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Revista Colombiana de Gastroenterologia

Print version ISSN 0120-9957

Rev Col Gastroenterol vol.27 no.2 Bogotá Apr./June 2012

 

Randomized study of seven days of standard treatment for Helicobacter Pylori vs. ten days of standard treatment for Helicobacter Pylori with one year follow-ups of patients

Rodrigo Castaño Llano MD. (1), Mario H. Ruíz Vélez MD. (2), Cristina Martínez Hincapié MD. (3), Fred A. Naranjo Aristizábal MD. (4), Germán Campuzano Maya MD. (5), Eugenio Sanín Fonnegra MD. (6), Juan D. Puerta Díaz MD. (7), Víctor Calvo Betancur (8), Luis Miguel Ruiz Velásquez Est. (9)

(1) Gastro-hepatology Group at the Universidad de Antioquia and Hospital Pablo Tobón Uribe in Medellín-Colombia.

(2) General Surgery and Endoscopy at the Hospital Pablo Tobón Uribe in Medellín, Colombia.

(3) General Surgeon in Medellín, Colombia.

(4) General Surgeon in Medellín, Colombia.

(5) Clinical Medicine Specialist and Director of Hematology and Pathology at the Laboratorio Clínico Hematológico, Professor at the Universidad de Antioquia in Medellín, Colombia.

(6) Gastroenterologist in Medellín, Colombia.

(7) General Surgeon, Coloproctologist and Professor of General Surgery at the Universidad Pontificia Bolivariana and Clínica las Américas in Medellín, Colombia.

(8) Instituto de Alta Tecnología Médica de Antioquia-IATM in Medellín, Colombia.

(9) Universidad Pontificia Bolivariana in Medellín-Colombia.

Received: 18-01-12 Accepted: 15-05-12

Abstract

Background: The increasing resistance of H pylori to antibiotics has led to failures of eradication treatment. For this reason we intend to modify both the duration of treatment and the regime of antibiotics.

Methods: After random allocation, the standard treatment with omeprazole 20 mg orally every 12 hours, amoxicillin 1 g VO every 12 hours and clarithromycin 500 mg orally every 12 hours for 7 days (group 1) was compared with the same antibiotic regime over 10 days (group 2). Patients had either non-ulcer dyspepsia (NUD) or ulcer dyspepsia (UD). Effectiveness of eradication was evaluated with breathe tests. A year later, clinical responses to each therapy were compared for patients with NUD and DU. The tolerance to therapy was also evaluated for each group.

Results: 149 patients were randomly assigned to group 1 and 144 patients to group 2. The eradication rate as measured by ITT analysis was 67.8% in group 1 and 74.3% in group 2 (p = 0.24). It was 72.1% and 81. 1% (p = 0.08) respectively for per protocol analysis. The eradication rate was similar for both groups independently of the degree of H pylori infection (p = 0.22). Differences in the degree of infection and the presence of NUD or DU (p = 0.19) were not found. Adverse effects were more frequent in group 2 (27.5% vs. 36.1%), but without statistical relevance (p = 0.4). The eradication rate was similar for patients with NUD (73.8% vs. 81,1%) and DU (64.3% vs. 73%). Follow up examinations one year later showed that the clinical manifestations were not related to the whether or not bacteria had been eradicated (p = 0.7). Nevertheless, the clinical response of patients with DU was better than for those with NUD.

Conclusions: Standard therapy for either 7 or 10 days is insufficient for eradication of H pylori independent of the degree of H pylori infection or the type of endoscopic finding (NUD or DU). Both therapies show suboptimal eradication rates and poor clinical responses at one year follow-up in the group with NUD.

Key words

Helicobacter pylori, eradication therapy, peptic ulcer disease, functional dyspepsia, non ulcer dyspepsia.

INTRODUCTION

By the beginning of the 21st century, helicobacter pylori (H. pylori) had conquered over 50% of the world's stomachs to become the most common infection among human beings. Its prevalence is highest in third world countries (1). The presence of the H. pylori infection in Colombia is among the highest in the world, with rates that may reach 60% among children (2-4) and 80% among adults (5,6). The clinical spectrum indicating the presence of H. pylori in the stomach ranges from asymptomatic infections through manifestations such as gastritis and peptic ulcers (gastric or duodenal) all the way to neoplasms such as MALTs and gastric adenocarcinomas (7). There can even be extra gastric manifestations (8).

