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THE GOLDILOCKS FACTOR

The Baltimore Sun

One out of three adults takes an aspirin a day to prevent a heart attack. But after two decades of research, doctors are still divided over how much aspirin they should take.

Some researchers believe a low-dose, 81-milligram "baby aspirin" is good enough to reduce the risk of heart attacks -- and they say thousands suffer from unnecessary stomach bleeding because they take a standard 325-milligram pill.

"Too many people are taking a full dose of aspirin," said Dr. Jeffrey Berger, a cardiologist at Duke University Medical Center. "We need to be very careful in how much aspirin we prescribe."

But others argue that the risk of bleeding is minimal either way. They say both pills effectively prevent heart attacks and that one size does not fit all when it comes to aspirin therapy.

"I think to say to the public, 'If you take 325 milligrams you're going to bleed,' that's just disingenuous," said Dr. Charles H. Hennekens, a lead investigator of a 1988 report in the New England Journal of Medicine that was instrumental in spawning a daily aspirin habit among 50 million people.

Aspirin is one of the world's most widely used medications and has a 100-year track record of relieving pain from headaches, fevers, overworked limbs, arthritis and a variety of other ailments. It is also may be one of the most studied in history.

The American Heart Association and the U.S. Preventive Services Task Force, a government-sponsored advisory group, both recommend a daily aspirin for people whose family history, age, weight and other factors increase their risk of heart attack. But neither group recommends a specific dose: Instead, each advises patients to consult their doctors.

"There's a lot of controversy over whether a baby aspirin is enough aspirin for a patient with heart disease," said Dr. Paul Gurbel, director of the Center for Thrombosis Research at Sinai Hospital.

Aspirin's original 325-milligram tablet was developed because that was how much acetylsalicylic acid -- synthesized by the Bayer Co. in 1897 -- druggists could fit into a pill a century ago, said Steven Weisman, senior scientific adviser to Bayer HealthCare.

The 81-milligram dose, a quarter of the full-strength tablet, became available in 1922.

Those two sizes have been unchanged since because Bayer and other drug companies have had little incentive to vary dose sizes found to be generally safe and effective, experts say.

"We're kind of stuck with these dosage levels," Weisman said.

Although the term "baby aspirin" is still in widespread use to describe the 81-milligram dose, pediatricians strongly discourage giving aspirin to babies and children without a doctor's recommendation because of its links to Reye's syndrome, a potentially fatal swelling of the liver and brain.

Most doctors recommend a low-dose aspirin for patients at risk of heart attack who have never had one -- and a full dose for those who have had a heart attack, Weisman said. The trend, he said, is for more heart patients to go on low-dose aspirin, but it's a personal decision that can vary from one patient to the next.

"The physician is given responsibility for making the decision on dosage," Weisman said. "People shouldn't wait to get on aspirin therapy for someone to come up with the perfect dose."

At Sinai, Gurbel's work highlights the importance of tailoring aspirin therapy to individual needs. Last year, he gave 125 patients with coronary artery disease either 81, 162 or 325 milligrams of aspirin for four weeks and rotated treatment regimens so that after 12 weeks every patient had received each dosage level.

The results, published in the journal Circulation, showed that 81 milligrams gave maximum protection to most patients, but that diabetics saw increased protection from 162 milligrams because that amount also blocked a secondary pathway in their blood known to produce clots.

The findings suggest that different types of heart patients are likely to benefit from different dosage levels, Gurbel said.

"Right now, we don't even measure whether the drugs are working properly," he added.

Researchers need to find more ways to test patient responses, so that treatments can be individually tailored to aspirin, as well as other medications designed to prevent blood clots, Gurbel said.

"Big pharma loves 'one size fits all,' but that's not the way the human body works," he said.

At Duke, Berger's team published findings in January showing no significant difference between the two dosage levels in reducing the risk of heart attack among 9,853 cardiovascular patients. They were tracked for an average 33 months in six randomized clinical trials.

In another study, Berger found that of 50,000 patients in the early stages of a heart attack, those who got higher doses of aspirin experienced 15 percent more stomach bleeding.

"You're talking about bleeding in the stomach that can be pretty serious," Berger said.

Aspirin prevents blood platelets from clumping together to form clots that can cause heart attacks and inhibits production of chemicals called prostaglandins in ways that relieve pain.

But prostaglandins also play a role in forming the stomach's protective lining, so inhibiting them makes the stomach more susceptible to tiny "microbleeds," as well as gastritis and ulcers, which are more serious inflammations of the stomach lining.

About 60 percent of the people on aspirin therapy take 81 milligrams, but 35 percent are taking 325 milligrams. That's too many, according to researchers at the Gill Heart Institute at the University of Kentucky.

Some patients with arthritis or those taking blood thinners may take different dose levels, such as 162 milligrams, experts say.

"We think the higher doses are harder on your stomach," said Dr. Charles L. Campbell, a cardiologist at Gill.

Campbell's group reviewed a dozen major aspirin studies and found that a full dose is no better at preventing heart attacks than doses from 75 milligrams to 81 milligrams -- and the full dose is associated with increased risk of stomach bleeding.

The group's report, published in the Journal of the American Medical Association, concluded that up to 250,000 people a year may be hospitalized because they took a full-dose aspirin instead of a low-dose tablet.

"If we're going to give people medicine with potentially toxic side effects at certain levels, we need to have convincing evidence that it's better, and I just don't see it," Campbell said.

But other experts argue that the benefits from either dosage far outweigh the risk of heart attack and that the risk of bleeding is extremely small -- less than 5 percent.

"One of the things to keep in mind is that even taking 81 milligrams doesn't make the risk of bleeding go to zero," said Dr. Michael Pignone, an internist at the University of North Carolina medical school who studied aspirin's effects for the U.S. Preventive Services Task Force.

A bigger problem, according to some experts: Too few people at risk of heart attack take aspirin in the first place.

"We're not doing an incredible good job of promoting its use," said Pignone, who has received past research funding from Bayer.

dennis.obrien@baltsun.com

History of aspirin

400 B.C.

Hippocrates, a renowned Greek physician, prescribes the bark and leaves of the willow tree, rich in the compound salicin, for fever and pain relief.

1853

French chemist Charles Gerhardt synthesizes acetylsalicylic acid, the active ingredient of willow bark, in a lab.

1897

Chemists at the Bayer Co. synthesize the new drug in a powder to minimize nausea and gastric pain. They later name the drug after the Latin term for the meadowsweet plant that also contains salicylic acid, Spira, adding the "a" to acknowledge the acetylation process used to make it more palatable. The "in" is tacked to its ending to make it easier to pronounce.

1948

Dr. Lawrence Craven, a California doctor, begins recommending a daily aspirin to all his patients after noticing that 400 patients taking the drug haven't suffered any heart attacks.

1988

Preliminary findings of the Physicians' Health Study are published early in the New England Journal of Medicine because of the remarkable results: a 44 percent reduction of heart attacks among the 22,071 men studied. Later analysis of the completed study, along with four other reports, shows a 32 percent reduction in heart attacks and strokes.

Sources: Bayeraspirin.com and the British Medical Journal

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