CLINICIAN UPDATE
Antiplatelet Therapy and Proton Pump Inhibition
Clinician Update
George V. Moukarbel, MD; Deepak L. Bhatt, MD, MPH
A 77-year-old man with history of
diabetes mellitus and coronary
artery disease presented with angina
and evidence of ischemia despite max-
imal medical therapy. He underwent a
percutaneous coronary intervention
with a drug-eluting stent and was
started on long-term dual antiplatelet
therapy with aspirin and clopidogrel.
Downloaded from http://ahajournals.org by on November 27, 2018
His medical history was significant for
an episode of gastrointestinal (GI)
bleeding in the setting of using non-
steroidal antiinflammatory drugs.
Dual antiplatelet therapy, typically
the addition of an ADP receptor antag-
onist to aspirin, has become the cor-
nerstone of management of patients
with acute coronary syndromes and
after percutaneous coronary interven-
tion. However, along with the reduc-
tion of thrombotic outcomes, this ther-
apeutic strategy has the untoward
effect of increasing the risk of bleeding
events, including GI bleeding.1 The
use of gastroprotective strategies, most
notably proton pump inhibitors (PPIs),
has become a widely adopted and rec-
ommended practice in this patient pop-
ulation.2 Currently, the most com-
monly prescribed ADP receptor
antagonist is clopidogrel, a prodrug
that undergoes activation by the cyto-
From the Brigham and Women’s Hospital, Harvard Medical School (G.V.M., D.L.B.), and the VA Boston Healthcare System (D.L.B.), Boston, MA.
Correspondence to Deepak L. Bhatt, MD, MPH, FAHA, 1400 VFW PKWY, Boston, MA 02132. E-mail DLBHATTMD@post.harvard.edu
(Circulation. 2012;125:375-380.)
© 2012 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
chrome P450 system, in particular
CYP2C19. The importance of this re-
action on the overall platelet inhibitory
effects of clopidogrel is highlighted by
the fact that patients with reduced-
function CYP2C19 alleles exhibit a
reduced response to clopidogrel com-
pared with those with the wild-type
alleles. This finding might translate
into increased risk of adverse events
after acute coronary syndromes and
percutaneous coronary intervention.
Given that PPIs are inhibitors of
CYP2C19, coupled with reports sug-
gesting a clinically significant interac-
tion,3 regulatory agencies issued a cau-
tionary statement advising against the
combined use of PPIs (specifically
omeprazole and esomeprazole) and
clopidogrel.4
Risk of GI Bleeding
With Antiplatelet Therapy
and Effect of
Gastroprotective Strategies
Aspirin causes direct damage to the
gastric epithelium and inhibits prosta-
glandin production by the gastric mu-
cosa, leading to ulcerations and an
estimated 2-fold increased risk of GI
bleeding with low-dose aspirin alone.1
The risk increases with the additional
DOI: 10.1161/CIRCULATIONAHA.111.019745
375
use of antiplatelet and antithrombotic
agents, as well as steroidal and non-
steroidal antiinflammatory drugs.1,5 In
patients with heart disease, several
clinical characteristics that confer
added risk of GI bleeding such as
older age, male sex, nonwhite race,
diabetes mellitus, history of alcohol
abuse, heart failure symptoms, and
renal insufficiency can be identi-
fied.5 History of ulcers and prior GI
bleeding events are also very impor-
tant risk factors.6 The risk of bleed-
ing appears to be highest in the early
period after a cardiac event but con-
tinues to be present on long-term
follow-up (Figure 1). Gastroprotec-
tive strategies to reduce the risk of
GI bleeding in patients taking anti-
platelet agents have been tested in
several settings. Both H2 receptor
antagonists and PPIs reduce stomach
acid production, thus allowing gas-
tric ulcers and erosions to heal. Use
of PPIs in patients taking antiplatelet
therapy has been associated with a
significant reduction in the risk of GI
bleeding, ulcers, and erosions in data
from observational and randomized
clinical trials.7–11 Although there is
no large clinical trial with a head-to-
head comparison with PPIs, H2 re-
 376 Circulation January 17, 2012

nonrandomized studies and could lead

to erroneous association of PPI use
with increased cardiac events.13

PPIs and Aspirin Interaction

There have been recent concerns that
PPIs may interfere with the absorption
and bioavailability of aspirin by alter-
ing gastric acidity. Small platelet ag-
gregation studies in patients treated
with low-dose aspirin (75–100 mg)
and concomitant PPI showed opposing
results. 14,15 A propensity score–
matched study in ⬇20 000 patients
with first myocardial infarction who
were not treated with clopidogrel
showed that treatment with a PPI was
associated with up to 60% increased
Figure 1. Cumulative incidence of gastrointestinal (GI) bleeding during the Valsartan in
risk of cardiovascular death, myocar-
Acute Myocardial Infarction (VALIANT) follow-up. The dotted lines represent the 95% dial infarction, or stroke. There was no
confidence intervals (CIs) of the estimated rate. The monthly incidence rates of GI increased risk noted with H2 receptor
bleeding in the first 2 months and between 2 months and 2 years are noted. Reprinted antagonists.16 This study had 2 major
from Moukarbel et al5 with permission from the publisher. © 2009, European Society of
Cardiology. specific limitations: it relied on
prescription-filling data from a na-
ceptor antagonists appear to confer a cohort studies or secondary analyses of tional registry, and it was uncertain
Downloaded from http://ahajournals.org by on November 27, 2018

