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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Background : Helicobacter pylori eradication rates with triple therapies are decreasing, and few data in elderly patients are available. A 10-day sequential regimen succeeded in curing such H. pylori infection in unselected patients.

Aim : To compare this sequential regimen and the standard triple therapy for H. pylori eradication in geriatric patients with peptic ulcer.

Methods : Overall, 179 H. pylori-infected patients with peptic ulcer were enrolled (mean age: 69.5 years; range: 65–83). Patients were randomized to 10-day sequential therapy (rabeprazole 20 mg b.d. plus amoxicillin 1 g b.d. for the first 5 days, followed by rabeprazole 20 mg, clarithromycin 500 mg and tinidazole 500 mg, all b.d., for the remaining 5 days) or standard 7-day triple regimen (rabeprazole 20 mg, clarithromycin 500 mg and amoxicillin 1 g, all b.d.). Helicobacter pylori status was assessed by histology and rapid urease test at baseline and 4–6 weeks after completion of treatment.

Results : The sequential regimen achieved eradication rates significantly higher in comparison with the standard regimen at both intention-to-treat (94% vs. 80%; P = 0.008) and per-protocol (97% vs. 83%; P = 0.006) analyses. In both treatment groups, compliance to the therapy was high (>95%), and the rate of mild side-effects was similarly low (<12%). At repeated upper endoscopy, peptic ulcer lesions were healed in 97% patients, without a statistically significant difference between the sequential regimen and the standard triple therapy.

Conclusions : In elderly patients with peptic ulcer disease, the 10-day sequential treatment regimen achieved significantly higher eradication rates in comparison with standard triple therapy.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

It is well-known that the life-expectation is rising worldwide, and that the percentage of people aged more than 65 years is noticeably increased in the last five decades, particularly in developed countries.1, 2 Ageing is claimed to increase the risk for several gastroduodenal disorders, such as gastric atrophy with intestinal metaplasia, peptic ulcer disease, ulcer bleeding and gastric cancer.3–6 Interestingly, the prevalence of Helicobacter pylori infection in developed countries has been definitely reported to be higher in the elderly than in young patients, a ‘cohort effect’ being invoked as a likely explanation.7Helicobacter pylori infection habitually causes chronic active gastritis, which significantly enhances the risk for intestinal metaplasia in the stomach, and it is undoubtedly involved in gastric carcinogenesis.8 Moreover, this infection is the main pathogenetic factor of gastric and duodenal ulcer, including peptic ulcer complications, such as bleeding or stenosis.9, 10 Furthermore, an intricate – and only partially unravelled – relationship between H. pylori and non-steroidal anti-inflammatory drugs (NSAIDs) use in gastroduodenal lesion onset has been reported in elderly.11–13 Therefore, this infection should be considered as a clinically relevant issue in geriatric patients.14 Despite all these considerations, only scanty data are currently available on H. pylori treatment in aged people. Disappointing eradication rates were reported following dual therapies with omeprazole plus amoxicillin, or clarithromycin or azithromycin,15, 16 whilst severe side-effects have been described using either a quadruple therapy,17 tetracycline-based therapy,18 or a high-dose clarithromycin regimen (1.5 g/day).19 As far as standard triple therapy is concerned, few studies have purposely assessed its efficacy in elderly patients.20–26 A cure rate ranging from 78 to 86% was observed in these trials, the only exception being an eradication rate higher than 90% in one, non-randomized study.26 It has been found that no significant difference emerged regarding the proton-pump inhibitor (PPI) used (omeprazole, lansoprazole, pantoprazole) or the antibiotic combination chosen (clarithromycin plus amoxicillin or metronidazole; amoxicillin plus metronidazole).16 Recently, we have identified a novel 10-day sequential regimen, consisting in a simple dual therapy given for the first 5 days followed by a triple therapy for the remaining 5 days.27 Such a sequential regimen was proved to be highly successful for H. pylori eradication in a very large, multicentre study when compared with the standard 7-day triple therapy.28 Therefore, the present study was purposely aimed to assess the eradication rate of this new sequential therapeutic regimen in a prospective, controlled study in geriatric patients with peptic ulcer.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Patients

This was a prospective, open-label, three-centre, randomized trial. The study population consisted of consecutive dyspeptic patients aged >65 years who were referred by primary care doctors for diagnostic upper endoscopy. Patients were enrolled if both peptic ulcer and H. pylori infection were detected. For the purpose of the study, peptic ulcer was defined as a mucosal lesions ≥5 mm in diameter. Patients previously treated for H. pylori infection were not enrolled in the present study. Moreover, patients were excluded if they were taking PPIs, histamine-2 (H2)-receptor antagonists, or antibiotics in the 4 weeks preceding the study. Similarly, NSAIDs or aspirin user patients (at least one time/week), as well as those patients with known antibiotic allergy, and those with liver cirrhosis, kidney failure or intellectual impairment were not enrolled. All participants gave written informed consent. After overnight fast, patients underwent endoscopy with biopsies for histology (two samples from the antrum and two samples from the corpus), and a rapid urease test (one sample from the antrum). Further biopsy specimens were taken on gastric ulcer in order to exclude malignancy. Patients were considered H. pylori-positive if both tests (histological assessment on Giemsa staining plus rapid urease test) were positive. Intestinal metaplasia [haematoxylin and eosin (H & E) staining] was recorded as present when described either in antrum or in gastric body.29

