hon p.1 [100%]YAKUGAKU ZASSHI 130(12) 1743―1750 (2010)  2010 The Pharmaceutical Society of Japan

1743―Regular Article―

E‹cacy and Safety of Concomitant Use of Rabeprazole during Dual-antiplatelet
Therapy with Clopidogrel and Aspirin after Drug-eluting Stent Implantation:
A Retrospective Cohort Study
Takeo YASU,,a Ryota IKEE,b Yoshiyuki MIYASAKA,a Hideo CHUBACHI,a and Shigeru SAITOc
aDepartment of Pharmacy, bDepartment of Nephrology and Kidney and Dialysis Center, and cDepartmentof Cardiology and Catheterization Laboratory and Heart Center, Shonan Kamakura General
Hospital, 12021 Yamasaki, Kamakura, Kanagawa 2478533, Japan(Received May 2, 2010; Accepted August 30, 2010; Published online September 9, 2010)
After coronary stent implantation, dual-antiplatelet therapy (DAT), such as aspirin and clopidogrel, is essential toprevent stent thrombosis. Proton-pump inhibitors (PPIs) may be used to prevent gastrointestinal (GI) bleeding during
DAT, but there is no evidence for the e‹cacy of PPIs in this setting. Because both clopidogrel and PPIs are metabolized
by cytochrome P450 (CYP) 2C19, there is a possibility that, through drug interaction, PPIs diminish the antiplatelet
eŠect of clopidogrel. In this retrospective cohort study, we evaluated the e‹cacy and safety of rabeprazole in patients
receiving DAT of clopidogrel and aspirin after drug-eluting stent implantation. In 199 patients treated with DAT alone(control group) and 103 patients treated with rabeprazole plus DAT (rabeprazole group), we examined the incidencesof GI bleeding and major adverse cardiac events (MACE) including stent thrombosis. The incidence of GI bleeding was
not signiˆcantly diŠerent between the groups (hazard ratio 0.47 [95％ conˆdence interval 0.151.42], P＝0.18; P＝0.17
in log-rank test), although no patient with severe bleeding was observed in the rabeprazole group. The use of rabeprazole did not increase the incidence of MACE (hazard ratio 1.28 [95％ conˆdence interval 0.54
3.00], P＝0.56; P＝0.56
in log-rank test). One patient who developed subacute stent thrombosis under DAT was genetically proven to be a
CYP2C19 poor metabolizer. The eŠect of rabeprazole to prevent GI bleeding is limited in patients receiving DAT. It
remains to be conˆrmed whether these results may depend on CYP2C19 polymorphisms or a class of PPIs.
Key words―clopidogrel; rabeprazole; GI bleeding; stent thrombosis; drug interaction; CYP2C19

INTRODUCTION
The standard dual-antiplatelet therapy (DAT) consisting of clopidogrel and aspirin is quite important toprevent stent thrombosis after coronary stent implantation. After drug-eluting stent (DES) implantation,
DAT is recommended to be continued for at least one
year.1) However, aspirin leads to the risk of uppergastrointestinal (GI) bleeding, and its combination
with clopidogrel further increases the risk of
bleeding.2) Therefore, prophylactic use of protonpump inhibitors (PPIs) with DAT is recommended
by consensus guidelines.3)
Clopidogrel, which irreversibly binds to the platelet
P2Y12 receptors and blocks their activation and aggregation, is a safer drug with a lower incidence ofhematologic and liver complications than ticlopidine.
Clopidogrel is a pro-drug, which needs to be activatedthrough the action of cytochrome P450 (CYP) 1A2,
2B6, 2C9, 2C19, and 3A. CYP2C19 polymorphisme-mail: yasutakeo＠gmail.com

