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HEART HEALTH MIND & MOOD PAIN STAYING CANCER DISEASES & MEN'S HEALTH WOMEN'S
HEALTHY CONDITIONS HEALTH

Harvard Men's Health Watch

Aspirin and your heart: Many questions, some answers

Published: December, 2010

First marketed by the Bayer Company in 1897, aspirin (acetylsalicylic acid) is one of our oldest modern medications — and its parent compound
is much older still, since Hippocrates and the ancient Egyptians used willow bark, which contains salicylates, to treat fever and pain. Over the
past 100 years, aspirin has made its way into nearly every medicine chest in America. Indeed, this old drug is still widely recommended to control
fever, headaches, arthritis, and pain.

Although aspirin remains an excellent medication for fever and pain, other drugs can ll these roles equally well. But aspirin has a unique role
that was not even suspected by its early advocates. In patients with coronary artery disease, aspirin prevents heart attacks.

The rst evidence that aspirin could protect the heart did not come from an academic medical center but from a general practitioner. Beginning
in the 1940s, Dr. Lawrence L. Craven advised all his male patients between the ages of 40 and 65 to take aspirin every day to prevent coronary
thrombosis (clots in the heart's arteries). It seemed to work; Dr. Craven reported that surprisingly few of his patients had heart attacks or strokes.

Dr. Craven's observations were astute, and they support Yogi Berra's belief that you can observe a lot just by watching. Still, even the most careful
clinical observations must be con rmed by scienti c research. It took some 40 years, but in 1989 Harvard's Physicians' Health Study provided
impressive evidence that aspirin can indeed protect a man's heart. More than 22,000 men between the ages of 40 and 84 volunteered to take
either a standard 325-milligram (mg) aspirin tablet or a placebo every other day. Over the next ve years, the men taking aspirin su ered 44%
fewer heart attacks than their peers taking placebo. That would make low-dose aspirin seem like a sure winner, but the Harvard researchers
noted some nuances: although aspirin protected against heart attacks, it did not reduce the risk of cardiac death, and all the bene t was
con ned to men older than 50. And even in low doses, aspirin increased the risk of bleeding.

Scientists have continued to learn a lot about aspirin. Although the research has con rmed some ndings of the Harvard study from the 1980s, it
has also produced many complexities. Doctors still have a lot of questions about aspirin, and since every man must decide if aspirin for
prevention is right for him, you may have questions, too. Here are some answers — and some questions for additional research to puzzle out.

How does aspirin protect the heart?

The short answer is fairly straightforward. In the early stages of heart disease, cholesterol builds up in the walls of one or more coronary arteries.
The deposits trigger in ammation, eventually producing plaques that narrow the artery. Large blockages may prevent the heart muscle from
getting all the blood it needs, often causing the pain of angina. But a heart attack requires an additional insult, and in most cases, a small,
relatively new plaque is the culprit. First, the plaque develops a ssure or rupture, exposing its contents to the bloodstream. Tiny blood cells
called platelets stick to the ruptured plaque, and the sticky, activated platelets rapidly form a clot that completely blocks the artery, killing the
heart muscle cells that rely on that particular artery for their oxygen-rich blood.

Aspirin prevents heart attacks by stopping platelets from sticking together and forming artery-blocking clots.

What's the long answer?

The long answer is a bit complicated, but it's important since it explains aspirin's side e ects as well as its bene ts.

Aspirin's actions begin with its e ects on two important enzymes, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Think of COX-1 as a
"housekeeping" enzyme because it's present in many tissues, where it helps maintain various functions. For the most part, COX-1 does its job by
stimulating a family of chemicals called prostaglandins.
A particular prostaglandin (thromboxane A2) is the "glue" that makes platelets stick together and form clots. By inhibiting COX-1, aspirin
interrupts this chain of events and reduces the risk of heart attacks. But since platelets also trigger the "good" clots that stanch bleeding from
injured tissues, aspirin increases bleeding, whether from a shaving nick or a serious wound.

Prostaglandins in the stomach stimulate gastric blood ow and the production of acid-neutralizing bicarbonate and protective mucus. By
inhibiting COX-1, aspirin reduces prostaglandins that protect the stomach, increasing the risk of bleeding and ulcers.

Prostaglandins also help regulate kidney function and blood ow. By inhibiting COX-1, aspirin can reduce these protective chemicals, sometimes
raising blood pressure or reducing kidney function, especially in the elderly or in patients with kidney disease.