Treatments and follow-up

In each centre, patients were randomized by using a computer-generated list to receive either a 10-day sequential therapy (rabeprazole 20 mg b.d. plus amoxicillin 1 g b.d. for the first 5 days, followed by rabeprazole 20 mg b.d., clarithromycin 500 mg b.d. and tinidazole 500 mg b.d. for the remaining 5 days) or the standard 7-day triple therapy (rabeprazole 20 mg b.d., clarithromycin 500 mg b.d. and amoxicillin 1 g b.d.). For each therapy regimen, the PPI was prescribed before breakfast and dinner, whereas all antibiotics were immediately given after such meals. The use of alcohol was discouraged during the sequential regimen in order to avoid possible side-effects because of the interaction with the imidazole. Neither additional PPI nor H2-antagonist therapy was given following the antibiotic therapy, whilst antacids on demand were allowed. Patients were asked to return at the end of the treatment to assess the compliance with therapy, and to determine possible side-effects. Compliance was defined as consumption of >90% of the prescribed drugs and it was determined by pill count at the follow-up visit. Side-effects were evaluated using a structured questionnaire by personal interview. Bacterial eradication was checked in all patients 4–6 weeks after treatment by using an upper endoscopy with biopsies as performed at entry. The infection was considered cured when both rapid urease test and the histological examination (Giemsa staining) were negative, together with the absence of neutrophil infiltrate in gastric mucosa (H & E staining). The rapid urease test was evaluated according to manufacturer's suggestions by an experienced nurse. In each centre, both nurse and pathologist were unaware of the therapy regimen used.

Statistical analysis

The differences between the proportions eradicated and their 95% confidence intervals for the two treatments were calculated at both intention-to-treat (ITT) and per-protocol (PP) analyses. For all other variables, chi-squared, Fisher's exact test and t-test were used as appropriate, and P-values of <0.05 were considered significant. The difference between the proportions eradicated using the two treatments (ITT and PP analysis) was estimated for each centre. Before pooling that estimates, a Fisher's exact test was applied to investigate heterogeneity between the differences.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Eradication rates

Overall, 179 patients were enrolled in the study. There were 106 males and 73 females. The mean age was 69.5 years with a range of 65–83. At endoscopy, a duodenal ulcer was diagnosed in 154 (86%) patients and a gastric ulcer in the remaining 25 (14%) patients. As shown in Table 1, the two treatment groups did not differ for age, sex, peptic ulcer type prevalence, gastritis distribution and intestinal metaplasia prevalence in the gastric mucosa. Overall, five patients (one male and one female with duodenal ulcer from sequential therapy and three males with duodenal ulcer from standard therapy) were withdrawn from the study because failing to undergo the scheduled endoscopic control. Therefore, the final PP population consisted of 174 patients. Before pooling the data, no significant difference in the cure rate emerged among the three participating centres for each treatment schedule (Table 2). The eradication rates achieved by the sequential regimen were significantly higher than those of triple therapy, at both ITT (94.4% vs. 80%; P = 0.008) and PP (96.6% vs. 82.8%; P = 0.006) analyses. The overall study results are provided in Figure 1.

Table 1.  Demographic and clinical characteristics of patients at entry
 10-day sequential7-day triple
  1. DU, duodenal ulcer; GU, gastric ulcer.

Number of patients8990
Sex (M/F)50/3956/34
Age, mean (range; years)69 (65–83)70 (65–78)
DU/GU75/1479/11
Antral gastritis5258
Pangastritis3732
Intestinal metaplasia27 (30.3%)31 (34.4%)
Table 2. Helicobacter pylori eradication rates at ‘intention-to-treat’ (ITT) and ‘per-protocol’ (PP) analyses in the participating centres
TherapyRomeFoggiaBolognaP-value
 ITTPPITTPPITTPP 
Sequential28/3028/2927/3027/2929/2929/29N.S.
Standard24/3024/2923/3023/2925/3025/29N.S.
image

Figure 1. Flow chart showing the eradication rates at both ‘intention-to-treat’ (ITT) and ‘per-protocol’ (PP) analyses following the two treatment regimens.

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As far as peptic lesions are concerned, ulcer healing was overall achieved in 168 patients, accounting for a 93.8% and 96.6% cure rate, at ITT and PP analyses, respectively. In detail, at endoscopic control, the peptic ulcer was healed in all but two patients following the sequential regimen (one of whom failed bacterial eradication) and in all but four patients after the triple therapy (two of whom failed eradication). Therefore, no statistically significant difference in the ulcer-healing rate was observed between the two treatment groups (ITT analysis: 95.5% vs. 92.2%).

