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Clopidogrel controversy
Mark D Feldman MD
Assistant Professor of Medicine
Director, Interventional Research
Associate Director, Cardiac Catheterization Laboratory
University of Texas Health Science Center at San Antonio
San Antonio TX
Steven R Steinhubl MD
Director, Cardiac Catheterization Laboratory
Director, Cardiovascular Research
Wilford Hall Medical Center
San Antonio, TX
TTP and clopidogrel
11 patients developed TTP
6 women and 5 men, aged 35 to 70 years (median=55)
6 patients received clopidogrel for coronary artery
disease, 3 of whom received clopidogrel after placement
of a coronary artery stent
10 patients used clopidogrel for fewer than 14 days,
1 patient used clopidogrel for 330 days
Concomitant medications
5 patients were taking atorvastatin or simvastatin, 2 of
whom began taking the cholesterol-lowering drug 3
weeks before TTP onset
3 patients were on long-term atenolol therapy
1 kidney-pancreas transplantation patient was on longterm cyclosporine therapy
www.nejm.org/content/bennett/1.asp
Bennett CL, Connors JM, Carwile JM, et al. N Engl J Med 2000 (June 15)
TTP and clopidogrel
Use of antiplatelet agents
10 patients stopped taking clopidogrel when
TTP began.
1 patient discontinued clopidogrel 3 weeks
before the onset of TTP, and TTP occurred
after 21 days of atorvastatin therapy.
1 patient had received ticlopidine 2 years
before the onset of TTP, and no
thrombocytopenia or hemolysis had occurred
during the earlier treatment.
www.nejm.org/content/bennett/1.asp
Bennett CL, Connors JM, Carwile JM, et al. N Engl J Med 2000 (June 15)
TTP and clopidogrel
Patient outcomes
1 patient died.
8 patients had complete resolution of TTP
after discontinuation of clopidogrel and
treatment with plasma exchange.
2 patients had relapses up to 7 months after
the onset of TTP, with rapid recovery after
plasma exchange.
www.nejm.org/content/bennett/1.asp
Bennett CL, Connors JM, Carwile JM, et al. N Engl J Med 2000 (June 15)
Clopidogrel use
Antiplatelet agents
Clopidogrel has largely replaced ticlopidine in
clinical practice because ticlopidine has been
associated with thrombotic thrombocytopenic
purpura (TTP).
Clopidogrel has been considered a benign drug
with very few side effects.
www.nejm.org/content/bennett/1.asp
Bennett CL, Connors JM, Carwile JM, et al. N Engl J Med 2000 (June 15)
Media coverage
Promoting awareness
The media publicized the idea that this is
another drug being used by millions that might
not be as safe as was thought.
Clopidogrel may be associated with TTP, but
the incidence of clopidogrel-induced TTP is not
anywhere near that of ticlopidine-induced TTP.
The media coverage has made physicians
aware of TTP.
Drug-induced TTP
Incidence
Drug-induced TTP is a very rare disorder,
occurring in 1 patient in several million.
The incidence of ticlopidine-induced TTP has
been reported to be from 1 in 6001 patients to
1 in 50002 patients.
The incidence of clopidogrel-induced TTP is not
known.
1. Bennett CL, et al. Arch Intern Med 1999 Nov 22;159(21):2524-2528
2. Steinhubl SR, et al. JAMA 1999 Mar 3;281(9):806-810
Clinical presentation
Diagnosing TTP
The clinical presentation of TTP is difficult to
diagnose.
Ticlopidine-induced TTP didn’t become widely
recognized until 7 years after FDA approval.
Because the chemical structure between
clopidogrel and ticlopidine is similar, an
association with TTP was considered likely.
Therefore association between clopidogrel and
TTP was recognized 1 year after FDA approval.
Antiplatelet agents
Safety
1 million patients per year worldwide receive
coronary stents.
Data from STARS (STent Anti-thrombotic
Regimen Study) show the incidence of stent
thrombosis is reduced from about 2% to 1%
with this class of medication.
