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Evaluation of the Benefits and Risks of Low-Dose Aspirin in the Secondary Prevention of Cardiovascular and Cerebrovascular Events
Steven M. Weisman, PhD;
David Y. Graham, MD
Arch Intern Med. 2002;162:2197-2202.
ABSTRACT
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Background In spite of the clear evidence of benefit of aspirin in the secondary
prevention of cerebrovascular and cardiovascular thrombotic events, its use
in patients at high risk due to a previous event remains suboptimal. A possible
explanation for this underuse is concern regarding the relative benefit in
relation to the potential risk for serious gastrointestinal events.
Objective To compare the benefit and gastrointestinal risk of aspirin use for
the secondary prevention of thromboembolic events.
Design A meta-analysis was conducted using 6 trials (6300 patients) meeting
the inclusion requirement of use of low-dose aspirin ( 325 mg/d) in approved
secondary prevention indications.
Results Aspirin reduced all-cause mortality by 18%. In addition, aspirin use
reduced the number of strokes by 20%, myocardial infarctions by 30%, and other
"vascular events" by 30%. Alternately, patients who took aspirin were 2.5
times more likely than those in the placebo group to have gastrointestinal
tract bleeding. The number needed to treat for aspirin to prevent 1 death
from any cause of mortality was 67, while 100 needed to be treated to detect
1 nonfatal gastrointestinal tract bleeding.
Conclusion Aspirin use for the secondary prevention of thromboembolic events has
a favorable benefit-to-risk profile and should be encouraged in those at high
risk.
INTRODUCTION
SINCE ITS introduction in 1899, aspirin has been recognized as a drug
with a favorable benefit-to-risk ratio. Ironically, aspirin was advertised
in the 1920s with the claim that it did not affect the heart, unlike other
drugs of the time, which were thought to have an "enfeebling" effect. More
than 100 years after its introduction, it is now clear that aspirin can positively
affect the heart, especially in the management of acute evolving myocardial
infarction. Data from numerous controlled clinical trials provided the basis
for its approval by the US Food and Drug Administration (FDA) for use in prevention
of thromboembolic events in individuals who had a previous myocardial infarction,
transient ischemic attack (TIA), or stroke. In spite of the clear evidence
of benefit of aspirin in the secondary prevention of vascular events, its
use in patients at high risk due to a previous event remains suboptimal.1 One possible explanation for underuse of aspirin by
physicians is concern regarding the potential for serious adverse effects
on the gastrointestinal tract (GI).
Cardiovascular disease, which includes myocardial infarction, stroke,
and peripheral vascular diseases, is a leading cause of death in the United
States and other major developed countries, accounting for more than 900 000
deaths annually in the United States alone.2 Long-term
aspirin administration has been shown to confer a benefit on risk of subsequent
myocardial infarction, stroke, and vascular death among patients with underlying
cardiovascular disease, primarily by inhibiting platelet aggregation. The
1994 Antiplatelet Trialists' Collaboration3 overview
analysis of randomized trials of antiplatelet therapy involving more than
54 000 high-risk patients with prior evidence of cardiovascular disease
demonstrated that 40 events could be avoided per 1000 patients with prior
myocardial infarction, stroke, or TIA when treated with aspirin for 2 to 3
years. Furthermore, these results provided no evidence that higher doses (500-1500
mg) were more effective than lower doses (325 mg). Based on these and
other findings, the American College of Cardiology and the American Heart
Association2 recommended that daily aspirin
therapy at a dose of at least 75 to 325 mg be considered for all patients
at elevated risk of subsequent events due to a history of vascular disease.
Today, aspirin is widely used as a thromboprophylactic agent, with tens
of millions of tablets consumed each day. As millions of individuals use aspirin
for the secondary prevention of cardiovascular and cerebrovascular events,
our goal was to compare benefits of treatment with the potential risk of GI
injury under conditions of appropriate use. Earlier analyses4-5 have
included patient populations at various levels of risk (ie, those in primary
and secondary prevention trials), as well as aspirin at doses higher than
currently recommended. As a result, these analyses may have either underrepresented
the benefit or exaggerated the risk. This overview analysis focuses only on
the FDA-approved uses of low-dose aspirin (50-325 mg/d) in the secondary prevention
of myocardial infarction and stroke, with the aim of providing additional
insight to physicians and patients regarding the benefits and risks of aspirin
use in this high-risk population.
