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Cardiovascular Drugs That Prolong The QT Interval

Cardiovascular Drugs That Prolong The QT Interval. Douglas C. Throckmorton, M.D. U.S. Food & Drug Administration Division of Cardio-Renal Drug Products. Issues. Approval of anti-arrhythmic drugs that prolong the QT interval Sotalol and Dofetilide

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Cardiovascular Drugs That Prolong The QT Interval

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  1. Cardiovascular Drugs That Prolong The QT Interval Douglas C. Throckmorton, M.D. U.S. Food & Drug Administration Division of Cardio-Renal Drug Products

  2. 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

  3. 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

  4. 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

  5. D o s e S o t a l o l ( m g t w i c e - a - d a y ) Sotalol: Mean QTc Prolongatation and TdP X 4.0 4 0 X Mean QTc (msec) X 7/ 185 TdP (%) X 3 5 X 3.0 3 0 X X X 2 5 23/ 893 20/ 775 Incidence of Torsades (%) Change in Mean QTc (msec) 2.0 2 0 1 5 X X 1.0 21/ 2371 1 0 X 5 1/ 350 5/ 1802 X X 0 0 7 0 1 0 0 7 0 0 N= 6736 Patients

  6. 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%

  7. 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.

  8. 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

  9. Dofetilide: Dose-Effect on TdP and VF* *NDA SVA Population N=1,346

  10. 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%)

  11. Dofetilide: Mortality in Supraventricular Arrhythmia Trials

  12. 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

  13. Dofetilide: Effect of Dose-Adjusting for Renal Fxn

  14. 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)

  15. 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

  16. 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

  17. 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

  18. Bepridil: Summary • Dose-dependent effect on QT, QTc and clear association with TdP • Effective in resistant patient population

  19. 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

  20. 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

  21. 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

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