If COX-1 is a housekeeping enzyme, COX-2 is more of a troubleshooter. Instead of hanging around in healthy cells and tissues, it gets red up in
response to assaults such as infection and in ammation. COX-2 generates chemicals that trigger fever and pain; drugs that inhibit COX-2 do a
nice job of reducing pain and lowering high temperatures. But COX-2 is not all bad; it also produces prostacyclin, a chemical that widens arteries
and ghts blood clotting. Drugs that inhibit COX-2 may increase the risk of heart attack and stroke by reducing prostacyclin. That's why the
selective COX-2 inhibitors rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn from the market, while a third one, celecoxib (Celebrex)
requires extreme care. And it's also why the many nonsteroidal anti-in ammatory drugs (NSAIDs) that inhibit both COX-1 and COX-2 have a
mixed reputation (more on that later).

How much aspirin do I need for my heart?

Aspirin is 170 times more active against COX-1 than COX-2. That's why tiny doses can protect the heart and why they can also increase the risk of
bleeding. Most experts now recommend 81 mg (a "baby" aspirin) a day for prevention. Much higher doses are needed to inhibit COX-2 and treat
pain and fever.

Should I take aspirin if I develop heart attack symptoms?

Yes.

Because the clotting process is already under way as a heart attack develops, speed is essential. To get aspirin into your bloodstream as quickly
as possible, chew and swallow an uncoated 325 mg (full adult size) tablet as soon as possible. And call 911 just as quickly.

I've recovered from my heart attack; do I still need aspirin?

Yes.

The goal is to prevent another attack (doctors call it secondary prevention), and aspirin does help. Unless there is a speci c reason not to take
aspirin, everyone with coronary artery disease should take an aspirin every day; 81 mg is a reasonable daily dose.

I don't have heart disease, but I do have blockages in my leg arteries; should I take aspirin?
This one is a bit tricky. Your blockages represent peripheral artery disease (PAD). Like coronary artery disease, PAD is a manifestation of
atherosclerosis. Because PAD signals a substantial increase in the risk of heart attack preventive aspirin is logical. Logical or not, careful trials have
failed to demonstrate that aspirin reduces the risk of heart attacks in PAD patients. But since these same trials suggest possible protection
against stroke, and since aspirin may reduce the risk of troublesome clots in partially blocked leg arteries, the answer is not entirely clear.

I don't have heart disease, but I do have diabetes; should I take aspirin?
Another tricky one. Diabetes is such an important cardiovascular risk factor that it's often considered a heart disease equivalent; that's why the
goals for cholesterol and blood pressure are more stringent for diabetics than nondiabetics, and it's why the American Diabetes Association
(ADA) and the American Heart Association (AHA) recommended low-dose aspirin for cardiac prevention in diabetics over 40 in 2007. Since then,
however, studies have failed to demonstrate clear bene t, and the ADA and AHA have replaced their blanket recommendation with a call for
individual decisions based on cardiac risk. More research is needed; until it's completed, the answer for diabetics without heart disease is similar
to that of nondiabetics.

I am a healthy man; should I take aspirin to reduce my risk of heart attack?

This is the hardest question of all because it applies to so many men, and the evidence is complex and sometimes contradictory. As in the use of
any medication, it's a question of balancing the potential bene ts of a drug against its possible risks. In the case of low-dose aspirin for
cardiovascular prevention in men, the major bene ts and risks have been evident since the 1980s, when the Physicians' Health Study
documented protection against heart attacks at the cost of an increased risk of bleeding.

The respected United States Preventive Services Task Force (USPSTF) has analyzed the many studies on aspirin for prevention in healthy people
(primary prevention), and has o ered a helpful set of guidelines. For average men between 45 and 79, the USPSTF encourages daily low-dose
aspirin when the bene t (protection against heart attacks) outweighs the risks (bleeding). The USPSTF does not recommend aspirin for healthy
men younger than 45, and it doesn't have enough data to o er advice to men above 79.

Individual decisions are best, ideally based on a discussion between a man and his doctors. But to help you estimate your risk of heart attack, you
can plug your numbers into an online calculator to determine your Framingham Risk Score (http://health.harvard.edu/heartrisk). Like the risk of
heart attacks, the risk of aspirin-induced complications increases with age. Based on an average risk of complications, men between 45 and 59
who have a 10-year heart attack risk of 4% or more are likely to bene t from low-dose aspirin; between 60 and 69, a 10-year cardiac risk of 9% or
more suggests bene t; and between 70 and 79, a 10-year cardiac risk of 12% or more signals probable bene t.