METHODS
A review of the computerized literature databases MEDLINE, EMBASE, and
Excerpta Medica was performed to identify all published reports after 1970
of aspirin use for FDA-approved secondary prevention indications, as summarized
in the FDA's 1998 rule and updated professional labeling for aspirin.6 The approved indications include stroke in those who
had a previous event or a TIA and myocardial infarction in those who had a
previous myocardial infarction or have a history of angina. In addition, reference
lists of published secondary prevention trials and overviews were examined
for additional sources. Studies included in this review were limited to randomized,
placebo-controlled interventions with an aspirin-only arm, with low-dose aspirin
defined as daily doses of 50 to 325 mg. Furthermore, reports were required
to provide both efficacy and safety end points. Trials were excluded if aspirin
was (1) administered for less than 3 months; (2) prescribed short term for
thromboprophylaxis in procedures such as angioplasty or coronary artery bypass
grafts; (3) used for nonprevention indications, such as pain, headache, or
arthritis; (4) coadministered with another agent; or (5) used to prevent cardiovascular
events in otherwise healthy individuals (primary prevention).
Data from each published study were abstracted by the same 2 individuals,
then reabstracted by a third for quality control. Data related to inclusion
and exclusion criteria, health status on entry, and outcomes were collected
on specially developed forms and entered into corresponding Microsoft Excel
(Microsoft Corp, Redmond, Wash) data cells that were checked against hard
copy entries. As the objective of this analysis was to evaluate aspirin alone,
treatment arms involving other antithrombotic therapies or aspirin in combination
with other agents were not abstracted.
Consistent with the desire to assess both benefit and risk, detailed
information was collected on all fatal and nonfatal vascular events from all
randomized subjects. Outcome data consisted of myocardial infarction, stroke,
vascular death, vascular event (ie, any stroke, myocardial infarction, or
other vascular events defined as possibly or definitely of cardiac, cerebral,
embolic, hemorrhagic, or unknown cause), and all-cause mortality. In addition,
we collected data on serious adverse events related to bleeding. We focused
our review on GI bleeding, a common and expected adverse effect of aspirin
therapy. Bleeding events were abstracted regardless of their severity. Subjective
tolerability was not evaluated because the collection of such events across
the trials was not consistent.
We included all studies for the secondary prevention of cardiovascular
or cerebrovascular disease meeting the above-mentioned criteria regardless
of precipitating event. Each of these studies varied in the outcome data collected,
duration of treatment, and length of follow-up. Because outcome data were
reported differently across the studies, results for categories were pooled
only if they were reported the same way. To facilitate comparison across studies
with differing end points, the summary measure "vascular events," defined
as myocardial infarction, stroke, or other vascular event (including vascular
death), was used. Individual outcome variables (eg, myocardial infarction,
stroke, and death) are presented for the trials providing data with respect
to these outcomes (Table 1). While
follow-up times varied across studies, placebo and aspirin arms within each
study had the same follow-up time.
Relative risks were estimated using standard statistical approaches.
The data were transferred to SPSS version 10 (SPSS Inc, Chicago, Ill) for
sorting, listing, and production of descriptive statistics. Risk, test for
homogeneity of results across all studies with reported outcomes, and estimates
of the common risk ratio were calculated using the exact method, performed
with StatXact4 (Cytel Software Corp, Cambridge, Mass).
Because of differences in the length of follow-up across the studies,
we could not use the Peto fixed-effects model to calculate a pooled odds ratio.
Instead, we computed the relative risk for each outcome assuming a constant
follow-up time for each study. Absolute risk reductions and 95% confidence
intervals (CIs) were also calculated for each outcome variable. Absolute risk
reductions were not aggregated because of differences in follow-up periods
across studies. As such, they are only presented descriptively. The common
risk and 95% CI were calculated using all studies with reported outcomes.
Homogeneity of risk across studies was calculated using the method of Breslow
and Day.7 The numbers needed to treat (NNT)8 for GI bleeding events and all-cause mortality were
calculated by using the pooled risk ratio and the pooled placebo event rates.
