Download Are medication restrictions before FOBT necessary?

Clinical Review
Are medication restrictions before FOBT necessary?
Practical advice based on a systematic review of the literature
Gerald Konrad
MD MSc CCFP Alan Katz
MB ChB MSc CCFP FCFP
Abstract
Objective To determine whether medication interventions enhance the sensitivity and specificity of guaiac-based
fecal occult blood testing (FOBT) when screening for colorectal cancer (CRC).
Data sources We searched PubMed-MEDLINE, CINAHL, and the Cochrane databases using the MeSH headings
occult blood, feces/analysis, and guaiac/analysis, linking them to variations of anticoagulants, heparin, warfarin, iron,
aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), clopidogrel, cyclooxygenase-2 inhibitors, and ascorbic acid
(vitamin C). Study selections were limited to English studies involving humans.
Study selection All resulting titles and abstracts were reviewed for studies that included manipulation of
medications associated with guaiac-based FOBT. If the study’s relevance was unclear from the abstract, the full
article was reviewed. The search resulted in 31 pertinent studies.
Synthesis No studies addressed the effects of medication interventions on the sensitivity or specificity of FOBT screening.
Randomized controlled trials, however, showed no increase in the rate of positive results among those taking NSAIDs.
The literature is mixed regarding the effect of NSAIDs on the positive predictive value of a positive FOBT result, although
no change in positive predictive value has been shown for warfarin. Iron will not affect FOBT results in vivo. Ascorbic acid
might inhibit positive FOBT results both in vitro and in vivo, but it has not been studied in screening populations.
Conclusion Studies evaluating the effects of medication intervention on FOBT screening for CRC are limited by
their lower quality and because they do not address sensitivity and specificity. Available evidence, however, does
not suggest a benefit from withholding NSAIDs, anticoagulant medications, or iron during the screening period.
These recommendations should be abandoned in order to maximize
KEY POINTS Fecal occult blood testing
adherence to screening. Positive FOBT results obtained among patients
(FOBT) remains an effective screening
taking these medications deserve full evaluation for CRC. Until further
option for colorectal cancer. However, it
studies clarify the effect of ascorbic acid on FOBT screening, withholding
is frequently limited by lack of patient
this medication before testing seems prudent.
F
ecal occult blood testing (FOBT) remains an appropriate screening option for colorectal cancer (CRC).1,2 However, FOBT is limited
by a lack of patient adherence. A consistently reported barrier is the
lack of physician endorsement for screening.3-9 Other barriers include
embarrassment or unpleasantness (the “yuk” factor), anxiety regarding
results, lack of symptoms or health concerns, and practical issues such as
inconvenience and cost.10 Dietary restrictions11-13 and medication restrictions13,14 have also been implicated as barriers to screening.
The most recently reported survey data, published in 2007, showed
that only 30.2% of eligible Canadians were adherent to CRC screening
guidelines.15 Clearly, addressing barriers to screening is a worthy task for
physicians who endorse screening for CRC. A recent systematic review
suggested that dietary restrictions were unnecessary when performing
FOBT,16 a position endorsed by Cancer Care Ontario.17 The Ontario panel
also advised against restricting medications other than ascorbic acid before
FOBT screening. A systematic review of bleeding risks among patients
This article has been peer reviewed.
Cet article a fait l’objet d’une révision par des pairs.
Can Fam Physician 2012;58:939-48
adherence. Among the barriers is patients’
willingness to follow recommended
medication interventions. This systematic
review explores the evidence regarding
medication restrictions before screening
with guaiac-based FOBT. Most of the
literature fails to reveal significant
differences in the rates of positive
test results or positive predictive value
among patients taking nonsteroidal
anti-inflammatory drugs, anticoagulant
medications, or iron supplements.
Ascorbic acid can theoretically inhibit
positive guaiac reactions, so until further
research clarifies its effect on sensitivity,
withholding high-dose ascorbic acid
supplementation during FOBT screening
seems to be a reasonable recommendation.
This article is eligible for Mainpro-M1 credits.
To earn credits, go to www.cfp.ca and click on the Mainpro link.
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La traduction en français de cet article se trouve à www.cfp.ca dans la
table des matières du numéro de septembre 2012 à la page e480.
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Clinical Review | Are medication restrictions before FOBT necessary?
taking anticoagulant or antiplatelet medications concluded that these medications did not diminish the positive predictive value (PPV) of the FOBT.18
Manufacturers of guaiac-based FOBTs available in
Canada continue to recommend medication restrictions
before testing. The patient instructions for Hemoccult II
and Hemoccult II SENSA recommend avoiding nonsteroidal anti-inflammatory drugs (NSAIDs) for 7 days, but
allow up to 1 adult acetylsalicylic acid (ASA) tablet daily.
