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Meta-analysis: Duration of First-Line Proton-Pump Inhibitor–Based Triple Therapy for Helicobacter pylori Eradication

Lorenzo Fuccio, MD; Maria Eugenia Minardi, MD; Rocco Maurizio Zagari, MD; Diego Grilli, PhD; Nicola Magrini, MD; and Franco Bazzoli, MD
[+] Article and Author Information

From the University of Bologna, Bologna, Italy; University of South Florida, Tampa, Florida; and Centre for the Evaluation of the Effectiveness of Health Care, Local Health Authority, Modena, Italy.


Acknowledgments: The authors thank Dr. Catherine Henderson for editorial support.

Potential Financial Conflicts of Interest: Honoraria: F. Bazzoli (AstraZeneca, Takeda, Altana Pharma).

Requests for Single Reprints: Franco Bazzoli, MD, Dipartimento di Medicina Interna e Gastroenterologia, Università di Bologna, Policlinico S. Orsola, Via Massarenti, 9, 40138 Bologna, Italy; e-mail, franco.bazzoli@unibo.it.

Current Author Addresses: Drs. Fuccio, Minardi, Zagari, and Bazzoli: Dipartimento di Medicina Interna e Gastroenterologia, Università di Bologna, Policlinico S. Orsola, Via Massarenti, 9, 40138 Bologna, Italy.

Dr. Grilli: University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620.

Dr. Magrini: Centre for the Evaluation of the Effectiveness of Health Care, Local Health Authority, Viale Muratori 201, 41100 Modena, Italy.


Ann Intern Med. 2007;147(8):553-562. doi:10.7326/0003-4819-147-8-200710160-00008
Text Size: A A A

Background: Proton-pump inhibitor (PPI)–based triple therapy is the recommended first-line treatment for Helicobacter pylori infection. A consensus on treatment duration is lacking.

Purpose: To summarize the benefits and harms of different durations of PPI-based triple therapy.

Data Sources: PubMed, EMBASE, the Cochrane Library, and proceedings of major meetings through May 2007.

Study Selection: English-language reports of randomized, controlled trials that compared duration (7, 10, or 14 days) of triple therapy and in which adequate testing confirmed the initial H. pylori infection and its eradication.

Data Extraction: Two authors independently extracted data on study design, treatment, number of patients enrolled and number of patients with successful eradication, disease at enrollment, testing, adverse effects, year of publication, publication format, and country.

Data Synthesis: Of 21 included studies, 11 compared 7-day therapy with 10-day therapy, and 13 compared 7-day therapy with 14-day therapy. Meta-analysis yielded relative risks (RRs) for eradication of 1.05 (95% CI, 1.01 to 1.10) for 7-day compared with 10-day amoxicillin-containing triple therapy (10 studies) and 1.07 (CI, 1.02 to 1.12) for 7-day compared with 14-day therapy (11 studies). Meta-analysis of the 3 studies that compared 7-day with 14-day metronidazole-containing therapy yielded an RR of 1.08 (CI, 0.96 to 1.22). The 7-day versus 10-day comparisons yielded RRs of 1.03 (CI, 0.97 to 1.10) for peptic ulcer disease and 1.10 (CI, 1.02 to 1.20) for nonulcer dyspepsia. For the 7-day versus 14-day comparisons, the RRs were 1.04 (CI, 0.99 to 1.09) and 1.03 (CI, 0.88 to 1.20), respectively. The RRs for frequency of adverse events were 0.98 (CI, 0.85 to 1.14) and 1.08 (CI, 0.84 to 1.40) for 7-day therapy compared with 10- and 14-day therapy, respectively. Diarrhea and taste disturbance were the most frequently reported adverse events (5%).

Limitations: Subgroup analyses were limited by the few studies evaluating different drug regimens and disease at enrollment. Seventeen of the included studies had poor methodological quality or inadequate reporting.

Conclusion: Available data suggest that extending triple therapy beyond 7 days is unlikely to be a clinically useful strategy.

