Catherine Dubé,
M.D., M.Sc.a; Alaa Rostom, M.D., M.Sc.a; Gabriela Lewin, M.D.b; Alexander Tsertsvadze, M.D.,
M.Sc.b; Catherine Code, M.D.c;
Margaret Sampson, M.L.I.S.b; and David Moher, Ph.D.b
The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the U.S. Agency for Healthcare Research and Quality (AHRQ) or the U.S. Department of Health and Human Services.
Address correspondence to: Alaa Rostom M.D., M.Sc (Epi), FRPC, Division of Gastroenterology, University of Calgary Medical Clinic, 3330 Hospital Drive, NW G176, Calgary, Alberta, Canada T2N 4N1, E-mail: arostom@calgary.ca
This systematic review was first published in the Annals of Internal
Medicine. Select for copyright and
source information.
Contents
Abstract
Introduction
Methods
Results
Discussion
References
Acknowledgments
Notes
Abstract
Background: Aspirin for prevention of colorectal cancer is controversial.
Purpose: To examine the benefits and harms of aspirin chemoprevention.
Data Sources: MEDLINE®, 1966 to December 2006; EMBASE, 1980
to April 2005; CENTRAL, Cochrane Collaboration's registry of clinical
trials; Cochrane Database of Systematic Reviews.
Study Selection: Two independent reviewers conducted multilevel
screening to identify randomized, controlled trials (RCTs), case-control studies, and cohort studies of aspirin chemoprophylaxis. For
harms, systematic reviews were sought.
Data Extraction: In duplicate, data were abstracted and checked
and quality was assessed.
Data Synthesis: Regular use of aspirin reduced the incidence of
colonic adenomas in RCTs (relative risk [RR], 0.82 [95% CI, 0.7 to
0.95]), case-control studies (RR, 0.87 [CI, 0.77 to 0.98]), and
cohort studies (RR, 0.72 [CI, 0.61 to 0.85]). In cohort studies,
regular use of aspirin was associated with RR reductions of 22% for
incidence of colorectal cancer. Two RCTs of low-dose aspirin failed
to show a protective effect. Data for colorectal cancer mortality
were limited. Benefits from chemoprevention were more evident
when aspirin was used at a high dose and for periods longer than
10 years. Aspirin use was associated with a dose-related increase in
incidence of gastrointestinal complications.
Limitations: Important clinical and methodological heterogeneity in
the definitions of regular use, dose, and duration of use of aspirin
necessitated careful grouping for analysis.
Conclusions: Aspirin appears to be effective at reducing the incidence
of colonic adenoma and colorectal cancer, especially if used
in high doses for more than 10 years. However, the possible harms
of such a practice require careful consideration. Further evaluation
of the cost-effectiveness of chemoprevention compared with, and
in combination with, a screening strategy is required.
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Introduction
Cancer accounts for 23% of all deaths in the United
States. It is the second leading cause of death after
heart disease, and the leading cause of death in those
younger than age 65 years. Colorectal cancer is the third
most common type of cancer in both men and women and
is the second and third leading cause of cancer-related
deaths in men and women, respectively. In 2006, an estimated
148,610 new cases of colorectal cancer occurred and
51,170 patients died of this disease.1,2
It is widely accepted that colorectal adenomatous polyps
are the precursors of the vast majority of colorectal
cancer cases, so the early detection and removal of these
lesions are presumed to reduce the incidence and mortality
of colorectal cancer. In addition, cases of cancer detected
by screening may be in the early stage and therefore curable.
Colorectal cancer has many characteristics of a disorder
that would be amenable to screening, as recently reviewed
by the U.S. Preventive Services Task Force
(USPSTF).3 Several screening methods are available, but
despite the evidence of effectiveness, widespread routine
screening of eligible individuals by any method continues
to be low in the United States.4-7
An alternative and possibly complementary strategy to
screening is prevention. This can include a variety of lifestyle
and dietary changes or, as is the focus of this review,
aspirin chemoprevention. Several basic science, population-based, and clinical trials have suggested a protective
effect of aspirin as well as nonaspirin nonsteroidal antiinflammatory
drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, against colorectal adenomas and
colorectal cancer. Since age is a major risk factor for colorectal
cancer, with approximately 90% of cases occurring
after age 50,1 aspirin may be a particularly attractive
intervention; it has documented efficacy in both the primary
and the secondary prevention of cardiovascular disease.3
However, aspirin is not risk free; it can increase the
risk for hemorrhagic stroke and gastrointestinal bleeding.3 Potential harms must be considered in light of the
possibly long period of aspirin exposure used for colorectal
cancer prevention. Furthermore, reductions in colorectal
cancer mortality with chemoprevention would have to be great enough to compete with the 21% mortality reduction
achieved with simple biannual fecal occult blood testing, or
with the 60% mortality reduction seen with flexible sigmoidoscopy
for lesions within reach of the sigmoidoscope.
