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Proton Pump Inhibitors

Current Advances in Long-term Proton Pump Inhibitor Use

Proceedings from a Satellite Symposium held at the 19th European
Gastroenterology Week, Stockholm, Sweden, October 2011
Kat Mountfort
Medical Writer, Touch Briefings

Abstract
Proton pump inhibitors (PPIs) are now widely used for the suppression of gastric acid secretion in the treatment of various conditions
including gastro-oesophageal reflux disease (GERD). These drugs have proven efficacy and safety. However, with the incidence of GERD
and other gastric diseases rising, there will be an increased need for long-term PPI therapy. The following symposium proceedings
address concerns regarding the safety of long-term PPI use. Chronic inhibition of intragastric acid induces hypergastrinaemia leading
to hyperplasia without provoking neoplastic changes and potentially affects nutrient absorption from food. Susceptibility to gastrointestinal
and non-gastrointestinal infections when using PPIs will also be discussed. The latter half of the report addresses the interactions of
PPIs with other drugs and the impact this may have. Mechanisms through which PPIs act to influence the absorption of other drugs are
described with a particular focus on their effects on the commonly used antiplatelet agent clopidogrel.

Keywords
Proton pump inhibitor, gastro-oesophageal reflux disease, long-term safety, hypergastrinaemia, nutrient absorption, infection, drugdrug
interaction, bioavailability, clopidogrel, cytochrome P450 enzymes
Disclosure: Kat Mountfort is an employee at Touch Briefings.
Received: 27 January 2012 Accepted: 15 February 2012 Citation: European Gastroenterology & Hepatology Review, 2012;8(1):916
Correspondence: Kat Mountfort, Touch Briefings, Saffron house, 610 Kirby Street, London, EC1N 8TS, UK. E: kat.mountfort@touchbriefings.com

Support: The publication of this article was supported by Janssen EMEA. The views and opinions expressed are those of the author and not necessarily those of
Janssen EMEA.

Introduction
Carmelo Scarpignato
Professor of Clinical Pharmacology and Professor of Pharmacology and Therapeutics, Laboratory of Clinical Pharmacology,
Division of Gastroenterology, University of Parma, Italy

There are two major classes of drugs used for the inhibition of gastric
acid secretion: the H2 receptor antagonists, which were introduced in
the 1970s,1 and proton pump inhibitors (PPIs), which were introduced in the
1980s.2 The aim of this symposium was to present and discuss the latest
understanding of the risks and benefits of long-term PPI treatment. When
first introduced, PPIs represented a significant advance over H2 receptor
antagonists in the treatment of gastric ulcers and related diseases.2,3
Both drug types target the parietal cells, reduce gastric acid secretion
and limit oesophagitis, but PPIs are more effective in relieving heartburn,
have sustained efficacy in acid-related disorders and favourable safety.46

conditions but can now be treated medically.7 Peptic ulcer disease can
now be resolved and oesophageal issues healed with just one pill per
day. The benefits of PPIs have expanded to other instances of peptic
disease but one of their most important indications is for GERD.8 GERD is
a chronic relapsing disease for which surgery is often an option but is
not always completely successful; new symptoms may be triggered by
the surgery itself.7,9 PPIs can be used to control GERD but do not cure the
disease.8,10 Some patients may require life-long PPI treatment and after
stopping the drug, symptoms may return within six months.3 However,
PPIs enable patients to maintain a good quality of life.10

The sustained efficacy and safety of PPIs have made their use
widespread and they have provided a new approach to the treatment of
some important conditions like peptic ulcer and gastro-oesophageal
reflux disease (GERD), which were previously considered surgical

PPIs have been considered a safe drug class. They are associated with
an increased risk of adverse events (AEs) in the gastrointestinal (GI)
tract, kidney, respiratory tract and bone, which have been reported as
uncommon occurrences.2,1114 However, the number of reported side

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Proton Pump Inhibitors

effects and drug interactions involving PPIs has risen in recent years.
The incidence of GERD is increasing and it is becoming more difficult
to treat due to rising obesity levels, ageing populations, and greater
use of non-steroidal anti-inflammatory drugs (NSAIDs) that irritate the
gastric/oesophageal mucosa.1519 The management of GERD is also

more complicated in patients with comorbidities as they are often

polymedicated.18,20,21 The increased incidence of GERD will lead to a
rise in the need for long-term treatment with PPI. This symposium
addressed several key clinical questions regarding the long-term
GERD patient management.

