One-week clarithromycin triple therapy regimens for eradication of Helicobacter pylori

Authors


J. R. Wood, Department of Gastroenterology, Glaxo Wellcome Research and Development, Stockley Park West, Uxbridge UB11 1BU, UK.

Abstract

Background:

One-week triple therapies have been endorsed as the treatment regimens of choice for eradication of Helicobacter pylori infection. Those that include clarithromycin appear to be the most effective.

Aim:

To review reports of triple therapies that include clarithromycin.

Methods:

Reports were identified from the literature to May 1998. The variation between study designs prevents a formal meta-analysis. A measure of the relative efficacies of regimens has, however, been gained by comparison and by pooling of intention-to-treat eradication rates.

Results:

One hundred and ninety-two studies were identified which included 264 treatment arms of a 1-week triple therapy composed of clarithromycin with amoxycillin or a nitroimidazole (metronidazole or tinidazole), and either ranitidine bismuth citrate or a proton pump inhibitor (omeprazole, lansoprazole or pantoprazole). From reports of these studies, an intention-to-treat H. pylori eradication rate could be determined from 210 treatment arms of 151 studies.

Conclusions:

There is little to choose between the efficacies of 1-week clarithromycin-based triple therapy eradication regimens. However, those comprising clarithromycin, a nitroimidazole and either ranitidine bismuth citrate or a high dose of omeprazole are, in general, the most effective. Against antibiotic-resistant strains of H. pylori, regimens including ranitidine bismuth citrate may be more effective than those including a proton pump inhibitor.

INTRODUCTION

There has been uniform agreement from consensus conferences world-wide that all peptic ulcer patients who are infected by H. pylori should be given treatment to eradicate the organism.1[2][3]–4 The marked reduction in ulcer recurrence following eradication of H. pylori has been firmly established.5[6]–7

Numerous different drug regimens have been evaluated, but none eradicates H. pylori in 100% of patients. It has been recommended that treatment should achieve an eradication rate of greater than 80% on a rigorous intention-to-treat analysis, albeit that inclusion criteria may differ significantly.1, 4 Treatment regimens should be simple, well tolerated, easy to comply with and be cost-effective.

Bazzoli et al.8 first described the use of a 7-day regimen consisting of clarithromycin, tinidazole and omeprazole. Many studies with 1-week triple regimens of clarithromycin, a nitroimidazole or amoxycillin, and a proton pump inhibitor have subsequently been carried out.

In September 1996, the European Helicobacter Pylori Study Group (EHPSG) recommended such a regimen for eradication of H. pylori.1 The group deferred judgement on the use of ranitidine bismuth citrate in place of a proton pump inhibitor on the grounds that more data were required.

The following year, at a meeting to update statements from the Consensus Development Conference Panel convened by the United States National Institutes of Health,9 it was concluded from a review of the literature (to 1996) that proton pump inhibitor triple therapies including clarithromycin seemed to have the highest efficacy.10 There were still only limited published data on clarithromycin triple therapies including ranitidine bismuth citrate, although it was recognized that such a regimen may be equally efficacious.11

The Asia-Pacific Consensus Conference advocated 1-week regimens including clarithromycin and amoxycillin or metronidazole, plus a proton pump inhibitor or ranitidine bismuth citrate.4 It was, however, noted that there were more published data supporting a combination with a proton pump inhibitor than with ranitidine bismuth citrate. Subsequently, new data have been accumulating. Recognizing this, Malfertheiner et al.,12 on behalf of the EHPSG, have noted that ranitidine bismuth citrate-based treatments now meet the criteria agreed by the EHPSG. In this review, H. pylori eradication rates from reports of studies with clarithromycin 1-week triple therapies with ranitidine bismuth citrate or a proton pump inhibitor are examined.