Furthermore, data suggest that sigmoidoscopy followed by
colonoscopy when polyps are found could decrease colorectal
cancer incidence by up to 80%.8 The USPSTF
strongly recommends screening of men and women older
than age 50 years (grade A recommendation).9 A preventive
strategy using aspirin may still have a role as an
adjunct treatment, but the benefits would have to balance
increased risks; in addition, the cost-effectiveness of this
strategy would need to be favorable. Finally, although adherence
to colorectal cancer screening is poor, long-term
adherence to therapy with a chemopreventive agent in otherwise
healthy individuals will probably have a similar
limitation.
We conducted this systematic review to examine the
evidence on the effectiveness of aspirin for chemoprevention
of colorectal adenomas, colorectal cancer, and colorectal
cancer mortality, as well as the harms of aspirin use in
this setting.
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Methods
Data Sources
The search strategy was developed in MEDLINE® and
modified for the other databases. The search was limited to
English-language reports of human studies. Databases
searched were MEDLINE®, 1966 to December (week 4)
2006; preMEDLINE®, through 5 April 2005; EMBASE,
1980 to week 14 of 2005 (publication years 2003 to
2005); and CENTRAL and the Cochrane Library, Issue 4,
2004. Beyond these dates, we surveyed several sources to
ascertain additional potentially eligible studies. The
PubMed Cancer subset was searched for non-MEDLINE®
material. Terms were derived from the National Cancer
Institute cancer topic searches for colorectal cancer and
adenomatous polyps. A comprehensive retrieval strategy
was derived from the indexing in both MEDLINE® and
EMBASE, investigator-nominated terms, and previous reviews.10-12
A search strategy to find recent systematic reviews of
aspirin that appeared to address harm was developed and
run in MEDLINE® (2003 to December [week 4] 2006).
The Cochrane Database of Systematic Reviews and Database
of Abstracts of Reviews of Effects (DARE) (Cochrane
Library, third quarter 2004) were searched for all systematic
reviews related to aspirin, without date restrictions.
Study Selection
At each screening level, 2 members of the review team
independently selected articles for inclusion, after an initial
calibration exercise. After identifying potentially relevant
articles in the initial screening level, team members assessed
whether each article met the inclusion criteria. Conflicts
were resolved by consensus. A third level of screening was
included to discriminate the different study designs. Data
were abstracted by one reviewer and checked by a second
reviewer.
Randomized, controlled trials (RCTs); controlled clinical
trials; and observational studies (cohort and case-control
studies) of the efficacy or effectiveness of aspirin were
considered for inclusion if they fulfilled the population and
outcome criteria: Participants were at "average" risk for
colorectal cancer (that is, they had no known risk factors
for colorectal adenoma or colorectal cancer other than age);
could have a personal or family history of colorectal adenoma;
and could have a family history of sporadic colorectal
cancer ("higher risk").
Studies of familial adenomatous polyposis or hereditary
nonpolyposis colon cancer syndromes (Lynch I or II)
were excluded because these syndromes account for a small
percentage of colorectal cancer cases. Secondary prevention
studies of patients with a history of colorectal cancer were
also excluded. Included studies addressed the incidence of
colorectal adenoma or colorectal cancer and reductions in
colorectal cancer mortality or overall mortality.
We sought studies on gastrointestinal, cardiovascular,
and renal harms associated with the aspirin use by identifying
systematic reviews; we chose to identify reviews because
of the large number of reviews on harms of aspirin
already performed.
Data Extraction and Quality Assessment
Several members of the team extracted data independently
by using a computerized Web-based system (SRS
4.0; Trialstat Corp., Ottawa, Ontario, Canada). The PICOS
(participant, intervention/exposure, comparator, outcome
and study design) approach was applied for data extraction.
