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Antisecretory Drug 1 Drug 2 Duration No. of Cure rate Cure rate Cure rate (sensitive
Study drug (mg) (mg) (mg) (days) patients (ITT) (%) (PP) (%) strains) (%)
A, amoxicillin; C, clarithromycin; F, famotidine; ITT, intention-to-treat; M, metronidazole; N, nizatidine; PP, per protocol; R, ranitidine.
Table 2. Triple therapy comparing a histamine-2 receptor antagonist with a proton pump inhibitor
Antisecretory Drug 1 Drug 2 Duration No. of Cure rate Cure rate Cure rate (sensitive
Study drug (mg) (mg) (mg) (days) patients (ITT) (%) (PP) (%) 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. T 500 b.d. 22 81 (18/22)
(15 days) (10 days)
O 22 A 1000 b.d. T 500 b.d. 22 86 (19/22)
(15 days) (10 days)
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.
results of all studies that satisfied our criteria, we H. pylori eradication was achieved in 47 of 50 (94%)
decided a priori to examine the pooled results from: (i) (95% CI, 83–99%) patients in the nizatidine group
studies containing clarithromycin in both treatment compared with 44 of 51 (86%) (95% CI, 74–94%)
groups; (ii) studies containing no clarithromycin in patients in the lansoprazole group (P ¼ 0.33). The 95%
either treatment group; (iii) studies with a treatment CI for the difference in proportions overlapped zero
duration of 1 week; and (iv) studies with a treatment () 21% to + 5%).
duration of 2 weeks. One of the seven patients who failed treatment in the
A random (DerSimonian–Laird) model assumption lansoprazole group had negative histology at the initial
was used in the meta-analysis.35 Tests of homogeneity post-therapy evaluation, but H. pylori was detected at a
were performed for all studies, as well as for the 4-month follow-up visit. Although it is not known
subgroups defined above. The results of the meta- whether this finding represented re-infection or recru-
analysis were expressed as pooled odds ratios (ORs) for descence, the case was scored as a failure. Inclusion of
the eradication of H. pylori using H2-receptor antago- this case as a success would not change the outcome
nists compared with proton pump inhibitors, and their significantly.
accompanying 95% CIs. 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
RESULTS patient in the nizatidine group and one in the lanso-
prazole group. All ulcers were healed in 42 (84%)
Randomized controlled study
patients in the nizatidine group compared with 49
One hundred and one patients were randomized, (96%) in the lansoprazole group (P ¼ 0.09).
including 50 in the nizatidine group and 51 in the
lansoprazole group. The nizatidine group consisted of
Meta-analysis
45 men and five women between 24 and 80 years of
age (median, 52 years), and the lansoprazole group In the systematic review, we identified 11 studies
consisted of 36 men and 15 women between 22 and (including the present study) containing 12 relevant
76 years of age (median, 49 years). There were no comparisons that satisfied our criteria; these studies
differences in the demographic characteristics (Table 3). were included in a meta-analysis. All studies were
All patients had active H. pylori infection by histology randomized, controlled and with intention-to-treat
and had at least one ulcer in the stomach, duodenum or analyses. The number of patients included in each
both. All randomized patients completed the study and treatment arm ranged from 15 to 194, the duration of
there was a 100% follow-up. The combinations were therapy from 7 to 14 days and the H. pylori eradication
well tolerated and adherence was > 95%. rate from 75% to 94%. The overall eradication rate with
H2RA PPI OR OR
Study 95%CI Random) 95%CI Random)
29 12/15 13/15 0.62[0.09,4.34]
25 31/37 23/26 0.67[0.15,2.98]
28 18/22 19/22 0.71[0.14,3.63]
26 137/178 169/194 0.49[0.29,0.85]
27 48/60 50/60 0.80[0.32,2.02]
this study 47/50 44/51 2.49[0.61,10.25]
16 44/48 40/43 0.82[0.17,3.91]
23 51/80 46/80 1.30[0.69,2.45]
Figure 1. A Peto graph showing the indi- 22 47/60 44/60 1.31[0.57,3.04]
24 34/ 40 36/ 40 0.63[0.16,2.43]
vidual study’s odds ratios (ORs) and the 25 43/50 46/50 0.53[0.15,1.95]
23 60/80 62/80 0.87[0.42,1.81]
pooled OR for all studies comparing suc-
cessful Helicobacter pylori eradication Total(95%CI) 572/720 592/721 0.83[0.63,1.09]
Test for heterogeneity chi-square=9.68 df=11 P =0.56
between combinations that contained
histamine-2 receptor antagonist (H2RA) 0.1 0.2 1 5 10
vs. proton pump inhibitor (PPI). Favours treatment Favours control
H2-receptor antagonist-containing combinations was rate was 306 of 392 (78%; 95% CI, 74–82%) in studies
549 of 701 (78%) patients, whereas that of proton with H2-receptor antagonist-containing combinations
pump inhibitor-containing combinations was 575 of vs. 336 of 397 (85%; 95% CI, 80.7–88%) in studies
714 (81%) patients. Only the results of intention-to- using proton pump inhibitors.
