by Joel M. Kauffman - posted by Eric Krieg April 7 00
"Nothing is Simple." --Harry Rowe Mimno, Professor
of Applied Physics, Harvard University
Introduction
| Recent advice given in books and articles for general audiences is in total disagreement. 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 found 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-reviewed papers will allow you to draw conclusions about whom could benefit by taking aspirin which are at odds with some strongly-held opinions. (The meaning of medical terms may be found in ordinary or medical dictionaries, or http://www.drkoop.com/search/query.) |
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 [1]. It was first synthesized by Carl R. Gerhardt in 1853 [2].
The major therapeutic 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 salicylates already in use. ASA was not "invented" in
1897 as in the book The Aspirin Wars [3] ("Wars", p7 and cover).
First trademarked in 1899 by Bayer AG [4], 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 [5]. 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 arthritis-strength tablets contain 500 mg. For
other uses tablets containing 160 and 81 mg are available. Enteric-coated
aspirin tablets resist the acidic environment 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 [6]. "Buffered"
aspirin is no faster than plain aspirin (Wars, p164) and only slightly
less irritating, if at all (www.mayohealth.org).
Because it may be important for preventing heart attacks, a Bufferin? tablet,
besides 325 mg of ASA, has an actual alkali content of 158 mg of calcium
carbonate, 63 mg of magnesium oxide and 34 mg of magnesium carbonate; the
latter pair provide a total of 48 mg of magnesium. 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 potential MIs from occurring by taking small doses of aspirin
for a long period. Any side effects of aspirin can be serious if
a great number of people begin taking it at age 45-50 and continue for
30-40 years. Secondary prevention means that 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 period.
Any recommendation for or against aspirin that does not make the distinction
can be disregarded as superficial.
Wars distinguished between primary prevention of first heart
attacks and secondary prevention on p11 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 prescient decision. But by p334 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 preventive 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 T. R. Fleming and D.
L. DeMets in Annals of Internal Medicine 125, 605-613 (1996). Clinical
trials are the standard scientific method for evaluating a new drug or
a new use for an old drug. The true endpoint 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 endpoint is
a laboratory measurement or a physical sign used as a convenient substitute
for a clinically meaningful endpoint that measures survival directly. Changes
induced by a therapy on a surrogate endpoint are supposed to reflect changes
in a clinically real endpoint; but all too often, they do not.
Examples of surrogate endpoints 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, lowered cholesterol levels an average of 10%, but
there was a 1% increase in overall mortality. A meta-analysis of
trials of calcium channel blockers that really do lower blood pressure
showed possibly harmful effects overall. In addition, two new antiarrythmia
drugs approved by the FDA, encainide and flecainide, clearly suppressed
arrythmias, probably as seen by electrocardiograms, as the surrogate endpoint.
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 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
prevention of MI was reported in the British Medical Journal (BMJ) in 1988
[7]. 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 attack, 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 aspirin treatment was actually primary
showed no difference in mortality.
This BMJ article was cited in Science, a publication of the American
Association 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 explanation of how to do one [8]. The secondary nature of the trials
was indicated only by the word "recurrence" and the endpoint was implied
to be only "heart attack", while the legend (in Figure 2) includes as endpoints
MI, stroke, and other vascular death.
The Science article was cited by Dean Radin in the book The Conscious
Universe as an example of the power of meta-analysis [9]. 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 advice to take aspirin for primary prevention of heart attacks.
Here are a few:
Consumer Reports (CR), with 5 million subscribers and 20 million
readers, recommended that postmenopausal women, men over 35 with risk factors
such as smoking cigarets, and possibly men over 45 without risk factorsall
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 cautious, 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 [10]. 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 [11]. (This will be called PHS 89.)
Julian Whitaker, M. D., 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 physicians, 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 [12].