Safety Issues Linked to Long-term Proton

Pump Inhibitor Treatment
Stanislas Bruley des Varannes
Professor of Gastroenterology, Institut des Maladies de lAppareil Digestif, CHU Htel Dieu, Nantes, France

Assessing the Impact of Proton Pump

Inhibitor-induced Hypergastrinaemia and
Risk of Neoplasms in the Long Term
The first question the symposium considered regarding the long-term
safety of PPI was whether PPI-induced hypergastrinaemia is safe in
the long term. Gastrin is normally secreted in response to falling
gastric acid levels and acts both directly on parietal cells and via
enterochromaffin-like cells to stimulate acid secretion thereby
restoring the normal stomach pH. This stimulates somatostatin
release which in turn suppresses gastrin secretion.6 Long-term PPI
treatment, however, inhibits acid secretion and maintains an elevated
pH leading to sustained gastrin secretion and hypergastrinaemia in
nearly all patients.2
Indeed, enterochromaffin-like (ECL) cell hyperplasia has been reported
in hypergastrinaemic rats, but this phenomenon has never been
observed in humans.2,22 During long-term gastric acid inhibition, serum
chromogranin A levels reflect the presence and severity of fundic ECL
cell hyperplasia. Chromogranin A is therefore a useful biomarker for
gastric ECL cell proliferative changes in cases of elevated gastrin levels
(five-fold higher serum chromogranin A levels in linear or micronodular
versus diffuse patterns of hyperplasia). Sustained high chromogranin A
levels may indicate a need for gastric biopsy to test for dysplasia.23
Chronic PPI therapy is not associated with a risk of colorectal cancer.
A Danish registry study reported 5,589 cases of colorectal cancer with
55,890 controls. In this study, patients who were regular users of PPI
were compared with patients who were never or rare users (30 pills
during observation period). No evidence of increased risk (OR 1.11; 95 %
CI 0.971.27) of colorectal cancer was found. Similarly, a comparison
of the most intense users (receiving PPIs more than every other day)
with never or rare users showed no increase in cancer risk. This
lack of increased risk was true in both short-term (adjusted OR, 1.07;
95 % CI, 0.861.34) and long-term users (>7 years; OR 1.09; 95 % CI
0.582.06).24 PPIs are linked with an increased risk of inflammatory
fundic gland polyps but surveillance is unnecessary unless there
is a history of familial adenomatous polyps, as suggested by a
case-control study.2
Another point to consider regarding the effects of gastric acid
secretion is the role of Helicobacter pylori. It is known that an
increased annual incidence of atrophic gastritis (gastric atrophy) is
seen in H. pylori-infected patients compared with non-infected

10

patients.25 Whether gastric body-predominant atrophic gastritis is a

risk factor for gastric cancer remains controversial.26 However
eradicating H. pylori before long-term PPI therapy may be justified to
cure H. pylori gastritis in the corpus and thus avoid the development
of atrophy.6,27
In summary, although PPI therapy leads to hypergastrinaemia in
nearly all patients, PPI-induced hypergastrinaemia stimulates
hyperplasia of ECL cells without provoking any neoplastic changes.

Evaluating the Clinical Significance of Proton

Pump Inhibitors Effect on Electrolyte or
Vitamin Absorption
Another relevant question regarding the long-term safety of PPIs is
whether they have any clinically significant effects on electrolyte (Mg,
Ca and Fe) and vitamin (B12) absorption. Altered pH (hypochlorhydria)
could be expected to affect nutrient absorption due to reduced salt
production and therefore reduced ionisation necessary for efficient
absorption. Insoluble calcium salts release ionised calcium in an
acidic environment and animal data have linked PPIs with reduced
calcium absorption.28,29 Omeprazole may impair bone resorption and
may also block microfracture repair by blocking the H+-K+ pump
in osteoclasts.30 However, a large prospective study (n=161,806) of
post-menopausal women found that the use of PPIs was not
associated with hip fractures. The results showed that PPIs
were modestly associated with clinically apparent spine fractures (HR
1.47, 95 % CI 1.181.82), forearm or wrist fractures (HR 1.26, 95% CI,
1.051.51), and an overall increased risk of any fracture (HR 1.25, 95%
CI, 1.151.36). Use of PPIs was associated with a marginal reduction
in bone mineral density at the hip (p=0.05) but not at other sites.31
Prophylaxis for osteoporosis in PPI-treated patients is probably
unnecessary, but long-term follow-up of large populations would be
valuable to confirm what relationship, if any, exists. It seems prudent
that long-term PPI therapy should use the lowest effective dose,
and be accompanied by adequate dietary calcium intake and
supplementation when needed.10,31
Other minerals of interest are magnesium and iron. Hypomagnesaemia
is a rare, but potentially fatal side effect of PPI use which has emerged
only recently with mass use of PPIs. The cause of hypomagnesaemia
remains poorly understood, but it is rapidly reversed by PPI
withdrawal.32 Early studies found no evidence linking PPI therapy

