Proton pump inhibitor, clarithromycin and either amoxycillin ornitroimidazole: a meta-analysis of eradication of Helicobacter pylori

J. P. GISBERT*, L. GONZAÂ LEZ*, X. CALVET  , N. GARCIÂA  , T. LOÂ PEZ  , M. ROQUEÂ à , R. GABRIEL§

& J. M. PAJARES*

*Department of Gastroenterology and §Department of Clinical Epidemiology, University Hospital of `La Princesa', Madrid;

 Servei de Medicina, Corporacio SanitaÁria Parc TaulõÂ, Sabadell; àCenter d'Estudis, Programes i Serveis Sanitaris (CEPSS),

Barcelona, Spain

Accepted for publication 26 June 2000

INTRODUCTION

At present, a 7-day quadruple therapy with a proton

pump inhibitor, bismuth, tetracycline and metronidaz-

ole, and triple therapies with proton pump inhibitor,

clarithromycin and amoxycillin or a nitroimidazole are

considered the most effective combinations for the

treatment of Helicobacter pylori infection. Because of

their safety, cost-effectiveness and simplicity, proton

pump inhibitor-based triple therapies are the most

frequently recommended treatments world-wide.1±6

The two most widely used are a combination of a

proton pump inhibitor, clarithromycin and amoxycillin,

and a combination of a proton pump inhibitor, clari-

thromycin and a nitroimidazole. It has not been

established whether one regimen is superior to the

other. Although several meta-analyses of H. pylori

eradication regimens have been published recently,

none has been speci®cally designed to compare these

two regimens. The aim of the present study was to

perform a meta-analysis of the studies comparing these

SUMMARY

Aim: To perform a meta-analysis of studies comparing

twice daily, one-week triple therapy with a proton pump

inhibitor, clarithromycin (C) and amoxycillin (A) (PCA)

vs. those using proton pump inhibitor, clarithromycin

and a nitroimidazole (N) (PCN) for H. pylori eradication.

Review methods: Selection criteria: Comparative ran-

domized trials of PCA vs. PCN were included. Data

sources: PubMed database and abstracts from congresses

until September 1999. Statistics: Meta-analysis was

performed combining the Odds Ratios (OR) of the

individual studies in a global OR (Peto method) both

on an intention-to-treat (ITT) and on a per protocol (PP)

basis.

Results: Twenty-two studies ful®lled the inclusion

criteria. Eighteen studies reported ITT and 20 PP

analysis. Mean H. pylori eradication rates were 81%

(95% CI: 79±83%) ITT, and 84% (82±86%) PP with

PCA, and 81% (78±83%) ITT and 84% (82±86%) PP

with PCN; the odds ratio for the effect of PCA vs. PCN

was 1 (0.83±1.22) on an ITT, and 0.98 (0.8±1.2) on a

PP basis. Subanalysis showed that mean H. pylori

eradication ef®cacy with PC(250 b.d.)A was 81% (78±

85%) ITT, vs. 86% (83±89%) with PC(250 b.d.)N. The

odds ratio for this comparison was 0.68 (0.48±0.98).

Finally, when comparing PC(500 b.d.)A against

PC(250 b.d.)N ITT cure rates were 77% (74±80%), and

75% (72±78%) with an odds ratio of 1.18 (0.93±1.5).

Conclusion: Overall, one-week combination regimens of

PCA and PCN present similar H. pylori eradication

ef®cacy. Nevertheless, the PCN regimen obtains signi®-

cantly better results when using low doses of C (250 mg

b.d.).

Correspondence to: Dr J. P. Gisbert, Playa de MojaÂcar 29, Urb. Bonanza,

28669 Boadilla del Monte, Madrid, Spain.E-mail: gisbert@meditex.es

Aliment Pharmacol Ther 2000; 14: 1319±1328.

Ó 2000 Blackwell Science Ltd 1319

two 1-week proton pump inhibitor-based triple thera-

pies for H. pylori infection.