has been suggested as the cause of clopidogrel
resistance4) and aŠects clinical outcomes.5,6)
CYP2C19 is also involved in the metabolism of PPIs
such as omeprazole, lansoprazole, and rabeprazole.7)
Therefore, PPIs may interact with clopidogrel. In
fact, several studies have shown the possibility that
PPIs, especially omeprazole, might diminish the antiplatelet eŠects of clopidogrel through inhibition of
CYP2C19.8) On the other hand, there are also con‰icting data that the interaction between clopidogrel
and PPI had no eŠect on clinical outcome.9) Thus,
the clinical signiˆcance of concomitant administration of PPI and clopidogrel remains to be determined.
The frequency of CYP2C19 poor metabolizer inJapan is about 20％,10) which is higher than that inWestern countries. Therefore, we hypothesized thatJapanese patients receiving DAT and PPI might be atincreased risk of major adverse cardiac events(MACE) including stent thrombosis. To our knowledge, this issue has not been determined in Japanesepatients to date. The objectives of this study are to in-hon p.2 [100%]1744

Vol. 130 (2010)

vestigate whether rabeprazole reduces the risk of GI
bleeding, and increases the incidence of MACE during DAT after DES implantation in Japanese patients.
METHODS
Patients
We performed a retrospective cohort
study in 423 patients who underwent DES implantation in the Department of Cardiology and Catheterization Laboratory of our hospital between June 2006
and March 2009. Exclusion criteria were as follows:
the discontinuation of DAT or losts from the followup within one year, concomitant use of nonsteroidal
anti-in‰ammatory drugs (NSAIDs), cyclooxygenase2 inhibitors, corticosteroids, histamine H2-receptor
antagonist, or other PPIs such as omeprazole andlansoprazole for more than one week. The use of gastric mucosal protective agents (other than histamine
H2-receptor antagonist, omeprazole, or lansoprazole), warfarin, antiplatelet drugs, or over-the-counter drugs was not restricted.
Finally, 302 patients were included in this study(Fig. 1). Of these patients, 103 were treated withDAT and rabeprazole at 10 mg/day for one year after
DES implantation (rabeprazole group). On the other
hand, 199 patients were treated only with DAT (control group). In both groups, the maintenance regimen
of DAT was clopidogrel (5075 mg/day) and aspirin(100200 mg/day) for at least one year. Enteric-coat-Fig. 1.

Design of Study.

ed tablets of aspirin were used in all patients. All
patients underwent coronary angiography one year
after DES implantation.
Clinical Assessment
In these patients, we assessed whether rabeprazole reduces the risk of GI
bleeding during DAT. Upper GI bleeding was deˆned
as hematemesis or melena with bleeding erosions conˆrmed by endoscopy. The severity of upper GI bleeding was determined based on Thrombolysis In Myocardial Infarction (TIMI) trial bleeding criteria11)
with modiˆcation: mild bleeding was deˆned as adecrease in hemoglobin 3 g/dl, moderate bleeding
as a decrease in hemoglobin ＞3 g/dl but 5 g/dl,
and severe bleeding as a decrease in hemoglobin ＞5 g/dl. Lower GI bleeding was deˆned as melena, rectal
bleeding, or a positive fecal occult blood test withnegative results on upper endoscopy. The severity oflower GI bleeding was deˆned as the same as that ofupper GI bleeding. The relationship of triple antithrombotic therapy (TAT), DAT plus warfarin orcilostazol, with GI bleeding was also examined.
In addition, we assessed whether rabeprazole increases the risk of MACE. During the follow-up
period, rabeprazole was temporarily used for upper
GI bleeding or gastroesophageal re‰ux disease in 11of the 199 patients in the control group. Therefore,
the relationship between rabeprazole and MACE wasinvestigated in the remaining 188 patients (Fig. 1).
MACE was deˆned as cardiac death, acute coronary
syndrome, stent thrombosis, and target lesion revascularization. Stent thrombosis was deˆned according
to the Academic Research Consortium deˆnition, andclassiˆed as acute (within 24 hours after DES implantation), subacute (24 hours to 30 days), or late (30days to one year).12)
During the follow-up period of 395.1±27.7 days,
the information on complete blood count, blood chemistry, drug adherence, other medication, and clinical outcomes was collected from medical records.
This study was conducted according to the Ethical
Guidelines for Epidemiological Research. The ethicalcommittee of our hospital approved this study. One
patient who underwent genotyping gave informed
consent for genotyping.
Statistical Analysis
Data are expressed as mean
±S.D. Characteristics were compared between thetwo groups using the Mann-Whitney U test or x2 test,
as appropriate. For each end-point category, KaplanMeier time-to-event curves were used to estimate thehon p.3 [100%]

