Reducing Adverse Effects of Proton Pump Inhibitors

66 American Family Physician www.aafp.org/afp Volume 86, Number 1

◆

July 1, 2012

Reducing Adverse Effects of Proton

Pump Inhibitors

PAUL W. AMENT, PharmD; DANIEL B. DICOLA, MD; and MARY E. JAMES, MD

Excela Health Latrobe Family Medicine Residency Program, Latrobe, Pennsylvania

n 1990, the U.S. Food and Drug Admin-

istration (FDA) approved omeprazole

(Prilosec), the ﬁrst proton pump inhib-

itor (PPI), for the short-term treatment

of gastroesophageal reﬂux disease, active

duodenal ulcer, severe erosive esophagitis,

and pathologic hypersecretory conditions.

The mechanism of action for PPIs involves

blocking the terminal pathway that stimu-

lates gastric acid release.

2,3

The PPI class now

includes at least seven other drugs, including

parenteral and over-the-counter formula-

tions (Table 1).

Currently, the PPI class is the third high-

est selling drug category in the United States,

accounting for more than 113 million pre-

scriptions annually with sales exceeding

$14 billion.

Patients often continue therapy

for extended durations without an end point.

Studies have found that up to 70 percent of

PPI use is for unapproved indications.

Adverse Effects

The overuse and misuse of PPIs are con-

cerning. PPIs cause few adverse effects with

short-term use; however, long-term PPI use

has been associated with an increased risk of

all-cause mortality in two cohorts of insti-

tutionalized older persons,

in addition to

being linked to a number of adverse effects

(Table 2

6-23

). Adults 65 years and older are at

higher risk of these adverse effects because of

the higher prevalence of chronic diseases in

this population.

HIP FRACTURE

A retrospective study in the United King-

dom found a substantially higher incidence

of hip fractures in patients older than 50

years who used PPIs for more than one year,

with higher fracture risk associated with

longer treatment duration.

A similar study

found an increased fracture risk in patients

using long-term PPIs who had at least one

other risk factor, including diabetes mellitus,

chronic renal diseases, and glucocorticoid

use.

In 2010, the FDA revised the labeling

of all PPIs to include the increased risk of

fractures of the hip, wrist, and spine.

CARDIAC EVENTS

Risk factors for gastrointestinal bleeding in

patients taking clopidogrel (Plavix) include

previous gastrointestinal bleeding; advanced

age; concomitant use of warfarin (Couma-

din), glucocorticoids, or nonsteroidal anti-

inﬂammatory drugs; and Helicobacter pylori

infection. In 2007, the American College of

Cardiology and the American Heart Associa-

tion recommended the use of gastroprotec-

tive agents in patients with unstable angina

or non–ST segment elevation myocardial

Proton pump inhibitors effectively treat gastroesophageal reﬂux disease, erosive esophagitis,

duodenal ulcers, and pathologic hypersecretory conditions. Proton pump inhibitors cause few

adverse effects with short-term use; however, long-term use has been scrutinized for appropri-

ateness, drug-drug interactions, and the potential for adverse effects (e.g., hip fractures, cardiac

events, iron deﬁciency, Clostridium difﬁcile infection, pneumonia). Adults 65 years and older

are more vulnerable to these adverse effects because of the higher prevalence of chronic diseases

in this population. Proton pump inhibitors administered for stress ulcer prophylaxis should be

discontinued after the patient is discharged from the intensive care unit unless other indica-

Family Physicians.)

▲

Patient information:

A handout on side effects

of proton pump inhibitors,

written by the authors

of this article, is avail-

able at http://www.

aafp.org/afp/2012/0701/

p66-s1.html. Access to

the handout is free and

unrestricted. Let us know

what you think about

AFP

putting handouts online

only; e-mail the editors at

afpcomment@aafp.org.

Editor’s note: In violation of our conﬂict of interest policy, Dr. Ament failed to disclose

ﬁnancial relationships with two pharmaceutical companies that existed at the time of

submission and publication of this article. His disclosure statement has been corrected.

mercial use of one individual user of the Web site. All other rights reserved. Contact copyrights@aafp.org for copyright questions and/or permission requests.

