Famotidine Is Inferior to Pantoprazole in Preventing Recurrence of Aspirin-Related Peptic Ulcers or Erosions

Article Outline

• Abstract
• Patients and Methods
  • Study Population
  • Study Protocol
    • Detection of H pylori
    • Initial treatment and eradication of H pylori
      • Patients with H pylori infection
      • Patients without H pylori infection
    • Randomization
    • Follow-up
    • End point
  • Statistical Analysis
• Results
  • Characteristics of the Patients
  • Follow-up and Outcome
• Discussion
• Acknowledgment
• Supplementary data
• Video Abstract
• References
• Copyright

Background & Aims

Little is known about the efficacy of H₂-receptor antagonists in preventing recurrence of aspirin-related peptic ulcers. We compared the efficacy of high-dose famotidine with that of pantoprazole in preventing recurrent symptomatic ulcers/erosions.

Methods

We performed a randomized, double-blind, controlled trial of 160 patients with aspirin-related peptic ulcers/erosions, with or without a history of bleeding. Patients were given either famotidine (40 mg, morning and evening) or pantoprazole (20 mg in the morning and placebo in the evening). All patients continued to receive aspirin (80 mg daily). The primary end point was recurrent dyspeptic or bleeding ulcers/erosions within 48 weeks.

Results

A total of 130 patients (81.1%) completed the study; 13 of 65 patients in the famotidine group reached the primary end point (20.0%; 95% one-sided confidence interval [CI] for the risk difference, 0.1184–1.0) compared with 0 of 65 patients in the pantoprazole group (P < .0001, 95% one-sided CI for the risk difference, 0.1184–1.0). Gastrointestinal bleeding was significantly more common in the famotidine group than the pantoprazole group (7.7% [5/65] vs 0% [0/65]; 95% one-sided CI for the risk difference, 0.0226–1.0; P = .0289), as was recurrent dyspepsia caused by ulcers/erosions (12.3% [8/65] vs 0% [0/65]; 95% one-sided CI for the risk difference, 0.0560–1.0; P = .0031). No patients had ulcer perforation or obstruction.

Conclusions

In patients with aspirin-related peptic ulcers/erosions, high-dose famotidine therapy is inferior to pantoprazole in preventing recurrent dyspeptic or bleeding ulcers/erosions.

Abbreviations used in this paper: CI, confidence interval, H2RA, H₂-receptor antagonist, PPI, proton pump inhibitor

Low-dose aspirin can prevent cerebral and cardiovascular events in individuals with symptomatic atherothrombotic disease.¹ Its use is frequently limited by gastrointestinal side effects, ranging from dyspepsia (31%) to life-threatening bleeding or perforation of gastroduodenal ulcers (3.1%) over a period of 4 years.²

The best approach for the secondary prevention of low-dose aspirin–induced symptomatic peptic ulcers or erosions in patients who need to continue aspirin remains uncertain. At present, eradication of Helicobacter pylori infection³ and long-term maintenance with a proton pump inhibitor (PPI)⁴ appear to be the best options. In PPI-treated patients, the substitution of aspirin by clopidogrel was not superior to the continuation of aspirin during ulcer healing. Furthermore, clopidogrel without PPI therapy was associated with a high incidence of ulcer rebleeding.⁵, ⁶, ⁷

The role of H₂-receptor antagonists (H2RAs) after healing of aspirin-induced peptic ulcers or erosions is unclear. At present, there is no randomized controlled trial with a clinical outcome.⁸ This can only be inferred from the randomized controlled studies on the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced endoscopic gastroduodenal ulcer.⁹, ¹⁰ In a meta-analysis, standard doses of H2RAs reduced the risk of endoscopic duodenal but not gastric ulcers. Double-dose H2RAs were effective in reducing the risk of both gastric and duodenal ulcers.¹¹

The objective of this randomized, double-blind, controlled study was to compare the efficacy of high-dose famotidine with pantoprazole in the prevention of recurrent dyspeptic or complicated ulcers/erosions in patients taking low-dose aspirin.

