). At a success rate of$60%, the PPI-on-demand therapy was the most cost-ef-fective strategy.

Costs of Office VisitsThe total costs of office visits for all treatment arms wereuncertain. We assumed that the number of office visitswould be similar among all treatment arms, and we per-formed sensitivity analyses to assess the effects of the pa-tients in the drug arms seeing their physicians more oftenthan patients in the lifestyle arm. Even if office visits cost$1000 more per year, the PPI-demand strategy is still themost cost effective. We believe that the cost lies close to thelower end of the range, because typically patients who aretaking PPIs see their doctors less often than do patientstreated with lifestyle modification (who have more visits fortherapy modification and symptom control).

Lifestyle Arm Success RateAnother uncertain variable in the model was the annualsuccess rate of the lifestyle arm. Although few physicianstreat GERD without drugs, there is a subset of GERDpatients who elect a trial of conservative measures beforethey take medications; for this study, we assumed a 5%annual success rate for lifestyle modification. Using successrates of 10% and 15% did not change the results signifi-cantly. At a success rate of 50%, the PPI-on-demand armremained the preferred strategy.

DISCUSSION

Our analysis of empirical treatment strategies for patientswith heartburn reveals that an 8-wk course of PPIs for initialsymptom relief, followed by repeat courses of therapy ini-tiated when symptoms recur, is more cost-effective thanstep-up or step-down strategies, or continuous therapy witheither H2RAs or PPIs. The cost-effectiveness ratio for on-demand PPI treatment of $20,934 per QALY falls wellwithin the range generally reported as acceptable (71), andcompares favorably to other accepted medical interventions,

such as HMG-CoA reductase-inhibitor therapy for maleheart-attack survivors who are aged 55–64 yr and havecholesterol levels.250 mg/dl ($2158 per QALY) (72),screening for hypertension in men.40 yr old ($27,519 perQALY) and women ($42,222 per QALY) (73), and breast-cancer screening with mammography in women aged 55–65yr ($41,008 per QALY) (74). For symptoms of mild GERDthe cost-effectiveness ratio was $37,923. Once the decre-ment in QALYs from GERD symptoms reached#0.99, theC/E ratio fell into the range of#$50,000 or less (Fig. 3).

We believe that our model adds several new contributionsto the previously published cost-effectiveness studies for thetreatment of GERD. First, whereas the prior studies evalu-ated short time horizons (#1 yr), our analysis used a life-time perspective. Because GERD is a chronic disease, webelieve that an analysis of lifetime costs is appropriate andmore accurate. One limitation to our model using this per-spective, however, is that we did not include repeat Nissenfundoplication(s) for patients undergoing surgical therapy,because the probability of undergoing a Nissen in our studywas so low (approximately 1027). It is not known at thistime how long patients can expect symptomatic relief froma Nissen fundoplication. In one follow-up study, 17.5% ofthe patients required medication for recurrent GERD symp-toms 5 yr after the Nissen (75). A recent retrospective studysuggested that 2.5% of patients undergoing Nissen fundo-plication will require repeat surgical repair or revised fun-doplication (76).

Second, only a few of the prior studies used QALYs as autility measurement, and obtained their estimates through amodified Delphi process. Because GERD is a chronic dis-ease that adversely affects quality of life, we feel that the useof utilities is justified in this setting. By using a wide rangeof utility measurements, we are able to assess the cost-effectiveness of treatment strategies by degree of disutilityfrom chronic GERD symptoms. Third, prior models eitherdid not allow patients to switch from H2RAs to PPIs withoutendoscopy, often did not include the option of Nissen fun-doplication, or sent patients without response to PPI for aNissen without consideration of promotility therapy. Byincluding the options of high-dose PPI therapy, followed bypromotility agents and then a Nissen fundoplication, webelieve that our model defines further therapeutic optionsavailable to the physician and patient more completely thanprior models. Fourth, none of the models included patientswith nonerosive disease, a patient group that deserves at-tention because the severity of their symptoms can be equalto or greater than that of patients with erosive disease.Finally, this is the first model to evaluate on-demand therapyfor GERD, a strategy that is effective for a majority ofpatients.

Surprisingly, although the PPI-on-demand strategy is themost cost effective, it is the least frequently used. In manysettings, administration of H2RAs is the first line of therapy,and documentation of erosive disease with diagnostic testsis required before PPI therapy is initiated. One of the main


reasons that the PPI-on-demand strategy is most cost effec-tive is that this strategy eliminates the need to performdiagnostic tests that drive up costs, but do not necessarilychange the course of therapy. For example, for a cohort of1000 patients (Table 4), approximately 780 patients wouldrequire endoscopy in the H2RA arm, compared with 216 inthe H2RA-PPI arm, and 89 in the PPI arm.

We found that PPI-on-demand therapy raised QALYs by1.25, compared with lifestyle modification, translating to again of 456 quality-adjusted days for patients using the PPItreatment strategy, a gain greatly exceeding the QALYsgained by screening for hypertension in men.40 yr of age(1–20 quality-adjusted days gained) (60), mammography inwomen 50–59 yr of age (11.7 days of life saved per personscreened) (77), or hormone-replacement therapy in womenaged 55–65 yr (14 quality-adjusted days gained) (78). Inaddition, the number of quality-adjusted days gained repre-sents an average effect in a representative population (40-yr-old patients who present with heartburn); the benefitsmight be greater for patients who are older or who havemore severe disease.