PATIENTS AND METHODS

Search strategy

Bibliographical searches were performed in the PubMed

(Internet) database, including studies available until

September 1999, looking for the following words:

Helicobacter or pylori (all ®elds) and each of the

following terms: clarithromycin, amoxycillin, amoxy-

cillin, metronidazole, tinidazole, imidazole, nitroimida-

zole, omeprazole, lansoprazole, pantoprazole, proton

pump inhibitor, `proton pump', 7, seven, triple, week,

weeks (titles). We also conducted a manual search of

abstracts from 1995 to 1999 from the International

Workshop on Gastroduodenal Pathology and Helico-

bacter pylori, and American Digestive Disease Week.

We included abstracts from congresses on the grounds

that many negative or redundant studies are never

published as a full paper, and the inclusion of abstracts

thus prevents, or at least reduces, publication bias.

Abstracts of the articles selected in each of these

multiple searches were reviewed and those meeting the

inclusion criteria were recorded. References of reviews

on H. pylori treatment with proton pump inhibitor plus

two antibiotics, and from the articles selected for the

study, were also examined in searches of articles

meeting the inclusion criteria. Articles published in

any language were included. The bibliographic

searches were performed independently by two

different reviewers.

Selection criteria

The selection criteria were as follows: (i) Articles had to

report comparative randomized trials. (ii) They had to

include at least two branches of treatment consisting of

(a) a proton pump inhibitor (omeprazole, lansoprazole

or pantoprazole, which were pooled together in the

present meta-analysis), clarithromycin and amoxycillin,

and (b) a proton pump inhibitor, clarithromycin and

nitroimidazole (metronidazole or tinidazole, also pooled

together). (iii) All drugs were given twice a day and for a

period of 7 days. (iv) Only studies prescribing a twice a

day proton pump inhibitor standard dose (omeprazole

20 mg b.d., lansoprazole 30 mg b.d., or pantoprazole

40 mg b.d.) were included; the extended use of a proton

pump inhibitor was allowed for ulcer healing. (v)

Assessment of eradication had to be performed by at

least one reliable method (histology or 13C-urea breath

test) at least 4-weeks after therapy. (vi) Studies evalu-

ating these therapies as second-line treatment for

previous eradication failures were not included. (vii)

Only studies that had clearly stated information about

the number of treated patients in each therapeutic

group, drug dosage and schedule and H. pylori eradi-

cation rates were included. Publications identi®ed as

duplicates were excluded.

Subanalyses were planned to compare studies in

subgroups using different doses of clarithromycin (e.g.

250 mg b.d. or 500 mg b.d.), different doses of

nitroimidazole (e.g. 250 mg b.d. or 400±500 mg

b.i.d) or different nitroimidazoles (metronidazole or

tinidazole). A meta-analysis included proton pump

inhibitor plus clarithromycin at high doses (500 mg

b.d.) and amoxycillin vs. proton pump inhibitor plus

clarithromycin at low doses (250 mg b.d.) and

nitroimidazole.

Statistics

The main outcome considered was eradication of

H. pylori. Eradication was analysed both on an

`intention-to-treat' (ITT) and on a `per protocol' (PP)

basis. Articles that did not specify the type of analysis

were assumed to report per protocol data. Separate

comparisons depending on the type of antibiotics

prescribed (clarithromycin plus amoxycillin on the

one hand, and clarithromycin plus nitroimidazole on

the other) were performed. Before combining the size

effects of the individual studies, the homogeneity of

effects throughout studies was appraised using a

homogeneity test based on the v2 test. Due to the

low power of this test, a minimum cut-off P-value of

0.20 was established as a threshold for homogeneity:

lower values indicated heterogeneity and prevented us

from relying on the combination of the study results.

The meta-analysis was performed combining the Peto

Odds Ratios (OR) of the individual studies in a global

OR, under the assumption-free model (or ®xed effects

model). Signi®cance and 95% con®dence intervals

(95% CI) are provided for the combined OR. All

calculations were performed with the freeware pro-

gram REVIEW MANAGER 4.0. The statistical methods

and formulae are described in the Handbook of the

Cochrane Collaboration and the RevMan User Guide.7

1320 J. P. GISBERT et al.

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 1319±1328

RESULTS

Description of studies

Twenty-two studies ful®lled the inclusion criteria and

contained data for at least one of the planned compar-

isons. For the main comparison, 18 studies reported ITT

analysis and 20 PP analysis.8±29 Detailed characteristics

of the studies are shown in Table 1.

