Published: July 20, 2004
More than 20 million Americans take aspirin regularly to help prevent
heart attacks and strokes. But new evidence suggests that for many of
them, the pills do little if any good. Recent studies have found that
anywhere from 5 percent to more than 40 percent of aspirin users are "nonresponsive"
or "resistant" to the medicine. That means that aspirin does not inhibit
their blood from clotting, as it is supposed to.
"They are taking it for stroke and heart attack prevention, and it's not
going to work," said Dr. Daniel I. Simon, the associate director of
interventional cardiology at Brigham and Women's Hospital in Boston and
an associate professor at Harvard.
A vast majority of doctors do not test patients for aspirin resistance.
Several doctors said even resistant patients would probably still be
better off taking aspirin than dropping it. Also, people who use aspirin
to fight pain or inflammation are not affected by the new findings.
Scientists are racing to clarify further the significance of aspirin
resistance and how to counteract it. What they learn could influence how
one of the oldest and most widely consumed medicines is used, perhaps
leading to more customized therapies.
"You're talking about a huge number of people" who might not be
benefiting, said Dr. Michael J. Domanski, head of the clinical trials
unit of the National Heart, Lung and Blood Institute.
Although some experts have known about aspirin resistance for years, it
is a topic of growing interest as studies have confirmed that aspirin
takers who are resistant have a higher rate of heart attacks and strokes
than nonresistant aspirin users.
"Aspirin resistance is associated with a worse outcome,"' Dr. Deepak L.
Bhatt, director of the interventional cardiology fellowship program at
the Cleveland Clinic, said. "The literature is pretty consistent about
that."
New tests make it far easier than in the past to measure response to
aspirin. Companies selling such tests are calling attention to aspirin
resistance to help in their marketing.
Some experts caution that not enough is understood about the meaning of
resistance to justify routine tests. Moreover, the experts say, it is
unclear what to do for aspirin-resistant patients. Should aspirin be
dropped? Should the doses be increased? Should patients be switched to
other anticlotting drugs?
A small but growing number of doctors are starting to test patients.
They argue that even without conclusive evidence it is reasonable to
alter therapy rather than have a patient continue to take a drug that a
test shows is ineffective.
Dr. Mark A. Goodman, president of Cardiovascular Medical Associates in
Garden City, N.Y., said he tested all his patients and found that 20 to
25 percent were aspirin resistant. For those people, Dr. Goodman said,
he first tries a higher dose, because that is the least expensive
alternative.
If that does not work - and it usually does not - he prescribes another
anticlotting drug, Plavix, that can cost $3 or more a day, compared with
pennies a day for aspirin.
Aspirin resistance could be one reason many people continue to have
heart attacks and strokes even though they take aspirin. But, experts
said, it is quite likely that some people have heart attacks or strokes
even if aspirin is providing the desired anticlotting effect.
It is widely believed that the main way aspirin provides cardiovascular
protection is by blocking the ability of platelets in the blood to stick
together, a vital step in forming clots that can lead to a heart attack
or stroke. Aspirin blocks an enzyme, cyclo-oxygenase, that is involved
in producing thromboxane, a substance that induces platelets to clump.
The standard test of how readily platelets clump is called aggregometry.
It is usually performed in a specialized laboratory and can take two to
three hours.
New tests are far less cumbersome, allowing doctors themselves to
measure aspirin resistance. Accumetrics, a small company in San Diego,
received clearance from the Food and Drug Administration last year for
its VerifyNow test, a version of aggregometry that doctors can perform
in their own offices.
A tube of blood is collected from the patient's arm, allowed to settle
for about half an hour and is then inserted with a test cartridge into a
$5,000 desktop machine. The result is ready in minutes.
The tests range in price from $30 for the Accumetrics test to $100 or
more for the others.
In a study of 326 patients with cardiovascular disease, at the Cleveland
Clinic, 9.5 percent were found to be resistant using the PFA-100 test.
