AHA antiplatelets PPI report 2012

Antiplatelet Therapy and Proton Pump Inhibition: Clinician Update
George V. Moukarbel and Deepak L. Bhatt
Circulation. 2012;125:375-380
doi: 10.1161/CIRCULATIONAHA.111.019745
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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 maximal 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.
His medical history was significant for
an episode of gastrointestinal (GI)
bleeding in the setting of using nonsteroidal antiinflammatory drugs.
Dual antiplatelet therapy, typically
the addition of an ADP receptor antagonist to aspirin, has become the cornerstone of management of patients
with acute coronary syndromes and
after percutaneous coronary intervention. However, along with the reduction of thrombotic outcomes, this therapeutic 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 recommended practice in this patient population.2 Currently, the most commonly prescribed ADP receptor
antagonist is clopidogrel, a prodrug
that undergoes activation by the cyto-

chrome P450 system, in particular
CYP2C19. The importance of this reaction on the overall platelet inhibitory
effects of clopidogrel is highlighted by
the fact that patients with reducedfunction CYP2C19 alleles exhibit a
reduced response to clopidogrel compared 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 suggesting a clinically significant interaction,3 regulatory agencies issued a cautionary 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 prostaglandin production by the gastric mucosa, 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

use of antiplatelet and antithrombotic
agents, as well as steroidal and nonsteroidal 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 identified.5 History of ulcers and prior GI
bleeding events are also very important risk factors.6 The risk of bleeding appears to be highest in the early
period after a cardiac event but continues to be present on long-term
follow-up (Figure 1). Gastroprotective strategies to reduce the risk of
GI bleeding in patients taking antiplatelet agents have been tested in

several settings. Both H2 receptor
antagonists and PPIs reduce stomach
acid production, thus allowing gastric 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-tohead comparison with PPIs, H2 re-

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
(Circulation. 2012;125:375-380.)
© 2012 American Heart Association, Inc.
Circulation is available at

DOI: 10.1161/CIRCULATIONAHA.111.019745

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January 17, 2012

nonrandomized studies and could lead

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

PPIs and Aspirin Interaction

Figure 1. Cumulative incidence of gastrointestinal (GI) bleeding during the Valsartan in
Acute Myocardial Infarction (VALIANT) follow-up. The dotted lines represent the 95%
confidence intervals (CIs) of the estimated rate. The monthly incidence rates of GI
bleeding in the first 2 months and between 2 months and 2 years are noted. Reprinted
from Moukarbel et al5 with permission from the publisher. © 2009, European Society of
Cardiology.

ceptor antagonists appear to confer a
more modest protection from GI
events in this setting according to
observational and retrospective studies.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 interaction between antiplatelet agents and
PPIs comes mostly from retrospective

cohort studies or secondary analyses of
randomized controlled trials. Inherent
to the design of such studies, the main
issue is the inability to adjust for residual confounding factors that might
drive the decision to initiate PPI therapy 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

Figure 2. Proposed algorithm for use of proton pump inhibitors (PPIs) in patients requiring antiplatelet therapy. GI indicates gastrointestinal; NSAID, nonsteroidal antiinflammatory drug; and GERD, gastroesophageal reflux disease.

There have been recent concerns that
PPIs may interfere with the absorption
and bioavailability of aspirin by altering gastric acidity. Small platelet aggregation 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 Ϸ20 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
risk of cardiovascular death, myocardial infarction, or stroke. There was no
increased risk noted with H2 receptor
antagonists.16 This study had 2 major
specific limitations: it relied on
prescription-filling data from a national registry, and it was uncertain
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, important lessons can be learned from the
results. In the 3761 patients analyzed,
treatment with omeprazole was associated 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 clinical (as opposed to endoscopic) GI end
points. Additionally, there was no difference in the occurrence of cardiovascular events in the 2 groups in the early
period after acute coronary syndromes
or percutaneous coronary intervention,

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Moukarbel and Bhatt

Antiplatelets and PPI

377

gested. Pantoprazole and rabeprazole
interfere minimally with the cytochrome P450 system and may potentially not exhibit a similar interaction.19,34 The use of prasugrel instead
of clopidogrel in acute coronary syndromes patients undergoing percutaneous coronary intervention can be considered 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 clopidogrel showed inconsistent results in
the studies that evaluated this strategy.
It is unclear whether the release pharmacokinetics of the particular omeprazole formulation used in COGENT
had any impact on the results of the
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
the Optimization of Gastrointestinal Events (COGENT). A, Kaplan-Meier estimates of
the probability of remaining free of primary gastrointestinal events according to
study group. The event rate for the primary gastrointestinal end point at day 180
was 1.1% in the omeprazole group and 2.9% in the placebo group. B, Kaplan-Meier
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
day 180 was 4.9% in the omeprazole group and 5.7% in the placebo group.
Reprinted from Bhatt et al8 with permission from the publisher. © 2010, Massachusetts Medical Society.