Ef®cacy on H. pylori eradication (overall results)

The main results of the meta-analysis comparing the

two regimens on an ITT basis are summarized in

Figure 1. Mean H. pylori eradication ef®cacy (pooled

data) with proton pump inhibitor, clarithromycin and

amoxycillin was 81% (95% CI: 79±83%) ITT, and 84%

(82±86%) PP (Table 1). H. pylori eradication rates

(pooled data) with proton pump inhibitor, clarithromy-

cin and nitroimidazole were 81% (78±83%) and 84%

(82±86%), respectively, by ITT and PP analysis

(Table 1). The OR for the effect of proton pump inhibitor,

clarithromycin and amoxycillin vs. nitroimidazole on

H. pylori eradication was 1 (95% CI: 0.83±1.22) for ITT,

and 0.98 (0.8±1.2) for PP. Chi-square homogeneity test

was 24 (P: 0.14) by ITT, and 39 (P: 0.01) by PP; the

P-value was lower than 0.2, indicating heterogeneity.

Subanalysis on H. pylori eradication

The initial intention was to perform separate compar-

isons for the two types of nitroimidazole used, metron-

idazole or tinidazole; however, almost all studies

prescribed metronidazole, and only two protocols (ITT)

used tinidazole, so we were unable to combine and

compare the study results. Again, when trying to

perform separate comparisons depending on the nitro-

imidazole dose, we found that almost all studies gave

400±500 mg b.d., and only three protocols (ITT)

prescribed 250 mg b.d., precluding an adequate com-

parison of the study results.

A range of comparisons of clarithromycin doses were

performed. Firstly, both regimens (with amoxycillin and

with nitroimidazole) using clarithromycin at low doses

(e.g. 250 mg b.d.) were compared. Results of the meta-

analysis based on this comparison on an ITT basis are

summarized in Figure 2. Mean H. pylori eradication

ef®cacy (pooled data) with proton pump inhibitor,

clarithromycin 250 mg b.d. and amoxycillin was 81%

(78±85%) ITT, while mean eradication rate with proton

pump inhibitor, clarithromycin 250 mg b.d. and nitro-

imidazole was 86% (83±89%). The OR for this compar-

ison was 0.68 (95% CI: 0.48±0.98).

Finally, proton pump inhibitor plus clarithromycin at

high doses (500 mg b.d.) and amoxycillin was com-

pared with proton pump inhibitor plus clarithromycin

at low doses (250 mg b.d.) and nitroimidazole. Meta-

analyses on an ITT basis are summarized in Figure 3.

Mean H. pylori eradication ef®cacy (pooled data) with

proton pump inhibitor, clarithromycin 500 mg b.d. and

amoxycillin was 77% (74±80%) ITT, and mean eradi-

cation rate with proton pump inhibitor, clarithromycin

250 mg b.d. and nitroimidazole was 75% (72±78%).

The OR for this comparison was 1.18 (0.93±1.5).

