Triple vs. quadruple therapy for treating ... - Wiley Online Library

Aliment Pharmacol Ther 2003; 17: 1137–1143.

doi: 10.1046/j.0269-2813.2003.01566.x

Triple vs. quadruple therapy for treating Helicobacter pylori infection: a meta-analysis E. GENE´ *, X. CALV ET , R. AZAGR Aà & J. P. GISBER T§ *Servei de Medicina and Unitat de Malalties Digestives, Hospital de Sabadell, Institut Universitari Parc Taulı´, Barcelona, Spain; àCAP Badıá del Valle´s, Barcelona, Spain; §Servicio de Aparato Digestivo, Hospital de la Princesa, Madrid, Spain Accepted for publication 9 March 2003

SUMMARY

Background: Triple therapy (proton pump inhibitor, clarithromycin and amoxicillin or an imidazole) is the first-line treatment for Helicobacter pylori infection. However, the effectiveness of triple therapy is decreasing due to the increase in antibiotic resistance. Quadruple therapy (proton pump inhibitor, tetracycline, metronidazole and a bismuth salt) is a very effective regimen even in areas of high prevalence of antibiotic resistance, and may be an alternative first-line treatment. Aim: To compare triple vs. quadruple therapy for the first-line treatment of H. pylori infection. Methods: An extensive literature search was performed to identify randomized trials comparing triple vs.

INTRODUCTION

Since Warren and Marshall first described the infectious aetiology of peptic ulcer disease in 1984,1, 2 a great deal of evidence has accumulated to suggest that Helicobacter pylori eradication therapy cures peptic ulcer disease.3–7 First-line H. pylori therapy should ideally be short, easy to administer, well tolerated and relatively cheap.8 However, over and above these considerations, the prime objective of any treatment is to eradicate the infection in the maximum number of patients.9 Correspondence to: Dr X. Calvet, Unitat de Malalties Digestives, Hospital de Sabadell, Institut Universitari Parc Taulı´ (UAB), Parc Taulı´, s/n 08208 Sabadell, Barcelona, Spain. E-mail: [email protected] Ó 2003 Blackwell Publishing Ltd

quadruple therapy. Selected trials were included in a meta-analysis using Review Manager 4.1. Results: Four studies met the inclusion criteria. Eradication rates with quadruple therapy were slightly higher in both the intention-to-treat (81% vs. 78%; odds ratio, 0.83; 95% confidence interval, 0.61–1.14) and per protocol (88% vs. 85%; odds ratio, 0.81; 95% confidence interval, 0.55–1.20) analysis, although the differences were not statistically significant. Nor were there significant differences in compliance or adverse effects between the therapies. Conclusion: Triple and quadruple therapies seem to be roughly equivalent in terms of effectiveness, compliance and side-effects profile when administered as first-line treatment for H. pylori infection.

Guidelines for treating H. pylori infection have changed progressively since 1984.10–14 Monotherapies and dual therapies consisting of a proton pump inhibitor and one antibiotic have generally produced disappointing results.15, 16 Most current consensus reports recommend triple therapy combining a proton pump inhibitor with two antibiotics, normally clarithromycin plus amoxicillin or an imidazole. The recommended length of treatment ranges from 7 days in Europe10 to 14 days in the USA.17 One of the first effective treatments for H. pylori infection was ‘classical triple therapy’, comprising a bismuth salt, tetracycline and metronidazole. This treatment achieved eradication rates of between 80% and 90%. However, it was reported to have severe adverse effects18 and poor compliance because of the 1137