RESULTS
The literature review through March 31, 2000, resulted in the identification
of 6 trials,9-14 which
contributed 6300 patients to the analysis: 3127 to aspirin alone and 3173
to placebo (Table 2). Of these
6300 patients, 2427 evaluated patients experienced a previous myocardial infarction,
and 1757 had a history of TIA or stroke. Among these patients, there were
558 subsequent myocardial infarctions, 424 strokes (265 thrombotic, 24 hemorrhagic,
and 135 undefined), and 91 other vascular events. There were 532 deaths and
58 reports of GI bleeding of any severity. Cases were included regardless
of whether they required hospitalization or surgery. There were no cases of
GI bleeding that were fatal. Studies contributed to the analysis of a specific
outcome only when at least 1 occurrence of that outcome was reported. Studies
varied in both the definition and number of outcomes reported. Many used aggregate
end points that included combinations of stroke, myocardial infarction, and
vascular death.
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Table 2. Randomized Placebo-Controlled Trials of Low-Dose Aspirin Therapy
(325 mg/d) in Secondary Prevention of Myocardial Infarction and Stroke*
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As depicted in Table 3,
all 6 studies reported total mortality. Myocardial infarction and GI bleeding
were reported in 5 of the 6 studies, while stroke was reported in only 2 studies.
To include all studies, we created the event category "vascular events" to
summarize all reports of myocardial infarction, stroke, and other vascular
events including vascular death. Because vascular death was not reported consistently
across studies, we used the more conservative all-cause mortality to assess
the effects of aspirin on mortality.
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Table 3. All-Cause Mortality*
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Relative risk estimates for all-cause mortality are also summarized
in Table 3. In the aspirin and
placebo groups, there were 241 and 291 deaths, respectively. Relative risk
calculations for each of the individual studies ranged from 0.5 (95% CI, 0.2-1.1; P = .08) to 1.0 (95% CI, 0.3-3.0; P>.99),
suggesting that numbers were too small in individual studies to determine
with confidence whether there is an impact on all-cause mortality, in spite
of directional support. The findings of our analysis demonstrate that the
results are homogeneous across the studies (test for homogeneity, P = .7), allowing the calculation of common risk ratio of 0.82 (95%
CI, 0.7-0.99; P = .03) for aggregation of these studies.
Thus, the data suggest that aspirin reduces the risk of death by approximately
20% in the studied population. Absolute risk reductions ranged from 2.0% ±
3.1% (12-month follow-up) to 8.7% ± 6.3% (20-month follow-up).
Risk ratio estimates and 95% CIs for all outcomes are summarized in Table 4. As a result of differences in
outcome ascertainment across studies, many of these analyses have either too
little power or lack homogeneity across studies; therefore, significant conclusions
can not be supported. Nonetheless, all of these assessments demonstrate a
trend in favor of aspirin reducing the risk of cardiovascular (myocardial
infarction) and cerebrovascular events (stroke), with relative risk reductions
between 20% and 30%. Absolute risk reductions ranged from 0.9% ± 3.7%
(52-month follow-up) to 18.6% ± 7.7% (3-month follow-up).
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Table 4. Risk Ratio Estimates and 95% Confidence Intervals by Outcome
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These findings support the conclusion that the reduction in the risk
of death attributed to aspirin use is accompanied by similar degrees of risk
reduction in myocardial infarction (30%) and vascular events (30%). Because
the stroke findings involved only 2 studies, the results are suggestive of
a benefit of aspirin, but are not sufficiently conclusive.
The risk of GI bleeding, the most common serious adverse event associated
with extended aspirin use, was similarly evaluated (Table 5). Five of the 6 studies meeting the inclusion criteria reported
GI bleeding.10-14 Because
adequate information on the severity of this variable was lacking, we included
any report of GI bleeding in our analyses. In spite of this conservative approach,
GI bleeding was a rare finding, with only 58 reports across the 6 studies
(41 in the aspirin groups; 17 in the placebo groups). Only about half of the
cases of GI bleeding were deemed severe enough to require withdrawal. Importantly,
there were no reported deaths related to GI bleeding (Table 6), and GI bleeding led to almost no permanent morbidity (that
was reported by the investigators). Only 1 report, the United Kingdom Transient
Ischaemic Attack (UK-TIA) trial,10 demonstrated
a statistically significant increased risk of GI bleeding as a result of aspirin
intake. The analysis of GI bleeding across all studies suggests a common risk
ratio of 2.5 (95% CI, 1.4-4.7; P = .001), as given
in Table 4. The formal test of
homogeneity confirms that a summary measure is appropriate (P = .5). Absolute risk increases ranged from less than 0% to 2.0% ±
1.4% (52-month follow-up).
