Clinical trial NCT02418312
Conditions: Peptic Ulcer
Keywords: histamine-2 receptor antagonist peptic ulcer thienopyridine prevention
Sponsor: Kaohsiung Veterans General Hospital.
Start date: 2012-01-01; Completion date: 2017-10-01
Enrollment: 228 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Whether H2 receptor antagonist can prevent thienopyridine-related peptic ulcer remains unclear.

Detailed description:
The aim of the prospective, randomized study is investigate the efficacy of H2 receptor antagonist in prevention of thienopyridine-related peptic ulcer and gastrointestinal bleeding in patients with an ulcer history. We plan to enroll 236 thienopyridine (clopidogrel or ticlopidine) users with a peptic ulcer history who don't have baseline gastroduodenal ulcers at initial endoscopy . The patients will be randomly assigned to receive either (1) famotidine (40 mg qd) plus thienopyridine used previously or (2) placebo plus thienopyridine treatment alone for 6 months. The ulcer recurrence rate between the treatment gruops will be compared.

Arms: arm 1: famotidine 40mg qd for 6 months. arm 2: placebo for 6 months.
Interventions: intervention 1: histamine-2 receptor antagonist intervention 2: Placebo
Intervention descriptions: intervention 1: famotidine 40 mg qd plus thienopyridine intervention 2: placebo plus thienopyridine

Protocol documents:
Prot_SAP_000.pdf: 
VGHKS11-CT12-10
Institution/Department：Kaohsiung Veterans General Hospital
Principal Investigator (PI)：Prof. Ping-I Hsu 
Research Project Title：Efficacy of H2 receptor antagonist in prevention of 
thienopyridine-related peptic ulcer
NCT Number：NCT02418312 
Date of the document：  11 
    09   2018  （MM/DD/YYYY） 
ABSTRACT
Background:  Current U.S. guidelines  recommended thienopyridine （e.g. clopidogrel ） for 
patients who have major gastrointestinal intolerance or complications of aspirin. However, a recent 
study demonstrated that 12% of patients with a history of ulcer who took clopidogrel had ulcer 
bleeding within one year. Although proton pump inhibitor (PPI) can prevent recurrent peptic ulcer 
in clopidogrel users with a history of peptic ulcer, the interaction between PPIs and clopidogrel has 
drawn much attention recently. Several studies reported that certain PPIs could reduce clopidogrel's 
antiplatelet  effects  and  increase  cardiovascular  events.  Theses  data  suggested  that  PPIs  may 
potentially inhibit the CYP2C19 pathway and interfere with the conversion of clopidogrel to active 
form. Therefore, searching for other gastroprotective agents to prevent gastrointestinal events for 
clopipogrel users is urgently needed in clinical practice.
Aims:  To investigate the efficacy of histamine-2 receptor antagonist in the prevention of ulcer 
recurrence for thienopyridine users.
Methods: 228 thienopyridine (clopidogrel or ticlopidine) users with an ulcer history who do not 
have gastroduodenal ulcer at initial endoscopy are included. The patients will be randomly assigned 
to receive either (1) famotidine (40 mg before bedtime) or (2) placebo  (before bedtime) for 6 
months.  Blood  sampling  for  genotyping  of  CYP2C19  is  carried  out  on  enrollment.  Platelet 
aggregation tests are performed in Day 1 and Day 28. Follow-up endoscopy is carried out at the end 
of the 6th month and whenever severe epigastric pain, hematemesis or melena occurs. Additionally, 
the episodes of acute coronary syndrome and cerebral vascular accident will be carefully evaluated 
during the treatment period. Finally, the ulcer recurrence rate, ulcer bleeding rate, incidence of acute 
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coronary syndrome and cerebral vascular accident between the treatment groups will be compared 
by  chi-square  test.  Additionally,  the  independent  factors  predicting  ulcer  recurrence  will  be 
investigated by multivariate analysis. Furthermore, the effect of CYP2C19 genetic polymorphism 
on the development of cardiovascular events and platelet aggregation will be analyzed.
