AHA antiplatelets PPI report 2012

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

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George V Moukarbel and Deepak L Bhatt

Antiplatelet Therapy and Proton Pump Inhibition: Clinician Update

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231

Circulation

doi: 10.1161/CIRCULATIONAHA.111.019745

2012;125:375-380

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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.

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-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,3regulatory 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

use of antiplatelet and antithrombotic agents, as well as steroidal and non-steroidal antiinflammatory drugs.1,5In 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.5History 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-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.)

375 by guest on June 26, 2014

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ceptor antagonists appear to confer a

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

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 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

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 risk of cardiovascular death, myocar-dial 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 na-tional 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, 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,

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

Cardiology

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

376 Circulation January 17, 2012

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when risk of cardiac events would be

expected to be highest (Figure 3B).

The Table summarizes the large

non-randomized published studies

examin-ing this issue in different patient

pop-ulations These studies vary in terms of

patient inclusion criteria, outcomes

measured, and analysis methods In

general, studies reporting a positive

association found ⬇25% to 80%

in-creased risk of cardiovascular events

in patients treated with a PPI in

addi-tion to dual antiplatelet therapy

Inter-estingly, 2 recent meta-analyses of

published studies found no association

between PPI use and mortality.32,33A significant association with cardiovas-cular events was found in observa-tional studies but not in those using propensity matching or participants of randomized trials The presence of sig-nificant 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-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 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.

Conclusions and Summary

of Recommendations

The totality of evidence available to date does not support a clinically sig-nificant impact of any pharmacoki-netic or pharmacodynamic interactions between PPIs and the current widely used antiplatelet agents Further evi-dence that will shed more light on this matter should come only from ran-domized clinical trials because new retrospective studies, no matter how statistically sound, will only add con-fusion 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

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

Massachu-setts Medical Society

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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

References

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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

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PPI, 626; no PPI, 384 1 y MI OR, 4.3 (95% CI, 2.2–8.4)

Ho et al18(2009) Retrospective

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3678

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Registry MI PPI, 1453; no PPI,

900

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(2011)

Registry; propensity matching

Post-PCI PPI, 751; no PPI,

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

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