Compliance and side-effects

Overall, compliance to the therapy was good in all but three (1.7%) patients who stopped earlier the treatment because of side-effects (two vomiting, one urticaria). Nine (10.3%) patients treated with the 10-day sequential regimen complained of side-effects (diarrhoea: three; abdominal pain: three; glossitis: two; vomiting: one), causing treatment interruption in one of them. Ten (11.5%) patients receiving the 7-day triple therapy complained of side-effects (diarrhoea five; abdominal pain two, vomiting two; urticaria one), and two of them interrupted the treatment. No statistically significant difference in the incidence of side-effects emerged between the two treatment regimens. All side-effects were self-limiting after therapy ending.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The aged population is increasing worldwide. Indeed, it has been estimated that by 2020, nearly 132 million in Europe – nearly one-thirds of the general population – will be aged more than 65 years, and elderly people will account for 16% of the USA population.1, 2 Geriatric patients are at increased risk of developing several gastroduodenal diseases, more likely for a reduction of defensive mechanisms in gastrointestinal mucosa.4 Gastric cancer, for instance, is definitely more frequent in geriatric than in young patients.6 In addition, it has been showed that peptic ulcer and related complications occur much more commonly in aged patients when compared with young people, resulting in a dramatically higher mortality.30, 31 Similarly, it has been widely reported that NSAIDs cause gastroduodenal lesions and gastrointestinal bleeding more frequently in aged patients.32, 33 Although the relationship between H. pylori infection and NSAIDs in damaging gastroduodenal mucosa is not fully understood, it has been found that each factor independently acts damaging the mucosa of elderly patients.11–13, 34 Therefore, it has been recently proposed that in those aged patients with comorbid illnesses or a history of peptic ulcer and who require long-term NSAIDs or aspirin treatment, H. pylori infection should be eradicated before starting such a therapy.13 All the aforementioned considerations suggest that H. pylori treatment in elderly should be regarded as a meaningful issue in primary clinical practice.16 Few data are currently available on the use of 7-day triple therapy to cure H. pylori infection in elderly patients.20–26 In the present study, the standard triple therapy regimen achieved an eradication rate of 80% at ITT analysis, which is in whole agreement with the success rate of 82.4% computed from five previous studies – overall including 499 elderly patients – performed in Italy.22–26 This indicates that as much as one of every five patients with peptic ulcer continues to be infected following the standard triple therapy, undoubtedly increasing the cost of infection management. Indeed, infected patients remain at risk of both ulcer recurrence and ulcer complications, which have been proved to be more frequent and clinically more severe in elderly than in younger patients.5, 34 On the contrary, the eradication rate achieved by the sequential therapy in aged people is very high – more than 94%– and significantly higher at both ITT and PP analyses when compared with the standard triple therapy, confirming the data observed in several previous studies performed in unselected patients.27, 28, 35–40 The significantly higher eradication rate of the sequential regimen when compared with the standard 7-day therapy seems to be due to the drug administration schedule rather than the longer duration of treatment. Indeed, in two previous studies, we have found that cure rate following the sequential regimen was significantly higher when compared with the 10-day triple therapy which, in turn, gave a similar success rate of the standard 7-day regimen.38, 39 The latter finding has been also documented in a large meta-analysis.41 It is worthy to note that, in the present study, both side-effect incidence and treatment interruption did not occur more frequently in the sequential than in the standard therapy. All these observations coalesce to define the usefulness of the sequential therapy in geriatric patients. Moreover, the cure rate achieved by the sequential regimen is so high that it should be questioned whether 100 diagnostic tests should be performed to detect less than six therapy failure patients, further favouring both cost-effectiveness of such therapy and patient's benefit.

With regard to peptic ulcer healing, we found that both standard triple therapy and sequential regimen, even without prolonging PPI treatment over the antibiotic course, achieved a very high (>93%) cure rate of peptic lesions. This is in agreement with our and other previous studies performed in unselected patients.36, 42 Therefore, our data seem to confirm that such practice is an adequate and cheap therapeutic approach to manage peptic ulcer lesions in geriatric patients.

One possible limitation of the present study could be its open design. However, it should be considered that both compliance and dropout rates were comparable between the two therapy groups, and that the H. pylori assessment is a relatively objective end-point. Moreover, both histological examination and rapid urease test were performed by operators unaware of the purpose of the study as well as the therapy regimens used. Therefore, although the study was not blinded, the procedures used provide an adequately impartial evaluation of data.

In conclusion, this is the first study purposely designed to assess the eradication rate of the 10-day sequential regimen in geriatric patients with peptic ulcer. As in younger patients, our data indicate that such a therapy regimen is very effective and safe, achieving an eradication rate significantly higher when compared with the standard triple therapy.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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