Lansoprazole heals erosive reflux oesophagitis in patients with Barrett's oesophagus

Aliment Pharmacol Ther 1997; 11: 147–156.

Lansoprazole heals erosive reflux oesophagitis in patients with

Barrett’s oesophagus

S. J. SONTAG, T. G. SCHNELL, G. CHEJFEC, C. KURUCAR, J. KARPF & G. LEVINE

Departments of Medicine and Pathology, Veterans Affairs Hospital, Hines, Illinois, Loyola University of Chicago Stritch

School of Medicine, Maywood, Illinois, USA

Accepted for publication 3 September 1996

SUMMARY

Background : Barrett’s oesophagus is thought to be a

complication of severe gastro-oesophageal reflux.

Aim : To determine whether the proton pump inhibitor,

lansoprazole, is effective in healing erosive reflux

oesophagitis in patients with Barrett’s oesophagus.

Methods : An 8-week, randomized, double-blind study

was conducted using patients with both erosive reflux

oesophagitis and Barrett’s oesophagus. Erosive reflux

oesophagitis was defined as grades 2–4 oesophagitis ;

Barrett’s oesophagus, as specialized columnar

epithelium obtained by biopsy from the tubular

oesophagus ; and healing, as a return to grade 0 or 1

oesophageal mucosa (complete re-epithelialization).

One-hundred and five (105) patients from one centre

were randomized to receive either lansoprazole 30 mg

daily or ranitidine 150 mg twice daily. Unhealed or

symptomatic lansoprazole patients at week 4 were

INTRODUCTION

Barrett’s oesophagus is generally believed to be a com-

plication of long standing, severe gastro-oesophageal

reflux." Patients with co-existing Barrett’s oesophagus

and erosive reflux oesophagitis are therefore considered

to have severe gastro-oesophageal reflux requiring potent

anti-reflux therapy to achieve healing. Two lansoprazole

studies have been performed on refractory erosive reflux

oesophagitis patients, some of whom have had Barrett’s

oesophagus.#,$ One study of 13 patients with Barrett’s

Correspondence to : Dr S. J. Sontag, Veterans Affairs Hospital, PO Box 5000

(11C3) Hines, IL 60141–5000, USA.

randomized to receive the same 30 mg dose daily or an

increased dose of 60 mg daily. Endoscopy was

performed at baseline and at weeks 2, 4, 6 and 8.

Results : The treatment groups were similar in regards

to baseline characteristics, erosive reflux oesophagitis

grades and length of Barrett’s oesophagus. At each 2-

week interval, lansoprazole patients had significantly

greater healing rates and less day and night heartburn

and regurgitation than ranitidine patients. There were

no significant differences between treatment groups in

antacid use, quality of life parameters, or rate of

reported adverse events. Median values for fasting

serum gastrin levels remained within the normal range

for both groups.

Conclusion : In patients with both Barrett’s oesophagus

and erosive reflux oesophagitis, lansoprazole is

significantly more effective than ranitidine in relieving

reflux symptoms and healing erosive reflux

oesophagitis.

oesophagus demonstrated that high dose lansoprazole

healed the erosive oesophagitis for up to 3 years.%

Another refractory oesophagitis study showed that a

subset of patients with Barrett’s oesophagus healed in 16

weeks with 40 mg omeprazole daily.& No lansoprazole

study to our knowledge has made the presence of

Barrett’s oesophagus the major inclusion criterion.

Since no comparative or placebo-controlled studies have

been conducted with proton pump inhibitors exclusively

in patients with Barrett’s oesophagus, it is not known

whether anti-reflux therapy with the proton pump

inhibitor, lansoprazole, is more effective than therapy

with the H#

receptor antagonist, ranitidine, in healing

# 1997 Blackwell Science Ltd 147

148 S. J. SONTAG et al.

the erosive reflux oesophagitis in the presence of Barrett’s

oesophagus.

To determine whether anti-reflux therapy is effective in

healing the erosive reflux oesophagitis in patients with

co-existing Barrett’s oesophagus, we conducted a study

using the new proton pump inhibitor, lansoprazole, and

the histamine#-receptor antagonist, ranitidine.

