You might expect that by now doctors and researchers would know everything they need to know about aspirin, a hundred-year-old drug that is taken by nearly half of Americans over age 55. But that isn't the case. Some important uncertainties still linger regarding the use of the ubiquitous white pill. Two unsettled issues are who should take aspirin to prevent a heart attack or stroke and how much to take.
Some people who should be taking it aren't, while others who don't need to take it are. About one-third of aspirin users pop a regular-strength tablet containing 325 milligrams (mg) of acetylsalicylic acid, the active ingredient in aspirin. Most of the others take a baby aspirin containing 81 mg.
Some important uncertainties still linger regarding the use of the ubiquitous white pill.
If aspirin were a completely benign drug, who takes it - and at what dose - wouldn't matter much. But it has unwanted side effects that can offset its benefits. This means aspirin isn't the kind of drug to start taking on a whim without first talking with a doctor. Over the past few years, various recommendations from the American Heart Association, the US Preventive Services Task Force, and other groups have helped bring into focus who should take aspirin. Although these recommendations are fairly general, they help indicate who should be taking aspirin and how much of it.
How aspirin works
Willow, myrtle, and other plants provided humans with salicin, a natural painkiller, for thousands of years. Although it eased aching joints, fever, and labour pain, salicin came with a price - it caused nausea, vomiting, ulcers, and sometimes bleeding in the stomach or intestines. In 1897, a young chemist named Felix Hoffmann was searching for an alternative to salicin as a remedy for his father's crippling arthritis.
While working for the German chemical company Bayer, he discovered how to synthesise acetylsalicylic acid, a chemical relative of salicin. Not only did acetylsalicylic acid relieve pain more powerfully than salicin, but it was far gentler on the stomach.
Bayer, eager to tout the compound's few side effects, often proclaimed in ads that aspirin "Does Not Affect the Heart." Little did the company suspect that, decades later, aspirin would be a mainstay for preventing heart attacks and strokes.
One of aspirin's most surprising side effects is its ability to keep blood from clotting as readily as it normally does. It does this by inactivating an enzyme called cyclooxygenase 1 (COX-1). Without COX-1 activity, platelets can't manufacture thromboxane A2.
This compound is the glue that makes platelets stick together when they are activated by inflammation or injury. Without it, platelets don't clump as readily while careening around the bloodstream, especially when passing small ruptures in plaque, the cholesterol-laden patches embedded in the lining of blood vessels. Ruptured plaques, and the clots that form to seal the breaks, are the ultimate triggers of heart attacks. They are also the source of the most common kind of stroke, called ischemic stroke.
But there are dark sides to aspirin's effect on COX-1. By making blood less likely to clot, aspirin can increase the risk of a bleeding (haemorrhagic) stroke. These are less common than ischemic strokes, but tend to be more damaging. In the stomach and intestines, COX-1 makes hormone-like compounds called prostaglandins that protect the stomach and intestines against acids and digestive enzymes.
Ratcheting down prostaglandin production can lead to everything from a mild feeling of heartburn to ulcers - patches of worn-away and inflamed tissue. And since blood doesn't clot as readily, a bleeding ulcer can lead to serious blood loss.
How aspirin affects platelets
Aspirin helps prevent blood clots by preventing platelets from clumping together - an early step in the formation of blood clots - when they are activated by inflammation or injury.
Finding the tipping point
Recommendations for the use of aspirin aim to balance the benefits against the hazards. In general, the greater your chances of having a heart attack or stroke, the bigger the bang you get from aspirin.
In contrast, the chances that aspirin will cause a haemorrhagic stroke, ulcer, or gastrointestinal bleeding are much the same no matter what shape your heart is in. Aspirin reduces the chances of having a heart attack or stroke by about 25%. If a patient is at high risk of having one of these, that 25% reduction swamps the small increase in the odds of having a problem with aspirin. If one's risk is low, then the hazard can exceed the benefit.
Let's put this idea into practice. The simplest way to estimate one's risk of having a heart attack or dying of heart disease is by calculating one's Framingham risk score or Reynolds risk score. These can be calculated by visiting www.health.harvard.edu/116. The big difference between the two is that the Reynolds score includes family history and C-reactive protein; the Framingham score does not.