Almost 30 years after H. pylori was first described (9) researchers have not yet defined the ideal treatment protocol even though it is well established and universally accepted that the threshold of response to eradication treatment should not be less than 80% (10,11).

H. pylori eradication is considered to be the most important treatment strategy for peptic ulcers since it prevents relapses and facilitates rapid healing (12). The ideal H. pylori treatment must be simple, low cost, free of side effects, and effective in all cases.

The first line standard H. pylori eradication treatment is triple treatment for 7 to 14 days. A proton pump inhibitor (PPI) is combined with two antibiotics which are usually clarithromycin (500 mg twice daily) and either amoxicillin (1 g twice daily) or metronidazole (500 mg twice daily) according to internationally accepted management guidelines, including the Maastricht III Consensus (10,11,13). The success rate reported in different publications varies from 80 to 96% (14).

Over 10 years ago a local study showed satisfactory success rates (90%) for triple treatment (15), but recent Colombian studies have shown that antibiotics like metronidazole and clarithromycin have reached prohibitively high levels of bacterial resistance for routine use (15-17). Current data show success rates for H. pylori eradication decreasing to the lower inferior limits (18). The failure of eradication results either from patient intolerance to treatment or bacterial resistance to antibiotics. The extensive use of macrolide antibiotics for respiratory infections and consequent increased bacterial resistance to clarithromycin play an important role here (19).

There are also doubts about optimal triple treatment treatment time. A minimum of 7 days of treatment is recommended by the European group for the study of the H. pylori (10), the second Asia-Pacific (20) consensus, and by Japanese data (21). American guidelines suggest 10 to 14 days of treatment (22). Latin American reports can be found with widely varying results. In Mexico one study found 14 days eradication was superior (92.3%) to 7 days (62.2%) while the 2005 Brazilian consensus recommends triple treatment for 7 days (23, 24). An Ecuadoran study reveals a higher success rate for eradication with 10 day treatment (83.8%) than with 7 day treatment (68%) (25), but a Peruvian study showed no differences between 7 and 10 day therapies: both had 86% eradication rates (26). There are also reports of good results with 3 day and 5 day quadruple treatment (27, 28). The contradictory findings of two meta-analyses regarding the treatment times add up to a lack of unanimity and consensus. The first by Calvet (29) justifies the use of longer treatment times (10 days) while the most recent one by Fuccio (30) finds no differences between longer treatment times and 7 day H. pylori eradication.

Given the widespread uncertainty regarding the optimal treatment time for eradication of H. pylori, this study compares the efficacy of standard triple treatment for eradication of H. pylori combining a proton pump blocker plus clarithromycin and amoxicillin administered for 7 days with the same treatment administered for 10 days.

MATERIALS AND METHODS

This was an open randomized clinical trial in an urban population of outpatients who consulted the authors of this study between January 2007 and May 2010.

Study population

Patients between 18 and 70 years were included in this study when they had histological diagnoses of H. pylori infection in samples obtained through endoscopy. Samples were tinted with hematoxylin-eosin. Patients were excluded if they had had gastrectomies, peptic ulcer complications such as stenosis or bleeding, if they were pregnancy or lactating, if their endoscopic examination showed MALT or gastric cancer, and if they had been treated for H. pylori before.

To prevent interference with H. pylori treatment, patients who had taken antibiotics, bismuth compounds, histamine H2-receptor antagonists, probiotics or PPI were excluded. In addition patients with major psychiatric disorders, allergies to penicillin or concurrent histories of malignancies, liver failure and kidney failure were also excluded.

Design of the study

Patients who had had biopsies which tested positive for H. pylori at various medical institutions in Medellin and in the private practices of several of the authors were included in this study. Two standard H. pylori eradication therapies were tested, one of 10 days and the other for 7 days.

