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Sequential Therapy versus Standard Triple-Drug Therapy for Helicobacter pylori Eradication: A Randomized Trial

Dino Vaira, MD; Angelo Zullo, MD; Nimish Vakil, MD; Luigi Gatta, MD; Chiara Ricci, MD; Federico Perna, PhD; Cesare Hassan, MD; Veronica Bernabucci, MD; Andrea Tampieri, MD; and Sergio Morini, MD
[+] Article, Author, and Disclosure Information

From the University of Bologna, Bologna, Italy; “Nuovo Regina Margherita Hospital,” Rome, Italy; University of Wisconsin, Madison, Wisconsin; and University of Brescia, Brescia, Italy.

Acknowledgments: The authors thank Dr. Alessandra Stancari, S. Orsola Pharmacy, for preparing the medication packages and for maintaining the randomization schedule, and Mrs. Alessandra Guarini, “Nuovo Regina Margherita Hospital,” for nursing assistance.

Grant Support: Dr. Vakil was a paid attendee at a conference on a gastroesophageal reflux disease diagnostic questionnaire sponsored by Altana Pharma (now Nicomed) (manufacturer of pantoprazole) and was an investigator for a multicenter trial that subsequently evaluated this questionnaire in patients with gastroesophageal reflux disease.

Potential Financial Conflicts of Interest: Consultancies: N. Vakil (Altana Pharma [now Nicomed]); Stock ownership or options (other than mutual funds): D. Vaira (Meridian Bioscience); Grants received: N. Vakil (Altana Pharma [now Nicomed]).

Requests for Single Reprints: Dino Vaira, MD, Department of Internal Medicine and Gastroenterology, S. Orsola Hospital, Via Massarenti 9, 40138 Bologna, Italy; e-mail, vairadin@med.unibo.it.

Current Author Addresses: Drs. Vaira, Gatta, Perna, Bernabucci, and Tampieri: Department of Internal Medicine and Gastroenterology, S. Orsola Hospital, Via Massarenti 9, 40138 Bologna, Italy.

Drs. Zullo, Hassan, and Morini: Gastroenterologia ed Endoscopia Digestiva, Ospedale “Nuovo Regina Margherita,” Via E. Morosini 30, 00153, Rome, Italy.

Dr. Vakil: Aurora Sinai Medical Center, 945 North 12th Street, Room 4040, Milwaukee, WI 53233.

Dr. Ricci: Gastroenterology Unit, Spedali Civili, University of Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy.

Author Contributions: Conception and design: D. Vaira, A. Zullo, N. Vakil, L. Gatta, C. Ricci.

Analysis and interpretation of the data: D. Vaira, A. Zullo, N. Vakil, L. Gatta.

Drafting of the article: D. Vaira, A. Zullo, N. Vakil, L. Gatta.

Critical revision of the article for important intellectual content: D. Vaira, A. Zullo, N. Vakil, L. Gatta.

Final approval of the article: D. Vaira, A. Zullo, N. Vakil, L. Gatta, C. Ricci, F. Perna, C. Hassan, V. Bernabucci, A. Tampieri, S. Morini.

Provision of study materials or patients: D. Vaira, A. Zullo, L. Gatta, C. Ricci, F. Perna, C. Hassan, V. Bernabucci, A. Tampieri, S. Morini.

Statistical expertise: A. Zullo, N. Vakil, L. Gatta.

Obtaining of funding: D. Vaira.

Administrative, technical, or logistic support: D. Vaira.

Collection and assembly of data: D. Vaira, A. Zullo, L. Gatta.

Ann Intern Med. 2007;146(8):556-563. doi:10.7326/0003-4819-146-8-200704170-00006
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The results of this study show that sequential therapy is superior to triple therapy for the eradication of H. pylori infection. The study also demonstrates that triple therapy, which is the current standard treatment, has low eradication rates. Both treatments were well tolerated and had similar rates of side effects and low rates of patients who withdrew from the study.

