ASP (PPI_H2RA) Study-H2RA Versus PPI for the Prevention of Recurrent UGIB in High-risk Users of Low-dose ASA

Histamine-2 Receptor Antagonist Versus Proton-Pump Inhibitor for the Prevention of Recurrent Upper Gastrointestinal Bleeding (UGI) in High-risk Users of Low-dose Aspirin (ASA)

Peptic ulcer bleeding associated with ASA or NSAIDs is a major cause of hospitalization in Hong Kong. The investigators previously showed that ASA or NSAIDs accounted for about half of all cases of hospitalizations for peptic ulcer bleeding. Currently, ASA use has contributed to about one-third of the bleeding ulcers admitted to the investigators hospital that serves a local population of 1.5 million.

In patients with acute coronary syndrome or acute ischemic stroke who develop ASA-induced bleeding peptic ulcers, whether ASA should be discontinued before ulcers have healed is a major dilemma. In another double-blind randomized trial, the investigators have shown that discontinuation of ASA after endoscopic treatment of bleeding ulcers was associated with a significantly increased in mortality within 8 weeks.

In the absence of safer aspirins, co-therapy with a gastroprotective drug remains the dominant preventive strategy. Given the vast number of people taking ASA, however, it is only cost-effective to identify and treat those who are at high risk of ulcer bleeding and who have a strong indication for ASA use. Data from observational studies and randomized trials have consistently shown that PPIs are effective in reducing the risk of ulcer bleeding associated with ASA. Other potential preventive strategies include eradication of H. pylori infection, substitution of ASA for other non-aspirin anti-platelet drugs, and co-therapy with misoprostol or H2RAs.

Study Overview

• Status: Completed
• Conditions: Upper Gastrointestinal Bleeding
• Intervention / Treatment: Drug: Rabeprazole; Drug: Famotidine

Detailed Description

No dose of "low-dose" aspirin (ASA) is safe in terms of the risk if ulcer bleeding. Even at a dose as low as 75 mg daily, ASA doubles the risk of ulcer bleeding when compared to the risk in non-users. This rise in the incidence was associated with a 44% increase in usage of ASA. In Hong Kong, ASA is also a major cause of peptic ulcer complications.

In the absence of safer aspirins, co-therapy with a gastroprotective drug remains the dominant preventive strategy. Given the vast number of people taking ASA, however, it is only cost-effective to identify and treat those who are at high risk of ulcer bleeding and who have a strong indication for ASA use. Data from observational studies and randomized trials have consistently shown that PPIs are effective in reducing the risk of ulcer bleeding associated with ASA. Other potential preventive strategies include eradication of H. pylori infection, substitution of ASA for other non-aspirin anti-platelet drugs, and co-therapy with misoprostol or H2RAs. Among these preventive strategies, co-therapy with a PPI for prevention of ulcer bleeding in high-risk ASA users remains the most studied and best proven strategy.

H2-receptor antagonists (H2RAs) are relatively weak acid suppressing drugs when compared to PPIs. Very few studies have evaluated the efficacy of H2RAs in the prevention of peptic ulcer bleeding with ASA. Two case-control studies yielded conflicting results with regard to the efficacy of H2RAs in reducing the risk of hospitalizations for ulcer bleeding with ASA. There is a limited data on the efficacy of H2RAs, however, our local health authority has endorsed the use of H2RA as a co-therapy in high-risk ASA users since 2001.

On the other hand, H2RAs have two potential advantages over PPIs. First, generic H2RAs are much cheaper than generic PPIs in Hong Kong. Second, unlike the interaction between PPIs and clopidogrel, concomitant use of H2RAs and clopidogrel is not associated with an increased risk of recurrent myocardial infarction. Thus, H2RA might be a cheap and safe gastroprotective drug in patients requiring dual anti-platelet therapy (i.e., ASA and clopidogrel) who require coronary stents.

In patients with acute coronary syndrome or acute ischemic stroke who develop ASA-induced bleeding peptic ulcers, whether ASA should be discontinued before ulcers have healed is a major dilemma. In another double-blind randomized trial, we have shown that discontinuation of ASA after endoscopic treatment of bleeding ulcers was associated with a significantly increased in mortality within 8 weeks.

