Should You Take Aspirin to Prevent Heart Attack ?

Journal of Scientific Exploration, Vol. 14, No. 4, pp. 623–641, 2000
0892-3310/00
© 2000 Society for Scientific Exploration
Should You Take Aspirin to Prevent Heart Attack?
JOEL M. KAUFFMAN
Research Professor Chemistry
University of the Sciences in Philadelphia
600 South 43rd Street
Philadelphia, PA 19104
“Nothing is Simple.”—Harry Rowe Mimno,
Professor of Applied Physics,
Harvard University
Abstract—The majority of physicians in the USA recommend aspirin for
prevention of first heart attacks to almost everyone over the age of 50, even
though women have not been included in the clinical trials of aspirin. While
aspirin does prevent about 1/3 of first heart attacks, its side-effects are so se-
vere as to cause a higher death rate overall than placebo. Non-fatal side-ef-
fects, such as internal bleeding and cataracts, are significant after years of as-
pirin use. The major study on which most recommendations are based did not
utilize aspirin alone; therefore, the calcium and magnesium present in the
buffered aspirin actually taken may have been responsible for some of the
beneficial effects. Supplemental magnesium and vitamin E have been shown
to be more effective than aspirin in lowering heart attack rates as well as over-
all death rates. Aspirin does reduce the incident of second heart attacks by
about 1/5 when taken for a few weeks. Supplemental magnesium and coen-
zyme Q10 have been shown to be more effective than aspirin in treatment of
cardiovascular disease.
Keywords: Aspirin—heart attack—cardiovascular disease—stroke—vita-
min E—coenzyme Q10—magnesium—potassium.
Introduction
Recent advice given in books and articles for general audiences is contradicto-
ry. Many practicing cardiologists and other physicians still do not understand
the findings in clinical studies and believe that this was all settled 10 years
ago. Flaws have been claimed to exist in some of the largest and formerly best-
regarded studies, including the supposed lack of an exact specification of what
was taken that was supposed to be aspirin. As a result, studies of the supposed
benefits of aspirin in preventing heart attacks continued during the 1990s. A
skeptical examination of the benefits of aspirin attributed to the peer-reviewed
medical literature shows frequent misinterpretation or worse by writers for lay
audiences. This article will show that careful examination of original peer-re-
viewed papers will allow you to draw conclusions about who could benefit by
taking aspirin which are at odds with some strongly held opinions. (The mean-
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Fig. 1. Structural formula of aspirin (acetylsalicylic acid or ASA).
ing of medical terms may be found in ordinary or medical dictionaries, or
www.netscope.drkoop.com/search/query/ asp.)
What Is Aspirin?
The structural formula for aspirin is shown in Figure 1. The most common
chemical name for this organic compound is acetylsalicylic acid (ASA). There
are at least 32 other names for it, mostly trade names (Windholz, 1976). It was
first synthesized by Carl R. Gerhardt in 1853 (Mustard, 1982). The major ther-
apeutic use of ASA in providing relief from the pain of rheumatoid arthritis
was recognized by Felix Hoffman, an employee of Bayer AG, in 1897, who
administered ASA to his father, who tolerated ASA much better than other sal-
icylates already in use. ASA was not “invented” in 1897 as in the book The As-
pirin Wars (hereafter Wars, Mann & Plummer, 1991) (Wars, p. 7 and cover).
First trademarked in 1899 by Bayer AG (Vane & Botting, 1992), Leverkusen,
Germany, the name Aspirin™ became a generic term for ASA in the manner of
Kleenex and Frigidaire. For most of a century aspirin has been the preferred
treatment for arthritis pain and has been used for headache, fever, and, in the
last decade, prevention of heart attacks. It has been called the most successful
drug in history. A decade ago 1 in 5 Americans took aspirin every day (Wars,
cover).
Not until the 1970s was the mode of action of aspirin worked out! Sir John
Vane was awarded the Nobel Prize for uncovering the mode of action of ASA
(Feinman, 1993). ASA inhibits the enzyme cyclooxygenase, preventing the
cells of the body from making certain prostaglandins that cause inflammation
and other ones that cause the clumping of blood platelets to form clots. The
clots, or thromboses, are responsible for “ischemic events,” which are the local
anemias, or blood shortages, caused by blockage of arteries. When these are
coronary arteries, the blockages are called “heart attacks” of the myocardial
infarction (MI) type. The common slogan “aspirin thins the blood” is not
strictly true; aspirin prevents clot formation by platelets.
