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Meta-analysis: proton pump inhibitor or H2-receptor antagonist for

Helicobacter pylori eradication

D. Y. GRA H A M , F . H A M M O UD, H . M . T. E L - Z I M A I TY, J . G. KI M , M . S . O S A TO & H . B. E L - S E RA G

Department of Medicine, Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA

Accepted for publication 4 December 2002

SUMMARY

Aim: To compare H2-receptor antagonists and proton

pump inhibitors as adjuvants to triple therapy for

Helicobacter pylori eradication.Methods: H. pylori-infected patients with peptic ulcer

were randomized to receive either 300 mg nizatidine or

30 mg lansoprazole plus 1 g amoxicillin and 500 mg

clarithromycin taken b.d. for 7 days. H. pylori eradica-

tion was assessed 4 weeks after therapy. Using meta-

analytical techniques, we combined the results of this

study with other randomized controlled comparisons of

H2-receptor antagonists and proton pump inhibitors as

adjuvants to triple therapy.

Results: One hundred and one patients were randomi-

zed. H. pylori eradication was 94% (47/50) [95%

confidence interval (CI), 8399%] (intention-to-treat)

in the H2-receptor antagonist group vs. 86% (44/51)

(95% CI, 7494%) in the proton pump inhibitor group

(P 0.3). There has been a total of 12 similar

studies (1415 patients). The overall efficacy was similar

in intention-to-treat analysis: 78% (549/701) with

H2-receptor antagonists vs. 81% (575/714) with pro-

ton pump inhibitors (odds ratio, 0.86; 95% CI, 0.661.12). A non-significant trend favouring H2-receptor

antagonist (79% vs. 69%; odds ratio, 1.14; 95% CI,

0.761.71; P 0.5) was seen in the comparison of

clarithromycin-containing regimens. In contrast, in non-

clarithromycin-containing trials, there was a slight, but

significant, advantage with proton pump inhibitors

(85% vs. 78%; odds ratio, 0.64; 95% CI, 0.450.92;

P 0.02).

Conclusion: Overall, proton pump inhibitor and

H2-receptor antagonist antisecretory agents appear to

be similarly effective as adjuvants for H. pylori triple

therapy. It is unlikely that the direct anti-H. pylori effect

of proton pump inhibitors is responsible for their ability

to enhance anti-H. pylori therapy.

INTRODUCTION

Helicobacter pylori infection is aetiologically associated

with peptic ulcer disease, gastric lymphoma, chronic

gastritis and gastric adenocarcinoma.1, 2 H. pylori

eradication from the stomach has become the primary

approach for the therapy of peptic ulcer disease and

primary gastric lymphoma, and is likely to be effective

for the prevention of most cases of gastric cancer.1, 2

Successful eradication therapy requires a combination

of antimicrobial agents, typically combined with anti-

secretory agents or bismuth.3, 4

The trend has been to use proton pump inhibitors

instead of histamine-2 receptor antagonists (H2-receptor

antagonists) as antisecretory agents, in part because

proton pump inhibitors are more effective as acid

suppressants and also have antibacterial effects in vitro

and in vivo.510 The most commonly used antimicrobial

therapies include a combination of clarithromycin and

amoxicillin or clarithromycin and metronidazole

together with a proton pump inhibitor. The original

study showing that triple therapy with amoxicillin,

Correspondence to: Dr D. Y. Graham, Veterans Affairs Medical Center, RM

3A-320 (111D), 2002 Holcombe Boulevard, Houston, TX 77030, USA.

