Transcript Torsades de pointes

The EP show: Drug-induced
torsades de pointes
Eric Prystowsky, MD
Director
Clinical Electrophysiology Laboratory
St Vincent Hospital
Indianapolis, IN
Dan Roden, MD
Director
Division of Clinical Pharmacology,
Vanderbilt University School of Medicine
Nashville, TN
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Scope of the problem
Incidence drug induced torsades is 1-5% in
patients receiving QT-prolonging antiarrhythmic drugs
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Withdrawals due to torsades
DRUG
Date withdrawn
Terfenadine (Seldane) Feb 1998
Sertindole
Dec 1998
Astemizole
Jun 1999
Grepafloxacin
Nov 1999
Cisapride
July 2000
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Drug-drug interactions
In 1990’s life-threatening arrhythmias were
discovered with Seldane.
It took millions of prescriptions to detect the
problem - interaction with erythromycin and
ketoconazole.
D Roden
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Too many drugs
The problem is there are so
many drugs, and so many
interactions, no one can
keep track of it all.
We need to flag the major
dangerous combinations,
and a better understanding
of mechanisms to predict
future problems.
D Roden
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Computers to the rescue
“I think the savior in all this is
going to be, and is, the internet
and computerized prescribing
programs, which won’t let you
make prescriptions that will be
life threatening.”
Dan Roden
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Repolarization reserve
How does the concept of “repolarization
reserve” work, and how can we take
advantage of it as clinicians?
Example:
In a patient who underwent a Holter monitor,
the QT interval got alarmingly long at night
time. No family history of problems
Is this a person we need to worry about
giving a drug that prolongs the QT interval?
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Redundant systems
The heart has redundant systems to create
repolarization
Reduced efficiency of one repolarizing
mechanism might not cause a problem, but it
makes the heart less able to cope with a drug
that prolongs the QT-interval
Each hit to the system makes it more likely
that a drug will be what pushes you over the
edge to torsades
D Roden
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Patient possibilities
1) Something else going on in their life that is
extending the QT-interval (i.e. intermittent
LBBB, transient hypokalemia
2) Patient has congenital long-QT syndrome.
(used to be 1 in 10,000 – but now we are
much more sensitized to it)
3) Perhaps this is reduced repolarization
reserve, and the patient is at higher risk
when taking QT-interval prolonging drugs
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Clinical decision making
Should everyone get a Holter before getting
QT-prolonging drugs?
A great theoretical idea, but simply not
practical
No simple test to screen for susceptibility yet
The repolarization reserve concept lets us
risk-stratify the patients, but we can’t
measure the reserve directly
D Roden
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Clinical decision making
Mrs. Smith gets a potassium channel blocker
and has long QT – does this rule out all QTprolonging drugs? Or can you go after a
different ionic channel?
We have other therapies, so why risk exposing
them to another QT-prolonging drug?
The theory makes no distinction between the
drug mechanisms that might provoke the long
QT.
D Roden
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Amiodarone
There’s something very different about
amiodarone.
The mechanism by which it prolongs the QT
is not much different than other drugs, so it
must have some other pharmacologic action
that is potently anti-arrhythmic, even in the
face of long QT.
The actual mechanism remains unclear.
D Roden
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Secondary proarrythmia
What is it that causes a patient to develop a
late problem responding to QT-prolonging
drugs?
Two possibilities for the late effect:
1) The drug is producing a greater effect: a
change in concentration, hypokalemia
accentuates the effect
2) something else has changed about their
heart’s environment – ischemia, some
more heart failure
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Something has changed
“It’s sort of self-evident that
if somebody behaves in one
way on July 1st and on August
1st they behave a different
way then something has
changed. Something has
changed. And our job is to
figure out what those things
might be.”
Dan Roden
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Why late torsades appears
Most people who present with torsades after
leaving the hospital have a fairly evident
cause:
Recent bad heart failure
Severe hypokalemia
Bradycardia
Acquired heart block
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Appropriate follow up?
The incidence of torsades is not terribly high
because we’ve become attuned to the
problem
Must make sure the patient is well informed
of situations with risk of torsades
Follow the patients with intermittent ECG
Don’t need to worry about it excessively
Dan Roden
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Inpatient initiation?
A vexing issue
Patients should be started on these drugs as
inpatients
May not be highly cost-effective, but you
need to reduce risks to the patients as much
as possible
Dan Roden
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Do no harm
“In every patient, you just
think of the worst thing that
could happen and then say, ‘If
I could live with that, then
fine. If I can’t, then I better
figure out a way of minimizing
the chances that that will
happen or find another drug,
or another therapy.’”
Dan Roden
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Outpatient initiation
I am more willing to start
certain patients I consider
safe on an outpatient basis.
There probably is not a right
or wrong answer, you have to
go with a sense of your
comfort level.
Eric Prystowsky
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