MATERIALS AND METHODS

Study design

The study was conducted as a double-blind, randomized,

active-controlled, single-centre clinical trial in which

patients with erosive reflux oesophagitis co-existing with

Barrett’s oesophagus were randomized to receive (in a

1:2 allocation) ranitidine 150 mg twice daily or lanso-

prazole 30 mg once daily. Lansoprazole patients who

were still unhealed or symptomatic at week 4 received

either the same dose of lansoprazole 30 mg or an

increased dose of lansoprazole 60 mg daily before break-

fast for the final four weeks ; ranitidine patients continued

to receive ranitidine 150 mg twice daily. To achieve the

described dosing in a blinded fashion, all patients who at

week 4 were not healed or had reflux symptoms received

an additional bottle that contained lansoprazole 30 mg

or placebo. The ‘double-dummy’ technique was used to

maintain the double-blind status. Gelusil tablets,

9.7 mmol}per tablet (Parke-Davis, Morris Plains, NJ), to

be taken for heartburn, were dispensed at each visit

along with the study medication. Randomization was

performed within 7 days of the baseline endoscopic

demonstration of erosive reflux oesophagitis and Barrett’s

oesophagus.

Patient Selection

One-hundred and five (105) patients, 18 years of age or

older, from one Veterans Affairs Hospital (Hines, IL) were

enrolled in the study. Patients were eligible for enrolment

if they had endoscopic evidence of at least grade 2

(erosive) oesophagitis (Table 1) and histological evidence

of Barrett’s oesophagus, which included specialized

columnar epithelium obtained from biopsy specimens of

the tubular oesophagus. Table 1 shows the oesophagitis

grading scale, which was modified to include patients

with Barrett’s oesophagus. Patients were not eligible for

the study if they had any of the following: oesophageal

stricture requiring dilation; oesophagitis associated with

Table 1. Oesophagitis grading scale

Grade Description

0 Normal-appearing mucosa

1 Mucosal oedema, hyperaemia, and}or friability

2 One or more erosions involving less than 10% of the

distal 5 cm of the oesophagus proximal to the

squamocolumnar junction*

3 Erosions involving 10% to 50% of the distal 5 cm of the

oesophagus proximal to the squamocolumnar

junction,* or a single ulcer measuring 3–5 mm in

diameter

4 Multiple erosions involving more than 50% of the distal

5 cm of the oesophagus proximal to the

squamocolumnar junction,* or a single large ulcer

greater than 5 mm in diameter

* To adjust for the Barrett’s columnar epithelium, the distal 5 cm

of the oesophageal mucosa was considered as the 5 cm segment

above the endoscopically determined squamocolumnar junction.

scleroderma; active ulcer in the stomach, pyloric chan-

nel, or duodenum; current malignancy; clinically signifi-

cant abnormal laboratory values or disease ; or con-

current need for anticoagulants, motility drugs, cortico-

steroids or non-steroidal anti-inflammatory drugs.

Endoscopic assessment

Endoscopy was performed at baseline and at weeks 2, 4,

6 (if not healed at week 4) and 8. At each endoscopy, the

severity of the oesophagitis was scored from grade 0 to

grade 4 (Table 1). Oesophageal mucosal healing was

defined as complete re-epithelization of all ulcers and

erosions (grade 0 or grade 1). Directed mucosal biopsies

of the oesophagus were obtained at baseline to document

the presence of specialized columnar epithelium in the

tubular oesophagus. Patients were eligible for the study

only if there was histological evidence of Barrett’s

oesophagus.

Histological assessment

Four directed mucosal biopsies of the greater curvature of

the gastric body were taken at the initial and final

endoscopies. Two of the biopsy specimens were placed in

Bouin’s solution for later analysis of the following: (i)

inflammation and neoplasia using haematoxylin & eosin

staining and (ii) gastric endocrine cell growth using

Grimelius silver stain.',( The two remaining biopsy

specimens were placed in 2.5% glutaraldehyde in 0.1

molar phosphate buffer at pH 7.4 for future analysis by

# 1997 Blackwell Science Ltd, Aliment Pharmacol Ther 11, 147–156

149LANSOPRAZOLE IN BARRETT’S OESOPHAGUS

electron microscopy. Biopsy specimens were analysed at

the Medical College of Pennsylvania, Philadelphia, PA.

Symptom assessment

Symptoms were assessed using three methods : (i) no-

tation of symptoms at each study visit by study

coordinator, (ii) patient diary, and (iii) quality-of-life

questionnaire.