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Current Advances in Long-term Proton Pump Inhibitor Use

with iron deficiency, although they concluded that iron absorption

could in theory be reduced at raised intragastric pH.33 However,
anaemia has recently been reported in PPI-treated patients. In a
cohort study, among adult patients receiving chronic PPI therapy
(>1 year), there was a significant decrease in haematological indices
from baseline.34

Figure 1: Risk Factors for Community-acquired

Clostridium difficile Infection
PPI
1.6

IBS
3.4

Intragastric acid reduction could impair vitamin B12 release from

food, since the proteolytic process involved in releasing the vitamin
from the proteins in ingested food is facilitated by gastric acid.
But studies have yielded discrepant results and B12 deficiencies
have only been reported with prolonged high-dose PPI use. 35
Most evidence to date has been from small non-randomised
retrospective studies or case reports and has not appeared to
be clinically significant. 36

Analysis of the Impact of Proton Pump

Inhibitors on the Frequency of Gastrointestinal
and Non-gastrointestinal Infections
The third question addressed regarding long-term safety was
whether GI and non-GI infections are more frequent in PPI users.
Recently, cases of community-acquired pneumonia have been
reported in patients taking PPI37 and there have also been cases of
spontaneous bacterial peritonitis in patients with cirrhosis taking
PPIs.38 Diarrhoea is one of the most commonly reported adverse
events with PPIs.39,40 Reducing intragastric acidity may allow more
micro-organisms to survive and promote bacterial overgrowth in the
small intestine.41,42
Several studies have indicated an increased risk of Clostridium
difficile infection in patients taking PPIs. The exact mechanism of this
increased risk however, is unclear. C. difficile spores are resistant
to acid but the vegetative form of C. difficile is usually killed by acid
and may contribute to disease pathogenesis since it remains viable
for approximately six hours on moist surfaces in room air.43 It has also
been hypothesised that germination of C. difficile spores is initiated
in the stomach,44 although animal data suggests that only minimal
germination occurs in the stomach.45 When spores are ingested, there
is first an increase of free bile acids, which enhances germination
of the spores. This fixes the binding of the germinant and it also
facilitates germination initiated in the stomach, which continues in
the duodenum and increases rapidly in the small bowel. Animal

Renal
failure
1.7

Cephalosporins
14.9

10

Gatifloxacin
16.7

Clindamycin
31.8

20

30

RR

IBD
4.1

PPI = proton pump inhibitor; IBD = inflammatory bowel disease; IBS = irritable bowel
syndrome. Source: adapted from Dial et al., 2008.48

studies have shown that about 80 % of C. difficile spores can

germinate within one hour in the small bowel.44,45
A UK population-based study found that PPI use is associated with
an increased risk of community-acquired C. difficile.46 Conversely, a
cohort study during the Qubec epidemic revealed a significant
association between C. difficile infection and antibiotics, mainly
fluoroquinolones, but none with PPI use.47 Another large-scale
population study found that PPIs were associated with an increased
risk of C. difficile (RR: 1.6, 95% CI 1.32.0), but again, antibiotic use
was identified as the main risk factor (RR: 10.6, 95% CI 8.912.8 for
any antibiotic; RR: 31.8, 95 % CI 17.657.6 for clindamycin) (see
Figure 1).48 Current data on C. difficile-associated disease remains
disparate and controversial and the majority of reported cases
are hospital-based.49,50 The discrepancies between studies may
be explained by a number of confounding effects including
co-morbidities and co-therapies.46,47
A recent study demonstrated that bacterial overgrowth in the small
intestine occurs significantly more frequently among long-term PPI
users than patients with irritable bowel syndrome or control
subjects.51 Theoretically, long-term PPI users may therefore have an
increased susceptibility to bacterial diarrhoea and an increased risk
of acquired enteric infections during travel to tropical regions. The
International Society of Travel Medicine has indicated PPI as a risk
factor for developing travellers diarrhoea and has recommended that
daily chemoprophylaxis be taken by individuals during travel to
high-risk areas.52