For sample selection, different population proportions were used. We assumed a Type 1 error of 0.05 and defined a 90% eradication rate as successful for the 10 day treatment group, but defined an eradication rate of 78% as successful for the 7 day treatment groups with an absolute difference of 12% between the two proportions. We used an assignment ratio of 1.0 for the two groups. Using these parameters the sample size calculated by Sample Size version 1.1 was 140 patients per study group.

The following findings from patients' demographic characteristics and endoscopic assessments were considered: gastritis without erosive components, gastritis associated with erosive components, and gastric ulcer or duodenal ulcers. The density of H. pylori infections found after histological examinations using only hematoxylin-eosin staining of at least two antral biopsies were categorized into two groups: low (1 or 2 crosses) or heavy (3 or 4 crosses).

Follow up examinations were conducted from 1 to 3 weeks after treatment completion. We assessed any adverse effects related to the treatment and treatment tolerance, and we recorded whether or not treatment had been carried out completely. This was defined as the consumption of over 70% of the prescription (5 of the 7 days or 7 of the 10).

Study groups

Patients received 20 mg omeprazole orally every 12 hours for 30 days. They were treated with 1 g amoxicillin and 500 mg clarithromycin orally every 12 hours for either seven days (Group 1) or ten days (Group 2) depending on the group they had been randomly assigned to. A randomization sequence was generated using EPIDAT ® 3.01. Once the sequence was obtained patient were assigned to treatment groups. Patients were urged not to smoke during administration of the treatment.

Evaluation of eradication

Optimized breath tests were performed at the Laboratorio Clínico Hematológico S.A. in Medellin, Colombia from 4 to 6 weeks after treatment. The optimized breath test has sensitivity, specificity, positive predictive value and negative predictive values of 100% (31).

The primary assessment indicator was eradication of H. pylori infection as measured by a negative result reported by the Carbon 13 based laboratory breath test. A secondary indicator was an assessment of patient adherence to treatment which was defined as consumption of 70% or more of prescribed medication. This was evaluated at a follow up appointment after the completion of the antibiotic treatment. Protocol analyses were taken into account.

The breath tests were blinded: performed by an investigator who had no knowledge of patients' treatments.

One year evaluation of treatment

Evaluations of patients' clinical conditions based on the validated Spanish version of the Rome III criteria for functional gastrointestinal disorders in adults (32, 33) were performed at the time treatment was prescribed and one year after H. pylori eradication treatment had been completed. Clinical condition was recorded a year after the treatment to determine whether H. pylori infections had gotten better, worse or had remained the same. One year analyses especially emphasized comparisons of initial endoscopic diagnoses of patients and the ratio of H. pylori eradication in the one year follow up assessment of clinical conditions.

Statistical analysis

The demographic characteristics of both groups were compared by chi-square tests. Rates of H. pylori eradication were analyzed by intention to treat (ITT) or per protocol analysis (PPA). All the patients of the study were evaluated by intention to treat (ITT) analysis. Only the patients who had completed treatment were considered for PPA. Differences in H. pylori eradication rates and 95% confidence intervals were calculated for ITT and PPA. We expected that the eradication rate for the 7 day treatment group (group 1) would be lower than that for the 10 day treatment group (group 2). A non-inferiority margin of 12% based on previous controlled studies was considered (34, 35). We also compared incidences of adverse effects between the two groups using the chi-square test. Clinical response at one year was assessed by comparing the two treatment groups using the chi-square test. P values <0.05 were considered statistically significant.

Ethical issues

This research was classified as a safe investigation without biological, physiological, psychological or social hazards according to the International Declaration of Helsinki, the Belmont Report and Colombian Resolution 8430 of 1993. Resolution 1999 of 1995 which establishes rules for handling medical records was also taken into account.

RESULTS

Patients

Between January 2007 and May 2010 a total of 293 patients were treated for H. pylori eradication. Patients had been diagnosed with H. pylori infections by endoscopic biopsies taken within the month prior to start of the treatment. Of the 293 patients in the study a total of 149 patients were randomized into the 7 day treatment group (group 1) and 144 patients were assigned to receive 10 days of treatment (Group 2). Endoscopic findings of gastritis, erosive gastritis and duodenal or gastric ulcer were similar for the two treatment groups. There were no significant demographic differences between the two groups (Table 1).