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complex dosage.4, 19 Quadruple therapy (‘classical triple therapy’ plus a proton pump inhibitor) has been demonstrated to be a safe and very effective second-line treatment after the failure of triple therapy.20, 21 In addition, pilot studies have shown that simplified quadruple therapy may be used as a firstline option.22 Recent reports have suggested that the efficacy of 7-day triple therapies is falling far below the recommended figure of 90%, probably as a consequence of the increasing prevalence of antimicrobial resistance.16, 23–25 Prolonging therapy to 14 days increases the eradication to some degree; per protocol eradication rates approach 90%.26 However, prolonging therapy is not a costeffective strategy because the increase in effectiveness is modest, and does not outweigh the marked increase in drug expenses.27 In recent years, many studies have compared the effectiveness of triple vs. quadruple therapy. The results show slight differences in effectiveness, usually in favour of quadruple therapy, although individual studies have not found statistically significant differences.28–31 The aim of this study was to compare the effectiveness of triple vs. quadruple regimens as first-line H. pylori treatment by performing a meta-analysis of published trials.

MATERIALS AND METHODS

Search strategy We searched the PUBMED database for studies published from 1995 to August 2002. The search strategy included the following keywords: Helicobacter pylori (all fields) and triple OR quadruple OR clarithromycin OR amoxycillin, metronidazole OR tinidazole OR imidazole OR bismuth OR omeprazole, lansoprazole OR pantoprazole OR proton pump inhibitor OR PPI (all fields). Abstracts of the articles selected in this search were reviewed and those meeting the inclusion criteria were recorded. We also conducted a manual search of the abstracts submitted to the American Gastroenterological Association congresses from 1998 to 2002 and of the abstracts from the European Helicobacter pylori Study Group congresses from 1998 to 2001 dealing with H. pylori treatment. The references of reviews on H. pylori treatment and the articles selected for the study were also examined

in the search for articles meeting the inclusion criteria. Selection criteria The selection criteria were as follows. (a) Articles had to report comparative randomized trials. (b) Articles had to include at least two branches of treatment consisting of: (i) triple therapy (proton pump inhibitor, clarithromycin, amoxicillin or an imidazole); (ii) quadruple therapy (proton pump inhibitor, bismuth salt, tetracycline and an imidazole). (c) Both therapies had to be administered for the same number of days. (d) H. pylori infection had to be demonstrated by histology, urease or breath test. (e) Histology or 13C-urea breath test had to be used to confirm eradication. Assessment of the quality of the studies The quality of the studies was assessed using the criteria proposed by Chalmers et al.32 This method evaluates the design, implementation and analysis of randomized controlled trials. The overall index of trial quality was weighted as follows: trial design and protocol, 0.6; statistical analysis, 0.3; presentation of results, 0.1. The final quality score was in the range 0–1, with maximum quality studies having a score of 1. Statistics The main comparison was the efficacy of triple vs. quadruple therapy for the treatment of H. pylori infection. The outcomes considered were H. pylori eradication by both intention-to-treat and per protocol analysis, and side-effects. Prior to combining the effect sizes of the individual studies, the homogeneity of the effects across studies was appraised using a homogeneity test based on the chi-squared test. Due to the low power of this test, a minimum cut-off of P ¼ 0.20 was established as a threshold of homogeneity: lower values indicated heterogeneity, and did not allow the study results to be combined.

Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 17, 1137–1143

META-ANALYSIS OF TRIPLE VS. QUADRUPLE THERAPY

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Table 1. Studies excluded from meta-analysis

RESULTS

Study

Twelve studies were initially evaluated. All studies compared triple vs. quadruple therapy for H. pylori eradication. Eight were excluded from further analysis;34–41 the reasons for exclusion are outlined in Table 1.

Reason for exclusion 41

Phull et al.

