# Presentation: 594557

## Drug-Induced QT Interval Prolongation andTorsades de Pointes

## Slide 2

## Drug-Induced Torsades de Pointes

-  Low frequency event
-  Potentially life threatening
-  Not highly predictable despite    known risk factors

## QT Prolongation & Torsades de Pointes

-  Cardiac electrophysiology
-  Clinical pharmacology
-  Genetics
-  Regulatory medicine
-  Clinical Practice

## QT Prolongation & Torsades de Pointes

-  Mechanisms of QT prolongation and TdP
-  Drug effects on the QT interval
-  Specific drugs associated with TdP
-  Risk factors for drug-induced TdP
-  Clinical and regulatory implications

## Drugs Which Prolong the QTc 

- http://www.dml.georgetown.edu/depts/pharmacology/torsades.html
- http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/publicat/adrv8n1_e.html

## QT Prolongation & Torsades de Pointes

-  Congenital LQTS
-  Acquired LQTS
-  Drugs
-  Bradycardia
-  Hypokalemia
-  CHF & LVH

## Slide 8

## Action Potential and Ionic Currents

## Ventricular Action Potential

- Na+

- IKr

- Ca++

- IKs

**Notes:**
It is likely that no one in this room is completely naïve to the QT interval, and I will spend only a short time on some general orientation.
This is a stylized ECG complex, with a P wave, QRS complex and T wave illustrated.  The QT interval of course is measured from the beginning of the Q wave to the end of the T wave, representing the time required for depolarization and repolarization of the ventricles.  At a standard paper speed of 25 mm/sec, one of these small (1 mm ) boxes  = 40 msec. 10 msec therefore is equal to one quarter of one box.
So, the QT interval in this drawing is 10 mm long, or 400 msec in duration. 

Source:The CIBA Collection of Medical Illustrations, Vol.  5 Heart, 1992

## Mechanisms Of Drug - Induced QT Prolongation and Tdp

- Block of repolarizing K+ currents
- Stimulation of ICa-l
- Stimulation of INa

## HERG Channel

##  Early afterdepolarizations

-  Early afterdepolarizations
-  Transmural reentry

## Yan & Antzelevitch Circulation. 1998;98:1921-1927

## Yan & Antzelevitch Circulation. 1998;98:1928-1936

**Notes:**
The discovery of cells in the midmyocardial layers of ventricular myocardium with unique repolarization properties has prompted investigations into the distinctive electrophysiological, pharmacological, and pathophysiological characteristics of these cells. The chief attribute of the M cell is the ability of its action potential to prolong disproportionately compared with that of other myocardial cells in the ventricle in response to a slowing of rate and/or to agents that prolong APD.1 2 5 The ionic basis for these features of the M cell includes the presence of a smaller slowly activating IKs20 as well as a larger late INa.21 The present study examines the characteristics and distribution of M cells within the intact wall of the canine left ventricle using floating glass microelectrodes to simultaneously record transmembrane action potentials from the transmural sites along the ventricular wall of an arterially perfused wedge preparation. 
Antzelevitch

## Torsades de Pointes

**EPI**

**M**

**ENDO**

## Torsades de Pointes

## ECG - QT Interval

**Notes:**
It is likely that no one in this room is completely naïve to the QT interval, and I will spend only a short time on some general orientation.
This is a stylized ECG complex, with a P wave, QRS complex and T wave illustrated.  The QT interval of course is measured from the beginning of the Q wave to the end of the T wave, representing the time required for depolarization and repolarization of the ventricles.  At a standard paper speed of 25 mm/sec, one of these small (1 mm ) boxes  = 40 msec. 10 msec therefore is equal to one quarter of one box.
So, the QT interval in this drawing is 10 mm long, or 400 msec in duration. 

Source:The CIBA Collection of Medical Illustrations, Vol.  5 Heart, 1992

## Automated QT and QTc Analysis 

-  Reliable with normal T waves at   physiologic heart rates
-  Unreliable:
-  High heart rates
-  Abnormal T waves
-  Prominent U waves
-  T-U wave complex morphology

**Notes:**
One of the reasons for this variability across a population is variability within each person.  Three carefully conducted studies have examined this, by measuring QTc a number of times within individuals.  This slide summarizes the findings of these three studies.  As you can see, the range of QTc, that is the longest minus the shortest, for individuals within these populations ranged from 66 to 95 msec, and is partially dependent upon the number of times the measurement was taken - for the Molnar study, measures were taken every 5 minutes for 24 hours.  
In addition to diurnal influences, it has also been demonstrated that the QTc will increase following a meal, by approximately 20 msec. 