Figures

Grahic Jump Location
Figure 1.
Flow diagram of trials identified and selected.

DDW = Digestive Disease Week; UEGW = United European Gastroenterology Week.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Forest plot of the 11 studies comparing 7-day with 10-day proton-pump inhibitor–based triple therapy.

Results of the Cochran Q tests for heterogeneity were not statistically significant (P = 0.93), and the Higgins test failed to reject the hypothesis of homogeneity between studies (I2 = 0%). The Galbraith plots confirmed that no studies fell outside the 95% limit area. The area of the boxes corresponds to the weight of each study. RR = relative risk.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Forest plot of the 13 studies comparing 7-day with 14-day proton-pump inhibitor (PPI)–based triple therapy.

No statistical evidence of heterogeneity was detected (I2 = 0%; P = 0.61 for Cochran Q test; no studies fell outside the 95% limit area in the Galbraith plots). The area of the boxes corresponds to the weight of each study. A = amoxicillin; C = clarithromycin; M = metronidazole; RR = relative risk.

Grahic Jump Location

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Duration of PPI-containing triple therapy: Meta-analysis or Shmeta-analysis?
Posted on October 29, 2007
David Y. Graham
Michael E. DeBakey VAMC and Baylor College of Medicine
Conflict of Interest: None Declared

A recent meta-analysis concluded there is no clinical reason to extend the duration of legacy triple therapies for Helicobacter pylori infection beyond 7 days (1). The overall eradication rates reported were 73% and 78% for 7 vs. 14 days and both are grade F cure rates using the Report Card grades of A, B, C, D or F (2). Two studies included in the meta-analysis even questioned whether triple therapy should still be used at all

Clarithromycin resistance converts amoxicillin-containing triple therapy into PPI plus amoxicillin dual therapy (3) the outcome of which is duration dependent. The cure rate for a 7 day PPI plus amoxicillin therapy is approximately one-half of that achieved after 14 days (eg, 25% vs. 50%) such that the outcome will in part depend on the size of the clarithromycin resistant population (eg, if one considered triple therapy to be 100% effective with susceptible strains the differences would be 5%, 7%, and 9% for populations with 10, 20 or 30% resistance rates). The differences would be larger if increasing the duration of therapy also improved the outcome of the triple therapy as it is thought to do based on prior meta-analyses and early studies generally showing a rank order with success being directly related to duration up to 14 days (3). Legacy triple therapy is a dual therapy-based triple therapy and improvements in the outcome of the dual therapy component will raise the overall cure rates irrespective of clarithromycin resistance (4). Amoxicillin- containing triple therapy can therefore be improved by increasing the effectiveness of the dual component (eg, by increasing the PPI dose, duration or both). This was actually seen in the meta-analysis (1)

The authors of the meta-analysis seem to have gotten the right answer to the wrong question. Any simplification (eg, shorter duration) of a treatment regimen must maintain efficacy (ie, remain a Grade A or B therapy with >90 cure rates). The meta-analysis evaluated whether duration would change an unacceptable cure rate to an acceptable one. The answer was "no" and the conclusion should have been that the different durations tested yielded unacceptable results clinically. THE QUESTION is really "how can I ensure that I cure all, or almost all of the patients I treat". Studies showing that this can be done in large patient populations are available and should serve as the models for treatment of this serious infection (5).

References (1) Fuccio L, Minardi ME, Zagari RM, Grilli D, Magrini N, Bazzoli F. Meta -analysis: duration of first-line proton-pump inhibitor based triple therapy for Helicobacter pylori eradication. Ann Intern Med. 2007;147:553- 62. (2) Graham DY, Lu H, Yamaoka Y. A report card to grade Helicobacter pylori therapy. Helicobacter. 2007;12:275-78. (3) Graham DY, Dore MP. Variability in the outcome of treatment of Helicobacter pylori infection: a critical analysis. In: Hunt RH, Tytgat GNJ, eds. Helicobacter pylori Basic mechanisms to clinical cure 1998. Dordrecht: Kluwer Academic Publishers; 1998: 426-40. (4) Furuta T, Shirai N, Takashima M, Xiao F, Hanai H, Sugimura H et al. Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther. 2001;69:158-68. (5) Lee YC, Wu HM, Chen TH, Liu TY, Chiu HM, Chang CC et al. A community- based study of Helicobacter pylori therapy using the strategy of test, treat, retest, and re-treat initial treatment failures. Helicobacter. 2006;11:418-24.