Both recommend avoiding ascorbic acid supplements
and citrus juices.19,20 The insert for Tri-Slide suggests consideration of avoiding gastric irritants such as NSAIDs and
anticoagulant medications after discussion with the physician. Avoidance of ascorbic acid is also recommended.21
ColoScreen and Hema-Screen recommend continuing
usual medications with the exception of ascorbic acid.22,23
Despite a lack of recommendations from manufacturers, 16% of primary care physicians,24 32% of gastroenterologists,25 and 10% of internal medicine residents26 have
reported discontinuing anticoagulant medications before
FOBT. Forty-seven percent of gastroenterologists have
reported withholding iron supplements.25
This systematic review explores the evidence for
medication restrictions before CRC screening with
guaiac-based FOBT.
Data sources
PubMed-MEDLINE, the Cochrane databases, and
CINAHL were searched using the key words and MeSH
terms occult blood, feces/analysis, and guaiac/analysis.
These terms were linked to variations of anticoagulants,
heparin, warfarin, clopidogrel, iron, aspirin, NSAIDs,
cyclooxygenase-2 inhibitors, and ascorbic acid (vitamin
C). The search was limited to English studies involving
humans. References from relevant articles were also
explored for further resources.
Study selection
Our PubMed search revealed 417 articles. Cochrane and
CINAHL database searches revealed no additional studies. All titles and abstracts were reviewed for studies
that included the manipulation of medications before or
during guaiac-based FOBT. If the study’s relevance was
unclear from the abstract, the full article was reviewed.
The resulting 31 pertinent studies are summarized in
Tables 1 to 3.27-57
Synthesis
Nonsteroidal anti-inflammatory drugs
There is a common assumption that FOBT screening for
patients taking NSAIDs or anticoagulant medications
940 Canadian Family Physician • Le Médecin de famille canadien
is adversely affected by the increased predisposition to
upper gastrointestinal (GI) bleeding and by increased
false-positive rates among these patients. If so, this
reduction in specificity would result in unnecessary
follow-up evaluations. There might also be a danger if
one assumes that a positive FOBT from a patient taking
these medications has a reduced PPV. Attributing a positive result to a medication effect could mistakenly result
in neglecting further necessary evaluations.
Unfortunately, there are no studies that evaluate the
effects of NSAIDs and anticoagulant medications on the
sensitivity and specificity of guaiac-based FOBT screening. Such studies would necessitate evaluating subjects
with negative FOBT results for lower GI pathology. Most
studies look at either the rate of positive FOBT results or
the PPV of a positive result.
Only 2 randomized controlled trials compared rates
of positive guaiac-based FOBT results between users
of NSAIDs and control subjects, with no significant difference found between groups.27,28 Several randomized
trials compared rates of positive FOBT results between
ASA and ibuprofen,29 between various formulations of
ibuprofen,30 and among ASA, warfarin, or both in combination.31 None showed differences between groups,
but there were no control groups.
Cross-sectional studies reported low rates of positive
Hemoccult results (0% to 5.5%) among patients taking
anti-inflammatory agents.32,33 The PPV for CRC or large
adenomas of a positive FOBT result, however, was 25%
in a group of rheumatoid disease clinic patients using
NSAIDs,32 which compares favourably with the PPV for
positive Hemoccult screening of up to 17.9% in the general population reported in a large Minnesota trial. 58
This substantial PPV makes it clear that a positive result
should not be attributed solely to NSAID use.
Two cohort studies looking at the effects of NSAIDs on
FOBT showed inconsistent results. A non-randomized
prospective crossover study of medical patients taking
either no ASA, 81 or 325 mg of ASA daily, or warfarin
showed no difference in the rates of positive Hemoccult
II results between the control period and different treatments.34 Quantified fecal blood in controls increased
slightly when they switched to 325 mg of ASA daily
(P = .02). This difference, however, disappeared when
controls were compared with all patients taking ASA in
the study (P = .14). Conversely, in a cohort study of subjects screened with Hemoccult II, NSAID users had a
significantly higher rate of positive results at 27% compared with 4% for those not taking NSAIDs (P < .01).35
These results, however, might not be valid because they
relied on self-reported adherence to the instructions to
withhold NSAIDs during the screening period. Only 26
of 1797 subjects admitting to continuing NSAIDs during
the testing. Neither study reported follow-up of positive
FOBTs, so PPV was undetermined.