Say a patient's Framingham risk score is 15%. That means among 1,000 people with the same risk factors, 150 will have a heart attack or stroke over the next 10 years. Taking aspirin every day lowers the risk to 11%, or 110 events among 1,000 people over 10 years. That's 40 fewer.
But what if the Framingham risk is down near 1%? Taking aspirin would lower it to 0.75%. Translated to a group of 1,000 similarly low-risk individuals, aspirin would prevent just 2 to 3 heart attacks over a 10-year period.
On the negative side, daily aspirin use by 1,000 people for 10 years is estimated to cause up to 2 haemorrhagic strokes and about 12 episodes of gastrointestinal bleeding, regardless of heart attack risk.
Two Tufts University researchers put the hazards into perspective this way: The chances of dying from an aspirin-related complication are the same as the chances of dying in an automobile accident - about 1 per 1,000 people over a 10-year period.
Thanks to some extraordinary science, [aspirin] has been transformed into a lifesaving heart medication.
The American Heart Association and the US Preventive Services Task Force place the tipping point at a 10-year heart disease risk of 6% to 10%. Above this, the benefits of aspirin use outweigh the risks; below it, the risks outweigh the benefits.
An online calculator at www.health.harvard.edu/117 has been developed by researchers at the University of North Carolina at Chapel Hill, one of whom helped the Task Force devise its recommendations. It offers a peek at a person's chances of having a heart attack or other cardiovascular event with and without aspirin. (No paper-and-pencil version of this tool is available.)
So that a person can get an idea of where they stand with aspirin without doing these calculations, we summarise here the recommendations for various situations, from being in the midst of a heart attack to being healthy with no signs of heart disease.
Heart attack in progress
If a person thinks they are having a heart attack, they should call emergency services and then take a plain, regular-strength (325 mg) aspirin, or four baby aspirin if that's all that is at hand. Chewing the tablet(s) gets the aspirin into the bloodstream faster than just swallowing the aspirin whole.
Prior heart attack or stroke
Patients who have had a heart attack, ischemic stroke, or transient ischemic attack (TIA, a so-called mini-stroke) are prone to having another. Virtually everyone in this camp should be taking aspirin every day - unless, of course, there is a reason not to, such as an allergy to aspirin or the use of medications that might interact with it.
Existing cardiovascular disease
If a person has been diagnosed with angina (chest pain brought on by exertion or stress), peripheral artery disease, an abdominal aortic aneurysm, or cholesterol-narrowed coronary or carotid arteries, the latest recommendations encourage taking aspirin daily.
No diagnosed cardiovascular disease
This is where things start to get fuzzy. Doing everything you can to make sure you never have a heart attack or stroke is an admirable goal. It makes excellent sense when the prevention strategies have no downsides and probably offer body-wide benefits - things like not smoking, adopting a heart-healthy diet, exercising, and losing weight, if needed. Aspirin isn't in this group because it has potentially harmful side effects.
Here, in what doctors call primary prevention, is where benefit-risk calculations are most important. In particular, the presence of certain conditions or risk factors may tip the scales for an individual's decision.
Diabetes.When it comes to the circulatory system, diabetes is on a par with angina or artery-clogging atherosclerosis as a risk factor for heart disease. The American Diabetes Association and American Heart Association recommend a daily low-dose aspirin for all individuals with type 1 or type 2 diabetes who are over age 40, as well as those ages 30 to 40 who have other risk factors, such as smoking, high blood pressure, high cholesterol, a family history of heart disease, or protein in the urine.
Kidney disease.Chronic kidney disease is also strongly linked to heart disease. Although there isn't nearly as much information on this as there is for diabetes, the National Kidney Foundation recommends that people with kidney disease, especially those who require dialysis, take a daily aspirin.
At risk for heart disease.A variety of factors can predispose you to atherosclerosis, the disease that underlies heart attacks and most strokes. These include having a parent or sibling who had a heart attack at a young age (under 55 for a man and under 65 for a woman), smoking, having high blood pressure or cholesterol, being substantially overweight, or not exercising. One or more of these plus older age - over 55 for men or over 65 for women - tips the balance toward taking aspirin. The more risk factors a person has, the more they stand to benefit from aspirin.
Low risk for heart disease.If a person is healthy, hasn't been diagnosed with cardiovascular disease, and doesn't have risk factors for it, aspirin probably isn't for them. Patients reap little good from it while exposing themselves to its risks.
