Eric Prystowsky, MD Director Clinical Electrophysiology Laboratory St Vincent Hospital

1. 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

2. Torsades de pointes Scope of the problem • Incidence drug induced torsades is 1-5% in patients receiving QT-prolonging anti-arrhythmic drugs

3. Torsades de pointes Withdrawals due to torsades

4. Torsades de pointes 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

5. 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

6. 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 won’t let you make prescriptions that will be life threatening.” • Dan Roden

7. 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?

8. 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

9. Torsades de pointes Patient possibilities • Something else going on in their life that is extending the QT-interval (i.e. intermittent LBBB, transient hypokalemia • Patient has congenital long-QT syndrome. (used to be 1 in 10,000 – but now we are much more sensitized to it) • Perhaps this is reduced repolarization reserve, and the patient is at higher risk when taking QT-interval prolonging drugs

10. 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 can’t measure the reserve directly • D Roden

11. 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

12. Torsades de pointes 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

13. 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 heart’s environment – ischemia, some more heart failure

14. Torsades de pointes 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

15. Torsades de pointes Why late torsades appears • Most people who present with torsades after leaving the hospitalhave a fairly evident cause: • Recent bad heart failure • Severe hypokalemia • Bradycardia • Acquired heart block

16. Torsades de pointes 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

17. 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

18. 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 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

19. 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

20. Torsades de pointes Torsades de pointes