FDA 7.00

Cardiovascular Drugs That Prolong The QT Interval

Douglas C. Throckmorton, M.D.

U.S. Food & Drug Administration

Division of Cardio-Renal Drug Products

FDA 7.00

Issues• Approval of anti-arrhythmic drugs that prolong

the QT interval– Sotalol and Dofetilide

• Approval of cardiac drugs that prolong the QT interval, excluding the anti-arrhythmics– Bepridil

• Relationship between QT prolongation, Torsade de Pointes (TdP), and Clinical Events– Sotalol and Dofetilide

FDA 7.00

I. Approval for Atrial Arrhythmias• Sotalol and Dofetilide have a dose-

dependent effect on QTc and cause TdP

• Effect on QT intrinsic to their effect as an anti-arrythmic

• Approval was based on – Demonstration of symptomatic benefit – Obtaining sufficient information to adequately

describe the nature of the arrhythmic risk

FDA 7.00

d, l,-Sotalol• Class III anti-arrhythmic

– Approved for • Treatment of life-threatening ventricular

arrhythmias • Maintenance of Normal Sinus Rhythmn in

patients with atrial arrhythmias

• Mean effect on QTc– 10 to 40 msecs at doses from 160 to 640

mg/ day

• Dose-dependent effect on QTc prolongation and TdP

FDA 7.00

Sotalol: Mean QTc Prolongatation and TdP

XX

X

X

X

X X

X

X X

X

0

5

10

15

20

25

30

35

40

0

1.0

2.0

3.0

4.0

70 100 700

Ch

an

ge

in M

ea

n Q

Tc

(mse

c)

Ch

an

ge

in M

ea

n Q

Tc

(mse

c)

Inci

den

ce

of

To

rsa

de

s (%

)In

cid

enc

e o

f T

ors

ad

es

(%)

DDoossee SSoottaallooll ((mmgg ttwwiiccee--aa--ddaayy))

X

N= 6736 Patients

X

Mean QTc (msec)TdP (%)

21/ 2371

5/ 18021/ 350

23/ 89320/ 775

7/ 185

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Sotalol: Effect on Mortality

• Post-Myocardial Infarction Trial (Julian Study); n=1,456– Early (<10 Days) Excess Mortality with

Sotalol

– Mortality on Sotalol at one year 7.3%– Mortality on Placebo at one year 8.9%

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Sotalol: Effect on Mortality• Patients with Atrial Fibrillation and Atrial

Flutter*; n=1191– Sotalol: 3/747 (0.44%)

• 2 sudden deaths

– Quinidine: 1/86 (0.12%)• 0 sudden deaths

– Placebo: 2/358 (0.56%)• 1 sudden death

* Double-Blind portion of the trials only.

FDA 7.00

Dofetilide• Class III anti-arrhythmic

– Approved for • Maintenance of normal sinus rhythmn (NSR) • Conversion of atrial fibrillation/flutter to NSR

• Mean effect on QTc– 34 msec placebo-subtracted QTc

prolongation in phase II/III trials (n=976)

• Dose-dependent effect on mean QTc– 5 to 20 msecs QTc prolongation at doses

of 125 to 500 mcg BID

FDA 7.00

Dofetilide: Dose-Effect on TdP and VF*

0 0.3 0.9

10.5

0

4

8

12

<250mcgBID

250mcgBID

500mcgBID

>500mcgBID

Dofetilide Dose

Inci

de

nce

of T

dP

or

VF

TdP (%)

VF (%)

*NDA SVA PopulationN=1,346

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Dofetilide: Mortality Effect in High-Risk Population

• DIAMOND CHF and MI– Patients with structural heart disease

and CHF• Dofetilide: 541/1511 (36%)• Placebo: 560/1517 (37%)

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Dofetilide: Mortality in Supraventricular Arrhythmia Trials

DofetilideMortality

PlaceboMortality

Hazard Ratio(95% CI)

AF/AFl +pSVT

12/1346(0.9%)

3/677(0.4%)

1.1 (0.3, 4.3)

AF/AFl 11/1270(0.9%)

2/614(0.3%)

1.4 (0.3, 6.9)

FDA 7.00

Dofetilide: Dose-Adjustment to Minimize Cardiac Toxicity

• Measure baseline ECG, determine appropriateness of use

• Calculate creatinine clearance, choose appropriate starting dose

• Start Dofetilide under continuous ECG monitoring, dose-adjust as needed

FDA 7.00

Dofetilide: Effect of Dose-Adjusting for Renal Fxn

0

2.5

5

SVA DIAMONDCHF

DIAMONDMI

To

rsad

e d

e P

oin

tes

(%)

TdP Before

TdP After

FDA 7.00

Dofetilide/ Sotalol Summary• Dose-dependent effect on QT, QTc, TdP and

Ventricular Fibrillation– Effects on QTc and TdP rate expected

• Overall mortality in high-risk and target populations not adverse

• Characterization of factors affecting risk of TdP– Exploration of broad dose-range– Exploration of other risk factors (e.g., Dofetilide and

Renal Fxn)

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II. Approval As Second-Line Therapy

• Bepridil prolongs QT and causes TdP

• Not seen with other anti-anginals

• Approval based on demonstration of symptomatic benefit in a population resistant to available therapy

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Bepridil• Calcium Channel Blocker

– Approved for treatment of chronic stable angina in patients intolerant or resistant to other anti-anginals

• Mean Effect on QTc– 30 to 70 msec– 5% of patients on Bepridil >25% increase

(appr. 100 msec)

• TdP: 7 cases in 840 angina patients in the U.S. population (0.8%), with 3 fatalities

FDA 7.00

Bepridil

• Effective in Resistant Populations– 86 patients with angina, refractory to Diltiazem,

randomized to Diltizem or Bepridil– Bepridil more effective anti-anginal in this

population, measured by exercise stress testing:• time to onset of angina• time to 1 mm ST-segment depression• total exercise time

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Bepridil: Summary

• Dose-dependent effect on QT, QTc and clear association with TdP

• Effective in resistant patient population

FDA 7.00

Division of Cardio-Renal Drug Products Summary/Conclusions

• Use of cardiovascular drugs that prolong the mean QT in a dose-dependent fashion is associated with an increased risk for Torsade de Pointes and Sudden Death

FDA 7.00

Division of Cardio-Renal Drug Products Summary/Conclusions

• Cardiac drugs treating symptoms (e.g., atrial arrhythmias) have been approved with the following– Demonstration of symptomatic benefit – Sufficient information to adequately describe the

nature of the arrhythmic risk • Description of the drug-effect over a broad

dose-range• Exploration of potential factors that modify the

arrhythmic risk• Point estimates of total mortality in high-risk

population and in target population

FDA 7.00

Division of Cardio-Renal Drug Products Summary/Conclusions

• Cardiac drugs that cause QT prolongation can also be approved as second-line therapy by demonstrating a symptomatic benefit in a resistant population