Table 1. Demographic and clinical characteristics of treatment groups.

Eradication rates

The eradication rate for patients treated for 7 days was lower than that for those treated for 10 days in both ITT analysis and PPA. Nevertheless, neither treatment achieved optimal eradication rates (Table 2).

Table 2. Eradication rates for both groups.

By determining whether eradication rates were related to the degree of H. pylori infection according to biopsy data, we found that eradication rated were similar for both treatment groups independent of the amount of bacteria (Table 3).

Table 3. H. pylorieradication rates and relation to degree of infection.

No significant differences were found in relation to degree of H. pylori infection or type of endoscopic finding (NUP or UD). (Table 4).

Table 4. Relation of the endoscopic findings and the H. pylori infection degree.

Adverse reactions

Out of 149 patients treated for 7 days, 11 were suspended from treatment due to intolerance. Of the 144 patients treated for 10 days, treatment of 17 patients was not completed. 120 patients from group 1 and 107 patients from group 2 were included for PPA. Adverse effects were seen in 27.44% of the patients treated for 7 days and in 36.09% of the patients treated for 10 days but without any significant statistical difference (p=0.392).

The most common symptoms in both groups were epigastric pain, nausea and vomiting (with a metallic taste in the mouth), diarrhea, and skin rashes. There were no evident differences between both groups.

Typically symptoms were more intense for the first two or three days and then decreased (Table 5).

Table 5. Adverse effects for both treatment groups.

Response to eradication treatment according to initial diagnosis

There were similar rates of elimination for both treatment regimes according to endoscopic findings (Table 6).

Table 6. Response to eradication treatment according to endoscopic findings.

One year Follow-up

One year after treatment patients were personally or telephonically contacted. Gastrointestinal manifestations, when there were any, were assessed according to the Rome III criteria. We recorded whether symptoms were worse, better or the same. Emphasis was placed on whether initial endoscopic diagnosis indicated functional dyspepsia or peptic ulcer disease with a structural component (erosions or ulcer). No significant differences were found between different treatment regimes at one year follow up examinations.

Nevertheless, evaluations of clinical responses according to initial diagnoses showed that from a hundred patients with ulcer dyspepsia (duodenal or gastric ulcer or erosive gastritis) 72 (72%) improved while from the 193 patients with non-ulcer dyspepsia only 34 (38%) improved (Table 7).

Table 7. Evaluation of clinical behavior according to initial diagnoses one year after H. pylori eradication.

DISCUSSION

Triple treatment with a PPI and antibiotics is renowned as the first line treatment for H. pylori infections. Currently, optimal treatment duration has not been established, and duration varies around the world. The most common standards are between 7 and 14 days of treatment. According to different reports in the Colombian and Latin American literature (36,37,38) the duration of most H. pylori treatments range from 7 to 10 days.

Besides differences in treatment times there is widespread medical ignorance regarding what is the most appropriate treatment for H. pylori eradication. This has already been evaluated in Colombia (37). Treatment regimes differ in terms of duration, number and types of drugs, and triple or quadruple treatment. The latter often uses bismuth with unacceptable local results in terms of eradication rates and with high percentages of side effects (39,40). Other alternatives which use furazolidone have been described as having good eradication rates (41,42).

These wide variations in the different treatment regimens for H. pylori are largely due to rising rates of H. pylori resistance to different drugs used in its eradication. Currently, high Colombian rates of bacterial resistance to metronidazole (16,43) and clarithromycin (17) make it valid to think that longer treatment time may lead to higher rates of eradication. Nevertheless, if this treatment fails due to antibiotic resistance, independent of treatment duration, higher rates of eradication will not result.

In this study ITT analysis did not show a higher eradication rate for 10 day standard treatment. The 10 day treatment group's eradication rate was 74.3% while the 7 day treatment group's rate was 67.8%. There were no differences in terms of adverse effects (36.1% versus 27.5%) or necessity to suspend treatment (15.7% versus 8.72%). However, these numbers do show that both therapies have below the optimal eradication rate. These rates should both be above the 80%. Moreover, longer treatment time results in a larger proportion of undesirable effects.