Proton Pump Inhibitors

July 1, 2012

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Volume 86, Number 1 www.aafp.org/afp American Family Physician 67

infarction who were taking aspirin and clopidogrel,

and who had a history of gastrointestinal ulceration.

Since that time, studies have suggested an increased risk

of reinfarction in patients taking clopidogrel and a PPI

other than pantoprazole (Protonix).

There also may be

an increased risk of rehospitalization with concomitant

use of a PPI and clopidogrel following percutaneous angi-

ography and treatment for acute coronary syndrome.

18,21

Therefore, the American College of Cardiology and the

American Heart Association suggest that physicians

prescribe drugs other than PPIs, such as histamine H

antagonists (e.g., ranitidine [Zantac]), for patients taking

aspirin and clopidogrel who require gastroprotection.

Studies show that PPIs block the effects of clopi-

dogrel by inhibiting cytochrome P450 2C19 isozyme

(CYP2C19), which converts clopidogrel to its active

form. Although data strongly suggest an interaction

between omeprazole and clopidogrel, the clinical sig-

niﬁcance of this interaction is unknown.

Pantoprazole

may be preferred over other PPIs in the setting of acute

coronary syndrome or coronary stenting because it has a

lower potential to inhibit CYP2C19.

In patients with concomitant atherosclerosis and a high

risk of gastrointestinal bleeding, physicians should weigh

the potential cardiovascular risks of PPIs against less effec-

tive alternatives, such as H

antagonists.

22,25

The product

information for clopidogrel has been changed to recom-

mend avoiding concurrent use with omeprazole because

it decreases the antiplatelet effectiveness of clopidogrel.

IRON DEFICIENCY

An increase in gastric pH is a normal physiologic change

in the gastrointestinal tract of older persons and is exac-

erbated by long-term PPI use. It is unlikely that patients

with normal iron stores will develop iron deﬁciency

anemia solely from PPI use. However, patients with low

baseline iron stores may be more susceptible to further

iron depletion with concurrent PPI therapy.

ENTERIC INFECTIONS

Studies indicate an increased risk of diarrhea from Clos-

tridium difﬁcile and of other enteric infections in hos-

pitalized patients taking PPIs and antibiotics.

6,7

There is

also an increased risk of recurrent C. difﬁcile infection

Table 1. Availability, Formulations, and Dosages for Proton Pump Inhibitors in Adults

Drug Availability

Route of

administration Starting dosage*

Cost of generic

(brand)†

Dexlansoprazole (Dexilant) Prescription Oral 30 mg per day NA ($153)

Esomeprazole (Nexium) Prescription Oral or IV Oral: 20 mg per day

IV: 20 mg per day for 10 days

Oral: NA ($201)

IV: NA ($381)‡

Lansoprazole (Prevacid) Prescription Oral 15 mg per day $106 ($196)

Lansoprazole (Prevacid 24H) Over-the-counter Oral 15 mg per day for 14 days§ NA ($13)

Omeprazole (Prilosec, Zegerid) Prescription Oral 20 mg per day $33 ($196)

Omeprazole (Prilosec OTC,

Zegerid OTC)

Over-the-counter Oral 20.6 mg (Prilosec OTC) or 20 mg

(Zegerid OTC) per day for 14 days§

$7 ($13)

Pantoprazole (Protonix) Prescription Oral or IV Oral: 40 mg per day

IV: 40 mg per day for 7 to 10 days

Oral: $16 ($186)

IV: $42 ($42)‡

Rabeprazole (Aciphex) Prescription Oral 20 mg per day NA ($250)

IV = intravenous; NA = not available.

*—Number of weeks of recommended treatment varies.

†—Estimated retail price of one month’s treatment (unless otherwise speciﬁed) based on information obtained at http://www.drugstore.com

(accessed January 31, 2012) or at a national retail chain.

‡—Estimated wholesale price based on information obtained at Red Book online. Micromedex 2.0. Micromedex Healthcare Series [Internet database].

Greenwood Village, Colo.: Thomson Reuters (accessed January 31, 2012).