Notation of symptoms. Patients were asked about an

overall symptom assessment and were questioned about

the presence of specific symptoms, including upper

abdominal burning, day and night heartburn, painful

swallowing, dysphagia, belching, regurgitation,

fullness}bloating}early satiety, abdominal distension,

anorexia, nausea, vomiting, day abdominal pain, night

abdominal pain, flatulence and}or abdominal rumbling,

diarrhoea, constipation, haematemesis, and melena.

Symptoms were recorded as none, mild (symptom of

short duration that was easily tolerated), moderate

(symptom that caused discomfort and that interrupted

usual activities), or severe (symptom that was potentially

incapacitating and that greatly interfered with usual

activities).

Patient diary. Patients were seen at baseline and at the

end of weeks 2, 4, 6 and 8 of treatment. At each visit,

patients were given diary cards to record daily antacid

use, missed doses of study medications, and the frequency

and severity of day and night heartburn. The severity of

symptoms was similarly recorded as none, mild, mod-

erate or severe.

Quality-of-life questionnaire. The patients completed a

‘quality-of-life ’ questionnaire that was designed to

evaluate the effect of oesophagitis on physical, psycho-

logical, and social functioning. The questionnaire was

completed at each study visit prior to all other procedures.

Clinical laboratory determinations

The clinical laboratory tests were analysed at SciCor Inc.,

Indianapolis, IN. Patients fasted for at least 8 h before

blood samples were drawn. Laboratory tests consisted of

a complete blood count and blood chemistries, which

included liver enzymes, lipid determinations, electrolytes,

glucose, albumin and total protein. Fasting serum gastrin

levels were drawn prior to or 24 h after the endoscopy

procedure. Except for baseline screening results,

investigators were blinded to the results of the serum

gastrin levels for the duration of the study.

Statistical analysis

The database remained blinded until all the data were

screened to identify protocol violators. As specified in the

protocol, analyses combined the two lansoprazole groups

(lansoprazole 30 mg for all 8 weeks and lansoprazole

30 mg for 4 weeks followed by lansoprazole 60 mg for 4

weeks) so that all patients receiving lansoprazole are

referred to as the lansoprazole group.

Data were analysed using two approaches : The ‘per

protocol ’ approach, which includes only data considered

acceptable for efficacy evaluation; the ‘all-patients-

treated’ approach (also known as the ‘ intention-to-treat ’

approach), which includes all patients who entered the

study regardless of whether their outcomes were known

or the protocol was followed. In the ‘per protocol ’

analysis, a patient with no endoscopy in a given time

interval was considered healed if healing was docu-

mented previously ; otherwise the patient is not included

in the analysis of that time interval. The ‘all-patients-

treated’ analysis considers all patients to be treatment

failures unless proven to be healed by endoscopy.

Baseline analyses. Baseline demographic data and clinical

characteristics were compared between the two treat-

ment groups (ranitidine group and lansoprazole group)

using a χ# test or a one-way analysis of variance ().

The severity of oesophageal symptoms (including day

and night heartburn, upper abdominal burning, painful

swallowing, belching and regurgitation) was compared

between the two treatment groups using Cochran–

Mantel–Haenszel methodology for ordered response

variables.

Efficacy analyses. The proportions of patients healed

(cumulatively) at each time point were compared be-

tween treatment groups using the Mantel–Haenszel

method. The effect on healing adjusting for various

concomitant factors was assessed using Cochran–

Mantel–Haenszel methodology. Treatment-by-factor in-

teraction was determined using the Breslow–Day Test.

Symptom changes were compared between treatment

groups using the Cochran–Mantel–Haenszel method for

ordered response variables with baseline value as a

stratification factor.



Differences between treatment groups were determined

using Wilcoxon two-sample test for average daily heart-

burn scores, percentage of days with heartburn, per-

centage of days antacid was used, and number of antacid

tablets taken.

Eleven measures were derived and validated from the

‘quality-of-life ’ questionnaire. Changes from baseline to

week 8 were compared within and between treatment

groups using analysis of variance.

Safety analysis. Clinical adverse experiences were

analysed using Fisher’s Exact Test. The analysis of the

distribution of patients by predefined limits of change for

clinical laboratory measurements was performed using

the Cochran–Mantel–Haenszel method for ordered re-

sponse categories and mean change analysed using one-

way . The percentage change from baseline of the

serum gastrin levels was calculated for each patient ;

between-group comparisons were made using the

Wilcoxon Two-Sample Test. Changes in gastric biopsies

were compared between both treatment groups using a

one-way analysis of covariance with baseline density as

a covariate.