treat analyses were pooled. Where reported, the dropout
rates were low (< 11%); two studies were published in
DISCUSSION
abstract form only.29, 30
Tests of homogeneity were negative for all calculations The efficacy of both clarithromycin and amoxicillin as
(P > 0.05), indicating that there were no significant antimicrobials is enhanced by antisecretory drug ther-
differences in the results of the individual studies and apy. Proton pump inhibitors not only directly block the
thus that it was appropriate to pool the results. When proton pump on parietal cells in the stomach, but also
all 12 comparisons were combined in the random model have antibacterial activity against H. pylori both in vivo
(i.e. more conservative), the pooled OR for the eradica- and in vitro. In contrast, H2-receptor antagonists have
tion of H. pylori using H2-receptor antagonists compared no intrinsic antibacterial activity. This randomized
with proton pump inhibitors was 0.86 (95% CI, 0.66– study, as well as the meta-analysis, showed that H. pylori
1.12; P ¼ 0.3) (Figure 1). In other words, combinations eradication triple therapy using twice-daily amoxicillin
containing proton pump inhibitors were 14% more and clarithromycin was similarly effective independent
likely to cause H. pylori eradication than those contain- of whether the antisecretory agent was a proton pump
ing H2-receptor antagonists; this was not statistically inhibitor or an H2-receptor antagonist. This conclusion
significantly different. is consistent with the notion that the adjuvant effect
There were no significant differences in the rates of with antisecretory therapy is related more to the drugs’
H. pylori eradication between the combinations con- ability to suppress acid secretion than to its antibacterial
taining H2-receptor antagonists or proton pump inhib- activity.
itors when pooling the results of 1-week studies (seven Most studies of H. pylori eradication using triple
studies; pooled OR, 0.86; 95% CI, 0.64–1.17) and therapy have used proton pump inhibitors as the
2-week studies (three studies; pooled OR, 0.96; 95% CI, antisecretory component. Many of the large controlled
0.48–1.94). There was a non-significant trend favour- trials were performed to obtain approval for different
ing H2-receptor antagonists (69% vs. 79%; six studies; antimicrobial therapies for the treatment of H. pylori
OR, 1.14; 95% CI, 0.76–1.71; P ¼ 0.5) when clarithro- infection, and were sponsored by pharmaceutical com-
mycin-containing regimens were compared. Conversely, panies manufacturing proton pump inhibitors. Thus,
the pooled OR from studies not using clarithromycin in the majority of studies of amoxicillin and clarithromycin
either treatment group revealed a small but significant or metronidazole and clarithromycin have used a pro-
benefit in H. pylori eradication favouring proton pump ton pump inhibitor. One rationale for this choice was
inhibitor-containing regimens (six studies; OR, 0.64; that proton pump inhibitor antisecretory therapy had
95% CI, 0.45–0.92; P ¼ 0.02). The overall eradication been shown to be superior to H2-receptor antagonists in
ulcer healing, pH control and the rapidity of pain relief. In conclusion, 1 week of treatment with either an
All of these benefits were likely to be present when H2-receptor antagonist or a proton pump inhibitor,
proton pump inhibitors were used as part of the therapy together with amoxicillin and clarithromycin, was
of H. pylori infection in patients with peptic ulcer similarly effective in the eradication of H. pylori and in
disease. the healing of peptic ulcers. As the outcomes of
Most of the studies in which a proton pump inhibitor and H2-receptor antagonist and proton pump inhibitor triple
H2-receptor antagonist have been compared have shown therapy are similar, and both are well tolerated by
no significant difference in the eradication of H. pylori. patients, one might use cost to choose between them.
High eradication rates have been reported with both Generally, H2-receptor antagonists cost less than proton
antisecretory agents. Given the lack of statistically pump inhibitors, which favours their use, especially in
significant heterogeneity between the results of the developing countries.
studies examined, pooling the results in a meta-analytical
approach was appropriate. The results of the meta-
ACKNOWLEDGEMENTS
analysis confirm the lack of significant differences in the
rate of H. pylori eradication between studies with This work was supported in part by the Office of
proton pump inhibitors or H2-receptor antagonists. These Research and Development Medical Research Service
results are consistent with those of a previous analysis Department of Veterans Affairs and by Public Health
that examined fewer studies.36 However, when the Service grant DK56338 which funds the Texas Gulf
results of studies that contained or did not contain Coast Digestive Diseases Center. Dr El-Serag is the
clarithromycin were pooled, there was a slight, but recipient of a Veterans Affairs Health Services Research
significant, advantage of proton pump inhibitor-contain- and Development (HSR&D) Research Development
ing combinations in non-clarithromycin-containing reg- Award (RCD 00-013-2).
imens. The reason for this difference is unclear and
deserves further study. One possibility is related to the fact
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