The ASA content of a standard aspirin tablet is 325 mg. Extra-strength or

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Does Aspirin Prevent Heart Attack?
625
arthritis-strength tablets contain 500 mg. For other uses tablets containing 160
and 81 mg are available. Enteric-coated aspirin tablets resist the acidic envi-
ronment of the stomach; the aspirin is absorbed in the alkaline small intestine.
You would not expect “fast, fast, FAST relief of headache” with these, but
some studies showed that stomach erosions and ulcers were less frequent (Mc-
Donald, 1982). “Buffered” aspirin is no faster than plain aspirin (Wars, p. 164)
and only slightly less irritating, if at all (www.mayohealth.org). Besides con-
taining 325 mg of ASA, a Bufferin™ tablet has an actual alkali content of 158
mg of calcium carbonate, 63 mg of magnesium oxide, and 34 mg of magne-
sium carbonate; the latter pair provide a total of 48 mg of magnesium, which
may be important for preventing heart attacks. Bayer Aspirin with Stomach
Guard is the same.
Primary vs. Secondary Prevention of Heart Attacks
One must be skeptical about any recommendation for or against aspirin that
does not distinguish between primary and secondary prevention. Primary
means that people not at any particular risk of MI may prevent a fraction of po-
tential MIs from occurring by taking small doses of aspirin for a long period.
Any side effects of aspirin can be serious if people begin taking it at age 45–50
and continue for 30–40 years. Secondary prevention means that actual victims
of MI or unstable angina, a high-risk group, may prevent a fraction of further
cardiovascular problems by taking moderate doses of aspirin for a limited peri-
od. Any recommendation for or against aspirin that does not make the distinc-
tion can be disregarded as superficial.
The Aspirin Wars distinguished between primary prevention of first heart at-
tacks and secondary prevention on p. 11 quite well and described the U.S.
Food and Drug Administration (FDA) decision to allow advertising for second
heart attacks, but not for first heart attacks, due to an unusual number of
strokes in the aspirin-using group in a large study on primary prevention, a pre-
scient decision. But by p. 334 in Wars:
Aspirin is the drug of doctors’ dreams. It is hugely effective. One aspirin a day, or every
other day, will save hundreds of thousands of lives a year. It can be taken safely by more
people than almost any other drug … It is likely to remain the only heart attack preven-
tive sold in grocery stores for years to come.
Surrogate End Points in Clinical Trials: Are We Being Misled?
This is the title of an unusual paper by Fleming and DeMets (1996). Clinical
trials are the standard scientific method for evaluating a new drug or a new use
for an old drug. The true end point in most trials would be cure of a disease or
condition, or, at least, reduction of symptoms, as indicated by longer lifespan
of good quality. A surrogate end point is a laboratory measurement or a physi-

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cal sign used as a convenient substitute for a clinically meaningful end point
that measures survival directly. Changes induced by a therapy on a surrogate
end point are supposed to reflect changes in a clinically real end point, but all
too often, they do not.
Examples of surrogate end points are reduction of cholesterol level or blood
pressure, two parameters easy to measure in the short term. A meta-analysis of
50 cholesterol-lowering interventions, including diet, resins, and lovastatin,
showed that cholesterol levels were lowered an average of 10%, but there was
a 1% increase in overall mortality. (This should not have been a surprise, since
high blood cholesterol level and low LDL + HDL/HDL ratio are merely corre-
lated with cardiovascular trouble, not an actual cause of it, as homocysteine is;
McCully & McCully, 2000, and references to peer-reviewed papers therein). A
meta-analysis of trials of calcium channel blockers, even though they really do
lower blood pressure, showed possibly harmful effects overall. In addition,
two antiarrythmia drugs approved by the FDA, encainide and flecainide, clear-
ly suppressed arrythmias, probably as seen by electrocardiograms, as the sur-
rogate end point. However, it was found that 3 times as many patients in the
drug group died as in the placebo group.
