International Journal of Clinical Pharmacology and Therapeutics, Vol. 47 No.

1/2009 (1-10)

Proton pump inhibitors for prevention of

bleeding episodes in cardiac patients with
dual antiplatelet therapy between Scylla
and Charybdis?
Original
2009 Dustri-Verlag Dr. K. Feistle
ISSN 0946-1965 D. Trenk

Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany

Proton pump inhibitors for bleeding prevention in antiplatelet therapy

Key words Abstract. Guidelines from national and
antiplatetet drugs international cardiac societies recommend
acetylsalicylic acid dual antiplatelet therapy with aspirin and
thienopyridine bleed- thienopyridines (clopidogrel, ticlopidine) in
ing risk proton pump patients with acute coronary syndrome and
inhibitor patients undergoing percutaneous coronary
intervention. The most-feared complication
of antiplatelet therapy is hemorrhage. Long-
term treatment with aspirin increased bleed-
ing rates compared to placebo and similar
bleeding rates were observed on clopidogrel.
Dual antiplatelet therapy increased hemor-
rhage with the dose of aspirin administered
impacting on increased bleeding rates. Con-
comitant treatment with a proton pump inhib-
itor (PPI) decreased bleeding rates in patients
on antiplatelet therapy. An analysis of medi-
cal and pharmacy databases indicated a more
than 3-fold increase in the incidence of myo-
cardial infarction within 12 months after
starting treatment with clopidogrel in patients
on concomitant treatment with a PPI. This
might be attributed to a drug-drug interaction
between PPIs and clopidogrel because recent
clinical studies showed that treatment with
the PPI omeprazole attenuated the antiplatelet
effect of clopidogrel most likely by inhibiting
the formation of the active metabolite which
carries the antiplatelet activity of the drug.
Therefore, sufficiently powered prospective
clinical studies in cardiac patients on dual
antiplatelet therapy investigating the poten-
Received tial drug interaction between PPIs and the
August 1, 2008; antiplatelet effect of clopidogrel are awaited
accepted in revised form eagerly.
November 4, 2008
Correspondence to Introduction
Dr. D. Trenk
Department of Clinical
Pharmacology, Platelet aggregation and thrombus forma-
Herz-Zentrum Bad tion are cornerstones in the pathogenesis of
Krozingen, Suedring 15, atherothrombosis [Fuster et al. 2005, Ruggeri
79189 Bad Krozingen,
2002]. The efficacy of antiplatelet therapy in
Germany
dietmar.trenk@ preventing serious vascular events has been
herzzentrum.de shown both during short-term and long-term
treatment in patients with atherosclerotic ar-
terial disease [Antithrombotic Trialist
Collaboration 2002].
Progress in the field of adjunctive anti-
thrombotic therapy has had a decisive role in
improving the outcome of percutaneous coro-
nary interventions [Topol and Serruys 1998].
Dual antiplatelet therapy with aspirin and a
thienopyridine has strikingly improved both
the efficacy and the safety of coronary-artery
stenting [Leon et al. 1998, Schmig et al.
1996]. Initial studies used the first generation
thienopyridine ticlopidine, but the CLopido-
grel ASpirin Stent International Cooperative
Study (CLASSICS) demonstrated better
tolerability of clopidogrel over ticlopidine
and also introduced the concept of adminis-
tering a loading dose (LD) of clopidogrel at
the time of percutaneous coronary interven-
tion (PCI) [Bertrand et al. 2000].
The short-term and long-term benefits of
dual-antiplatelet therapy with aspirin and
clopidogrel have been established for patients
with acute coronary syndromes [Chen et al.
2005, Sabatine et al. 2005, Yusuf et al. 2001]
and those undergoing percutaneous coronary
intervention [Mehta and Yusuf 2003, Stein-
hubl et al. 2002].
This benefit with regard to the prevention
of thrombotic events is accompanied by an in-
crease in hemorrhagic events, the most-
feared complication of antiplatelet therapy.