The investigators aim to test the hypothesis that PPI is superior to H2RA for the prevention of recurrent upper gastrointestinal bleeding in ASA users with a history ulcer bleeding

• Study Type: Interventional
• Enrollment (Actual): 264
• Phase: Phase 3

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Prince of Wales Hospital
• Japan
  • Izumo, Japan
    • Second Department of Internal Medicine, Shimane University Faculty of Medicine, Izumo, Japan
  • Kyoto, Japan
    • Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • Osaka, Japan
    • Department of Gastroenterology, Osaka City General Hospital, Osaka, Japan (Satellite hospital of Osaka City University)
  • Osaka, Japan
    • Department of Gastroenterology, Osaka City University Graduate School of Medicine
  • Osaka, Japan
    • Department of Gastroenterology, Takarazuka Municipal Hospital, Hyogo, Japan (Satellite hospital of Osaka City University)
  • Osaka, Japan
    • Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
  • Saga, Japan
    • Department of Internal Medicine and Gastroenterology, Saga Medical School, Saga, Japan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. A history of documented peptic ulcer bleeding (self-reported history without confirmation by the clinician is not acceptable)
2. Negative tests for H. pylori or successful eradication of H. pylori based on urease test or histology
3. Expected regular use of ASA for the duration of the trial
4. Age ≥ 18
5. Written informed consent obtained

Exclusion Criteria:

1. A history of gastric or duodenal surgery other than patch repair
2. Severe erosive esophagitis (LA grade C or D)
3. Gastric outlet obstruction
4. Terminal illness
5. Active malignancies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Rabeprazole; Tablet 20mg daily for 12 months	Drug: Rabeprazole; Rabeprazole 20 mg daily; Other Names: Pariet
ACTIVE_COMPARATOR: Famotidine; Tablet 40mg daily for 12 months	Drug: Famotidine; Famotidine 40mg daily; Other Names: Pepcidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
recurrent non-variceal upper GI bleeding	defined as hematemesis, melena or a decrease in hemoglobin of at least 2 g/dL with ulcers or bleeding erosions confirmed by endoscopy, and adjudicated by an independent committee	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
lower GI bleeding	defined by either melena or rectal bleeding causing hospital admission or transfusion, with negative results on upper endoscopy, or by a decrease in hemoglobin of at least 2 g/dL in association with negative results on upper endoscopy and no other explanations for the anemia.	12 Months
atherothrombotic events	atherothrombotic events	12 months
A composite of recurrent upper GI bleeding or recurrent endoscopic ulcers	defined as hematemesis, melena or a decrease in hemoglobin of at least 2 g/dL with ulcers or bleeding erosions confirmed by endoscopy, and adjudicated by an independent committee	12 months

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong

Publications and helpful links

General Publications

• Chan FK, Kyaw M, Tanigawa T, Higuchi K, Fujimoto K, Cheong PK, Lee V, Kinoshita Y, Naito Y, Watanabe T, Ching JY, Lam K, Lo A, Chan H, Lui R, Tang RS, Sakata Y, Tse YK, Takeuchi T, Handa O, Nebiki H, Wu JC, Abe T, Mishiro T, Ng SC, Arakawa T. Similar Efficacy of Proton-Pump Inhibitors vs H2-Receptor Antagonists in Reducing Risk of Upper Gastrointestinal Bleeding or Ulcers in High-Risk Users of Low-Dose Aspirin. Gastroenterology. 2017 Jan;152(1):105-110.e1. doi: 10.1053/j.gastro.2016.09.006. Epub 2016 Sep 15.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (ACTUAL): November 1, 2015
• Study Completion (ACTUAL): November 1, 2016

Study Registration Dates

• First Submitted: August 2, 2011
• First Submitted That Met QC Criteria: August 2, 2011
• First Posted (ESTIMATE): August 3, 2011

Study Record Updates

• Last Update Posted (ACTUAL): April 21, 2017
• Last Update Submitted That Met QC Criteria: April 20, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: aspirin; PPI; H2RA
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Hemorrhage; Gastrointestinal Hemorrhage; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Histamine Antagonists; Histamine Agents; Histamine H2 Antagonists; Rabeprazole; Famotidine
• Other Study ID Numbers: APH Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO