Step-Down Management of Gastroesophageal Reflux Disease
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GASTROENTEROLOGY 2001;121:1095–1100
Step-Down Management of Gastroesophageal Reflux Disease
JOHN M. INADOMI,*,‡ ROULA JAMAL,§,㛳 GLEN H. MURATA,§,㛳 RICHARD M. HOFFMAN,§,㛳
LAURENCE A. LAVEZO,§,㛳 JUSTINA M. VIGIL,§,㛳 KATHLEEN M. SWANSON,§,㛳 and
AMNON SONNENBERG§,㛳
*Veterans Administration Center for Practice Management and Outcomes Research, Ann Arbor, Michigan; ‡Division of Gastroenterology,
Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan; §VA Albuquerque Medical Center, Albuquerque,
New Mexico; and 㛳Department of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
Background & Aims: As the economic burden of gastro- efficacious therapy, but rather establishing which pa-
esophageal reflux disease (GERD) is largely weighted to tients may be effectively treated using less expensive
maintenance as opposed to initial therapy, switching medication.
from more potent to less expensive medication once Both initial and maintenance treatment of patients
symptoms are alleviated (step-down therapy) may prove presenting with symptoms of GERD is debated. Advo-
to be most cost-effective. This study aimed to prospec-
cates of “step-up” therapy argue that the most econom-
tively evaluate the feasibility of step-down therapy in a
cohort of patients with symptoms of uncomplicated
ical strategy begins with less potent, less expensive med-
GERD. Methods: Patients whose GERD symptoms were ication before institution of more potent, more expensive
alleviated by proton pump inhibitors (PPIs) were re- medication if the initial therapy fails.8,9 Proponents of
cruited from outpatient general medicine clinics. After “step-down” therapy, whereby less expensive medica-
baseline demographic and quality of life information tions are instituted only after symptom relief has been
were obtained, PPIs were withdrawn from subjects in a achieved with PPIs, claim that this strategy serves the
stepwise fashion. Primary outcome was recurrence of patient’s best interests.10,11 “Step-in” management,
symptoms during follow-up that required reinstitution of whereby maintenance therapy is withheld unless relapses
PPIs. Secondary outcomes included changes in quality occur, has also been considered.12
of life and overall cost of management. Predictors of Economic analyses have been performed to determine
nonresponse to step-down were assessed. Results: Sev-
the most cost-effective strategy to treat GERD.10,12–15
enty-one of 73 enrolled subjects completed the study.
Forty-one of 71 (58%) were asymptomatic off PPI ther-
These studies show that the economic burden of this
apy after 1 year of follow-up. Twenty-four of 71 (34%) disease is heavily weighted towards maintenance therapy,
required histamine 2-receptor antagonists, 5/71 (7%) not initial management. Attempts to model this disease
prokinetic agents, 1/71 (1%) both, and 11/71 (15%) process have also revealed a deficit of information regard-
remained asymptomatic without medication. Quality of ing the feasibility of step-down therapy in unselected
life did not significantly change, whereas management populations. Studies evaluating relapse rates of GERD
costs decreased by 37%. Multivariable analysis revealed using maintenance PPIs or H2RAs have been limited to
younger age and a dominant symptom of heartburn to the subpopulation of GERD subjects with erosive esoph-
predict PPI requirement. Conclusions: Step-down ther- agitis. It has been shown that in this subgroup, mainte-
apy is successful in the majority of patients and can nance therapy with PPIs prevents relapse,16 and alterna-
decrease costs without adversely affecting quality of life.
tive agents such as H2RAs or prokinetic agents may not
be effective.4,6,17
ontroversy exists concerning optimal management As the population with erosive esophagitis represents
C of patients with symptoms of gastroesophageal re-
flux disease (GERD). Although proton pump inhibitors
only a minority of all patients with GERD,18 we wished
to evaluate a more inclusive population representative of
(PPIs) heal esophagitis more quickly and effectively than patients managed in a primary care setting. The primary
histamine 2-receptor antagonists (H2RAs),1–3 as well as
maintain remission in a greater proportion of patients,4 – 6 Abbreviations used in this paper: GERD, gastroesophageal reflux
they are considerably more expensive. Additionally, it is disease; H2RA, histamine 2-receptor antagonist; PPI, proton pump
likely that the therapeutic success of alternative medica- inhibitor.