INTRODUCTION
Platelet activation and aggregation play an important role in the pathogenesis of arterial 
thrombosis and lead to ischemic events. Thienopyridine (clopidogrel or ticlopidine) inhibits 
platelet function by selectively and irreversibly blocking the adenosine diphosphate (ADP) 
receptor on platelets, thereby affecting ADP-dependent activation of the GpIIb-IIIa complex, 
the major receptors for fibrinogen present on the platelet surface.1, 2 Alone or in association 
with aspirin, clopidogrel is a thienopyridine, which has successfully proved to be beneficial in 
the treatment of acute coronary syndrome3 and prevention of ischemic events in patients with 
atherosclerotic diseases.4,5 
The CAPRIE study showed that long-term administration of clopidogrel to patients 
with atherosclerotic vascular disease is more effective than aspirin in reducing the combined 
risk of ischemic events.6 Additionally, Clopidogrel induced fewer episodes of gastrointestinal 
bleeding than aspirin.6,7 The American College of Cardiology-American Heart Association 
guidelines therefore recommend clopidogrel as an alternative to aspirin for patients with 
unstable angina or non-ST-segment elevation myocardial infarction who have an aspirin 
intolerance.8 
However, a recent study demonstrated that 12% of patients with a history of ulcer who 
took clopidogrel had ulcer bleeding within one year.9 Furthermore, the cumulative incidence of 
recurrent bleeding in clopidogrel users who had ulcer bleeding history (subjects with high 
gastrointestinal risk) was higher than that in patients who took aspirin plus proton pump 
inhibitor (PPI).10 The mechanisms leading to recurrent ulcer bleeding among patients receiving 
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clopidogrel are unclear. Nonetheless, an animal study revealed that platelet ADP-receptor 
antagonists impair the healing of gastric ulcers by suppressing the release of platelet-derived 
growth factors.11 We therefore speculate that clopidogrel may also hinder ulcer healing and/or 
precipitate ulcer formation in humans. 
    Recently, we have proved that proton pump inhibitor can effectively prevent recurrent 
peptic ulcers among atherosclerotic patients with a history of peptic ulcer.12 However, the 
interaction of PPIs and clopidogrel has raised the concern for the safety of combination use of 
the two medicines.13-15 Clopidogrel is a prodrug, which must be absorbed in the gastrointestinal 
tract, and metabolized in the liver to generate active metabolites and acquires its anti-platelet 
properties. The metabolism of clopidogrel involves CYP2C19 isoenzyme, which is also the 
key enzyme for the metabolism of most PPIs.16 This has led to the assumption that some PPIs 
may potentially inhibit the CYP2C19 pathway and interfere with the conversion of clopidogrel 
to  active  form.  Three  large  retrospective  observation  studies  also  reported  that  patients 
prescribed clopidogrel who also took PPIs had significant increases in cardiovascular events.17-
19 
Famotidine is a histamine H2-receptor antagonist that has proved to be well tolerated and 
able to prevent and heal peptic ulcers in patients receiving conventional NSAIDs.20-22 The 
FAMOUS (Famotidine for the Prevention of Ulcers in Users of Low-dose Aspirin) trial 
documented  that  famotidine  is  effective  in  the  prevention  of  peptic  ulcers  and  erosive 
esophagitis  in  patients  taking  low-dose  aspirin.23 However,  famotidine  is  inferior  to 
pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions in patients 
with aspirin-related  peptic ulcers/erosions.24 The  current study is  designed to assess  the 
efficacy  of  histamine-2  receptor  antagonist  in  the  prevention  of  ulcer  recurrence  for 
thienopyridine users.  
References
1. Savi P, Nurden P, Nurden AP, Levy-Toledano S, Herbert JM. Clopidogrel: a review of 
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its mechanism of action. Platelets 1998;9:251-255. 