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Submit a Comment/Letter
No Title
Posted on April 23, 2007
David Y Graham
Michael E. DeBakey Veterans Affairs Medical Center
Conflict of Interest: None Declared

Ethical considerations of comparing sequential and traditional anti- H. pylori therapy

Vaira and colleagues recently reported that a sequential therapy regimen led to high cure rates and that it was better than legacy triple therapy (a proton pump inhibitor, amoxicillin and clarithromycin) for eradicating H. pylori infection in Italian patients with dyspepsia or peptic ulcers. The sequential regimen was much more effective than triple therapy among patients with clarithromycin resistant bacteria (1). These investigators and others have compared identical or very similar regimens and have reported similar high cure rates several times (Figure 1) (2-6). While one might question the decision to repetitively compare identical or very similar sequential and triple therapy regimens in Italian populations, we certainly think that Vaira and colleagues should have modified their study when the results of the other studies became known. At study onset (2003), the superiority of sequential therapy was not definitively proven. However, as the study progressed through 2006, the superiority of sequential therapy was firmly established primarily by the same authors and the ethics of continuing the trial unchanged should have been considered. The authors should have changed the patient's consent form. They should have notified institutional review boards and study sponsors of the results of the other trials and how those results impacted their ongoing trial. By 2004, truly informed consent would have required informing the patients, the institutional review boards, and the sponsors that one of the therapies was clearly inferior as the average eradication rates were approximately 75% for triple therapy compared to 92% for sequential therapy. In addition, patients, institutional review boards, and sponsors would need to be informed that those who received legacy triple therapy had increased future risks: the associated inferior cure rates could lead to a high percentage of patients who developed clarithromycin resistant organisms which might prejudice their ability to be subsequently be cured of their infection. This is particularly important considering that all patients were symptomatic, some had peptic ulcers, and others had pangastritis and intestinal metaplasia and were thus at increased risk for gastric cancer (1). Finally, knowingly including an inferior therapy increases the responsibility to confirm successful H. pylori eradication for all "treatment failures". The authors should detail how they ensured that these patients subsequently received appropriate therapy and how many were subsequently cured.

A secondary question of the Vaira study related to the effect of pretreatment antimicrobial resistance on the success rate of sequential therapy. The secondary question took on greater importance as the outcome of comparisons of more than 2,000 patients receiving sequential vs. triple therapy established the superiority of sequential therapy. Because the effect of antimicrobial resistance in legacy triple therapy was well known, the result that triple therapy was inferior to sequential therapy suggested that there was little justification for continuation of the triple therapy group, especially the one regimen chosen. If the investigators felt strongly that a control group was needed, they should have chosen a different one such as a proton pump inhibitor plus tinidazole, and clarithromycin or a proton pump inhibitor plus amoxicillin and plus tinidazole, and clarithromycin. There were already data available regarding the use of the same four drugs used in sequential therapy given as concomitant therapy and providing cure rates in the same range as achieved with sequential therapy (7-9). The investigators may have missed an opportunity to provide new knowledge regarding sequential therapy. The mean intention-to-treat eradication rate from the prior studies of sequential therapy was only 91.5% (1089 of 1200) suggested that the success of sequential therapy could be improved by changes in dose, duration, or formulation. In summary, we think that the investigators should explain why they continued to subject patients to an inferior therapy after it became known that triple therapy was clearly inferior. They must also provide evidence that the patients, the institutional review boards, and the sponsors were promptly informed and given full disclosures especially as soon as new findings that would affect the study became evident.

David Y. Graham, M.D. Yoshio Yamaoka, M.D., PhD. Michael E. DeBakey Veterans Affairs Medical Center RM 3A-320 (111D) 2002 Holcombe Boulevard Houston, TX 77030 Phone: 713-795-0232 FAX: 713-790-1040 dgraham@bcm.tmc.edu


(1) Vaira D, Zullo A, Vakil N, Gatta L, Ricci C, Perna F et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: A randomized trial. Ann Intern Med. 2007;146:556-63.

(2) De Francesco V, Zullo A, Hassan C, Della VN, Pietrini L, Minenna MF et al. The prolongation of triple therapy for Helicobacter pylori does not allow reaching therapeutic outcome of sequential scheme: a prospective, randomised study. Dig Liver Dis. 2004;36:322-26.

(3) Francavilla R, Lionetti E, Castellaneta SP, Magista AM, Boscarelli G, Piscitelli D et al. Improved efficacy of 10-Day sequential treatment for Helicobacter pylori eradication in children: a randomized trial. Gastroenterology. 2005;129:1414-19.