Antiplatelet drugs
The clinical use of acetylsalicylic acid
(ASA, aspirin) as platelet inhibitor was trig-
gered by the work of Sir John Vane, who was
Trenk
the first to describe the inhibition of prosta-
glandin synthesis by acetylsalicylic acid [Vane
1971]. The Antithrombotic Trialist Collabo-
ration [2002] succeeded in demonstrating in a
large meta-analysis that treatment of patients
with low dose aspirin (75 150 mg o.i.d.)
caused a marked reduction (32%) of non-fa-
tal myocardial infarction and vascular death in
patients with a high risk for vascular events.
The stimulating effect of arachidonic acid
or the formed metabolite thromboxane A2,
however, is only one of various pathways to
activate platelets. Three distinct receptors for
adenosine diphosphate (ADP) have been de-
scribed on platelets. ADP-induced platelet
aggregation is the result of the interplay be-
tween ADP and two distinct G-protein cou-
pled receptors named P2Y1 and P2Y12. The
P2Y12 receptor is the target for the thieno-
pyridine drugs ticlopidine and clopidogrel
[Geiger et al. 1999, Humphries et al. 1994].
Both drugs have close chemical relationships,
are pharmacologically inactive in vitro and
require metabolic activation after absorption
from the gastrointestinal tract. The active me-
tabolite formed exert the inhibitory effect on
platelet activation by inhibiting selectively
and irreversibly the P2Y12 receptor on the
platelet membrane for the entire lifespan of
the platelet [Hollopeter et al. 2001, Savi and
Herbert 2005, Savi et al. 2000, 2001].
Dual antiplatelet therapy in
cardiac patients
Dual antiplatelet therapy with aspirin in
combination with thienopyridine-like antag-
onists of P2Y12-receptors (ticlopidine, clopi-
dogrel) has become the standard treatment of
patients undergoing percutaneous coronary
intervention (PCI) with stent implantation.
Large prospective clinical studies were initi-
ated early after introduction of coronary
stents into clinical practice to investigate ap-
propriate antiplatelet and antithrombotic
treatment strategies. These studies compared
aspirin alone either with dual antiplatelet
therapy (aspirin + ticlopidine/clopidogrel) or
with triple therapy using two antiplatelet
drugs and a coumarin-like oral anticoagulant
drug. The superiority of dual antiplatelet ther-
apy with regard to the prevention of ischemic
events has consistently been shown [Bertrand
2
et al. 1998, 2000, Leon et al. 1998, Schmig
et al. 1996, Schhlen et al. 1997, Urban et al.
1998].
Antiplatelet therapy and
bleeding complications
Besides investigating the clinical efficacy
with regard to the prevention of ischemic
events, bleeding complications as an adverse
event with potentially life-threatening com-
plications were evaluated carefully in all
large scale clinical studies in which patients
received antiplatelet therapy. The majority of
studies made an attempt to outweigh the ben-
efits of antiplatelet therapy considering the
cardiovascular risk of the study population
versus the potential harmfulness of long-term
antiplatelet therapy.
A meta-analysis comprising 24 random-
ized controlled trials assessed the incidence
of gastrointestinal hemorrhage associated
with long-term aspirin therapy prescribed in
daily doses of 50 1,500 mg for various indi-
cations [Derry and Loke 2000]. Overall, gas-
trointestinal hemorrhage occurred in 2.47%
of patients taking aspirin compared with
1.42% taking placebo (Odds Ratio 1.68; 95%
Confidence Interval (CI) 1.51 1.88; p <
0.0001) (Figure 1). The incidence of hemor-
rhage was only slightly lower at aspirin doses
below 163 mg/day, at which gastrointestinal
bleeding occurred in 2.30% of patients taking
aspirin compared with 1.45% taking placebo
(1.59; CI 1.40 1.81; p < 0.0001). Meta-re-
gression failed to demonstrate a relation be-
tween gastrointestinal hemorrhage and dose
of aspirin. Treatment with modified release
formulations of aspirin resulted in a similar
odds ratio of 1.93 (CI 1.15 to 3.23). Thus,
long-term antiplatelet therapy with aspirin
solely is associated with a significant increase
in the incidence of gastrointestinal hemor-
rhage and no evidence could be obtained that
reducing the dose or the prescription of modi-
fied release formulations would reduce the in-
cidence of gastrointestinal hemorrhage.