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Table 1. Studies examining FOBT and NSAIDs and anticoagulant medications
Study
Study Population
Study Groups
Design
Results
Comments
Fries and
Britton
(1973)27
Rheumatoid
arthritis (N = 27)
(mean age 56.3 y)
Fenoprofen (1.4-2.4 g/d) for 6 wk
High-dose ASA (4-6 g/d) for 6 wk
Placebo for 3 wk
RCT,
double-blind
crossover
with
temporal
controls
Unspecified guaiacbased FOBT; true
positives not
determined
Greenberg
et al
(1999)28
Healthy house
officer volunteers
(mean age 29.8 y)
ASA (30, 81, or 325 mg/d)
for 30 d (n = 10 in each group)
Placebo for 30 d (n = 10)
RCT, double
blind
Brooks et al Rheumatoid
(1970a)29
arthritis
(mean age 51.5 y)
Ibuprofen (600 mg/d) for 4 wk
(n = 41)
ASA (3.6 g/d) for 4 wk (n = 45)
U-24568 (600 mg/d) for 4 wk
(n = 41)
Ibuprofen (900 mg/d) for 4 wk
(n = 60)
ASA (3.6 g/d) for 4 wk (n = 62)
Randomized,
double blind
Placebo: 15.4% positive
FOBT results
ASA: 17.1% positive
results
Fenoprofen: 20% positive
results
No significant difference
between groups
0 positive results using
Hemoccult II or
Hemoccult SENSA, in all
groups
Total positive FOBT
results not clarified
No significant differences
between groups
No control group;
unspecified guaiacbased FOBT
Ibuprofen tablet (800 mg/d)
for 7 d (n = 18)
Ibuprofen fast-melting tablets
(800 mg/d) for 7 d (n = 18)
ASA (160 mg/d) for 3 mo (n = 94)
Warfarin (INR 2.8-4.2) for 3 mo
(n = 84)
ASA (75 mg/d) plus warfarin
(INR 2.0-2.5) for 3 mo (n = 89)
Twosequence
crossover
Total positive FOBT
results not clarified
No significant differences
between groups
0 positive FOBT results
ASA: 8.5% positive
hemo FEC results
Warfarin: 7.1% positive
results
ASA with warfarin:
5.6% positive results
No significant differences
between groups
Anti-inflammatory: 5.5%
positive results using
Hemoccult
No control group;
14 of 19 positive
results retested
(3 remained positive,
2 with diverticulosis
and 1 with normal
findings on
colonoscopy)
No control group;
all positive results
evaluated
(2 colonic neoplasms [PPV 25%])
Brooks et al Rheumatoid
(1970b)29
arthritis
(mean age 53.1 y)
Zuin et al
(2000)30
Healthy volunteers
(mean age 27.7 y)
Hurlen et al AMI survivors
(2006)31
(mean age 60.9 y)
Randomized,
double blind
Randomized
Bahrt et al
(1984)32
Rheumatoid disease Unspecified NSAID, salicylate,
clinic patients
or steroid use (n = 145)
(age not reported)
Crosssectional
Norfleet
(1983)33
Healthy volunteers
(N = 27)
Control period for 3 d
ASA (1300 mg/d) for 7 d
Greenberg
et al
(1996)34
Medical, cardiac,
and anticoagulation
clinic patients
(mean age
approximately 60 y)
Control for 1 wk, then ASA
325 mg/d for 8 wk (n = 25)
ASA 325 mg/d for 1 wk, then
ASA 81 mg/d for 8 wk (n = 46)
ASA 81 mg/d for 1 wk, then
ASA 325 mg/d for 8 wk (n = 4)
Warfarin (unspecified INR) for
4-6 wk (n = 25)
Temporally
controlled
trial
Crosssectional
with
crossover
Niv (1987)35 Israeli screening
population taking
NSAIDs
(aged > 40 y)
Self-reported discontinuing
NSAIDs during FOBT (n = 1771)
Self-reported NSAID use during
FOBT (n = 26)
Cohort
0 positive Hemoccult II
test results during both
test periods
Control week: 0 positive
results using Hemoccult II
ASA 81 mg/d: 14%
positive results
ASA 325 mg/d: 4%
positive results
Warfarin: 12% positive
results
No significant differences
between groups
NSAID users: 27%
positive results using
Hemoccult II
Nonusers: 4% positive
results (P < .01)
No control group;
unspecified guaiacbased FOBT
No control group;
unspecified FOBT
Blood loss
quantified with
HemoQuant; no
difference between
groups
Relied on
self-reporting of
compliance with
FOBT instructions
Continued on page 942
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Clinical Review | Are medication restrictions before FOBT necessary?