Conflict of Interest:

Dr. Graham has received small amounts of grant support and/or free drugs or urea breath tests from Meretek, Jannsen/Eisai, TAP, and BioHit for investigator initiated and completely investigator controlled research in the area of H. pylori infections. In addition, Dr. Graham is a paid consultant for Otsuka Pharmaceuticals the manufacturer of the US version of the 13C-urea breath test. Dr. Graham is a consultant to Novartis with regards to H. pylori vaccine development. Dr. Graham also receives royalties on the Baylor College of Medicine patent covering the serologic test, HM-CAP.

Increasing the length of triple therapy could be a clinically useful strategy
Posted on November 14, 2007
Xavier Calvet
Digestive Diseases Unit.CIBEREHD. Hospital de Sabadell.
Conflict of Interest: None Declared

We would like to congratulate Fuccio1 et al on their well-performed meta-analysis comparing different lengths of triple therapy for Helicobacter pylori infection. However, we disagree with their conclusion that prolonging treatment is unlikely to be a clinically useful strategy. In our opinion, this statement is not supported by their results. The authors confirm previous findings2,3 that extending length of treatment from 7 to 10 days and from 7 to 14 days increases cure, although the improvement rates (4% in the first case and 5% in the second) were slightly lower than some of the previously reported (3% and 8%-12% respectively) 2,3 . They also found that lengthening treatment from 7 to 10 days increases efficacy in patients with non-ulcer dyspepsia (RR difference of 11%) but not in patients with ulcer (RR difference 2%) 4. We disagree with the final statement that prolonging treatment is unlikely to be a clinically useful strategy, for three reasons: First, because Fuccio et al.'s conclusion is based on a sub-analysis of only 4 studies with high Jadad scale scores5 which did not find significant differences. Any sub-analysis limited to 4 studies is likely to give negative results because of the small sample size and the consequent type beta error; it cannot be used to argue for the lack of an effect. Second, their results show that the increase in cure rates depends on the proportion of patients with non-ulcer dyspepsia included in the meta- analysis. Therefore the inclusion of two large studies with ulcer patients only could have led to an underestimation of the benefit of prolonging treatment. In fact, as we currently treat more patients with non-ulcer dyspepsia than with ulcer it is likely that the benefit of lengthening treatment will be greater in clinical practice than Fuccio et al.'s study suggests. Finally, cure rates with triple therapy seem to be decreasing and second- line and third-line therapies often achieve suboptimal results as well. In this scenario, even a 4%-5% increase in cure rates is probably worth the greater cost, especially since there is no increase in side effects. In conclusion, we believe that the correct inference from the meta- analysis is that prolonging Helicobacter pylori treatment significantly increases cure rates. Whether or not it represents a clinically useful strategy remains a matter of opinion until new evidence emerges.

1- Fuccio L, Minardi ME, Zagari RM, Grilli D, Magrini N, Bazzoli F. Meta-analysis: duration of first-line proton-pump inhibitor based triple therapy for Helicobacter pylori eradication. Ann Intern Med. 2007;147:553- 562.

2- Calvet X, Ducons J, Bujanda L, Bory F, Montserrat A, Gisbert JP. Seven versus ten days of rabeprazole triple therapy for Helicobacter pylori eradication: a multicenter randomized trial. Am J Gastroenterol 2005;100:1696"“1701.