Drug-drug Interactions of Proton Pump Inhibitors and their

Clinical Relevance
Philippe Ducrott
Professor of University Hospital Practitioner, Department of Hepatogastroenterology, CHU Hpital Charles Nicolle, Rouen, France

The latter part of the symposium considered the potential

consequences of the interactions of PPIs with other drugs. PPIs
can influence GI drug absorption and metabolism via three main
mechanisms: modulation of intragastric pH, interaction with
intestinal adenosine triphosphate-dependent P-glycoproteins that
are involved in drug uptake and interaction with cytochrome P450
(CYP) enzyme systems in both the intestines and liver. As a result,

EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW

PPIs affect both intestinal first-pass metabolism and hepatic

clearance of other drugs.53

Impact of Gastric pH on Drug Absorption

Certain drugs are affected by pH, including acid/alkaline labile
agents, weak acids and bases, and pH-dependent formulations.
The majority of commonly-prescribed drugs are weakly acidic

11

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Proton Pump Inhibitors

Figure 2: Drug Transporters

linked with increased absorption of nifedipine, digoxin, and

particularly alendronate. 58

Interaction of Proton Pump Inhibitors with

Intestinal Epithelial Drug Transporters

Drug efflux
Plasma
membrane

ATP-binding
domain

Etoposide
Daunomycin
Taxol
Vinblastine
Doxorubicin

ATP = adenosine-5-triphosphate. Source: adapted by permission from Macmillan Publishers

Ltd: Nature Reviews Cancer,59 copyright 2002.

Figure 3: Influence of CYP2C19 Reduced Function

Polymorphisms on Rates of Stent Thrombosis in
Clopidogrel-treated Patients

While changes in gastric pH induced by PPIs and interactions with

the intestinal P-glycoprotein efflux transporter system may alter drug
absorption,55 the risk of clinically relevant reductions in concomitant

Definite or probable stent thrombosis

3.0
2.6

2.5

Carriers

2.0
p=0.02

1.5
1.0

Non-carriers

Carriers
Non-carriers

0.8

0.5
0.0

0 30

90

Number at risk
375 368
1,014 1,004

366
1,001

180
270
Days since randomisation
359
989

316
885

360

450

279
765

186
547

Source: Adapted from Mega et al., 2009,73 with permission from the Massachusetts
Medical Society.

therefore their dissociation is pH-dependent. Suppression of gastric

acid secretion may therefore profoundly alter their absorption. For
example, aspirin is a weak acid and within the upper small intestinal
tract, where there is a more basic environment, the bioavailability of
the drug may be reduced.54
Co-administration of PPIs and ritonavir with the antiretroviral
drug atazanavir decreases the bioavailability of the latter by 48
to 62% because its solubility is much higher at lower pH. 55 A 60 mg
dose of lansoprazole has been reported to reduce the mean
area under the concentration-time curve during the 24 hours
after atazanavir administration by 94% (p<0.01). 56 However, recent
findings suggest that dose adjustment to 20 mg can significantly
reduce the impact of omeprazole on atazanavir pharmacokinetics. 57
Other drugs that are poorly absorbed when gastric acid secretion
is suppressed include ketoconazole, itraconazole, cefpodoxime,
enoxacin and dipyridamole. 58 Conversely, antacid therapy is