The amount of damage with stent thrombosis
if these agents are discontinued would far
exceed the danger of taking this medication.
Cutlip DE, et al. J Am Coll Cardiol 1999; 34(3):698-706
Possible associations
Early release of the article by the New England
Journal of Medicine and related publicity has
drawn attention to the possible association
between clopidogrel and TTP.
No association has yet been shown between
TTP and the statins and clopidogrel, but
perhaps this association will be found in the
future.
Clopidogrel & ticlopidine
Guilt by association?
The association between clopidogrel and TTP may
only be compelling because clopidogrel is so closely
related to ticlopidine.
There are a lot of data on ticlopidine-induced TTP;
the first case was recognized in 1983, among the
first 3000 patients studied.
Ticlopidine was released in the US in 1991; by
1994, before ticlopidine was used widely in
stenting, 25 spontaneous cases had been reported
to the FDA.
No clopidogrel-induced TTP cases have been
observed among the 20 000 closely monitored
patients treated in phase 3 clinical trials and cohort
studies.
Monitoring for TTP
It is unlikely that asymptomatic TTP will be
diagnosed by lab monitoring.
Physician monitoring will be the key to
diagnosing TTP.
TTP is not clinically silent, eventually patients
will end up at the hospital.
Prescribing physicians
The 11 clopidogrel-induced TTP patients
described were not identified by their
neurologist or cardiologist; they were identified
by hematologists, often from plasmapheresis
centers.
Physicians who were prescribing clopidogrel
were not even aware that the diagnosis was
being made.
Neurologists and cardiologists prescribing
clopidogrel should become more aware of
potential complications.
Blood testing for TTP
Patients with idiopathic and ticlopidineassociated TTP have an immune-mediated
deficiency of von Willebrand factor-cleaving
protease activity in plasma, distinguishing this
syndrome from the clinically related hemolyticuremic syndrome.
For 2 of the 11 patients with clopidogrel-induced
TTP, plasma samples were available.
In these 2 patients, during episodes of TTP, the
von Willebrand factor-cleaving protease activity
was undetectable and IgG inhibitors of the
protease were present.
Clopidogrel vs ticlopidine
Patients may present earlier with clopidogrelinduced TTP than with ticlopidine-induced TTP.
10 of the 11 patients presented within 2 weeks
of initiating clopidogrel, as opposed to
ticlopidine cases, most of whom present after 3
or 4 weeks.
The average number of plasmapheresis is
slightly higher with clopidogrel-induced TTP
than with ticlopidine-induced TTP.
Clopidogrel-induced TTP was prone to
recurrence.
Antiplatelet therapy
Shortening duration of treatment
Most stent thromboses occur within the first
2 weeks of therapy with these antiplatelet
agents.
With ticlopidine, many of the cases of TTP
occur within 3 or 4 weeks of initiating
therapy; it therefore makes sense to limit
treatment to 2 weeks.
With clopidogrel, TTP is occurring in the first
2 weeks, and shortening the duration of
treatment may not help.
Other causes
Because these 11 cases are so different from
the ticlopidine-induced TTP cases, the TTP
may not be related to clopidogrel.

2 of the patients had relapsed, which
usually occurs with re-exposure to the drug
that induced TTP

1 of the patients who relapsed did so only
after re-exposure to atorvastatin, with no
re-exposure to clopidogrel
Ongoing studies
Data are already available on 20 000
patients.
There are currently 3 different trials ongoing,
providing data on 10 000 more patients.
11 study patients
Evidence for clopidogrel-induced TTP
The evidence for these 11 patients is as strong as
the cases identified for ticlopidine.
Most of these patients were on numerous
medications, as were ticlopidine patients reported.
These patients were diagnosed by clinicians as
having TTP before the association with clopidogrel
was known.
10 of 11 of these patients were on therapy for a
very short duration.
The timing is very suggestive of an association
between clopidogrel and TTP.
Clopidogrel labeling
Because of the study released by the New
England Journal of Medicine, the labeling
on clopidogrel has changed.
The warning now states that clopidogrel
can cause TTP.