Healing NSAID-induced gastric ulcers: have we found the optimal antisecretory agent?

Original Citation

Agrawal NM, Campbell DR, Safdi MA, Lukasik NL, Huang B, Haber MM for the NSAID-Associated Gastric Ulcer Study Group.  Superiority of lansoprazole vs. ranitidine in healing non-steroidal anti-inflammatory drug-induced gastric ulcers.

Overall Study Question

This study was a prospective, multicentre, double-blind, parallel group study designed to identify the optimal antisecretory therapy for healing of gastric ulcers in patients using an nonsteroidal anti-inflammatory drug (NSAID) and the impact of Helicobacter pylori infection on gastric ulcer healing.

Patients aged 18 years or older with an active non-malignant gastric ulcer (primary lesions >5 mm in diameter) documented by endoscopic and biopsy findings and who were receiving a stable dose of an NSAID for at least the previous month were eligible for enrollment into the study.  The primary study endpoint was gastric ulcer healing rate at 8 weeks. Secondary endpoints included gastric ulcer healing rate at 8 weeks in H. pylori-infected and non-infected patients.  Patient symptoms were also assessed using a patient diary that was completed on a daily basis.

Are the Results of the Study Valid?

Was assignment of patients randomized?

Yes.  All patients were assigned randomly in a 1:1:1 ratio to receive ranitidine 150 mg orally twice daily, or lansoprazole 15 or 30 mg orally once daily for 8 weeks.

Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes.  Endoscopy was performed on 669 patients of which 353 met study criteria for presence of a gastric ulcer and were randomized to received ranitidine 150 mg twice daily (n=117), lansoprazole 15 mg daily (n=119) or lansoprazole 30 mg daily (n=117).  Three patients were excluded from all  efficacy analysis (2 patients had no gastric ulcer and one patient did not receive an NSAID before and during treatment).  In addition, 9 patients were not included in the analysis of patient diary data because they did not record data.

Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Yes.  A double-dummy blind design was used to maintain the double-blind nature of the study. Patients administered one capsule before breakfast and dinner for 8 weeks.
Were the groups similar at the start of the trial?

Yes.  All three groups demonstrated similar baseline parameters at the start of the trial.

Aside from the experimental intervention, were the groups treated equally?

Yes.  Patients also received antacid tablets (400 mg each of aluminum hydroxide and magnesium hydroxide and 25 mg of simethicone) and were instructed only to use them for symptom relief as needed.  Patients were also instructed to avoid any other antiulcer (e.g. H2-receptor antagonist,> misoprostol, or sucralfate) or ulcerogenic medications (except an NSAID or low dose aspirin) other than the study medications until completion of the study.

Overall, are the results of the study valid?
Yes.

What were the Results?

How large was the treatment effect? 

The primary endpoint, gastric ulcer healing at 8 weeks, occurred in 53% patients treated with ranitidine compared to 69% of patients who received lansoprazole 15 mg (p=0.01 vs. ranitidine, 95% confidence interval [CI] for the difference between groups 3.2-28.0) and 73% of patients who received lansoprazole 30 mg, (p=0.009 vs. ranitidine, 95% CI 7.4-31.8).  This correlates to an absolute risk reduction (ARR) of 16-20% and a number needed to treat of 5 and 7 for lansoprazole 15 and 30 mg daily, respectively, as compared to ranitidine for ulcer healing at 8 weeks.

The secondary endpoint of gastric ulcer healing rate at 8 weeks in H. pylori-infected and non-infected patients was not different between the groups.  As with the total population, the lansoprazole 15 mg and 30 mg recipients had higher gastric ulcer healing rates at 8 weeks in both the H. pylori-infected (67% and 82%, respectively) and non-infected patients (70% and 69%, respectively) as compared to ranitidine (60% and 51% for H. pylori positive and negative patients, respectively).

During the 8 treatment weeks, there was no difference in the improvement in symptom relief, however a statistically significant reduction in antacid use was observed with lansoprazole 15 mg (p<0.01) and 30 mg (p<0.05) use as compared to ranitidine. In particular, there were fewer antacid tablets per day (ranitidine 1.11 vs. lansoprazole 15 mg 0.86 (p<0.05) vs. lansoprazole 30 mg 0.78 (p<0.01)) and a smaller percentage of days of antacid use (ranitidine 35.6% vs. lansoprazole 15 mg 30.9% (p=ns) vs. lansoprazole 30 mg 28.7% (p<0.05)). The authors did not provide information regarding any actual OTC use of H2-receptor antagonists or other medications.

Overall, treatment-related adverse effects occurred in 11% of ranitidine-treated patients and 8% and 9% of lansoprazole 15 mg and 30 mg recipients, respectively. The most common adverse effect reported by the patients was diarrhea. There were no statistically significant differences among treatment groups for any specific drug-related adverse effect.

How precise was the estimate of the treatment effect?

The 95% CI for the primary endpoint of gastric ulcer healing at 8 weeks did not include zero, thus indicating statistical significance.  In this author’s opinion, the lower end of the CI range still represents a clinically significant difference between treatment groups.

Will the Results Help Me in Caring for My Patients?

Can the results be applied to my patient care?
Yes.  The results of this trial can be applied to the care of patients as the data provides additional evidence that proton-pump inhibitors (PPI) appear to be the agents of choice for the treatment of NSAID-induced gastric ulcers.  Prior to this trial, omeprazole was the only agent that has been shown to improve gastric ulcer healing and prevent NSAID-induced gastric ulcers.  With the additional information from this trial, the use of lansoprazole brings up the question of whether a class effect for the PPI exists for this indication. Clearly, the use of lansoprazole is superior to ranitidine for this indication.

Were all clinically important outcomes considered?

Yes, although health-related quality of life and pharmacoeconomic analyses would have been useful.

Are the likely treatment benefits worth the potential harms and costs?
Probably.

Commentary

This clinical trial adds to the growing body of evidence that PPI are the antisecretory agents of choice in the treatment and prevention of NSAID-induced gastric ulcer disease regardless of H. pylori status. The ASTRONAUT trial has established that omeprazole appears to be superior to ranitidine in healing both gastric and duodenal ulcers at 8 weeks and for the maintenance of remission at 6 months for NSAID-induced gastric ulcer disease in patients who continue NSAID therapy for a primary inflammatory disorder.  The OMNIUM trial has demonstrated that omeprazole appears to be as effective as misoprostol in healing ulcers at 8 weeks, but is superior at maintaining remission at 6 months. The addition of the results of the current trial confirms these findings and supports the use of PPI for both the treatment and prevention of NSAID-induced gastric ulcers.

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