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Patients and Methods 

Study Population 

This prospective, randomized, controlled trial was conducted at the Ruttonjee Hospital between August 2004 and November 2008, in accordance with the principles of good clinical practice and the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Hong Kong East Cluster (HKEC 2004-016) and was registered at www.clinicaltrials.gov (identifier NCT00843063). All patients gave written informed consent. Patients were screened if they presented to the endoscopy room with a history of upper gastrointestinal bleeding or dyspepsia due to peptic ulcers/erosions while receiving low-dose aspirin with a daily dose ranging from 80 to 320 mg and met the following criteria: endoscopy revealed gastric or duodenal ulcers ≥3 mm in diameter with unequivocal depth or more than 5 erosions in the stomach or duodenum; required continuous low-dose aspirin for the secondary prevention of coronary heart disease, peripheral vascular disease, or ischemic stroke or transient ischemic attacks; and were 18 years of age or older. Erosions were defined as a mucosal break of <3 mm. The size of the lesion was estimated by an open biopsy forceps. Mucosal erythema alone did not qualify for the definition of erosions.

Major exclusion criteria were concurrent erosive or ulcerative esophagitis; pyloric stenosis; previous gastric or duodenal surgery other than oversewing of a perforation; thrombocytopenia; renal failure with estimated creatinine clearance <10 mL/min; active cancer; known allergy to aspirin, famotidine, or pantoprazole; pregnancy; lactation; childbearing potential in the absence of contraception; psychosomatic disorder; planned coprescription of an NSAID, corticosteroid, or anticoagulant; or disorders that might modify the absorption of study drugs. Patients who had been taking nonaspirin NSAIDs or PPIs before the peptic ulcers/erosions were also excluded.

Study Protocol 

Two antral biopsy specimens were obtained to determine H pylori status by histologic examination. Two antral and 2 corpus biopsy specimens were taken from patients taking H2RAs or PPIs.

Patients with H pylori infection 

Aspirin 80 mg/day could be prescribed at the discretion of the attending physician or surgeon during the healing phase for the prevention of cardiovascular or cerebrovascular diseases. Patients with H pylori infection were given standard PPI-based triple therapy for 7 days, followed by PPI alone for 7 weeks. Endoscopy was performed at 8 weeks to check for healing of the ulcers/erosions and eradication of H pylori infection. Unhealed erosions were defined when there were more than 5 erosions. Patients in whom endoscopy revealed an unhealed peptic ulcer/erosion were given a course of PPI therapy for another 8 weeks. Patients in whom H pylori infection was not eradicated, as indicated by a positive result on histologic examination of antral and corpus biopsy specimens, received a 1-week course of triple therapy consisting of ranitidine bismuth citrate 400 mg, amoxicillin 1 g, and metronidazole 400 mg, all given twice daily. Patients with unhealed ulcers/erosions and/or who failed to respond to 2 attempts to eradicate H pylori infection were excluded from the study.

Patients without H pylori infection 

If there was no H pylori infection, patients were prescribed a PPI daily for 8 weeks. Endoscopy was performed at 8 weeks to check for healing of the ulcers/erosions.

Patients who satisfied all the following criteria were invited to enroll in the study: insignificant dyspeptic symptom limited to grade 0 or 1 (Table 1), healed peptic ulcers/erosions, and absence of H pylori infection. Patients were randomly assigned to receive either aspirin 80 mg and famotidine 40 mg (2 tablets of Famolta 20 mg; Jean-Marie Pharmacal Co Ltd, Hong Kong) twice daily or aspirin 80 mg and matching pantoprazole 20 mg (Byk Gulden, Germany) in the morning with a matching placebo in the evening. (Famolta 20 mg is registered in Hong Kong [registration no. HK48086] and was bioequivalent to the reference product, Pepcidine Tablet 20 mg.¹²) In patients with creatinine clearance ranging from 10 to 50 mL/min, the dose of famotidine was reduced by 50%. All tablets were repackaged with identical appearance and taste. Computer-generated random numbers for the treatment group were assigned by the pharmacy. The pharmacist dispensed the medication. The investigators and patients were blinded to the treatment group assignments.

Table 1. Scoring System for Dyspepsia During the Preceding 7 Days

Grade
0	Absent
1	Mild (easily tolerated)
2	Moderate (interfering with normal activities)
3	Severe (incapacitating; leaving the patient unable to perform normal activities)

NOTE. Dyspepsia was defined as epigastric or abdominal pain, heartburn, nausea, vomiting, upper abdominal bloating, and empty feeling in the stomach.