In the current issue of Life Extension Magazine the recommendation
for taking 81 mg of aspirin per day with food is unequivocal: "A lot of
people in alternative medicine criticize The Life Extension Foundation
for recommending 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 supplements do not." [13]
Of the 34 references cited at the end of the article in such a way that
one cannot tell which one backs each aspect of the article, just 9 are
to peer-reviewed 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 art work so
that it ends on the top half of its last page. The bottom half of
the page is an advertisement for Life Extension Foundation'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 protective 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 magnesium tablet instead!)"
"Possibly the largest collaborative study ever performed in medicine,
this meta-analysis (BMJ 8 Jan 94) pooled the results of some 174 clinical
trials from around the world, testing an aggregate of ll0,000 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-significant' increase in nonfatal stokes. 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
of for those with so-called risk factors like high cholesterol, hypertension,
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 hemorrage 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." Thus wrote the editors of the
newsletter What Doctors Don't Tell You [14].
And from William Campbell Douglass, MD: "I'm sure you've heard
about the study [PHS 89, Ref. 11] showing that an aspirin a day prevents
heart attacks. In that study, men who took a daily aspirin had 47%
[sic] fewer heart attacks than men who didn't. What you haven't heard,
and what I'm sure the aspirin companies 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 absorption
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 attacks, there wasno 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." [15]
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:
Should You Take Aspirin to Prevent a First Heart Attack?
In the Antiplatelet Trialists' Collaboration [7] reported in 1988
there were some low-risk men aged 55-74 for whom aspirin treatment was
actually primary. The paper concludes with the opinon 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 patients 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 endpoint is life extension, not merely
minimizing MIs.
Figure 3 is reproduced from PHG 89 [11]. This massive study
on 22,071 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=0.64),
thus the difference was not considered significant. A big reduction
in fatal MIs of 69% (P=0.004) was countered by nearly equal increases in
the totals for sudden death (P=0.09), stroke and other cardiovascular deaths.
The reduction in MI was seen only in those aged Ú 50. Using
the endpoint of life extension, not MI, there was hardly any benefit from
taking aspirin. With respect to non-fatal bleeding of several types
the aspirin group had a relative risk of 1.32 (P=0.00001). Furthermore,
48 in the aspirin group and 28 in the placebo group required blood transfusions
(P=0.02, all 95% conf.). There really was a significant (P<0.00001)
reduction in non-fatal MIs of 44%. But what did this mean in real
benefit? It meant that in a 1-year period the chance of having a
non-fatal MI was cut from 0.44 % to 0.25%.
There is no doubt that PHG 89 used Bufferin, not aspirin.
Monthly calendar packs containg either Bufferin or placebo were provided
by Bristol-Myers Products. Domenick Mellace of Bristol-Myers was
acknowledged for his logistic 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 catagory [16]. 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 1000. 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.
Randomized clinical trials testing aspirin in 5011 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 4-fold increase in hemorrhagic stroke
(P=0.003) and a 1.6- to 1.8-fold increase in ischemic stroke [17].
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 [18]. This was based on a questionaire, so
the reduction, mostly in older women, of large-artery occlusive infarction
by half (1 to 6 aspirin per week) or a doublng 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 (2X) and enteric-coated aspirin with lower
risk (0.5X) compared with plain aspirin." [19] 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 5500 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 non-fatal MI (less effective than PHG 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 [20]. 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 PHG 89.
Could this "non-significant" difference have been a lack o the beneficial
effect of the magnesium in Bufferin? Another difference from PHG
89 is that the men in this study were recruited from the quintile 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 internal bleeding, hemorrhagic stroke, fatal MI, and
sudden death, to which has been added wet macular degneration (in 1988)
and twice the risk of cataracts (in 1998), in trade for a probable reduction
of only 0.2% absolute per year in total (mostly non-fatal) MIs, especially
when safer alternatives exist, such as magnesium.
Now it is time to ask the more difficult question...
Should You Take Aspirin to Prevent a Second Heart Attack?