© 2001 by the American Gastroenterological Association
tions depends on severity of disease.7 Thus, the key 0016-5085/01/$35.00
management issue may not be determination of the most doi:10.1053/gast.2001.286491096 INADOMI ET AL. GASTROENTEROLOGY Vol. 121, No. 5
goal of this study was to determine the feasibility of medical conditions, concurrent medication use, height, and
step-down therapy in patients with symptoms of GERD weight.
rendered asymptomatic with PPIs. We also aimed to Step-down management was initiated in the following man-
determine whether there existed clinical factors that ner. The prescribed dose of PPI was halved; those already on
predicted the ability of patients to be maintained with the lowest dose available had PPIs discontinued. The subjects
were seen again in the pharmacy GERD clinic 2 weeks after
less expensive medication.
the initial step-down. If symptoms of heartburn or acid regur-
gitation recurred in the interim, subjects were instructed to
Materials and Methods contact the GERD clinic before this visit. Symptoms were
assessed and if heartburn or acid regurgitation had recurred,
The population studied was composed of outpatients the patient was placed back on their original dose of PPI. If
in the general medicine clinics at the Veterans Administration after 2 weeks, heartburn or acid regurgitation had not re-
(VA) Albuquerque Regional Medical Center. A list of patients curred, PPIs were discontinued altogether if they had not
in whom PPIs were prescribed was generated through the already been stopped. Subjects were followed at 3-month
pharmacy module of VISTA, the computer database of the intervals in the GERD clinic to assess for symptom recurrence.
medical center. Because PPIs were also prescribed for non- Additionally, subjects were instructed to contact the GERD
GERD indications, such as ulcer disease or Helicobacter pylori clinic if heartburn or acid regurgitation recurred. For symptom
eradication, only those prescriptions filled for greater than 8 recurrence, the following protocol was used: high-dose H2RAs
weeks were considered. The local institutional review board were first prescribed (800 mg cimetidine twice daily or 300
approved the protocol for this project; informed consent was mg ranitidine twice daily). Prokinetics (20 mg cisapride twice
obtained for administration for quality of life questionnaires. daily while available or 10 mg metoclopramide twice daily to
However, because it was the policy of the medical center to 4 times daily) could be used in conjunction with H2RAs. If
initiate step-down therapy in patients with reflux symptoms GERD symptoms persisted despite H2RAs and prokinetic
rendered asymptomatic on PPIs, consent was not required for therapy, the subjects were placed back on the dose of PPIs to
implementation of step-down therapy. which they had responded before onset of the study.
A clinic was formed in the outpatient general medicine area Six months after undergoing step-down, the SF-36 and
of the clinics staffed by clinical pharmacists where patients disease severity instruments were readministered to subjects.
from the pharmacy list of long-term (⬎8 weeks) PPIs were Subjects continued to be followed for 1 year after initiation of
evaluated for eligibility of intervention (the GERD clinic). step-down through the GERD clinic.
During the initial visit, patients were interviewed and the The primary outcome of the study was successful step-down
chart reviewed to determine the indication for PPI initiation. defined as continued alleviation of GERD symptoms without
Patients were considered eligible for step-down management if the use of PPIs after 1 year of follow-up. Note that subjects in
the indication for PPI therapy was heartburn or acid regurgi- whom GERD symptoms had recurred but were eliminated by
tation. Dyspepsia defined by the Rome criteria19 could be H2RA and/or prokinetic agents were considered to be success-
present in conjunction with heartburn or acid regurgitation fully stepped down. Secondary outcomes included quality of
and could in fact be the dominant symptom; however, patients life and disease severity as measured by the SF-36 and disease
in whom dyspepsia was the only complaint were excluded from severity instruments. Predictors of the inability to successfully
this study. Finally, patients had to be free of symptoms of step-down (defined as the requirement of PPIs to alleviate
heartburn and/or acid regurgitation while on PPI therapy to be GERD symptoms) were also determined, as was the difference
considered for entry into this study. Because this was a symp- in costs required to manage patients between baseline and
tom-based protocol, neither an endoscopic diagnosis of erosive follow-up.
esophagitis nor abnormal ambulatory pH monitoring was The primary outcome of successful step-down was measured
required for entry into the study. Exclusion criteria con- by descriptive statistics. Changes in quality of life as measured
sisted of the following: previous diagnosis of peptic stricture, by SF-36 and disease-specific instruments were analyzed by
extra-esophageal manifestations of GERD, anemia or occult paired t tests. Univariate methods and multivariable logistic
gastrointestinal bleeding, intermittent PPI use, documented regression examined variables associated with unsuccessful
Barrett’s metaplasia, scleroderma, or previous gastric or esoph- step-down (the requirement of PPIs to alleviate symptoms).