No. 121745

absolute risk of each event at 1 year for each group,with log-rank test. To determine whether rabeprazole
aŠect the risk of each end-point, univariate Cox
proportional hazards regression analysis was performed. A p-value ＜0.05 was considered statisticallysigniˆcant. All statistical analyses were performed using SPSS version 11.0 (SPSS, Chicago, Illinois,
USA).
RESULTS
Baseline characteristics of the patients are shown in
Table 1. Age, gender, body mass index, the prevalence of diabetes mellitus, hypertension, dyslipidemia, and smoking were similar between control andrabeprazole groups. However, previous myocardial
infarction and family history of ischemic heart disease were more frequently found in rabeprazole
group, with statistically signiˆcant diŠerences. The
number of implanted DES was signiˆcantly larger inrabeprazole group. The rabeprazole group was more
frequently treated with calcium-channel blocker andb-blocker. The gastromucosal protective agents usedwere rebamipide (n＝9), sucralfate (n＝3), andtepurenone (n＝14) in control group, and rebamipide(n＝5), sucralfate (n＝1), tepurenone (n＝1), andecabet (n＝1) in rabeprazole group. The DAT regimens in control group were: aspirin 100 mg＋
clopidogrel 75 mg in 63 patients (31.7％), aspirin 200
mg＋clopidogrel 50 mg in 82 (41.2％), and aspirin
200 mg＋clopidogrel 75 mg in 54 (27.1％). The DAT
regimen in rabeprazole group were: aspirin 100 mg＋
clopidogrel 75 mg in 50 patients (48.5％), aspirin 200
mg＋clopidogrel 50 mg in 26 (25.2％), and aspirin
200 mg＋clopidogrel 75 mg in 27 (26.2％).
Table 2 shows GI bleeding in the follow-up. Upper
GI bleeding occurred in 7 patients of control groupand 1 of rabeprazole group. The incidences of upper
GI bleeding were not diŠerent between the groups, as
shown in Fig. 2 (P＝0.19 in log-rank test). In addition, the incidences of lower GI bleeding were not
diŠerent between the groups (Fig. 3, P＝0.50 in logrank test). The causes of lower GI bleeding were as
follows: diverticular bleeding in 6 patients, ischemic
enteritis in 2, colon cancer in 1, colon polyp in 1,
hemorrhoid in 1, and small colon ulcer in 1. Diverticular bleeding was the leading cause, but asymptomatic in all patients. Total incidence of upper andlower GI bleeding was not diŠerent between thegroups (Fig. 4, P＝0.17 in log-rank test). In univari-

Table 1.

Patient Baseline Characteristics
Control Rabeprazole
group
group

n
Age (year)
Male patients (n, ％)Body mass index (kg/m2)
Hypertension (n, ％)Diabetes mellitus (n, ％)Dyslipidemia (n, ％)Current smoking (n, ％)Chronic kidney disease 1(n, ％)
Hemodialysis/peritoneal
dialysis (n, ％)

p

199
103
67.4±10.1 69.0±9.6
144(72.4) 69(67.0)
23.2±3.2 23.6±3.9129(64.8) 66(64.1)
79(39.7) 36(35.0)
115(57.8) 70(68.0)
54(27.1) 25(24.3)

0.113
0.332
0.514
0.898
0.421
0.085
0.591

75(37.7)40(38.8)

0.846

9( 4.5)1( 1.0)0.102

Previous myocardial infarction
35(17.6)(n, ％)

33(32.0)0.00430(15.1)

29(28.2)

0.007

23(11.6)

11(10.7)

0.189

18( 9.0)11(10.7)

0.648

9( 4.5)Gastroesophageal re‰ux
8( 4.0)disease (n, ％)Stable angina pectoris (n, ％) 114(57.3)

7( 6.8)0.403

5( 4.9)0.735

57(55.3)

0.746

28(27.2)