Five earlier studies on secondary prevention of MI by ASA were
reported from 1974-1980. There was said to be no beneficial effect
overall [21]. One multicenter study, nevertheless, the earliest of
this type I have seen, had positive results. A single daily dose of 300
mg of aspirin in a gelatine capsule or a similar-looking placebo was to
be taken before breakfast to ensure rapid absorption by 1,239 men who had
had a recent MI. The aspirin group showed a reduction in total mortality
of 12% at 6 months, 25% in 1 year, and 28% at 2 years. The authors
modestly acknowledged that the results were statistically inconclusive,
but they were in the range of what was observed in later trials.
The much larger size of the later trials was needed to obtain results that
would be statistically solid [22].
Reported in 1988, the second International Study of Infarct Survival
(ISIS-2) Collaborative Group in the UK determined the effect of aspirin
vs. placebo in 17,187 people entering 417 hospitals after the onset of
suspected acute MI. The aspirin used was clearly stated to be 162.5
mg in an enteric coated tablet given daily for 1 month. All-cause
mortality was said to be similar to vascular mortality. After 5 weeks
aspirin produced 23% fewer vascular deaths overall (2P<0.00001), cut
MIs from an absolute value of 2% to 1%, cut non-fatal stroke from 0.6%
to 0.3%, and did not cause any increase in cerebral hemorrhages.
Survival rates after 2 years were 81.7% in the aspirin group vs. 80.0 %
on placebo [23].
In 1988 the Antiplatelet Trialists' Collaboration [7] on 29,000
patients, a majority with a history of transient ischemic attack, stroke,
unstable angina, or MI, were treated by a variety of methods, including
with ?300 mg ASA daily, which did not differ greatly in results from other
drug regimens employed in the trials, as shown by this meta-analysis (see
Figure 2). The authors thought that vascular mortality was reduced
by 1/6, and non-vascular undesirable events by 1/3 in high-risk patients.
By 1994, now up to 70,000 high-risk patients, the Antiplatelet Trialists'
Collaboration [16] found similar results; but now the daily aspirin dose
was 75-325 mg.
By 1998 ISIS-2 was still following 6,213 high-risk patients in
the UK of the 17,187 originally in the trial. During the first 35
days of follow-up the use of aspirin during the first month reduced the
death rate by 22%. Hence all of the survival benefit of an early,
one-month course of oral aspirin (162.5 mg enteric coated, daily) seemed
to accrue during the first month, with little further benefit between day
36 and the end of year 10, by when the death rate was down 1% relative
to placebo [24].
This then was the background of the North of England Aspirin
Guideline Development Group's recommendations to physicians: Aspirin
should be used in patients with acute MI at 150 mg daily for one month,
then 75 mg daily for several years. In patients with MI, anginas,
stroke, or transient ischemic attack, aspirin should be used at 75
mg daily for several years. There was no evidence that higher doses
were more effective [25]. The Group did not mention either buffer
or enteric coating. The latter seems desirable to this writer.
So the answer for secondary protection from recurrence of several
types of undesirable vascular conditions is: Yes, take aspirin in low doses,
and not forever, in order to obtain a moderate (16-22%) protection from
fatal MI. But is aspirin the best protection there is, either from
the standpoint of effectiveness or freedom from side effects? Probably
not.
What Else Could You Take to Prevent Heart Attacks?
Vitamin E for primary protection
The Nurses Health Study involved 87,245 female nurses aged 34-59
in 1980, who were free from diagnosed cardiovascular disease and cancer,
and who completed dietary questionaires every two years up to eight years.
Women who took vitamin E supplements containing, on average, 200 IU (International
Units) for more than 2 years had 41% fewer instances of coronary disease
of several types, and and overall mortality 13% lower than those who did
not (P=0.05) [26]. The amount of vitamin E in multivitamin capsules
at that time was typically ? 30 IU.