Patients were followed up as outpatients, with clinic visits every 16 weeks for 48 weeks. The use of antacid was allowed for symptomatic relief of mild dyspepsia. Patients were advised to avoid taking NSAIDs. Compliance was assessed by pill counts. Upper gastrointestinal symptoms and hemoglobin level were assessed at every visit. Patients were asked to report to the designated outpatient clinic if they had recurrent dyspeptic symptoms (grade 2 or greater) despite antacid therapy and to report to the emergency department if they had melena, hematemesis, or severe epigastric pain (grade 3). With these 2 occurrences, endoscopy was repeated to document any recurrent ulcers/erosions. Otherwise, no scheduled endoscopy was performed.

The overall severity grading of dyspepsia and definition of ulcer complications were prespecified (Table 1, Table 2).¹³ The scoring system for dyspepsia graded the overall composite severity of epigastric or abdominal pain, heartburn, nausea, vomiting, upper abdominal bloating, and empty feeling in the stomach during the preceding 7 days. The primary end point was the recurrence of dyspeptic or complicated ulcers/erosions. The end point was determined by an independent investigator (C.P.) who did not participate in the design and implementation of the study and was unaware of the patients' treatment group assignments. Events that were confirmed and that occurred during treatment or within 7 days after the discontinuation of treatment were included in the primary analysis.

Table 2. Prespecified Criteria for Ulcer/Erosion Complications

Statistical Analysis 

The main aim of the study was to compare the rate of occurrence of the primary end point during the 48-week follow-up period between patients treated with high-dose famotidine and patients treated with pantoprazole. The study was designed to have a power of at least 80% for a one-sided test at the .05 level of significance. This study recruited only patients with ulcers/erosions successfully healed and dyspepsia resolved with a standard dose of PPIs, such as pantoprazole 20 mg daily. Furthermore, extremely low rates of ulcer rebleeding among patients taking low-dose aspirin who were treated with PPIs have been reported in 3 randomized control studies. After a follow-up of 1 year, the rebleeding rate was 1.6% (1/62), 0.7% (1/159), and 0% (0/86) in the patients treated with lansoprazole 30 mg daily,⁴ esomeprazole 20 mg twice daily,⁶ and esomeprazole 20 mg/day,⁷ respectively. Therefore, we assumed the rate of primary end point to be almost zero. A one-sided test was used because the worst scenario for comparison would be famotidine as effective as pantoprazole.

Unfortunately, there has been no clinical outcome study to estimate the event rate for the high-dose famotidine group. In an endoscopic outcome study, the probability of recurrent gastroduodenal ulcer was 26% (95% confidence interval [CI], 12%–40%) in patients who continued NSAID therapy and received concomitant famotidine 40 mg twice daily.¹⁰ We assumed the recurrent endoscopic ulcers were asymptomatic in ∼50% of patients. Therefore, we estimated that the primary end point would occur in 12% of patients in the famotidine group and in 0.25% in the pantoprazole group. Based on the formula¹⁴ for small proportions, at least 71 patients were required in each treatment protocol. Assuming premature termination occurred in 10% of patients, 79 patients were required in each arm of the study.

The homogeneity of the treatment groups at baseline was analyzed by the χ² test or Fisher exact test for categorical data and the Mann–Whitney U test for continuous variables. The probabilities of a recurrence of primary end point in both groups were compared using the Fisher exact test. The asymptotic 95% CI for the difference in the rate of occurrence of the primary end point between the 2 groups was calculated.

The criteria for premature termination of study drug were prespecified. The reasons included adverse drug reaction such as significant dyspepsia (grade 2 or greater) but patient refused endoscopic examination, skin rash, central nervous symptoms, decline in creatinine clearance level to <10 mL/min, nonoral feeding, termination of aspirin therapy, conversion of study drug to open-label PPI because of a higher risk of gastrointestinal bleeding such as long-term NSAIDs and corticosteroid therapy, shock and mechanical ventilation, withdrawal of consent, and death. When these conditions occurred, they were considered a protocol violation and were excluded from analysis.

All analyses were performed with SPSS software (version 13; SPSS Inc, Chicago, IL).

The written consent form and the database were audited by an independent respiratory physician (W.W.L.) who did not participate in the design, implementation, and analysis of the study.