## Slide 20

**Notes:**
17 yo female HS athlete with vague dizzy spells and ex-induced PVCs.  No FH of syncope or SD.  Echo, ETT nl.  Dizzy spells resolved with high CHO drink before sports.  ECG shows slightly long QTc and ?morphologically abnormal T waves ????  Would you restrict this pt ?  Treat ?  How to workup further.

## Rate-Corrected QT Interval (QTc)

- QT Interval corrected for heart rate = QTc (Bazett)
- QTc =
- General Population Average QTc = 380-400 msec
- Bazett correction has major limitations

**Notes:**
The duration of the QT interval is affected by a number of physiologic and pathologic factors, including - importantly - by the heart rate at which the QT is measured.  As you can see in the six seconds of ECG displayed in each of these two sample tracings, the presence of more complexes per unit time will simply have the effect of shortening the intervals between each complex.  In addition however, the QT intervals within each complex are shortened as well.  So, a perfectly normal heart has a longer QT interval at a lower heart rate than at a higher heart rate.  One option for expression of QT might be to include the heart rate at which the QT was measured, e.g. QT 420 at 66 bpm.  However, by convention, the QT interval is instead “corrected for heart rate” by application of a mathematical correction formula.  The formula incorporates terms for heart rate and QT, producing a QTc.  The correction formula first proposed by Bazett in 1920 became the standard used in the literature, and remains the most commonly employed.  However there are others, and I will later review the effect of correction formula upon the findings of our comparative QTc trial.
While it is true that an average QTc in an average population is a difficult number to pin down, 400 msec is a reasonable estimate, consistent with much of the epidemiological literature.

Source: QT scans submitted by Eric Watsky 66 and 83bpm
Tracking Number: QT 17.1 QT scans

## QT Correction Formulae

**Notes:**
As I  mentioned earlier, the Bazett formula may have been the first, but there are at least 17 unique QT correction formulas which have been published over the years, six of which we are showing you here.  Since each handles the RR term differently, then a QT measured at a heart rate of say 80 bpm, will calculate to a different QTc with each formula.  Among this group of formulas, the Bazett formula will produce the longest QTc, for heart rates above 60 bpm; and the shortest QTc for heart rates below 60 bpm. 
To understand the effect of the correction formula upon the magnitude of QTc in Study 054, let’s take a look at the effects of the study drugs on the QT interval and on the heart rate.

## Normal QTc Interval - Criteria

-  _QTc (msec)__	_          _Male__	__	__ Female_
-   Normal		     	<430	  	   	<450
-   Borderline		 431-450	   	 451-470
-   Prolonged		>450	            	>470

##  QT Intervals in Drug Induced TdP

- Makkar et al *JAMA *1993; 270: 2590-2597.
- Bednar & Ruskin (personal communication)

- Drug-Induced TdP - Gender Distribution

- Makkar et al *JAMA *1993; 270: 2590-2597.
- Bednar & Ruskin (personal communication)

## TdP - High Risk Drugs (> 1%)

-  Quinidine
-  Disopyramide
-  Sotalol
-  Ibutilide
-  Dofetilide

- Therapeutic Effect Is Linked to IKr Block

## TdP - Low Risk Drugs (< 0.1%)

-  Antihistamines
-  Antibiotics
-  Antiviral agents
-  Psychotropics
-  Many others

- Therapeutic Effect Is _Independent_ of IKr Block

## Drug-Induced Torsades de Pointes

-  Primary: Drug effect (IKr block)
-  Secondary: Effect Amplifiers
-  Bradycardia
-  Hypokalemia
-  Heart disease (LVH or CHF)
-  Atrial fibrillation
-  Female gender
-  Undetected HERG mutation
-  High doses
-  Metabolic inhibitors (PK)
-  Concomitant IKr blockers (PD)