The study was approved by the Hines Veterans Affairs

Hospital Internal Review Board.

RESULTS

One-hundred and five (105) patients (104 males and 1

female) were randomized to the two treatment groups :

lansoprazole, 69 patients ; ranitidine, 36 patients. Figure

1 shows the demographic and clinical characteristics of

Figure 1. Demographic and clinical characteristics of evaluable

patients. There were no significant differences between

lansoprazole and ranitidine patients at baseline. Both groups

were comparable in regards to age, sex, race, baseline

oesophagitis grade, and use of tobacco, alcohol and caffeine.

the 95 evaluable patients that were included in the ‘per

protocol ’ efficacy evaluations. The two treatment groups

were comparable at baseline with respect to age, sex,

race, baseline grade of oesophagitis, smoking and alcohol

habits, caffeine use, and the presence of hiatal hernia.

Healing rates

Per-protocol analysis. Ten patients (9 in the lansoprazole

group and 1 in the ranitidine group) were excluded from

the per-protocol analysis for reasons shown in Table 2.

Large and significant differences in healing rates were

noted between lansoprazole treatment and ranitidine

treatment. At week 4, the percentage of patients with

complete oesophageal mucosal healing was 85.7% for

the lansoprazole group and 48.4% for the ranitidine

group (P!0.001). After 8 weeks of treatment the

healing rates were 91.4% and 58.1% for the two groups,

respectively, (P!0.001). The healing rates for the 95

evaluable patients are shown in Figure 2.

All-patients-treated analysis. The results of the all-patients-

treated analysis were similar to those of the per-protocol

analysis. At week 4 the percentage of patients with

complete mucosal healing was 76.8% for the lanso-

prazole group and 41.7% for the ranitidine group (P!0.001). After 8 weeks of treatment, the healing rates

were 84.1% and 50.0% for the two groups, respectively,

(P!0.001).

Concomitant factor analysis. Concomitant factors, includ-

ing age, tobacco, alcohol and caffeine consumption,

baseline oesophagitis grade, length of Barrett’s oesoph-

agus, and hiatal hernia were analysed to determine

whether they influenced the healing of oesophagitis or

explained the treatment group differences. Figure 3

shows the percentage of patients with complete healing

stratified by concomitant factors. The differences between

the lansoprazole group and the ranitidine group prevailed

regardless of the concomitant factors considered.

Effect of higher dose lansoprazole. Doubling the dose of

lansoprazole for the final 4 weeks of study did not appear

to influence healing. Of the 7 patients unhealed at 4

weeks, 2 of 3 patients who continued on 30 mg lanso-

prazole healed compared with 3 of 4 who had the dose

increased to 60 mg lansoprazole.



Group Lansoprazole Ranitidine

Number of patients entered 69 36

Number of patients excluded 9 1

Reason excluded

E endoscopic grade not appropriate for entry 1 0

E no histological evidence of Barrett’s oesophagus 3 0

E no data after start of treatment 1 0

E received less than 14 days of therapy 3 1

E malignancy (adenocarcinoma of oesophagus) 1 0

Number of patients evaluable 60 35

Table 2. Reasons for exclusion from per

protocol analysis of efficacy

Figure 2. Percentage of patients with complete endoscopic

healing. At 2, 4, and 8 weeks of treatment, lansoprazole had

statistically significantly greater healing rates in evaluable

patients when compared to ranitidine at all time points (P!0.01).

Symptom Improvement

Notation of symptoms. Of the six primary symptoms of

reflux oesophagitis (including day and night heartburn,

upper abdominal burning, painful swallowing, belching

and regurgitation) lansoprazole was superior to

ranitidine in producing symptom relief in two: day

heartburn and night heartburn.

Lansoprazole patients had statistically significantly

greater relief of day and night heartburn than ranitidine

patients at week 8 (P!0.05). There were no significant

differences between lansoprazole and ranitidine at week

8 in other primary symptoms. The effect on symptom

relief of higher doses of lansoprazole for the final 4 weeks

of study could not be determined because of an

insufficient number of symptomatic patients.

Quality-of-life assessment. Quality-of-life questionnaires

were used to assess the impact of lansoprazole as

compared to ranitidine on certain measures of both

functional status and quality-of-life. Both treatment

groups showed significant improvement from baseline in

the following quality-of-life measures : limitations in

social activities, current health perceptions, health dis-

tress and health index, transitional rating of symptoms,

problem index, sleep index and the overall assessment

index. The lansoprazole group also had significant

improvement in the limitation in daily activity measure

while the ranitidine group improved on the energy}fatigue measure. There were no differences between the

lansoprazole 30 mg group and the lansoprazole 60 mg

group for any of quality-of-life measure.