0.993

3.1±1.962(60.2)
55(53.4)31(30.1)

0.004
0.720
0.663
0.307

38(19.1)

21(20.4)

0.788

67(33.7)

34(33.0)0.90870(35.2)

49(47.7)

0.037

60(30.2)
HMG-CoA reductase inhibitor
137(68.8)(n, ％)

44(42.7)

0.029

80(77.7)

0.106

26(13.1)

8( 7.8)0.167

7( 3.5)7( 3.5)9( 8.7)5( 4.9)

0.055
0.573

Family history of ischemic
heart disease (n, ％)Stroke (n, ％)Peripheral arterial disease(n, ％)
Peptic ulcer (n, ％)Acute coronary syndrome54(27.1)(n, ％)
Number of implanted stents
2.5±1.6
Sirolimus-eluting stent (n, ％) 124(62.3)
Paclitaxel-eluting stent (n, ％) 101(50.8)
DES＋bare metal stent (n, ％) 49(24.6)
Angiotensin converting
enzyme-inhibitor (n, ％)Angiotensin II receptor
blocker (n, ％)Calcium-channel blocker(n, ％)
b-blocker (n, ％)Gastric mucosal protective
agent (n, ％)Warfarin (n, ％)Cilostazol (n, ％)1 Chronic kidney disease was deˆned as estimated glomerular ˆltration＜60 ml/min/1.73 m 2. DES, drug-eluting stent.

ate Cox proportional hazards regression analysis,
hazard ratio of rabeprazole administration was 0.27
[95％ conˆdence interval (CI) 0.032.22, P＝0.22]
for upper GI bleeding, 0.64 (95％ CI 0.172.38, P＝0.51) for lower GI bleeding, and 0.47 (95％ CI 0.15
1.42, P＝0.18) for GI bleeding.
As shown in Table 3, 3 patients of control groupexperienced severe upper GI bleeding, but none ofhon p.4 [100%]1746

Vol. 130 (2010)

Table 2.

GI Bleeding in Follow-up
Control Rabeprazole
group
group

n
GI bleeding (n, ％)Upper GI bleeding (n, ％)Mild bleeding
Moderate bleeding
Severe bleeding
Lower GI bleeding (n, ％)199
16(8.0)7(3.5)
3
1
3
9(4.5)

103
4(3.9)
1(1.0)01
03(2.9)

5
3
1
Hospitalization for GI bleeding (n, ％) 8(4.0)

2012(1.9)

Mild bleeding
Moderate bleeding (n, ％)Severe bleeding (n, ％)Fig. 3.

Cumulative Rate of Lower Gastrointestinal Bleeding

The solid line indicates control group and the broken line indicatesrabeprazole group. There was no diŠerence in the incidence of lower GI
bleeding in the follow-up (P＝0.50, log-rank test).

Fig. 2.

Cumulative Rate of Upper Gastrointestinal Bleeding

The solid line indicates control group and the broken line indicatesrabeprazole group. There was no diŠerence in the incidence of upper GI
bleeding in the follow-up (P＝0.19, log-rank test).

Fig. 4.

those in rabeprazole group experienced. The control
group included 9 patients with a history of peptic ulcer, and upper GI bleeding occurred in 3 of them during DAT. In rabeprazole group, however, none of the
7 patients with a history of peptic ulcer had upper GI
bleeding.
Of the 302 patients, 28 received TAT for atrialˆbrillation or peripheral arterial disease. Upper GI
bleeding occurred in 1 (3.6％) of the patients receiving TAT and in 7 (2.6％) of those not receiving TAT,
which was not signiˆcantly diŠerent (P＝0.87 in logrank test). Lower GI bleeding occurred in 3 (10.7％)of those receiving TAT and in 9 (3.3％) of those notreceiving TAT. This diŠerence was marginally signiˆcant (P＝0.27 in log-rank test).

Cumulative Rate of Gastrointestinal Bleeding

The solid line indicates control group and the broken line indicatesrabeprazole group. There was no diŠerence in the incidence of upper andlower GI bleeding in the follow-up (P＝0.17, log-rank test).