The Health Professionals Follow-up Study involving >40,000 males
aged 40-75 in 1986 who were free of diagnosed coronary heart disease, diabetes,
or hypercholestemia completed detailed dietary questionaires every two
years until 1990. Men who took 100-250 IU of vitamin E as supplements
for 2-10 years had 37% fewer instances of coronary disease of several types,
including fatal (P=0.05). Higher doses of vitamin E were no more
effective. By contrast, the intake of vitamin C and beta-carotene
did not lower risk [27].
These results are far more impressive than the ones for aspirin,
especially because side-effects were so minimal as not to be mentioned.
And vitamin E could be bought at almost any grocery store.
Vitamin E for secondary protection
The Cambridge Heart Antioxidant Study [CHAOS (English humor?)]
was a single-center, double-blind, placebo-controlled study with 2002 patients
who had angiographically proven coronary atherosclerosis (fatty deposits).
Doses of 400 or 800 IU of vitamin E were used in half, and the group was
followed or a median of 510 days. Vitamin E gave a significant reduction
in non-fatal MI of 77% (P=0.005); however, there was a non-significant
excess (18%, P=0.61) of cardiovascular deaths in the combined Vitamin E
groups. The lower dose of vitamin was better on both counts, including
a lower death rate on 400 IU than on placebo. So here, too, vitamin
E is far more effective than aspirin, and, again, side effects were negligible
[28].
Magnesium for primary protection
The Caerphilly Heart Disease Study of men aged 45-59 years at
the beginning of a 5-year period examined the relation of magnesium in
the diet to the incidence of MIs, both fatal and non-fatal. Of the
627 men in the study 38 suffered MIs. The mean daily intake of magnesium
in these was 12% lower than in men who did not have MIs. This is
difference of about 38 mg per day, less than the amount in a Bufferin tablet
[29]. The inverse relation of magnesium concentrations in drinking
water to rate of heart attacks has been noted many times [30].
The usual recommendations for dietary supplements are to take
300-600 mg of magnesium in a compound (not the metal) daily with food [31].
The most common form in which to take magnesium is as the compound magnesium
oxide, one of the alkalis in Bufferin; but equally persuasive is advice
to take it as potassium magnesium aspartate for fast absorption [32].
Women at risk of osteoporosis are advised to take also about twice the
mass of calcium [33]. But calcium, as well a vitamin D and phosphates,
increase the amount of magnesium needed [34]. Mildred Seelig, MD,
also wrote that the typical daily intake of magnesium in American college
students was 250 mg, not ?385 mg recommended for a 140-lb woman, or ?500
mg for a 185-lb man. Unfortunately, I have not found a report on
a large clinical study on primary protection using supplements in humans.
A prospective study of 10-year duration in 400 "high-risk" subjects
(selected about as in Ref. 20), of whom 93.5% were male, living in Moradabad,
India, was carried out by assigning half the group to a high-magnesium
diet (1,142 mg per day vs. 418 mg in the control group from fruits, green
vegetables, cereals and nuts) and tracking medical events. The high-magnesium
group had 35% fewer deaths from all causes (P < 0.001), and a 61% reduction
of non-fatal cardiovascular events (P < 0.001), including a 54% reduction
in strokes [35]. Unfortunately, this report was marred by a
number of arithmetical errors in the table of results. There was
also a confounding factor in that the high-magnesium diet was also a high
calcium diet (880 vs. 512 mg daily) and a high-potassium diet (3,080 vs.
548 mg daily). Since serum levels of magnesium and potassium were
raised, and those of calcium were not, it is most likely that the magnesium
and potassium were responsible for the differences in outcomes, which also
included significant reductions in serum total cholesterol and glucose.
Use of magnesium supplements in many people is probably justified
by inference based on their effectiveness on secondary prevention, the
clinical experience of a number of physicians, the drinking water studies,
and the above diet study. The diet study would support using potassium
magnesium aspartate as the supplement most resembling the high-magnesium
diet.