Sakaki et al.40 Wermeille et al.39

Liu et al.38 Nagahara et al.37

Phillips et al.36

Kumar et al.35 Wong et al.34

Not proton pump inhibitor-based triple therapy Use of amoxicillin and clarithromycin in quadruple therapy Different length for triple and quadruple therapies and use of amoxicillin in quadruple therapy Not proton pump inhibitor-based therapies Different length for triple and quadruple therapies and use of amoxicillin in quadruple therapy Different length for triple and quadruple therapies and use of amoxicillin in quadruple therapy Use of amoxicillin in quadruple therapy Different length for therapies

Meta-analysis was performed by combining the Peto odds ratios of the individual studies into a global odds ratio, under the assumption-free model (or fixed effects model). The significance and 95% confidence intervals (CIs) are provided for the combined odds ratio. All calculations were performed with the freeware program Review Manager. The statistical methods and formulae are described in the Cochrane Reviewer’s Handbook and the RevMan User Guide.33

Description of the studies included Four studies were included in the meta-analysis.28–31 The characteristics of these studies are shown in Table 2. The evaluation of antibacterial resistance was performed in only two studies. Quality assessment The articles included ranged in quality from 0.7 to 0.72 (‘well designed’). The individual assessment of quality is shown in Table 2. Quadruple vs. triple therapy for H. pylori eradication treatment By intention-to-treat analysis, eradication was achieved in 398 of 489 patients with quadruple therapy (81%; 95% CI, 77–84%) and in 386 of 492 patients with triple

Table 2. Characteristics of the trials included in the meta-analysis

Study Gomollon et al.

Quality score 29

Number of patients (n)

Pathology treated

Days treated

Triple therapy

Quadruple therapy Ome, 20 mg b.d. Met, 250 mg t.d.s. Tetra, 500 mg q.d.s Bi subcitrate, 120 mg Ome, 20 mg b.d. Met, 500 mg t.d.s. Tetra, 500 mg t.d.s. Bi subcitrate, 120 mg Pant, 40 mg b.d. Met, 200 mg t.d.s and 400 mg nocte Tetra, 500 mg q.d.s. Bi subcitrate, 108 mg Ome, 20 mg b.d. Met, 375 mg q.d.s. Tetra, 375 mg q.d.s. Bi subcitrate, 120 mg

0.7

97

Peptic ulcer

7

Ome, 20 mg b.d. Amox, 1 g b.d. Cla, 500 mg b.d.

Calvet et al.28

0.72

339

Peptic ulcer

7

Ome, 20 mg b.d. Amox, 1 g b.d. Cla, 500 mg b.d.

Katelaris et al.31

Not determined (abstract)

268

Chronic active gastritis

7

Pant, 40 mg b.d. Amox, 1 g b.d. Cla, 500 mg b.d.

Laine et al.30

Not determined (abstract)

277

Duodenal ulcer

10

Pant, 40 mg b.d. Amox, 1 g b.d. Cla, 500 mg b.d.

q.d.s.

t.d.s.

q.d.s.

q.d.s.

Amox, amoxicillin; Bi subcitrate, bismuth subcitrate; Cla, clarithromycin; Met, metronidazole; Ome, omeprazole; Pant, pantoprazole; Tetra, tetracycline. Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 17, 1137–1143

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Comparison: 01 TRIPLE vs QUADRUPLE ITT Outcome: 01 ITT CURE RATES Study CALVET et al.28 GOMOLLON et al.29 KATELARIS et al.31 LAINE et al.30

TRIPLE QUADRUPLE n /N n /N 132 / 171 40 / 49 104 / 134 110 / 138

Peto OR (95%CI Fixed)

139 / 168 33 / 48 110 / 134 116 / 139

Total(95%CI) 386 / 492 398 / 489 Test for heterogeneity chi-square=3.93 df=3 P =0.27 Test for overall effect z =–1.14 P =0.3 .1 .2 Favours QUADRUPLE

1

Weight %


34.5 11.6 27.4 26.5

0.71[0.42,1.20] 1.98[0.79,4.96] 0.76[0.42,1.38] 0.78[0.43,1.43]

100.0

0.83[0.61,1.14]

Figure 1. Triple vs. quadruple therapy: intention-to-treat (ITT) analysis. CI, confidence interval; OR, odds ratio.