more modest protection from GI
events in this setting according to
observational and retrospective stud-
ies.10,12 Clinical characteristics can
be used to guide the need for PPIs in
patients taking antiplatelet therapy
(Figure 2).
The weight of the evidence for and
against a clinically significant interac-
tion between antiplatelet agents and
PPIs comes mostly from retrospective
Figure 2. Proposed algorithm for use of proton pump inhibitors (PPIs) in patients requir-
ing antiplatelet therapy. GI indicates gastrointestinal; NSAID, nonsteroidal antiinflamma-
tory drug; and GERD, gastroesophageal reflux disease.
randomized controlled trials. Inherent
to the design of such studies, the main
issue is the inability to adjust for re-
sidual confounding factors that might
drive the decision to initiate PPI ther-
apy in patients who are at high risk.
Additionally, patients could have been
prescribed PPIs for symptoms that
were misdiagnosed as having a GI
rather than a cardiac origin. Such an
occurrence would be captured in these
why these patients were not treated
with dual antiplatelet therapy.
PPIs and Clopidogrel:
Evidence for and
Against a Clinically
Significant Interaction
Only 1 randomized controlled trial,
Clopidogrel and the Optimization of
Gastrointestinal Events (COGENT),
has addressed treatment with PPIs in
patients with coronary artery disease
treated with dual antiplatelet therapy.8
Unfortunately, the trial was stopped
prematurely owing to loss of funding
by the sponsor. Nevertheless, impor-
tant lessons can be learned from the
results. In the 3761 patients analyzed,
treatment with omeprazole was associ-
ated with a significant 66% reduction
in the incidence of GI events at 6
months (Figure 3A). COGENT was
the first large randomized trial to find
that prophylactic PPI use reduced clin-
ical (as opposed to endoscopic) GI end
points. Additionally, there was no dif-
ference in the occurrence of cardiovas-
cular events in the 2 groups in the early
period after acute coronary syndromes
or percutaneous coronary intervention,
 Moukarbel and Bhatt Antiplatelets and PPI 377

gested. Pantoprazole and rabeprazole

interfere minimally with the cyto-
chrome P450 system and may poten-
tially not exhibit a similar interac-
tion.19,34 The use of prasugrel instead
of clopidogrel in acute coronary syn-
dromes patients undergoing percutane-
ous coronary intervention can be con-
sidered and has been shown to cause
platelet inhibition even in the face of
clopidogrel nonresponsiveness, albeit
at the expense of increased bleeding.
Newer antiplatelet agents that are not
dependent on the cytochrome P450
isoenzymes such as ticagrelor could be
used in acute coronary syndromes
treated invasively or conservatively.
Administration of the PPI at a different
time than the administration of clopi-
dogrel showed inconsistent results in
the studies that evaluated this strategy.
It is unclear whether the release phar-
macokinetics of the particular omepra-
zole formulation used in COGENT
had any impact on the results of the
Downloaded from http://ahajournals.org by on November 27, 2018

trial. Finally, different gastroprotective

drugs such as H2 receptor antagonists
can be used, although they have been
shown to confer a somewhat more
modest protective effect than PPIs.
Figure 3. Efficacy (A) and safety (B) of concomitant proton pump inhibitor (PPI)
(omeprazole) treatment in patients on dual antiplatelet therapy in Clopidogrel and Conclusions and Summary
the Optimization of Gastrointestinal Events (COGENT). A, Kaplan-Meier estimates of
the probability of remaining free of primary gastrointestinal events according to of Recommendations
study group. The event rate for the primary gastrointestinal end point at day 180 The totality of evidence available to
was 1.1% in the omeprazole group and 2.9% in the placebo group. B, Kaplan-Meier date does not support a clinically sig-
estimates of the probability of remaining free of primary cardiovascular events
according to study group. The event rate for the primary cardiovascular end point at
nificant impact of any pharmacoki-
day 180 was 4.9% in the omeprazole group and 5.7% in the placebo group. netic or pharmacodynamic interactions
Reprinted from Bhatt et al8 with permission from the publisher. © 2010, Massachu- between PPIs and the current widely
setts Medical Society. used antiplatelet agents. Further evi-
dence that will shed more light on this
when risk of cardiac events would be between PPI use and mortality.32,33 A matter should come only from ran-
expected to be highest (Figure 3B). significant association with cardiovas- domized clinical trials because new
The Table summarizes the large non- cular events was found in observa- retrospective studies, no matter how
randomized published studies examin- tional studies but not in those using statistically sound, will only add con-
ing this issue in different patient pop- propensity matching or participants of fusion to the matter. Until then, the
ulations. These studies vary in terms of randomized trials. The presence of sig- benefit of PPIs in reducing bleeding
patient inclusion criteria, outcomes nificant heterogeneity again indicates events (and treating GI symptoms)
measured, and analysis methods. In the biased and confounded nature of must be factored into decision making
general, studies reporting a positive the evidence. when faced with patients with high GI
association found ⬇25% to 80% in- bleeding risk requiring antiplatelet
creased risk of cardiovascular events Strategies to Avoid the therapy.
in patients treated with a PPI in addi- Effects of an Interaction Our patient was treated with 20 mg
tion to dual antiplatelet therapy. Inter- Several approaches to circumvent the omeprazole once per day, given the
estingly, 2 recent meta-analyses of potential for significant interference history of prior GI bleeding events,
published studies found no association with clopidogrel effect have been sug- other risk factors, and the need for
 378 Circulation January 17, 2012