Magnesium for secondary protection
In a double-blind, placebo-controlled study involving 273 patients
with suspected acute MI, 74 received placebo, while 130 received 1.2 g
of magnesium as the chloride intravenously during 24 hours, followed by
0.3 g in the next 24 hours. Treatments were begun within 3 hours
of hospital admission. During the first 4 weeks after treatment mortality
was 7% in the magnesium group and 19% in the placebo group, a reduction
of 63% (P=0.045). In the magnesium group 21% of the patients had
arrhythmias that needed treatment vs. 47% in the placebo group, a reduction
of 55% (P=0.004). No adverse effects of intravenous magnesium were
observed [36].
Reported in 1992, the second Leicester Intravenous Magnesium
Intervention Trial (LIMIT-2) on 2316 patients with suspected acute MI found
a 24% reduction (P=0.05) in 28-day mortality from treatment with intravenous
magnesium sulfate. Reported in 1995, the fourth International Study
of Infarct Survival (ISIS-4) showed no benefit of similar treatment of
29,000 patients.
By 1996 the discrepancy was explained as follows: LIMIT-2
was double-blind and placebo controlled, and only 30% of the patients had
received treatment for thrombosis (streptokinase) by the time magnesium
was begun on average 3 hours after onset of symptoms. ISIS-4 was
non-blinded, had no placebo, the alternate treatments being the drugs isosorbide
mononitrate or captopril; and 70% of the patients had received treatment
(which raises blood magnesium concentrations) for thrombosis (clotting
in major blood vessel), and 94% had received aspirin by the time magnesium
was begun on average 8 hours after onset of symptoms. It in interesting
that captopril is a product of Bristol-Myers Squibb, the sponsor of ISIS-4,
at a cost of about $10 million.
A study appeared simultaneously involving 194 patients considered
unsuitable for treatment for thrombosis. In-hospital mortality was
4.2% in the magnesium group and 17.3% in controls, a reduction of 76% [37].
Where confounding treatments are absent, rapid treatment of patients
suffering from MI with intravenous magnesium is of great benefit in secondary
prevention, not only of MI, but of arrhythmias. The 3 studies not
confounded showed, on average, a greater 4-week benefit than from aspirin,
and LIMIT-2 showed that concurrent aspirin did not change the outcome.
Side-effects of magnesium were minimal and could be avoided altogether.
The medical establishment has accepted the role of oral magnesium
supplements in countering hypertension, MI, congestive heart failure, and
arrhythmias [38].
Coenzyme Q10 for primary protection
Coenzyme Q10 is an oily organic compound, like vitamin E, and
is found in every cell of the body. It has a number of functions,
among which are preventing the oxidation of LDL, and transporting oxygen
from hemoglobin into the parts of cells where ATP, the main source of cellular
energy, can be formed. Sharing its status with magnesium, the value
of oral coenzyme Q10 supplements for better health in a low-risk population
has not been investigated in large-scale controlled experiments [39]. Its
use in older people with some definite symptoms, such as congestive heart
failure, is probably justified by inference based on its effectiveness
on secondary prevention, and the clinical experience of a number of physicians.
For details see the website of The International Coenzyme Q10 Association
(wwwcsi.unian.it/coenzymeQ).
Coenzyme Q10 for secondary protection
The New York Heart Association (NYHA) has grouped heart failure
into 4 classes of severity. A cardiac patient in class IV, the most
serious, is unable to perform any physical act without discomfort, and
symptoms of heart failure, including anginal pain, may be present even
at rest. Cardiologists know that such patients are on a relentless
downhill course to death in spite of all conventional therapy. In
a study in which all patients in hospitals were in NYHA classes III and
IV, and all received conventional therapy (bypass surgery, digitalis, diuretics,
vasodilators), about 25% survived for 3 years. The 88 patients treated
with Coenzyme Q10 had a 75% survival rate. Putting this finding in
the same form as used above, the reduction in 3-year death rate was 67%!