As cardiac risk increases, potential bene t increases — but as the risk of complications increases, the reverse is true. In addition to age, risk
factors for complications include a history of ulcers or gastrointestinal bleeding; regular use of any NSAID; taking other antiplatelet drugs such as
clopidogrel (Plavix), prasugrel (E ent), or dipyridamole (Persantine); taking anticoagulants such as warfarin (Coumadin); and having
uncontrolled hypertension or a previous hemorrhagic stroke.

Dr. Craven was onto something big in the 1940s, but his across-the-board recommendations for aspirin based simply on age and gender are
dated, to say the least.

What should I tell my wife when she asks about taking aspirin?
Aspirin is every bit as e ective and important for women with heart disease as it is for men. But for healthy women, it's another story; aspirin
does not appear to reduce the risk of heart attack, but it does o er protection against strokes caused by blood clots (ischemic strokes). The
USPSTF recommends that women between 55 and 79 consider aspirin when their risk of stroke exceeds their risk of gastrointestinal bleeding.

What about stroke in men?

Way back in the 1940s, Dr. Craven noticed that aspirin protected his male patients from ischemic strokes. He worried about hemorrhagic strokes
(strokes from bleeding), but did not observe any, though the Physicians' Health Study did report a slight increase in men taking aspirin. And
that's more or less where we stand today. Healthy men should not take aspirin strictly to prevent a rst ischemic stroke, but low-dose aspirin may
protect patients who have already had this type of stroke. And since ischemic strokes are about nine times more common than hemorrhagic
strokes, the potential protection against strokes caused by clots should o set the possible risk for strokes caused by bleeding. However, men
with hypertension should not take aspirin until their blood pressure is well controlled, and men who have recovered from hemorrhagic strokes
should check with their doctors before starting low-dose aspirin.

Will enteric-coated aspirin reduce my risk of ulcers and bleeding?

Unfortunately, no.

Aspirin in the stomach is not the problem; aspirin in the blood inhibits COX-1, reducing the prostaglandins that protect the stomach.

Does enteric-coated aspirin work as well as uncoated aspirin?

Some doctors have worried that it might not, but since enough gets into the blood to increase the risk of bleeding, enough gets in to inhibit
platelets and protect the heart. In fact, COX-1 and platelets are so sensitive to aspirin that doses as small as 30 mg will inhibit all the platelets in
the body. And a head-to-head trial that compared 81 mg of coated and uncoated aspirin in 50 volunteers showed that they are equally e ective
in inhibiting platelets. But since rapid action is essential during a heart attack, chew an uncoated aspirin if you develop worrisome symptoms.

Is there any way to protect my stomach from aspirin-induced bleeding?

Yes.
Low doses of aspirin appear to pose less risk than higher doses, so sticking to 81 mg a day should help. It is even more important to avoid other
NSAIDs, or if you have to use one, to take the lowest e ective dose for the shortest time possible. And it's also important to be careful with
alcohol and other things that can irritate the stomach.

If you are at high risk for gastrointestinal bleeding but still need aspirin, you can get protection by taking a powerful acid-suppressing proton
pump inhibitor, such as omeprazole (generic, Prilosec) or the synthetic prostaglandin misoprostol (generic, Cytotec). Although popular H2-
blocking drugs such as famotidine (Pepcid), cimetidine (Tagamet), and ranitidine (Zantac) reduce gastric acid, they are less able to reduce the
risk of aspirin-induced bleeding.

Can I be allergic to aspirin? And if I am, what can I do?

It's not common, but some people are allergic to aspirin. For others, the drug is ine ective. A number of strategies are available for these folks;
the most straightforward is to take a di erent antiplatelet drug, such as clopidogrel.

If I take low-dose aspirin but need more help for pain or fever, what should I choose?
Acetaminophen (Tylenol and other brands). It does not target either COX enzyme, so it doesn't inhibit platelets or increase the risk of bleeding.
Acetaminophen won't protect your heart, but it is very e ective for fever and mild to moderate pain. Like all medications, though, it has
potential side e ects of its own. To avoid liver injury, take acetaminophen every four to six hours as needed, but don't exceed a total dose of
4,000 mg a day.

What about other NSAIDs and my heart?

Aspirin is much, much more active against COX-1 than COX-2; that's why it can protect the heart but also cause gastrointestinal bleeding. At the
other end of the spectrum is the selective COX-2 inhibitor celecoxib; by inhibiting COX-2, it can ght pain and in ammation, but it also increases
the risk of cardiovascular problems.