In evaluating aspirin, it is, therefore, not enough to show reduction in the
rate of MI or other undesirable vascular events; one must determine total death
rates for a reasonable period of several years in order to find whether some
toxic effect of aspirin is countering a positive effect on MI. On the other hand,
one does not want to carry on for too many years since the ultimate death rates
of treatment and placebo groups converge—to 100%.
Whisper Down the Alley
This is one name for a grade-school game in which someone in a classroom
whispers a phrase of a few words to the nearest student, who whispers the same
phrase (supposedly) to the next student. The output of the 30th or so student is
compared with the input and all have a good laugh, since the two are never
equal.
Adult scientists are not supposed to scramble the input—but some do.
A massive meta-analysis of 25 completed clinical trials of secondary preven-
tion of MI was reported in the British Medical Journal (BMJ) in 1988 (An-
tiplatelet Trialists’ Collaboration, 1988). The title: “Secondary Prevention of
Vascular Disease by Prolonged Antiplatelet Treatment,” makes clear that most
of the patients involved had already suffered from MI, transient ischemic at-
tack, unstable angina, or minor stroke. “Antiplatelet Treatment” indicates that
aspirin was not the only drug tested; these facts are, of course, confirmed in the
text and tables, of which one of the key tables is reproduced here as Figure 2.
Note that only 12 of the trials employed aspirin alone. Overall reduction in
mortality was about 25%, mostly in the first 2 years of treatment. A special note
was made that men aged 55–74 with no history of vascular disease for whom as-
pirin treatment was actually primary showed no difference in mortality.

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Fig. 2. Meta-analysis of antiplatelet treatment from McCully & McCully (1999). Odds ratios
(active treatment : control) for first stroke, myocardial infarction, or vascular death dur-
ing scheduled treatment period in completed antiplatelet trials. Filled square: Trial results
and 99% confidence intervals (area of square proportional to amount of information con-
tributed). Open diamond: Overview results and 95% confidence intervals. Dashed verti-
cal line represents odds ratio of 0.75 suggested by overview of all trial results. Solid verti-
cal line represents odds ratio of unity (no treatment effect).
This BMJ article was cited in Science, a publication of the American Associ-
ation for the Advancement of Science, with reproduction of that same figure,
as an excellent example of how to do a meta-analysis, along with an explana-
tion of how to do one (Mann, 1990). The secondary nature of the trials was in-

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dicated only by the word “recurrence,” and the end point was implied to be
only “heart attack,” while the legend (in Figure 2) includes as end points MI,
stroke, and other vascular death.
The Science article was cited by Dean Radin in the book The Con-
scious Universe as an example of the power of meta-analysis (Radin, 1997).
Now Radin wrote implying that only aspirin was involved, and only for heart
attacks, and the secondary nature of the treatment was not mentioned at all,
which led me to believe, when I read this, that I should have continued using
aspirin myself after all.
Recommendations for You to Take Aspirin for Primary Prevention of Heart
Attacks
In publications for the general public there are a number of sources of ad-
vice to take aspirin for primary prevention of heart attacks. Here are a few:
Consumer Reports (CR), with Å 5 million subscribers and Å 20 million read-
ers, recommended that postmenopausal women, men over 35 with risk factors
such as smoking cigarettes, and possibly men over 45 without risk factors all
take aspirin. No dose level was given, although the study quoted was based on
“one ‘aspirin’ tablet every other day,” and the use of enteric coated aspirin was
advised only if uncoated aspirin caused damage to the stomach. “The ... study
found that one aspirin tablet every other day cut the rate of initial heart attacks
almost in half … The implications were stunning.” But then CR was very cau-
tious, noting that the clinical study they were citing showed significantly more
hemorrhagic strokes (rupture of blood vessel in the brain), ulcers, and allergic
reactions, and that no benefit was observed in another trial on healthy male
physicians in the UK (Consumer Reports, 1988). While the studies used did
not get proper citations, the first was certainly the Physicians Health Study in
which 22,071 male physicians were studied for 5 years (Steering Committee of
the Physicians Health Study Research Group, 1989; hereafter PHS 89.)