12

Intestinal drug absorption is mediated by membrane-bound

transporter systems, such as the P-glycoprotein, on superficial
columnar cells in the small intestine (see Figure 2).59 The MDR1 gene
is the best studied of the transporter genes and encodes a
P-glycoprotein that mediates dependent efflux of a wide range of
drugs including anti-cancer agents, cardiac drugs, HIV protease
inhibitors, immunosuppressants, antibiotics and lipid-lowering
agents.6062 If the glycoprotein system is inhibited, the absorption of
some drugs will be increased. On the other hand, if an agent
stimulates the glycoprotein, the impact will be decreased absorption
of this drug. An in vitro study reported that omeprazole,
pantoprazole and lansoprazole all inhibited P-glycoprotein-mediated
efflux of digoxin (IC50 values were 17.7, 17.9 and 62.8 mol/l,
respectively).63 The MDR1 gene promoting this transporter shows
polymorphism and there is wide inter-individual variation in
P-glycoprotein function making it difficult to quantify the real impact
of PPI treatment in different patients based on results from small
numbers of subjects or cell lines.64

drug bioavailability due to PPIs is probably low, however, more

research is needed to confirm this.

Metabolic and Cytochrome P450-induced

Drug Interactions
CYP is a family of isoenzymes responsible for the biotransformation
of many drugs. Drug metabolism via the CYP system is responsible
for numerous drug interactions that can result in toxicities,
reduced pharmacological effect and adverse reactions. Recognising
whether the drugs involved act as enzyme substrates, inducers,
or inhibitors can prevent clinically significant interactions from
occurring. A list of drugs metabolised by the CYP system is given
in Table 1 and includes commonly prescribed drugs such as
warfarin. The impact of PPIs on the CYP system is therefore of
considerable concern. 65,66

Role of Proton Pump Inhibitors in Clopidogrel

Metabolism and Efficacy
Particular attention has focused on clopidogrel, an antiplatelet agent
that has become a mainstay of atherosclerotic cardiovascular disease
therapy. Clopidogrel is commonly co-administered with aspirin
following surgical interventions such as angioplasty with stent
placement.67,68 These regimens, however, carry a risk of GI bleeding so
guidelines recommend the use of PPIs.69,70 Recent studies have raised
concerns regarding the concomitant use of PPIs and clopidogrel.
Clopidogrel is a prodrug which requires hepatic bioactivation via
several CYP enzymes, mainly CYP2C19 but also CYP3A4 and CYP3A5.
The active metabolite of clopidogrel then acts via the P2Y12 receptor
on platelet cell membranes.71,72
Genetic polymorphisms of P2Y12 can influence the efficacy of
clopidogrel. The impact of polymorphisms on the ability of this
drug to prevent platelet aggregation is of great clinical

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Current Advances in Long-term Proton Pump Inhibitor Use

Table 1: Drugs that Could be Affected by Cytochrome P450-mediated Drug-drug Interactions

P450 Isozyme
Function

CYP1A2

CYP2C19

CYP2C9

CYP2D6

CYP2E1

CYP3A4

Substrates of

Caffeine

Amitriptyline

Amitriptyline

Amitriptyline

Acetaminophen

Alprazolam

isozyme

Clozapine

Citalopam

(demethylation)

Clomipramine

Chlorzoxazone

Astemizole

Cyclobenzaprine

Clomipramine

Celecoxib

Codeine

Dapsone

Buspirone

Fluvoxamine

Cyclophosphamide

Diclofenac

Desipramine

Enflurane

Calcium-channel

Imipramine

Diazepam

Flurbiprofen

Dextromethorphan

Ethanol

blockers

Mexiletine

Imipramine

Ibuprofen

Imipramine

Halothane

Carbamazepine

Olanzapine

Lansoprazole

Losartan

Metoprolol

Isoflurane

Cisapride

Pimozide

Nelfinavir

(not candesartan)

Nortriptyline

Isoniazid

Cyclosporine

Propranolol

Omeprazole

Naproxen

Oxycodone

Tacrine

Phenytoin

Phenytoin

Paroxetine

Erythromycin

Piroxicam

Propafenone

Etoposide

Theophylline
Warfarin

Doxorubicin

Sulfamethoxazole

Risperidone

Felodipine

Tolbutamide

Thioridazine

Fentanyl

Warfarin

Timolol

HIV protease inhibitors

Tramadol

Ifosphamide

Venflaxine

Lovastatin
(not pravastatin)
Midazolam
Nifedipine
Pimozide
Quinidine
Quinine
Simvastatin
Tacrolimus
Terfenadine
Triazolam