METHODS

Reports of clinical studies were identified from the medical literature available to May 1998. On-line commercial biomedical databases (Medline, Embase, Derwent Drug Files, Current Contents) were searched thoroughly for full manuscripts and conference abstracts. The following were also manually reviewed for any additional data: (i) abstracts submitted to meetings of the American Gastroenterological Association at Digestive Diseases Week to May 1998; (ii) abstracts submitted to American College of Gastroenterology meetings to 1997; (iii) abstracts in proceedings of the EHPSG at the International Workshops on Gastroduodenal Pathology and Helicobacter pylori to 1997; (iv) abstracts presented to the British Society of Gastroenterology to March 1998; and (v) abstracts accepted for United European Gastroenterology Week to 1997. In addition, reports were identified from routine review of medical journals. All papers and reviews were evaluated to identify citations to other studies. Duplicate reports of studies were eliminated and only the most recent abstract or full paper reviewed. All of the studies that we were able to identify are included in this review.

To pool data and to allow comparison between regimens, eradication rates were recorded from an intention-to-treat (ITT) analysis. This was defined as the number of H. pylori-negative patients at least 4 weeks after treatment divided by the number of H. pylori-positive patients allocated to a particular drug regimen who took at least one dose of medication. This is at variance with some reported ITT results reported because such analyses do differ.

RESULTS

A total of 192 studies were identified, which included 264 treatments with 1-week triple therapy regimens of clarithromycin (C) with amoxycillin (A) or a nitroimidazole (metronidazole (M) or tinidazole (T)) and either ranitidine bismuth citrate (R) or a proton pump inhibitor (omeprazole (O), lansoprazole (L) or pantoprazole (P)). Of these, patient numbers and ITT eradication rates could be determined from 151 studies with 210 treatment arms.

Clarithromycin plus amoxycillin

Ranitidine bismuth citrate.

Reports of 10 studies with ranitidine bismuth citrate, clarithromycin and amoxycillin (RCA) were found.13–22 ITT eradication rates were available from all but one,22 giving a pooled rate of 82.0% (n = 427/521); range 39–94%.1920 Treatment regimens were R 400 mg b.d. with C 500 mg b.d.14–21 or 250 mg t.d.s.13 and A 1 g b.d. The pooled eradication rate with C 500 mg b.d. was 81.5% (n =  396/486) compared with 88.6% (n = 31/35) with C 250 mg t.d.s.

Double-blind, randomized studies were reported by Hetzel et al.16 and by Wetterhus et al.21 Both included patients with non-ulcer dyspepsia, with or without a history of duodenal ulcer. ITT eradication rates were 82.7% (n = 91/110) and 86.0% (n = 98/114), respectively.

Omeprazole.

Forty-seven studies of 1-week triple therapy with omeprazole, clarithromycin and amoxycillin (OCA) were identified, from which the ITT eradication rate could be determined.14, 17, 19, 20, 23[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64]–65 It was unavailable from another 19 studies.66[67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83]–84

From 51 treatments of OCA, the pooled ITT eradication rate was 82.7% (n = 2886/3489); range 50–98%.40, 55, 60 The most frequently studied regimen was O 20 mg b.d. + C 500 mg b.d. + A 1 g b.d.14, 19, 20, 25, 26, 28, 29, 34, 35, 38, 41, 42, 44[45][46][47][48][49]–50, 52, 56, 57, 59, 62, 64 giving a pooled eradication rate of 82.3% (n = 1439/1749); range 61–95%.19, 29 Studies have been carried out with the same doses of O + A with C 250 mg b.d.24, 30[31]–32, 43, 48, 53, 58, 65 Pooling these data gave a rate of 80.2% (n = 497/620); range 60–88%.24, 43 Other doses of C that have been used include 250 mg t.d.s.,61 500 mg t.d.s.,27 600 mg t.d.s.,54 400 mg b.d.37, 60 and 800 mg b.d.60 In the latter study,60 the regimen including C 800 mg b.d. resulted in an eradication rate of 98.0% (n = 100/102).

In the majority of studies A 1 g b.d. was used. Other doses include 400 mg b.d.,37, 60 500 mg b.d.,36 750 mg b.d.39 and 1.5 g t.d.s.54

Twice daily O 20 mg has been studied most frequently14, 19, 20, 24[25][26][27][28][29][30][31]–32, 34, 35, 37[38]–39, 41[42][43][44][45][46][47][48][49]–50, 52, 53, 56[57][58][59][60][61]–62, 64, 65 with a pooled eradication rate of 82.3% (n = 2364/2871). In two studies,33, 55 O 40 mg b.d. was used with C 500 mg b.d. + A 1 g b.d. giving eradication rates of 88.9% (n = 80/90) and 98.5% (n = 64/65), respectively.