The other NSAIDs inhibit both COX-1 and COX-2, though the exact balance varies from drug to drug. The pessimist would note that these
medications' side e ects encompass the worst of both worlds, since they increase the risk of gastrointestinal bleeding and heart attacks. Indeed,
since 2005, the FDA requires a "black box" warning about cardiovascular risk for all NSAIDs except aspirin.

Still, millions of Americans take NSAIDs, and they are helpful for arthritis and pain. Don't use an NSAID unless you really need it, and then use the
lowest e ective dose for the shortest time possible. Follow directions carefully, stay alert for side e ects, and consider a medication to protect
your stomach if you are at high risk of bleeding (see above).

Two widely used NSAIDs deserve special attention. Ibuprofen (Advil, Motrin, other brands) appears to interfere with the heart-protective
platelet-inhibiting e ect of low-dose aspirin. Although it's not clear if this laboratory phenomenon is clinically important, you can avoid a
potential con ict by switching to another NSAID or, if you really want ibuprofen, by taking your aspirin two hours before your ibuprofen.

Naproxen (Naprosyn, Aleve, generic) does not interfere with aspirin, and it may have a lower cardiovascular risk than other NSAIDs.

Does low-dose aspirin have other bene ts?

Possibly. In particular, there is reason to hope that it may reduce the risk of colon cancer and possibly other malignancies, including prostate
cancer. At present, though, it is premature to recommend low-dose aspirin to prevent cancer (though patients who have had colon cancer might
be wise to consider it to help lower their risk of a recurrence).

Should I take my low-dose aspirin in the morning or at night?

It's another interesting question. Platelets are so sensitive to aspirin that a single 81-mg dose will inhibit the stickiness of all the platelets in your
body — and the inhibition is irreversible. But if the inhibition is permanent, platelets are not. In fact, they are short-lived cells that are constantly
being removed from your blood and replaced by a steady stream of new platelets that pour out from your bone marrow. You need to take
aspirin on a regular basis to inhibit these new platelets. Doctors now recommend daily dosing, but the decades-old Physicians' Health Study
showed that taking aspirin every other day also works.

Heart attacks and strokes peak in the early morning hours, even before most men would have a chance to take their preventive aspirin. In theory,
then, taking aspirin at bedtime would provide maximum platelet inhibition and protection during this vulnerable period. And a 2005 Spanish
study found that morning doses of aspirin raise blood pressure, while bedtime doses lower it.
Bedtime aspirin would seem ideal — if you can remember to take it. Most people nd it easier to remember to take their medications rst thing
in the morning than later in the day. If you're one of these, you're much better o taking aspirin faithfully in the morning than erratically at night.

Should I stop taking my aspirin before elective surgery?

Another good question, again with a nuanced answer. After you stop aspirin, its e ects slowly wear o as new platelets replace older, inhibited
cells. Bleeding tests return to normal after four days, and detailed tests of platelet function are entirely normal by six days.

If you are having only minor surgery, you may not need to stop aspirin at all. If you are free of heart disease and are taking aspirin for primary
prevention, it's reasonable to stop aspirin six days before your operation. But if you've had a heart attack or have angina, the situation is tricky;
your cardiologist would like you to continue aspirin as long as possible, but your surgeon would probably prefer to have you o it for about six
days. Let them duke it out, but if they can't decide, you might split the di erence by stopping your aspirin a few days before surgery.

Should I take aspirin for prevention?

If you have angina or have had a heart attack, you should take 81 mg a day unless you have a compelling reason not to take aspirin. If your
reason is previous gastrointestinal bleeding, consider taking a proton pump inhibitor or misoprostol to protect your stomach while you take
aspirin. If you have a true aspirin allergy, consider taking clopidogrel instead.

If you don't have heart disease, the answer is more complex. Don't take aspirin if you are below 45, and think twice about it if you are 79 or older.
If you are between 45 and 79, you should consider taking 81 mg of aspirin a day if your risk of heart attack exceeds your risk of aspirin-induced
bleeding. And since only 7.5% of American adults have a low heart attack risk factor pro le, and over 600,000 have rst heart attacks each year,
that means most men should think seriously about aspirin.

If you are one of the many American men at risk, aspirin can help. But prevention requires much more than a baby aspirin a day. To keep your
heart healthy, avoid tobacco in all its forms; keep your cholesterol, blood pressure, and blood sugar low; exercise regularly; eat right; stay lean;
and avoid excessive stress. And if you do all that, you won't need aspirin at all — unless, of course, you get a headache.

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