DISCUSSION

This meta-analysis studied 22 comparisons of H. pylori

eradication ef®cacy with 1-week combination regimens

of proton pump inhibitor plus clarithromycin and

amoxycillin vs. nitroimidazole (Table 1).8±29 The overall

results show that the effectiveness of the two therapies is

similar (Figure 1) with an OR for these two regimens of

1 (0.83±1.22) on an ITT basis, and 0.98 (0.8±1.2) on a

PP basis. Nevertheless, results were heterogeneous, thus

preventing us from relying on the combination of the

overall study results, and advising dividing the treat-

ments by subanalysis (e.g. depending on clarithromycin

doses). The ef®cacy of both regimens seemed to be

relatively low (at least, lower than that previously

reported in initial studies), with eradication rates of only

80±85%. These results coincide with previously pub-

lished systematic reviews. For example, Laheij et al.30

reported an ITT cure rate of 80% and 83%, respectively,

with proton pump inhibitor, clarithromycin and amoxy-

cillin or nitroimidazole; Pipkin et al.6 calculated a pooled

ITT eradication rate of 83% with omeprazole-clarithro-

mycin-amoxycillin, and 83% with omeprazole-clarithro-

mycin-metronidazole regimens. Huang & Hunt4 reported

slightly higher ITT rates, 85%, with the amoxycillin

regimen. Finally, Unge3 calculated a mean ef®cacy of

only 83% (ITT) with proton pump inhibitor plus amoxy-

cillin and a macrolide, while higher eradication rates,

90% (ITT), were obtained with nitroimidazole regimens.

Some consensus reports have advised against the use

of nitroimidazoles in ®rst line therapies,5 due to locally

high rates of resistances to this antibiotic.31 In dual

therapy and bismuth-based triple therapy, it has become

accepted that in vitro measurement of metronidazole

A META-ANALYSIS OF H. PYLORI ERADICATION THERAPY 1321

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 1319±1328

Table 1. Characteristics of studies comparing H. pylori eradication ef®cacy with one-week combination regimens of proton pump inhibitor plus clarithromycin and amoxycillin

vs. proton pump inhibitor plus clarithromycin and nitroimidazole

Authors (Ref.) Country

Type of

disease

PPI

(type and dose)

Dose of

clarithromycin

Dose of

amoxycillin

Dose of

nitroimidazole

(M or T)

% ITT (PCA)

(no. patients)

% PP (PCA)

(no. patients)

% ITT (PCN)

(no. patients)

% PP (PCN)

(no. patients)

Battaglia et al.8 Italy PUD Pantoprazole 40 mg b.d. 500 mg b.d. 1 g b.d. T 500 mg b.d. Ð 75.4% (77/102) Ð 87.2% (96/110)

Cammarota et al.9 Italy PUD + NUD Omeprazole 20 mg b.d. 500 mg b.d. 1 g b.d. T 500 mg b.d. Ð 83% (35/42) Ð 72% (47/65)

Franceschi et al.10 Italy PUD + NUD Lansoprazole 30 mg b.d. 250 mg b.d. 1 g b.d. M 250 mg b.d. 81.2% (26/32) 92.8% (26/28) 87.5% (35/40) 92.1% (35/38)

Frevel et al.11 Germany PUD Pantoprazole 40 mg b.d. 500 mg b.d. 1 g b.d. M 500 mg b.d. 93.1% (135/145) Ð 95.7% (132/138) Ð

Gisbert et al.12 Spain PUD Omeprazole 20 mg b.d. 500 mg b.d. 1 g b.d. M 500 mg b.d. 90.7% (49/54) 92.4% (49/53) 93% (25/27) 96.1% (25/26)

or Lansoprazole 30 b.d.

Harris et al.13 UK, Ireland PUD Lansoprazole 30 mg b.d. 250 mg b.d. 1 g b.d. M 400 mg b.d. 90% (54/60) 90% (53/59) 84% (46/55) 85% (44/52)

Houben et al.14 The Netherlands NUD Omeprazole 20 mg b.d. 500 mg b.d. 1 g b.d. 86.8% (53/61) 91.2% (52/57)

Omeprazole 20 mg b.d. 250 mg b.d. M 400 mg b.d. 81.9% (50/61) 83.6% (46/55)

Jonaitis et al.15 Lithuania PUD Omeprazole 20 mg b.d. 500 mg b.d. 1 g b.d. 71% (39/55) 74% (39/53)

Omeprazole 20 mg b.d. 250 mg b.d. M 400 mg b.d. 55% (18/33) 60% (18/30)

Laine et al.16 USA Healthy Omeprazole 20 mg b.d. 500 mg b.d. 1 g b.d. 82% (56/68) 85% (51/60)

Omeprazole 20 mg b.d. 250 mg b.d. M 500 mg b.d. 67% (41/61) 75% (40/53)