Diary assessment. Figure 4 shows the mean severity of

daily and nightly heartburn in evaluable patients ac-

cording to the results of the diary. Compared to ranitidine

patients, lansoprazole patients reported significantly

fewer days and nights with heartburn, and less severe

day and night heartburn, (P!0.01). Although the

lansoprazole group used numerically less Gelusil than

the ranitidine group, the difference was not statistically

significant.

Safety

Adverse events. The incidence of adverse events was

similar in both lansoprazole and ranitidine patients.

Table 3 shows the most frequently reported ‘possibly ’ or

‘probably ’ treatment-related adverse events. The table

includes the adverse events that occurred in either group

with an incidence of at least 3% and were judged by the

investigator to be possibly or probably related to the

study drug. The most commonly reported adverse

reactions with lansoprazole were headache, diarrhoea

and asthenia.



Figure 3. Effect of concomitant factors on

healing of oesophagitis at week 8 for

evaluable patients. Concomitant factors,

including age, habits, baseline oesophagitis

grade, length of Barrett’s oesophagitis, and

hiatal hernia did not influence healing of

oesophagitis or explain the treatment

group healing differences. The difference in

healing rates between groups prevailed

regardless of the concomitant factors

considered.

Figure 4. Heartburn severity. From the

symptom severity score, as recorded in the

daily diary, lansoprazole patients had

significantly less severe day and night

heartburn as compared with ranitidine

patients (P!0.01).

Table 4 lists the adverse events contributing to with-

drawal from the study. Eight patients (six in the lanso-

prazole group and two in the ranitidine group) withdrew

from the study at least in part due to adverse reactions.

There were no clinically significant treatment-related

changes in either the lansoprazole or the ranitidine group

in physical examinations, electrocardiograms, blood

chemistries or haematology or urinalysis parameters.

Serum gastrins. The lansoprazole group had statistically

significantly larger increases from baseline in fasting

serum gastrin values at weeks 4 and 8 than the ranitidine

groups (P!0.05). Figure 5 shows the median per-

centage increases from baseline for both groups. After

week 4 there was no further increase in median gastrin

levels in the lansoprazole-treated patients. No significant

differences were noted among patients receiving lanso-

prazole 60 mg for the final weeks (although the number

of patients was small) compared to those continuing on

lansoprazole 30 mg. The median percentage increases in

serum gastrin levels from baseline to weeks 4 and 8 were

74% and 76% for the lansoprazole group, compared

with 36% and 25% for the ranitidine group, respectively,

(P!0.05 between groups for week 4 and week 8).

Figure 6 shows the final gastrin levels in patients with

normal baseline gastrins. The percentage of patients that

remained in the normal range at week 8 (% 100 pg}mL)

was 63% in the lansoprazole group and 79% in the

ranitidine group.



Table 3. Percentage of patients with possible or probable

treatment-related adverse events occurring with a prevalence of

at least 3% (n[%])

Adverse Lansoprazole Ranitidine

event (n¯69) (n¯36)

Headache 12 (17.4) 2 (5.6)

Diarrhoea 4 (5.8) 0 (0.0)

Asthenia 3 (4.3) 1 (2.8)

Table 4. Adverse events contributing to withdrawal of eight

patients from study

Treatment Reason for Relation to

Patient Group withdrawal study drug

1 Lansoprazole Nausea Possible

2 Lansoprazole Headache Possible

3 Lansoprazole Aesthenia Possible

4 Lansoprazole Dizziness, Aesthenia Possible

5 Lansoprazole Diarrhoea Possible

6 Lansoprazole Asthenia, Dizziness, Possible

Abnormal Thinking,

Headache

7 Ranitidine Migraine Possible

8 Ranitidine Acute diverticulitis None

Figure 5. Fasting serum gastrin levels. The median percentage

increases in serum gastrin levels from baseline to the final visit

(weeks 4 and 8) were 74% and 76% for the lansoprazole group

compared with 36% and 25% for the ranitidine group,

respectively (P!0.05 between groups for weeks 4 and 8).