E-mail: [email protected]

Aliment Pharmacol Ther 2003; 17: 12291236. doi: 10.1046/j.0269-2813.2003.01583.x

2003 Blackwell Publishing Ltd 1229


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clarithromycin and an antisecretory drug was effective

used the H2-receptor antagonist, ranitidine. The erad-

ication rate in that study was 86% [95% confidence

interval (CI), 7899%].11

A subsequent study evaluated

clarithromycin, amoxicillin and nizatidine and reported

a cure rate of 96%, with one of the two treatment

failures having H. pylori with pre-treatment resistanceto clarithromycin.12

There have now been a number of studies showing the

effectiveness of amoxicillin and metronidazole or clarith-

romycin and metronidazole in combination with an

H2-receptor antagonist1322

(Table 1), as well as studies

comparing triple therapy with a proton pump inhibitor

or H2-receptor antagonist2331 (Table 2). The most

recent comparison was of a proton pump inhibitor or

H2-receptor antagonist and four antibiotics.32

The aim of this report was to present a new

randomized controlled study comparing the H2-receptor

antagonist, nizatidine, and the proton pump inhibitor,lansoprazole, as adjuvants for H. pylori eradication

using the twice-daily combination of amoxicillin and

clarithromycin. We also performed a systematic review

of the literature, and used meta-analytical techniques to

pool the results of this study with those of several other

randomized controlled trials to compare the effective-

ness of H2-receptor antagonists and proton pump

inhibitors as adjuvants for clarithromycin-containing

triple therapy for H. pylori eradication.

METHODS

Randomized controlled study

We performed a randomized controlled trial to compare

two H. pylori eradication regimens: twice-daily amoxi-

cillin and clarithromycin triple therapy using either

twice-daily nizatidine or lansoprazole as antisecretory

agent. All patients had endoscopically documented

peptic ulcers and evidence of H. pylori infection. At

endoscopy, antral and corpus mucosal biopsies were

taken and, after fixation in formalin, were sent to the

Gastrointestinal Pathology Laboratory at Baylor College

of Medicine Veterans Affairs Hospital, Houston, TX, USA

for analysis. H. pylori status was defined by histology

using a Genta triple stain. This approach has been

proven to be reliable for the confirmation of eradic-

ation.33, 34

Potential candidates eligible to participate in the study

were seen at the Korea University College of Medicine,Seoul, South Korea. The inclusion criteria were the

presence of an active peptic ulcer, the presence of active

H. pylori infection and the willingness to participate

in the trial. Participants were randomized to receive

amoxicillin, 1 g, plus clarithromycin, 500 mg, and

either lansoprazole, 30 mg, or nizatidine, 300 mg,

twice daily for 7 days. The study was open labelled in

that the drugs were not identical. Compliance was

assessed by pill count.

Table 1. Triple therapy with a histamine-2 receptor antagonist

Study

Antisecretory

drug (mg)

Drug 1

(mg)

Drug 2

(mg)

Duration

(days)

No. of

patients

Cure rate

(ITT) (%)

Cure rate

(PP) (%)

Cure rate (sensitive

strains) (%)

Breuer et al.12 N 300 at

bedtime

C 500 t.d.s. A 750 t.d.s. 14 72 96

Lo et al.21 N 300 b.d. C 500 q.d.s. A 500 q.d.s. 14 25 80

Gschwantler et al.18 F 80 b.d. C 500 b.d. A 1000 b.d. 7 107 88 90

Al-Assi et al.11 R 300 at

bedtime

C 500 t.d.s. A 750 t.d.s. 10 29 86

Adamek et al.17 R 300 b.d. C 500 t.d.s. M 500 t.d.s. 7 15 100

Gotz et al.15

R 300 b.d. C 500 t.d.s. M 500 t.d.s. 14 20 95Yousfi et al.13 R 300 b.d. C 250 b.d. M 500 b.d. 14 27 78 89 (16/18)

sensitive to both

Goh et al.14 F 40 A 1000 b.d. M 500 b.d. 12 59 75 76 91

Goh et al.14 F 40 A 750 t.d.s. M 500 t.d.s. 12 65 79 83 100

Hentschel et al.19 R 300 A 750 t.d.s. M 500 t.d.s. 12 52 89

Talley et al.22 N 150 b.d. C 500 b.d. A 1000 b.d. 14 77 78 84

Talley et al.22 N 300 b.d. C 500 b.d. A 1000 b.d. 14 83 70 78

A, amoxicillin; C, clarithromycin; F, famotidine; ITT, intention-to-treat; M, metronidazole; N, nizatidine; PP, per protocol; R, ranitidine.