3- Ford A, Moayyedi P. How can the current strategies for Helicobacter pylori eradication therapy be improved? Can J Gastroenterol. 2003;17 Suppl B:36B-40B.

4- Zagari RM, Bianchi-Porro G, Fiocca R, Gasbarrini G, Roda E, Bazzoli F. Comparison of 1 and 2 weeks of omeprazole, amoxicillin and clarithromycin treatment for Helicobacter pylori eradication: the HYPER Study. Gut. 2007 Apr;56(4):475-9.

5- Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12.

Conflict of Interest:

None declared

Proton-pump inhibitor-based triple therapy needs upgrade
Posted on December 17, 2007
Liu Hong
State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital
Conflict of Interest: None Declared

To the editor:

As Fuccio L et al (Ann Intern Med. 2007 Oct 16; 147(8): 553-62) reported, the proton-pump inhibitor (PPI)-based triple therapy is considered as valuable strategy for traditional H.pylori eradication. However, the strategy is becoming doubtful for patients with simultaneous gastritis and esophagitis, because it may lead to high incidence rate of esophageal carcinoma [1].

H.pylori infection is usually accompanied with increased amount of ammonia and injured gastric mucosa, which are both anti-acid factors. H.pylori infection may also trigger a marked local inflammatory response and a systemic immune response, which is valuable for controlling tumor outgrowth and progression. Thus, H.pylori eradication may lead to increased amount of gastric acid and unbalanced immune response, which is responsible for chronic injured esophageal mucosa and high risk of tumor. As most patients receive PPI therapy, H.pylori eradication-related immunologic imbalance is assumed to be responsible for the high incidence rate of esophageal carcinoma. These results are consistent with the report of Koebel CM et al, indicating that immunotherapy should be recommended to add to the strategy of H.pylori eradication [2].

However, traditional H.pylori eradication has been proved to be effective for prevention of gastric cancer. H.pylori eradication seems lead to equilibrium for occult gastric cancer cells, but lead to imbalance for occult esophageal cancer cells. In a word, it leads to dialectical equilibrium for tumor cells. We should try to prevent different kind of occult cancer by maintaining different kind of equilibrium state. Therefore, PPI-based triple therapy needs upgrade, especially for the patients with simultaneous gastritis and esophagitis. Immunotherapy, such as acupuncture, should be recommended to add to the strategy of H.pylori eradication. More immunomodifiers need to be investigated to reverse the PPI-based triple therapy related immunologic imbalance.

References:

1 Layke JC, Lopez PP. Esophageal cancer: a review and update. Am Fam Physician. 2006;73(12):2187-94.

2 Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007; 450(7171): 903-7.

Conflict of Interest:

None declared

Extending triple therapy beyond 7 days is unlikely to be a clinically useful strategy
Posted on December 19, 2007
Franco Bazzoli
Department of Internal Medicine and Gastroenterology, University of Bologna
Conflict of Interest: None Declared

We appreciate the comments of Dr. Xavier Calvet, which disagree with our conclusion that prolonging treatment is unlikely to be a clinically useful strategy.

One of the aims of our meta-analysis was to verify whether current European and American recommendations (1;2), supporting 14 days as the duration of choice, reflect the available data. Undoubtedly, lengthening treatment from 7 to 14 days, significantly increase the eradication rate by a 5% (95%CI: 2%-8%), however this improvement is substantially lower than that previously believed (12%) (3).

A statistically significant finding is not necessarily clinically significant in the daily clinical practice. In the U.S. trial comparing different lengths of triple therapy, two regimens were considered therapeutically equivalent if the 95%CI was within the equivalence range, set at -15% to 15% (4). Of note, this cut-off was decided in consultation with the Food and Drug Administration (4). The result of our meta-analysis was largely within this equivalence range (95%CI: 2%-8%).

Dr. Calvet sustained that the inclusion of the two large studies with peptic ulcer patients could have provided an underestimation of the benefit of prolonging treatment. We performed a sensitivity analysis excluding the two large studies with peptic ulcer patients and the result did not substantially change (7%; 95%CI: 3%-11%). As expected, the difference slightly increases, but the range was, again, largely within the equivalence range.