(4) Scaccianoce G, Hassan C, Panarese A, Piglionica D, Morini S, Zullo A. Helicobacter pylori eradication with either 7-day or 10-day triple therapies, and with a 10-day sequential regimen. Can J Gastroenterol. 2006;20:113-17.

(5) Zullo A, Vaira D, Vakil N, Hassan C, Gatta L, Ricci C et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment Pharmacol Ther. 2003;17:719-26.

(6) Zullo A, Gatta L, De Francesco V, Hassan C, Ricci C, Bernabucci V et al. High rate of Helicobacter pylori eradication with sequential therapy in elderly patients with peptic ulcer: a prospective controlled study. Aliment Pharmacol Ther. 2005;21:1419-24.

(7) Nagahara A, Miwa H, Ogawa K, Kurosawa A, Ohkura R, Iida N et al. Addition of metronidazole to rabeprazole-amoxicillin-clarithromycin regimen for Helicobacter pylori infection provides an excellent cure rate with five-day therapy. Helicobacter. 2000;5:88-93.

(8) Treiber G, Ammon S, Schneider E, Klotz U. Amoxicillin/metronidazole/omeprazole/clarithromycin: a new, short quadruple therapy for Helicobacter pylori eradication. Helicobacter. 1998;3:54-58.

(9) Treiber G, Wittig J, Ammon S, Walker S, van Doorn LJ, Klotz U. Clinical outcome and influencing factors of a new short-term quadruple therapy for Helicobacter pylori eradication: a randomized controlled trial (MACLOR study). Arch Intern Med. 2002;162:153-60.

Figure 1. Results of the 5 previous comparisons of legacy triple and sequential therapy. Each bar shows the mean and the upper 95% confidence interval and refer to the references in the order cited (2-6) All comparisons between sequential and triple therapy were significant (P<0.05).

Competing Interests: 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 and a member of the Board of Directors of Meretek, Diagnostics, the manufacturer 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. Dr. Yamaoka has no potential conflicts of interest to declare.

Conflict of Interest:

See below

Author response
Posted on May 7, 2007
Dino Vaira
Conflict of Interest: None Declared

The Antigen for Detection of Helicobacter pylori after Eradication Therapy

"Sequential therapy: Minimizing risk and maximizing outcome"

There are several misstatements in the letter which we will address first: (a) there was no sponsor for our study; (b) triple therapy is a "legacy" therapy solely in a fantasy world. Triple therapy was recently reaffirmed by an International Consensus Group as the principal therapy to be used worldwide and by US and Japanese guidelines. (1-3) It is therefore an appropriate control group for any new therapy. Our study began in 2003 when it was uncertain whether sequential therapy was truly effective in large cohorts. A fundamental question remained unanswered until now- Was sequential therapy the answer to Clarithromycin resistance? An expert International Consensus group reviewed the data on sequential therapy in 2005 and concluded that it was promising but more data were needed,particularly with regard to clarithromycin resistance. (1) As there were no safety issues with either treatments in our study and as the international community of experts felt that more data were needed, it was imperative that we continue the trial. We have already demonstrated that a triple therapy with levofloxacin is an effective salvage therapy for patients who fail sequential therapy. (4) Therefore, a perfectly satisfactory alternative therapy of proven efficacy was available for failures. Data on failures will be reported elsewhere.

Ethical trial designs minimize risk to patients and maximize the likelihood of a meaningful outcome for patients and society. Early termination of a trial requires the demonstration of a serious unanticipated side-effect or an unanticipated difference between treatments that is much larger than expected. (5) Individuals taking a decision to terminate a trial early have a heavy responsibility to both those who have taken part in the trial already and to society. (5) The results of our study were within the anticipated treatment estimates and there were no safety issues, therefore our responsibility to the patients who volunteered, to society, and to the scientific community was to continue.The suggestion that we not have a control group is inappropriate. The limitations of uncontrolled studies are well known to all serious researchers. Underpowered, uncontrolled trials continue to be published, sometimes with unsafe agents, These studies yield biased results with wide confidence intervals that mislead rather than illuminate, and place patients at risk of drug toxicity and resistant organisms. These should be deplored rather than encouraged. The benefits of our study to individual patients and to society in general should be obvious to impartial observers.