Julian Whitaker, MD, in his popular newsletter Health & Healing, properly
referenced PHS 89 and recommended that everyone take aspirin for primary
protection from MI, but at the rate of 162 mg every other day, or 81 mg every
day, half the dose used in PHS 89. While the study involved only male physi-
cians, Whitaker did not restrict his recommendations to males. Whitaker wrote
that the usual side effects of aspirin could be avoided by taking the low dose he
recommended with a meal (Whitaker, 1996).1
In the February, 2000 issue of Life Extension magazine, the recommenda-
tion for taking 81 mg of aspirin per day with food is unequivocal:
1 Dr. Whitaker is one of the most courageous advocates of new or alternate treatments for many condi-
tions. He has risked life, liberty, and financial ruin in trying to protect other practitioners from the FDA
and in campaigning for easy availability of supplements.

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A lot of people in alternative medicine criticize The Life Extension Foundation for rec-
ommending the daily use of low-dose aspirin, but The Foundation stands firm on the
recommendations it made in 1983: most healthy people should take low-dose aspirin to
specifically reduce their risk of heart attack. Aspirin may protect in ways that supple-
ments do not. (Knorr, 2000)
Of the 34 references cited at the end of the article in such a way that one can-
not tell which one backs each aspect of the article, just nine are to peer-re-
viewed journals. PHS 89 is not cited, nor is any peer-reviewed paper that
shows lower total mortality in low-risk subjects. The article is cleverly laid out
with a large space taken up by artwork so that it ends on the top half of its last
page. The bottom half of the page is an advertisement for Life Extension Foun-
dation’s brand of aspirin. Does this fact make you skeptical?
Recommendations for You Not to Take Aspirin for Primary Prevention of
Heart Attacks
From an anonymous author on a website (www.internetwks.com/pauling/
lie/mag.html):
We have been told that all the aspirin studies that ‘prove’ an aspirin a day keeps a heart
attack away—were with buffered aspirin, i.e., with added magnesium. Our sources
point out that it is unlikely that further studies using ‘plain’ aspirin will be undertaken
because preliminary studies always show ‘plain’ aspirin does not show the same pro-
tective effect against heart attacks. So if you still believe what you read in the mass
media, make sure that your daily aspirin is buffered! (Or much better yet, take a magne-
sium tablet instead!)
From the editors of the newsletter What doctors don’t tell you (McTaggart,
1995):
Possibly the largest collaborative study ever performed in medicine, this meta-analysis
(Antiplatelet Trialists’ Collaboration, 1994) pooled the results of some 174 clinical tri-
als from around the world, testing an aggregate of 110,000 patients … The overview
was designed to determine whether medium-dose aspirin (75 mg to 325 mg per day) …
could prevent … nonfatal heart attacks, strokes, or deaths in [mostly] high-risk patients
…. The researchers reckoned that this sort of therapy reduced the risk of [premature]
death [a solid endpoint] from one of these causes by one-sixth …. This isn’t the case
with low-risk patients; the study showed that among those taking aspirin as ‘primary
prevention’, although heart attacks were reduced by a third, there was a ‘non-signifi-
cant’ increase in nonfatal strokes. However, that increase was cited as 21% (hardly a
‘non-significant’ increase in our view) …. However, the study makes quite clear that
for low-risk people or for those with so-called risk factors like high cholesterol, hyper-
tension, or smoking, but without vascular disease, there is no evidence that this so-
called preventive therapy does any good. In fact, the risks (particularly of hemorrhage
or stroke) may outweigh the benefits. Therefore, there is no scientific justification for
your doctor’s view that you should start taking aspirin just in case.

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And from William Campbell Douglass, Jr., MD:
I’m sure you’ve heard about the study [PHS 89] showing that an aspirin a day prevents
heart attacks. In that study, men who took a daily aspirin had 47% [sic] fewer heart at-
tacks than men who didn’t. What you haven’t heard, and what I’m sure the aspirin com-
panies don’t want you to know, is that the subjects in that study took buffered aspirin—
aspirin mixed with magnesium. Numerous studies have proven that magnesium has a
powerful protective effect on your heart. It dilates blood vessels … aids potassium ab-
sorption into your cells (preventing heartbeat irregularities) … acts as a natural blood
thinner … and keeps your blood cells from clumping together [the anti-platelet effect];
indeed autopsies of heart attack victims almost always find a magnesium deficiency!