Five double-blind studies have been reported in patients with duodenal48, 49, 59, 64 or gastric ulcer disease50 given O 20 mg b.d. + C 500 mg b.d. + A 1 g b.d. The pooled ITT rate in duodenal ulcer (active or in remission) was 81.2% (n = 385/474). Lind et al.48 included a comparator arm of the lower dose of C 250 mg b.d.; the eradication rate was 79.5% (n = 93/117). In gastric ulcer, Malfertheiner et al.50 reported eradication of H. pylori in 79.2% (n = 38/48) of patients.

Lansoprazole.

The pooled eradication rate from 23 treatments with lansoprazole, clarithromycin and amoxycillin (LCA)23, 31, 40, 51, 62, 85[86][87][88][89][90][91][92][93][94][95][96][97][98][99]–100 was 76.8% (n = 975/1270). Rates ranged from 24%40 to 92%.100 Five additional reports were identified—four from which ITT rates could not be determined101[102][103]–104 and one of H. pylori eradication in routine clinical practice as opposed to a controlled clinical study.105

Clarithromycin 250 mg b.d. has been most often studied with A 1 g b.d. and L 30 mg o.d. 31, 40, 86, 87, 93 or 30 mg b.d.31, 88, 94[95][96]–97 The pooled eradication rate from these studies was 73.1% (n = 459/628); range 24–88%.40, 96 A higher pooled rate was obtained from studies with L 30 mg b.d. (80.4% (n = 299/372)) compared with L 30 mg o.d. (62.5% (n = 160/256)).

In five studies, C 500 mg b.d. was given with A 1 g b.d. and either L 30 mg o.d.87 or L 30 mg b.d.62, 85, 98, 99 with a pooled rate of 77.2% (n = 277/359). The lowest rate was 72.0% (n = 134/186) reported by Spinzi et al.62 and the highest by Sierra et al.100 with H. pylori eradicated from 92.5% (n = 49/53) of patients given L 30 mg b.d. + C 500 mg t.d.s. + A 1 g b.d.

There has been only one report of a double-blind study from which an ITT eradication rate can be determined. Lamouliatte et al.93 used a low dose regimen of L 30 mg b.d. + C 250 mg b.d. + A 1 g b.d. which resulted in an eradication rate of only 46.2% (n = 24/52).

Pantoprazole.

Fourteen studies have been reported with pantoprazole, clarithromycin and amoxycillin (PCA)106[107][108][109][110][111][112][113][114][115][116][117][118]–119 with an ITT eradication rate available from nine. The pooled eradication rate from 11 treatments was 76.7% (n = 541/705); range 48–92%.109, 113

A regimen of P 40 mg b.d. + C 500 mg b.d. + A 1 g b.d. was reported in four studies108, 110[111]–112 with a pooled eradication rate of 83.6% (n = 296/354). Lamouliatte et al.,111 in a comparative study, found only a 56.3% (n = 54/96) eradication rate with P 40 mg o.d. Three times daily doses of C 250 mg107, 109, 113 or 500 mg106, 114 have been given with P 40 mg b.d. + A ≥ 2 g/day, resulting in eradication rates of 69.9% (n = 93/133) and 80.3% (n = 98/122).

Clarithromycin plus metronidazole

Ranitidine bismuth citrate.

Pooling data from nine studies with 10 treatment arms of R 400 mg b.d. + C + M16, 21, 120[121][122][123][124][125]–126 gave an ITT eradication rate of 88.7% (n = 702/791); range 82–98%.120, 123 Little difference was found between C 500 mg b.d.120[121][122]–123, 126 and C 250 mg b.d.16, 21, 124, 125 with pooled eradication rates of 89.9% (n = 417/464) and 87.2% (n = 285/327), respectively. Similarly, regimens of M 500 mg b.d. (or 250 mg q.d.s.) 122[123][124][125]–126 or 400 mg b.d.16, 21, 120, 121 were equally effective with respective pooled rates of 88.2% (n = 300/340) and 89.1% (n = 402/451).