Predefined criteria from the USPSTF were used to
assess the quality of included systematic reviews, trials, and
observational studies, which were rated as "good," "fair," or
"poor."13 This scale relies on 4 criteria for systematic
reviews, 6 criteria for case-control studies, 7 criteria for
cohort studies, and 7 criteria for RCTs. Studies with a
"good" rating met all criteria, "fair" studies met at least
80% of criteria and had no fatal flaw, and "poor" studies
met fewer than 80% of criteria or had a fatal flaw.
Data Synthesis and Analysis
An analytic framework was used to facilitate study
grouping and subsequent data analysis in an effort to produce
logical groupings and to minimize clinical heterogeneity.
Studies were initially grouped by the disorder (that
is, colorectal adenoma vs. colorectal cancer), study design,
study sample, and medication exposure and were subsequently
subcategorized according to measures of dose effect,
duration of exposure, and secondary outcomes when
reported. Definition of such categories as "regular use" can
be found elsewhere.13
Harms data from the included systematic reviews were
summarized and presented as a qualitative systematic review.
Results were combined numerically only if clinically
and statistically appropriate. The effect measure chosen for
synthesis was the relative risk (RR). In case-control studies,
a direct estimate of the RR is not possible. The odds
ratio (OR) may be estimated, however, and when event
rates are low, as is the case here, the OR closely approximates
the RR. In what follows, we simply refer to the RR.
Heterogeneity was assessed by using the I2 statistic. Studies
were combined when the I2 value was 50% or less.14
Point estimates of the adjusted RRs and their 95% CIs
were directly abstracted from the reports of primary studies.
One source of heterogeneity may be study-to-study
variation in the method of selecting confounders to adjust
for and the final set of confounders chosen. Appendix Tables 1 and 2 summarize these
characteristics for each study. Furthermore, the USPSTF
report discusses the methodologic considerations in detail.13 Standard errors were computed by dividing the CI
width by (2 X 1.96). For 1 study that did not report CIs,15 the standard error was calculated by using a CI imputed
from 2 different estimates in the report. Quantitative
synthesis was conducted by using inverse-variance weighting
and a random-effects model.16
Role of the Funding Sources
The evidence synthesis upon which this article was
based was funded by the Centers for Disease Control and
Prevention (CDC) for the Agency for Healthcare Research
and Quality (AHRQ) and the USPSTF. Its design, conduct,
and reporting were based on specific directives from
these agencies.
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Results
Data Synthesis
Study Selection
The literature search for the comprehensive USPSTF report13 yielded 1790 potentially relevant bibliographic records addressing the use of aspirin, COX-2 inhibitors,
and other nonaspirin NSAIDs (Figure). Aspirin chemoprophylaxis of colorectal cancer was the focus of 8 case-control studies,17-24 7 cohort studies,15,25-30 and 2 RCTs,31,32 and aspirin chemoprophylaxis of colorectal adenoma was the focus of 7 case-control studies,19,33-38 4 cohort studies,26,30,39-41 and 3 RCTs31,42,43 (Appendix Table 3). A table of duplicate and companion articles is available in the AHRQ report.13 Twelve systematic reviews of the harms of aspirin3,44-53,57 were also identified.
Mortality
The Woman's Health Study (WHS)32 was a large good-quality RCT in which female health care providers who were older than age 45 years and had no history of cancer, cardiovascular disease, or other diseases were randomly assigned to either 100 mg of aspirin every other day or placebo and followed for 10 years. No statistically significant benefit of aspirin on colorectal cancer mortality
was observed. A large, 6-year, fair-quality cohort study28
of adults treated with various aspirin doses found that regular aspirin use for longer than 15 years was associated with a significant reduction in colorectal cancer mortality in both men and women, whereas shorter durations of use yielded a protective effect in men only (Table 1).
Colorectal Cancer Incidence
Table 1 summarizes the effects of regular aspirin use on colorectal cancer incidence.
RCTs
One fair-quality RCT31 and 1 good-quality RCT32 from the United States assessed the effect of low-dose
aspirin on colorectal cancer incidence. In the Physicians' Health Study,31 aspirin (325 mg every other day) for 5 years did not significantly reduce colorectal cancer incidence.
