Clinical trial NCT02551744
Conditions: Peptic Ulcer
Keywords: histamine-2 receptor antagonist proton pump inhibitor thienopyridine clopidogrel prevention
Sponsor: Kaohsiung Veterans General Hospital.
Start date: 2012-07-01; Completion date: 2018-07-01
Enrollment: 101 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Whether pantoprazole versus famotidine for the prevention of recurrent peptic ulcers in thienopyridine users remains unclear.

Detailed description:
The aims of the randomized double-blind comparison study are to compare the efficacy of Proton Pump Inhibitor and H2 receptor antagonist for the prevention of recurrent peptic ulcers in thienopyridine users. We plan to enroll 334 thienopyridine (clopidogrel or ticlopidine) users without baseline gastroduodenal ulcer at initial endoscopy. The patients will be randomly assigned to receive either (1) pantoprazole (40 mg qd) or (2) famotidine (40 mg qd) for 6 months.The ulcer recurrence rate between the treatment groups will be compared.

Arms: arm 1: Pantoprazole Tab 40mg qd for 6 monthrs. arm 2: famotidine Tab 40 mg qd for 6 months.
Interventions: intervention 1: histamine-2 receptor antagonist group intervention 2: proton pump inhibitor group
Intervention descriptions: intervention 1: famotidine tab 40 mg qd for 6 months. intervention 2: pantoprazole tab 40 mg qd for 6 months.