In contrast to our study, Calvet's meta-analysis (29) shows a higher eradication rate with 14 days of treatment than for 7 days of treatment, but the 7 studies included in the meta-analysis use different treatment schemes. Four studies combined a PPI with amoxicillin and clarithromycin, two others combined clarithromycin and metronidazole, and one study combined clarithromycin or amoxicillin. This makes it difficult to compare our results with those of this meta-analysis.

These results suggest that, in geographic areas with high rates of antibiotic resistance, this resistance to antibiotics, rather than treatment duration, is the primary cause of failure to eradicate. Even in the analysis by protocol, the success of eradication was barely above the lower limit expected.

As other series have described (44,45) eradication rates and long term symptom control are better for patients with UD than for those with NUD. This study shows that, once H. pylori have been eradicated and the follow-up has been done, clinical improvement in patients with duodenal ulcers (72%) was higher than that for patients with ulcer dyspepsia (17.6%). It has been argued that differences in the types of H. pylori strains that cause the infections are the most likely explanation (46). Some meta-analyses affirm that the more virulent strains (vacA s1, cagA-negative) are easier to eradicate than the less virulent strains (vacA s2, cagA-negative) (47). It is possible that, because the less virulent strains reach higher population densities in the mucus, patients become more difficult to cure as a result of high bacterial loads. The more virulent strains cause more inflammation (48). Increased inflammation facilitates arrival of antibiotics at the bacteria colonization site. Different studies, in contrast to this series, have shown that patients with greater inflammation had more chances of being cured of their H. pylori infections (49,50). Patients with ulcer dyspepsia are more frequently infected with the more virulent strains than patients with non ulcer dyspepsia. This may explain the differences between success rates and manifestations of poorer health in the NUP group at the one year follow up. No correlation between virulence factors and antimicrobial resistance has been described.

The data described raises several questions. Should treatment time be increased up to 14 days? This would increase not only treatment duration but also costs and potentially adverse effects from medication? Which drugs should be used? Should the various schemes described as alternative, sequential or concurrent treatment that use metronidazole, which is prohibitively expensive for use in Colombia, be tried because of the high resistance to other drugs described above? Should Levofloxacin be the alternative of choice, considering that two meta-analyses support using it as rescue treatment when the initial standard treatment has failed? (51,52). This study raises more questions than it answers, but it evokes the B commitment of the medical community to conduct research in this area. In this way we can offer our patients better management alternatives, based on our own numbers. This is especially important considering that H. pylori infections are so frequent and so serious.

CONCLUSIONS

10 day H. pylori eradication treatment is not superior to 7 day H. pylori eradication treatment, but it does result in higher incidence of adverse effects and treatment desertions. Results for both eradication treatments are not satisfactory which suggests reduced eradication rates due to increased bacterial resistance.

Conflict of interests

The authors declare that they have no conflict of interests.

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47. Saxena A, Shukla S, Prasad KN, Ghoshal UC. Virulence attributes of Helicobacter pylori isolates & their association with gastroduodenal disease. Indian J Med Res 2011; 133: 514-20.

48. Ruggiero P. Helicobacter pylori and inflammation. Curr Pharm Des 2010; 16(38): 4225-36.

49. Tsai HF, Hsu PN. Interplay between Helicobacter pylori and immune cells in immune pathogenesis of gastric inflammation and mucosal pathology. Cell Mol Immunol 2010; 7(4): 255-9.

50. Li Y, Huang X, Yao L, Shi R, Zhang G. Advantages of Moxifloxacin and Levofloxacin-based triple therapy for second-line treatments of persistent Helicobacter pylori infection: a meta analysis. Wien Klin Wochensch 2010; 122(13-14): 413-22.

51. Saad RJ, Schoenfeld P, Kim HM, Chey WD. Levofloxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infection: a meta-analysis. Am J Gastroenterol 2006; 101(3): 488-96.

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