Table 1 continued from page 941
Pye et al
(1987)36
Asymptomatic
subjects with
positive screening
results on
Hemoccult or
Feca-EIA
(aged 50-74 y)
NSAID use according to
self-report (n = 50)
No NSAID use according to
self-report (n = 405)
Crosssectional
Kahi and
Imperiale
(2004)37
VA patients referred
for colonoscopy
with positive
Hemoccult II FOBT
results (N = 193)
(mean age 66 y)
ASA or NSAID use according
to self-report and record review
(n = 135)
No ASA or NSAID use according
to self-report and record review
(n = 58)
Crosssectional
Self reported ASA, NSAID,
or anticoagulant use (n = 301)
No ASA, NSAID, or anticoagulant
use (n = 308)
Crosssectional
ASA, NSAID, or
anticoagulant users: PPV
47.5% for colorectal
neoplasia
Nonusers:
PPV 56.5% (P = .012)
No medications according
to review of pharmacy
profile (n = 518)
ASA (n = 264)
NSAIDs (n = 218)
Warfarin (n = 85)
Clopidogrel (n = 41)
Crosssectional
Temporal control without
ASA, then ASA (600 mg/d)
for 3 d (n = 50)
Age-matched subjects with
temporal control, then ASA
(600 mg/d) for 3 d (n = 50)
Temporally
controlled
trial with
control
cohort
component
Controls: PPV 30.5%
for advanced neoplasia
ASA users:
PPV 20.5% (P < .01)
NSAID users:
PPV 19.7% (P < .01)
Warfarin users:
PPV 20% (P = .05)
Clopidogrel users:
PPV 7.3% (P < .01)
CRC patients during
temporal control:
70% positive
Hemoccult II results
CRC patients taking ASA:
82% positive results (P = .07)
Age-matched cohort:
single subject with
positive Hemoccult II
results before and while
taking ASA
15% positive results using
Hemoccult II
PPV 19% for CRC and
adenomas among
79 subjects evaluated
further (57 of 67 with
≥ 3 of 6 positive samples;
22 of 61 with < 3 of 6
positive samples)
Clarke et al Scottish patients
referred for
(2006)38
colonoscopy with
positive Hema
Screen (guaiac)
FOBT results
(aged 50-69 y)
Sawhney et VA patients referred
al (2010)39 for colonoscopy
with positive
Hemoccult II results
(mean age
approximately 68 y)
Doran and
Hardcastle
(1982)40
CRC patients and
age-matched
controls
Dicumarol, unspecified dose
Kewenter et Patients taking
al (1984)41 dicumarol (N = 849)
(mean age 67 y)
Crosssectional
4.2% total positive
Hemoccult or Feca-EIA
results from screening
population of 10 931
All positive results
evaluated with
colonoscopy
NSAID users: PPV 20%
for neoplasia
Nonusers: PPV 32%
No significant difference
(P = .1)
ASA or NSAID users: PPV
21% for “abnormality”
Nonusers: PPV 19%
No significant differences
between groups
Hemoccult and
Feca-EIA
(immunologic test)
results not reported
separately
No correlation
between ASA dose
and colonoscopic
pathology; not a
screening
population; large
polyps and CRC
were not reported
separately from
other colonic
pathology
PPV for CRC with
no significant
differences between
groups (P = .7);
anticoagulants
made up only 7.7%
of prescriptions
Not a screening
population;
included positive
FOBT results for
evaluation of
symptoms
51
Cr-RBC labeling in
CRC patients
(n = 25) showed no
correlation between
blood volume and
ASA use or tumour
location
No correlation
between positive
Hemoccult result
and anticoagulation
index
Continued on page 943
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Table 1 continued from page 942
Jaffin et al
(1987)42
Patients taking
warfarin, heparin,
or both (n = 256)
and age- and
diagnosis-matched
inpatient controls
(n = 164)
(mean age 64 y)
Kershenbaum Israeli CRC
et al (2010)43 screening program
participants
(aged 50-74 y)
Bini et al
(2005)44
Anticoagulant users
(Hemoccult completed in n = 175)
Age- and diagnosis-matched
controls (Hemoccult completed
in n = 74)
Controlled
crosssectional
Anticoagulant users:
12% positive results
using Hemoccult
Controls: 3% positive
results (P < .01)
Warfarin treatment
(n = 1356 FOBTs)
No antithrombotic or
anticoagulant use
(n = 64 088 FOBTs)
Cohort
Warfarin users: 7.7%
positive results using
Hemoccult SENSA
Nonusers: 3.6% positive
results (P < .01)
Warfarin users: PPV
19.8% for CRC or
clinically significant