Lamouliatte et al.17 France PUD + NUD Lansoprazole 30 mg b.d. 250 mg b.d. 1 g b.d. T 500 mg b.d. 56.2% (18/32) 69.2% (18/26) 69.6% (23/33) 79.3% (23/29)

Laurent et al.18 France NUD Omeprazole 20 mg b.d. 500 mg b.d. 1 g b.d. M 500 mg b.d. 71.8% (58/95) 77.5% (68/80)

Omeprazole 20 mg b.d. 250 mg b.d. 61.4% (58/95) 62.9% (58/92)

Lee et al.19 China PUD Omeprazole 20 mg b.d. 250 mg b.d. 1 g b.d. M 500 mg b.d. 77% (4/31) 89% (24/27) 81% (30/37) 91% (30/33)

Lind et al.20 UK, Ireland, PUD Omeprazole 20 mg b.d. 500 mg b.d. 1 g b.d. 90.5% (106/117) 98% (100/102)

Canada,

Germany,

Omeprazole 20 mg b.d. 250 mg b.d. 1 g b.d. 79.4% (93/117) 85% (91/107)

Sweden Omeprazole 20 mg b.d. 500 mg b.d. M 400 mg b.d. 85.5% (106/124) 92.5% (98/106)

Omeprazole 20 mg b.d. 250 mg b.d. M 400 mg b.d. 89.7% (109/117) 94.3% (99/105)

Lind et al.21 UK, Ireland, PUD Omeprazole 20 mg b.d. 500 mg b.d. 1 g b.d. 94% (119/127) 95% (104/110)

Germay,

Sweden,

Omeprazole 20 mg b.d. 250 mg b.d. M 400 mg b.d. 87% (110/127) 91% (105/116)

Norway,

France

Malferteiner et al.22 Germany, PUD Omeprazole 20 mg b.d. 500 mg b.d. 1 g b.d. 79% (34/48) 83% (34/41) 93% (38/41)

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A META-ANALYSIS OF H. PYLORI ERADICATION THERAPY 1323

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 1319±1328

resistance accurately predicts eradication failure.32

However, the correlation between in vitro H. pylori

resistance to nitroimidazoles and the clinical repercus-

sion on proton pump inhibitor-based triple therapies is

not as clear, and several studies have demonstrated that

metronidazole resistance does not negatively in¯uence

treatment outcome when using proton pump inhibi-

tor, clarithromycin and nitroimidazole in combina-

tion,14, 33±41 although other studies have reached the

opposite conclusion.23, 42±49 However, the negative

effect of nitroimidazole resistance seems to be of limited

importance,32, 50 according to the MACH 2 multicentre

study: eradication rates in primary metronidazole-

susceptible and resistant strains were 95% and 76%,

respectively.21 In another multicentre study, Misiewicz

et al.23 showed that amoxycillin and metronidazole-

based regimens (both combined with proton pump

inhibitor and clarithromycin) were equally effective in

patients with pre-treatment nitroimidazole-resistant

organisms. Finally, in a randomized study, Houben

et al.14 eradicated the infection in 82% of the patients

despite the fact that the strains were metronidazole-

Study

PC250A

n/N

PC250N

n/N

Peto OR

(95%CI Fixed)

Weight

%

Peto OR

(95%CI Fixed)

Franceschi 1997 26 / 32 35 / 40 7.9 0.62[0.17,2.24]

Harris 1998 54 / 60 46 / 55 11.0 1.74[0.59,5.14]

Lamouliatte 1997 18 / 32 23 / 33 12.9 0.57[0.21,1.54]

Lee 1999 24 / 31 30 / 37 9.4 0.80[0.25,2.59]

Lind 1996 93 / 117 109 / 117 23.3 0.32[0.15,0.66]

Misiewicz 1997 104 / 121 103 / 118 23.4 0.89[0.42,1.87]

Susi 1998 41 / 50 42 / 50 12.0 0.87[0.31,2.45]

Total(95%CI) 360 / 443 388 / 450 100.0 0.68[0.48,0.98]