5 10 Favours TRIPLE

Comparison: 02 TRIPLE vs QUADRUPLE PP Outcome: 01 PP CURE RATES Study CALVET et al.28 GOMOLLON et al.29 KATELARIS et al.31 LAINE et al.30

TRIPLE QUADRUPLE n /N n/N 132 / 154 40 / 48 94 / 114 110 / 125


139 / 157 33 / 45 92 / 105 115 / 125

Total(95%CI) 376 / 441 379 / 432 Test for heterogeneity chi-square=3.09 df=3 P =0.38 Test for overall effect z =–1.03 P =0.3 1 .1 .2 Favours QUADRUPLE

Weight %


34.4 15.6 27.7 22.3

0.78[0.40,1.51] 1.80[0.67,4.81] 0.67[0.32,1.40] 0.64[0.28,1.47]

100.0

0.81[0.55,1.20]

Figure 2. Triple vs. quadruple therapy: per protocol (PP) analysis. CI, confidence interval; OR, odds ratio.

5 10 Favours TRIPLE

therapy (78%; 95% CI, 74–81%). The Peto odds ratio (Figure 1) was 0.83 (95% CI, 0.61–1.14; P ¼ 0.3). The per protocol analysis did not differ from the intention-to-treat analysis. Eradication was achieved in 379 of 432 patients with quadruple therapy (88%; 95% CI, 84.1–90.5%) and in 376 of 441 patients with triple therapy (85%; 95% CI, 81.4–88.3%). The Peto odds ratio was 0.81 (95% CI, 0.55–1.20; P ¼ 0.3). Although the eradication rates were somewhat better with quadruple therapy, the differences were not statistically significant (Figure 2). Side-effects tended to be more frequent in triple therapy than in quadruple therapy, although again

the differences were not statistically significant: 37% vs. 34%, respectively. The Peto odds ratio was 1.14 (95% CI, 0.76–1.71; P ¼ 0.54). A number of consensus meetings have recommended the administration of metronidazole at daily doses over 1 g in quadruple therapy in order to achieve optimal results.14 Gomollon et al. used lower metronidazole doses and obtained lower eradication rates than the other studies with quadruple therapy (69% by intention-to-treat analysis).29 We empirically defined ‘high’ metronidazole doses as 1 g or more per day, and performed a sub-analysis of the studies using such ‘high’ doses (Figure 3). Excluding the study by

Comparison: 01 TRIPLE vs QUADRUPLE ITT Outcome: 01 ITT CURE RATES Study CALVET et al.28 KATELARIS et al.31 LAINE et al.30

TRIPLE QUADRUPLE n /N n/N 132 / 171 104 / 134 110 / 138


139 / 168 110 / 134 110/ 139

Total(95%CI) 346 / 443 365 / 441 Test for heterogeneity chi-square=0.06 df=2 P =0.97 Test for overall effect z =–1.74 P =0.08 1 .1 .2 Favours QUADRUPLE

Weight %


39.1 31.0 29.9

0.71[0.42,1.20] 0.76[0.42,1.38] 0.78[0.43,1.43]

100.0

0.74[0.53,1.04]

5 10 Favours TRIPLE

Figure 3. Triple vs. quadruple therapy: intention-to-treat (ITT) analysis excluding low metronidazole doses. CI, confidence interval; OR, odds ratio.



Gomollon et al.,29 intention-to-treat eradication rates were 83% (95% CI, 78.8–86%) with quadruple therapy and 78% (95% CI, 73.9–81.8%) with triple therapy. The Peto odds ratio was 0.74 (95% CI, 0.53–1.04; P ¼ 0.08). Per protocol eradication rates were 89% (95% CI, 85.8–92.2%) with quadruple therapy and 85% (95% CI, 81.4–88.7%) with triple therapy. The Peto odds ratio was 0.70 (95% CI, 0.46–1.08; P ¼ 0.10). DISCUSSION