An anamnesis of a previous ulcus-related
GI-bleeding was identified as the most impor-
tant risk factor for a subsequent bleeding epi-
sode during treatment with aspirin [Garcia
Rodriguez and Jick 1994, Lanas et al. 2000].
Annual bleeding rates up to approximately
Proton pump inhibitors for bleeding prevention in antiplatelet therapy
Figure 1. Antiplatelet drug therapy and hemor-
rhagic adverse events. Panel A: Gastrointestinal
hemorrhage in patients treated with aspirin for vari-
ous indications. Modified from Derry and Loke
[2000]. Panels B and C: Impact of the daily dose of
aspirin on major bleeding and life-threatening
bleedings in patients in the CURE Study patients
were treated either with aspirin alone or with aspirin
plus clopidogrel 75 mg daily. Modified from Peters et
al. [2003].
15% were reported from aspirin-treated pa-
tients with an ulcus anamnesis [Lai et al. 2002].
The CAPRIE (Clopidogrel versus Aspirin
in Patients at Risk of Ischaemic Events) Study
randomized patients with atherosclerotic vas-
cular diseases to treatment with either aspirin
or clopidogrel and assessed the relative effi-
cacy of clopidogrel (75 mg once daily) and
3
aspirin (325 mg once daily) in reducing the risk
of a composite outcome of ischemic stroke,
myocardial infarction, or vascular death as well
as the safety of the treatment regimens
[CAPRIE Steering Committee 1996]. Analy-
sis according to intention-to-treat showed
that patients treated with clopidogrel had an
annual 5.32% risk of ischemic stroke, myo-
cardial infarction, or vascular death com-
pared with 5.83% with aspirin. These rates re-
flect a statistically significant (p = 0.043)
relative risk reduction of 8.7% in favor of
clopidogrel (95% Confidence Interval (CI):
0.3 16.5). There were no significant differ-
ences with regards to bleeding events be-
tween the antiplatelet regimens investigated.
Any bleedings were observed in 9.3% of the
patients irrespective of treatment with clopi-
dogrel or aspirin. Major bleedings were ob-
served in 1.4% of clopidogrel-treated patients
and in 1.6% of patients treated with aspirin.
The rate of gastrointestinal bleedings was
2.0% and hospitalization due to a bleeding
event was 0.7% in patients on clopidogrel,
while 2.7% and 1.1% of aspirinated patients
incurred these adverse events.
The CURE (Clopidogrel in Unstable an-
gina to prevent Recurrent Events) Study in-
vestigated the effect of clopidogrel in addi-
tion to aspirin in patients with acute coronary
syndromes without ST-segment elevation
[Yusuf et al. 2001]. The combined incidence
of cardiovascular death, myocardial infarc-
tion, or stroke was reduced in patients ran-
domized to dual antiplatelet therapy (9.3% of
the patients) compared with patients on aspi-
rin alone (11.4%). There were significantly
more patients with major bleeding in the
clopidogrel group than in the placebo group
treated with aspirin only (3.7% vs. 2.7%; p =
0.001), but there were no significant differ-
ences with regard to episodes of life-threaten-
ing bleeding (2.2% vs. 1.8%, p = 0.13) or
hemorrhagic strokes (0.1% in both treat-
ments). The excess major bleeding episodes
in patients treated with clopidogrel + aspirin
were gastrointestinal hemorrhages and bleed-
ing at the sites of arterial punctures (1.6% vs.
1.0%). Minor bleedings were also observed
more frequently in patients receiving dual
antiplatet therapy (5.1% vs. 2.4%).