Four double-blind studies have been reported in patients with dyspepsia120 or with recent dyspeptic symptoms but without active ulcer.16, 21, 121 The resultant pooled eradication rate was 89.1% (n = 402/451).

Omeprazole.

Of 46 reported studies,35, 36, 38, 39, 44, 48[49]–50, 56, 64, 125, 127[128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149][150][151][152]–153 ITT rates could be determined from all but eight.69, 78, 154[155][156][157][158]–159 The pooled eradication rate was 83.0% (n = 2003/2414); range 45–100%136, 139 from 42 treatment arms.

The dose of C most frequently used was 250 mg b.d.36, 38, 44, 48[49]–50, 64, 125, 127[128][129][130][131]–132, 134, 135, 137[138][139]–140, 143, 144, 146, 148[149][150][151]–152 giving an average eradication rate of 82.9% (n = 1335/1622); range 45–97%.139, 143 Doubling the dose to C 500 mg b.d.35, 39, 48, 56, 132, 133, 142, 153 gave a marginally increased rate of 86.9% (n = 443/510); range 50–95%.39, 153

M 500 mg b.d.35, 44, 56, 125, 127, 128, 130[131][132]–133, 135, 139, 140, 147, 152, 153 and 400 mg b.d.36, 38, 39, 48[49]–50, 64, 129, 134, 137, 138, 142, 143, 146, 151 have been used in about equal numbers of studies. The higher dose was associated with a lower pooled rate of 75.3% (n = 566/752); range 45–91%130, 139 compared with 86.9% (n = 1061/1221); range 75–97%.129, 143 Studies have been reported with M 750 mg b.d.,150 250 mg t.d.s.,148 250 mg q.d.s.144, 149 and 250 mg b.d.125, 141 Eradication rates ranged from 80 to 86%.

Regimens with higher daily doses of omeprazole were associated with greater efficacy. O 40 mg/day (usually given as 20 mg b.d.)35, 38, 39, 44, 48[49]–50, 56, 64, 127, 128, 130[131][132][133][134][135][136]–137, 142[143][144][145][146]–147, 149[150]–151, 153 resulted in 85.0% (n = 1469/1729) eradication compared with 78.0% (n = 534/685) with O 20 mg/day.36, 125, 129, 131, 132, 138[139][140]–141, 144, 148, 152

ITT data were available from five48[49]–50, 64, 137 of six double-blind studies reported. Overall eradication rate was 86.6% (n = 454/524) with similar rates in patients with duodenal (86.9%)48, 49, 137 and gastric ulcer (85.6%).50, 64

Lansoprazole.

An ITT eradication rate could be determined from 15 reports,39, 85, 88, 97, 140, 160[161][162][163][164][165][166][167][168]–169 but was unobtainable from two.102, 104 Overall, the eradication rate was 86.7% (n = 801/924); range 68–100%.166, 168 The former was the smallest of the studies with only 13 patients.

C 250 mg b.d. was given in most studies39, 85, 88, 97, 140, 162[163]–164, 167 with a pooled eradication rate of 88.3% (n = 522/591). Only three studies used a higher dose of C 500 mg b.d. with rates of 67.8%,168 75.4%161 and 100%.166 Kihira et al.165 and Takimoto et al.169 used C 200 mg b.d., eradicating H. pylori from 90.9% (n = 140/154) of patients.

The most frequently studied dose of M was 400 mg b.d.,39, 97, 162[163]–164, 166, 167 overall eradication rate being 87.8% (n = 397/452); range 79–100%.162, 166 The pooled rate with M 500 mg b.d.85, 140, 161, 168, 169 was 83.6% (n = 234/280), range 68–95%.168, 169

Regimens including L 30 mg o.d.85, 162, 163, 165, 169 seem almost as effective as L 30 mg/day,39, 88, 97, 140, 161, 164, 166[167]–168 with pooled data of 88.2% (n = 285/323) and 85.8% (n = 473/551), respectively.

Pantoprazole.

