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Super-aspirin is turning out to be a super-failure, perhaps
even a deadly one.
Five years ago, when large-scale testing began, researchers were
optimistic that the drug would improve on the plain 2-cent variety,
which is still the most important medicine for heart disease.
But study after study has ended badly - even shockingly. Now some
believe the pharmaceutical industry should call it quits. Stop the
testing, they say, because super-aspirin may actually kill more
volunteers than it saves.
The drugs are a class of blood thinners known technically as IIb/IIIa
antagonists. They are already injected to keep blood vessels flowing
smoothly after angioplasties and mild heart attacks. But drug companies
envisioned a larger market for these medicines in a new pill form.
The medicines are not to be confused with an entirely different
class of drugs - the cox-2 inhibitors, including Celebrex - which
are used to treat arthritis and are also sometimes called super-aspirin.
Instead, they would be taken by millions of people with bad hearts
to ward off heart attacks, strokes and death. Just like aspirin,
the thinking went, only more effective - and of course, a lot more
expensive.
The companies have spent hundreds of millions to prove super-aspirin
works as well in practice as it ought to in theory. About 42,500
volunteers have tested four slightly different kinds in five large
studies.
Each time, though, the outcome was the same.
Super-aspirin not only fails to prevent
heart attacks; it apparently kills people.
Reasons For, Against Going On
Enough, says Dr. Eric Topol, cardiology chief at the Cleveland
Clinic. He figures that in those five studies - two of which he
directed - between 150 and 200
volunteers probably died from the treatment itself.
Nevertheless, the testing continues. A study of DuPont Pharmaceutical's
super-aspirin, called roxifiban, began last July. It will enroll
2,200 patients in North America and Europe by the end of this year.
Should DuPont let the study go on? Is it even ethical to do so?
Top-tier cardiologists argue both sides.
Some agree with Topol. Considering the results so far, these
drugs are too dangerous to keep testing on people. Others contend
the study's risks will be slight if it is stopped at the first hint
of trouble. Furthermore, there are reasons to think roxifiban will
work better than the other super-aspirins, they say, and it would
be tragic to give up on a treatment that could still prove to be
a life saver.
An effective super-aspirin could certainly be that. As good as
aspirin is, it reduces the risk of death from heart disease by only
about 20 percent.
A Troubling Discovery
But doubts that super-aspirin will ever be the answer have grown
over the past two years. The latest setback came shortly before
Christmas. A committee of doctors held its quarterly meeting at
a Boston hotel to go over data from BRAVO, a big study of a super-aspirin
called lotrafiban. (Cardiologists love to give their studies catchy
acronyms. BRAVO stands for Blockade of the IIb/IIIa Receptor to
Avoid Vascular Occlusion.)
The committee, called the data and safety monitoring board, worked
independently of the study's lead doctors and corporate sponsor,
SmithKline Beecham. Its job was to make sure the study was not hurting
anyone. It had the authority to peek at the ongoing results, something
the other doctors involved could not do.
The study was massive, involving 9,200 patients on four continents.
In the mathematics of heart research, such large numbers are necessary
to reveal small effects of the drug.
On that December day, the numbers showed that the death rate
was actually higher among the volunteers getting lotrafiban
- 2.7 percent, versus 2 percent
in the people taking dummy pills.
This amounted to 30 extra deaths among
the lotrafiban users - 30 deaths that may have been caused by the
drug itself.
An SOS for BRAVO
But was the drug truly to blame? Committee members wondered. Those
extra deaths might have happened by chance. Just two weeks earlier,
the number of deaths in the two groups was the same. Maybe in time
the numbers would go the other way.
"If this had been the first time through with an oral IIb/IIIa
antagonist, we might not have stopped the trial. We would have assumed
that it might have been just a blip," says one committee member,
Dr. James Tcheng of Duke University.
But this was not the first time through. It was the fifth. And
each study showed essentially the same thing, more deaths in
people taking super-aspirin. It was time to stop BRAVO.
The committee sent a letter, headed "URGENT PLEASE READ,"
to the 700 hospitals in 30 countries with patients in the study.
The message: Take them off the drugs.
36 Percent Higher Death Risk
Also signing the letter was Topol, the study's chairman. It was
his second bad experience with a super-aspirin. Two years ago, Topol
headed a study called SYMPHONY, which looked at Roche's sibrafiban.
It also ended in failure.
Now Topol toted up the results. Combining the five big studies,
he found that taking super-aspirin increases people's risk of
death by 36 percent. A statistical
fluke? Unlikely. The chance of that was perhaps one in 100,000.
Many of the extra deaths seemed to be cardiac arrests, which could
have been triggered by blood clots, the very thing super-aspirin
is supposed to prevent. But still, no one was sure.
