Iatrogenic Sudden Death: 11th International Symposium on Heart Failure & CoReggiadi Caserta

1. IATROGENIC SUDDEN DEATH11th International Symposium Heart Failure & CoReggiadi Caserta; April 30, 2011; 12:05 P.M. Maria Rosa Costanzo, M.D., F.A.C.C, F.A.H.A Medical Director, Midwest Heart Specialists Heart Failure and Pulmonary Arterial Hypertension Programs Medical Director, Edward Hospital Center for Advanced Heart Failure Naperville, Illinois, U.S.A.

2. Prolonged QT Interval The corrected QT interval (QTc) is calculated by dividing the QT interval (0.60 seconds) by the square root of the RR interval (0.84 seconds). In this case, the QTc is 0.65 seconds.

3. Torsades des Pointes The electrocardiographic rhythm strip shows torsades de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet. This is an atypical, rapid, and bizarre form of ventricular tachycardia that is characterized by a continuously changing axis of polymorphic QRS morphologies.

4. The Ionic Basis of Ventricular Repolarization James AF et al. Prog Biophysics Molecular Biol 2007; 94: 265-319

5. Proposed Cellular Mechanism for the Development of TdP in the LQTS LQTS Intrinsic Heterogeneity QT Prolonging drugs and ion channel mutations Net Repolarizing Current ↓IKr, ↓IKs, ↑ICa, ↑late INa Prolongation of APD, Preferentially in M cells EAD-induced triggered beat Long QT ↑ Dispersion of refractoriness Torsade de Pointes (Reentry) Harvekamp W et al. EHJ 2000; 21: 1216-31

6. Terfenadine-Induced Brugada-Like Phenotype Di Diego JM et al. Circulation 2002; 106: 2004-11

7. Risk Stratification for ACA or SCD in LQTS Patients Very High Risk (Secondary Prevention): Post-CPR or Spontaneous TdP 14% 5 year K-M Rates of ACA or SCD High Risk (Primary Prevention): Either one or more: QTc > 500msec Prior Syncope 3% Low Risk: QTc ≤ 500 msec and No Prior Syncope 0.5% Moss AJ et al. Circulation 2000:101:616-23

8. QT Prolonging Drugs and Sex-Related Differences in TdP (http://www.torsades.org)

9. Association between Effective Free Therapeutic Plasma Concentration and the Composite End Point of CA, SD, TdP, VT or VF OR 1.00 ETCP/IC50 De Bruin ML et al. EHJ 2005; 26: 590-7

10. Prolongation of the QT Interval, APD, and Transmural Gradient After Exposure to Representative Drugs in an Arterially Perfused Rabbit LV Wedge Preparation Liu T et al. Heart Rhythm 2006; 3: 948-56

11. Conditions Predisposing to TdP • Cardiac Abnormalities • Ventricular Hypertrophy • Heart Failure • Previous anti-arrhythmic therapy • Electrolytes and Metabolic Disorders • Hypokalemia • Hypmagnesemia • Hypocalcemia • Severe hypothyroidism • Anorexia nervosa • Hypo-/Hyperglycemia • Bradyarrhythmias • Sympathetic activity • Female gender

12. Transmural Action Potentials in the Rabbit LVH Renovascular Model Yan GX et al. Am J Physiol Circ Physiol 2001; 281: H1968-75

13. Risk Factors for Drug-Induced TdP • Drug regimen • High drug doses or concentrations (except quinidine • Rapid IV infusion • Concurrent use of other drugs that can prolong the QT interval or that slow drug metabolism due to inhibition of hepatic cytochrome P450 enzymes (erythromycin, cimetidine, grapefruit juice

14. Risk Factors for Drug-Induced TdP • ECG abnormalities • Baseline QT prolongation or T wave lability • Development of marked QT prolongation, T wave lability , or T wave morphologic changes during therapy • Bradycardia which may be related to a fall in local extracellular [K], leading to enhanced drug-induced inhibition of Ikr • Congenital long QT syndrome or “silent” mutations in LQTS genes