With the older aggregometry test, 5 percent were resistant and 24
percent partly resistant.
In that study, published last year in The Journal of the American
College of Cardiology, the patients deemed resistant by the aggregometry
test had three times the rate of death, heart attack or stroke compared
with nonresistant patients in the subsequent two years or so. But the
patients deemed resistant by the PFA-100 test did not have a
significantly higher incidence of problems afterward.
Such results are convincing some doctors that aspirin resistance does
raise risk. The next question, however, is what to do about it.
Experts say the first thing is to rule out some simple explanations why
a person's blood might not be showing the anticlotting effect of
aspirin. The patient might not really be taking the aspirin regularly or
might be taking ibuprofen, a painkiller that can interfere with
aspirin's cardiovascular protection. Patients taking coated aspirin to
minimize stomach irritation may not be absorbing enough of it into the
bloodstream. A study led by Dr. Mark J. Alberts, director of the stroke
program at Northwestern University, found that 65 percent of those
taking the coated aspirin tested resistant, as against 25 percent of the
people taking the uncoated type.
There is some evidence that increasing the dose may help. In Dr.
Alberts's study, 28 percent of those taking a high dose were aspirin
resistant, compared with 56 percent on a low dose.
The side effects of aspirin include gastrointestinal bleeding and an
increased risk of a type of stroke caused by bleeding in the brain. Some
doctors say people who receive an anticlotting effect from aspirin would
probably not be at risk for such side effects.
Other doctors say that is not at all clear.
Some doctors interviewed said they would not have patients drop aspirin
even if they were resistant; aspirin has anti-inflammatory effects that
may also stave off heart attacks, even if the anticlotting effect is
absent.
Some doctors said they might drop aspirin if a patient switched to
Plavix, which inhibits platelets by a different mechanism from
aspirin's. Plavix, known generically as clopidogrel, is jointly marketed
by Sanofi-Synthélabo and Bristol-Myers Squibb.
Dr. Timothy G. Jayasundera, assistant professor at the Temple University
School of Medicine, said he found that in patients undergoing
angioplasty and stenting to open clogged arteries he could overcome
aspirin resistance by giving intravenous antiplatelet drugs during and
immediately after the procedure and then have patients take Plavix long
term.
Louis Cancelliere, a worker in a fruit store in Philadelphia who was in
Dr. Jayasundera's study, found out about aspirin resistance the hard
way. Mr. Cancelliere was found to be aspirin resistant after having a
mild heart attack and receiving a stent last autumn. But his doctor took
him off Plavix after 30 days and left him on aspirin alone. In March, he
had another heart attack and got another stent.
Now Mr. Cancelliere, 56, is on Plavix.
"If you don't get tested, you could be in my boat," he said.
Still, neither Dr. Jayasundera's small study, which is yet to be
published, nor Mr. Cancelliere's experience prove that adding Plavix
lowers the risk of future heart attacks for aspirin-resistant people.
Some studies, however, are under way to answer that question.
Of course, studies are also finding that people can be nonresponsive to
Plavix. The extent of overlap between aspirin resistance and Plavix
resistance is not clear.
The causes of aspirin resistance are also not known. Experts say other
mechanisms in the body can cause platelets to clump besides the one that
aspirin interrupts. Genetic variations may explain why some patients are
resistant.
Dr. Marc Ladenheim, a cardiologist in Burbank, Calif., who has tested
patients for several years, said more severe disease correlated with
greater rates of aspirin resistance. Some studies have found the degree
of resistance can change over time.
Scientists say it is not surprising that aspirin does not work for
everyone. Virtually no drug does. Still, the emerging awareness of
aspirin resistance suggests that 107 years after aspirin was first
synthesized, mysteries remain about the pill that millions of people pop
without a second thought.
"It's the most common cardiovascular drug in the world," Dr. Bhatt said,
"and we still don't know everything about aspirin that we probably ought
to."
Copyright 2004 The New York Times Company
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