Pantoprazole versus one-week Helicobacter pylori eradicationtherapy for the prevention of acute NSAID-related gastroduodenaldamage in elderly subjects

A. PILOTTO*, F. DI MARIO  , M. FRANCESCHI*, G. LEANDROà , G. BATTAGLIA§,

B. GERMANAÁ ± , R. MARIN** & G. VALERIO*

*Digestive Pathophysiology Center, Department of Geriatrics, Vicenza, Italy;  Department of Gastroenterology, Padova, Italy;

àDepartment of Gastroenterology, Castellana Grotte (BA), Italy; §Department of Gastroenterology, Venezia, Italy;

±Department of Gastroenterology, Belluno, Italy; and **Department of Gastroenterology, Dolo (VE), Italy

Accepted for publication 5 April 2000

INTRODUCTION

Helicobacter pylori (H. pylori) infection and nonsteroidal

anti-in¯ammatory drug (NSAID) use account for over

75% of gastric and duodenal ulcers in elderly sub-

jects.1, 2 H. pylori is present in approximately 50% of

patients with NSAID-associated gastroduodenal injury,3

yet it is still not clear if a signi®cant relationship exists

between these two factors in inducing gastroduodenal

damage.4, 5

Previous studies have shown that prophylactic therapy

with misoprostol,6 famotidine7 or omeprazole8, 9 is

effective in the prevention of NSAID-induced ulcers,

while reports are con¯icting about whether eradication

therapy for H. pylori may prevent NSAID-induced peptic

ulcers.10, 11

The aim of the present study was to compare the effect

of eradication of H. pylori infection using a one-week

triple therapy to that of a maintenance therapy with the

SUMMARY

Aim: To compare the ef®cacy of pantoprazole vs. a one-

week Helicobacter pylori eradication therapy for the

prevention of NSAID-related gastroduodenal damage.

Methods: Patients over 60 years old with symptoms

and/or a history of ulcer who needed NSAID treatment

were evaluated by endoscopy. H. pylori positive subjects

who had no severe gastroduodenal lesions were ran-

domized to take, concomitantly with NSAID therapy,

either: (i) pantoprazole 40 mg daily plus amoxycillin

1 g b.d. and clarithromycin 250 mg b.d. for 1 week (35

subjects, Group PAC) or (ii) pantoprazole 40 mg daily

for 1 month (34 subjects, Group P). Endoscopy was

repeated after 1 month.

Results: A signi®cantly higher incidence of severe

gastroduodenal damage was found in Group PAC than

in Group P (29% vs. 9%, P < 0.05). The percentages of

patients worsened, unchanged and improved after

1 month were, respectively: Group PAC: 46%, 46%,

and 9% and Group P: 7%, 65%, and 29% (P < 0.0008).

The percentage of H. pylori-negative subjects was 89%

in Group PAC and 52% in Group P (P � 0.0009). The

incidence of gastroduodenal damage was higher in

Group PAC treatment failures than in cured patients

(50% vs. 25.8%, P � ns).

Conclusion: One month of pantoprazole was more

effective than a proton pump inhibitor-based triple

therapy in the prevention of gastroduodenal damage in

elderly H. pylori-positive NSAID users.

Correspondence to: Dr A. Pilotto, Centro di Fisiopatologia Digestiva dell¢Anziano, UnitaÁ Operativa di Geriatria, Ospedale S. Bortolo ± Via Rodol®,

37, 36100 Vicenza, Italy.E-mail: alberto.pilotto@libero.it

Aliment Pharmacol Ther 2000; 14: 1077±1082.

Ó 2000 Blackwell Science Ltd 1077

proton pump inhibitor, pantoprazole, for the prevention

of acute NSAID-related gastroduodenal damage in

H. pylori positive elderly NSAID users.

MATERIALS AND METHODS

Patients

Patients were recruited from March to October 1998.

Eligible patients were (a) older than 60 years of age; (b)

with musculoskeletal pain requiring NSAID treatment

for at least one month and (c) with dyspeptic symptoms

or a personal history of gastritis or peptic ulcer. Patients

received a clear explanation of the purpose of the study

and agreed to participate with informed consent.

Endoscopy

At endoscopy, ulcers, erosions and intramucosal hae-

morrhages were recorded separately for the oesophagus,

stomach and duodenum. An ulcer was de®ned as a

circumscribed mucosal break of 3 mm or more in

diameter with a well-de®ned ulcer crater, whereas

smaller or super®cial lesions were classi®ed as erosions.