adenoma in 81.9% of
positive FOBT results
Nonusers: PPV 27.7% in
74.7% of positive FOBT
results
No significant difference
in PPV between groups
Warfarin users:
PPV 27.2% for CRC
or adenomas
Nonusers: PPV 24.3%
for CRC or adenomas
No significant difference
in PPV between groups
(P = .58)
Warfarin users: PPV
16.1% for large polyps
or tumours
Nonusers: PPV 11.4%
No significant difference
in PPV between groups
after adjusting for age
and sex
Patients referred for Warfarin users (n = 210)
Age- and sex-matched controls
colonoscopy to
(n = 210)
evaluate positive
Hemoccult II results
(mean age 72 y)
Iles-Shih et Patients referred for Warfarin users (n = 372)
al (2010)45 colonoscopy to
Warfarin nonusers (n = 9265)
evaluate positive
screening results
using Hemoccult II
(aged < 50 to > 80
y)
Controlled,
crosssectional
Crosssectional
No correlation with
anticoagulation
index; evaluation of
16 of 21 positive
test results among
anticoagulant users
(2 with CRC [PPV
12.5%]); no
evaluation of
positive test results
in control group
Not a screening
population;
included positive
FOBT results
obtained for
evaluation of
symptoms
INRs not reported
51
Cr-RBC—chromium-51 red blood cell, AMI—acute myocardial infarction, ASA—acetylsalicylic acid, CRC—colorectal cancer, FOBT—fecal occult blood
testing, INR—international normalized ratio, NSAID—nonsteroidal anti-inflammatory drug, PPV—positive predictive value, RCT—randomized controlled
trial, VA—Veterans Affairs.
Several cross-sectional studies examined patients
with positive FOBT results to determine if the PPV was
affected by NSAIDs. Two showed a sizeable PPV of
around 20% among NSAID users with no difference from
controls.36,37 Two others, however, noted lower PPVs
among NSAID users than controls.38,39 However, as in
the previous studies, PPVs among the NSAID users were
substantial enough to justify further evaluation.
One study evaluated the effect of ASA on FOBT of
patients with known CRC.40 It found that 600 mg of ASA
given daily for 3 days did not increase the rate of positive Hemoccult II results in this group. Chromium-51 red
blood cell labeling confirmed no increase in quantified
fecal blood loss when taking ASA.
Anticoagulant medications
There is little literature exploring the effects of anticoagulant medications on FOBT results. A single
cross-sectional study of 849 patients taking dicumarol
revealed a rate of positive Hemoccult II results of 15%.41
Further evaluation of most of these patients showed a
PPV of 19% for CRC and adenomas.
Studies comparing the rates of positive FOBT results
for subjects taking anticoagulant medications with the
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Clinical Review | Are medication restrictions before FOBT necessary?
Table 2. Studies examining FOBT and iron
Study
Study Population
Study Groups
Design
Results
Comments
Control periods:
Temporally
1-wk control period
followed by 1 wk taking controlled trial, 0% positive Hemoccult results
300 mg of ferrous sulfate in vitro testing Ferrous sulfate:
65% positive Hemoccult results
3 times daily and 1 wk
Ferrous gluconate:
of 300 mg of ferrous
50% positive Hemoccult results
gluconate 3 times daily
In vitro testing: positive
(N = 10)
Hemoccult results with ferrous
sulfate 275 mg/L of sterile water
and ferrous gluconate 310 mg/L
Kulbaski et Medical students Control period followed Temporally
0% positive Hemoccult results for
al (1989)47
by 3 d taking 325 mg of controlled trial, control period and test period
in vitro testing In vitro testing: positive
ferrous sulfate 3 times
Hemoccult results with ferrous
daily (N = 4)
sulfate 324 mg/10 mL water
McDonnell Healthy
0% positive Hemoccult II results
Temporally
Control period for 3 d
et al
controlled trial, for control period and test period
followed by 7 d taking
volunteers
(1989)48
300 mg of ferrous sulfate in vitro testing In vitro testing: positive
(aged 22-35 y)
Hemoccult II results with ferrous
3 times daily (N = 25)
sulfate 0.3 mg/mL at pH < 6.0;