A subsequent analysis of CURE showed
that major bleeding could be related to the
dose of aspirin, while the beneficial effect of
Trenk
Figure 2. Risk of upper gastrointestinal (GI) bleed-
ing in various subgroups of users of antiplatelet
drugs (AP) and effect of concomitant treatment with
proton pump inhibitors (PPJ). Odds Ratios with 95%
Confidence Intervals. Data modified from Ibanez et
al. [2006].
clopidogrel was observed regardless of aspi-
rin dose [Peters et al. 2003]. The incidence of
major bleeding increased with increasing as-
pirin dose both in the placebo group (daily as-
pirin dose < 100 mg: 1.9%, 100 200 mg:
2.8%, and > 200 mg: 3.7%, respectively; p <
0.0001) and the clopidogrel group (3.0%,
3.4%, and 4.9%, respectively; p < 0.0009).
However, the major bleeding rates for com-
bined use of low-dose aspirin plus clopido-
grel were lower than for using aspirin alone at
higher doses (Figure 1B,C).
The current guidelines of the European
Society of Cardiology recommend therefore
to restrict the daily dose of aspirin to 100 mg
in patients after percutaneous coronary inter-
vention irrespective of the concomitant ad-
ministration of clopidogrel, after cessation of
clopidogrel or treatment with aspirin alone
[Silber et al. 2005].
Antiplatelet therapy and
protection from
gastrointestinal bleeding
Anticoagulant and antiplatelet therapy in
patients with acute coronary syndrome (ACS)
is associated with an increased risk of gastro-
intestinal (GI) bleeding [Al-Mallah et al.
2007, Ibanez et al. 2006] and avoiding bleed-
ing in these patients has grown importance
4
based on multiple studies showing adverse
outcomes in patients who have major bleed-
ing [Eikelboom et al. 2006, Rao et al. 2005].
Risks for bleeding have not systematically
been identified in a multivariate risk score, but
they include prior GI bleeding event [Lanas et
al. 2000, Serrano et al. 2002], aspirin dose [de
Abajo and Garcia Rodriguez 2001, Peters et al.
2003], use of oral anticoagulants [Laine 2006]
and use of non-steroidal anti-inflammatory
drugs (NSAIDs) [Laine 2001] which are
largely used in patients with arthritis.
Mucosal damage by aspirin (and NSAIDs)
is primarily a consequence of inhibition of
COX-1 in the upper GI tract. COX-1 inhibi-
tion reduces mucosal generation of protective
prostaglandins such as prostaglandin E2
(PGE2). One attempt to reduce the gastroin-
testinal risk associated with aspirin was to de-
crease the dose to the lowest effective
amount, but even the lowest doses required
for antiplatelet efficacy have considerable
risk: 75 mg aspirin caused a twofold increase
in risk of GI bleeding and even the sub-thera-
peutic dose of 10 mg daily substantially in-
hibits gastrointestinal COX and still causes
gastric ulceration [Cryer and Feldman 1999].
It was suggested that clopidogrel should be a
less ulcerogenic alternative for patients at
high risk for aspirin-induced ulcers, because
it does not affect mucosal prostaglandin syn-
thesis. However, the risk of subsequent bleed-
ing with the use of clopidogrel in those pa-
tients at highest risk due to a history of GI
bleeding was not diminished. Ng and co-
workers demonstrated that a history of a GI
bleeding was an important risk factor for GI
bleeding during treatment with clopidogrel
[Ng et al. 2003]. Thus, strategies to avoid this
damage during treatment with aspirin include
prescribing either a prostaglandin E analog
such as misoprostol or a potent inhibitor of
gastric acid production such as a proton pump
inhibitor together with aspirin or clopidogrel.
A recently published large population
based, case-control study estimated the risk
of upper GI bleeding associated with the use
of various antiplatelet drugs and its preven-
tion by gastroprotective agents [Ibanez et al.
2006]. The use of aspirin or any other anti-
platelet agent was associated in this lower risk
cohort with a 3.4-fold increase in the risk of
GI bleeding (95% CI 2.8 4.1) compared
with patients not taking antiplatelet agents.
