Rapid protection of the gastroduodenal mucosa against aspirin-induced damage by rabeprazole

Authors


Dr R. S. Fisher, Gastroenterology Section, Temple University Hospital, 800 Parkinson Pavilion, 3401 N Broad Street, Philadelphia, PA 19140, USA.
E-mail: robert.fisher@temple.edu

Summary

Background  The ability of a proton pump inhibitor to reduce or prevent NSAID-induced gastroduodenal damage during the first 24 h has not been tested.

Aim  To determine, whether oral rabeprazole, administered 5 h before the initiation of therapeutic dosing of aspirin protects the gastroduodenal mucosa.

Methods  Normal subjects were randomized into two groups – one received rabeprazole, 20 mg at 07:00 hours and the other placebo, before initiation of aspirin 650 mg at 12:00 hours, and then q4 h for 3 days. Upper endoscopic examinations were performed on all subjects at baseline, 24 and 72 h after initiation of aspirin. Gastroduodenal mucosal damage was scored.

Results  Thirty subjects were compliant with study medications and underwent three endoscopic examinations. Salicylate concentrations were similar for the placebo and the rabeprazole groups at all times. On rabeprazole, the Lanza scores were significantly lower compared with placebo at 24 h (1.3 ± 0.26 vs. 2.1 ± 0.26, P < 0.05) and at 72 h (1.3 ± 0.29 vs. 2.3 ± 0.28, < 0.05). Gastric antral erosion counts were less with rabeprazole than placebo at 24 (4.1 ± 1.3 vs. 7.6 ± 2.0, P > 0.05) and 72 h (5.3 ± 1.8 vs. 8.0 ± 1.5; P > 0.05).

Conclusions  Rabeprazole, initiated 5 h before the start of therapeutic dosing with aspirin, decreased Lanza scores and antral erosion counts at 24 h. These findings suggest that prophylaxis with rabeprazole could start concurrently with aspirin administration.

Introduction

Acute administration of therapeutic doses of aspirin (ASA) is known to cause gastroduodenal lesions in the form of submucosal haemorrhages, erosions and ulcers, which may lead to gastrointestinal bleeding. These lesions and associated bleeding can occur rapidly after initiation of ASA therapy. It is well known that acid inhibition by high-dose histamine-2 receptor antagonists (HRA) or regular dose proton pump inhibitors (PPI) can prevent and/or heal ASA and other nonsteroidal anti-inflammatory drug (NSAID)-induced gastroduodenal erosions and ulcers.1–3 There are little data, however, on the speed of onset of these effects. We have recently confirmed that the antisecretory effect of rabeprazole begins within 2½–3 h after its oral administration and is maximal within 5–6 h.4

Aspirin is often indicated in patients with chest pain, fever, musculoskeletal pain and in larger doses in various rheumatologic disorders.

Previous studies in our laboratory5, 6 and others7, 8 have demonstrated rapid suppression of intragastric acidity after administration of rabeprazole. The study design employed in this protocol was similar to those employed by earlier investigators9–12 to study the effects of ASA on the gastric mucosa.

The aims of this study were twofold. First, to determine whether oral rabeprazole, administered 5 h before the initiation of therapeutic dosing of ASA (650 mg, q4h), protects the gastroduodenal mucosa from damage during the initial 24 h; secondly, to investigate if once daily rabeprazole protects the gastroduodenal mucosa from damage during the 72 h of therapeutic dosing of ASA.

Materials and methods

This was a double-blinded, randomized, placebo-controlled study done in the Gastroenterology Section at Temple University Hospital.

Patient population

Thirty (30) normal subjects were recruited. The subjects chosen were between 18 and 60 years of age. They had no history of gastrointestinal disease, gastroduodenal surgery, upper gastrointestinal symptoms of any kind. There was no history of Helicobacter pylori infection or its treatment in the past. Study subjects had no allergy to ASA or rabeprazole. They had not ingested a salicylate, NSAID, HRA, PPI, misoprostol or carafate within 1 month of entering this study. He/she had not participated in any investigation study within 3 months of this protocol. Pregnant women and women not using an accepted method of birth control were excluded. For screening, normal subjects (volunteers) underwent an initial out-patient visit which involved a complete history and physical examination, a complete blood count, serological testing for H. pylori, serum salicylate level and stool testing for occult blood. Anaemia, iron deficiency, H. pylori positivity or elevated serum salicylate excluded a volunteer from participating in this protocol. A screening oesophagogastroduodenoscopy was performed to assess the presence of erosions or ulcers in the oesophagus, stomach or duodenum. Any such lesions excluded the subjects from the study.