Chi-Square 7.95 (df=6) P: 0.34 Z=2.09 P: 0.04

.1 .2 1 5 10

Favours PC250N Favours PC250A

Study

PCA

n/N

PCN

n/N

Peto OR

(95% CI Fixed)

Weight

%

Peto OR

(95%CI Fixed)

Franceschi 1997 26 / 32 35 / 40 2.3 0.62[0.17,2.24]

Frevel 1997 135 / 145 132 / 138 3.7 0.62[0.23,1.70]

Gisbert 1999 49 / 54 25 / 27 1.4 0.79[0.15,4.06]

Harris 1998 54 / 60 46 / 55 3.2 1.74[0.59,5.14]

Houben 1999 53 / 61 50 / 61 3.9 1.45[0.55,3.84]

Jonaitis 1999 39 / 55 18 / 33 4.6 2.03[0.83,4.99]

Laine 1997 56 / 68 41 / 61 5.9 2.24[1.01,4.97]Lamouliatte 1997 18 / 32 23 / 33 3.7 0.57[0.21,1.54]

Laurent 1999 62 / 95 58 / 95 10.8 1.20[0.66,2.16]Lee 1999 24 / 31 30 / 37 2.7 0.80[0.25,2.59]Lind 1996 199 / 234 215 / 241 12.9 0.69[0.40,1.18]

Lind 1999 119 / 127 110 / 127 5.5 2.22[0.97,5.05]

Malfertheiner 1999 38 / 48 42 / 49 3.4 0.64[0.23,1.81]Misiewicz 1997 104 / 121 103 / 118 6.7 0.89[0.42,1.87]

Perri 1999 88 / 150 102 / 150 17.0 0.67[0.42,1.07]

Susi 1998 41 / 50 42 / 50 3.5 0.87[0.31,2.45]Tzathas 1998 30 / 43 21 / 43 5.1 2.36[1.00,5.54]

Veldhuyzen 1999 39 / 50 40 / 48 3.8 0.71[0.26,1.93]

Total (95% CI) 1174 / 1456 1133 / 1406 100.0 1.00[0.83,1.22]

Chi-square 24.48 (df=17) P: 0.14 Z=0.04 P: 1

.1 .2 1 5 10

Favours PCN Favours PCA

Figure 1. H. pylori eradication with proton pump inhibitor, clarithromycin and amoxycillin vs. proton pump inhibitor, clarithromycin

and nitromidazole by intention-to-treat analysis. PCA: proton pump inhibitor, clarithromycin and amoxycillin. PCN: proton pump

inhibitor, clarithromycin and nitroimidazole.

Figure 2. H. pylori eradication with proton pump inhibitor, clarithromycin 250 mg b.d. and amoxycillin vs. proton pump inhibitor,

clarithromycin 250 mg b.d. and nitroimidazole by intention-to-treat analysis. PC250A: proton pump inhibitor, clarithromycin 250 mg

b.d. and amoxycillin. PC250N: proton pump inhibitor, clarithromycin 250 mg b.d. and nitroimidazole.

1324 J. P. GISBERT et al.

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 1319±1328

resistant (while ef®cacy in patients with metronidazole-

susceptible strains was only slightly higher, at 86%).

Consequently, the clinical value of measuring metron-

idazole resistance in vitro when a proton pump

inhibitor-clarithromycin-nitroimidazole regimen is pre-

scribed is still unclear.

Some authors have recommended a proton pump

inhibitor-clarithromycin-amoxycillin regimen to eradi-

cate H. pylori in geographical regions with high

metronidazole resistance.5, 42 As reviewed, previous

reports have suggested that H. pylori eradication with

proton pump inhibitor-clarithromycin-nitroimidazole in

metronidazole-resistant strains is still relatively high.

Bazzoli et al. calculated eradication rates to be about

75% in resistant strains. Those authors described a

model which allowed an estimation of the cure rates

according to the different prevalences of metronidazole

resistance and the mean eradication rates in a given

geographical area with a known frequency of metro-

nidazole resistance.50 Thus, the expected eradication

rate would still be greater than 85% in regions with a

metronidazole resistance of up to 50%.50 Therefore, the

recommendation that the proton pump inhibitor-clari-

thromycin-nitroimidazole regimen should not be pre-

scribed in areas with high metronidazole resistance only

seems to be valid for those rare geographical regions

with very high resistance rates (for example > 50%).