Proton pump inhibitors for bleeding prevention in antiplatelet therapy
Figure 3. Impact of concomitant treatment with
proton pump inhibitors (PPI) on 1-year acute myo-
cardial infarction (MI) rates in patients after starting
clopidogrel therapy. Panel A: Non-adjusted rates of
acute myocardial infarction. Numbers within the col-
umns represent number of patients with events and
total number of the subgroup. Panel B: Incidence of
MI in risk-adjusted members receiving clopidogrel
with and without concomitant PPI use. Percentage
of patients with MI (95% CI) in the subset of patients
who all had diagnoses of ischemic heart disease,
congestive heart failure, hypertension, hyperlipide-
mia, and diabetes before the start of clopidogrel
therapy. Data modified from Perzalla et al. [2008].
Concomitant treatment with a PPI markedly
reduced the risk which was decreased to a risk
similar to that of patients not taking antiplatelet
agents (OR = 1.1, 95% CI: 0.5 2.6) with a
beneficial effect through all subgroups (Figure
2). It has been shown that the concomitant use
of a proton pump inhibitor (PPI) can reduce the
risk of an upper GI bleeding in high-risk pa-
tients taking low-dose aspirin by more than
50% [Bardou et al. 2005, Chan et al. 2001, Lai
et al. 2002, Leontiadis et al. 2007]. Thus, addi-
tional treatment with a PPI is recommended
for patients with a high-risk of a GI bleeding
and indication for treatment with aspirin
[Laine 2001, Peura and Malfertheiner 2004].
A retrospective analysis of the Pravastatin
or Atorvastatin Evaluation and Infection
Therapy Thrombolysis in Myocardial In-
farction (PROVE IT-TIMI) 22 trial database
analyzed the use of PPI at baseline in patients
hospitalized for ACS and enrolled into the
study [Schreiner et al. 2007]. A score system
was used to evaluate the risk for development
of GI bleeding with age 65 years, prior GI
5
event, steroid use on day of randomization,
anticoagulant use on day of randomization
and combination of aspirin and NSAID use
on day of randomization. Of the 4,162 pa-
tients enrolled, 19% received a PPI during the
study and the use of PPI ranged from 14 to
67% across the number of GI risk factors
present. Thus, the use of PPI in patients fol-
lowing ACS is modest, although it increased
with an increasing number of previously
identified GI risk factors. However, prospec-
tive clinical studies on the clinical benefit
with regard to the reduction of gastrointesti-
nal bleeding by concomitant treatment with a
PPI in this patient cohort with dual
antiplatelet therapy are lacking so far.
Pezalla and coworkers [2008] analyzed
their medical and pharmacy databases for
acute myocardial infarction (MI) rates in pa-
tients receiving clopidogrel with or without
concurrent proton pump inhibitor (PPI) ther-
apy. The cohort comprised 9,307 patients be-
low 65 years who were studied for claims with
diagnoses indicative of MI for a period of one
year after starting clopidogrel therapy. Patients
in the low PPI exposure group incurred a 2.24
(95% CI: 1.327, 3.661) relative risk for MI
compared to the control group with no PPI (p <
0.003). Relative risk for MI was increased in
the high PPI exposure group to 3.66 (95% CI:
2.762, 4.903; p < 0.001; Figure 3A). To ac-
count for differences in comorbidity between
the groups, a subset of members was con-
structed within each group who all had diagno-
ses of ischemic heart disease, congestive heart
failure, hypertension, hyperlipidemia, and dia-
betes before the start of clopidogrel therapy.
Figure 3B shows that differences in acute MI
rates between the control and the PPI groups
remained significant when these comorbidity
differences were adjusted out of the analysis.
Relative risk for MI in the high PPI exposure
group was 337% greater than in the control
group. Unfortunately, detailed information on
the kind of PPI used was not provided.
Potential rationale for drug
interactions between PPI and
antiplatelet drugs
The risk of drug interactions increases ex-
ponentially with the number of drugs given to
Trenk
Figure 4. Platelet aggregation in CYP2C19 wild
type patients (n = 552) and carriers of at least one
CYP2C19*2 allele (n = 245). A loading dose of
clopidogrel 600 mg was administered before PCI
and the first maintenance dose of clopidogrel 75 mg
was given at day 1 after PCI 2 to 4 hours pre-dis-
charge. Platelet aggregation was determined as re-
sidual platelet aggregation after stimulation with
ADP 5 mM using light transmission aggregometry.