Study protocol

Thirty (30) eligible normal subjects were randomized to one of two study groups: rabeprazole 20 mg OD (n = 15) or placebo OD (n = 15). They were admitted to the Temple Clinical Research Center (CRC) for the duration of the study. This was done to ensure compliance with study medication and to have a controlled environment and diet to avoid any confounding variable such as alcohol or other medications. Study subjects arrived at the CRC at 8:00 pm on study day 0. Each study subject received a single dose of study drug (rabeprazole or placebo) at 7:00 am on study days 1, 2 and 3 – 1 h before breakfast. All research subjects received ASA, 325 mg tablets as two tablets with 240 mL water every 4 h at 8:30 am, 12:30 pm, 4:30 pm, 8:30 pm, 12:30 am and 4:30 am daily for study days 1, 2 and 3 (a total of 3900 mg ASA/day) except for study day 1 when the initial dose of ASA (two tablets, 650 mg) was administered at 12:00 pm. Oesophagogastroduodenoscopy was performed at 12:00 noon on days 2 and 4, i.e. 24 and 72 h, respectively, after initiation of ASA. During each endoscopy, the maximum number of submucosal haemorrhages and erosions in an endoscopic field from the anterior and posterior walls of the antrum were counted. In addition, a Lanza score was assigned for each endoscopic examination (Table 1). Endoscopic photographs were obtained during each endoscopic examination. Meals were standardized as follows for each day of the study:

Table 1.   Lanza scoring system
ScoreDescription
  1. * Mucosal haemorrhage with luminal bleeding.

  2. † Erosion is defined as a lesion producing a definite discontinuance in the mucosa but having no depth.

  3. ‡ Peptic ulcer is defined as a circumscribed mucosal break ≥5 mm in diameter with well-defined crater.

0No visible lesions
+11 haemorrhage* or erosion†
+22–10 haemorrhages or erosions
+311–25 haemorrhages or erosions
+4>25 haemorrhages or erosions or an invasive ulcer‡
  1. A blood sample was obtained at 7:00 am on study days 2, 3 and 4 for measurement of serum salicylate levels.

Breakfast: 8:00 am (study days 1, 2, 3 and 4)
 Study days 1 and 3: two eggs, two slices of white bread, 4 oz unsweetened orange juice
 Study days 2 and 4 (endoscopy days): one can of Ensure (240 calories)
Lunch: 1:00 pm (study days 1, 2 and 3)
 Turkey sandwich, two slices of wheat bread, lettuce, tomato, one orange, 8 oz apple juice
Dinner: 6:00 pm (study days 1, 2 and 3)
 Two plain hamburgers, ketchup, mustard, lettuce and tomato; tossed green salad with thousand island dressing, one cup of French fries, 8 oz whole milk
Snack: 10:00 pm (study days 1, 2 and 3)
 Four graham crackers, 4 oz orange juice

Statistics

The main data point for our study was the Lanza score assigned for each endoscopic examination. Lanza scores, after rabeprazole were statistically compared to those after placebo on days 2 and 4.

Prior studies have shown that acetylsalicylic acid (ASA) 3900 mg daily, provided a Lanza score of 3.6 with standard deviation of 0.52.9, 10 We hoped to detect a 20% decrease in the Lanza score with rabeprazole therapy, i.e. from 3.6 to 2.9. To detect this with a 0.05 confidence level and an 80% power; the number needed in each group was 13.2 normal subjects. To allow for potential dropouts, 15 normal subjects were enrolled in each group for a total of 30 subjects.

Results

All 30 patients were compliant with study medications and completed the entire study. There was no statistical difference between the study groups in terms of age, gender, body mass index (BMI) or any other demographic characteristic (Table 2). The mean age for the two groups was 31.9 (19–45) for the placebo group and 34.5 (20–48) for the rabeprazole group. The female to male ratio was comparable in the two groups with the placebo group being five females to 10 males while the rabeprazole group was four females to 11 males. The height was comparable in the two groups with a mean height of 1.7 m in the placebo group and 1.8 m in the rabeprazole group. The mean weight in the placebo group was 79.9 kg and in the rabeprazole was 81.8 kg, an insignificant difference. The corresponding BMIs were 24.8 and 26.8, respectively. The mean haemoglobin was comparable between the two groups at 13.6 and 13.7 respectively. Throughout the study, serum salicylate levels were similar for both rabeprazole and placebo groups at all times (baseline: <4 vs. <4; 24 h: 9 ± 2 vs. 10 ± 2; 72 h: 14 ± 2 vs. 14 ± 2 mg% (all P > 0.05). Of interest, was the difference between the number of volunteers who were H. pylori positive in the rabeprazole group (five) vs. the placebo group (two). It could be argued that with H. pylori infection being known to potentiate the ulcerogenic effects of ASA, the rabeprazole group has a slightly more difficult task to demonstrate its protective effects.

Table 2.   Demographic data of healthy volunteers in the placebo and rabeprazole group
 Placebo groupRabeprazole groupP-value
  1. BMI, body mass index; Hb, haemoglobin; F, Female; M, male.