…. Not only that, but recent studies link aspirin to macular degeneration—the # 1
cause of blindness in people over the age of 55! But the biggest strike against aspirin
may come from the very study touting its heart benefits. If you read the study’s fine
print, you’ll find that even though the group taking aspirin had 47% fewer heart at-
tacks, there was no difference in the death rates of the two groups. That means that
death from other causes was 47% higher in the aspirin group! So stop taking that daily
aspirin! Stick to magnesium instead. (Douglass, 1988)
Are these people crazy? Not entirely. Now we know enough to divide the
original question that is the title of this article into two separate questions: on
primary as distinct from secondary prevention of heart attacks. Let us go to the
peer-reviewed literature to answer the first of the properly posed questions:
TABLE 1
Actual Deaths in PHS 89 Trial From PHS 89.
Aspirin
Placebo
Relative
95% Confidence
Causea
group
group
risk
interval
P value
Total cardiovascular deathsb
81
83
0.96
0.60–1.54
.87
Acute myocardial infarction
(410 )
10
28
0.31
0.14–0.68
.004
Other ischemic heart disease
(411–414)
24
25
0.97
0.60–1.55
.89
Sudden death (798)
22
12
1.96
0.91–4.22
.09
Stroke (430, 431, 434, 436)c
10
7
1.44
0.54–3.88
.47
Other cardiovascular (402, 421,
424, 425, 428, 429, 437, 440,
441 )
15
11
1.38
0.62–3.05
.43
Total noncardiovascula r deaths
124d
133
0.93
0.72–1.20
.59
Total deaths with confirmed
cause
205
216
0.95
0.79–1.15
.60
Total deathse
217
227
0.96
0.80–1.14
.64
Person-years of observation
54,894.6
54,864.2
—
—
—
a Numbers are code numbers of the International Classification of Diseases, ninth revision.
b All fatal cardiovascular events are included, regardless of previous nonfatal events.
c This category includes ischemic (three in the aspirin group and three in the placebo group), he-
morrhagic (seven aspirin and two placebo), and unknown cause (zero aspirin and two placebo).
d This category includes one death due to gastrointestinal hemorrhage.
e Additional events that could not be confirmed because records were not available included 23
deaths (12 aspirin and 11 placebo), of which 11 were suspected to be cardiovascular (seven as-
pirin and four placebo) and 12 noncardiovascula r (five aspirin and seven placebo).

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Should You Take Aspirin to Prevent a First Heart Attack?
The Antiplatelet Trialists’ Collaboration (1988) reported there were some
low-risk men aged 55–74 for whom aspirin treatment was actually primary.
The paper concludes with the opinion that the absolute benefits in primary
prevention of MI were uncertain because they might be outweighed by a small
increase in cerebral or other serious hemorrhagic disease. “Thus only for pa-
tients with an appropriate history of vascular disease is there at present clear
evidence that antiplatelet treatment reduces the overall incidence of fatal or
disabling vascular disease.” This opinion recognizes that the real end point is
life extension, not merely minimizing MIs.
Table 1 is reproduced from PHS 89. This massive study on 22,071 male
physicians, half taking 325 mg of “aspirin” every other day, showed that total
deaths in the aspirin group over the 5-year period of the study were 4% fewer
total deaths than in the placebo group (P = .64); thus the difference was not
considered significant. A big reduction in fatal MIs of 69% (P = .004) was
countered by nearly equal increases in the totals for sudden death (P = .09),
stroke, and other cardiovascular deaths. The reduction in MI was seen only in
those aged 50. Using the end point of life extension, not MI, there was hard-
ly any benefit from taking aspirin. With respect to nonfatal bleeding of several
types, the aspirin group had a relative risk of 1.32 (P = .00001). Furthermore,
48 in the aspirin group and 28 in the placebo group required blood transfusions
(P = .02, all 95% conf.). There really was a significant (P < .00001) reduction
in nonfatal MIs of 44%. But what did this mean in real benefit? It meant that in
a 1-year period the chance of having a nonfatal MI was cut from 0.44% to
0.25%.