Intramucosal haemorrhages were de®ned as haemor-

rhagic lesions without overlying mucosal breaks.6, 7 The

severity of NSAID-related gastroduodenal injury was

classi®ed according to a modi®ed Lanza score12 from 0 to

4: 0 � no lesions; 1 � 1±3 erosions or petechie or

intramucosal haemorragic lesions; 2 � < 10 erosions

or petechie or intramucosal haemorragic lesions; 3 � >

10 erosions or petechie or intramucosal haemorragic

lesions; 4 � a well de®ned ulcer. We de®ned `severe'

gastroduodenal injury as the presence of an endoscopic

diagnosis of grade 3 or 4 using the Lanza scoring system.

H. pylori infection

During endoscopy, six gastric biopsies were taken from

both the antrum (three biopsies), and from the body

(three biopsies). Two antral and two body biopsies were

used for histological analysis, while one from each site

was used for the rapid urease test (CLO test, Delta West

Pty Ltd, Western Australia, Australia).

For histological examinations, biopsy specimens were

immediately ®xed in buffered neutral formalin and

embedded in paraf®n. Sections were stained with

haematoxylin±eosin and modi®ed Giemsa stains for

the detection of H. pylori.

At baseline, patients were considered to be H. pylori

positive if both their histology and rapid urease tests

were positive for H. pylori infection. After therapy, a

patient was considered as being H. pylori negative if

both histology and rapid urease tests were negative;

patients were considered H. pylori positive if either their

histology or rapid urease tests, or both, were positive for

H. pylori infection.

Therapy

Patients who were con®rmed to have: (a) the presence

of gastric H. pylori infection, and (b) no severe

gastroduodenal lesions (Lanza score £ 2), after endo-

scopy were included in the study.

After inclusion, elderly H. pylori-positive patients were

consecutively randomized to one of the following

treatments:

1 eradication therapy with pantoprazole 40 mg once

daily plus amoxycillin 1 g b.d. and clarithromycin

250 mg bi.d. for 1 week (Group PAC) or

2 pantoprazole 40 mg once a day (in the morning) for

1 month (Group P).

After 1 month, all patients had a repeated endoscopy,

with gastric biopsies for histology and the rapid urease

test. During the 1-month period of the study, patients of

both Groups PAC and P were treated daily with

diclofenac 50 mg (20 subjects of Group PAC and 18

subjects of Group P) or 100 mg (15 subjects of Group

PAC and 13 of Group P).

Statistics

Results were evaluated using both `per protocol' (PP)

and `intention-to-treat' (ITT) analyses. The ITT popula-

tion was de®ned as all patients initially enrolled who

had taken at least one dose of study medication. A

statistical analysis was performed using the v2 test with

standard deviations: these were de®ned as (O ± E)/ÖE

(where O is the observed frequency and E the expected

frequency). All P-values were two-tailed, with statistical

signi®cance set at P < 0.05.

RESULTS

Of 127 eligible subjects observed over 8 months, 108

consecutive patients agreed to take part and underwent

endoscopy for enrolment in the study. Of these patients,

1078 A. PILOTTO et al.

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 1077±1082

32 were not infected by H. pylori and seven had peptic

ulcers (®ve patients) or severe erosive gastritis with a

Lanza score of 3 (two patients) at initial endoscopy.

A total of 69 patients were therefore consecutively

assigned to the 1 week triple eradication therapy

regimen (Group PAC, n � 35, males � 18, mean

age � 74 years, range � 60±90 years) or to the

1-month pantoprazole treatment (Group P, n � 34,

males � 11, mean age � 76.9 years, range � 66±

89 years). Three patients in Group P withdrew from the

study after therapy because they refused to undergo a

second endoscopy. Thus, 66 patients completed the

study: 35 in Group PAC and 31 in Group P (Figure 1).

Table 1 reports the clinical characteristics of the two

groups of patients.

After 1 month, 10 of 35 patients (28.5%) in Group

PAC demonstrated severe gastroduodenal damage:

three patients (8.5%) had an active peptic ulcer and

seven subjects (20%) had severe erosive gastritis (Lanza

score � 3). Conversely, none of 31 subjects in Group P

demonstrated severe gastric or duodenal damage after

1 month (P � 0.001). Based on an intention-to-treat

analysis, a signi®cantly greater incidence of severe

gastroduodenal damage was found in the eradication

therapy treated Group PAC than in the pantoprazole

only treated Group P (28.5% vs. 8.8%, P < 0.05)

(Figure 2).