Age (mean/range)31.9/19–4534.5/20–48>0.5
Gender5 F/10 M4 F/11 M>0.5
Height (mean)1.7 m1.8 m>0.5
Weight (mean)79.9 kg81.8 kg>0.5
BMI24.826.8>0.5
Hb (mean)13.613.7>0.5
Salicylate level (day 0, 24 h, 48 h,72 h)<4, 9, 12.2, 13.8<4, 10.1, 12.2, 14>0.5
Helicobacter pylori serology pos. (number of patients)25>0.5

The mean maximal number of erosions per endoscopy field in the rabeprazole group vs. the placebo group was broken down into different regions of the gastroduodenal mucosa (Table 3; Figure 1). The mean number of erosions on the posterior wall of the stomach on day 2 was 3.1 vs. 1.3 in the placebo group vs. rabeprazole group (<0.05). On day 4, even though the mean number of erosions was less in the rabeprazole group vs. the placebo group, it did not reach statistical significance. On the anterior wall of the stomach, the mean number of erosions was less on both days 2 and 4, but did not reach statistical significance. In the duodenal bulb, on day 4, the mean number of erosions was significantly lower in the rabeprazole group vs. placebo group; 0.1 vs. 1.3 (<0.05).

Table 3.   Mean number of erosions after administration of aspirin: placebo vs. rabeprazole
 Mean number of erosions
Anterior wall of stomachPosterior wall of stomachDuodenal bulb
PlaceboRabeprazoleP-valuePlaceboRabeprazoleP-valuePlaceboRabeprazoleP-value
Screening00 00 00 
Day 23.52.10.153.11.3<0.0510.60.32
Day 42.82.60.433.92.50.161.30.1<0.05
Figure 1.

 Mean number of erosions after aspirin: rabeprazole vs. placebo. The mean ± S.E.M. number of erosions per endoscopic field of vision is shown on the vertical axis. The horizontal axis shows the time in days after initiation of aspirin (day 2 = 24 h; day 4 = 72 h) for the anterior and posterior walls of the antrum and for the duodenal bulb.

The global Lanza scores that were computed from the erosion and submucosal haemorrhage counts from the different regions of the gastroduodenal mucosa are illustrated in Figure 2. On days 2 and 4, the Lanza score in the placebo group vs. the rabeprazole group was 1.3 ± 0.26 vs. 2.1 ± 0.26 (P < 0.05) and 1.3 ± 0.29 vs. 2.3 ± 0.28 ( < 0.05) respectively (Table 4).

Figure 2.

 Lanza scores after administration of aspirin: rabeprazole vs. placebo. The mean ± S.E.M. Lanza scores are shown on the vertical axis. The horizontal axis shows the time in days after initiation of aspirin (day 2 = 24 h; day 4 = 72 h)

Table 4.   Lanza scores after administration of aspirin (ASA): placebo vs. ASA
 Lanza scoreP-value
ScreeningDay 2Day 4
Placebo02.12.30.02
Rabeprazole01.31.30.02

Discussion

The relationship between the use of ASA/NSAIDS and their ulcerogenic potential has been well established for a long time. With the advent of PPIs, these complications have decreased markedly; however, ASA/NSAID ulcers, haemorrhage and perforation still remain important as common problems. Many studies have been conducted to assess the response of intragastric pH to different PPIs without13, 14 and with15 use of NSAIDS.

Rabeprazole is a second-generation PPI with limited data on its use with concomitant NSAID administration. Studies have looked at its use with low-dose ASA (81 mg) to assess symptom relief from GERD.16, 17 Studies have also been conducted to show that 20 mg of rabeprazole can increase 24 h, daytime and night-time pH and the percentage of time that pH was >3 to a greater extent during the first 24 h after administration, than 30 mg of lansoprazole, 20 mg of omeprazole or 40 mg of pantoprazole.18 The investigators attributed this effect to the fact that rabeprazole’s pKa (5.0) is higher than those of omeprazole (4.0), lansoprazole (3.9) and pantoprazole (3.8).19

Of interest, there are little data showing that this rapid onset of action has a role in preventing erosions and ulcers. Against this background, this study has demonstrated the potential use of rabeprazole as a preventive drug in patients taking ASA. The rationale for using high-dose ASA was to create a model that shortened the duration for the occurrence of erosions/ulcers in a controlled environment in volunteers who were admitted to the CRC. This allowed the investigators to control confounding variables such as intake of alcohol or medications that could interfere with the results of the study.

As was demonstrated, there was a significant difference in the mean number of erosions in the placebo group, compared to the rabeprazole group; the Lanza scores were markedly lower in the rabeprazole group. The goal was to achieve a therapeutic gain of 20% which has far exceeded with a gain of 61% on day 2 and 77% on day 4.

In conclusion, this study showed that rabeprazole prophylaxis, initiated only 5 h before the use of high-dose ASA successfully prevented erosions and decreased the global Lanza scores as early as 24 h with continued benefit up to 72 h.

Acknowledgements

Declaration of personal interests: R. S. Fisher is a consultant for McNeil Pharmaceuticals, and he lectures for Pricara, TAP, Takeda, Sucampo, Santarus and Novartis Pharmaceuticals. Declaration of funding interests: This investigator-initiated study was funded by an unrestricted grant from Pricara Ltd.

Ancillary