1230 D . Y . G R A HA M et al.

2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther17, 12291236


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Outcomes were assessed at least 4 weeks after the end

of treatment by repeat endoscopy with gastric biopsy for

histology. Some patients underwent repeat testing when

they presented later with recurrent symptoms (not later

than 6 months). The primary outcome was eradication

ofH. pylori defined by negative histology for the antrum

and corpus. A single pathologist, who was blind to the

nature of the study, examined the histological slides

prepared from the gastric mucosal biopsies. The secon-

dary outcome was healing of the ulcer(s) as assessed by

repeat endoscopy.

The two treatment groups were compared with respect

to demographic features and baseline disease characteri-

stics. In an intention-to-treat analysis, the proportions of

patients achieving primary or secondary outcomes were

compared between the two treatment groups. For all

comparisons, v2 tests were used for dichotomous

variables and t-tests for continuous variables.

Systematic review of the literature/meta-analysis

We performed a systematic review of the literature to

identify therapeutic trials comparing the efficacy of

H. pylori therapy between H2-receptor antagonists and

proton pump inhibitors used in triple therapy combina-

tions. Medline and Embase searches were carried out

between 1990 and 2001. The bibliographies of the

articles were also searched for relevant papers or

abstracts. Only randomized controlled studies that

reported an intention-to-treat analysis or row numbers

that allowed for the calculation of an intention-to-treat

analysis were selected. Both abstracts and full articles

were included. Two independent investigators abstrac-

ted the relevant data (DYG, FH). Subsequently, the

results of the current study were pooled with those of

the studies identified in the systematic review that

satisfied our inclusion criteria. In addition to pooling the

Table 2. Triple therapy comparing a histamine-2 receptor antagonist with a proton pump inhibitor

Study

Antisecretory

drug (mg)

Drug 1

(mg)

Drug 2

(mg)

Duration

(days)

No. of

patients

Cure rate

(ITT) (%)

Cure rate

(PP) (%)

Cure rate (sensitive

strains) (%)

This study N 300 b.d. C 500 b.d. A 1000 b.d. 7 50 94 (47/50) 94 (47/50) 96

L 30 b.d. C 500 b.d. A 1000 b.d. 7 51 86 (44/51) 86 (44/51) 88

Savarino et al.24 R 300 b.d. C 250 t.d.s. A 1000 b.d. 7 80 64 (51/80) 70 (51/73)

O 20 b.d. C 250 t.d.s. A 1000 b.d. 7 80 57 (46/80) 67 (46/69)Gschwantler et al.23 F 80 b.d. C 250 b.d. M 500 b.d. 7 60 78 (47/60) 90 (47/52) 93

O 20 b.d. C 250 b.d. M 500 b.d. 7 60 73 (44/60) 77 (44/57) 84

Lazzaroni et al.25 R 300 C 250 b.d. M 500 b.d. 14 40 85 (34/40)

L 30 C 250 b.d. M 500 b.d. 14 40 90 (36/40)

Kihira et al.16 R 300 C 200 b.d. M 250 b.d. 7 48* 91 (44/48)

L 30 C 200 b.d. M 250 b.d. 7 43 94 (40/43)

Spadaccini et al.26 R 300 b.d. C 250 b.d. T 500 b.d. 7 50 86 (43/50)

O 20 b.d. C 250 b.d. T 500 b.d. 7 50 92 (46/50)

Grigoriev et al.30 R 150 b.d. A 1000 b.d. M 500 b.d. 14 15 80 (12/15)

O 20 b.d. A 1000 b.d. M 500 b.d. 14 15 87 (13/15)

Lamouliatte et al.29 R 300 A 1000 b.d.

(15 days)

T 500 b.d.

(10 days)

22 81 (18/22)

O 22 A 1000 b.d.

(15 days)

T 500 b.d.