Dino Vaira MD Dept of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy;

Angelo Zullo MD Gastroenterology Unit, Nuovo Regina Margherita Hospitalí, Rome, Italy;

Nimish Vakil MD University of Wisconsin School of Medicine and Public Health, Madison WI,USA and Marquette University College of Health Sciences, Milwaukee WI, USA

References: 1. Malfertheiner P, Megraud F, O'Morain C, Bazzoli F, El Omar E, Graham DY, et al. Current concepts in the management of Helicobacter pylori infection The Maastricht III Consensus Report. Gut 2006 Dec 14; [Epub ahead of print]. 2. Fujioka T, Yoshiiwa A, Okimoto T, Kodama M, Murakami K. Related Articles, Guidelines for the management of Helicobacter pylori infection in Japan: current status and future prospects. J Gastroenterol. 2007;42 Suppl 17:3-6. 3. Chey WD, Wong BCY. American College of Gastroenterology guideline for H pylori infection. Am J Gastroenterol 2007, in press. 4. Gatta L, Zullo A, Perna F, Ricci C, De Francesco V, Tampieri A,Bernabucci V, Cavina, M, Hassan C, Ierardi E, Morini S, Vaira D. A 10 days levofloxacin base triple therapy in patients who failed two eradication courses. Alimentary Pharmacology Therapeutics 2005; 22: 45-49. 5. Grant A. Stopping clinical trials early. BMJ 2004;329:525-6.

Conflict of Interest: They have been decalred in the paper and have not been changed since

Conflict of Interest:

See below

Sequential therapy for Helicobacter Pylori eradication
Posted on May 16, 2007
Mihalis Tzivras
University of Athens
Conflict of Interest: None Declared

To the editor: The paper by Vaira et al(1)adds to the notion that sequential therapy is more efficient than standard triple therapy for Helicobacter pylori eradication. In 1997 we treated with a sequential regimen 133 Greek patients with Helicobacter pylori infection and duodenal ulcer who had failed the standard of treatment by that time, meaning either a 14days dual therapy with omeprazole and amoxicillin or a 14days triple therapy with tripotassium dicitratobismuthate (TDB), tetracycline and metronidazole. All patients were given high dose omeprazole (60mg) with amoxicillin (500mg qid) for 10days followed by metronidazole (500mg tid) and TDB (120mg qid) for 10 days. TDB was thereafter continued for additional 4 weeks. Per protocol and intention-to-treat eradication rates were 95% and 85% respectively(2). Of note is that Helicobacter pylori primary resistance rate in metronidazole was then near 40% in Greece (3). It seems likely that pretreatment with proton pump inhibitors and amoxicillin, an antibiotic in which Helicobacter pylori rarely develops resistance, makes the bacterium vulnerable to the subsequent therapy with other antimicrobials.

Mihalis Tzivras Stavros Sougioultzis Athanasios Archimandritis

1. Vaira D, Zullo A, Vakil N, Gatta L, Ricci C, Perna F, Hassan C, Bernabucci V, Tampieri A, Morini S. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med. 2007; 146:556 -63. [PMID: 17438314]

2. Tzivras M, Balatsos V, Souyioultzis S, Tsirantonaki M, Skandalis N, Archimandritis A. High eradication rate of Helicobacter pylori using a four-drug regimen in patients previously treated unsuccessfully. Clin Ther. 1997; 19:906-12. [PMID: 9385479]

3. Boyanova L, Mentis A, Gubina M, Rozynek E, Gosciniak G, Kalenic S, Goral V, Kupcinskas L, Kantarceken B, Aydin A, Archimandritis A, Dzierzanowska D, Vcev A, Ivanova K, Marina M, Mitov I, Petrov P, Ozden A, Popova M. The status of antimicrobial resistance of Helicobacter pylori in eastern Europe. Clin Microbiol Infect. 2002; 8:388-96. [PMID: 12199848].

Conflict of Interest:

None declared

Unbalanced distribution of antibiotic resistance bacteria can explain Sequential Therapy success.
Posted on May 18, 2007
Julio A. Leey
Univesity Of Louisville
Conflict of Interest: None Declared

Based on their randomized, double blind, placebo-controlled trial, Vaira, Zullo, Vakil et al concluded that sequential therapy (pantoprazol for 10 days, amoxicillin for 5 days followed by both clarithromycin and tinidazol for 5 additional days) is more effective than conventional triple therapy (pantoprazol, amoxicillin and clarithromycin for 10 days) in eradicating H. pylori among symptomatic patients (1). Although the patient allocation in their study was randomized, we believe that there was an unbalanced distribution of patients as represented by the antibiotic resistance information provided in Table 3.

