Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers

 
Authors Chan F, Sung J, Chung S, To K, Yung M, Leung V, Lee Y, et al.
Source Lancet. 350:975-9. October 4, 1997. 
Institutions Prince of Wales Hospital and The Chinese University of Hong Kong, Hong Kong. 
Support None indicated. 

 

Background

Non-steroidal anti-inflammatory drugs are frequently prescribed medications which can cause gastric and duodenal ulcers. Prevention with misoprostol and/or proton pump inhibitors is effective but expensive; more cost-effective methods of prevention are needed. 

The role of H pylori in the pathogenesis of NSAID induced ulcers is not clear. This study was undertaken to study the effectiveness of H pylori eradication in preventing NSAID induced peptic ulcer disease. 

Methods

Patients

Patients over 18 years of age requiring NSAID therapy for musculoskeletal disorders were recruited from outpatient clinics. 

Exclusions: prior use of NSAIDS (including ASA) for over one month; prior anti-H pylori therapy; any use of NSAIDS, anti-ulcer therapy, steroids, anticoagulants or cytotoxic therapy in the previous 8 weeks; history of gastric ulcer disease, gastric surgery or renal impairment. 

Pre-randomization endoscopy

All patients who agreed to participate in the study underwent baseline endoscopy (all endoscopies performed by one endoscopist). The presence or absence of peptic ulcers was noted, and five antral biopsy specimens were obtained. Two of these specimens were used for a rapid urease (CLO) test, and three were submitted for histology (H&E and Warthin Starry stains). A patient was deemed infected with H pylori if both rapid urease and histology were positive. 

Intervention

Patients who had documented H pylori infection at baseline and who did not have an ulcer were randomized to one of two regimens: 

  • Treatment for 8 weeks with naproxen 750 mg daily (250 mg every 8 hours).

    •  
  • Pretreatment for one week with triple therapy (four times daily each: bismuth subcitrate 120 mg, tetracycline 500 mg and metronidazole 400 mg), followed by the same 8-week course of naproxen as above.
Additional pain relief with propoxyphene and acetaminophen was provided as needed. 

Follow-up

Information on smoking, alcohol consumption and other medical illnesses was obtained. 

Endoscopy was repeated after 8 weeks of naproxen therapy to ascertain the presence of peptic ulcer disease and eradication of H pylori (negative rapid urease test and histology). Patients with gastrointestinal symptoms requiring the discontinuation of naproxen or with GI hemorrhage underwent endoscopy earlier. 

Analysis

The primary endpoint was the cumulative incidence of gastric and duodenal ulcers in all patients who had a second endoscopy (intention to treat analysis). Analyses of patients who completed most of the therapy (per-protocol analysis), and according to H pylori cure rate were also performed. 

Results

Patients

202 patients underwent the first endoscopy. 91 were not infected with H pylori; 2 had ulcers at baseline; 9 refused to be randomized. 

As a result, 100 patients who were H pylori positive and without ulcers at baseline were randomized (50 to triple therapy plus naproxen, 50 to naproxen alone). 

There were 8 withdrawals prior to the second endoscopy (for various reasons), leaving 92 patients for analysis, 47 in the naproxen group, 45 in the triple therapy plus naproxen group. 

Patients in these two groups were well matched for age, smoking status, alcohol use and comorbidities. There were slightly more gastric erosions in the triple therapy group (7 vs. 2; p=0.09). The main reason for NSAID prescription was osteoarthritis. 

Triple therapy and H pylori eradication

41 out of the 45 patients in the triple therapy group completed at least 5 days of treatment. H pylori was eradicated in 40 out of the 45 patients (89%). 

H pylori was eradicated in none of the patients who did not receive triple therapy. 

Ulcer incidence

In the naproxen alone group, 12 out of 47 patients developed ulcers (26%). 9 patients had gastric ulcers, 2 duodenal and 1 had both. 6 of the 12 were symptomatic, requiring early endoscopy (5 for pain, 1 for bleeding). 

In the triple therapy plus naproxen group, 3 out of 45 patients developed ulcers (7%; p=0.01 for the comparison). These ulcers were all gastric. One patient underwent early endoscopy for pain. 

Looking at the 3 patients in the triple therapy group who developed ulcers, 2 of these failed to have eradication of H pylori. Thus, only one patient out of 40 (2.5%) who had eradication of H pylori developed an ulcer. 

Results were similar in the per-protocol analysis. 
 

Author's discussion

The authors note that previous studies on the role of H pylori in NSAID induced ulcer disease have yielded conflicting results. Previous studies of this issue have been of three types: 
  • Epidemiologic (cross-sectional) studies looking at:

    •  
    • the rates of H pylori infection in NSAID users with ulcers. Two studies (13, 20) found higher rates, but one (14) did not.