In our model, the PPI-on-demand strategy is most costeffective because it eliminates the diagnostic testing usuallyrequired before PPI therapy is initiated. This model has asthe most important clinical outcome symptom relief, ratherthan healing demonstrated by endoscopy. The endoscopichealing rates after 8 wk of therapy in patients with erosiveesophagitis taking H2RAs range from 32% to 60%; thepercentages for relief of symptoms are similar (5–14). Heal-ing and symptom relief reported in patient taking PPIsranges from 64% to 92%—superior to those seen withH2RAs for both nonerosive and erosive disease (44). Theuse of PPIs has been shown to relieve symptoms rapidly,often during the first week of treatment. Our model impliesthat an endoscopic examination is not necessary for a patientwho has uncomplicated GERD, because medical therapycan be guided by symptomatic response, and because pa-tients with either nonerosive or erosive disease can betreated cost effectively with the same medical regimen.

Although an endoscopic examination might not beneeded to direct medical therapy, prior studies recommendthat all patients who have chronic GERD symptoms haveendoscopy to screen for the presence of Barrett’s esophagus,a premalignant metaplastic change found in 8–20% patientswith GERD (45). Screening for Barrett’s esophagus com-plicates the decision about endoscopy in GERD patientsbecause screening for the condition and adenocarcinoma iscontroversial from an economic perspective (79). In a pro-spective study, the odds ratio for developing Barrett’s was3.0 in patients with symptoms for 1–5 yr when comparedwith patients with symptoms for,1 yr, and increased to 6.4when the duration of symptoms was.10 yr (80). Therefore,most physicians will perform endoscopy to screen for Bar-rett’s if GERD symptoms have been present for at least 5 yr.We did not include the cost of such screening in our decisionmodel because we chose a 40-yr-old patient as our base

case, and did not consider duration of symptoms as an entrycriterion. If we had included the cost of such a screeningendoscopy for all patients, however, the cost would havebeen applied to all of the treatment arms, and there wouldhave been no net effect on our analysis. Further studies areneeded to determine when screening should be performedand whether it is appropriate to screen all patients withGERD for Barrett’s esophagus. Once the diagnosis of Bar-rett’s has been made, endoscopic surveillance every 5 yr fordysplasia in this subgroup of patients has been shown tohave an incremental cost-effectiveness ratio of $27,400 perQALY gained (81). One endoscopic exam to screen forBarrett’s esophagus is sufficient, as it is highly unusual forpatients with uncomplicated GERD on initial endoscopicexamination to demonstrate stricture, ulceration, or Barrett’sesophagus on later examinations, even when they report achange in symptoms (82). In addition to the risk of Barrett’sesophagus, GERD has been associated with an increasedrisk of esophageal adenocarcinoma (83). Whether on-de-mand therapy would provide as much of a protective effectas continuous therapy for the development of adenocarci-noma is not known at this time.

We performed sensitivity analyses on the cost differencebetween the two therapies, the success rate of the on-de-mand therapy strategy, the length of on-demand therapy,costs of office visits, and success rate of the lifestyle arm.The PPI-on-demand strategy remained dominant in all sce-narios, except when the success rate of the on-demand armfell to #59%. In this situation, the PPI-on-demand arm costless but the H2RA-PPI arm was slightly more effective (by0.05 QALYs) and therefore had a preferable cost-effective-ness ratio. This was the only case in our model when theH2RA-PPI arm was the preferred strategy.

The option of over-the-counter (OTC) H2RAs was notaddressed explicitly in our model. After several weeks ofOTC therapy, many patients consult their physicians, eitherbecause their symptoms persist or because it may be possi-ble to obtain reimbursement for a prescribed drug but not foran OTC drug. There appears to be emerging evidence nowthat some patients will be able to tolerate intermittent H2RAtherapy (29). We considered intermittent H2RA therapy inthe H2RA and H2RA-PPI arms after patients had success-fully responded to H2RA therapy. Intermittent therapy wasnot modeled in the step-down arm, where the goal was totransition patients to the less expensive medication. How-ever, at the point that patients consult a physician, they mostlikely will have failed intermittent H2RA therapy and, at thatpoint, PPI-on-demand treatment is the most cost-effectivestrategy.

In summary, our decision analysis indicates that, forpatients who see their physicians for medical therapy forheartburn, on-demand therapy with PPIs is the most cost-effective medical regimen that is also associated with thehighest quality of life. Physicians and health-care plansshould consider using PPIs instead of H2RAs as first-linetreatment for GERD patients.


Reprint requests and correspondence:Lauren B. Gerson, M.D.,M.Sc., 111-GI, VA Palo Alto Health Care System, 3801 MirandaAvenue, Palo Alto, CA 94304.

Received Mar. 26, 1999; accepted Oct. 8, 1999.

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