Table. Summary of Recent Large (n >1000), Nonrandomized Studies Looking at Clinical Evidence of an Interaction Between
Clopidogrel and Proton Pump Inhibitors
Reference (Year) Design Population Treatment, n Follow-Up End Point Results
Evidence for
Pezalla et al17 Retrospective Heart disease and PPI, 626; no PPI, 384 1y MI OR, 4.3 (95% CI, 2.2–8.4)
(2008) cohort or risk factors
Ho et al18 (2009) Retrospective Post-MI, ACS PPI, 5244; no PPI, ⬇3 y Death, ACS OR, 1.25 (95% CI, 1.11–1.41)
cohort 2961
Juurlink et al19 Nested case-control Post-MI Cases, 734 (PPI, 194); 3 mo Death, MI OR, 1.27 (95% CI, 1.03–1.57)
(2009) controls, 2057 (PPI,
424)
Kreutz et al20 Retrospective Poststenting PPI, 6828; no PPI, 1y CVA, ACS, HR, 1.51 (95% CI, 1.39–1.64)
(2010) cohort 9862 Revascularization,
CV death
Huang et al21 Registry Post-PCI PPI, 572; no PPI, 6y ACS; death HR, 1.23 (95% CI, 1.07–1.41)
(2010) 2706 and 1.65 (95% CI, 1.35–2.01)
Stockl et al22 Retrospective Post-MI or stent PPI, 1033; no PPI, 1y MI, stent HR, 1.64 (95% CI, 1.16–2.32)
(2010) propensity 1033
matching
Van Boxel et al23 Retrospective Clopidogrel use PPI, 5734; no PPI, 2y Death, ACS, CVA HR, 1.75 (95% CI, 1.58–1.94)
(2010) cohort 12 405
Munoz-Torrero Registry Vascular disease PPI, 519; no PPI, 703 15 mo MI, CVA, CLI, HR, 1.8 (95% CI, 1.1–2.7)
et al24 (2011) death
Evidence against
O’Donoghue et al25 Post hoc analysis ACS and PCI PPI, 2257; no PPI, Up to 15 mo MI, CVA, CV No effect
Downloaded from http://ahajournals.org by on November 27, 2018

(2009) of RCT 4,538 death

Rassen et al26 Retrospective ACS or PCI PPI, 3996; no PPI, 6 mo MI, death, No effect
(2009) cohort 14 569 revascularization
Ray et al7 (2010) Retrospective MI, PPI, 7593; no PPI, 1y MI, CVA, CV No effect
cohort revascularization, 13 003 death
UA
Charlot et al27 Registry MI PPI, 6753; no PPI, 1y MI, CVA, CV No effect
(2010) 17 949 death
Sarafoff et al28 Retrospective Poststent PPI, 698; no PPI, 1 mo Stent thrombosis No effect
(2010) cohort 2640
Tentzeris et al29 Registry; propensity Poststent PPI, 691; no PPI, 519 1y Death, ACS No effect
(2010) matching
Banerjee et al13 Retrospective Post-PCI PPI, 867; no PPI, 6y MACE No effect
(2011) propensity 3678
matching
Simon et al30 Registry MI PPI, 1453; no PPI, 1y MI, CVA, Death No effect
(2011) 900
Harjai et al31 Registry; propensity Post-PCI PPI, 751; no PPI, 6 mo MACE No effect
(2011) matching 1900
ACS indicates acute coronary syndrome; CI, confidence interval; CLI, chronic limb ischemia; CV, cardiovascular; CVA, cerebrovascular accident; HR, hazard ratio;
MACE, major adverse cardiac events (death, myocardial infarction, revascularization); MI, myocardial infarction; OR, odds ratio; RCT, randomized controlled trial; and
UA, unstable angina.

long-term dual antiplatelet therapy.
For this patient, omeprazole was the
cheapest option because it was on the
hospital formulary. If cost were not an
issue, it would have been reasonable to
initiate therapy with a PPI that has less
effect on CYP2C19 in case future
studies show that the pharmacokinetic
and pharmacodynamic interactions
with clopidogrel translate into clinical
events.
Disclosures
Dr Bhatt receives research grants from Amarin,
AstraZeneca, Bristol-Myers Squibb, Eisai, Ethi-
con, Medtronic, Sanofi-aventis, and The Medi-
cines Company. He has collaborated with
Takeda and PLx Pharma on research studies.
He was the chair of the COGENT trial. Dr
Moukarbel reports no conflicts.
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