(10 days)

22 86 (19/22)

Ell et al.27 R 300 q.d. A 750 t.d.s. M 500 t.d.s. 7 178 77 (137/178) 76 87

O 40 q.d. A 750 t.d.s. M 500 t.d.s. 7 194 87 (169/194) 87 95

Tham et al.31 R 600 b.d. A 500 t.d.s. M 400 t.d.s. 14 18 44 (8/18) 100

O 20 b.d. A 500 t.d.s. M 400 t.d.s. 14 19 32 (6/19) 71

Savarino et al.24 R 300 b.d. A 1000 b.d. M 500 b.d. 7 80 75 (60/80) 85 (60/71)

O 20 b.d. A 1000 b.d. M 500 b.d. 7 80 77 (62/80) 89 (62/70)

Hsu et al.28 F 40 b.d. A 1000 b.d. T 500 b.d. 14 60 80 (48/60) 91 (48/53) 91

O 20 b.d. A 1000 b.d. T 500 b.d. 14 60 83 (50/60) 88 (50/57) 92

A, amoxicillin; C, clarithromycin; F, famotidine; ITT, intention-to-treat; L, lansoprazole; M, metronidazole; N, nizatidine; O, omeprazole; PP, per

protocol; R, ranitidine; T, tinidazole.

* Patients without previous Helicobacter pylori therapy.

META -A N A LYSIS: PPI OR H2 -A N TA GON IST FOR H. PYLORI 1231



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results of all studies that satisfied our criteria, we

decided a priori to examine the pooled results from: (i)

studies containing clarithromycin in both treatment

groups; (ii) studies containing no clarithromycin in

either treatment group; (iii) studies with a treatment

duration of 1 week; and (iv) studies with a treatment

duration of 2 weeks.A random (DerSimonianLaird) model assumption

was used in the meta-analysis.35 Tests of homogeneity

were performed for all studies, as well as for the

subgroups defined above. The results of the meta-

analysis were expressed as pooled odds ratios (ORs) for

the eradication of H. pylori using H2-receptor antago-

nists compared with proton pump inhibitors, and their

accompanying 95% CIs.

RESULTS

Randomized controlled study

One hundred and one patients were randomized,

including 50 in the nizatidine group and 51 in the

lansoprazole group. The nizatidine group consisted of

45 men and five women between 24 and 80 years of

age (median, 52 years), and the lansoprazole group

consisted of 36 men and 15 women between 22 and

76 years of age (median, 49 years). There were no

differences in the demographic characteristics (Table 3).

All patients had active H. pylori infection by histology

and had at least one ulcer in the stomach, duodenum orboth. All randomized patients completed the study and

there was a 100% follow-up. The combinations were

well tolerated and adherence was > 95%.

H. pylori eradication was achieved in 47 of 50 (94%)

(95% CI, 8399%) patients in the nizatidine group

compared with 44 of 51 (86%) (95% CI, 7494%)

patients in the lansoprazole group (P 0.33). The 95%

CI for the difference in proportions overlapped zero

()21% to + 5%).

One of the seven patients who failed treatment in thelansoprazole group had negative histology at the initial

post-therapy evaluation, but H. pylori was detected at a

4-month follow-up visit. Although it is not known

whether this finding represented re-infection or recru-

descence, the case was scored as a failure. Inclusion of

this case as a success would not change the outcome

significantly.

Pre-treatment cultures were available for eight of the

nine patients who failed therapy in both groups, and

clarithromycin resistance was present in only one

patient in the nizatidine group and one in the lanso-

prazole group. All ulcers were healed in 42 (84%)patients in the nizatidine group compared with 49

(96%) in the lansoprazole group (P 0.09).

Meta-analysis

In the systematic review, we identified 11 studies

(including the present study) containing 12 relevant

comparisons that satisfied our criteria; these studies

were included in a meta-analysis. All studies were

randomized, controlled and with intention-to-treat

analyses. The number of patients included in eachtreatment arm ranged from 15 to 194, the duration of

therapy from 7 to 14 days and the H. pylori eradication

rate from 75% to 94%. The overall eradication rate with

Table 3. Baseline characteristics of the

study patientsLansoprazole group Nizatidine group

Number of patients 51 50

Men 36 (71%) 45 (90%)

Age (years) 2276 (median, 49) 2480 (median, 52)