As shown in Table 4, MACE occurred in 9 patients(8.7％) of rabeprazole group and 13 (6.9％) in control group in the follow-up. Subacute stent thrombosis occurred in one patient of rabeprazole group.
There was no signiˆcant diŠerence in the incidence ofMACE, as shown in Fig. 5 (P＝0.56 in log-ranktest). Hazard ratio of rabeprazole for MACE was
1.28 (95％ CI 0.543.00, P＝0.56).
In one patient of rabeprazole group who experienced subacute stent thrombosis, CYP2C19 genotype was examined by using a genotyping service

hon p.5 [100%]

No. 12

1747

Table 3.

Patients with Upper GI Bleeding

Age

Group

Previous
peptic ulcer

Gastric mucosal
protective agents

Bleeding
severity

87

Control

Yes

No

56

Control

Yes

No

50

ControlNo

Sucralfate

70

Control

No

No

72

Control

No

No

SevereGU, DU
SevereGU
SevereGU
Moderate
GU
Mild
GU

64

Control

Yes

No

75

Control

No

No

69

Rabeprazole

No

No

Mild
GU
Mild
DU
Moderate
GU

DAT
Aspirin 100 mg
Clopidogrel 75 mg
Aspirin 100 mg
Clopidogrel 75 mg
Aspirin 200 mg
Clopidogrel 50 mg
Aspirin 200 mg
Clopidogrel 50 mg
Aspirin 100 mg
Clopidogrel 75 mg
Warfarin 2 mg
Aspirin 200 mg
Clopidogrel 50 mg
Aspirin 100 mg
Clopidogrel 75 mg
Aspirin 200 mg
Clopidogrel 75 mg

Time after DES
implantation
58 days
263 days
20 days
309 days
39 days

65 days
135 days
51 days

DAT, dual-antiplatelet therapy; DES, drug-eluting stent; DU, duodenal ulcer; GU, gastric ulcer.

Table 4.

Major Adverse Cardiac Events in Follow-up
Control Rabeprazole
group
group

n
Major adverse cardiac events (n, ％)Cardiac death (n, ％)Acute coronary syndrome (n, ％)Stent thrombosis (n, ％)188
13(6.9)2(1.1)0(0)1(0.5)

1039(8.7)0(0)1(1.0)
1(1.0)

Acute0
Subacute0
Late1
Target lesion revascularization(n, ％) 10(5.3)

0107(6.8)(BML, Inc., Japan). The result was a CYP2C19 3
homozygote (3/3), which indicated a poor
metabolizer.

Fig. 5.

Cumulative Rate of Major Adverse Cardiac Events

The solid line indicates control group and the broken line indicatesrabeprazole group. There was no diŠerence in the incidence of MACE in thefollow-up (P＝0.56, log-rank test).

DISCUSSION
The incidence of DAT-induced GI bleeding wasreported to be 2.52％ in MATCH trial13) and 1.0％ in
BAT study.14) In a previous case-control study, thehazard ratio of severe bleeding was 1.1 in clopidogrelmonotherapy, 1.8 in aspirin monotherapy, and 7.4 in
DAT compared with that in no antiplatelet
therapy.15) In patients receiving DAT, prophylactic
use of PPI is recommended, but the eŠects of PPI
remain to be elucidated. Two case-control studies

with limited sample size showed that PPIs prevented
clopidogrel-induced gastroduodenal bleeding.16,17) In
our study, the incidence of GI bleeding during DAT
was comparable between control group and rabeprazole group. Although it seems somewhat notable that
there was no severe bleeding in the rabeprazole group,
the e‹cacy of rabeprazole in reducing the risk of
DAT-induced upper GI bleeding was not found. As
shown in Table 3, administered doses of aspirin andhon p.6 [100%]1748