**Notes:**
DRUG-DRUG AND DRUG - GENE INTERACTIONS

## Effect of EC K+ on Drug Induced IKr Block

*Circulation* 1996 Feb 1;93(3):407-11Yang T, Roden DM

**Notes:**
IKr was measured in AT-1 cells, where contaminating outward currents are absent. The drug concentration producing 50% inhibition of IKr tails (IC50) was strikingly [K+]o-dependent. Elevating [K+]o from 1 to 8 mmol/L increased the IC50 for dofetilide block from 2.7±0.9 to 79±32 nmol/L and for quinidine block from 0.4±0.1 to 3.8±1.2 μmol/L. 
Conclusions (1) The increase in drug block with low [K+]o provides a mechanism to explain the link between hypokalemia and torsade de pointes. (2) Elevations in [K+]o occur with myocardial ischemia and with rapid pacing. Possible consequences of blunted drug block with high [K+]o include loss of drug efficacy with ischemia and with rapid pacing; the latter may contribute to "reverse use-dependent" action potential prolongation. Extracellular potassium is a critical determinant of drug block of IKr, with substantial clinical implications. 
Circulation 1996 Feb 1;93(3):407-11Yang T, Roden DM
Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence.

## Hepatic drug

**Hepatic drug**
**metabolism**

- Roden, D.  Cardiac Electrophysiology
- (Zipes & Jalife) Ch XIV WB Saunders 2000

**Notes:**
The traditional view is that this metabolism occurs in the liver. 1 However, evidence shows that presystemic metabolism can also occur in the enterocyte. Similarly, grapefruit juice (not orange juice) can increase plasma concentrations of a number of drugs, including lovastatin, felodipine, and terfenadine, The major drug-metabolizing enzyme in the intestine is a member of the CYP 3A superfamily, and the enterocyte also expresses drug transport molecules, such as P-glycoprotein.
PK interactions or abnormal metabolism or elimination resulting from impaired hepatic or renal function may increase 
Plasma concentrations and lead to QT prolongation.

T

## CYP450 3A4 Inhibitors

- Amiodarone
- Cimetidine
- Fluoxetine
- Grapefruit juice
- Protease inhibitors
- Ketoconazole; itraconazole
- Macrolide antibiotics (not Azithromycin)
- Nefazadone

## Drug Induced Torsades de Pointes

-  	_Drug__	__EP Effects__	__Metabolic Liability_
- 	Terfenadine	IKr blocker	3A4 substrate
- 	Cisapride	IKr blocker	3A4 substrate
- 	Mibefradil	IKr blocker	3A4 inhibitor
- 	Erythromycin	IKr blocker 	3A4 inhibitor
- 	Astemizole	IKr blocker	3A4 substrate
- 	Dofetilide	IKr blocker	Renal excretion
- 	Sotalol	IKr blocker	Renal excretion

## QTc Changes with Terfenadine Effect of CYP3A4 Inhibition with Ketoconazole

- Change
- In QTc
- (msec)

## Terfenadine (Seldane)   60 mg BID

- *   Pratt CM, *et al.*  Am Heart J 1996; 131:472-480
- **  Pratt CM, *et al.*  Am J Cardiol 1994; 73: 346-352
- *** Hanrahan JP, *et al.*  Ann Epidem 1995; 5:201-209
- **** Honig PK, *et al.*  JAMA 1993; 269:1513-1518

**> 100 million prescriptions**

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**Notes:**
Seldane was prescribed well over 100 million times between the time of its launch in 1979 and its withdrawal more than 15 years later.  The mean effect of terfenadine on the QTc has been characterized by a number of investigators as approximately 6-8 msec.  As described in the briefing document, a close review of hourly ECG data obtained in a trial conducted by Dr Craig Pratt and colleagues reveals that terfenadine was associated with a prolongation of 18 msec when measured at peak, that is at one hour after dosing. 
Importantly, examination of considerable epidemiological evidence has failed to demonstrate that terfenadine alone was associated with increased risk of sudden death, despite its ability to prolong QTc in this fashion.
However, as FDA's CardioRenal review mentions, the profile of  terfenadine changes considerably in the presence of CYP3A4 inhibition. Honig et al measured the QTc effect of  terfenadine administered with ketoconazole as 82 msec at trough, i.e. on ECG tracings taken in the morning, before terfenadine administration, and so may not be representative of the effect at Cmax.  
And concomitant administration of terfenadine and CYP3A4 inhibitors such as ketoconazole has been associated with a marked increase in the risk of sudden death.