In the real world
How well do we follow these recommendations? Three national surveys published in 2006 and 2007 show there's plenty of room for improvement. Among adults with cardiovascular disease or at very high risk for it, most of whom should be taking aspirin, between 20% and 30% aren't.
In this group, women were less likely to take aspirin than men. Nearly one-third of adults with diabetes aren't taking aspirin. In contrast, among adults at low risk for cardiovascular disease, most of whom shouldn't be taking aspirin, nearly one-third are.
What's the dose, Doc?
Given aspirin's Janus-faced effects, finding the ideal dose is another balancing act. You want to take enough aspirin so platelets won't clump but not so much that the stomach and intestines lose their protective prostaglandins.
It doesn't take much aspirin - 30 to 50 mg - to completely stop the production of platelet-clumping thromboxane. But since most people absorb only about half the aspirin from a pill, more than that is needed. How much more? There's the rub.
Clinical trials of aspirin for heart disease have used as little as 30 mg a day and as much as 1,300. Some tested every-other-day approaches. Two recent reviews have tried to make sense of the findings.
In a 2006 paper in the American Journal of Medicine, Dr. James E. Dalen of the University of Arizona relied on data from five large trials to argue that 75 mg, 81 mg, and 100 mg of aspirin a day weren't as good as 160 mg a day at preventing heart attack and stroke but had the same rates of side effects. In spring 2007, Dr. Charles L. Campbell and colleagues at the University of Kentucky, Lexington, published a review in the Journal of the American Medical Association based on eight clinical trials and three large observational studies. They concluded that taking 81 mg a day offers as much protection as higher doses with fewer side effects.
"The most important message is that 325 mg of aspirin a day is more than most people need," Dr. Campbell said. Although he advocates taking 81 mg a day, taking double that amount won't have a big impact on an individual's risk of developing bleeding problems, he said.
If patients take an 81 mg aspirin tablet each day, it should not be an enteric-coated one, urges Dr. Campbell. With low-dose aspirin, a person wants to get as much of it into their system as possible, something coated aspirin doesn't accomplish. What's more, taking coated aspirin does relatively little to prevent stomach and intestinal problems.
Protecting your stomach
Some people take aspirin without ever having a problem. Others develop low-grade stomach pain or get an ulcer. A few develop gastrointestinal bleeding severe enough to require a transfusion. How can a patient better protect themselves?
Coated or buffered aspirin doesn't work very well (see "Take off the coat"). You can try another common nostrum, taking aspirin with food, but that doesn't work much better. The class of drugs known as proton-pump inhibitors turn down acid production in the stomach, and so can protect against the harsh effects of aspirin, ibuprofen, and related drugs. A commonly used proton-pump inhibitor is over-the-counter omeprazole (Prilosec OTC); prescription versions are also available.
Most people don't need a drug to counter aspirin's possible effects in the stomach. But it might be worth it if a patient is at high risk for bleeding. That may be the case if one has an ulcer now or did in the past; regularly takes ibuprofen or another nonsteroidal anti-inflammatory drug for arthritis or some other condition; or takes warfarin or clopidogrel (Plavix), two medications commonly taken by people with heart disease.
Have the conversation
The lingering uncertainties over who should take aspirin to prevent a heart attack or stroke, how much to take, and how best to protect the stomach against aspirin-related damage isn't anyone's fault. It's the way science happens, by fits and starts, and sometimes with long pauses in between.
We've come a long way since the days when aspirin was little more than an over-the-counter remedy for aches and pains, fevers and hangovers. Thanks to some extraordinary science, it has been transformed into a lifesaving heart medication. We now know that aspirin is a key treatment for a heart attack in progress, and that taking low-dose aspirin every day can help some people cut their chances of having a heart attack or an ischemic stroke by 25%.
We also know that despite its popularity and the fact that you can buy it in convenience stores and vending machines, aspirin isn't entirely benevolent. So make sure patients talk with their doctor before starting, or stopping, aspirin. Aspirin isn't a miracle drug. Lifestyle changes, such as avoiding tobacco, exercising, and eating a healthier diet can have a bigger impact on one's chances of having a heart attack than any drug.
This article is provided courtesy of Harvard Medical International. © 2007 President and Fellows of Harvard College.
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