clopidogrel did not seem to be related to bleeding.
The exact reasons why we could not identify theeŠects of PPI in this study are unknown, but generally the incidence of upper GI bleeding is not high inpatients receiving DAT. In fact, Ray et al. recently
reported that, in a retrospective cohort study including 20,596 patients with coronary artery disease, concurrent use of PPI with clopidogrel was associatedwith reduced incidence of hospitalization for gastroduodenal bleeding.18) In addition, Helicobacter pylori
infection might aŠect the result, as in the previous
study,3) but we did not examine H. pylori infection in
our patients.
Stent thrombosis is a rare complication after stentimplantation, but is associated with high morbidity
and mortality. According to a study from Japan, theincidence of stent thrombosis was 0.68％ within one
year after stent implantation.19) In our study, the incidences of stent thrombosis were 1.0％ in rabeprazole
group and 0.5％ in control group. Rabeprazole was
not associated with increased risk of stent thrombosis
during DAT. Considering the fact that the patients ofrabeprazole group had severe coronary artery lesions
requiring more DES in PCI, it seems that PPIs do notdiminish the antiplatelet eŠects of clopidogrel. Similarly, the results obtained using vasodilator-stimulated phosphoprotein phosphorylation assay and aggregometry showed that pantoprazole and esomeprazol had little eŠect on the platelet inhibition byclopidogrel.20) Ray et al. recently reported that concurrent use of pantoprazole with clopidogrel was not
associated with increased risk for serious cardiovascular disease.18) However, there remains a possibility
that the eŠects of PPI on inhibiting clopidogrel action
may depend on the class of PPI used. For example,
omeprazole is a potent inhibitor of CYP2C1921) andreported to inhibit the antiplatelet eŠect ofclopidogrel.8) On the other hand, pantoprazole isreported not to inhibit CYP2C197,21) and not to in‰uence the eŠect of clopidogrel.20)
Another problem is CYP2C19 genotype. The frequency of CYP2C19 poor metabolizer in Japan ishigher than that in Western countries.10) Recent studies suggest that CYP2C19 polymorphism may be arisk factor for stent thrombosis and cardiac
events.2224) In the patients treated with DAT plus
PPI, however, it was reported that CYP2C19 genotype was not associated with cardiovascular events.9)
We identiˆed the genotype in one patient of rabepra-

Vol. 130 (2010)

zole group, who experienced subacute stent thrombosis in the follow-up. CYP2C19 enzyme activity is
divided into 3 categories based on genotype: extensive, intermediate, and poor. CYP2C19 2/2, 2/3,
and 3/3 indicate a poor metabolizer in Japanese
populations.25) As a result, the genotype of thepatient was homozygous (3/3) for the mutant
CYP2C19 3 allele. Homozygous mutation should
lead to a pronounced decrease in activation ofclopidogrel activation, although CYP3A4, 1A2, or
2B6 might partly compensate for clopidogrel metabolism. In fact, Sibbing et al. reported that the incidence of stent thrombosis within 30 days following
PCI was highest in patients with homozygous mutation (CYP2C19 2/2 genotype).26) Subacute stent
thrombosis observed in the patients of rabeprazole
group may be attributable to CYP2C19 genotype,
rather than the possible interaction between clopidogrel and rabeprazole.
TAT was used in 28 of our patients. Gao et al.
reported that, in the patients with atrial ˆbrillation,
warfarin plus DAT was associated with decreased incidence of MACE compared with DAT alone.27)
However, the data on bleeding complications related
to TAT seem con‰icting.2729) In our study, there wasa trend that TAT increased lower GI bleeding. Further studies are required to examine the e‹cacy andsafety of TAT.
Our study has some limitations. The ˆrst limitation
was a single-center, retrospective cohort study design.
Secondly, the diŠerences between control group andrabeprazole group, such as previous myocardial infarction and family history of ischemic heart disease,
could aŠect the occurrence of MACE in the followup. Finally, because of low incidence of GI bleedingand MACE, the obtained results were not deˆnitely
conclusive with low statistical power. The required
sample size of each group calculated using a two-sided log-rank test with a signiˆcance level of 0.05 and astatistical power of 80％ on the basis of our study
were 270 patients in GI bleeding and 2073 patients in
MACE.
In conclusion, in patients receiving DAT after DES
implantation, the clinical eŠect of rabeprazole to prevent GI bleeding is limited. The additional administration of rabeprazole in these patients does not increase the incidence of MACE including stent thrombosis. These results should be conˆrmed in genetically-proven CYP2C19 poor metabolizer, or in use

hon p.7 [100%]