Eleven studies have been reported. 77, 78, 89, 124[125][126][127]–128 The pooled ITT eradication rate from eight of these with 10 treatment arms106, 108, 127, 171[172][173]–174 was 83.5% (n = 673/806); range 63–100%.106, 127

Clarithromycin plus tinidazole

Ranitidine bismuth citrate.

Studies with R 400 mg b.d. and C 250 mg b.d.18, 178, 179 or C 250 mg t.d.s. 13 with T 500 mg b.d. have been reported. Respective eradication rates were 81.6% (n = 133/163) and 91.4% (n = 32/35). Overall, the pooled rate was 83.3% (n = 165/198).

Omeprazole.

Data pooled from 22 studies25, 63, 180[181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198]–199 with 27 treatment arms resulted in an eradication rate of 86.2% (n = 1289/1496); range 54–97%.193, 196 In four studies an ITT rate could not be determined154[155]–156, 200 and one report described a community study rather than a controlled clinical trial. 201

In all but one study,187 T 500 mg b.d. was used and in all but two reports,25, 187 C 250 mg b.d. was used. The pooled eradication rate was 86.2% (n = 1289/1496). Goddard et al.187 reported a single daily dosage regimen of O 20 mg + C 500 mg + T 500 mg, which resulted in an eradication rate of 73.3% (n = 22/30).

Regimens including a single daily dose of O 20 mg63, 180[181][182][183][184][185][186]–187, 190, 192, 198 gave a pooled eradication rate of 84.0% (n = 510/607), regimens using O 20 mg b.d.25, 188, 189, 191[192]–193, 195[196]–197, 199 the somewhat higher rate of 87.9% (n = 762/867).

Lansoprazole.

The pooled eradication rate from five studies40, 93, 94, 178, 202 with lansoprazole, clarithromycin and tinidazole (LCT) was 76.8% (n = 225/293). All five used C 250 mg b.d. + T 500 mg b.d. Two further reports were identified from which an ITT eradication rate could not be determined.105, 203

Pantoprazole.

Only one report was identified204 with P 40 mg/day + C 250 mg b.d. + T 500 mg b.d. giving an eradication rate of 85.7% (n = 48/56). The overall findings from this review are summarized in Table 1 and in Figures 1–33.

Table 1.  . Summary of data with 1-week clarithromycin triple therapy eradication regimens Thumbnail image of
Figure 3.

.  One-week triple therapy with ranitidine bismuth citrate or a proton pump inhibitor, clarithromycin and tinidazole. The size of each square is proportional to the number of patients allocated to that treatment regimen within a study. The horizontal bar indicates the pooled ITT eradication rate. C, clarithromycin; L, lansoprazole; O, omeprazole; P, pantoprazole; R, ranitidine bismuth citrate; T, tinidazole.

Comparative studies

While pooling data gives some idea of the relative efficacies of eradication regimens, the best indication is from comparative studies. Relatively few studies comparing different antisecretory drugs together with the same combination of clarithromycin plus a second antibiotic have been reported.

Comparative studies of proton pump inhibitors.

OCA and LCA have been compared in five studies.23, 31, 40, 51, 62 Various eradication regimens have been used: O 40 mg/day or L 60 mg/day + C 800 mg/day + A 2 g/day (ITT eradication rates; 91% vs. 85%);23 O 20 mg b.d., L 15 mg b.d. or L 30 mg b.d. + C 250 mg b.d. + A 1 g b.d. (85% vs. 71% vs. 82%);31 O 20 mg b.d. or L 30 mg b.d. + C 500 mg b.d. + A 1 g b.d. (62% vs. 72%).62 Miwa et al.51 compared three regimens of OCA, which eradicated H. pylori in 78–88% of subjects, with L 30 mg/day + C 400 mg b.d. + A 1.5 g/day which gave an eradication rate of 87%.