Median with interquartile range. Data modified from
Trenk et al. [2008].
a patient [Khler et al. 2000]. Drug-drug in-
teractions may impair drug tolerability or
may affect the pharmacological efficacy of
concomitantly prescribed drugs.
The antiplatelet effect of aspirin is not al-
tered by co-administration of a PPI. It was
suggested initially from studies in healthy
subjects [Anand et al. 1999] as well as from
animal experiments [Giraud et al. 1997], that
omeprazole may decrease the systemic avail-
ability of acetylsalicylic acid. It was specu-
lated that the increase in gastric pH caused by
omeprazole may increase the activity of mu-
cosomal esterases resulting in an increased
pre-systemic cleavage of acetylsalicylic acid
to salicylic acid which is devoid of antiplate-
let activity [Anand et al. 1999]. This mecha-
nism should then have major implications
with regard to PPI treatment of patients with
low-dose aspirin therapy. However, a subse-
quent clinical study failed to confirm any
drug-drug interaction between omeprazole
and aspirin [Inarrea et al. 2000].
Drug metabolism of acetylsalicylic acid to
salicylic acid removes the antiplatelet activity
of aspirin. This differs from the thienopyrid-
ine class of compounds like e.g. clopidogrel
which require bioactivation via cytochrome
P450-dependent metabolism of the inactive
parent drug into an active metabolite [Pereillo
et al. 2002, Savi et al. 1994]. This metabolite
is responsible for the antiplatelet effect of the
6
drug by irreversible inhibition of the P2Y12
receptor on the platelet membrane [Hollo-
peter et al. 2001, Savi and Herbert 2005, Savi
et al. 2000, 2001]. Various CYP isoenzymes
(CYP3A4/A5, 1A2, 2B6, 2C9, and 2C19)
contribute to the metabolism of clopidogrel
[Farid et al. 2007]. The key role of CYP2C19
was recently identified [Brandt et al. 2007,
Fontana et al. 2007, Giusti et al. 2007, Hulot
et al. 2006, Trenk et al. 2008]. The antiplatelet
effect of a loading dose of clopidogrel 600 mg
was investigated in 802 patients undergoing
elective percutaneous coronary intervention
with stent implantation [Trenk et al. 2008].
Residual platelet aggregation (RPA) was de-
termined by light transmission aggregometry
after stimulation with ADP 5 mM, and platelet
aggregation was associated with polymor-
phisms of CYP2C19. Patients carrying at
least one non-functional allele of CYP2C19
(CYP2C19*2) had an attenuated antiplatelet
effect of clopidogrel (Figure 4). The propor-
tion of patients with high on-treatment
platelet reactivity (RPA > 14%) either at the
time of coronary intervention or pre-dis-
charge at day 1 after PCI was significantly in-
creased in patients with at least one
CYP2C19*2 allele compared to wild type pa-
tients with preserved activity of CYP2C19
(62.4% vs. 43.4% at PCI and 41.3% vs.
22.5% at pre-discharge). Patients with high
on-clopidogrel platelet reactivity at pre-dis-
charge carried a 3.0-fold increased risk (95%
CI 1.4 6.8; p = 0.004) for myocardial infarc-
tion or death within 12-month follow-up.