15. Risk Factors for Drug-Induced TdP • Metabolic Factors • Electrolyte disturbances, such as hypokalemia, hypomagnesemia, hypocalcemia • Impaired hepatic and/or renal function • Other • Underlying heart disease, particularly heart failure and LV hypertrophy • Recent conversion from AF • Female sex

16. ESC-Proposed Algorithm for Evaluating QT Effects of Drugs in Development Critical Evaluation of the Expected Clinical Value of New Compound MOLECULE STRUCTURE Any similarities to compounds known to prolong ADP/QT? IN VITRO TESTS Cloned Channels Isolated cells/tissue Isolated heart Use model with which you have greatest experience Use reference compounds known to affect ADP/Qt Use appropriate experimental conditions (long cycle length, ↓K Include “major” metabolites ADP/QT↑ No Effect Reevaluate IN VIVO TESTS Use models applied in toxicology/safety pharmacology Perform serial ECG measurements Abandon Proceed QT↑ No Effect Reevaluate PHASE I/II CLINICAL TRIALS Abandon Proceed Use appropriate study design, adjust ECG recordings with plasma levels. timing should include “active metabolites, assess gender-related effects

17. Schematic of Representative Design of Thorough QT Study Link M G et al. Circ Heart Fail 2010;3:547-555

18. Management of LQTS • Acquired LQTS • Pharmachologic • Magnesium Sulfate • Isoproterenol • Lidocaine • Phenytoin • Sodium bicarbonate (for quinidine-mediated arrhythmias) • Non-Pharmachologic • Temporary Pacing (atrial or ventricular) • Congenital LQTS • Pharmacologic • Beta blockers • Mexiletine • Nonpharmacologic • Permanent dual chamber pacemaker • Left cardiac sympathetic denervation (cardiothoracic sympathectomy) • ICD

19. Magnesium Sulfate • First Line Therapy • Effective for both treatment and prevention of LQT-related ventricular ectopic beats or TdP • Benefit occurs without QT shortening • Benefit occurs in pts. with normal serum [Mg] at baseline • Standard regimen: • 2 g IV bolus of 50% MgSo4 over 1-2 min followed in 15 min by another such bolus if required. • Some pts. receive 3-20 mg/min continuous infusion • Bolus dose in children 25-50 mg/Kg • No data on IV maintenance dosing in children

20. Temporary Transvenous Overdrive Pacing • Generally reserved for pts. with LQT-related TdP unresponsive to IV Mg • Pacing rates of ≈ 100 bpm ↓ dispersion of refractoriness and EADs development and may shorten surface QT, especially with bradycardia • Many class IA and III antiarrhythmic drugs that cause TdP have “reverse use dependency” mediated in part by changes in the extracellular [K] changes

21. Isoproterenol • Initial dose 0.05-0.1 mcg/Kg/min in children and 2mcg/min in adults, then titrated to achieve HR of 100 bpm • Can be used to ↑ sinus rate and ↓ QT • Can be used as temporizing measure before pacing

22. Other Acute Therapy • Alkalinization of the Plasma: • Sodium bicarbonate • Useful when TdP is due to quinidine • Qud +OH- <-> QudOH • IV K • May be useful in pts. with nl. [K] • 0.5 meq/Kg to a maximum of 40 meq ↑ plasma [K] by 0.7 meq/L, reverses QT prolongation and QT morphologic changes and ↓ QT dispersion • Effectiveness in preventing or reversing Tdp uncertain

23. Chronic Management of Acquired LQTS • Treatment of underlying cause • Discontinuation of offending drug • Correction of metabolic abnormalities • Avoidance of drugs that prolong QT interval • Nutritional rehabilitation in pts. with eating disorders • PPM in pts. with chronic bradycardia or pause-dependent TdP • Thorough history and ECG screening of immediate family members because of occasional association with congenital LQTS

24. Cumulative Probability of Death in Patients with LQTS with ACA or Recurrent Syncope Zareba W et al. J Cardiovasc Electrophysiol 2003; 14: 337-41