when risk of cardiac events would be

expected to be highest (Figure 3B).
The Table summarizes the large nonrandomized published studies examining this issue in different patient populations. These studies vary in terms of
patient inclusion criteria, outcomes
measured, and analysis methods. In
general, studies reporting a positive
association found Ϸ25% to 80% increased risk of cardiovascular events
in patients treated with a PPI in addition to dual antiplatelet therapy. Interestingly, 2 recent meta-analyses of
published studies found no association

between PPI use and mortality.32,33 A
significant association with cardiovascular events was found in observational studies but not in those using
propensity matching or participants of
randomized trials. The presence of significant heterogeneity again indicates
the biased and confounded nature of
the evidence.

Strategies to Avoid the
Effects of an Interaction
Several approaches to circumvent the
potential for significant interference
with clopidogrel effect have been sug-

Conclusions and Summary
of Recommendations
The totality of evidence available to
date does not support a clinically significant impact of any pharmacokinetic or pharmacodynamic interactions
between PPIs and the current widely
used antiplatelet agents. Further evidence that will shed more light on this
matter should come only from randomized clinical trials because new
retrospective studies, no matter how

statistically sound, will only add confusion to the matter. Until then, the
benefit of PPIs in reducing bleeding
events (and treating GI symptoms)
must be factored into decision making
when faced with patients with high GI
bleeding risk requiring antiplatelet
therapy.
Our patient was treated with 20 mg
omeprazole once per day, given the
history of prior GI bleeding events,
other risk factors, and the need for

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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

Pezalla et al17
(2008)

Retrospective
cohort

Heart disease and
or risk factors

PPI, 626; no PPI, 384

1y

MI

OR, 4.3 (95% CI, 2.2–8.4)

Ho et al18 (2009)

Retrospective
cohort

Post-MI, ACS

PPI, 5244; no PPI,
2961

Death, ACS

OR, 1.25 (95% CI, 1.11–1.41)

Nested case-control

Post-MI

Cases, 734 (PPI, 194);
controls, 2057 (PPI,
424)

Death, MI

OR, 1.27 (95% CI, 1.03–1.57)

Kreutz et al20
(2010)

Retrospective
cohort

Poststenting

PPI, 6828; no PPI,
9862

1y

CVA, ACS,
Revascularization,
CV death

HR, 1.51 (95% CI, 1.39–1.64)

Huang et al21
(2010)

Registry

Post-PCI

PPI, 572; no PPI,
2706

6y

ACS; death

HR, 1.23 (95% CI, 1.07–1.41)
and 1.65 (95% CI, 1.35–2.01)

Stockl et al22
(2010)

Retrospective

propensity
matching

Post-MI or stent

PPI, 1033; no PPI,
1033

1y

MI, stent

HR, 1.64 (95% CI, 1.16–2.32)

Van Boxel et al23
(2010)

Retrospective
cohort

Clopidogrel use

PPI, 5734; no PPI,
12 405

2y

Death, ACS, CVA

HR, 1.75 (95% CI, 1.58–1.94)

Registry

Vascular disease

PPI, 519; no PPI, 703

15 mo

MI, CVA, CLI,
death

HR, 1.8 (95% CI, 1.1–2.7)

Post hoc analysis
of RCT

ACS and PCI

PPI, 2257; no PPI,
4,538

Up to 15 mo

MI, CVA, CV
death

No effect

Rassen et al26

(2009)

Retrospective
cohort

ACS or PCI

PPI, 3996; no PPI,
14 569

6 mo

MI, death,
revascularization

No effect

Ray et al7 (2010)

Retrospective
cohort

MI,
revascularization,
UA

PPI, 7593; no PPI,
13 003

1y

MI, CVA, CV
death

No effect

Charlot et al27
(2010)

Registry

MI

PPI, 6753; no PPI,
17 949

1y

MI, CVA, CV
death

No effect

Sarafoff et al28
(2010)

Retrospective
cohort

Poststent

PPI, 698; no PPI,
2640

1 mo

Stent thrombosis

No effect

Tentzeris et al29
(2010)

Registry; propensity
matching

Poststent

PPI, 691; no PPI, 519

1y

Death, ACS

No effect

Banerjee et al13
(2011)

Retrospective

propensity
matching

Post-PCI

PPI, 867; no PPI,
3678

6y

MACE

No effect

Simon et al30
(2011)

Registry

MI

PPI, 1453; no PPI,
900

1y

MI, CVA, Death

No effect

Harjai et al31
(2011)

Registry; propensity
matching

Post-PCI

PPI, 751; no PPI,
1900

6 mo

MACE

No effect

Evidence for

Juurlink et al19
(2009)

Munoz-Torrero
et al24 (2011)

Ϸ3 y
3 mo

Evidence against
O’Donoghue et al25

(2009)

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.

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.

Disclosures

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