positive Hemoccult II results with
ferric chloride 0.1 mg/mL
(pH = 2.75)
Lifton and Healthy male
Kreiser
hospital
(1982)46
employees (aged
20-27 y)
Ahlquist et Healthy,
al (1985)49 asymptomatic
volunteers and
patients with GI
symptoms or
abnormal
laboratory test
results (aged
15-88 y, mean
age 59 y)
Cross-sectional
Volunteers: no difference in
Hemoccult II results between users
and nonusers of iron supplements
GI symptoms, taking iron: 17.4%
positive Hemoccult II results
GI symptoms, not taking iron:
9.8% positive Hemoccult II results
(P = .04)
Morris et
al (1976)50
Cohort
0% false-positive Hemoccult
results in patients taking iron
16% false-positive Hemoccult
results in patients not taking
iron (P = .02)
28% false-negative Hemoccult
results in patients taking iron
47% false-negative Hemoccult
results in patients not taking iron
(P = .24)
All Hemoccult II results before
and after iron supplementation
were negative (single equivocal
trace result)
Healthy volunteers
self-reporting use
or nonuse of iron
supplements (n = 106)
Symptomatic patients
self-reporting iron
supplementation (n = 86)
Symptomatic patients
self-reporting no iron
supplementation
(n = 577)
US veterans with Stool samples from
patients taking
known GI
unreported dose of
pathology or
iron (n = 55 samples)
bleeding
Stool samples from
patients not taking
iron (n = 185 samples)
Laine et al Healthy
volunteers
(1988)51
(aged 23-50 y)
Control testing followed
by 325 mg of ferrous
sulfate 3 times daily for
14 d (n = 14)
Control testing followed
by 325 mg of ferrous
sulfate 3 times daily for
7 d (n = 13)
Temporally
controlled trial
×2
Negative Hemoccult
II results for ferrous
sulfate 0.3 mg/mL
when pH titrated to
≥ 6.0
Iron use not defined;
specific Hemoccult II
results for volunteers
not reported; true
positives not
reported
differentially for iron
use and nonuse;
control group not
compared with
symptomatic group
False positives
determined by
51
Cr-RBC labeling,
≤ 2 mg Hb/g stool;
false negatives
determined by
51
Cr-RBC labeling,
> 2 mg Hb/g stool
Stool blood
quantified with
HemoQuant
unchanged with
iron; upper GI
endoscopy showed
increased erythema,
subepithelial
hemorrhage, and
erosions following
iron for 14 d in
12 of 14 subjects
Continued on page 945
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Are medication restrictions before FOBT necessary? | Clinical Review
Table 2 continued from page 944
Eliakim et Patients with
al (1988)52 anemia treated
with iron (aged
18-65 y)
Coles and
Starnes
(1991)53
Healthy
volunteers
(aged 27-42 y)
Anderson
et al
(1990)54
Healthy
volunteers
(aged 19-40 y)
Patients treated > 2 wk with 500 mg of
ferrous calcium citrate
3 times daily (n = 13),
160 mg of ferrous sulfate
daily (n = 6), or 308 mg
of ferrous fumarate
twice daily (N = 6)
7-d control periods
followed by 324 mg of
ferrous sulfate 3 times
daily for 7 d and ferrous
gluconate 3 times daily
for 7 d (N = 14)
Placebo for 2 wk, then
600 mg of ferrous
gluconate twice daily,
300 mg every night for
2 wk (n = 25)
Ferrous gluconate
600 mg twice daily,
300 mg every night for
2 wk, then placebo for
2 wk (n = 25)
Placebo for 2 wk, then
325 mg of ferrous sulfate
3 times daily for 2 wk
(n = 25)
325 mg of ferrous sulfate
3 times daily for 2 wk,
then placebo for 2 wk
(n = 25)
Cross-sectional
All Hemoccult II results negative
Temporally
controlled trial
All Hemoccult results during
Stool blood
control and treatment weeks were quantified with
negative
HemoQuant;
unchanged with iron
supplementation
Randomized,
crossover
Ferrous gluconate: All Hemoccult
II and Hemoccult SENSA results
were negative during treatment
phase; single positive Hemoccult
SENSA result during placebo phase
Ferrous gluconate: All Hemoccult
II and Hemoccult SENSA results
were negative during treatment
and placebo phases
78 subjects
completed study;
4 subjects completed
only treatment phase
Cr-RBC—chromium-51 red blood cell, FOBT—fecal occult blood testing, GI—gastrointestinal, Hb—hemoglobin.