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Table 5. Gastrointestinal Tract Bleeding*
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Table 6. Number of Severe Gastrointestinal Tract Bleeding Events*
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Cerebral hemorrhage, which is a potential serious outcome of long-term
aspirin therapy, could not be adequately evaluated in this study. Only 2 of
the 6 trials reported cases of hemorrhagic stroke (UK-TIA10 and
the Swedish Aspirin Low-Dose Trial [SALT]12)
and, importantly, in both trials, cerebrovascular ischemic events were the
qualifying events for study inclusion. Despite these limitations, and while
the numbers are small, the findings in these 2 studies suggest an excess risk
of hemorrhagic stroke in those allocated aspirin (18 vs 6) that is similar
to the risk of GI bleeding. It is also important to point out that both trials
in which cases of hemorrhagic stroke were reported, aspirin significantly
reduced the risk of stroke or death, suggesting a favorable benefit-to-risk
relationship. A comprehensive analysis of hemorrhagic stroke risk has been
recently addressed by He et al,15 who concluded
that the risk of hemorrhagic stroke, while real, is acceptable based on the
level of benefit received in secondary prevention To evaluate the relative
benefit and risk of aspirin in the secondary prevention of myocardial infarction
and stroke, we compared the benefit observed in reducing the risk of death
with the potentially serious outcome of GI bleeding. This comparison was made
by calculating the NNT with aspirin to either prevent 1 death or cause 1 GI
bleeding event. All-cause mortality occurred in 9.2% of the placebo group
and 7.7% of the aspirin group. Conversely, 1.6% of the aspirin group had a
GI hemorrhage compared with 0.6% in the control group. Based on the differences
between the rates of the aspirin- and placebo-treated patients, we determined
that 1.5 deaths could be prevented for every nonfatal GI bleeding attributed
to the use of aspirin.
COMMENT
Aspirin remains one of the most widely used and consequently most studied
therapies in the history of medicine. It is used at high doses to alleviate
the pain and inflammation of arthritis, at moderate doses for short-term management
of acute pain, and at low doses for cardiovascular and cerebrovascular disease
prevention. Within the vascular disease management arena, aspirin is indicated
for use in a variety of patient risk strata.
Recently, there has been significant discussion over the relative benefits
and risks of aspirin therapy in the prevention of cardiovascular and cerebrovascular
events. While it is widely accepted that aspirin is beneficial, there is controversy
with respect to which patients receive the greatest benefit with the least
risk. It is likely that confusion over the relative benefits and risks of
treatment has been in part responsible for underuse of this highly effective,
inexpensive therapy among the large group of patients at risk for cardiovascular
disease. Misunderstanding of the benefits of aspirin may result from the diverse
nature of the conditions for which aspirin is indicated, as well as the attribution
of risk from various conditions in which the dose, formulation, or the benefit-to-risk
relationship may differ. For instance, in the long-term management of inflammatory
conditions in which high-dose aspirin is used, a greater frequency of adverse
effects would be expected than would be observed in the short-term management
of acute pain. Therefore, the suggestion that an individual would experience
the same potential for an adverse event whether treating acute pain as using
it in the long-term management of arthritis would not be appropriate. Likewise,
in patients at high risk of cardiovascular events, the absolute benefit would
be expected to be greater than that of lower-risk patients, while the rate
of adverse GI events might be expected to remain constant. As such, the benefit-to-risk
relationship can vary tremendously and can only be intelligently discussed
in the context of intended use.
The adverse effects of aspirin have been well studied and characterized.