25. Diuretic (n=2901) No Diuretic (n=3896) N Incidence N Incidence P value Death: all cause 1013 12.8 586 5.3 0.001 CV Death 903 11.4 510 4.6 0.001 Sudden Death 241 3.1 183 1.7 0.001 Diuretic Use and the Risk of Mortality in Patients with Left Ventricular Dysfunction Mortality Risk by Diuretic Use at Baseline SOLVD database Cooper HA et al. Circulation. 1999; 100(12): 1311

26. Side Effects of Aldactone • Aldactone complications more frequent vs. trials • Dosing tends to be higher in the community • RALES dose 12.5-25 mg/d Bozkurt et. al., JACC 2003;41:211

27. after RALES: RX Juurlink et al. NEJM 2004;351:543

28. after RALES:Death Juurlink et al. NEJM 2004;351:543

29. In-Hospital Outcomes Abraham WT etal. JACC 2005;46(1):57-64

30. Mortality Odd RatiosPair-Wise Treatment Comparisons Hosmer-Lemeshow goodness-of-fit test not significant at 5% levels for the models adjusted for risk factors and/or propensity, except for covariate-adjusted NTG vs. DOB comparison, where p 0.04. Area under the receiver operator curve 0.70 or higher. Because of multiple pair-wise comparisons, only p values 0.008 were considered significant using Bonferroni correction. *Patients taking both medications were excluded from each pair-wise analysis. †-p 0.005. ‡-p 0.58. §-p 0.021 for covariate adjustment and 0.027 for covariate and propensity score adjustment.aCovariates include age, gender, SBP, DBP, BUN, creatinine, sodium, heart rate, and dyspnea. bCovariates included in the propensity score by treatment comparison are: NES vs. DOB: SBP, sodium, BUN, creatinine, age, weight, LVEF, edema; NES vs. MIL: SBP, age, LVEF, dyspnea, weight; NTG vs. DOB: SBP, sodium, BUN, heart rate, LVEF, symptom duration; NTG vs. MIL: SBP, BUN, LVEF, symptom duration, dyspnea, QRS 120 ms, previous revascularization; NES vs. NTG: SBP, BUN, creatinine, LVEF, symptom duration, edema, previous HF, QRS 120 ms; DOB vs. MIL: SBP, age, hemoglobin, heart rate, dyspnea, VTF. Abraham WT etal. JACC 2005;46(1):57-64

31. ; OPTIME-CHF: Etiology and Mortality Survival Felker GM et al. J Am Coll Cardiol. 2003

32. Effect of Levosimendan on Mortality Days Following Randomization 5 14 31 90 REVIVE II Placebo 1 5 12 35 Levosimendan 5 14 20 45 REVIVE I Placebo 0 1 4 5 Levosimendan 0 1 1 4 REVIVE I + II Placebo 1 6 16 40 Levosimendan 5 15 21 49 Circ.in press

33. Use of Inotropes in HF Therapy • Dobutamine is know to be associated with an increase in myocardial oxygen consumption, heart rate and risk of arrhythmias1,2 • Milrinone produces tachycardia and other arrhythmias, and is limited by hypotension in many patients2,3 • Stimulation of the B-adrenergicpathway has been linked to HF disease progression4 • MOA on heart for both Milrinone and Dobutamine • Rationale for use of B-blockers in chronic HF therapy • Other observations, including RCTs, have shown worse outcomes with positive inotropic agents in the treatment of ADHF2,5,6 1. Burger AJ, etal. Am Heart J 2002;144:1102– 8 2. Monrad ES etal. Circulation 1986;73 Suppl III:III168 –74. 3. Cuffe ES etal. JAMA 2002;287:1541–7. 4. Sackner-Bernstein J, Mancini DM. JAMA1995;274:1462–7 5. Felker GM etal. J Am Coll Cardiol 2003;41:997–1003. 6. Felker GM, Oconner CM. Am Heart J 2001;142:393– 401.

34. Conclusions • The majority of iatrogenic sudden deaths are due to the effects of drugs on cardiac repolarization • Drugs-induced QT prolongation is more common in women than in men • The occurrence of iatrogenic sudden death is influenced by drug regimen, ECG abnormalities, cardiac and metabolic abnormalities • The risk of individual patients must be carefully assessed • Knowledge of the acute and chronic treatment of iatrogenic sudden death is lifesaving