Protocol documents:
Prot_000.pdf: 
VGHKS12-CT7-08
Institution/Department：Kaohsiung Veterans General Hospital
Principal Investigator (PI)：Prof. Ping-I Hsu 
Research  Project  Title ：Pantoprazole  versus  famotidine  for  the  prevention  of 
recurrent peptic ulcers in thienopyridine users — a double-
blind randomized controlled trial
NCT Number：NCT02551744
Date of the document：From  07   31   2018  （MM/DD/YYYY） 
ABSTRACT
Background: 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. These 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 such as 
histamine-2 receptor antagonist (H2RA) to prevent gastrointestinal events for clopipogrel 
users is urgently needed in clinical practice. 
Aims: To compare the efficacy of PPI and H2RA for the prevention of recurrent peptic ulcers 
in thienopyridine users.
Methods: We plan to enroll 334 thienopyridine (clopidogrel or ticlopidine) users without baseline 
gastroduodenal ulcer at initial endoscopy. The patients will be randomly assigned to receive either 
(1) pantoprazole (40 mg qd) or (2) famotidine (40 mg qd) for 6 months. Blood sampling for 
genotyping of CYP2C19 is carried out on enrollment. Follow-up endoscopy is carried out at the 
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end of the 6th month and whenever severe epigastric pain, hematemesis or melena occurs. The 
primary end point is the occurrence of gastric and/or duodenal ulcers during the 6-month study 
period.
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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 from our center demonstrated that 11% of the patients with a peptic 
ulcer history who took clopidogrel for the prevention of ischemic events had recurrent peptic 
ulcer during a 6-month follow-up period.9 Another prospective study also showed 9% of patients 
with a history of peptic ulcer bleeding who took clopidogrel had recurrent ulcer bleeding within 
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one year.10 The mechanisms leading to recurrent peptic ulcers and ulcer bleeding among patients 
receiving 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 Platelet aggregation plays an important role in ulcer healing through the 
release of platelet-derived growth factors that promote angiogenesis, which is important for ulcer 
healing. An endoscopic study revealed that a point prevalence of peptic ulcer was 1.3% in the 
adult general population.12 Although clopidogrel might not be primarily responsible for the 
development of peptic ulcer, it may impair healing of background ulcers and convert silent ulcers 
to bleeding lesions. 
Our previous study has proved that esomeprazole can effectively prevent recurrent peptic ulcers 
among clopidogrel users with a history of peptic ulcer.9 Currently, very few studies have evaluated 
the efficacy of histamine-2 receptor antagonist (H2RA) in the  prevention  of GI injury with 
antiplatelet agents. Ng et al. showed that H2RA is inferior to proton pump inhibitor (PPI) in 
preventing recurrence of aspirin-related peptic ulcers or erosions in patients with aspirin-related 
peptic ulcers/erosions.13 A recent case-control study by Lanas et al. revealed that, compared with 
patients undergoing antiplatelet therapy without protective co-therapy, H2RAs can significantly 
reduce the risk of upper GI bleeding in patients taking low-dose aspirin but not in those taking 
clopidogrel.14 Another cohort study also reported that 22% of clopidogrel users taking concomitant 
H2RAs had recurrent upper GI bleeding after a 1-year follow up, whereas no patient taking 
clopidogrel plus a PPI had recurrent bleeding.15
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Recently, the interaction of PPIs and thienopyridines has raised the concern for the safety of 
combination use of the two medicines.16-18 Thienopyridines are prodrugs, which must be absorbed 
in the gastrointestinal tract, and metabolized in the liver to generate active metabolites and 
acquire  their anti-platelet  properties. The metabolism of thienopyridines  involve CYP2C19 
isoenzyme, which is also the key enzyme for the metabolism of most PPIs.19 This has led to the 
assumption that some PPIs may potentially inhibit the CYP2C19 pathway and interfere with the 
conversion of thienopyridines to active form. Three large retrospective observation studies also 
reported that patients prescribed clopidogrel who also took PPIs had significant increases in 
cardiovascular events.20-22 However, Bhatt et al.23 recently conducted a double-blind, prospective 
randomized trial (COGENT; Clopidogrel and the Optimization of Gastrointestinal Events Trial) 
to investigate the effect of omeprazole in patients receiving both aspirin and clopidogrel. The data 
demonstrated that prophylactic use of omeprazole reduces the rate of upper GI bleeding among 
patients receiving aspirin and clopidogrel, and there were no differences in CV events between 
omeprazole and placebo groups.
Our  recent  study9 demonstrated  that  esomeprazole  does  not  influence  the  action  of 
clopidogrel on platelet aggregation when doses of esomeprazole and clopidogrel are widely 
separated. However, whether H2RA may interfere with the conversion of thienopyridines to 
active form remain unclear. Therefore, we design the randomized double-blind comparison study 
to investigate whether proton pump inhibitor is superior to H2RA in the prevention of recurrent 
peptic ulcers in thienopyridine users.
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References
1. Savi P, Nurden P, Nurden AP, Levy-Toledano S, Herbert JM. Clopidogrel: a review of 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 
events. N Engl J Med. 2006;354:1706-1717.
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 
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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, 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. 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.
10. Chan FKL, Ching JYL, Hung LCT, et al. Clopidogrel versus aspirin and esomeprazole for the 
prevention of recurrent ulcer bleeding. N. Engl. J. Med. 2005; 352: 238-44.
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: 6470-5.
12. Laine L, Maller ES, Yu C, Quan H, Simon T. Ulcer formation with low-dose enteric-coated 
aspirin and the effect of COX-2 selective inhibition: a double-blind trial.  Gastroenterology 
2004; 127: 395 - 402.
13. Ng FH, Wong SY, Lam KF, et al. Famotidine is inferior to pantoprazole in preventing recurrence 
of aspirin-related peptic ulcers or erosions. Gastroenterology 2010; 138: 82-8.
14. Lanas A, Garcıa-Rodrıguez LA, Arroyo MT, et al. Effect of antisecretory drugs and nitrates on 
the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet 
agents, and anticoagulants. Am. J. Gastroenterol. 2007; 102: 507–15.
15. Ng FH, Wong SY, Chang CM, et al. High incidence of clopidogrel-associated gastrointestinal 
bleeding in patients with previous peptic ulcer disease.  Aliment. Pharmacol. Ther.  2003; 18: 
443-9.
16. Laine L, Hennekens C. Proton pump inhibitor and clopidogrel interaction: Fact or fiction? Am J 
Gastroenterol 2010;105:34-41.
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17. Sibbing D, Kastrati A. Risk of combining PPIs with thienopyridines: fact or fiction? Lancet 
2009;374:952-954.
18. Norgard NB, Mathews KD, Wall GC. Drug-drug interaction between clopidogrel and proton 
pump inhibitors. Ann. Pharmacotherapy 2009; 43: 1266-74.
19. 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-Elevation Myocardial 
Infarction  (FAST-MI)  Investigators.  Genetic  determinants  of  response  to  clopidogrel  and 
cardiovascular events. N Engl J Med 2009;360:363-375.
20. 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.
21. 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.
22. 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
 
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http://www.scai.org/pdf/20090506Medcoabstract.pdf (Abstract).
23. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary 
artery disease. N. Engl. J. Med. 2010; 363: 1909-17.
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 334 
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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 patients are randomly assigned to receive either (1) 40 mg of famotidine daily or (2) 
40 mg of pantoprazole daily for 6 months. Randomization is carried out with the use of a computer-
generated list of random numbers. An independent staff member assigns the treatments according to 
consecutive  numbers  that  are  kept  in  sealed  envelopes.  Anticoagulants,  cyclooxygnease-2 
inhibitors, conventional NSAIDs, aspirin, over-the-counter analgesics, corticosteroids, misoprostol, 
sucrafate are prohibited. The administration of an antacid (Iwell, Everest, Taiwan) is permitted for 
the control of dyspeptic symptoms. Compliance with the regimen is 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. Urea breath test is performed at four weeks 
after the end of anti-H pylori therapy. 
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 
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(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).
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 
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 is 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. 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. 
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