Using the v2 test with standard deviations, a signi®cant

difference was found for the outcome of gastroduodenal

damage between Group PAC and Group P: 45.7% of

patients worsened in Group PAC and 6.5% of patients

worsened in Group P, while an improvement was

observed in 8.5% of Group PAC and in 29% of Group P

(P < 0.0008) (Figure 3).

After 1 month, the percentage of H. pylori-negative

subjects was 88.5% in Group PAC (30 of 34 patients)

Figure 1. Study design.

Table 1. Baseline characteristics of 66

elderly H. pylori-positive acute NSAID users

who were treated with either (i) 1-week

triple therapy for H. pylori eradication

(Group PAC) or (ii) 1-month pantoprazole

therapy (Group P)

Group PAC (n = 35) Group P (n = 31) P

Men/women 18/17 11/20 N.S.

Mean age (range) in years 74.0 (60±90) 76.9 (66±89) N.S.

Co-morbidity (%)2 23/35 (65.7%) 23/31 (74.2%) N.S.

Co-treatments (%) 21/35 (60.0%) 23/31 (74.2%) N.S.

NSAID

Diclofenac 50 mg daily 20 18 N.S.

Diclofenac 100 mg daily 15 13

Endoscopy (Lanza score)

Grade 0 23 21 N.S.

Grade 1 3 2

Grade 2 9 8

PANTOPRAZOLE VS. H. PYLORI CURE TO PREVENT NSAID DAMAGE 1079

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 1077±1082

and 51.6% (16 of 31 patients) in Group P (P � 0.0009).

A higher incidence of severe gastroduodenal damage

was found in Group PAC treatment failures who were

still H. pylori-positive after therapy (two of four patients,

50%) than in cured H. pylori-negative subjects (eight of

31 patients, 25.8%). In particular, an active peptic ulcer

was observed in 25% (one of four patients) of treatment

failures and in only 6.4% (two of 31 patients) of

successfully eradicated H. pylori-negative subjects.

DISCUSSION

This study demonstrated that treatment with panto-

prazole for 1 month concomitantly with NSAID therapy

was more effective than a 1-week anti-

H. pylori triple therapy for the prevention of acute

gastroduodenal injury in elderly H. pylori-positive

NSAID users. A previous study reported that patients

treated with a 1-week anti-H. pylori triple therapy

(bismuth subcitrate 120 mg, tetracycline 500 mg and

metronidazole 400 mg, each given four times daily),

before administration of naproxen 750 mg daily for

2 months, had a signi®cant reduction in the occurrence

of NSAID-induced peptic ulcer (6.7%) compared with

patients treated with naproxen alone (25.5%).10 Con-

versely, another study demonstrated that H. pylori

eradication did not affect the incidence of peptic ulcer

after 6 months of follow-up in H. pylori-positive long-

Figure 2. Incidence of severe gastroduode-

nal damage (modi®ed Lanza score ³ 3) in

elderly acute NSAID users. ITT � inten-

tion-to-treat; PP � per protocol analysis.

Figure 3. Gastroduodenal damage as evaluated by modi®ed Lanza score (see text) at baseline and after 1 month in acute NSAID-users

treated with a 1-week H. pylori eradication triple therapy (Group PAC, on the left) or with pantoprazole for 1 month (Group P, on the

right). The ®gure in each cell gives the number of patients. The main diagonal (tinted) illustrates the subjects whose gastroduodenal

damage did not change during treatment. Above the main diagonal, the improved subjects are in evidence, below the diagonal, those who

had worsened. The statistical analysis was performed using v2 test with standard deviations which takes into account the variation

around the main diagonal. The data indicate a signi®cantly greater worsening in Group PAC in comparison with Group P (P < 0.008).