Finally, a cost-effectiveness analysis performed in Spain by Dr. Calvet (5), and based on a 9% increase in eradication with the longer therapy duration, concluded that "7-day therapy seems the most cost- effective strategy" (5).

Lorenzo Fuccio, MD

Department of Internal Medicine and Gastroenterology

University of Bologna, Bologna, 40138, Italy

Rocco Maurizio Zagari, MD

Department of Internal Medicine and Gastroenterology

University of Bologna, Bologna, 40138, Italy

Franco Bazzoli, MD

Department of Internal Medicine and Gastroenterology

University of Bologna, Bologna, 40138, Italy

References

1. Malfertheiner P, Megraud F, O'Morain C, Bazzoli F, El-Omar E, Graham D, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut. 2007;56(6):772-781

2. Chey, William D. & Wong, Benjamin C.Y. American College of Gastroenterology. Guideline on the Management of Helicobacter pylori Infection. The American Journal of Gastroenterology 2007; 102(8):1808-1825

3. Ford A, Moayyedi P. How can the current strategies for Helicobacter pylori eradication therapy be improved? Can J Gastroenterol. 2003;17 (Suppl B):36B-40B.

4. Vakil N, Lanza F, Schwartz H, et al. Seven-day therapy for Helicobacter pylori in the United States. Aliment Pharmacol Ther 2004;20(1):99-107

5. Calvet X, Gené E, López T, Gisbert JP. What is the optimal length of proton pump inhibitor-based triple therapies for H. pylori? A cost- effectiveness analysis. Aliment Pharmacol Ther. 2001;15(7):1067-76

Conflict of Interest:

None declared

Re: Proton-pump inhibitor-based triple therapy needs upgrade
Posted on January 9, 2008
Chunhu Su
Acupuncture Center of Zhonghua, China
Conflict of Interest: None Declared

We quite agree with the hypothesis of Liu Hong et al, which is consistent with our clinical data.

From 2002 to 2006, 875 patients (577 men, 298 women, 22-68 years) with simultaneous gastritis and esophagitis were investigated for their follow-up therapy. According to the therapeutic strategy, they could be divided into four groups. Group 1 involved 387 (44%) patients, who received intermittent antiacid therapy. Group 2 involved 295 (34%) patients, who received intermittent antiacid therapy and H.pylori eradication. Group 3 involved 142 (16%) patients, who received intermittent antiacid therapy, H.pylori eradication and intermittent acupuncture. Another 52 patients (6%) belonged to group 4, who received other therapy.

From 2006 to 2007, 126 patients (94 men, 32 women, 35-71 years) with esophageal carcinoma were investigated. They had been diagnosised as patients with simultaneous gastritis and esophagitis for more than three years. According to the same group-discriminate strategy, group 1 involved 36 (29%) patients, group 2 involved 77 (61%) patients, group 3 involved 5 (4%) patients, and group 4 involved 8 (6%) patients.

The incidence rate of esophageal carcinoma is the highest in Group 2. The reason may be what Liu Hong et al reported. The incidence rate of esophageal carcinoma is the lowest in Group 3. Obviously, it may result from the effect of acupuncture. Acupuncture is an important part of Chinese medicine theory and it is approved to be highly effective in treatment of more than 300 diseases [1]. The patients have received different kinds acupuncture, whose same purpose is to induce immunity regulation and endocrine balance through complex reflex. Here, acupuncture seems to be necessary for the upgrade of traditional H.pylori eradication. Thus, immunotherapy, such as acupuncture, should be recommended to add to the strategy of H.pylori eradication.

References:

1 Witt C, Brinkhaus B, Jena S, et al. Acupuncture in patients with osteoarthritis of the knee: arandomised trial. Lancet 2005; 366: 136¨C43

Conflict of Interest:

None declared

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