Comparing OCT, LCT, OCA and LCA, Jonas et al.40 found ITT eradication rates of 55%, 62%, 50% and 24%, respectively. It should be noted, however, that the regimens included the low doses of O 20 mg/day or L 30 mg/day + C 250 mg b.d. Regimens of O 20 mg b.d. + C 500 mg b.d. plus either M 400 mg b.d. or A 750 mg b.d. and L 30 mg b.d. + C 500 mg b.d. + M 400 mg b.d. were all equally effective, eradicating H. pylori from 95%, 93% and 96% of patients, respectively.39 Mullhaupt et al.140 reported eradication rates of 83% and 89% with O 20 mg b.d. or L 30 mg b.d. + C 250 mg b.d. + M 500 mg b.d. Finally, with either O or P 40 mg o.d. + C 250 mg b.d. + M 500 mg b.d., H. pylori was eradicated from 88% and 100% of patients.127

Comparative studies of proton pump inhibitors vs. ranitidine bismuth citrate.

Six studies have been reported. 14, 17, 19, 20, 125, 178 In four, R 400 mg b.d. + C 500 mg b.d. + A 1 g b.d. was compared with O 20 mg b.d.14, 19, 20 or O 40 mg/day17 plus the same doses of antibiotics. Respective H. pylori eradication rates were 76% vs. 77%,14 39% vs. 61%,19 94% vs. 88%20 and 88% vs. 88%.17 The low eradication rates from the preliminary report by Spinzi et al.19 with both regimens is the result of a large number of patients who declined follow-up examination. Similar findings have been previously reported by this group.62, 205

Savarino et al.125 compared R 400 mg b.d. + C 250 mg b.d. + M 500 mg b.d. with O 20 mg o.d. + C 250 mg b.d. + M 500 mg b.d. RCM was significantly more effective than OCM (< 0.003), with an ITT eradication rate of 87% compared with 52%. An interim analysis showed that 48% and 12% of H. pylori strains were resistant before treatment to metronidazole and to clarithromycin, respectively, suggesting that regimens with ranitidine bismuth citrate may be more effective than those with a proton pump inhibitor in areas with a high prevalence of H. pylori resistant to antibiotics.

Lastly, Spadaccini et al.178 treated patients with R 400 mg b.d. or L 30 mg b.d. + C 250 mg b.d. + T 500 mg b.d. Similar ITT eradication rates were found— 73% with RCT and 77% with LCT.

DISCUSSION

In this pooled analysis we have summarized the large body of disparate data on 1-week clarithromycin-based triple therapy regimens for eradication of H. pylori infection. It should be stressed that we have not carried out a formal meta-analysis which combines independent studies with a design sufficiently similar to enable statistical integration of results.206, 207

All studies that we were able to identify are accounted for in this review. Differences in patient populations and drug regimens, the limited information relating to study designs—due mainly to so many reports being in abstract form only—and the lack of clear reporting of data on all patients according to a true intention-to-treat basis, all conflict with the principles associated with meta-analysis.206[207]–208 This present paper should therefore be regarded as a systematic review of data. However, bearing in mind these limitations to enable an indication of relative efficacies, only intention-to-treat data based on all H. pylori-positive patients who received treatment have been included.

Overall, this review suggests that when available data are pooled, there is little to choose between 1-week clarithromycin-based triple therapy regimens. However, regimens which include clarithromycin, a nitroimidazole and either ranitidine bismuth citrate or a high dose of omeprazole are generally associated with higher eradication rates.

The observation from Savarino et al.,125 that a 1-week regimen including ranitidine bismuth citrate is effective against antibiotic-resistant strains of H. pylori is of interest. It is known that pre-treatment resistance to nitroimidazoles209 or to macrolides210, 211 is a significant factor in the failure of some eradication regimens. Indeed, in studies of 1 week of treatment with a proton pump inhibitor, clarithromycin and metronidazole, a reduction in eradication rates has been seen when pre-treatment isolates of H. pylori were resistant to metronidazole,97, 163, 212, 213 although conflicting data have been reported.191 Whereas others have also found that 1-week eradication regimens containing ranitidine bismuth citrate are effective against resistant strains,120, 126 this requires some confirmation.

In conclusion, 1-week triple therapy regimens consisting of clarithromycin, a nitroimidazole and either ranitidine bismuth citrate or a high dose of a proton pump inhibitor are likely to be the most effective choice for eradication of H. pylori infection. Regimens including ranitidine bismuth citrate may be more effective than those including a proton pump inhibitor against antibiotic-resistant strains of H. pylori.

Ancillary