2. Boeynaems  JM,  van  Giezen  H,  Savi  P,  Herbert  JM.  P2Y receptor  antagonist  in 
thrombosis. Curr Opin Investig Drugs 2005;6:257-282. 
3. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel 
in addition to aspirin in patients with acute coronary syndrome without ST-segment 
elevation. N Engl J Med 2001;345:494-502.
4. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, 
Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston 
SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, 
Brennan  DM,  Fabry-Ribaudo  L,  Booth  J,  Topol  EJ;  CHARISMA  Investigators. 
Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic 
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5. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, 
Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA; Clopidogrel in Unstable 
angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment 
with clopidogrel and aspirin followed by long-term therapy in patients undergoing 
percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-533.
6. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin 
in patients at risk of ischemic events (CAPRIE). Lancet 1996;348:1329-1339.
7. Fork FT, Lafolie P, Toth E, Lindgarde F. Gastroduodenal tolerance of 75 mg clopidogrel 
versus 325 mg aspirin in healthy volunteers: a gastroscopic study. Scand J Gastroenterol 
2000;35:464-469.
8. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey 
WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, 
Wenger NK, Wright RS, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman 
EM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, 
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Ornato JP, Page RL, Riegel B.  ACC/AHA 2007 guidelines  for the management of 
patients  with  unstable  angina/non-ST-elevation  myocardial  infarction.  Circulation 
2007;116:e138–304.
9. Ng FH, Wong SY, Chang CM, Chen WH, Hng C, Lanas AI, Wong BC. High incidence 
of clopidogrel-associated gastrointestinal bleeding in patients with previous peptic ulcer 
disease. Aliment Pharmacol Ther 2003;18:443-449.
10. Chan FK, Ching JY, Hung LC, Wong VW, Leung VK, Kung NN, Hui AJ, Wu JC, Leung 
WK, Lee VW, Lee KK, Lee YT, Lau JY, To KF, Chan HL, Chung SC, Sung JJ. 
Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl 
J Med 2005;352:238-244.
11. Ma L, Elliott SN, Cirino G, Buret A, Ignarro LJ, Wallace JL. Platelets modulate gastric 
ulcer healing: role of edostatin and vascular endothelial growth factor release. Proc Natl 
Acad Sci USA 2001;98:6470-6475.
12. Hsu  PI,  Lai  KH,  Lau  CP.  Esomeprazole  with  clopidogrel  reduces  peptic  ulcer 
recurrence,  compared  with  clopidogrel  alone,  in  patients  with  atherosclerosis. 
Gastroenterology 2011;140:791-8.
13. Laine L, Hennekens C. Proton pump inhibitor and clopidogrel interaction: Fact or 
fiction? Am J Gastroenterol 2010;105:34-41.
14. Sibbing D, Kastrati A. Risk of combining PPIs with thienopyridines: fact or fiction? 
Lancet 2009;374:952-954.
15. Gilard M, Arnaud B, Cornily JC,  Le Gal G, Lacut K, Le Calvez G, Mansourati J, 
Mottier D, Abgrall JF, Boschat J. Influence of omeprazole on the antiplatelet action of 
clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole 
Clopidogrel Aspirin) study. J Am Coll Cardiol 2008;51:256-260.
16. Simon T, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, 
Danchin  N, Becquemont  L;  French  Registry of  Acute  ST-Elevation  and Non-ST-
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Elevation  Myocardial  Infarction  (FAST-MI)  Investigators.  Genetic  determinants  of 
response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-375.
17. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS. Risk of 
adverse outcomes associated with concomitant use of clopidogrel and proton pump 
inhibitors following acute coronary syndrome. JAMA 2009;301:937-944. 
18. Juurlink D, Gomes T, Ko  DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, 
Mamdani MM. A population-based study of the drug interaction between proton pump 
inhibitors and clopidogrel. CMAJ 2009;180:713-718.