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Results 

Characteristics of the Patients 

During the study period from August 2004 to November 2008, there were 237 eligible patients. Seventy-six patients were excluded (Supplementary Figure 1). A total of 161 patients were randomized. One patient withdrew consent and had never taken any study drug. No patients were lost to follow-up. Premature termination occurred in 13 (16.7%) and 17 (20.7%) patients in the pantoprazole and famotidine groups, respectively. The details are listed in Table 3. One patient (1.3%) in the pantoprazole group and 10 patients (12.2%) in the famotidine group had significant dyspepsia but refused upper endoscopy or refused to continue the study drug despite an insignificant endoscopic finding. One patient in the pantoprazole group had suspected small bowel bleeding due to NSAID therapy. Upper endoscopy and colonoscopy revealed normal findings.

Table 3. Premature Termination and Time to Occurrence

	Pantoprazole		Famotidine
	No. (%)	At wk	No. (%)	At wk
Noncompliant to study protocol	1(1.3)		10(12.2)	4(2–8)a
Significant dyspepsia
Refused endoscopy	1	23	9(11.0)	4(2–8)a
Gastritis, refused to continue			1(1.2)	1
Termination of study drug	4(5.1)		4(4.9)
Skin rash	2(2.6)	4,9	1(1.2)	16
Nonspecific symptom	2(2.6)	16,26	3(3.7)	1,16,17
Stopped aspirin	4(5.1)		1(1.2)
Normal coronary angiogram or treadmill	2	12,26
Massive stroke	1	12
Intracranial bleeding	1	46
Switch to clopidogrel			1	16
Protocol violation	2(2.6)		1(1.2)
Required long-term NSAID therapy	1	16
Required warfarin therapy	1	26	1	12
Nonoral feeding for pneumonia	1(1.3)	8	1(1.2)	40
Suspected small bowel bleeding due to NSAID therapyb	1(1.3)	19
Overall premature termination	13(16.7)		17(20.7)

Sixty-five patients in the pantoprazole group and 65 patients in the famotidine group completed the study. The 2 treatment groups were similar with respect to baseline demographic characteristics, clinical presentation (dyspepsia or bleeding), severity of bleeding (the requirement for blood transfusion or endoscopic treatment), history of previous ulcer bleeding, the location and size of ulcers, and coexisting illnesses (Table 4).

Table 4. Baseline Characteristics of the Patients

	Pantoprazole group	Famotidine group	P value
n	65	65
Mean (SD) age (y)	68.2(11.3)	69.5(9.6)	.47
Male sex, n (%)	45(69.2)	37(56.9)	.15
Current smoking, n (%)	5(7.7)	1(1.5)	.21
Current alcohol use, n (%)	0(0)	0(0)
Medical history
Cerebrovascular accident, n (%)	22(33.8)	25(38.5)
Ischemic heart disease, n (%)	44(67.7)	43(66.2)
Peripheral vascular disease, n (%)	1(1.5)	0(0.0)
Serum creatinine level (μmol/L)	101.9(41.8)	99.5(36.6)
Creatinine clearance 10–50 mL/min, n (%)	2(3.1)	2(3.1)a
Ulcer history, n (%)
History of peptic ulcer	10(15.4)	10(15.4)	1.00
History of ulcer bleeding	7(10.8)	7(7.7)	.55
Medication before index peptic ulcers/erosions
Duration of aspirin therapy (mo)	38.9(43.1)	40.7(37.1)	.79
Coprescribed with H2RA, n (%)	16(14.6)	15(13.1)	.84
Famotidine 20 mg daily	5	7
Famotidine 40 mg daily	10	8
Ranitidine 150 mg daily	1	0
Peptic ulcer disease
Dyspepsia, n (%)	27(41.5)	23(35.4)	.75
Gastrointestinal bleeding, n (%)	38(53.4)	42(67.7)
Subtype
Hematemesis/melena, n (%)	30(46.2)	34(52.3)
Lowest hemoglobin level (g/dL)	10.0(2.7)	9.2(2.3)
Decrease in hemoglobin level, n (%)	8(12.3)	8(12.3)
Lowest hemoglobin level (g/dL)	9.1(1.27)	7.8(1.9)
Shock at presentation, n (%)	1(1.5)	0(0)
Transfusion required, n (%)
None	56(86.2)	56(86.2)
1–2 units	7(10.7)	7(10.7)
3–4 units	2(3.1)	2(3.1)
Type of lesion, n (%)
Gastric ulcer	30(46.2)	38(58.5)
Duodenal ulcer	9(13.8)	10(15.4)
Gastroduodenal ulcer	5(7.7)	6(9.3)
Gastric or duodenal erosions	21(31.3)	11(16.9)
Ulcer size >10 mm, n (%)	23(38.5)	31(47.6)	.15
Endoscopic hemostasis required, n (%)	3(4.6)	7(10.8)	.19
H pylori infection, n (%)	23(35.4)	20(30.8)	.58
Aspirin continued during ulcer healing phase, n (%)	58(89.2)	57(87.7)	.78