Compared to the Sequential Therapy group, more patients in the Standard Therapy group were resistant to clarithromycin. There were 9 and 21 patients with clarithromycin-resistant cultures in the Sequential and Standard Therapy groups, respectively. According to the intention-to treat analysis, these numbers represent resistant rates of 6% (9/150) and 14% (21/150). However, if we consider only the positive cultures, the prevalence increases to 7% (9/127) and 17.6% (21/119) respectively. If the data are reconstructed by equalizing the denominators in the clarithromycin resistant group (15 persons each, instead of 9 and 21), applying the same eradication rates of 0.889 and 0.286 as reported for the clarithromycin subgroups, and keeping the other data constant, overall eradication rates of 91% for Sequential and 81% for Standard Therapy were obtained (p=0.045, chi-square with Yates correction). This figure is substantially higher than the p value of 0.0010 reported in Table 2 for the Per-Protocol Analysis.

This analysis shows that the data are quite sensitive to the unequal distribution of clarithromycin resistant strains. This makes the status of the patients not accounted for between the total number with bacterial culture results (n=255) and those listed in Table 3 (n=246) in the Per Protocol Analysis especially critical to the final interpretation of the study results.

Julio A. Leey, MD Resident in Internal Medicine University of Louisville

W. Paul McKinney, MD Professor of Medicine University of Louisville

REFERENCES 1. Vaira D, Zullo A, Vakil N, et al. Sequential Therapy versus Standard Triple-drug Therapy for Helicobacter pylori Eradication. Ann Intern Med. 2007; 146:556-563.

Conflict of Interest:

None declared

Re: Sequential therapy for Helicobacter Pylori eradication
Posted on May 24, 2007
Dino Vaira
Department of Internal Medicine & Gastroenterology
Conflict of Interest: None Declared

We appreciate to know that another, totally different, sequential therapy has been able to cure 85% of first-line eradication failure patients. It is likely that the "induction" phase with amoxicillin favours the efficacy of the following treatment with another antibiotic.

Conflict of Interest:

conflict of interest have been declared in the paper and have not been changed since.

Re: Unbalanced distribution of antibiotic resistance bacteria can explain Sequential Therapy success
Posted on May 24, 2007
Dino Vaira
Department of Internal Medicine & Gastroenterology
Conflict of Interest: None Declared

Leey and McKinney recalculate our data but the results with the re- calculation remain statistically significant. Adjusting for baseline co- variates is debated in the literature and in one study most such calculations did not change the conclusions (as in this study). In the per protocol analysis we show a difference between the sequential treatment group and standard therapy of 14 % (95% CI 6-21%) and in the modified intent to treat analysis a difference of 13% (95%CI 5-21%). Leey and McKinney also show a statistically difference but make the mistake of suggesting that a p value <0.05 is somehow inferior to a p value of p<0.001. Both are statistically significant. The adjusted and unadjusted calculations are best analyzed by measuring the clinical impact of the results. This is accomplished by measuring the number needed to treat (NNT). With the unadjusted per protocol or modified intent to treat analysis presented in our paper, the number needed to treat is 7 ( per protocol) or 8 (modified intent to treat), i.e. for every 7-8 patients treated with sequential therapy there will be one additional responder. With the adjusted data of Leey and McKinney, the NNT is 10. Therefore both the unadjusted and adjusted results are clinically and statistically significant. When we add the cost of therapy to the treatment, the differences become even more apparent. As a course of sequential therapy is less expensive than triple therapy, we cure more patients at lower cost with sequential therapy than with traditional therapy.

Conflict of Interest:

conflict of interest have been declared in the paper and have not been changed since.

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Summary for Patients

Sequential Therapy versus Standard Triple-Drug Therapy for Helicobacter pylori Eradication

The summary below is from the full report titled “Sequential Therapy versus Standard Triple-Drug Therapy for Helicobacter pylori Eradication. A Randomized Trial.” It is in the 17 April 2007 issue of Annals ofInternal Medicine (volume 146, pages 556-563). The authors are D. Vaira, A. Zullo, N. Vakil, L. Gatta, C. Ricci, F. Perna, C. Hassan, V. Bernabucci, A. Tampieri, and S. Morini.


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