What
was the state-of-the-art of treatment for venous thromboembolism when
you became head of the thromboembolism unit at Chedoke-McMaster
Hospital in 1989?
When we identified deep vein thrombosis (DVT) or pulmonary
embolism—and that is a tricky matter in and of itself—the
treatment consisted of intravenous heparin. The patient had to be
admitted to the hospital for five to ten days, walk around with an
intravenous drip, get a blood test done two or three times a day,
and then be transferred over to a pill form of blood thinner, known
as warfarin or coumadin (they’re the same thing). That had to be
monitored, and then they could go home once the blood thinning took
effect. It takes a while—three to five days—before you can say
the blood is thin enough from the coumadin to get rid of the
heparin. So they are on the two simultaneously.
How
has treatment progressed in the intervening years?
There has been a major shift from treating patients with
intravenous heparin in-hospital to treating patient out-of-hospital
with a group of drugs called low-molecular-weight heparin. These
drugs are injectable, subcutaneously, once or twice a day. They don’t
require monitoring, and can be given on weight-adjusted fixed doses.
Nowadays in Canada, about 90% of patients are treated at home. We
still use coumadin or warfarin for the long-term management, and we
still stop the low-molecular-weight heparin when the coumadin or
warfarin has shown its effect, as indicated by a blood test. So the
biggest change is that we can now treat people out-of-hospital.
What
has been the major lesson you’ve learned in how best to treat your
patients over that time?
Well, what we’ve been learning is that there are different
categories of patients. Back in the 1980s and early ‘90s, when I
was first in training and then a junior faculty member, we used to
have a one-size-fits-all, irrespective-of-circumstances philosophy:
you would treat the first episode of clotting for three months; the
second for a year; the third for life. We now know, on the basis of
clinical and laboratory factors, that patients can be categorized
according to the risk of recurrence. For example, in patients who
develop unprovoked clotting, where it just comes out of the blue, a
big fat swollen leg with chest pain, where they have DVE or PE, that
patient has a much higher risk of recurrence than, say, somebody who
developed DVT after major surgery, such as a hip replacement. In the
latter case, the risk is transient. In the first case, after you
discontinue coumadin, you’re putting the patient back in the
environment in which the clot developed. In the second situation,
that’s not the case. We’ve also identified a number of blood
tests that seem to be associated with venous thrombosis, so now we
tailor our duration of therapy to the individual patient. The
patient who develops unprovoked venous thrombosis (who is more
likely to have a laboratory abnormality) we tend to treat longer.
Whereas we would treat somebody who broke his or her hip, was
immobilized and had surgery, and then got DVT for a shorter period
of time.
Are
you satisfied with the progress you’ve made, or is there a long way
to go?
I think there’s a long way to go. There are still a number of
unanswered questions and still special populations in which
treatment is problematic: pregnant women, for instance. They
represent a large group in whom clotting is relatively common.
Diagnosing clots during pregnancy is tricky because you try not to
expose the women to radiation, for obvious reasons, and then some of
the physiological effects of being pregnant affect the diagnostic
testing. So there are challenges in diagnosis and also challenges in
how to treat pregnant women. If you use coumadin in North America
and anything happens to the baby, you’re likely to get sued. It
really leaves us only with the injectables, the heparins and
low-molecular-weight heparins. And those are onerous. The woman has
to inject herself once or twice a day during pregnancy. And there
are side effects to worry about: bleeding, which is common to both
coumadin and heparin—but you can get osteoporosis with the latter,
as well as thrombocytopenia, which is a lowering of the platelet
counts. So pregnancy is a problem. Patients who have had kidney
failure are a problem. I could go on for hours.
The other challenge we have is that warfarin is a difficult drug;
the anticoagulant response to it is unpredictable. And so the dose
requirements are entirely unpredictable, which means it has to be
monitored on a regular basis. So patients have to have periodic drug
tests for the entire duration they are on the drug. It also
interacts with other drugs. If somebody is on warfarin or coumadin
and they start an antibiotic, for instance, that can enhance the
effect on the clotting system and actually make the blood thinner
and make the patient susceptible to bleeding. Warfarin also has a
long half-life, which is a problem, for instance, if the patient is
going for surgery. You can’t just wait a few hours and it’s out
of their system. You have to reverse the effects with the antidote.
There’s a tremendous drive at the moment to come up with new oral
blood-thinning therapies that don’t need to be monitored and that
don’t interact with other drugs—that has been one of my major
interests.
Is
there one in the pipeline that makes you optimistic?
Yes. There is a drug called ximelagatran. It’s made by
AstraZeneca, and it appears very promising. AstraZeneca is probably
the leader in the field in coming up with the next generation
blood-thinning drug, but they are being chased by about five other
companies who have their own oral anti-coagulant or anti-thrombotic
that are being developed. So I’m optimistic. Something out there
will work.
What’s
been your most trying professional moment?
I think the frustration early in my career in getting funded by
peer-reviewed funding agencies.
Because
you were a newcomer?
Yes. It’s a bit of a crapshoot in the sense that you’ve got
to be a little lucky, and you’ve got to be a little good. You’ve
got to be in the right place at the right time. Early on it was a
struggle. I had trouble getting grants. But once you break through,
it’s like you can do no wrong. All of a sudden, you go from being
Joe Schmo to being a senior researcher.
Jeffrey Ginsberg, M.D., F.R.C.P.
McMaster University
Hamilton, Ontario, Canada
n the
interview below, Special Topics correspondent Gary Taubes
talks with Dr. Jeffrey Ginsberg from McMaster University about
his highly cited work in deep vein thrombosis. Dr. Ginsberg
ranks at #8 among scientists publishing in this field over the
past decade in our analysis, with 79 papers cited a total of
2,648 times. He is also a co-author on the paper ranked at #8
in our analysis with 497 cites: "A comparison of
low-molecular-weight heparin administered primarily at home
with unfractionated heparin administered in the hospital for
proximal deep vein thrombosis," (New England Journal
of Medicine 334[11]: 677-81, 14 March 1996). In the 
Web product, his work can be found in the field of Clinical
Medicine. Dr. Ginsberg is the Director of the Thromboembolism
Unit at Chedoke and McMaster Hospitals in Ontario, Canada.