Gastric histology. Histological specimens were obtained

from the greater curvature of the gastric body at baseline

and the final visit in all patients. Figure 7 shows the effect

Figure 6. Final gastrin levels in patients with normal baseline

gastrins. The percentage of patients that remained in the normal

range (% 100 pg}mL) was 63% in the lansoprazole group and

79% in the ranitidine group. Gastrin levels greater than

200 pg}mL were found in 8% of the lansoprazole group and 8%

of the ranitidine group.

of treatment on gastric mucosal histology. Assessment of

acute inflammation in the lansoprazole group showed

that 50% of patients remained unchanged, 4.2% showed

improvement, and 45.8% showed worsening. In the

ranitidine group, 58.3% of patients remained unchanged

from baseline, 25% showed improvement, and 16.7%

showed worsening.

Assessment of chronic inflammation in the lansoprazole

group showed that 60.4% of patients remained un-

changed from baseline, 4.2% showed improvement, and

35.4% showed worsening. In the ranitidine group,

47.8% of patients remained unchanged from baseline,

17.4% showed improvement and 34.8% showed

worsening.

There were no statistical differences between the lanso-

prazole and ranitidine treatment groups in mean change

from baseline in Grimelius-positive cell densities, Solcia

classification of gastric endocrine growth,',( or level of

inflammation. Furthermore, no cells in either group were

classified as greater than simple (diffuse) hyperplasia.

Light microscopic examination of biopsy specimens

revealed no evidence of carcinoid tumours or of any

visible neuro-endocrine proliferation in any patient.



Figure 7. Effect of treatment on gastric mucosal histology. There

were no statistically significant differences between the treatment

groups in changes in mucosal histology.

DISCUSSION

The results of this single-centre study of patients with

reflux oesophagitis co-existing with Barrett’s oesophagus

demonstrated that despite the presence of Barrett’s

oesophagus, lansoprazole was effective in healing the

oesophagitis in 91% of the patients and was more

effective than ranitidine. The superiority of lansoprazole

over ranitidine is reflected by the greater oesophageal

mucosal healing rate and the greater relief of day and

night heartburn.

Clinical trials. Seven studies of lansoprazole in the

treatment of erosive reflux oesophagitis have been

published: two trials of H#RA-resistant oesophagitis ;#,$

three positive-controlled trials using different doses of

lansoprazole ;)–"! one placebo-controlled dose ranging

study;"" and one comparative trial using omeprazole."#

Although none of these studies excluded patients with

Barrett’s oesophagus from entering the study, most of the

enrolled patients had erosive reflux oesophagitis without

Barrett’s oesophagus.

The two resistant oesophagitis studies produced results

similar to ours.#,$ In the first study, Robinson et al.#

reported on 50 patients with H#RA-resistant oesophagitis

who were randomized to receive either lansoprazole

30 mg or 60 mg daily. By 8 weeks, 96% and 89% of the

patients receiving lansoprazole 30 mg and 60 mg, re-

spectively, had healed. In the second study, using a

multi-centre, randomized, double-blind approach similar

to ours, Feldman et al.$ treated 95 patients with resistant

erosive oesophagitis. At eight weeks, 89% of

lansoprazole-treated patients as opposed to 38% of

ranitidine-treated patients had complete endoscopic

healing (P!0.001). As in our study, intervention with

lansoprazole 30 mg was superior throughout the 8 week

trial to continued therapy with ranitidine and was more

effective in relieving symptoms of heartburn and re-

ducing the need for antacid tablets.

The three positive-controlled studies compared 8 weeks

of once daily doses of lansoprazole 15 mg, 30 mg or

60 mg to twice daily doses of 150 mg ranitidine in the

healing of erosive oesophagitis.)–"! By 8 weeks,E90% of

the patients receiving any dose of lansoprazole were

healed compared with 53–70% of those receiving

ranitidine. The high healing rate of 70% in ranitidine-

treated patients"! is substantially higher than that

reported in most other H#-RA studies,"$ and may be

related to very aggressive lifestyle modifications

encouraged by highly experienced study coordinators.

In the placebo-controlled dose-ranging study, patients

with moderate to severe erosive oesophagitis were

randomized to receive placebo or lansoprazole 15 mg,

30 mg or 60 mg daily."" Of patients receiving any dose of

lansoprazole, 91% to 95% healed, as compared with

53% of patients receiving placebo. The placebo healing

rate was unusually high for patients with moderate to

severe oesophagitis and cannot be easily explained.