Inhibitors of

Cimetidine

Cimetidine

Amiodarone

Amiodarone

Disulfiram

Amiodarone

isozyme

Ciprofloxacin

Felbamate

Fluconazole

Chlorpheniramine

Water cress

Cimetidine

Citalopram

Fluoxetine

Fluoxetine

Fluoxetine

Diltiazem

Fluvoxamine

Fluvastatin

Haloperidol

Danazo

Enoxacin

Ketoconazole

Isoniazid

Indinavir

Diltiazem

Erythromycin

Lansoprazole

Metronidazole

Paroxetine

Fluconazole

Fluvoxamine

Omeprazole

Paroxetine

Propafenone

(large doses)

Mexiletine

Paroxetine

Phenylbutazone

Quinidine

Grapefruit juice

Ofloxacin

Ticlopidine

Cyclosporine

Sulfamethoxazole/

Ritonavir

HIV protease

Tacrine

trimethoprim

Sertraline

inhibitors

Ticlopidine

Sulfaphenazole

Thioridazine

Itraconazole

Ticlopidine

Ticlopidine

Ketoconazole
Macrolides
(not azithromycin)
Miconazole
Nefazadone
Omeprazole
Quinidine
Ritonavir
Verapamil

Inducers of

Carbamazepine

Carbamazepine

Phenobarbital

Chronic ethanol

Carbamazepine

isozyme

Tobacco

Norethindrone

Rifampin

Isoniazid

Rifabutin

(not phenobarb)

Secobarbital

Tobacco

Rifabutin
Ritonavir

Source: adapted from Ogu and Maxa, 2000, DiPiro, 1999, Cupp and Tracy, 1998, Belpaire and Bogaert, 1996, and Abramowicz, 1999.7478

importance, as the following study demonstrates. Data from a

cohort of 1,477 patients demonstrated a significantly increased
risk of stent thrombosis (2.6 versus 0.8%, HR 3.09, p=0.02) and a
composite outcome of cardiovascular death, myocardial
infarction, or stroke during up to 450 days follow-up (12.1 versus
8.0 %, HR: 1.53, p=0.01) among carriers of a reduced-function
CYP2C19 allele treated with clopidogrel (see Figure 3). 73 CYP2C19
polymorphisms that are associated with poor metabolism are

EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW

common in some populations, particularly in Southeast Asian

countries and range between 123% in different ethnic groups. 79
Extrapolating the outcome results from the above cohort to these
prevalence data suggests that 123 % of clopidogrel-treated
patients already have a 1.53-fold increased intrinsic risk of
cardiovascular death, myocardial infarction, or stroke, even
without any pharmacokinetic or pharmacodynamic interactions
with other drugs. 73,79

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Proton Pump Inhibitors

Table 2: Effects of Proton Pump Inhibitor on Clinical
Outcome in Patients Treated with Clopidogrel
Clinical
Endpoint

No of
Studies

Total No
of Patients

Risk Ratio
with PPI

p-value

MACE

20 (1 RCT)

139,517

1.29

<0.001

(50,261 with

1.31

<0.001

CYP3A4

(30,583 with

(1.121.53)

Pantroprazole

Omeprazole
CYP2C19

CYP3A4

CYP2C19

CYP3A4

5-Hydroxyomeprozole Omeprazole sulphone

Demethylated pantoprazole
Sulfotransferase

5,881

1.88

(1,897 with

(0.973.62)

0.06

CYP3A4

CYP2C19

1.04

(36,021 with

(0.931.16)

Pantoprazole sulfate

0.53

H
N

O
S

96,109

Pantoprazole
sulphone

Omeprazole hydrosulphone

without)
14

CYP2C19

81,966

PPI, 3,984
Death

5-0 Desmethylomeprazole 3-Hydroxyomeprozole

without)
thrombosis

N
H

(1.151.44)

PPI, 51,383
Stent

without)
12

N
O

PPI, 89,256
MI

Figure 4: Hepatic Metabolism of Proton Pump Inhibitors

N
H

without)

Table 3: Platelet Reactivity Index Values in Patients on

Clopidogrel Without Concomitant Proton Pump
Inhibitor, Clopidogrel plus Rabeprazole, or
Clopidogrel plus Esomeprazole
Clopidogrel
Without PPI (C)

Clopidogrel
plus
Rabeprazole (CR)

Clopidogrel
plus
Esomeprazole (CE)

79

64

35

Abnormal PRI

11 (13.9 %)

8 (12.5 %)

7 (20.0 %)