Gastrointestinal tract perforation, ulceration, and bleeding are expected
adverse effects associated with long-term aspirin therapy. Because inhibition
of prostaglandin synthesis is the common mechanism for both the beneficial
thromboprophylactic effects and the adverse effects on the GI tract, it is
unlikely that the benefits can be achieved without some degree of risk. A
number of studies have examined the relationship between aspirin dose and
toxic effects with conflicting results. Cameron16 demonstrated
an exponential increase in the relative risk of developing a chronic gastric
ulcer relative to the number of aspirin tablets consumed per week. In patients
taking 10 or fewer tablets per week, the relative risk was 1 or less; at 40
tablets per week, the relative risk was nearly 6.0. Two trials have directly
compared different doses of aspirin.10, 17 The
UK-TIA study10 found that patients randomized
to 1200 mg/d were more likely to experience subjective GI symptoms, as well
as hemorrhage, than patients who were randomized to 300 mg/d. Likewise, the
Dutch TIA Trial Study Group17 found that patients
randomized to 30 mg/d had a modest reduction in serious bleeding and GI symptoms
compared with patients randomized to 283 mg/d. Results from meta-analyses,
including that of the Antiplatelet Trialists' Collaboration,3 support
the benefits of low doses of aspirin. In contrast to these findings, a recent
meta-analysis published in the British Medical Journal4 suggests that lower doses may not enhance the benefit-to-risk
relationship. However, this conclusion, as well as that of previous analyses,
is confounded by the inclusion of low-risk individuals without underlying
cardiovascular disease. Inclusion of such patients may distort the benefit-to-risk
ratio because the absolute benefit in many of these patients would be expected
to be significantly less than that observed in secondary prevention studies.
Given the previous evidence of equal antithrombotic effectiveness of
high, medium, and low doses of aspirin3 and
the possibility that the lower doses increasingly being used might enhance
GI safety, we sought to carefully evaluate the benefit-to-risk relationship
of low-dose aspirin therapy in the secondary prevention of myocardial infarction
and stroke. The purpose of our evaluation was to provide insight regarding
the relative benefits and risks of aspirin treatment in the currently FDA-approved
uses of aspirin as described in Internal Analgesic, Antipyretic,
and Antirheumatic Drug Products for Over-the-Counter Human Use: Final Rule
for Professional Labeling of Aspirin, Buffered Aspirin, and Aspirin in Combination
with Antacid Drug Products.6 As the
dose-response relationship for adverse events could be an important clinical
determinant of risk, we restricted our evaluation to currently approved doses
for the above-mentioned indications. As such, our analysis focused on the
long-term use of low-dose aspirin at dosages less than or equal to 325 mg/d
(1 regular-strength tablet) for the prevention of cardiovascular events in
patients who have previously experienced a myocardial infarction (or unstable
angina), TIA, or stroke. This restriction resulted in the exclusion of many
of the early secondary prevention trials that used dosages in excess of 325
mg/d.
Our findings confirm the benefits of low-dose aspirin therapy (325
mg) in high-risk patients seen previously. Our overview analysis of the 6
randomized, placebo-controlled, secondary prevention studies, in contrast
to other meta-analyses that included broader indications and risk strata,
demonstrate an 18% reduction in the risk of death. While each of the 6 studies
on its own showed a directional trend toward reducing the risk of death, no
single study achieved statistical significance. When evaluated together, these
studies demonstrate a statistically significant reduction in all-cause mortality,
a finding that has not been previously described for aspirin. Previous findings
of a mortality benefit have been restricted to vascular death. The finding
of a statistically significant benefit in reducing all-cause mortality is
a powerful indicator of the life-saving properties of aspirin, since all-cause
mortality is the ultimate end point for establishing effectiveness.
The benefits observed in preventing fatal outcomes were evaluated in
conjunction with the potential for serious GI adverse effects. We confirmed
findings by other groups4-5 that
long-term aspirin intake significantly increases the risk of GI bleeding.
Our analysis demonstrates a 2.5-fold increase in the risk of such an event.
Nonetheless, the number of events were few, with only 58 nonfatal cases reported
out of 6300 patients evaluated for a minimum of 3 months. In all cases, the
GI adverse event was managed effectively, with no reports of death.
Our analysis included all GI bleeding events and not only those that
were serious or major. It does not, however, address occult GI blood loss,
which may be of concern to practicing physicians, since it would not be reported
as a bleeding "event." While numerous studies have indicated that low doses
of aspirin might increase occult blood loss,18-20 prior
studies showed that the amount was trivial and dose related.21 To
our knowledge, the clinical significance of aspirin-induced GI microbleeding
with low-dose aspirin use has never been demonstrated.