19. Stanek EJ, Aubert RE, Flockhart DA.  A National Study of the Effect of  Individual 
Proton  Pump  Inhibitors  on  Cardiovascular  Outcomes  in  Patients  Treated  with 
Clopiodogrel Following Coronary Stenting: The Clopidogrel Medco Outcomes Study. 
http://www.scai.org/pdf/20090506Medcoabstract.pdf (Abstract)
20. Taha AS, Hudson N, Hawkey CJ, et al. Famotidine for the prevention of gastric and 
duodenal  ulcers  caused  by non-steroidal  anti-inflammatory drugs.  N  Engl  J  Med 
1996;334:1435-9.
21. Hudson N, Taha AS, Russell RI, et al. Famotidine for the healing of and maintenance in 
nonsteroidal  anti-inflammatory  drugs-associated  gastroduodenal  ulceration. 
Gastroenterology 1997;112:1817-22.
22. Taha AS, Dahill S, Morran C, et al. Neutrophil, Helicobacter pylori, and nonsteroidal 
anti-inflammatory drug ulcers. Gastroenterology 1999;116:254-9.
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PATIENTS AND METHODS
Study population
We will screen for eligible patients who have a past history of gastroduodenal ulcer and underwent 
endoscopy for dyspeptic symptoms or routine screening, while receiving thienopyridine(either 
clopidogrel or ticlopidine) therapy to prevent ischemic events. We enroll patients in the study if they 
meet the following criteria: endoscopic examination reveals normal appearance or pictures of 
gastritis only; they have received thienopyridine for at least two weeks; they have an atherosclerotic 
disease such as ischemic heart disease or stroke; they require long-term anti-platelet therapy; and 
they are adult patients aged 20 years. Patients are excluded if they have a history of gastric or
≧
 
duodenal surgery other than oversewing of a perforation; if they are allergic to the study drugs; if 
they  require  long-term  treatment  with  non-steroidal  anti-  inflammatory  drugs  (NSAIDs), 
corticosteroids, aspirin, or anticoagulant agents; if they are pregnant; if they have active cancer, 
acute serious medical illness or terminal illness; and if they have gastroesophageal reflux disease.
Study Protocol
Randomization and treatment
Eligible 228 patients are randomly assigned to receive either (1) 40 mg of famotidine (40 mg before 
bedtime) or (2) placebo (before bedtime) for 6 months. Randomization was carried out with the use 
of a computer-generated list of random numbers. An independent staff member assigned the 
treatments according to consecutive numbers that were kept in sealed envelopes. Anticoagulants, 
cyclooxygnease-2  inhibitors,  conventional  NSAIDs,  aspirin,  over-the-counter  analgesics, 
corticosteroids, misoprostol, PPIs, sucrafate are prohibited. The administration of an antacid (Iwell, 
Everest, Taiwan) was permitted for the control of dyspeptic symptoms. Compliance with the 
regimen are assessed by counting the pills that are returned. If  Helicobacter pylori  (H pylori) 
infection  is  documented  on  recruitment,  a  seven-day  course  of  anti-H  pylori  therapy  is 
administered.25 Urea breath test26 is performed at four weeks after the end of anti-H pylori therapy. 
Patients in whom H pylori infection is not eradicated, as indicated by positive results of urea breath 
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tests, receive a ten-day course of quadruple therapy consisting of esomeprazole 40 mg b.d., bismuth 
subcitrate 120 mg q.d.s., tetracycline 500 mg q.d.s., metronidazole 250 mg q.d.s, An additional 13C 
urea breath test was conducted to assess the final H pylori status two weeks following the six-month 
trial for all the patients who have H pylori infection on recruitment. Eradication is defined as a 
negative result of the final urea breath test.