The present meta-analysis suggests that quadruple therapy is slightly more effective than triple therapy for the initial treatment of H. pylori infection. Nevertheless, the differences were not statistically significant. Compliance and side-effects were also very similar and could not distinguish between triple and quadruple therapy as first-line treatment. Excluding the ‘low metronidazole dose’ study of Gomollon et al.,29 quadruple therapy achieved eradication rates that were 4% and 5% (per protocol and intention-to-treat analysis, respectively) better than those of triple therapy. The sample necessary to effectively detect such small differences between the two therapies is much greater than the accumulated number of patients included in the meta-analysis. Indeed, to detect a difference of this kind with an a risk of 0.05 and a power of 0.9, the sample would have to include 2144 patients (1077 patients per treatment group). Antibiotic resistance has a major influence on the effectiveness of eradication therapy. Only two of the studies included here determined this factor.30, 31 Primary clarithromycin resistance dramatically reduced the eradication rates in triple therapy.42 In contrast, ‘in vitro’ metronidazole resistance may be overcome in quadruple therapy by lengthening the regimen to 7 days or beyond, and by using high doses of metronidazole.43 Eradication rates with quadruple therapy were 79% in patients harbouring metronidazole-resistant strains and 85% in those with metronidazole-sensitive bacteria. Therefore, the results of these trials suggest that metronidazole resistance has less effect on the efficacy of quadruple therapy.30, 31 It was also interesting that, in all the studies included, triple therapy remained a very effective treatment, with per protocol eradication rates of 85%, in contrast with the poor eradication rates reported recently world-

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wide.16, 23–25 Unlike triple therapy, whose effectiveness is considerably reduced by clarithromycin resistance, quadruple therapy seems to perform nearly as well in metronidazole-resistant as in metronidazole-sensitive H. pylori. Therefore, quadruple therapy might be expected to perform well in high-resistance areas where triple therapy achieves sub-optimal results. It would be very interesting to compare triple and quadruple therapies in areas in which eradication rates with triple therapy have been reported to be poor. A major disadvantage of quadruple therapy is its complicated dosage. Reduced quadruple therapy regimens administered thrice daily for 7 days, or even twice daily for 14 days, have been shown to be highly effective in pilot studies, and may improve treatment compliance.22, 44 In addition, formulations combining tetracycline, metronidazole and a bismuth salt, like that used in the trial by Laine et al.,30 would facilitate compliance and tolerability and thus overcome a major drawback of quadruple therapy. Triple therapy as first-line treatment, followed by quadruple therapy for failures, achieves global eradication rates in the range 96–99%,45 and is a well-known and widely accepted strategy amongst general practitioners.46 In areas in which triple therapy works well, the small differences observed in the meta-analysis probably do not justify the effort of trying to modify current recommendations on H. pylori treatment.47 On the other hand, in areas of poor performance of triple therapy, reversing the usual strategy — that is, giving quadruple therapy first — may be a useful alternative. Finally, we should stress that none of the current therapies can be considered as ideal. Current recommendations must change to include new effective antibiotics, such as rifabutin,48, 49 furazolidone50, 51 or the new quinolones.52, 53 It makes sense to continue the search for new therapies that can obtain 100% eradication rates with the first treatment. In a very large randomized trial, Zullo et al. recently obtained extremely good results with a 10-day sequential therapy consisting of 5 days of dual plus 5 days of triple therapy.54 This regimen is probably the first treatment to show significantly better results than triple therapy in a large randomized trial and deserves further evaluation. In conclusion, quadruple therapy provides similar or slightly better results than triple therapy for H. pylori eradication. The advantages at present do not seem clear enough to change current policies for H. pylori treatment.


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However, it would be worthwhile to test the efficacy of quadruple therapy as first-line treatment in areas in which triple therapy does not achieve optimal results. ACKNOWLEDGEMENT

14

15

The authors are indebted to Michael Maudsley for help with the English. The study was supported in part by a Grant of the Instituto de Salud Carlos III (C03/02).

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