Regardless of the in¯uence of primary nitroimidazole

resistance, one argument against the use of nitroimidaz-

ole-based regimens as ®rst-line therapy is that, in cases of

eradication failure, secondary (acquired) H. pylori resist-

ance may appear. This would limit the usefulness of the

widely used quadruple `rescue' therapy, which includes

metronidazole among its components.

It remains to be seen whether a low dose of clarithro-

mycin (250 mg b.d.) is suf®cient for H. pylori eradica-

tion when 1-week proton pump inhibitor-based triple

therapies are used. The initial 1994 study by Bazzoli

suggested that this low dose of clarithromycin was

suf®cient when the proton pump inhibitor-clarithromy-

cin-nitroimidazole regimen was prescribed: an eradica-

tion rate of 95% was achieved.51 Furthermore, several

other studies have con®rmed favourable results using

low doses of clarithromycin when prescribing this

regimen, with eradication rates ranging from 86% to

95%.34, 52±56 The present study evaluates both regimens

(proton pump inhibitor-clarithromycin-amoxycillin and

proton pump inhibitor-clarithromycin-nitroimidazole)

using clarithromycin at low doses (250 mg b.d.;

Figure 2), and the results of our meta-analysis indicate

better results with the nitroimidazole regimen (86%)

than with the amoxycillin regimen (81%). Nevertheless,

although the differences were statistically signi®cant,

the upper 95% con®dence interval limit of the OR was

0.98, very close to 1. Finally, a proton pump inhibitor

plus clarithromycin at high doses (500 mg b.d.) and

amoxycillin were compared with a proton pump

inhibitor plus clarithromycin at low doses (250 mg

b.d.) and nitroimidazole (Figure 3), and eradication

rates of 77% and 75% were obtained (OR 1.18; 0.93±

1.5), indicating that the effectiveness of the therapies

hardly differed.

Study

PC500A

n/N

PC25ON

n/N

Peto OR

(95%CI Fixed)

Weight

%

Peto OR

(95%CI Fixed)

Houben 1999 53 / 61 50 / 61 6.1 1.45[0.55,3.84]

Jonaitis 1999 39 / 55 18 / 33 7.2 2.03[0.83,4.99]

Laine 1997 56 / 68 41 / 61 9.1 2.24[1.01,4.97]

Laurent 1999 62 / 95 58 / 95 16.8 1.20[0.66,2.16]Lind 1996 106 / 117 109 / 117 6.6 0.71[0.28,1.81]

Lind 1999 119 / 127 110 / 127 8.5 2.22[0.97,5.05]Malfertheiner 1999 38 / 48 42 / 49 5.3 0.64[0.23,1.81]

Perri 1999 88 / 150 99 / 150 26.6 0.73[0.46,1.17]

Tzathas 1998 30 / 43 21 / 43 7.9 2.36[1.00,5.54]Veldhuyzen 1999 39 / 50 40 / 48 5.8 0.71[0.26,1.93]

Total(95%CI) 630 / 814 588 / 784 100.0 1.18[0.93,1.50]

Chi-square 16.27 (df=9) P: 0.09 Z=1.33 P: 0.18

.1 .2 1 5 10

Favours PC250N Favours PC500A

Figure 3. H. pylori eradication with proton pump inhibitor, clarithromycin 500 mg b.d. and amoxycillin vs. proton pump inhibitor,

clarithromycin 250 mg b.d. and nitroimidazole by intention-to-treat analysis. PC500A: proton pump inhibitor, clarithromycin 500 mg

b.d. and amoxycillin. PC250N: proton pump inhibitor, clarithromycin 250 mg b.d. and nitroimidazole.