No. 121749

of other class of PPIs.
REFERENCES
1)

2)
3)

4)
5)

6)

7)

8)

9)

10)

11)

King S. B III., Smith S. C Jr., Hirshfeld J. W
Jr., Jacobs A. K., Morrison D. A., Williams
D. O.; 2005 WRITING COMMITTEE MEMBERS, Feldman T. E., Kern M. J., O'Neill W.
W., SchaŠ H. V., Whitlow P. L., Adams C.
D., Anderson J. L., Buller C. E., Creager M.
A., Ettinger S. M., Halperin J. L., Hunt S.
A., Krumholz H. M., Kushner F. G., Lytle B.
W., Nishimura R., Page R. L., Riegel B., Tarkington L. G., Yancy C. W., Circulation, 117,
261295 (2008).
McQuaid K. R., Laine L., Am. J. Med., 119,624638 (2006).
Bhatt D. L., Scheiman J., Abraham N. S.,
Antman E. M., Chan F. K., Furberg C. D.,
Johnson D. A., MahaŠey K. W., Quigley E.
M.; American College of Cardiology Foundation Task Force on Clinical Expert Consensus
Documents, Circulation, 118, 1894 1909(2008).
Kim K., Park P., Hong S., Park J. Y., Clin.
Pharmacol. Ther., 84, 236242 (2008).
Ho M. P., Maddox T. M., Wang L., Fihn S.
D., Jesse R. L., Petreson E. D., Rumsfeld J.
S., JAMA, 301, 937944 (2009).
Juurlink D. N., Gomes T., Ko D. T., Szmitko
P. E., Austin P. C., Tu J. V., Henry D. A.,
Kopp A., Mamdani M. M., CMAJ, 180, 713
718 (2009).
Li X. Q., Andersson T. B., Ahlstrom M.,
Weidolf L., Drug Metab. Dispos., 32, 821827(2004).
Gilard M., Arnaud B., Cornily J. C., Le Gal
G., Lacut K., Le Calvez G., Mansourati J.,
Mottier D., Abgrall J. F., Boschat J., J. Am.
Coll. Cardiol., 51, 256260 (2008).
O'Donoghue M. L., Braunwald E., Antman
E. M., Murphy S. A., Bates E. R., Rozenman
Y., Michelson A. D., Hautvast R. W., Ver Lee
P. N., Close S. L., Shen L., Mega J. L., Sabatine M. S., Wiviott S. D., Lancet, 374, 989
997 (2009).
Furuta T., Shirai N., Sugimoto M., Nakamura A., Hishida A., Ishizaki T., Drug
Metab. Pharmacokinet., 20, 153167 (2005).
Chesebro J. H., Knatterud G., Roberts R.,