In the comparative trial, patients with erosive oeso-

phagitis received either lansoprazole 30 mg daily or

omeprazole 20 mg daily for 8 weeks."# The healing rate

at 8 weeks was about 85% in both groups.

Baseline severity of oesophagitis. In general, the greater the

severity of oesophagitis, the poorer the healing in both

treatment groups. Only one-third of grade 4 oesophagitis

patients, as opposed to two-thirds of those with grade 2

and 3, healed with 8 weeks of ranitidine ; and only three-

fourths of grade 4 oesophagitis patients, as opposed to

almost all those with grade 2 and 3, healed with 8 weeks

of lansoprazole.

Tobacco use. Tobacco use did not appear to affect the

healing rates in either treatment group, but lansoprazole

remained significantly more effective than ranitidine in

tobacco users as well as non-users.

Length of Barrett’s oesophagitis. The length of Barrett’s



oesophagus did not affect the healing rates in either

group. Lansoprazole healed 85% of patients with greater

than 3 cm of Barrett’s oesophagus and 97% of those with

less than 2 cm. Lansoprazole was significantly more

effective than ranitidine in healing the oesophagitis

regardless of the length of Barrett’s oesophagus.

Quality-of-life. The quality-of-life questionnaire, designed

to detect a change in the feeling of relative well being,

revealed an improvement in well-being for both

lansoprazole- and ranitidine-treated patients.

Safety. Lansoprazole and ranitidine were well-tolerated.

There were no clinically significant changes in physical

examination, ECGs or standard clinical laboratory tests.

Adverse reactions occurred in both treatment groups

with similar frequency.

As expected, the increase in serum gastrin levels was

greater in patients treated with lansoprazole than in

those treated with ranitidine. Median fasting serum

gastrin levels increased by 74% after 4 weeks of

lansoprazole therapy and by 76% after 8 weeks of

lansoprazole therapy. Corresponding increases in serum

gastrin with ranitidine at 4 and 8 weeks were 36% and

25%.

In the 24 ranitidine-treated patients with normal

gastrin levels at baseline, 19 (79%) remained within

normal limits at week 8, and 3 (13%) had 8-week levels

between 100 and 200 pg}mL. Two (8%) ranitidine-

treated patients had gastrin levels greater than

200 pg}mL. The differences in gastrin levels were un-

doubtedly due to the more potent acid inhibitory property

of lansoprazole as compared with ranitidine.

Of the 49 lansoprazole patients with normal baseline

fasting serum gastrin levels, 31 (63%) at week 8

remained within normal limits, 14 (29%) at week 8 had

levels between 100 and 200 pg}mL, and 4 (8%) at week

8 had levels above 200 pg}mL. Of the 8 patients with

levels greater than 200 pg}mL at week 8, one had a level

of 795 pg}mL at 8 weeks and one had a level of

390 pg}mL at 8 weeks. In general, serum gastrin levels

increased from baseline to week 4 of lansoprazole

therapy, and appeared to taper off with no additional

increase after week 4.

Biopsies of the gastric mucosa taken from the greater

curvature of the stomach in this study failed to reveal any

increase in enterochromaffin-like cell density or neuro-

endocrine cell proliferation.

CONCLUSION

From previous studies it is apparent that in patients with

reflux oesophagitis and H#-RA-resistant reflux oeso-

phagitis, lansoprazole in doses of 30 and 60 mg daily is

superior to ranitidine in the complete healing of moderate

and severe reflux oesophagitis and in the complete relief

of primary and secondary symptoms associated with

gastro-oesophageal reflux. From our present study we

conclude that lansoprazole is equally effective for healing

of reflux oesophagitis in patients with coexisting Barrett’s

oesophagus.

ACKNOWLEDGEMENTS

This study was supported by a grant from TAP Holdings.

This material is based upon work supported by the Office

of Research and Development (R&D) at the Department

of Veteran Affairs (VA), Hines, IL. We gratefully ac-

knowledge the support of Jean Seidel for her expertise

in preparing this manuscript, Larry Brand for the high

quality figures and Kathy Franke, Sue O’Connell and

Rose Todd for clinical assistance. We also thank the

Hines VA pharmacy staff for their assistance in dis-

tributing the medications. Additionally, we thank Dr

Marion Haber (TAP Holdings) for reading all the biopsy

material.

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Lansoprazole heals erosive reflux oesophagitis in patients with Barrett's oesophagus