19 (24.1 %)

11 (17.2 %)

16 (45.7 %)

(>50 %) n (%)

PPI, 60,088

MACE = major adverse cardiac event; MI = myocardial infarction; PPI = proton pump
inhibitor; RCT = randomised controlled trial. Source: adapted from Siller-Matula et al., 2010.85

O
S

F
Rabeprazole

Lansoprazole
CYP3A4

CYP2C19
5-Hydroxyomeprozole

Lansoprazole
sulphone

CYP3A4

CYP2C19
Demethylated
rabeprazole

Rabeprazole
sulphone
(major)
Non-enzymatic
pathway

Rabeprazole
thiother

Arrow thickness is indicative of the dominance of each biotransformation pathway.

Source: Ishizaki et al., 1999,79 Sharara, 2005,87 and Abelo et al., 2000.88 Adapted from
Expert Review of Anti-infective Therapy, December 2005, Vol. 3, No. 6, Pages 86387087
with permission from Expert Reviews Ltd.

Is the Clopidogrel Drug Interaction Risk

Different Between Proton Pump Inhibitors?

Aside from P2Y12 polymorphism, other factors may also impact the
efficacy of clopidogrel. For instance, the reduced antiplatelet activity
of this drug could be due to impaired intestinal absorption. Poor
adherence to treatment regimens is common, but often unreported80
and could be one explanation for the discrepancies between studies
of interactions between PPIs and clopidogrel. Patients receiving
long-term clopidogrel treatment may also have co-morbidities that
affect efficacy.81

Most PPIs undergo hepatic metabolism, predominantly via the same

cytochrome as clopidogrel CYP2C19 and also CYP3A4. This results in
competitive inhibition of CYP2C19 and reduced production of the active
metabolite of clopidogrel.69,86 However, rabeprazole differs from the other
PPIs in having a mainly non-enzymatic route of hepatic metabolism (see
Figure 4).87 This explains the observed differences between individual
PPIs in terms of metabolism and CYP inhibition: in an in vitro study,
lansoprazole and omeprazole were the strongest CYP2C19 inhibitors,
while rabeprazole was the weakest. It is also important to consider in
vitro data within a clinical context. Esomeprazole seems to show weaker
inhibition of CYP2C19 than omeprazole but appears to have a similar
interaction potential to omeprazole in clinical use, perhaps due to the
higher dose of esomeprazole and longer clearance time.89

An ex vivo assessment of responsiveness to clopidogrel in 544 subjects

(including 450 patients) yielded a bell-shaped distribution curve, which
is highly consistent with multifactorial influences and supports other
evidence that no single dominant factor determines clopidogrel
responsiveness.82 A number of recent studies have heightened
concerns that PPIs could interfere with the antiplatelet activity of
clopidogrel.83,84 A recent systematic review and meta-analysis
concluded that concomitant PPI use might be associated with an
increased risk of cardiovascular events in patients taking clopidogrel
but does not influence the risk of death. There was considerable
heterogeneity among results, however, and there is a need for
prospective randomised trials to further investigate this relationship
and to explore whether other PPIs worsen clinical outcomes in
clopidogrel-treated patients since the PPI-clopidogrel drug-drug
interaction does not seem to be a class effect (see Table 2).

The first results of a study directly comparing the antiplatelet activity

of clopidogrel in patients (n=178) taking concomitant rabeprazole,
esomeprazole or no PPI were recently presented (see Table 3).90
Median platelet reactivity index (PRI) values were similar in patients
on clopidogrel without a concomitant PPI (C) and patients taking
clopidogrel plus rabeprazole (CR) and numerically higher but
not significantly different in patients taking clopidogrel plus
esomeprazole (C versus CR p=0.32; C versus CE p=0.107).
Significantly more patients in the CE group had PRI values over 30%
versus either C or CR (p=0.02 and 0.002, respectively).90 Four
patients with PRIs over 50% (mean 81.1%) on CE had improved PRI
values (mean 24.3 %) after either stopping esomeprazole (n=1) or
switching to rabeprazole (n=3). Esomeprazole use was the only
independent variable associated with PRI values over 30 % after
multivariate regression (OR 2.7, 95 % CI [1.26.5], p=0.021). While