ageal surgery. Potential predictors included in the logistic regression model
Before intervention, eligible subjects were asked to com- were selected based on current understanding of GERD. They
plete 2 questionnaires, the SF-36 and a disease-specific assess- included age, gender, dominant symptom, alcohol intake,
ment of disease severity. This latter instrument was chosen cigarette use, concurrent medication, and comorbid condi-
because of its previous validation in patients with GERD in a tions. Of the potential predictor variables listed above, pre-
VA setting.20 Baseline demographic information was also ob- liminary correlation analyses were performed to screen for
tained including age, gender, dominant or most bothersome multicolinearity. Stepwise procedure was used to arrive at the
symptom (heartburn, acid regurgitation, or dyspepsia), dura- final model for the derivation set. Step selections were based on
tion of PPI therapy, previous GERD treatment, comorbid the maximum likelihood method with an alpha of 0.10 toNovember 2001 STEP-DOWN MANAGEMENT OF GERD 1097
Table 1. Excluded Patients
Symptomatic despite PPI therapy
Heartburn or acid regurgitation 7
Dyspepsia 22
Peptic stricture 17
Extraesophageal GERD 11
Anemia or occult GI bleeding 10
PPI use intermittent 9
Barrett’s esophagus 4
Previous gastric surgery 2
GI, gastrointestinal.
enter and 0.10 to remove. Interactions were examined for
terms with significant main effects. The improvement at each
step was tested by the likelihood ratio 2 analysis. The good- Figure 1. Proportion of patients asymptomatic off PPIs.
ness-of-fit for the final method was tested by the Hosmer–
Lemeshow method. A variable was considered predictive of
nonresponse if it was included in the final model and the 95% The remaining 73 patients underwent step-down
confidence interval for its odds ratio did not include one. management. Baseline characteristics are shown in Table
Costs were limited in this analysis to the cost of medications 2: 95% were men, mean age was 62.1 years (median, 64
assessed by actual expenditures at a VA Medical Center, as well years), 85% were on lansoprazole (the VA pharmacy
as the direct cost of operating the GERD clinic, including contract PPI), and mean duration of PPI use was 21.3
salary and benefits of the clinical pharmacists staffing the
months. Two thirds had been treated with an H2RA or
clinic.
prokinetic agent before prescription of a PPI. One hun-
dred percent of subjects had complete follow-up to 6
Results
months and 71 of 73 (97%) followed for 1 year. Incom-
Three hundred seventy-six patients were identi- plete follow-up was because of death (1) and inability to
fied as having been prescribed PPIs for 8 weeks or longer contact (1).
from our medical center. One hundred fifty-five consec- After the 1-year follow-up, 41 of 71 (58%) of those in
utive patients were evaluated in the GERD clinic. Of whom step-down was implemented were asymptomatic
these, 82 were excluded (Table 1); the largest group of on either non-PPI therapy or no therapy to treat GERD
patients excluded were those still symptomatic despite (Figure 1). Of the subjects who remained off PPIs, 24 of
PPI use. Subsequent evaluation of these excluded sub- 41 (59%) required H2RAs, 5 of 41 (12%) were on
jects revealed that 6 of 82 (7%) had GERD documented prokinetic agents, 1 of 41 (2%) were on both, and 11 of
either by erosive esophagitis on esophagogastroduode- 41 (27%) were asymptomatic without the use of acid
noscopy, 24-hour ambulatory pH monitoring DeMeester suppressive or prokinetic agents. Figure 2 illustrates the
score ⬎14.72, or alleviation of symptoms on higher
doses of PPI. Additional exclusions were due to the
presence of peptic strictures, extra-esophageal manifesta-
tions of GERD, or anemia. Also of note were 9 patients
who had already decreased PPI use to an “as-needed”
basis and 4 patients in whom a diagnosis of Barrett’s
esophagus had been established.
Table 2. Baseline Demographics
Mean (range) or
Characteristic percentage
Age 62.1 (29–85)
Follow-up (days) 370 (167–426)
Duration of PPI use (mo) 21.3 (4–45)
Body mass index 27.8 (18–42.9)
% Treated with H2RA or prokinetic before PPI 69.9%
% With weekly consumption of alcohol 32.8%
Figure 2. Distribution of subjects on therapy. pro ⫹ H2, prokinetic ⫹
% With daily cigarette use 27.8%
histamine2-receptor antagonist; none, no medication to treat GERD.1098 INADOMI ET AL. GASTROENTEROLOGY Vol. 121, No. 5
Table 3. Risk of Nonresponse to Step-down From PPIs: GERD symptoms, were not significantly associated with
Univariate Analysis response to step-down.