In their injected form, IIb/IIIa antagonists are widely used and
considered highly effective. They work by subduing platelets, the
blood cells that form clots. When injected, the drugs can stifle
platelets' tendency to clump together by 90 percent or more. This
is useful in some hospital situations when the risk of dangerous
clots is especially high. But the probability of unintended and
possibly disastrous bleeding is too high to continue this treatment
indefinitely.
The pill form is less powerful. It inhibits platelets about 50
percent. Still, this is potent medicine, and it seemed logical it
would help people with serious heart disease, since misguided clots
are the primary trigger of heart attacks and strokes.
"Everybody thought this would be the next zillion-dollar drug,"
says Dr. John Ambrose of St. Vincent's Hospital in New York City.
A Paradoxical Effect?
Researchers have several theories about what went wrong. Maybe
super-aspirin somehow triggers heart cells to commit suicide. Or
perhaps it sets off a wave of inflammation.
However, the leading theory is that the pills fail because of their
halfway action. In hindsight, it appears
that partially disabling the body's clot-making machinery this way
is a bad idea.
These drugs, whether injected or swallowed, work by sticking to
something called the fibrinogen receptor. This blocks the spot on
the surface of platelets that ordinarily lets in chemical signals
telling them to form clots.
After someone takes a pill, the amount of medicine in the bloodstream
gradually falls until it's time to take another one. As these drug
levels grow low, more and more of the platelets' fibrinogen receptors
are uncovered. But the cells do not like to have their receptors
blocked and then reopened this way. It leaves them in a twitchy,
hair-trigger state, ready to clump into clots with little provocation.
So as a result, many think super-aspirin has a paradoxical effect:
It inhibits platelets, but it also activates
them, and the net effect is more clots, not fewer.
New Study, New precautions
While there is evidence supporting this theory, Topol cautions
that no one knows for certain whether this explains why the first
four super-aspirins tested were dangerous. Therefore, he says, there
is only one safe option.
"I think there should be a moratorium on this drug class,"
he says. "At this point, I think it's unethical to continue
the PURPOSE trial."
PURPOSE is DuPont Pharmaceutical's study of roxifiban, the only
super-aspirin pills now in human testing.
Criticism of the minutiae of study design is common in academic
medicine. But calls for big studies to stop in their tracks are
rare, especially coming from experts of Topol's stature.
Word of his opinion quickly spread on the Internet. Among other
things, Topol is editor-in-chief of theheart.org, a Web site read
by heart specialists. It carried two stories about his misgivings.
The bad BRAVO results, along with Topol's criticism, could not
be ignored. So doctors running and monitoring PURPOSE met to reconsider
whether to continue.
The research had already been redesigned once. DuPont originally
intended a much larger study in people with mild heart attack and
unusually bad chest pain, the same patients involved in the other
five studies.
But after their rivals' early failures, they decided to try their
drug in patients with severely blocked arteries in the legs. These
people are also at high risk of heart attacks, and the company hoped
they would respond better to the drug.
The PURPOSE doctors voted to keep going, but with one major
change: They would tighten the guidelines for stopping the study
at the first hint of unexpected deaths.
However, the more conservative rules introduce a new risk - a 20
percent chance the study will be needlessly stopped because of a
statistically meaningless temporary uptick in the death rate.
"You can't ask for a more highly monitored trial than the
one we're doing," says its director, Dr. William Hiatt of the
University of Colorado. "Just a handful of excess mortality,
which could happen by chance, will stop this trial."
Will History Repeat?
He and others say the study should go on, because the super-aspirin
being tested is better than the ones that failed. It binds more
tightly to the platelets and does not fade away as dramatically
between doses.
"So far, it looks very good in every test done, and it is
perfectly reasonable to test it. We are doing that as carefully
as possible," says Dr. Christopher Cannon of Boston's Brigham
and Women's Hospital, a member of the data-monitoring board.
But opinions among cardiologists are split over whether the drug
is different enough to reasonably expect a better outcome. Among
those in doubt is Duke's Tcheng.
"I agree with Eric 100 percent," he says. "I
think the roxifiban trial should be stopped. Unless you have
a completely different therapeutic approach, not just a different
drug, you are more likely than not to repeat history."
Dr. Donald Easton, a neurologist from Brown University who co-chaired
BRAVO with Topol, also admits to misgivings about the study. But
he thinks it should continue because of the possibility it will
produce a useful, needed medicine to prevent the leading cause of
death.
"I try to keep in mind on the positive side that these drugs
do work in other situations, and the disease we are treating is
not acne," Easton says. "It's death and disability."
Seattle
Times
January 29, 2000
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