Follow-up and Outcome 

There were 63 patients (97%) in the pantoprazole group and 65 patients (100%) in the famotidine group with >90% compliance to study drug. The corresponding rate of good compliance (90%) to aspirin therapy was 98% (n = 64) and 100% (n = 65). During follow-up, concomitant treatment with clopidogrel was prescribed to one patient for 6 months in the pantoprazole group and one patient for 6 months in the famotidine group after the placement of a coronary stent. Recurrent gastrointestinal bleeding was not observed in these 2 patients.

The primary end point was reached in 13 patients (20.0%) in the famotidine group but none (0%) in the pantoprazole group (95% one-sided CI for the risk difference, 0.1184–1.0; P < .0001). Among these 13 patients, 8 (12.3%) presented with significant dyspepsia without gastrointestinal bleeding (pantoprazole group, 0%; 95% one-sided CI for the risk difference, 0.0560–1.0; P = .0031). Endoscopic examination revealed gastric ulcers in 6 patients and gastric erosions in 2 patients. In the 5 remaining patients (7.7%), 2 presented with melena and 3 presented with a significant decrease in hemoglobin level ≥2 g/dL (Table 5), whereas no patient in the pantoprazole group had complicated peptic ulcers/erosions (95% one-sided CI for the risk difference, 0.0226–1.0; P = .0289). All of these 13 patients were negative for H pylori by histologic examination from 2 antral and 2 corpus biopsy specimens and had good compliance (≥90%) to the study drugs and aspirin. The severity of gastrointestinal bleeding was classified as minor in 3 patients, major in 1 patient, and life threatening in 1 patient. None of the patients had perforated peptic ulcer or pyloric obstruction.

Table 5. Details of Patients With Recurrent Bleeding Ulcers/Erosions

NOTE. All patients received high-dose famotidine. During recurrent gastrointestinal bleeding, no patient required endoscopic hemostasis and blood transfusion. None had H pylori infection.

GU, gastric ulcer; DU, duodenal ulcer.

One patient in the pantoprazole group and 10 patients in the famotidine group had significant dyspepsia but refused upper endoscopy or refused to continue the study drug despite an insignificant endoscopic finding. They were considered as dropouts. If we assume all these patients had reached the primary end point with ulcers/erosions, the hypothetical rate of treatment success with pantoprazole (98.5%; 65/66) was still superior to that with famotidine (69.3%; 52/75) (Fisher exact test; P < .001).

The patient who was classified as having life-threatening bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) trial criteria¹⁵ presented with melena for 5 days. Hemoglobin level decreased from 15.4 to 7.6 g/dL. Endoscopy showed that it was due to duodenal ulcer bleeding. He refused hospital admission and blood transfusion. He was successfully treated with pantoprazole 20 mg daily and iron supplementation.

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Discussion 

This study showed that high-dose famotidine therapy was inferior to pantoprazole in preventing recurrence of aspirin-related peptic ulcers/erosions. Furthermore, pantoprazole was significantly better than high-dose famotidine in the prevention of ulcer/erosion complications. This supports the recommendation from the American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association 2008 Expert Consensus Document⁸ that the use of PPIs instead of double-dose H2RAs is preferred in preventing recurrent low-dose aspirin–related injury.

