Maria Rosa Costanzo, M.D., F.A.C.C, F.A.H.A

1. SUDDEN DEATH IN VARIOUS POPULATIONS:IS GENDER A RISK FACTOR?11th International Symposium Heart Failure & CoReggia di Caserta; April 29, 2011; 12:35 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. Incidence of SCD by Age and Gender Kannel WB et al. Am Heart J 1998; 136:205

3. Prospective Study of SCD in Women in the U.S. % of Cardiac Deaths Deemed SCD by Age Relative Risk of SCD by Age Albert CM et al. Circulation 2003;107; 2096-101

4. Structural Heart Disease in Cardiac Arrest Survivors Albert CM et al. Circulation 1998; 93: 1170-6

5. Factors Associated with PEA vs. VT/VFThe Oregon Sudden Unexpected Death Study Multivariable Odds Estimates of Factors Associated with PEA vs. VF/VT % of Patients Teodorescu C. et al. Circulation 2010; 122: 2116-22

6. Basic Electrophysiological Variables Affected by Gender Differences Cardiac Cycle Heart Rate QT Interval QT Dispersion QT-RR Relationship T Wave Morphology

7. Sex-Related Differences in Repolarization Action Potentials from Isolated Guinea Pig Ventricular Myocytes Baseline and Ibutilide-Induced QTc Change in Normal Volunteers James MJ et al. Basic Res Cardiol 2004;99: 183-92 Rodriguez I et al. JAMA 285: 1322-6

8. Relationship between Baseline QT Interval and Cycle Length Orchiectomy (Placebo) Orchiectomy + Dihydrotestosterone Liu XK et al. Cardiovasc Res 2003; 57:28-36

9. Effects of Dofetilide on APD and Incidence of EADs at a Cycle Length of 1000 ms in Rabbit RV Endocardial Papillary Muscles Female Ovariectomized Females Orchiectomized Males Male Pham TV et al. Circulation 2001; 103:2207-12

10. Effects of Dihydrotestosterone on Dofelitide-Induced Repolarization Changes in Rabbit RV Endocardial Papillary Muscles APD EAD Orchiectomized Males Females Males DHT-Orchiectomized Males DHT Females Pham TV et al. Circulation 2002; 106:2132-6

11. % Patients Age, Y James AF et al. Prog Biophysics Molecular Biol 2007; 94: 265-319

12. High Risk Subsets for ACA or ACA by Age GroupsGoldenberg I et al. Curr Prob Cardiol 2008; 33: 629-94

13. Probability of ACA or SCD in 3,774 LQTS Patientsfrom the International LQTS Registry

14. % of Patients Rashba EJ et al. Circulation 1998; 97: 451-6

15. JTc (msec) Lehman MH et al. Am J Cardiol 1999;83: 354-9

16. Lethal Arrhythmias Susceptibility and Myocardial Connexin-43 Expression Knezl V. et al. Neuroendocrinology Letters 2008; 29: 798-601

17. Gender Differences in the Clinical Manifestations of the Brugada Syndrome Males Females Benito, B. et al. J Am Coll Cardiol 2008;52:1567-1573

18. The Brugada Syndrome and Gender Kaplan-Meier Estimate of Cardiac Event-Free Survival According to Gender Benito, B. et al. J Am Coll Cardiol 2008;52:1567-1573

19. ICD Trials

20. Multivariable Predictors of ICD Use Adapted from Curtis LH et al. JAMA 2007; 298: 1517-24

21. 1 Year Mortality by ICD Use and Gender in a Large Medicare Population Primary Prevention Cohort Secondary Prevention Cohort Adapted from Curtis LH et al. JAMA 2007; 298: 1517-24

22. Effectiveness of ICD for the Primary Prevention of SCD in Women with Advanced HFBaseline Characteristics of Patients in Trials Included in the Meta-Analysis Ghambari H. et al. Arch Intern Med 2009; 169: 1500-6

23. Effectiveness of ICD for the Primary Prevention of SCD in Women with Advanced HFSex Differences in Mortality Rates Between ICD and Medical Therapy Groups Ghambari H. et al. Arch Intern Med 2009; 169: 1500-6

24. Effectiveness of ICD for the Primary Prevention of SCD in Women with Advanced HF MEN WOMEN Ghambari H. et al. Arch Intern Med 2009; 169: 1500-6

25. Gender Differences in Procedure-Related Adverse Events in Patients Receiving ICD Therapy 161.470 pts, 27% women Peterson PN et al. Circulation 2009; 119: 1078 - 84

26. Benefits of ICD in Women • No trial powered to separately examine outcomes in men and women or test for difference in ICD effectiveness • Small numbers of women enrolled • Limited post-hoc analyses for females do not clearly demonstrate a mortality benefit: • SCD-HeFT: benefit not clear (not powered for gender) • MADIT II: nonsignificant trend toward lower mortality in females but analysis limited by too few female subjects • Meta-analysis: 934 females in 5 trials; no difference in all-cause mortality for women with ICD vs medical Rx

27. Conclusions • Females with lower rates of SCD than males • Differences in arrhythmia susceptibility • 30% of ICDs are implanted in females • Even though the benefit is less, it may represent a clinically significant reduction in deaths

28. Conclusions A trial targeting women is needed • To detect the same ICD benefit in women as was observed in men with 90% power and α=0.05, a study larger than SCDHeFT would be required (1.585 women in each treatment arm, 3.170 total) • It may now even be considered “unethical” to withhold ICD therapy in women meeting the SCD-HeFT enrollment criteria.