§—Patients should not take more often than 14 days per month every four months.

Proton Pump Inhibitors

68 American Family Physician www.aafp.org/afp Volume 86, Number 1

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after hospital discharge in those taking PPIs.

Acid sup-

pression has been associated with an increased risk of

Campylobacter enteritis. An increase in acute viral gas-

troenteritis in children was reported in those treated

with PPIs for gastroesophageal reﬂux disease.

The pro-

posed mechanism of action is a less acidic gastric envi-

ronment, leading to increased bacterial colonization of

the upper gastrointestinal tract.

PNEUMONIA

Acid suppression allows ingested pathogens to colonize

the gastrointestinal tract and relocate to the respiratory

tract.

One study of older patients hospitalized for pneu-

monia found that initiating a PPI or H

antagonist at dis-

charge signiﬁcantly increased the likelihood of recurrent

community-acquired pneumonia.

Another study found

a statistically signiﬁcant increase in the risk of hospital-

acquired pneumonia with PPI use.

Physicians should

weigh the risks versus beneﬁts before initiating a PPI in

patients being treated for pneumonia.

GASTRIC ACID REBOUND

Several studies have demonstrated that asymptomatic

patients who are administered short-course PPI therapy

develop rebound gastrointestinal symptoms after dis-

continuation.

15,16

Patients reported clinically signiﬁcant

dyspeptic symptoms after discontinuation of a two-

month course of esomeprazole (Nexium) compared with

placebo (44 versus 15 percent).

A similar study of pan-

toprazole in asymptomatic, H. pylori–negative patients

showed persistent rebound gastrointestinal symptoms

for two weeks following discontinuation.

Discontinuation of PPIs may exacerbate the same

symptoms physicians are aiming to treat, possibly

because of rebound acid hypersecretion.

15,16

This may

explain why patients have difﬁculty discontinuing long-

term PPI therapy.

Stress Ulcer Prophylaxis

Many patients admitted to the intensive care unit (ICU)

have risk factors for stress ulcers, with active bleeding

producing a higher rate of mortality.

Signiﬁcant risk

factors associated with gastrointestinal bleeding include

coagulopathy and mechanical ventilation exceeding

48 hours’ duration.

Based on a review of 58 studies,

stress ulcer prophylaxis is recommended by the Eastern

Association for the Surgery of Trauma for patients with

any of the following: mechanical ventilation longer than

Table 2. Potential Adverse Effects of Proton Pump Inhibitors

Adverse effect Comments

Clostridium difﬁcile infection

6-8

Nosocomial and recurrent infection following hospital discharge

Proposed mechanism is C. difﬁcile overgrowth from elevated gastric pH

Community-acquired pneumonia and hospital-

acquired pneumonia

9 -11

Histamine H

antagonists and PPIs have been implicated in pneumonia

Sucralfate (Carafate) use does not alter gastric pH and may offer an

advantage over PPIs and H

antagonists

Fractures of the hip, wrist, and spine

12-14

The U.S. Food and Drug Administration requires labeling change for all PPIs

Higher fracture risk with PPI use than with H

antagonists

Mechanism is reduced calcium absorption from increased gastric pH

Gastric acid rebound or reﬂux symptoms after

discontinuation of PPIs

15,16

PPIs may exacerbate symptoms when discontinued

Iron deﬁciency anemia in patients with low

baseline iron stores

Acid suppression is proposed mechanism of reduced iron absorption

Major adverse cardiac events in the year following

percutaneous angiography in those taking PPIs

and clopidogrel (Plavix)

18,19

Clopidogrel label changed to recommend avoiding concurrent omeprazole

(Prilosec) use because it decreases the effectiveness of clopidogrel

Rehospitalization with concomitant use of PPIs

and clopidogrel after admission for acute

coronary syndrome

20-22

The American College of Cardiology and the American Heart Association

guidelines suggest that H

antagonists be considered for the treatment or

prevention of gastrointestinal injury in patients on dual antiplatelet therapy

Reinfarction in patients taking PPIs and clopidogrel

Pantoprazole (Protonix) use does not affect clopidogrel effectiveness

PPI = proton pump inhibitor.