A META-ANALYSIS OF H. PYLORI ERADICATION THERAPY 1325

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 1319±1328

Large multi-centre, international, randomized, double-

blind trials seem to support these ®ndings. The MACH I

study,20 for example, concluded that the two most

effective therapies were those combining omeprazole

with either amoxycillin plus clarithromycin (at high

doses, 500 mg b.d.), or metronidazole plus clarithro-

mycin (at low doses, 250 mg b.d.). With this last

regimen, the results were even better than with higher

doses of clarithromycin (90% vs. 85%). In contrast, the

results of omeprazole-clarithromycin-amoxycillin with

low doses of clarithromycin (250 mg b.d.) were disap-

pointing, with an eradication rate of only 79%. In the

MACH 2 study21 the eradication rate with omeprazole

and clarithromycin at low doses, and metronidazole,

was as high as 87%. In another multicentre compar-

ative study, Misiewicz et al.23 achieved H. pylori eradi-

cation in up to 87% of the patients with lansoprazole,

clarithromycin 250 mg b.d. and metronidazole.

Furthermore, a recent meta-analysis of H. pylori

eradication regimens concluded that the optimal dose

of clarithromycin is uncertain when combined with

proton pump inhibitor plus nitroimidazole, although

data from Europe suggest that a low dose of 250 mg

twice daily is suf®cient.3 In a recent meta-analysis which

evaluated the importance of clarithromycin dose in the

management of H. pylori infection, Huang & Hunt4

showed that, when using the proton pump inhibitor-

clarithromycin-amoxycillin regimen, signi®cantly better

results were obtained with high doses (500 mg b.d.) of

clarithromycin (87%) than with low doses (78% with

250 mg b.d.). In contrast, these authors found similar

results with high and low doses of clarithromycin when

proton pump inhibitor-clarithromycin-nitroimidazole

regimens were used (88% and 87%, respectively).

Finally, Pipkin et al.6 showed that doubling the dose of

clarithromycin from 250 mg b.d. to 500 mg b.d. in

metronidazole-based regimens only marginally

increased the eradication rate, from 83% to 87%.

One reason for the use of high-dose clarithromycin is

to avoid the possibility of primary clarithromycin

resistance in H. pylori.57 However, Cayla et al.58 have

shown that, irrespective of the dose of clarithromycin

used, the H. pylori cure rate is dependent on the pre-

treatment strain sensitivity to this antibiotic. These data

suggest that primary clarithromycin resistance is dif®-

cult to overcome, and a poor H. pylori cure rate of

proton pump inhibitor-clarithromycin-nitroimidazole

can be expected in patients carrying resistant strains,

despite the higher doses of clarithromycin.57

If low doses of clarithromycin are suf®cient when using

a proton pump inhibitor-clarithromycin-nitroimidazole

regimen, economic bene®ts could be inferred. A detailed

review of the different H. pylori eradication regimens

available at the present time concluded that the

inclusion of a proton pump inhibitor, clarithromycin

(250 mg b.d.) and nitroimidazole for 1 week was

associated with the best cost±bene®t ratio results.59

Duggan et al.60 used a decision analysis to examine the

cost effectiveness of several eradication strategies and

concluded that omeprazole, clarithromycin and

metronidazole therapy was the most cost effective.

In addition, if low doses of clarithromycin are suf®cient

when using proton pump inhibitor-clarithromycin-

nitroimidazole regimens, bene®ts in compliance and

tolerance could also be inferred. A recent systematic

review showed that signi®cantly more patients on a

proton pump inhibitor-clarithromycin-nitroimidazole

regimen experienced adverse events in the sub-group

taking clarithromycin 500 mg b.d. than in the clari-

thromycin 250 mg b.d. group.4

In summary, the results of the present meta-analysis

indicate that, overall, 1-week combination regimens of

proton pump inhibitor plus clarithromycin and amoxy-

cillin present roughly the same ef®cacy for H. pylori

eradication as proton pump inhibitor plus clarithromycin

and nitroimidazole. Nevertheless, when using low doses

of clarithromycin (250 mg b.d.), the nitroimidazole

regimens seem to obtain better results.

ACKNOWLEDGEMENTS

We are indebted to Brenda Ashley and Michael

Maudsley for assistance with the English.

This study was not funded by any pharmaceutical

company.

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