Similarly, 100 mg of aspirin every other day for 10 years in the similarly designed Women's Health Study did not show a statistically significant reduction in colorectal cancer incidence.32
Cohort Studies
The effect of regular use of aspirin on the incidence of colorectal cancer in average-risk individuals was assessed in 7 cohort studies.15,25-27,29,30,54 One of these30 is a followup to a previous study.54 One poor-quality study was excluded from the pooled analysis because of its incomplete data presentation.15 Four of the remaining 5 studies were conducted in the United States,25-27,54 while the other study was conducted in Denmark.29
The studies ranged in quality from fair to good and included
a range of followup periods and methods of ascertaining
aspirin use (Appendix Table 3). Quantitative synthesis
of the data was possible for regular use of aspirin
(that is, >2 to 3 times weekly for >1 year); this analysis
showed a statistically significant 22% RR reduction in the
incidence of colorectal cancer (Table 2). A large, good-quality,
long-term followup study of aspirin use in average-risk U.S. women revealed a protective effect with more
than 10 years of use (RR, 0.67 [CI, 0.54 to 0.85]) as well
as for higher doses.30,54
Case-Control Studies
Seven case-control studies assessed the effect of aspirin
use on colorectal cancer incidence.17-21,23,24 Six
studies were rated as fair quality, and 1 was rated as good
quality.17 Significant heterogeneity, explained predominantly
by differences in the methods of exposure and outcome ascertainment among these studies, precluded statistical
pooling for the effect of regular use of aspirin on colorectal cancer frequency. These studies reported widely
varying statistically significant reductions in the RR for colorectal cancer with regular aspirin use (RR, 0.3 to 0.7) 19,20,24 or nonsignificant trends in favor of aspirin use (RR, 0.3 to 0.9).17,18,21,23
The effect of duration of aspirin use on colorectal cancer frequency was assessed in 5 studies.17-19,55,56 Quantitative pooling of these results indicated that aspirin use lasting 1 to 3 years showed a nonsignificant trend in favor of aspirin (RR, 0.85 [CI, 0.72 to 1.0]), whereas longer duration of use was associated with a statistically significant protective effect (RR, 0.68 [CI, 0.54 to 0.87]).
Dose response was assessed in 1 small, fair-quality study17 and 1 larger, good-quality study.55 Statistically significant 40% RR reductions in colorectal cancer frequency were observed with aspirin dosages of 300 and 325 mg/d, but not for lower dosages.
Colorectal Adenoma Incidence
RCTs
The effect of aspirin on the incidence of colorectal adenomas was reported in 2 U.S. RCTs31,42 and 1 French RCT.43 Two of these studies were of good quality,42,43 and 1 was of fair quality.31 Aspirin, 325 mg every other day for 5 years, did not significantly reduce the incidence of adenomas in average-risk men.31 However, in patients with a history of colorectal adenomas, the use of
aspirin in dosages of 81 to 325 mg/d for 1 year resulted in a statistically significant reduction in the RR for adenoma (RR, 0.82 [CI, 0.7 to 0.95])42,43 (Table 1).
Cohort Studies
Two good-quality cohort studies in average-risk Americans revealed that regular aspirin use was associated with a statistically significant 28% RR reduction in the occurrence of colorectal adenomas.26,30,39 The reduction in adenoma risk was seen with the intake of at least six 325-mg aspirin tablets per week; the reduction was similar for small and large polyps and for polyps with advanced histologic features30,39 (Table 1).
The effect of regular use of aspirin in patients with a history of colorectal adenoma was assessed in 2 small cohort studies.40,41 In a good-quality study, aspirin used
in dosages greater than 325 mg/d was associated with a statistically significant protective effect;41 in the other, a fair-quality study, consistent aspirin use (dose not reported)
was also associated with a statistically significant risk reduction in adenomas40 (Table 1).
Case-Control Studies
In a combined analysis of 5 predominantly fair-quality studies lasting 3 to 10 years, the regular use of aspirin in average-risk individuals significantly reduced the incidence of colorectal adenomas19,33-35,37 (Table 1). A good quality database study revealed a nonsignificant trend in
favor of higher aspirin doses and longer duration of use.35
A fair-quality U.S. study in a mixed population of patients with and without a history of colorectal adenoma
did not show a statistically significant benefit of an intake of 15 aspirin tablets or more per month for at least 5 years.38 Another fair-quality study in patients with a history of adenomas showed a statistically significant reduction in the RR for adenomas in the subgroup of patients who used
aspirin 4 times per week for more than 5 years compared with hospital controls.36 Comparisons with patients who used aspirin for less than 5 years or comparisons with population controls were nonsignificant (Table 1).