Information from references 6 through 23.

Proton Pump Inhibitors

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Volume 86, Number 1 www.aafp.org/afp American Family Physician 69

48 hours, coagulopathy (e.g., platelet count less than

50 × 10

per µL [50 × 10

per L], international normal-

ized ratio greater than 1.5, partial thromboplastin time

greater than two times the normal control), traumatic

brain injury, and major burn injury (more than 30 per-

cent of body surface).

Effective options for stress ulcer prophylaxis include

PPIs, H

antagonists, antacids, and sucralfate (Carafate).

No medication has been shown to be superior to another.

Although the optimal duration of prophylaxis is not

known, most experts suggest continuing therapy while the

patient is in the ICU, when bleeding risk is highest. How-

ever, many patients

continue to receive

prophylaxis inap-

propriately when

they are transferred

to general medical

units and continue

therapy after dis-

charge without clear medical indications.

To minimize

adverse outcomes, physicians should discontinue PPIs in

patients when they are discharged from the ICU if there

are no other indications for therapy.

Data Sources: A literature search was performed in PubMed including

clinical reviews, randomized controlled trials, and meta-analyses. The fol-

lowing search terms were used: proton pump inhibitor, adverse effects,

side effects, indications, and cardiovascular. Additional sources were

obtained from the Eastern Association for the Surgery of Trauma Guide-

lines. Search dates: December 2010 to February 2011.

The Authors

PAUL W. AMENT, PharmD, is the clinical pharmacy manager and a fac-

ulty member at Excela Health Latrobe (Pa.) Family Medicine Residency

Program. Dr. Ament also is an instructor of family medicine at Jefferson

Medical College at Thomas Jefferson University in Philadelphia, Pa.; an

adjunct clinical instructor in the Department of Clinical Pharmacy, Mylan

School of Pharmacy at Duquesne University in Pittsburgh, Pa.; and an

associate clinical preceptor of pharmaceutical sciences in the School of

Pharmacy, Department of Pharmacy and Therapeutics at the University

of Pittsburgh.

DANIEL B. DICOLA, MD, is a faculty member at Excela Health Latrobe Fam-

ily Medicine Residency Program, and an instructor of family medicine at

Jefferson Medical College at Thomas Jefferson University.

MARY E. JAMES, MD, is a resident at Excela Health Latrobe Family Medi-

cine Residency Program.

Address correspondence to Paul W. Ament, PharmD, Excela Health,

One Mellon Way, Latrobe, PA 15650 (email: pament@excelahealth.

org). Reprints are not available from the authors.

Author disclosure: Dr. Ament reports that he serves on the speakers’

bureaus of Pﬁzer and Merck, and that he is on the speakers’ bureau of

Sanoﬁ Aventis regarding enoxaparin (Lovenox).

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Patients with normal iron

stores are unlikely to

develop iron deﬁciency

anemia solely from proton

pump inhibitor use.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation

Evidence

rating References Comments

PPI use is associated with an increased risk

of fractures of the hip, wrist, and spine.

B 12-14 —

PPI therapy in combination with clopidogrel

(Plavix) use may increase the risk of

cardiac events.

B 18-25 Limited clinical data supporting increased cardio-

vascular risk with this combination

Product labeling change recommends avoiding

combination therapy with omeprazole (Prilosec)

and clopidogrel

PPI use increases the risk of Clostridium

difﬁcile infection.

C 6-8 Consistent ﬁndings from prospective and retrospective

studies

PPI use increases the risk of community-

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B 9 -11 Consistent ﬁndings from case-control studies

Discontinuation of PPI therapy is associated

with symptoms of gastroesophageal reﬂux

disease from gastric acid rebound.

B 15, 16 Randomized double-blind studies demonstrate

symptomatic gastric acid rebound lasting several

weeks after discontinuation of PPI therapy

PPI use is effective in preventing stress

ulcers in patients in the intensive care unit.

B 30 Practice guideline recommends stress ulcer prophylaxis

in select patients admitted to the intensive care unit

PPI = proton pump inhibitor.

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oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.

org/afpsort.xml.

Proton Pump Inhibitors

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