Abnormal PRI
(>30 %) n (%)

p=0.007. Abnormal PRI was defined as PRI values >50 or >30 %. PPI = proton pump
inhibitor; PRI = platelet reactivity index. Source: adapted from Sharara et al., 2011.90

14

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Current Advances in Long-term Proton Pump Inhibitor Use

this patient population included 32 individuals (18%) with CYP2C19

loss-of-function polymorphism, there was no link found between
CYP2C19 polymorphism and abnormal PRI. The authors therefore
concluded that esomeprazole inhibited the antiplatelet efficacy of
clopidogrel independently of CYP2C19.90

Unfortunately, this trial was terminated early due to financial issues

of the sponsor and never achieved sufficient patient numbers to
reach a valid conclusion.92
Four randomised, placebo-controlled crossover studies have
recently been conducted on healthy individuals (n=282) to assess the
effect of omeprazole on clopidogrel metabolism and antiplatelet
activity as well as to test possible approaches to reducing this
impact. Giving omeprazole (80 mg) simultaneously with clopidogrel
(300 mg loading/75 mg maintenance dose) resulted in a 40% drop in
active metabolite production and an 8 % increase in adenosine
diphosphate-induced maximal platelet aggregation (MPA) versus no
PPI. Spacing the same clopidogrel and omeprazole doses 12 hours
apart produced a 5.6 % increase in MPA versus no PPI and a 47 %
reduction in clopidogrel active metabolite.

Another recent study comparing the effect on Clopidogrel efficacy

of concomitant administration of rabeprazole, omeprazole and
placebo (CLARA) revealed similar outcomes for rabeprazole versus
placebo. By using a measure of clopidogrel antiplatelet activity
(vasodilator-stimulated phosphoprotein [VASP] Platelet Reactivity
Index), the relative change in platelet reactivity under clopidogrel
was significantly reduced by concomitant omeprazole, but not
rabeprazole treatment in good antiplatelet responders. 91 As
expected, the CLARA trial also showed that the influence of PPI
therapy on the anti-platelet effect of clopidogrel is greater in
extensive metabolisers than in intermediate metabolisers. Thus in
the completers group, which included low, intermediate and
extensive responders, neither the addition of rabeprazole 20 mg nor
omeprazole 20 mg had a significant impact on the clopidogrel
antiplatelet activity compared with the clopidogrel and placebo
group. However, as an overall lower than expected effect of
omeprazole on clopidogrel was observed in this group, these results
need to be treated with caution.90

Doubling the clopidogrel dose to 600 mg/150 mg had no effect

on either the active metabolite or MPA compared with standard
dose (-41 and +8.1%, respectively). There was a smaller effect on
clopidogrel metabolism (-14 % active metabolite) and antiplatelet
activity (MPA +4.3 %) when clopidogrel was used in combination
with pantoprazole versus omeprazole. 93 Hence, in these studies, the
only approach that reduced PPI-induced inhibition of clopidogrel
was to substitute with a PPI that has a weaker inhibitory effect.

The Clopidogrel and the optimisation of gastrointestinal events

trial (COGENT) demonstrated the value of prescribing PPIs with
clopidogrel. After 180 days, patients receiving omeprazole 20 mg/day
and clopidogrel 75 mg/day had a 1.1 % Kaplan-Meier event rate for
GI bleeding, pain, erosions, obstruction or perforation, compared
with 2.9 % in patients on clopidogrel 75 mg/day alone (p<0.001).

In summary, PPIs may influence the pharmacokinetics and

pharmacodynamics of clopidogrel with the strongest evidence
demonstrated for omeprazole and esomeprazole. Rabeprazole, by
virtue of its predominant non-enzymatic metabolism, appears to have
no significant interactions with clopidogrel. Further studies are
needed to address this issue.

Conclusions

The presentations demonstrated that PPIs have a well-established

safety profile and can be prescribed with confidence in the
treatment of peptic ulcer, GERD and related disorders. Although
they induce hypergastrinaemia, leading to cellular hyperplasia and
polyps in some patients, there is no indication for surveillance
except in patients with a history of familial adenomatous polyposis.
Patients undergoing long-tem PPI therapy should use the lowest
effective dose, accompanied by adequate dietary calcium intake
and supplementation, when needed. Physicians should also be
aware of a possible increased susceptibility to bacterial infection
when taking PPIs, and can, for example, recommend prophylaxis
for travellers diarrhoea.

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