51
Table 3. Studies examining FOBT and ascorbic acid
Study
Study Population
Study Groups
Design
Results
Comments
Jaffe et al
(1975)55
Case report
In vitro stool testing
Iron deficiency
anemia patient
taking ascorbic acid
(500 mg 4 times daily)
Case report, in
vitro testing
Unreported blood
concentration in
stool
Jaffe and
Zierdt
(1979)56
Volunteer subjects (no Swallowed 20 mL
Temporally
further information
of autologous blood
controlled trial
given)
followed by increasing
doses of ascorbic acid
(N = 4)
Negative Hemoccult results
reverted to positive when
ascorbic acid was discontinued
Ascorbic acid level of
15.4 mg/dL (0.15 mg/g
wet-weight stool) completely
inhibited Hemoccult reaction
for lysed blood in stool
Hemoccult results initially
positive in all subjects
Required 1500 mg/d of
ascorbic acid for complete
inhibition of Hemoccult
reaction
Zierdt and
Zierdt
(1985)57
Hospitalized patients
requiring FOBT
Patients taking
ascorbic acid
(1 patient taking
1 g/d, other doses not
reported) (N = 4)
Cross-sectional All patients had negative
Hemoccult and ColoScreen
results, but 2 had positive
benzidine test results
(including patient taking
1 g/d of ascorbic acid)
Incomplete
inhibition at lower
doses
True and false
positives not
reported
FOBT—fecal occult blood testing.
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Le Médecin de famille canadien 945
Clinical Review | Are medication restrictions before FOBT necessary?
rates for controls showed mixed results. One study
showed no difference in the rate of positive FOBT
results between warfarin users and controls, nor was
there a difference in quantified fecal blood. 34 Two
others showed an increased rate of positive FOBT
results among those taking warfarin or heparin compared with controls.42,43 The PPV for CRC or adenomas
among users was 12.5% in the first study, but the PPV
for controls was not reported. In the second study the
PPV of 19.8% was not significantly different from that
for controls.
A single randomized trial compared rates of positive
FOBT results among survivors of myocardial infarction
who were randomized to receive warfarin, ASA, or a
combination.31 There were no significant differences in
the rates of positive results between the group receiving warfarin and those receiving ASA or ASA plus warfarin. Unfortunately, a control group was not included
in this study.
Four studies compared the PPV of a positive FOBT
result between users and nonusers of anticoagulant
medications. Three showed no statistically significant
difference in the PPV between users and nonusers.39,43,44
In the fourth, the PPV for large polyps or tumours was
higher for warfarin users at 16.1% compared with 11.4%
for nonusers (P < .01), but this difference disappeared
after adjusting for age and sex.45
Clopidogrel
Only a single study evaluated the effect of clopidogrel
on guaiac-based FOBT results. 39 This cross-sectional
study of patients who presented for colonoscopy following a positive screening FOBT result showed a PPV for
advanced neoplasia of 7.3% for those taking clopidogrel.
Among the control patients the PPV was 30.5% (P < .01).
Iron
The literature consistently shows that ferrous forms
of iron can produce positive results using standardized guaiac-based test cards such as Hemoccult in
vitro.46-48,56,59 However, it is inconsistent regarding the
effect of oral iron on in vivo testing using standardized guaiac-based cards. A single small trial reported an
increased rate of positive Hemoccult results in 10 subjects given 300 mg of ferrous sulfate 3 times daily and
300 mg of ferrous gluconate 3 times daily.46 Similarly, a
single cross-sectional study of patients with GI symptoms
compared subjects who reported taking and not taking
iron. The rate of positive Hemoccult II results was higher
among those reporting iron use.49 However, self-reported
iron use did not influence Hemoccult II results in a group
of healthy volunteers in this study. No previous or subsequent studies have been able to confirm the ability of oral
iron supplementation to cause false-positive results when
using standardized guaiac-based cards.47,48,50-54
946 Canadian Family Physician • Le Médecin de famille canadien
In the only randomized, prospective, double-blind
study reported, 78 healthy volunteers were treated with
placebo, 1500 mg of ferrous gluconate daily, or 975 mg
of ferrous sulfate daily for 2 weeks each in a crossover
trial.54 There was only 1 positive result among 326 samples tested with Hemoccult II and Hemoccult SENSA.
The lone positive sample was collected during the placebo phase of the study.
