Heart disease trials generally
exclude people with cancer, and cancer studies exclude
patients with heart disease. It makes sense, if you
don't want muddied results, but the inevitable consequence
is that we have very little evidence on how to treat
cancer patients with heart disease. Yet these very patients
are unusually susceptible to clotting disorders.
New evidence suggests this lack
of information has led us astray, but we could achieve
truly dramatic increases in survival by using the humblest
of super-drugs: aspirin. Cancer and heart patients with
platelet deficiencies actually stand to gain more than
anyone from the treatment, according to the study just
published in Cancer. In fact, they're almost sure to
die without it.
"This is the first paper that ever
described treatment of acute coronary syndrome in cancer
patients," says Dr Jean-Bernard Durand, a cardiologist
at M D Anderson Cancer Center in Texas and the lead
author of the Cancer study. "In our institution,
it's completely changed the way we view how to practise."
MIRACLE
DRUG
In non-cancer patients, guidelines recommend using aspirin
in heart attack, with or without more potent clotbusters.
But they say nothing at all about cancer patients, in
whom the whole clotting process is subtly different.
Moreover, they recommend against aspirin use in patients
with thrombocytopenia, which is five times as common
in cancer patients with heart attack as it is in the
general heart attack population.
Of 70 heart attack patients in
a cancer hospital, 43 had normal platelet counts, and
27 had thrombocytopenia, defined as fewer than 100,000
platelets per microlitre. Among the normal-platelet
patients, seven-day survival was 88% among those who
took aspirin, but just 45% among those who did not.
Among the patients with thrombocytopenia, seven-day
survival was 90% among those who took aspirin, but just
6% among those who did not.
There can't be many medicines out
there that will change survival rates so dramatically
but it certainly appears to have been the case here.
NO
BLEEDER
It's the menace of bleeding that has led guidelines
to call thrombocytopenia a "relative contraindication"
for aspirin use. But there were no serious bleeds in
this study. Minor bleeding occurred in 17% of patients
— naturally concentrated in those with thrombocytopenia
— but there was no significant association between
aspirin and bleeding, even in the patients with low
platelet counts.
A few extra minor bleeds may be
a price worth paying in these life-and-death cases.
Needless to say, cancer patients who have just suffered
a heart attack are not a very healthy population. "I
characterize them as having one foot in the grave and
the other standing on a banana skin," says Dr Durand.
Of 70 patients in the trial, 27 were dead when it ended
after seven days. The average patient age was just 54.
But if they do survive their heart
attack "they go on to live an average of two to five
years," says Dr Durand, in a bright tone of voice that
suggests this is considered a great result in his field.
"I think it's a travesty that patients should survive
a cancer only to die from a heart attack."
Among non-cancer patients who develop
acute coronary syndrome (ACS) in the US, 99% survive
the first week. Part of the reason for the extraordinarily
high death rate in this study is that the patients all
had frank heart attacks, while the term ACS can also
include unstable angina. But it's also indicative of
the dangerous effect of cancer — and cancer drugs
— on the blood and marrow.
PLATELET
PARADOX
Various half-understood factors make cancer something
of a hemodynamic nightmare. Studies suggest that cancer
patients are at increased risk of clotting, but they
also indicate they're at increased risk of bleeding.
Not surprisingly, given this conundrum, many physicians
aren't eager to tamper with the blood of cancer patients
with acute cardiovascular problems.
Giving blood-thinning medicine
to patients who lack platelets sounds completely illogical.
In fact it sounds like a recipe for a nasty malpractice
suit. But there's a "platelet paradox" in cancer, Dr
Durand says, that makes patients' blood unusually likely
to clot even when there don't seem to be enough platelets.
"One theory is that cancer cells release microparticles
which activate platelets independently. They become
hypercoagulable — very sticky. That's why the platelet
count has nothing to do with your ability to form a
clot."
Dr Durand and his team have been
using platelet assays to define just how sticky they
are. "If the count is low but the function is normal,
you can give anticoagulation," he says. They're currently
working on a prospective study, and have found that
platelets assays can actually predict which patients
are likely to bleed. This, he says, would also apply
to patients who don't have cancer. "Rather than give
them a drug according to their weight, you give them
a drug based on their platelet function," he explains.
Dr Durand says it's also possible
that transfusion results in extra-sticky platelets.
"When somebody has low platelets," says Dr Durand, "physicians
immediately start transfusing, even though there's no
bleeding. One theory is that when you receive a pool
of platelets, it's heterogenous — from many individuals.
There's an immune response, and the antibodies will
bind to the platelets, activate them and make them clot."
STRENGTH,
NOT NUMBERS
Understanding timing is also important. "It's not when
the platelets are falling that patients generally have
their clotting event, it's when the platelets are on
their way back up. Because they've been trying to compensate
for low numbers, they're working overtime," he explains.
Once the numbers of such platelets start rising, the
risk of cardiac event becomes highest.
So the best approach is to time
the transfusion carefully. When a patient's platelet
count starts falling, if there's no evidence of bleeding,
the physician shouldn't transfuse, but wait out the
few days while the count is at its nadir. Once it starts
rising again, that's when it's time to test platelet
function. If the platelets are highly active, then anticoagulation
is the answer. If you don't find a lot of immature platelets
that want to thrombose, then you generally don't.
Since sending the paper in to Cancer,
he says, the researchers have become even more convinced
that — in cancer patients at least — platelet
count is trivial compared to platelet function. Excessive
concern over thrombocytopenia could be killing patients,
he says. "It doesn't really matter what the platelet
count is, you have to treat all patients the same. Instead,
once the platelets fall below 100,000, we're withholding
therapy, including beta-blockers and aspirin, for fear
of complications, and they end up having a worse prognosis.
But if you treat them, they actually have the most to
gain. The sickest patients benefit the most from the
most aggressive therapy," he says.
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