Similar to clopidogrel, the majority of
registered PPIs are substrates of CYP2C19
[Ishizaki and Horai 1999]. Therefore, Gilard
and coworkers [2008] investigated in a dou-
ble-blind randomized clinical study if co-ad-
ministration of the CYP2C19 substrate ome-
prazole at a dose of 20 mg o.i.d. affects the
antiplatelet effect of clopidogrel assessed by a
specific VASP-phosphorylation assay in
PCI-patients. The study confirmed results
from a previous pilot study by the same group
of investigators [Gilard et al. 2006]: the
antiplatelet effect of clopidogrel was attenu-
ated in patients on omeprazole as evidenced
by a decreased difference in platelet reactivity
index (PRI) between baseline and on-
clopidogrel assessment (Figure 5). The Odds
Ratio of being a poor responder to clopido-
grel was 4.31 (95% CI: 2.0 9.2) in ome-
Proton pump inhibitors for bleeding prevention in antiplatelet therapy
Figure 5. Effect of concomitant treatment with
omeprazole (20 mg o.i.d.) on decrease of platelet
reactivity index (PRI) from baseline as a measure of
P2Y12-receptor inhibition after a 7-day treatment
period with clopidogrel 75 mg following loading with
clopidogrel 300 mg. Mean SD. Modified according
to Gilard et al. [2008].
prazole-treated patients. The authors suggest
a drug-drug interaction at the level of
CYP2C19 as the molecular basis for their ob-
servation, but the exact mechanism is cur-
rently not known.
The drug-drug interaction between lanso-
prazole and clopidogrel or the new thieno-
pyridine derivative prasugrel were investi-
gated in a phase I cross-over study in a small
cohort of 26 healthy subjects [Small et al.
2008]. Inhibition of ADP-induced platelet
aggregation was not affected by lansoprazole
in subjects on prasugrel, because CYP2C19
contributes less to the metabolism of pra-
sugrel [Brandt et al. 2007]. Lansoprazole
caused only a weak attenuation of the anti-
platelet effect of clopidogrel which was more
prominent in the tertile of subjects with a su-
perior response to clopidogrel without PPI
comedication. Thus, it remains to be investi-
gated if the attenuated extent of interaction
between clopidogrel and lansoprazole if com-
pared with clopidogrel/omeprazole can be at-
tributed to the lower affinity of this PPI to
CYP2C19.
Conclusions
Adequate platelet inhibition improves the
clinical benefit from dual antiplatelet therapy
in patients after PCI with stent implantation
by decreasing ischemic events. High on-treat-
ment platelet reactivity is particularly delete-
rious for patients with drug-eluting stents
[Buonamici et al. 2007, Price et al. 2008,
Trenk et al. 2008]. Concomitant treatment
7
with a proton pump inhibitor is warranted for
patients with an increased risk for gastroin-
testinal bleeding. A large claim-based analy-
sis raised evidence pointing toward a poten-
tially significant interaction between PPIs
and clopidogrel which may decrease the abil-
ity of clopidogrel to prevent acute MI events.
These concerns are supported by data show-
ing an attenuation of the antiplatelet effect of
clopidogrel ex vivo by concomitant treatment
with omeprazole [Gilard et al. 2006, 2008].
Prospective adequately powered random-
ized clinical studies or at least careful analy-
ses of large registries are needed to ensure the
clinical safety of the combination of PPIs
with clopidogrel. The ongoing COGENT-1
(Clopidogrel and the Optimization of Gastro-
intestinal Events; NCT00557921) Study is
randomizing 4,200 patients with coronary ar-
tery disease to aspirin plus clopidogrel in
combination with omeprazole 20 mg or pla-
cebo and will determine the protective effect
of omeprazole with regard to gastrointestinal
clinical events. Unfortunately, it seems that
comparison of the incidence of ischemic
events between the treatment arms is not a
pre-specified secondary endpoint of CO-
GENT-1, but the database might enable to an-
alyze the clinical relevance of the reported
drug-drug interaction between omeprazole
and clopidogrel at least on an hypothesis-gen-
eration basis. Furthermore, pharmacokinetic
pharmacodynamic studies should investi-
gate the mechanism of the suggested drug in-
teraction at the level of CYP2C19 metabo-
lism between omeprazole or other PPIs and
clopidogrel. The latter studies will also pro-
vide data on the question if the differences in
contribution of CYP2C19 in the metabolism
between the various PPIs (rank order: ome-
prazole/esomeprazole > pantoprazole > lanso-
prazole > rabeprazole [Klotz et al. 2004]) ac-
count for different effects in antiplatelet
response to clopidogrel.
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