## Cisapride (Propulsid)

- Gastric prokinetic (GERD)
- IKr blocker (modest QT effect)
- CYP 3A4 substrate
- Clarithromycin - 3X increase in conc
- Ketoconazole - 8X increase in conc
- 30 million Rx’s since 1993; no arrhythmia signal in large database review
- 1993-1999: 270 cases of serious arrhythmias reported to FDA (70 deaths)
- One AE per 111,000 and one fatality per 428,000 prescriptions (undetectable in controlled trials)

## TdP: Multiple-Hit Hypothesis

- Drug exposure (IKr blocker)
- Second risk factor
- Bradycardia
- Hypokalemia
- Female gender
- Metabolic inhibitor
- Other QT prolonging drugs
- Underlying heart disease (CHF, LVH, AF)
- Genetic polymorphism (IKr or IKs)

## Drugs Withdrawn for TdP

-  	_Drug__	__Class__	__Date Withdrawn_
- 	Terfenadine	Antihistamine		Feb 1998
- 	Sertindole	Antipsychotic		Dec 1998
- 	Astemizole	Antihistamine		Jun  1999
- 	Grepafloxacin      Antibiotic		Nov  1999
- 	Cisapride	GI Prokinetic		July  2000

## GAO

**GAO**
**01-286R**
**1/19/01**

## Drug Induced QT Prolongation

- Preclinical Screeing

-  *In vitro* ion channels effects
-  IKr - cloned HERG (HEK or AT-1 cells)
-  Ica & INa
-  *In vitro *APD effects
* *Isolated myocytes (dog,rabbit,g. pig)
-  Purkinje fibers (dog,rabbit)
-  Papillary muscle (guinea pig)
-  Wide range of concentrations (100-1000X)
-  Wide range of rates
-  Metabolites

## Drug Induced QT Prolongation

- Preclinical Screeing

## Evaluation of New Drugs - Risk Assessment

-  Preclinical profile
-  _*QT effects in humans*_
-  *Mean & mean max changes c/w PBO*
* **Categorical analysis*
* **Outliers*
* *_*Special populations*_
-  Torsades de Pointes
-  VT, VF & cardaic arrest
-  Syncope
-  Sudden death

## Drug-Induced TdP

- Drug - drug interactions
-  Pharmacokinetic
-  Pharmacodynamic
- Drug - gene interactions
- Genetic polymorphisms
- Acquired repolarization reserve (CHF)

## Drugs Which Cause TdP

- Almost all are IKr blockers
- Preclinical profile cannot exclude risk
- Many are CYP 450 3A4 substrates
- Numerous cofactors enhance risk
- TdP rarely detected in drug development

## Drug Induced QT Prolongation

-  Preclinical findings
-  QT effects in humans
-  Adverse event profile
-  Therapeutic target(s)
-  Relative efficacy
-  Unique advantages
-  Alternative options
-  Risk:benefit assessment

## Slide 45

## Post-CABG Day 4 (on Fluconazole)

- Post-CABG Day 4 (on Fluconazole)

- QT=380   QTc=460

- QT=380   QTc=460

**Notes:**
CASE 4
VF arrest on day 4 post CABG
Pt was on fluconazole for 2 days
QT=380   QTc=460
Fluconazole is a weal Ikr blocker and has been associated with raare cases of TdP

## Post-CABG Day 3

- QTc 516 ms on fluconazole
- QTc normal preop

**Notes:**
CASE 4

Baseline ECG 3 days post CABG
QTc is 516 on fluconazole
Was normal preop

## Slide 48

**Notes:**
ECG #2
60 you male with CABG 3 months ago. LVEF 25% admitted with angina and  CHF - intubated. Next ECG shows bradycardia and marked QT prolongation (>600).  Low dose chronic amio no other drugs.
Grafts open. What to do?

## Slide 49

**Notes:**
78 female with sick sinus syndrome on sotalol
For PAF
Bradycardia is a risk for QT prolongation
QTc was normal pre sinus arrest
Sinus arrest induced by Ca and beta blockers for PAF with RVR

## Amiodarone

**QT 621**
**QTc 747**
**HR 87**

**Long-short**
**-> TdP**

## Slide 51

**Notes:**
ARTIFACT - NOISE MIMICKING TDP
THOUGHT TO BE TDP ON ZELDOX  12/00
NOSX
SUBSEQUENT TRACINGS SHOW ARTIFACT