[40]
Congestive heart failure is always characterized by an energy
depletion status correlated with lowered coenzyme Q10 levels. In
a 1-year double-blind trial 641 patients of mean age 67 with chronic congestive
heart failure (NYAS classes III and IV) were randomly assigned to receive
either 2 mg/kg (˜100 mg) daily of coenzyme Q10 or placebo. The number
of patients who required hospitalization for worsening heart failure was
38% lower (P < 0.001) in the Q10 group; the incidence of pulmonary edema
was cut by 61%, and of cardiac asthma was cut by 51% (both P < 0.001)
[41]. A similar study on 2500 patients showed only 0.5% with side
effects thought due to Q10.
Summing Up
Not only the medical adviser to Consumers Union, but also some
health professionals who recommend aspirin, believe that there is a "high-risk"
but not-yet-diagnosed population who should take aspirin for primary prevention
of heart attack. You may check for yourself in the studies cited
- often there is no such group. True, males > 50 years old are at
higher risk than males or females < 50, but those males > 50 are actually
the low risk group in most of the large studies on health professionals.
The study with the most favorable results in terms of reducing MIs, PHG
89, used Bufferin, which contains a significant amount of magnesium, not
plain aspirin. This fact was lost on the author of The Medical Letter
42 (1072), 21 Feb 00, p18, who cited PHG 89 and did not believe that the
later European studies were valid.
There is no consensus even among cardiologists that use of aspirin
in the general population is advisable. For one, Prof. F. Verheught,
Dept. Cardiology, University Hospital, Nijmegen, Netherlands, warned that
“use of aspirin for primary prevention was inadvisable because its use
was investigated only in men, that the risk of non-fatal MI is < 0.5%
per year [and would be cut only by 0.2%], and that there was risk of gastric
discomfort and bleeding” [42]. The studies on low-risk males
were carried on for 5-7 years. Based on life-expectancies, advice
to take aspirin beginning at age 50 would mean ˜30 years of exposure to
its side-effects.
Vitamin E is both more effective and safer than aspirin, and
its value in primary protection has been demonstrated in both men and women.
Magnesium intake is inversely correlated with incidence of cardiovascular
problems, the effect being more pronounced in men than in women.
Up to at least 1,100 mg daily along with up to 3,000 mg of potassium is
strongly protective.
In secondary protection, aspirin has a limited but definite value,
and does not have to be taken forever; most of the benefit is obtained
in the first month. Based on available evidence, aspirin is preferred
for the majority of stroke or myocardial infarction (heart attack) patients
at risk of recurrences, according to The American Heart Association. But
studies have shown that vitamin E, magnesium, and coenzyme Q10 each provide
much greater benefits than aspirin with lesser side-effects. Not
even the skeptical website www.quackwatch.com
disagrees
with this.
A skeptical outlook is of great value in evaluating medical claims
of most types. Medical advice with no citations to peer-reviewed
papers on well-controlled studies can be ignored. You should spot-check
the original papers, but beware of the internet trap - you can get abstracts
free, but it is more difficult or costly to obtain the full papers from
websites. While all of the peer-reviewed papers in this field seem
very honestly presented, some important facts often do not appear in the
abstracts, and some studies were contrived to favor a pre-conceived result.
Acknowledgements: The following faculty at The University
of the Sciences in Philadelphia provided help: Eric G. Boyce, Donna
Gagnier, Daniel A Hussar, Jeannette McVeigh, and William A. Reinsmith,
were of great help, but do not necessarily agree with the conclusions.
Additonal aid was provided by Charles J.Kelley, Tom Miller and Mildred
Seelig, MD.
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send comments to: kauffman@SHRSYS.HSLC.ORG
Additional Note: In people under 55 years old to start taking
aspirin at more than 1 per
week for more than 10 years, the risk of getting cataracts goes up
2-5 fold.
