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DOI 10.1007/s10620-011-1589-y
ORIGINAL ARTICLE
Received: 15 November 2010 / Accepted: 18 January 2011 / Published online: 12 February 2011
Springer Science+Business Media, LLC 2011
Abstract
Background Proton pump inhibitors (PPIs) are widely
prescribed to treat gastrointestinal diseases. However,
concerns have been raised regarding their long-term use.
Gastric acid suppression may decrease iron absorption, and
it remains uncertain whether iron-deficiency anemia may
result from chronic PPI therapy.
Aims We aimed to explore the association between
chronic PPI use and iron-deficiency anemia.
Methods We conducted a retrospective cohort study of
adult patients in an academic outpatient setting who
received PPI therapy for at least 1 year between January 1,
2004 and January 1, 2006. We compared the change in
This work originated from the Department of Medicine, Michigan
State University.
E. Sarzynski (&) H. Laird-Fick
Department of Medicine, Michigan State University,
B-301 Clinical Center, East Lansing, MI 48824, USA
e-mail: erin.sarzynski@hc.msu.edu
H. Laird-Fick
e-mail: heather.lairdfick@hc.msu.edu
C. Puttarajappa
Department of Medicine, Renal-Electrolyte Division,
University of Pittsburgh, A919 Scaife Hall, 3550 Terrace Street,
Pittsburgh, PA 15261, USA
e-mail: drchethan81@gmail.com
Y. Xie
Center for Statistical Training and Consulting, Michigan State
University, 178 Giltner Hall, East Lansing, MI 48824, USA
e-mail: yxie@msu.edu
M. Grover
Division of Gastroenterology and Hepatology, Mayo Clinic,
200 First Street SW, Rochester, MN 55905, USA
e-mail: grover.madhusudan@mayo.edu
Introduction
Since their advent in the late 1980s, proton pump inhibitors
(PPIs) have become widely used for the treatment of many
upper gastrointestinal disorders, including gastroesophageal
reflux disease, peptic ulcer disease and stress ulcer prophylaxis. In 2009 in the United States alone, 119.4 million prescriptions for PPIs were dispensed totaling sales of $13.6
billion [1, 2]. Overutilization of PPIs is well documented [3].
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2350
Methods
Study Design
We conducted a retrospective cohort study to determine
whether chronic PPI use is associated with development of
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iron deficiency anemia. We used the Michigan State University Health Team electronic medical record database to
identify study participants. This database is a computerized
medical record system of approximately 150,000 patients
cared for by general medicine, family medicine, pediatrics,
surgery, obstetrics and gynecology, and subspecialty clinics. The database is representative of the urban population
of Lansing, Michigan and surrounding suburban areas. The
electronic medical record contains patient demographics,
current and previous diagnoses classified by ICD-9 codes,
current and previous medications and dosages, hospitalization records, and sub-specialty consultation records. Our
study was approved by the Michigan State University
Institutional Review Board.
Study Cohort
We identified 1,700 adult (age 1880) patients who were
initiated on PPIs (including esomeprazole, lansoprazole,
omeprazole, pantoprazole, and rabeprazole) between January 1, 2004 and December 31, 2006 in one of our primary
care practices. Of these subjects, 1,140 had at least one
hemoglobin value documented in their chart. Subjects were
excluded because of co-morbidities known to cause anemia
as identified by ICD-9 codes in their problems lists (i.e.,
gastrointestinal bleeding, dysfunctional uterine bleeding,
chronic kidney disease, inherited hemoglobinopathies,
chronic anticoagulation with coumadin or low-molecular
weight heparin, hemolysis, vitamin B12 or folate deficiency,
pregnancy, or active cancer) (n = 261) or lack of hematologic studies drawn prior to and 1 year after initiation of PPI
therapy (n = 781). Some patients met several exclusion
criteria. The remaining 98 subjects (8.6%) composed the
eligible study cohort (Fig. 1). Using a random number
generator, age and sex-matched controls were identified
using the same inclusion and exclusion criteria.
Data Extraction
The primary exposure of interest was PPI use for more than
1 year. Duration and dose of medication, as well as changes in medications, were tabulated. Hematologic indices
(including hemoglobin, hematocrit, red blood cell count,
mean corpuscular volume, white blood cell count, and
platelet count) were recorded prior to and after at least
1 year of PPI therapy. Additional laboratory data, including ferritin and iron studies, were recorded if available. If
multiple hematologic indices were available, we recorded
those values in closest proximity to the first year of PPI
therapy. Dates of laboratory results were recorded in order
to assess the length of time between collection and initiation of PPI therapy.