H. pylori at follow-up visits 44 cured (86%) 47 cured (94%)

7 failed (14%) 3 failed (6%)

Smoking 28 31

26 from cured group 30 from cured group2 from failed group 1 from failed group

Ulcer(s) healed at follow-up visits 49 47

42 from cured group 45 from cured group

7 from failed group 2 from failed group

Ulcer(s) not healed

at follow-up visits

1 from cured group 3

2 from cured group

1 from failed group

Unknown ulcer healing 1 from cured group None




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H2-receptor antagonist-containing combinations was

549 of 701 (78%) patients, whereas that of proton

pump inhibitor-containing combinations was 575 of

714 (81%) patients. Only the results of intention-to-

treat analyses were pooled. Where reported, the dropoutrates were low (< 11%); two studies were published in

abstract form only.29, 30

Tests of homogeneity were negative for all calculations

(P > 0.05), indicating that there were no significant

differences in the results of the individual studies and

thus that it was appropriate to pool the results. When

all 12 comparisons were combined in the random model

(i.e. more conservative), the pooled OR for the eradica-

tion ofH. pylori using H2-receptor antagonists compared

with proton pump inhibitors was 0.86 (95% CI, 0.66

1.12; P

0.3) (Figure 1). In other words, combinationscontaining proton pump inhibitors were 14% more

likely to cause H. pylori eradication than those contain-

ing H2-receptor antagonists; this was not statistically

significantly different.

There were no significant differences in the rates of

H. pylori eradication between the combinations con-

taining H2-receptor antagonists or proton pump inhib-

itors when pooling the results of 1-week studies (seven

studies; pooled OR, 0.86; 95% CI, 0.641.17) and

2-week studies (three studies; pooled OR, 0.96; 95% CI,

0.481.94). There was a non-significant trend favour-

ing H2-receptor antagonists (69% vs. 79%; six studies;

OR, 1.14; 95% CI, 0.761.71; P 0.5) when clarithro-

mycin-containing regimens were compared. Conversely,

the pooled OR from studies not using clarithromycin in

either treatment group revealed a small but significant

benefit in H. pylori eradication favouring proton pump

inhibitor-containing regimens (six studies; OR, 0.64;

95% CI, 0.450.92; P 0.02). The overall eradication

rate was 306 of 392 (78%; 95% CI, 7482%) in studies

with H2-receptor antagonist-containing combinations

vs. 336 of 397 (85%; 95% CI, 80.788%) in studies

using proton pump inhibitors.

DISCUSSION

The efficacy of both clarithromycin and amoxicillin as

antimicrobials is enhanced by antisecretory drug ther-

apy. Proton pump inhibitors not only directly block the

proton pump on parietal cells in the stomach, but also

have antibacterial activity against H. pylori both in vivo

and in vitro. In contrast, H2-receptor antagonists have

no intrinsic antibacterial activity. This randomized

study, as well as the meta-analysis, showed that H. pylori

eradication triple therapy using twice-daily amoxicillinand clarithromycin was similarly effective independent

of whether the antisecretory agent was a proton pump

inhibitor or an H2-receptor antagonist. This conclusion

is consistent with the notion that the adjuvant effect

with antisecretory therapy is related more to the drugs

ability to suppress acid secretion than to its antibacterial

activity.

Most studies of H. pylori eradication using triple

therapy have used proton pump inhibitors as the

antisecretory component. Many of the large controlled

trials were performed to obtain approval for different

antimicrobial therapies for the treatment of H. pylori

infection, and were sponsored by pharmaceutical com-

panies manufacturing proton pump inhibitors. Thus,

the majority of studies of amoxicillin and clarithromycin

or metronidazole and clarithromycin have used a pro-

ton pump inhibitor. One rationale for this choice was

that proton pump inhibitor antisecretory therapy had

been shown to be superior to H2-receptor antagonists in

2925282627this study162322

242523

12/1531/3718/22

137/17848/6047/5044/4851/8047/60

34/ 4043/5060/80

13/1523/2619/22

169/19450/6044/5140/4346/8044/60

36/ 4046/5062/80

592/721572/720Total(95%CI)Test for heterogeneity chi-square=9.68 df=11 P=0.56

0.1 0.2Favours treatment

1 5 10Favours control

0.62[0.09,4.34]0.67[0.15,2.98]0.71[0.14,3.63]0.49[0.29,0.85]0.80[0.32,2.02]2.49[0.61,10.25]0.82[0.17,3.91]1.30[0.69,2.45]1.31[0.57,3.04]

