1. 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 The EP show: Drug-induced torsades de pointes

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

3. Withdrawals due to torsades Torsades de pointes DRUGDate withdrawn Terfenadine (Seldane)Feb 1998 SertindoleDec 1998 AstemizoleJun 1999 GrepafloxacinNov 1999 CisaprideJuly 2000

4. 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 Drug-drug interactions Torsades de pointes

5. 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 Too many drugs Torsades de pointes

6. “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 Computers to the rescue Torsades de pointes

7. 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? Repolarization reserve Torsades de pointes

8. 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 Torsades de pointes

9. 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 Torsades de pointes

10. 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 Clinical decision making Torsades de pointes

11. 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 Clinical decision making Torsades de pointes

12. 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 Amiodarone Torsades de pointes

13. 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 Secondary proarrythmia Torsades de pointes

14. “It’s sort of self-evident that if somebody behaves in one way on July 1 st and on August 1 st 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 Something has changed Torsades de pointes

15. 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 Why late torsades appears Torsades de pointes

16. 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 Appropriate follow up? Torsades de pointes

17. 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 Inpatient initiation? Torsades de pointes

18. “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 Do no harm Torsades de pointes

19. 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 Outpatient initiation Torsades de pointes