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MSU HealthTeam
150,000 active patients
Inclusion Criteria
18-80 years old
PPI therapy 1 year
1 CBC documented in EMR
PPI users
Controls
P value
0.42
30.47 (7.40)
0.30
29.45 (6.09)
Gender, n (%)
1,140 Subjects
Exclusion Criteria
Alternate reason for anemia (261)
Missing hematologic data (781)
Female
57 (58.16)
57 (58.16)
Male
41 (41.84)
41 (41.84)
14.30 (1.33)
14.29 (1.13)
0.96
42.04 (3.64)
41.83 (2.87)
0.23
90.03 (4.64)
89.24 (4.69)
0.66
41 (41.84)
37 (37.76)
33 (33.67)
22 (22.45)
6 (6.12)
34 (34.69)
3 (3.06)
2 (2.04)
Documented colonoscopy
40 (40.82)
25 (25.51)
0.03
4 (4.08)
0 (0.00)
0.12
1.00
PUD
98 Subjects
Fig. 1 Flow chart of study design
Statistical Analysis
We performed descriptive statistical analyses on baseline
demographics, as well as a list of potential confounders
that could bias any association between PPI use and anemia, including body mass index, medications (e.g., aspirin,
clopidogrel, non-steroidal anti-inflammatory drugs, and
oral iron replacement therapy), surgery during PPI therapy,
H. pylori status, rates of peptic ulcer disease (PUD),
hematuria, epistaxis, and results of endoscopic studies
(esophagogastroduodenoscopy and colonoscopy). A general linear model was used to compare the change in
hematologic indices from baseline between PPI users and
controls, with and without adjustment for identified confounders (variables with P B 0.05). Matched paired t-test
was used to compare the change in hematologic indices.
Univariate and multivariate logistic regression was used to
calculate the odds ratios (ORs) and 95% confidence intervals for changes in hematologic indices between PPI-users
and matched controls. Data analysis was implemented
using Statistical Analysis Software (SAS) version 9.2.
Results
There were 98 subjects who met inclusion criteria and 98
controls. Baseline hematologic indices and medication use
were similar for both groups (Table 1). Only one PPI-user
and two controls had serial ferritin levels; only one PPIuser and two controls had serial iron studies documented in
their charts, and therefore these data are not reported. Rates
1.00
0.67
0.11
0.50
\0.01
Epistaxis
0 (0.00)
0 (0.00)
Hematuria
3 (3.06)
0 (0.00)
0.25
H. pylori
2 (2.04)
0 (0.00)
0.50
History of cancer
14 (14.29)
5 (5.10)
0.05
0 (0.00)
1 (1.02)
1.00
Iron supplementation
3 (3.06)
2 (2.04)
1.00
BMI body mass index, Hgb hemoglobin, HCT hematocrit, MCV mean
corpuscular volume, NSAID non-steroidal anti-inflammatory drug,
ASA aspirin, EGD esophagogastroduodenoscopy, PUD peptic ulcer
disease
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Percentage
Omeprazole
34.7
Esomeprazole
32.7
Lansoprazole
15.3
Pantoprazole
13.3
Rabeprazole
4.1
Discussion
1
0.8
PPI-users
Controls
0.56
0.6
0.4
0.23
0.2
0.2
0
-0.2
-0.19
-0.4
-0.6
-1
-0.49
-0.63
-0.8
Hgb (g/dL)
HCT (%)
MCV (fL)
Hematologic Index
Fig. 2 Change in hematologic indices ( SEM) in patients before
and after initiating proton pump inhibitor (PPI) therapy, compared
with patients not receiving PPI therapy. SEM standard error of mean
did not (Fig. 2). Compared with controls, PPI users had
significant decreases in mean hemoglobin and hematocrit
(P \ 0.01 for both), and this effect persisted after controlling for confounders (Fig. 2).
Among PPI-users, 21 subjects (21.4%) had a decrease in
their hemoglobin [1.0 g/dL while on therapy for more
than a year (Table 3). The adjusted odds ratio (OR) for a
1.0 g/dl decrease was 5.03 (95% CI, 1.7114.78). Similarly, the adjusted odds ratio of decreasing hematocrit by
Table 3 Odds ratios of decreasing hematologic indices after 1 year of proton pump inhibitor (PPI) therapy, before and after adjusting for
confounders (rates of EGD, colonoscopy, and remote cancer status)
Hematologic index
Group
OR (95% CI)
Unadjusted data
OR (95% CI)
Adjusted data
PPI-users
21
5.07 (1.8314.08)
\0.01
5.03 (1.7114.78)
\0.01
Controls
5
5.29 (1.7216.27)
\0.01
5.46 (1.6717.85)
\0.01
PPI-users
18
Controls
PPI-users
27
Controls
13
2.49 (1.205.17)
0.02
1.77 (0.774.05)
0.18
Hgb hemoglobin, HCT hematocrit, MCV mean corpuscular volume, EGD esophagogastroduodenoscopy, OR odds ratio, CI confidence interval
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