Eric%20Prystowsky,%20MD

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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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Torsades de pointes
Scope of the problem

• Incidence drug induced torsades is 1-5 in
  patients receiving QT-prolonging anti-arrhythmic
  drugs

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Torsades de pointes
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DRUG Date withdrawn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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Torsades de pointes
Drug-drug interactions

• In 1990s 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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Torsades de pointes
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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Torsades de pointes
Computers to the rescue

• I think the savior in all this is going to be,
  and is, the internet and computerized prescribing
  programs, which wont let you make prescriptions
  that will be life threatening.
• Dan Roden

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Torsades de pointes
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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Torsades de pointes
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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Torsades de pointes
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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Torsades de pointes
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 cant measure
  the reserve directly
• D Roden

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Torsades de pointes
Clinical decision making

• Mrs. Smith gets a potassium channel blocker and
  has long QT does this rule out all
  QT-prolonging 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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Torsades de pointes
Amiodarone

• Theres 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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Torsades de pointes
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
• The drug is producing a greater effect a change
  in concentration, hypokalemia accentuates the
  effect
• something else has changed about their hearts
  environment ischemia, some more heart failure

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Torsades de pointes
Something has changed

• Its 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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Torsades de pointes
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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Torsades de pointes
Appropriate follow up?

• The incidence of torsades is not terribly high
  because weve 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
• Dont need to worry about it excessively
• Dan Roden

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Torsades de pointes
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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Torsades de pointes
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 cant, 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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Torsades de pointes
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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Torsades de pointes
Torsades de pointes