1080 A. PILOTTO et al.

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 1077±1082

term NSAID users who continued NSAID treatment

without anti-ulcer treatment.11 Similarly, a study of

chronic NSAID users with healed ulcers followed for

6 months after stopping anti-ulcer therapy while con-

tinuing NSAIDs, failed to demonstrate any difference in

cumulative recurrence rates of peptic ulcer among

patients who were H. pylori-negative (27%), H. pylori-

negative after eradication therapy (31%) or H. pylori-

positive (46%).13 However, none of these studies had

evaluated the preventative effect of H. pylori eradication

compared to a maintenance therapy with effective anti-

ulcer drugs such as misoprostol or proton pump

inhibitors.

The only previous study that compared H. pylori

eradication with proton pump inhibitor therapy was

performed by Chan et al. in high risk NSAID users who

had developed NSAID-associated ulcer bleeding14 and

who had resumed NSAID use (naproxen 500 mg b.d.

for 6 months) after ulcer healing. A signi®cantly higher

incidence of recurrent ulcer bleeding was observed in

patients treated with a 1-week H. pylori eradication

therapy (20%) compared to patients who received

omeprazole as prophylactic treatment concomitantly

with naproxen (2%, P < 0.01).

The present ®ndings are in agreement with the

results of this last study. For the ®rst time, a

signi®cant effect of 1 month of 40 mg daily pan-

toprazole in the prevention of NSAID-related gas-

troduodenal damage was documented in high risk

(subjects with dyspeptic symptoms and/or a personal

history of gastritis or ulcer) elderly patients, who are

usually prescribed a gastroprotective therapy concom-

itant with NSAID treatment for musculoskeletal pain.

Furthermore, this study demonstrated that prevention

with proton pump inhibitors was effective during an

acute NSAID treatment of only 1 month. This ®nding

may be clinically relevant, since it is known that over

50% of NSAID-related gastroduodenal lesions, includ-

ing bleeding complications, occurred after occasional

(within 1 week) or acute (within 1 month) NSAID

treatment in elderly patients.3, 15, 16 Recently, several

studies have reported that proton pump inhibitors

such as omeprazole were very effective in the

prevention of NSAID-related gastric and duodenal

injuries.8, 9, 17±19 Such an activity has also been

previously been reported for pantoprazole,20, 21 but

not in the elderly.

None of the 34 patients treated with pantoprazole

(Group P) reported relevant side-effects, demonstrating

that the drug was safe and well tolerated in elderly

subjects who are affected with a high percentage (over

74%) of concomitant diseases and treatments. This high

level of tolerance may be due to the lack of pharmaco-

kinetic interaction between pantoprazole and other

drugs, including diclofenac, as has been reported in

previous studies.22, 23

The cure rate of H. pylori infection with pantopra-

zole 40 mg daily plus amoxycillin 1 g b.d. and

clarithromycin 250 mg b.d. was 88.5%, a very

similar result to those reported for non-NSAID-using

elderly subjects,24, 25 suggesting that concomitant

treatment with diclofenac did not in¯uence cure

rates for H. pylori infection. Successfully cured

H. pylori negative patients were shown to have a

lower incidence of severe gastroduodenal damage

than treatment failures still H. pylori-positive after

therapy. This difference was not statistically signi®-

cant, probably due to the small number of subjects

who remained H. pylori positive after therapy (only

four patients).

In Group P, 51.6% of patients treated with pantopra-

zole without antibiotics were H. pylori-negative after

1 month. To date, a direct effect of pantoprazole on

H. pylori infection has not been reported. However, a

temporary suppression of H. pylori activity during

proton pump inhibitor treatment,26 as well as a

proximal migration of H. pylori towards the gastric

fundus,27 may explain this ®nding. Indeed, no differ-

ences in terms of the prevention of NSAID-related

damage were found between H. pylori-negative and

H. pylori-positive subjects treated with pantoprazole.

This suggests that the control of gastric acid secretion

alone, may prevent acute NSAID-related damage in

elderly subjects, and that such an effect is independent

from H. pylori infection.

In conclusion, 1 month of concomitant pantoprazole

therapy was more effective than a proton pump

inhibitor-based triple therapy in the prevention of

severe acute NSAID-related gastroduodenal damage in

elderly H. pylori-positive NSAID users. The data suggest

that it appears less critical to test and treat H. pylori

infection in elderly patients who require acute NSAID

treatment than to prevent gastroduodenal injuries using

effective antisecretory drugs.28

ACKNOWLEDGEMENTS

This work was supported by the host institutions.1

PANTOPRAZOLE VS. H. PYLORI CURE TO PREVENT NSAID DAMAGE 1081

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 1077±1082

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