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

Borer J., Cohen L. S., Dalen J., Dodge H. T.,
Francis C. K., Hillis D., Ludbrook P., Circulation, 76, 142154 (1987).
Cutlip D. E., Windecker S., Mehran R., BoamA., Cohen D. J., van Es G. A., Steg P. G.,
Morel M. A., Mauri L., Vranckx P., McFadden E., Lansky A., Hamon M., KrucoŠ M.
W., Serruys P. W.; Academic Research Consortium, Circulation, 115, 23442351 (2007).
Diener H. C., Bogousslavsky J., Brass L. M.,
Cimminiello C., Csiba L., Kaste M., Leys D.,
Matias-Guiu J., Rupprecht H. J; on behalf ofthe MATCH investigators, Lancet, 364, 331
337 (2004).
Toyoda K., Yasaka M., Iwade K., Nagata K.,
Koretsune Y., Sakamoto T., Uchiyama S.,
Gotoh J., Nagao T., Yamamoto M., Takahashi J. C., Minematsu K., and for the Bleeding with Antithrombotic Therapy (BAT)
Study Group, Stroke, 39, 17401745 (2008).
Hallas J., Dall M., Andries A., Andersen B.
S., Aalykke C., Hansen J. M., Andersen M.,
Lassen A. T., BMJ, 333, 726730 (2006).
Lanas A., Garcia-Rodriguez L. A., Arroyo M.
T., Bujanda L., Gomollon F., Forne M., Aleman S., Nicolas D., Feu F., Gonzalez-Perez
A., Borda A., Castro M., Poveda M. J., Arenas J.; Investigators of the Asociaci áon Espa ãnola de Gastroenterologia (AEG), Am. J.
Gastroenterol., 102, 507515 (2007).
Chin M. W., Yong G., Bulsara M. K., Rankin
J., Forbes G. M., Am. J. Gastroenterol., 102,24112416 (2007).
Ray W. A., Murray K. T., Gri‹n M. R.,
Chung C. P., Smalley W. E., Hall K., Daugherty J. R., Kaltenbach L. A., Stein C. M.,
Ann. Intern. Med., 152, 337345 (2010).
Kimura T., Morimoto T., Nakagawa Y.,
Tamura T., Kadota K., Yasumoto H.,
Nishikawa H., Hiasa Y., Muramatsu T.,
Meguro T., Inoue N., Honda H., Hayashi Y.,
Miyazaki S., Oshima S., Honda T., ShiodeN., Namura M., Sone T., Nobuyoshi M., Kita
T., Mitsudo K., j-Cypher Registry Investigators, Circulation, 119, 987995 (2009).
Siller-Matula J. M., Spiel A. O., Lang I. M.,
Kreiner G., Christ G., Jilma B., Am. Heart.
J., 157, 148.e1e5 (2009).
Gerson L. B., Triadaˆlopoulos G., Eur. J.

hon p.8 [100%]

1750

22)

23)

24)

25)

Vol. 130 (2010)

Gastroenterol. Hepatol., 13, 611616 (2001).
Mega J. L., Close S. L., Wiviott S. D., Shen
L., Hockett R. D., Brandt J. T., Walker J. R.,
Antman E. M., Macias W., Braunwald E.,
Sabatine M. S., N. Engl. J. Med., 360, 354
362 (2009).
Simon T., Verstuyft C., Mary-Krause M.,
Quteineh L., Drouet E., Meneveau N., Steg P.
G., Ferrieres J., Danchin N., Becquemont L.;
French Registry of Acute ST-Elevation and
Non-ST-Elevation Myocardial Infarction(FAST-MI) Investigators, N. Engl. J. Med.,
360, 363375 (2009).
Collet J. P., Hulot J. S., Pena A., Villard E.,
Esteve J. B., Silvain J., Payot L., Brugier D.,
Cayla G., Beygui F., Bensimon G., FunckBrentano C., Montalescot G., Lancet, 373,
309317 (2009).
Furuta T., Shirai N., Sugimoto M., OhashiK., Ishizaki T., Pharmacogenomics, 5, 181
202 (2004).

26)

27)

28)

29)

Sibbing D., Stegherr J., Latz W., Koch W.,
Mehilli J., D äorrler K., Morath T., SchomigA., Kastrati A., von Beckerath N., Eur.
Heart. J., 30, 916922 (2009).
Gao F., Zhou Y. J., Wang Z. J., Shen H., Liu
X. L., Nie B., Yan Z. X., Yang S. W., Jia D.
A., Yu M., Circ. J., 74, 701708 (2010).
Olson K. L., Delate T., Johnson S. G., Wilson
E. D., Witt D. M., J. Thromb. Thrombolysis,
29, 316321 (2010).
Chen K. Y., Rha S. W., Li Y. J., Poddar K.
L., Jin Z., Minami Y., Wang L., Kim E. J.,
Park C. G., Seo H. S., Oh D. J., Jeong M. H.,
Ahn Y. K., Hong T. J., Kim Y. J., Hur S. H.,
Seong I. W., Chae J. K., Cho M. C., Bae J.
H., Choi D. H., Jang Y. S., Chae I. H., Kim
C. J., Yoon J. H., Chung W. S., Seung K. B.,
Park S. J., Korea Acute Myocardial Infarction
Registry Investigators, Circulation, 119, 3207
3214 (2009).