Variable Odds ratio P value Initial medication cost for this cohort was $43,994.36
Heartburn 2.7 0.025 per annum. Total medication cost at the end of study for
Regurgitation 1.6 0.071 this cohort was $2,724.77 per annum. Estimated direct
Dyspepsia 0.65 0.13
Alcohol use 1.2 0.46
costs for operating the GERD clinic were $25,200. Total
Cigarette use 0.73 0.32 cost saving for the institution per annum for this cohort
Concomitant medication 0.67 0.15 was $16,069.59. Assuming that a similar distribution of
Comorbid disease 0.71 0.22 eligibility and outcomes were realized for the entire
Age (per decade) 0.76 0.12
PPI duration 1.0 0.42 population treated with PPIs at this center, expected cost
Body mass index 0.99 0.84 savings would be $53,122.05 per annum.
Discussion
proportion of subjects on each therapy at the conclusion This study of patients with reflux symptoms
of the study. treated with PPIs in a primary care setting revealed that
Of those in whom step-down was unsuccessful (PPIs more than half could be maintained in remission without
required to alleviate GERD symptoms), the median time PPI therapy. Twenty-seven percent required no medica-
to reinstitution of PPIs was 14 days (range, 2–210). Of tion to treat their reflux symptoms, and the remaining
note, only 1 subject developed symptoms requiring PPIs 73% in whom step-down was successful required less
after 6 months of step-down initiation; the remaining expensive forms of anti-GERD therapy. Younger sub-
subjects presented with recurrent symptoms requiring jects required PPIs to alleviate recurrent symptoms more
PPIs within 4 months of follow-up. often than older subjects. A dominant symptom of heart-
Quality of life and disease severity did not signifi- burn also predicted the need for PPIs and inability to
cantly change between baseline and 6-month follow-up successfully step-down. Neither quality of life nor disease
intervals. SF-36 physical component summary scores severity was adversely impacted by this intervention as
were 37.9 (SD ⫾ 7.9) at baseline and 37.1 (SD ⫾ 8.6) at measured by validated instruments. Substantial eco-
follow-up (P ⫽ 0.42), whereas mental component sum- nomic benefit was realized in this cohort of patients.
mary scores were 45.0 (SD ⫾ 6.2) and 43.9 (SD ⫾ 6.8), Previous studies examining patients with endoscopi-
respectively (P ⫽ 0.25). Disease severity scores likewise cally documented erosive esophagitis have shown that
did not significantly change, from 21.0 (SD ⫾ 1.2) at the majority of patients require maintenance PPIs to
baseline to 21.8 (SD ⫾ 1.7) at follow-up (note: score of prevent relapse.4,6 Although erosive esophagitis is a firm
21 denotes absence of symptoms). endpoint, it includes only a minority of the total popu-
Univariate analysis of baseline demographic data and lation with gastroesophageal reflux disease.18 It was the
clinical information revealed that a dominant symptom intent of this study to examine a cohort of patients with
of heartburn was significantly associated with PPI re- reflux symptoms managed in a general internal medicine
quirements (Table 3). Stepwise logistic regression ex- outpatient setting. In this population, 24-hour pH mon-
panded upon this finding: younger age and heartburn itoring and/or upper endoscopy are rarely used before
predicted unsuccessful PPI step-down management. The empiric medical therapy. Our study was designed to base
odds ratio for unsuccessful step-down (requirement of management on symptoms in a manner consistent with
PPIs to alleviate symptoms) was 0.65 (95% confidence outpatient medical practice. Although every subject in
interval, 0.43– 0.98) per decade of life, whereas heart- the study experienced relief from symptoms of heartburn
burn as opposed to acid regurgitation or dyspepsia was and/or acid regurgitation with PPI therapy before enroll-
associated with an odds ratio of 6.5 (95% confidence ment, the presence or absence of erosive esophagitis was
interval, 1.4 –29.6). Addition of cigarette smoking to the not known. It is likely that our study population con-
logistic model improved the goodness of fit (Hosmer– sisted of a heterogeneous population of subjects with
Lemeshow); however, the variable itself was not signifi- GERD, and this may limit the application of the results
cantly associated with the success of step-down. Other of this trial to patients outside the scope of this study,
factors, including duration of PPI administration, trial of such as those with known erosive disease. Additionally, it
H2RAs, or promotility agents before PPI institution, should be noted that this study was designed to examine
alcohol, comorbid medical illness, body mass index, or the outcome of GERD patients undergoing step-down