Harms Due to Aspirin Use
Twelve good-quality systematic reviews addressed the
magnitude of harms due to aspirin use in an adult population.3,44-53,57 Eleven of these were systematic reviews
of RCTs and provide high-level evidence, while 1
considered observational studies only.51 None addressed
the nephrotoxicity of aspirin.
Six systematic reviews addressed general aspirin harms
in the adult population.3,44-47,57 All-cause mortality
was reported in all the reviews. However, mortality and
withdrawals due to harms with aspirin use were not consistently
reported.
Mortality
In the setting of primary prevention of cardiovascular
disease, the all-cause mortality rate with aspirin compared
with placebo was not statistically different.3,45,57 For
secondary prevention of cardiovascular disease, aspirin significantly
reduced the RR for death from any cause by
15% to 18% compared with persons not receiving aspirin.46,47
Cardiovascular Events
Eight systemic reviews addressed the magnitude of cardiovascular
harms associated with aspirin use in an adult
population.3,44-49,57 Cardiovascular events included
acute myocardial infarction (MI), stroke (all, hemorrhagic,
or ischemic), and associated death (Table 2).
Four reviews reported on the mortality due to cardiovascular
events.3,45,46,57 In a primary prevention
setting, mortality due to cardiovascular events was not significantly
different between aspirin and placebo.3,45,57 In the setting of secondary prevention, aspirin was
associated with a statistically significant 16% reduction in
the RR for mortality due to cardiovascular events.46
Seven reviews reported the risk for acute MI with aspirin
use.3,44-47,49,57 In the setting of primary
prevention, a significantly lower risk for MI with aspirin
compared with placebo was reported in 3 reviews.3,45,57 In a third review, although the data were not pooled,
a significant absolute risk reduction in MI was reported in
a trial that compared the use of aspirin with placebo in
patients with hypertension (absolute risk reduction, 0.5%;
number needed to treat for benefit, 200).49 In a secondary prevention setting, 2 reviews reported a significant 30%
reduction in the RR for MI with aspirin use compared
with placebo.46,47
Seven systematic reviews reported the risk for acute
stroke (hemorrhagic and ischemic) with aspirin use.3,45-49,57 In primary prevention trials, the risk for stroke did
not differ between aspirin and placebo,3,57 in healthy
patients,45 in patients with vascular risk factors,45 or
in patients with hypertension.49 One review also reported
a nonsignificant OR of 1.4 for hemorrhagic stroke.3 In secondary prevention, the overall risk for stroke was
not statistically different between aspirin and placebo.46,47 However, the risk for hemorrhagic stroke was increased
by 84% with aspirin.46 In secondary prevention
trials, higher rates of hemorrhagic stroke were seen with
higher dosages of aspirin (<100 mg/d, 0.3% [CI, 0.2% to
0.4%]; 100 to 325 mg/d, 0.3% [CI, 0.2% to 0.3%]; >325
mg/d, 1.1% [CI, 0.7% to 1.5%]),48 while the risk for
ischemic stroke was decreased by 18%.46 The recent
Women's Health Study32 suggests a possible differential
effect of aspirin on women compared with men in the
setting of cardiovascular primary prevention. While the
Physicians' Health Study demonstrated a reduction in MI
risk and no reduction in stroke, the Women's Health
Study found no significant reduction in MI but a significant
reduction in overall stroke and ischemic stroke.