      •  
    • the rates of ulcer disease in NSAID users who were H pylori positive/negative. Three studies found higher rates (12, 16, 19), whereas 3 did not (15, 17, 18).

      •  
  • Prospective cohort studies following patients who were treated with NSAIDS.  Three studies (21, 22, 23) in patients on short-term NSAID therapy found no interaction between H-pylori status and the severity of GI damage. One longer-term therapy study found an interaction (26), one did not (25).

    •  
  • Studies similar to this one, examining the effect of H pylori eradication on the subsequent development of ulcers. One study, in a small number of patients (27), found a benefit; another one (28) did not.
The authors feel that those studies that did not show a relationship between H pylori status and NSAID-related ulcers, failed to do so for a number of reasons. Many of these studies looked at patients who were chronic NSAID users and thus patients who had ulcer complications may have been naturally selected out.  Others were small, and the trial similar to the current one, which found no benefit to eradication (28), the actual rate of H pylori eradication was low. 

They conclude that eradication of H pylori infection prior to NSAID therapy is a cost-effective therapy, particularly if blood serology, rather than endoscopy, is used as a screening method. 

Comment

In this trial, patients starting NSAID therapy who were H pylori positive and who were pre-treated with one week of anti-H pylori therapy had a significantly lower rate of peptic ulcer disease than those who were not treated. The cumulative rate of gastric and duodenal ulcers after 8 weeks of NSAID therapy was 26% without treatment, vs. 7% with treatment. 

The trial appears to have been well-designed, although it was not fully blinded. Patients obviously knew whether they had undergone antibiotic therapy or not. It is stated that the endoscopist was blinded to the patient's treatment status. 

One limitation to the results presented here lies in the patient population: these patients all were "NSAID naive".  None of them had had prolonged NSAID therapy in the past. Since many ulcer complications of NSAID therapy occur early, these results probably do not apply to patients who have taken NSAIDS without problem in the past, and who are thus at a lower risk of complications. 

Although the authors state that endoscopy should not be necessary to apply their findings, they did not report H pylori serologies in their series, so the utility of the serologic approach cannot be directly extrapolated.
 

October 19, 1997

References

References related to this article from the NLM's PubMed database. 

Reader Comments

Date: Tue, 21 Oct 97
From: Masatoshi Matsumoto <matmo10@jb3.so-net.or.jp> 

Hello friends!

This paper is a well designed article, and supplies good information about the association between NSAIDs-induced peptic ulcer disease and H.pylori.

But following points seem to be necessary for the author's conclusion:

1. Direct trial of H. pylori serology to these patients.
2. Strict cost analysis between H. pylori eradication and misoprostol, high dose famotidine or PPI. 
 
 

    The question of H. pylori serology needs to be addressed.

    As for the cost comparison, the following costs to the pharmacist are from the Medical Letter, January 3, 1997:

    Bismuth subsalicylate 525 mg qid for one week -- approx. $5
    Metronidazole 500 mg qid -- approximately $2
    Tetracycline 500 mg qid -- approximately $2

    These prices will be higher for the consumer, and this is a particularly cheap regimen (which does not incorporate a PPI or clarithromycin). However, if this regimen is as effective as it was in this study, it is extremely cheap compared with the cost of misoprostol, famotidine or the Proton Pump Inhibitors for any length of time. In fact, even the most expensive regimen for H Pylori eradication plus the cost of determining serology will be cheaper than taking these other drugs for several months. This would not apply if the duration of NSAID use were short; a cost-effectiveness analysis would indeed be necessary for this case.    -- mj 

From the corresponding author of this study:

Date: Tue, 04 Nov 1997
From: "Dr. Francis KL Chan" <fklchan@cuhk.edu.hk>
Organization: The Chinese University of Hong Kong

Dear Dr. Jacobson and Dr. Matsumoto, 

Thank you for your interest in this study and your valuable comments are highly appreciated. 

1.Since ulcer complications tend to occur during the first few weeks of NSAID treatment especially in those without previous drug exposure, it would be more relevant to eradicate H. pylori in this group of patients than those who are at a lower risk of ulcer disease. 

2.We are now testing the H. pylori serology of these patients and will report the results in due course. 

3.Based on the price list from our local pharmacy, we have estimated that serology test plus one-week of bismuth triple therapy cost US$25, whereas 8 weeks of prophylactic treatment using misoprostol (200 ug q.i.d.) costs US$58. Eradication of H. pylori with a short course of antimicrobial therapy is cheaper than prophylaxis with antiulcer drugs. 

Yours sincerely, 

Francis K. L. Chan
Associate Professor
Division of Gastroenterology and Hepatology
Department of Medicine & Therapeutics
The Chinese University of Hong Kong 

December 1, 1997

One letter to the editor about this article appeared in the Lancet, November 22, 1997. 

January 5, 1998

More letters to the editor about this article, with authors response, in the Lancet, January 3, 1998. 
 

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