use of concurrent medication that could exacerbate management. As such, no recommendations regardingNovember 2001 STEP-DOWN MANAGEMENT OF GERD 1099 surveillance of symptomatic patients for Barrett’s esoph- GERD management; however, subjects in whom meto- agus or gastrointestinal malignancy can be made, and the clopramide was effective and devoid of side effects were decision to pursue upper endoscopy to evaluate GERD maintained on this medication. patients for the risk or presence of cancer must be made A considerable number of patients excluded from this outside the context of this trial. study were symptomatic despite PPI use. It was found on Age was a factor in predicting response to step-down further investigation that the majority of these patients therapy in the current study. We found advancing age to were prescribed PPIs for indications unlikely to be asso- predict the success of step-down from PPIs. Fass et al.21 ciated with acid production. Specifically, these patients noted older patients’ perception of GERD symptoms to were not found to have evidence of either peptic ulcer or be less severe compared with younger patients. Their GERD after having undergone upper endoscopy, 24- study noted that the frequency of heartburn and acid hour ambulatory pH monitoring, and a therapeutic trial regurgitation were lower and less severe in subjects aged of high-dose PPI therapy.26 Although not included as 60 years and older compared with those in younger “successes” in our final analysis, it further illustrated the subjects despite a higher frequency of erosive esophagitis usefulness of a disease-oriented pharmacy clinic to opti- in the older group. Additionally, time to symptom per- mally manage GERD patients. The use of nonphysicians ception and sensory intensity scores were higher in the to implement clinical practice guidelines was unique as younger population. It is likely that we observed a it applied to this setting of reflux patients. In this case, similar effect in our study. Because the response to in contrast to hypertension, anticoagulation, or diabetes therapy was gauged by symptoms, older subjects less clinics, in which laboratory or clinical parameters such as “sensitive” to acid exposure may have been tolerant of blood pressure, prothrombin time, or hemoglobin A1C less potent acid suppression. The median age of subjects are followed, the pharmacists involved in this project in our trial (64 years) may in part explain the success of were able to evaluate symptoms to manage a cohort of our study. Due to the age-dependence of response, it may GERD patients. be found that attempts to implement step-down man- Cost savings were realized in this cohort of veterans. agement in cohorts consisting of younger patients may As the VA contract price for the formulary PPI was not yield as encouraging results. $1.25 per standard dose at the time of the study, it is Heartburn as opposed to acid regurgitation or dyspep- likely that substantially greater savings could be gener- sia as a dominant symptom was also predictive, in this ated in environments where PPIs are discounted less case, of nonresponse to step-down (requirement of PPIs heavily. Generic PPIs will soon be available, thus de- to alleviate symptoms). The symptom of heartburn may creasing the cost to most consumers; however, it is signify more severe disease and thus the requirement for unlikely that even generic drugs will be priced lower more potent acid suppression. Although resolution of than the VA contract amount, and a significant differ- GERD symptoms on PPI was an entry criterion for the ence in costs between PPIs and H2RAs will persist. The study, it is also possible that in a subgroup of subjects, cost analysis was limited to the incremental expenditures functional dyspepsia represented the underlying medical incurred by the medical center for implementation of the condition. Previous randomized trials have illustrated step-down protocol, including the proportion of salary symptom resolution beyond placebo rates with PPIs in required to operate the pharmacy GERD clinic and patients with documented functional dyspepsia.22–25 It is expenditures for dispensed medication. Neither indirect possible that subjects with a dominant symptom of costs for items such as office space, ancillary staff, and dyspepsia may have less severe forms of GERD, or func- administrative support, nor direct costs of additional tional dyspepsia that may not require as potent acid health care visits, investigations related to the care of suppression. symptomatic subjects, or sick leave were considered, Concerning the use of promotility agents at the onset which may limit the generalizability of our results to of this trial, cisapride was frequently used as a second- other health care settings. line drug for the treatment of GERD. However, after its In conclusion, our study revealed that more than half removal from the market, prokinetics were not advocated of patients rendered asymptomatic on PPI therapy for because available replacements such as metoclopramide reflux symptoms can be successfully stepped-down to less possessed side effect profiles that were substandard com- expensive medication. The need for PPIs is increased in pared with alternative agents for the treatment of the younger population, as well as in those who present GERD. By study conclusion, only H2RAs and antacids with a dominant symptom of heartburn. In the course of were considered alternatives to PPI therapy for use in monitoring step-down therapy of gastroesophageal reflux
1100 INADOMI ET AL. GASTROENTEROLOGY Vol. 121, No. 5
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