Gastrointestinal Harms
Gastrointestinal harms of aspirin were considered in 7 systematic reviews.3,47,48,50-53 The included reviews
summarized data from RCTs,3,47,48,50,52,53,58 cohort studies,3,51,53 and case-control studies,51,52 and some considered low and high doses of aspirin.48,59
Aspirin was consistently associated with a statistically
significantly elevated risk for gastrointestinal bleeding. The
magnitude of this increased RR ranged from 1.6 to 2.5
times that seen among persons who did not use aspirin in
the systematic reviews of RCTs, 2.2 times in the systematic
review of cohort studies, and 3.1 times in the systematic
review of case-control studies. The use of aspirin was also
associated with an increased risk for adverse gastrointestinal
symptoms, such as nausea and dyspepsia (OR, 1.7 [CI, 1.5
to 1.8]).53
A dose effect has been suggested for aspirin-induced
gastrointestinal toxicity. One systematic review pooled gastrointestinal
bleeding incidence among large cardiovascular
studies and found that 2.5% (CI, 2.2% to 2.6%) of patients
taking more than 100 mg of aspirin per day had
gastrointestinal bleeding compared with 1.1% (CI, 0.9%
to 1.3%) of those taking fewer than 100 mg/d.48 Ulcer
bleeding or perforation occurred in 0.34% and 0.86% of
patients taking low-dose (325 mg every 2 days) and highdose
(2.5 to 5.2 g/d) aspirin, respectively (P < 0.05).52
Similarly, a greater risk for gastrointestinal bleeding was
seen with high-dose aspirin (1600 mg) (OR, 2.8 [CI, 1.3
to 5.7]) than with lower doses (300 mg/d) (OR, 1.6 [CI,
0.7 to 4.0]).53 Another systematic review of RCTs demonstrated
an increased risk for gastrointestinal bleeding
with low-dose aspirin (50 to 162.5 mg) (RR, 1.59 [CI,
1.40 to 1.81]), but the rate of gastrointestinal bleeding
with the somewhat higher dose (>162 mg) was not statistically
different (RR, 1.68 [CI, 1.51 to 1.88]).50
It was estimated that 3 of 1000 middle-aged men would have gastrointestinal bleeding over a 5-year period
of continuous aspirin use, and the rate would be as high as
2 per 1000 patients per year if older, higher-risk patients
were considered.3 It has also been suggested that the
gastrointestinal bleeding rate with aspirin (300 mg) is 60%
higher than with placebo and represents an attributable
rate of 2.5 events/1000 patient-years.53 The risk for
hospitalization due to gastrointestinal bleeding is also increased
(OR, 1.9 [CI, 1.1 to 3.1]), although death from
gastrointestinal bleeding itself is rare.53 Of the reviews
that reported on this latter outcome,47,52,53 only 1
death was recorded with aspirin use.53
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Discussion
Colorectal cancer is a frequent cause of illness and
death in the U.S. population. Chemoprevention with aspirin
is one possible "simple" strategy to reduce the burden
associated with this disease. Our results suggest that such a
strategy may be effective, but careful consideration of some
remaining inconsistencies in the literature, and the possible
harms of chemoprevention, is required before such a strategy
can be recommended.
The regular use of aspirin appears to reduce the incidence
of colorectal adenoma with RR reductions on the
order of 13% to 28% in average-risk individuals. On the
basis of a limited number of studies, the RR reductions for
individuals with a history of colonic adenoma are probably
higher than for those at average risk. Furthermore, it appears
that longer duration of aspirin use, as well as higher
doses, are associated with greater RR reductions than
shorter-term and lower-dose use.
The regular use of aspirin was associated with a pooled
22% RR reduction in colorectal cancer incidence among
the included cohort studies. There was significant heterogeneity
among the case-control studies, but the individual
study results were consistent with a protective effect of
aspirin.
Aspirin is a unique agent that may have preventive
health benefits. While relatively low doses of aspirin appear
to be sufficient for the cardiovascular benefits, it appears
that prolonged use of higher doses of aspirin for more than
10 years is required to realize benefits for the chemoprevention
of colorectal cancer. The widely cited Physicians'
Health Study31 and the recently published Women's
Health Study32 found no benefit of low-dose aspirin on
colorectal cancer incidence. These RCTs shared many similarities,
and the strength of their design adds weight to
these negative findings. They were conducted in male physicians
and female health care workers, respectively. Both
used a relatively low dose of aspirin (325 mg every other
day and 100 mg every other day, respectively), and both
used self-reporting of outcomes in mailed questionnaires,
as well as mailed medication packs. Both studies followed
patients for a long period (14 and 10 years, respectively),
but in the case of the Physicians' Health Study, the RCT
portion made up the first 5 years, followed by an observational
phase during which patients chose their intervention.
The Women's Health Study maintained the RCT
design for the entire study period. The Physicians' Health
Study could be criticized for its observational phase, which
could have introduced several forms of bias, including contamination
by intervention. In addition, study participants
had a lower rate of colorectal cancer than matched members
of the U.S. population, with a standardized mortality
ratio of 0.82 (CI, 0.75 to 0.90). Participants in both studies
were relatively young (mean age, 53.2 and 54.6 years,
respectively), and they were not necessarily free of colorectal
adenomas at study onset.
It is difficult to entirely reconcile the discrepancy between
the negative RCT data and the generally positive
observational data, other than saying that low-dose aspirin
every other day does not reduce colorectal cancer incidence
but that higher doses used for longer periods may be effective.