There is no doubt that PHS 89 used Bufferin, not aspirin. Monthly calendar
packs containing either Bufferin or placebo were provided by Bristol-Myers
Products. Domenick Mellace of Bristol-Myers was acknowledged for his lo-
gistic support. Bristol-Myers contrived to have a 1.5 page advertisement
placed just ahead of this paper in the journal, in which advertisement they were
careful to advertise Bufferin only for secondary prevention as directed by the
FDA. Is it possible that the reduction in MIs was due to the magnesium present
in the Bufferin and not the ASA content?
By 1994 the Antiplatelet Trialists’ Collaboration published a meta-analysis
that was now up to 100,000 patients, of whom 30,000 were in the low-risk cat-
egory (Antiplatelet Trialists’ Collaboration, 1994). The doses were 75–325 mg
of ASA per day, but the exact source of the ASA was not given. “There was no
clear evidence on the balance of risks and benefits of antiplatelet therapy in
primary prevention in low-risk subjects.” In fact a graph was shown with “%
free from a vascular event,” including fatal, as the ordinate, and “years to first
vascular event” as the abscissa. For low risk subjects after 4 years the treated
group had 0.4% fewer events, that is, 4 per 1,000. But this included all of the
antiplatelet treatments, including 2 trials with drugs that were more effective
than aspirin, so it is likely that aspirin was of no benefit in low-risk subjects.

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Randomized clinical trials testing aspirin in 5,011 elderly people, 58% of
whom were women, mean age 72 years, followed for a mean of 4.2 years,
showed that use of aspirin caused a fourfold increase in hemorrhagic stroke (P
= .003) and a 1.6- to 1.8-fold increase in ischemic stroke (Kronmal et al.,
1998).
Based on the Nurses’ Health Study involving 79,319 women aged 34–59
years at the beginning, the role of aspirin in primary prevention of stroke was
uncertain (Iso et al., 1999). This was based on a questionnaire, so the reduc-
tion, mostly in older women, of large-artery occlusive infarction by half (1 to 6
aspirin per week) or a doubling of the risk of hemorrhage (15 or more aspirin
per week) might have included the use of a large fraction of buffered aspirin.
This was not thought important. Total death rates were not included.
“No conventionally used prophylactic aspirin regimen seems free of the risk
of peptic ulcer complications … Alka-Seltzer may be associated with higher
risk (2 ) and enteric-coated aspirin with lower risk (0.5 ) compared with plain
aspirin” (Weil et al., 1995). Users of aspirin for long periods to relieve arthritis
pain have suffered so badly from side effects that a multitude of alternates,
such as ibuprofen and naproxen, were introduced.
And, most recently, reported in 1998, a study of about 5,500 physicians in
the UK on primary prevention of ischemic heart disease (which causes MIs)
was carried out with 75 mg of aspirin daily in a controlled-release formulation
for a median time of 7 years. The main effect of aspirin was a 32% reduction in
nonfatal MI (less effective than PHS 89, which used double the dose), but
there was an increase of 12% in fatal MI leading to an overall rise in death
from all causes of 6%, which was not considered significant (Meade, 1998).
The absolute reduction in all MIs per year was 0.23%. Note that there is a 10%
increase in overall death rate in the aspirin group in this study compared with
the Bufferin group in PHS 89. Could this “nonsignificant” difference have
been a lack of the beneficial effect of the magnesium in Bufferin? Another dif-
ference from PHS 89 is that the men in this study were recruited from the quin-
tile considered to be at highest risk for MI based on heredity, smoking, blood
pressure, and obesity; but this is still a lower risk group than the one composed
of actual victims of MI.
If delaying death is the real end point, not reduction in heart attacks per se,
then it seems pointless to take aspirin for primary protection, with its certainty
of obnoxious side effects, which may include gastritis, peptic ulcer, other in-
ternal bleeding, hemorrhagic stroke, fatal MI, and sudden death, to which has
been added wet macular degeneration (in 1988) and 2–5 times the risk of
cataracts in those people who were 55 and then took aspirin for 10 years
(Cumming & Mitchell, 1998), in trade for a probable reduction of only 0.2%
absolute per year in total (mostly nonfatal) MIs, especially when safer alterna-
tives exist, such as magnesium.
Now it is time to ask the more difficult question…

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