There are data suggesting an adverse interaction between nonsteroidal
anti-inflammatory drugs, including aspirin, and Helicobacter
pylori infection.22 For example, a recent
placebo-controlled, double-blind, randomized trial prospectively assessed
the effect of H pylori on gastric mucosal injury
in subjects receiving low-dose aspirin treatment and reported significantly
more gastric mucosal injury in patients using aspirin.23 Two
other studies24-25 also suggest
that H pylori infection may increase the risk of
clinical GI events including bleeding. Thus, eradication of H pylori infection may be one method of reducing the risk of GI bleeding
associated with aspirin use.26 This notion
is supported by a study by Chan et al,27 who
reported that eradication of H pylori infection reduced
rebleeding rates in patients requiring low-dose aspirin therapy who had previously
bled. While further studies are needed, the available data suggest that the
already favorable risk-benefit ratio associated with the use of aspirin for
prevention of cardiovascular events may be able to be improved.
To place the benefits and risks in better perspective, we calculated
the NNTs to prevent 1 death as well as to cause 1 GI bleeding event. We determined
that for every 67 patients treated to protect a subsequent myocardial infarction
or stroke, 1 life could be saved with low-dose aspirin therapy. This compares
favorably with NNTs required to prevent a death with the use of anticoagulants,  -blockers,
and angiotensin-converting enzyme inhibitors in the secondary prevention of
ischemic heart disease.28 In our evaluation,
we found that 100 is the number of patients needed to be treated to cause
a GI bleeding event. These findings suggest, ignoring H
pylori and other potential risk factors, that 1.5 lives can be saved
for every GI bleeding event attributed to aspirin use. Our results do not
differ appreciably from those of the SALT investigators,12 who
found the NNT with aspirin to prevent recurrent stroke to be 106 patients.
Using results from a meta-analysis including aspirin use for both primary
and secondary prevention, Derry and Loke4 conclude
that 2 recurrent strokes could be prevented for every 1 GI hemorrhage caused,
a finding virtually identical to ours.
While GI bleeding was increased with the use of aspirin in the secondary
prevention studies evaluated, this outcome was rare, manageable, and led to
no deaths. Furthermore, the potential for this adverse outcome must be compared
with the highly significant and clinically meaningful finding of a reduction
in all-cause mortality, the gold standard for drug effectiveness. This benefit,
coupled with substantial and comparable reductions in nonfatal vascular events,
leads to the conclusion that the benefit-to-risk ratio for aspirin in the
secondary prevention of cardiovascular and cerebrovascular events is highly
favorable.
While our analyses were restricted to the secondary prevention database,
there is significant evidence that the benefits of aspirin treatment accrue
to "at-risk" populations who have not had a previous thrombotic event. The
National Cholesterol Education Program29 recommends
that patients with an absolute 10-year risk of 20% or higher for developing
heart disease should be candidates for drug and dietary intervention regardless
of the occurrence of a previous event. Such an event rate is not uncommon
in individuals with multiple risk factors in which the risk of developing
heart disease is often equal to or higher than observed in many patients who
have had a previous event, but without additional risk factors. Patients with
an estimated 10-year risk between 10% and 20% may also benefit from drug and
dietary therapy. It is likely that the use of aspirin in these patients would
be associated with a positive benefit-to-risk relationship similar to that
demonstrated using the secondary prevention database. The overview analyses
conducted by Sanmuganathan and colleagues30 demonstrated
a threshold coronary event risk for the appropriate use of aspirin in primary
prevention to be equal or greater than 1.0% to 1.5% per year.
These findings should assist physicians and patients in understanding
the role and safety profile of aspirin in the secondary prevention of cardiovascular
and cerebrovascular events. Our overview analysis, coupled with the sheer
number of people worldwide who take this medication without incident and the
extensive historical and current evidence, clearly support broader use of
aspirin.
AUTHOR INFORMATION
Accepted for publication February 13, 2002.
This study was funded by Bayer Corporation, Consumer Care Division,
Morristown, NJ.
Corresponding author and reprints: Steven M. Weisman, PhD, 13 James
St, Morristown, NJ 07960 (e-mail: weisman{at}innovativescience.net).
From Innovative Science Solutions, LLC, Morristown, NJ (Dr Weisman);
and the Department of Medicine, Veterans Affairs Medical Center and Baylor
College of Medicine, Houston, Tex (Dr Graham).
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