The role of H2RAs in the prevention of aspirin-related gastrointestinal bleeding is unclear in the literature. There were only 2 prospective case-control clinical studies, but they showed conflicting results on the efficacy of H2RAs in the primary prevention of aspirin-related upper gastrointestinal bleeding.¹⁶, ¹⁷ In one case-control study (120 cases and 206 controls), the risk of upper gastrointestinal bleeding was not significantly reduced by concomitant H2RA therapy (adjusted odds ratio, 0.5; 95% CI, 0.2–1.2) but significantly reduced by PPI therapy (0.2; 95% CI, 0.1–0.9).¹⁶ On the contrary, another case-control study of larger sample size (372 cases and 381 controls) by the same group of investigators¹⁷ showed that the use of H2RAs (adjusted relative risk, 0.40; 95% CI, 0.19–0.73) or PPIs (0.32; 95% CI, 0.22–0.51) was significantly associated with a reduction in the risk of upper gastrointestinal bleeding. Recently, a randomized control study using an endoscopic end point at the 12th week showed that famotidine (20 mg twice daily) was superior to placebo in preventing gastric and duodenal ulcers as well as erosive esophagitis in low-risk patients taking low-dose aspirin.¹⁸ This study excluded patients treated with a PPI or an H2RA within 1 week at first endoscopy and had not reported the history of gastrointestinal bleeding. In contrast, all our patients were maintained on a PPI for ulcer healing for at least 8 weeks before endoscopy, and more than 50% of them had bled recently.

Concerning the efficacy of PPIs in relieving aspirin-induced dyspepsia, previous randomized trials have yielded conflicting results. Laheij et al showed that rabeprazole could significantly reduce heartburn but not other symptoms. However, this study might have recruited patients with aspirin-related nonulcer dyspepsia because baseline endoscopy was not performed.¹⁹ Our study recruited only patients in whom initial PPI therapy could heal the ulcers/erosions and resolve dyspepsia. Yeomans et al showed that esomeprazole 20 mg once daily reduced the risk of developing gastric and/or duodenal ulcers and symptoms associated with the continuous use of low-dose aspirin in patients aged 60 years or older without preexisting gastroduodenal ulcers.²⁰ Treatment with esomeprazole could significantly reduce the incidence of epigastric burning and heartburn among patients without symptoms at baseline and could reduce the incidence of epigastric pain, heartburn, and acid regurgitation among those with symptoms at baseline.

In our study, a composite end point of dyspepsia or ulcer bleeding was used. Firstly, we believed that recurrent dyspepsia might herald upper gastrointestinal bleeding. Secondly, dyspepsia had a negative impact on the quality of life in patients with vascular disease.²¹ Noncompliance to aspirin therapy due to dyspepsia is highly undesirable. However, in this study, upper gastrointestinal bleeding was not heralded by the occurrence of significant dyspepsia in 5 patients. This was consistent with previous reports that peptic ulcer hemorrhage or perforation occurred commonly in patients with hitherto silent ulceration, particularly in the elderly or in those taking NSAIDs.²², ²³ Fortunately, the severity of bleeding was usually minor in our study. In the famotidine group, there were 3 patients with insomnia or dizziness. Famotidine is known to cause toxicity of the central nervous system, particularly in patients with old age or renal failure.²⁴

This study has several limitations. First, the occurrence of significant dyspepsia was a criterion of endoscopic examination. We did not know the clinical outcome of the continuation of the study drug after the occurrence of dyspeptic ulcers/erosions. Second, biopsy-based tests for H pylori infection might have had diminished sensitivity among patients taking PPIs. However, all the 13 patients with recurrent peptic ulcers or erosions in the famotidine group were negative for H pylori.²⁵ Third, the patients were heterogeneous in their severity of aspirin-related gastrointestinal toxicity and types of lesions on endoscopy. However, 2 patients with dyspeptic ulcers/erosions reached the primary end point, indicating that dyspeptic index ulcers/erosions may bleed in the famotidine group. We included patients with gastric erosions because gastric erosions were the next most common source of gastrointestinal bleeding after acute myocardial infarction, apart from peptic ulceration.²⁶

To conclude, for patients with aspirin-related peptic ulcers/erosions, high-dose famotidine therapy was inferior to pantoprazole therapy in preventing recurrence of dyspeptic or complicated ulcers/erosions. There was also a significantly lower rate of significant dyspepsia in the pantoprazole group than the famotidine group.

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Acknowledgment 

The authors thank Dr W. L. Wong for the audit of the database.

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Supplementary data 

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Video Abstract 

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References 

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