Blood sampling for genotyping of CYP2C19 is carried out on enrollment. Platelet aggregation tests 
are performed in Day 1 and Day 28. The CYP2C19 genotype is determined using the polymerase 
chain reaction-restriction fragment length polymorphism (PCR-RFLP) as previous description.27,28 
Genotypes  are  classified  into  three  groups:  homogeneous  extensive  metabolizer  (homEM; 
CYP2C19*1/CYP2C19*1); heterogeneous extensive metabolizer (hetEM; CYP2C19*1/CYP2C19*2 
and
 CYP2C19*1/CYP2C19*3);  poor  metabolizer  (PM;
 CYP2C19*2/CYP2C19*2, 
CYP2C19*2/CYP2C19*3, and CYP2C19*3/CYP2C19*3).
Detection of H pylori on recruitment
On initial endoscopy, a biopsy specimen was obtained from the greater curvature within 5 
cm of the pylorus for rapid urease test. A negative CLO test was defined by the absence of a 
change in color after 24 hours. Additionally, one specimen taken from the greater curvature 
within 5 cm from the pylorus and another taken from the greater curvature of middle body were 
subjected to microscopic examination for H pylori with the use of hematoxylin and eosin stain 
and Warthin-Starry stain if necessary. H pylori was considered to be present if either one of the 
two tests was positive; it was considered to be absent when both tests were negative.
Follow-up
Patients  are  followed  up  as  outpatients  with  visits  every  month.  Upper  gastrointestinal  and 
cardiovascular symptoms are assessed at each visit. They are asked to return to the outpatient clinic 
if they have persistent dyspeptic symptoms (epigastric pain, fullness, nausea or vomiting) and to 
report to the emergency room if they have evidences of gastrointestinal bleeding (hematemesis, 
melena, or sudden onset of severe epigastric pain), cardiovascular events (chest pain, syncope, or 
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sudden  onset  of  severe  palpitation)  or  cerebrovascular  accidents  (conscious  disturbance, 
hemiparesis,  or  dysphagia).  Follow-up  endoscopy  with  biopsy  for  urease  test  is  performed 
whenever persistent dyspepsia, severe epigastric pain, hematemesis or melena occurred and at the 
end of the 6th month. The endoscopists who performed follow-up endoscopy are unaware of the 
treatment  group  assignments.  The  events  of  acute  coronary  syndrome  and  cerebral  vascular 
accidents during the study period are carefully monitored and assessed.
End points
The primary end point are the occurrence of gastric and/or duodenal ulcers, as determined by 
endoscopy, during the 6-month study period. An ulcer is defined as a circumscribed mucosal break 
at least 0.5 cm in diameter (measured using endoscopy forceps) and with a perceptible depth.10,12 
Only events that are confirmed by the adjudication committee and that occurred during treatment 
are included in the analysis. Patients who do not have follow-up endoscopic examination are 
assumed to have had normal findings. The secondary endpoints are: (1) the occurrence of ulcer or 
erosion bleeding as defined according to pre-specified criteria – namely, hematemesis or melena 
documented by the admitting physician, with ulcers or bleeding erosions confirmed on endoscopy, 
or a decrease in the hemoglobin level of at leas t 2 g deciliter in the presence of endoscopically 
documented ulcers or erosions.10 An erosion is defined as a flat mucosal break of any size;10 (2) the 
occurrence of unstable angina defined as rest angina (angina occurring at rest and prolonged more 
than 20 minutes), new-onset angina (of at least the Canadian Cardiovascular Society Class III 
severity)  and  increasing  angina  (angina  occurring  more  frequently,  longer  in  duration)  with 
ischemic changes in electrocardiogram;29  (3) acute myocardial infarction defined as at least two 
positive results of typical chest pain, evolutionary electrocardiogram changes and evolutionary 
cardiac  enzyme  changes;  (4)  the  occurrence  of  ischemic  stroke  defined  as  sudden  onset  of 
neurological deficit due to cerebral ischemia documented by computed tomography; (5) vascular 
death defined as death due to cardiovascular diseases or cerebrovascular accidents. Only events that 
are confirmed by the cardiovascular events review board are included in the analysis.
9