0.63[0.16,2.43]0.53[0.15,1.95]0.87[0.42,1.81]

0.83[0.63,1.09]

StudyH2RA PPI OR

95%CI Random)OR95%CI Random)

Figure 1. A Peto graph showing the indi-

vidual studys odds ratios (ORs) and the

pooled OR for all studies comparing suc-

cessful Helicobacter pylori eradication

between combinations that contained

histamine-2 receptor antagonist (H2RA)

vs. proton pump inhibitor (PPI).




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ulcer healing, pH control and the rapidity of pain relief.

All of these benefits were likely to be present when

proton pump inhibitors were used as part of the therapy

of H. pylori infection in patients with peptic ulcer

disease.

Most of thestudies in which a protonpump inhibitorand

H2-receptor antagonist have been compared have shownno significant difference in the eradication of H. pylori.

High eradication rates have been reported with both

antisecretory agents. Given the lack of statistically

significant heterogeneity between the results of the

studies examined,pooling the results in a meta-analytical

approach was appropriate. The results of the meta-

analysis confirm the lack of significant differences in the

rate of H. pylori eradication between studies with

protonpump inhibitors or H2-receptor antagonists. These

results are consistent with those of a previous analysis

that examined fewer studies.36 However, when the

results of studies that contained or did not containclarithromycin were pooled, there was a slight, but

significant, advantage of proton pump inhibitor-contain-

ing combinations in non-clarithromycin-containing reg-

imens. The reason for this difference is unclear and

deserves further study. One possibility is related to the fact

that clarithromycin is more dependent than metroni-

dazole on pH control. The elimination or reduction of

H. pylori in the stomach eliminates the ammonia

produced by the action of H. pylori urease and, at least

in the short term, H2-receptor antagonists are more

effective in controlling nocturnal pH than are protonpump inhibitors.

Antibiotic-related factors may be at least as important

as the choice of antisecretory agent in determining the

overall efficacy of H. pylori eradication therapy. For

example, antimicrobial resistance is a major cause of

treatment failure, and current data suggest that clarith-

romycin resistance cannot be overcome by increasing

the clarithromycin dosage or the duration of ther-

apy.37, 38 Some data suggest that increasing the dose

of antibiotic administered may achieve better results.

For example, in the study by Adamek et al., higher doses

of clarithromycin (500 mg b.d.) and metronidazole

(500 mg t.d.s.) were used, and a 100% cure rate was

achieved; that study also used a higher dose of

ranitidine (300 mg b.d.).17 Detailed comparisons of

the different combinations and permutations are gen-

erally lacking, and thus it is difficult to draw unassail-

able conclusions regarding drug combinations for

H. pylori eradication.

In conclusion, 1 week of treatment with either an

H2-receptor antagonist or a proton pump inhibitor,

together with amoxicillin and clarithromycin, was

similarly effective in the eradication of H. pylori and in

the healing of peptic ulcers. As the outcomes of

H2-receptor antagonist and proton pump inhibitor triple

therapy are similar, and both are well tolerated bypatients, one might use cost to choose between them.

Generally, H2-receptor antagonists cost less than proton

pump inhibitors, which favours their use, especially in

developing countries.

ACKNOWLEDGEMENTS

This work was supported in part by the Office of

Research and Development Medical Research Service

Department of Veterans Affairs and by Public Health

Service grant DK56338 which funds the Texas Gulf

Coast Digestive Diseases Center. Dr El-Serag is therecipient of a Veterans Affairs Health Services Research

and Development (HSR&D) Research Development

Award (RCD 00-013-2).

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