Ascorbic acid (vitamin C)
As early as 1936, Barrett noted the ability of ascorbic
acid to reverse the colour change of a positive guaiac
test. 60 The most consistent recommendation among
FOBT manufacturers regarding medication restrictions
is to withhold ascorbic acid during testing. The primary reference on which this is based is a case report in
which an anemic patient ingesting 2 g of ascorbic acid
daily was shown to have repeatedly negative Hemoccult
but positive benzidine-based FOBT results.55 Results of
Hemoccult testing became positive when ascorbic acid
was withheld. Subsequent in vitro studies showed that
complete inhibition of Hemoccult occurred with a fecal
ascorbic acid concentration of 15.4 mg/dL, although
the concentration of blood present in the stool was not
reported. Other in vitro studies have also confirmed the
ability of ascorbic acid to inhibit positive guaiac reactions.59,61,62 The 2 lone human studies involving a total of
8 subjects showed an inhibitory effect of ascorbic acid in
6 of the subjects taking 1000 to 1500 mg daily.56,57
Discussion
No research has studied the effects of NSAIDs and anticoagulant medications on the sensitivity and specificity
of guaiac-based screening FOBTs. However, randomized controlled trials showed no difference in the rate
of positive results among subjects taking these medications. Cohort studies revealed mixed findings, although
the 1 study showing an increase in positive results
depended on self-reported patient compliance with
instructions. Most cross-sectional PPV studies (5 of 7)
showed no difference in PPV among patients with positive FOBT results taking NSAIDs or anticoagulant medications. Such studies, however, are difficult to interpret
because it is unknown whether all patients with positive results agreed to colonoscopy or whether a cohort
existed that declined further investigation, a confounder
referred to as transfer bias.63 Neither study that quantified fecal blood showed a difference between users and
nonusers of these medications.
If such medications increase the risk of upper GI
bleeding, why would this not be reflected in a reduction
in specificity of guaiac-based FOBTs? This inconsistency
likely occurs because blood originating more proximally
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Are medication restrictions before FOBT necessary? | Clinical Review
looses its pseudoperoxidase activity as it transits the
gut.64 It is this pseudoperoxidase activity that allows
hemoglobin to oxidize guaiac, inducing the blue colour
change. During gut transit hemoglobin is broken down
to porphyrins, thereby losing this ability. While the specificity of guaiac-based FOBTs has not been evaluated for
patients taking NSAIDs or anticoagulant medications, a
study using immunochemical FOBTs demonstrated that
the use of NSAIDs or anticoagulant medications among
high-risk or minimally symptomatic individuals had no
adverse effect on specificity when explicitly studied.65
Most important, studies evaluating PPV in patients
taking NSAIDs and anticoagulant medications consistently show that the PPV is sufficiently high to justify further evaluation for CRC when a positive guaiac-based
FOBT result is encountered.
The effect of iron supplementation on guaiac-based
FOBTs has been laid to rest in the literature. While iron
can cause a positive guaiac response in vitro, this is not
the case in vivo.
While it is clear that as a strong reducing substance,
ascorbic acid is able to inhibit a positive guaiac reaction, it is challenging to apply these study results to
clinical situations because several unknowns remain.
It was shown that in elderly subjects taking 200 mg of
ascorbic acid daily, the average stool concentration of
ascorbic acid was 2.7 mg/dL.66 However, the degree
of absorption and, subsequently, the stool concentration of ascorbic acid when supplementing with higher
doses is unknown. Likewise, the amount of fecal occult
blood typically present in patients with early, asymptomatic CRC and the concentration of fecal ascorbic acid
required to inhibit a positive guaiac response for that
amount remain undetermined. Fortunately, daily dosing
of ascorbic acid is rarely required, so abstaining during
FOBT to prevent false-negative results seems reasonable.
Conclusion
The research evaluating the effects of medications on
guaiac-based FOBT screening is varied and of generally poor quality. The preponderance of the literature,
however, fails to reveal significant differences in the
rates of positive test results or PPV among patients taking NSAIDs, anticoagulant medications, or iron supplements. When positive screening results are encountered,
the PPV is sufficiently high to justify further workup in
these patients. Ascorbic acid can theoretically inhibit
positive guaiac reactions, although this has not been
shown in screening populations. However, until further
research clarifies its effect on sensitivity, withholding
high-dose ascorbic acid supplementation during FOBT
screening seems a prudent recommendation. Dr Konrad is Associate Professor in the Department of Family Medicine and
Unit Director for the Family Medical Centre teaching unit at the University
of Manitoba in Winnipeg. Dr Katz is Professor in the Department of Family
Medicine and the Department of Community Health Sciences at the University
of Manitoba, and Research Director for the University of Manitoba Family
Medicine Residency Training Program.
Contributors
Dr Konrad conducted the literature review and prepared and revised the manuscript. Dr Katz contributed to the concept and design of the review, revised
drafts of the manuscript, and read and approved the final manuscript.
Competing interests
None declared
Correspondence
Dr Gerald Konrad, Family Medical Centre, 500-400 Tache Ave, Winnipeg,
MB R2H 3E1; telephone 204 237-2863; fax 204 231-2648;
e-mail [email protected]
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