It is also fair to admit that the overall quality of the
observational studies was only "fair" and that these studies
exhibited considerable limitations in the ascertainment of
aspirin exposure in particular. As a result, it was not always
possible for us to pool the data. However, good-quality
data from large-scale, long-term studies, such as the 82,911
women in the Nurses' Health Study,30 support our
overall estimate that aspirin reduces the risk for colorectal
cancer. However, this benefit occurs with dosages in the
range of 14 or more standard aspirin tablets per week and
use lasting for 10 or more years.
The data on colorectal cancer mortality are also inconsistent.
One cohort study was positive, while the recently
published Women's Health Study also showed no effect of
aspirin on mortality. However, it is possible that dosage
and duration effects are important in this setting as well, so
that higher-dose aspirin for longer periods may still have a
beneficial effect on colorectal cancer mortality.
The use of aspirin is associated with an increased incidence
of important ulcer complications, with RRs of 1.5
to 3.0. Rates of gastrointestinal toxicity with aspirin appear
to be between rates associated with diclofenac and sulindac.60 Aspirin also appears to have a dose effect: The absolute
risks for gastrointestinal bleeding are 0.97% per year
with a dosage less than 100 mg/d and 2.69% per year for a
dosage greater than 200 mg/d.61 A dose effect was also
demonstrated with the risk for hemorrhagic stroke. Therefore,
the multiyear use of high-dose aspirin that appears to
be required for colorectal cancer chemoprevention can be
expected to be accompanied by important complications
that may adversely affect the overall benefit of a chemoprevention
strategy.
The cardiovascular outcomes associated with the use
of aspirin depend on the underlying cardiovascular risk
among the population under investigation. In low- to average-risk individuals (that is, those receiving primary cardiovascular
prevention), aspirin significantly reduces the
incidence of total cardiovascular events and myocardial infarction but has no effect on coronary heart disease mortality,
fatal and nonfatal stroke events, or all-cause mortality.
In low- to moderate-risk individuals, the use of aspirin
would prevent 3 to 8 fatal or nonfatal coronary heart disease
events, would not prevent an ischemic stroke event,
and would cause 1 hemorrhagic stroke and 1 major gastrointestinal
hemorrhage among 1000 treated patients.3
Data from the Women's Health Study suggest that the risk
for stroke (overall as well as ischemic) is significantly reduced
by aspirin use in women older than age 65 years.32 In high-risk patients with cardiovascular disease in a
secondary prevention setting, the use of aspirin significantly
reduces all-cause mortality and cardiovascular mortality,
despite the increased incidence of major gastrointestinal
hemorrhage. It is suggested that 67 patients would
need to be treated to prevent 1 death, at the cost of 1
nonfatal gastrointestinal bleeding episode.47,50 In the
setting of colorectal cancer chemoprevention with aspirin,
depending on the age at which the intervention is started,
most patients may be at low to moderate cardiovascular
risk and may have greater exposure to the harms of aspirin
than to its benefits. This may be especially true if one
considers that for colorectal cancer prevention, aspirin
would need to be used in doses higher than currently recommend
for cardiovascular prevention.
In average-risk populations and in the context of regular
endoscopic screening for colorectal cancer, aspirin chemoprevention
also must be weighted against the relatively
large costs associated with its adverse effects, as well as the
relative inefficacy of aspirin compared with colonoscopy
screening.13
In conclusion, aspirin appears to reduce the incidence
of colorectal adenomas and colorectal cancer. However, the
data on colorectal cancer incidence are inconsistent: Observational
studies tend to be positive, and 2 large RCTs
showed no benefit for low-dose aspirin every other day.
The effect of aspirin on colorectal cancer mortality is also
mixed, with 1 positive cohort study and negative findings
of the Women's Health Study. The available data would
suggest that for chemoprevention, aspirin would need to be
used in doses greater than used for cardiovascular prevention
and for a duration close to 10 years. Therefore, the
potential benefit of aspirin chemoprevention would need
to be carefully weighed against its harms. More information
is still required to clarify the optimal dose, starting
age, and duration of use of aspirin. In addition, its effect
on colorectal cancer incidence and mortality should be
clarified, particularly given the evidence that in patients at
average cardiovascular risk, use of aspirin does not reduce
all-cause mortality. Further evaluation of the cost-effectiveness
of chemoprevention compared with, and in combination
with, a screening strategy is required.
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