1. Tenth International Symposium HEART FAILURE & Co. CARDIOLOGY SCIENCE UPDATE FEMALE DOCTORS SPEAKING ON FEMALE DISEASES Milano 9 - 10 aprile 2010 ICD data in Women are Inconclusive: Do we need a sex specific trial? Valeria Calvi Università di Catania U.O. di Aritmologia Ospedale Ferrarotto

2. Cattedra di Cardiologia Università di Catania ICD Trials

3. Cattedra di Cardiologia Università di Catania 2004

4. Cattedra di Cardiologia Università di Catania Survival Free From Arrhythmic Death or Cardiac Arrest Overall Survival 2004

5. Cattedra di Cardiologia Università di Catania 1232 patients: 192 (16%) women and 1,040 (84%) men The cumulative probability of sudden cardiac death in conventionally treated patients was similar by gender In the ICD treatment arm, the 2-year mortality rate was found to be 16% in both men and women 2005

6. Cattedra di Cardiologia Università di Catania 2005 2-year probability of appropriate ICD therapy for VT/VF was significantly lower in women Cumulative probability of death after first appropriate ICD therapy was non significantly different Women presented with somewhath higher risk of hospitalization for CHF in both treatment groups

7. Cattedra di Cardiologia Università di Catania 458 patients: 326 man (71%), 132 women (29%) No difference in the incidence of arrhythmic death in men (n = 10; 6%) versus women (n = 4; 6%) No evidence for a sex difference in the effectiveness of the ICD in reducing mortality among patients with NISCM 2008

8. Cattedra di Cardiologia Università di Catania A total of 2,521 patients, 588 (23%) women and 1,933 (77%) men Treatment effects appear different between genders with a smaller ICD benefit among women; but this difference was not significant (P=0,54) 2008

9. Cattedra di Cardiologia Università di Catania No difference in risk of cardiac arrhythmic death in men versus women (36% vs. 39%, P = 0.34) No difference in the risk of appropriate shock therapy for men versus women (P = 0.25). 2008

10. Cattedra di Cardiologia Università di Catania 2008

11. Cattedra di Cardiologia Università di Catania 1.530 patients, women comprised 19% (293/1.530) After adjusting for baseline characteristics and medical therapy, there was no significant difference in the outcome and mortality between women and men (HR = 1.05, P = 0.83) 2009

12. Cattedra di Cardiologia Università di Catania A total of 6% of men and 8% of women received an appropriate ICD shock during the follow-up (HR = 1.37, P = 0.19) Adverse events (pulse generator-, lead-, and patient-related cardiovascular events) were observed more commonly in women 2009

13. Cattedra di Cardiologia Università di Catania Mortality among men with systolic dysfunction randomized to ICD implantation vs medical therapy for the primary prevention of SCD Mortality among women with systolic dysfunction randomized to ICD implantation vs medical therapy for the primary prevention of SCD

14. Cattedra di Cardiologia Università di Catania

15. Cattedra di Cardiologia Università di Catania 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 to 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

16. Cattedra di Cardiologia Università di Catania Number of Patients Enrolled Who Received ICDs in Clinical Trials

17. Cattedra di Cardiologia Università di Catania Am Heart J 1998

18. Cattedra di Cardiologia Università di Catania The prevalence of HF increases with age for both sexes, with more women than men having HF after 79 years of age Survival is better for women - Women with acute decompensated HF tend to have preserved LV function almost twice as often as men and those with impaired LV systolic function tend to present with a higher LVEF when compared with men - Women have less ischemic cardiomyopathy - Other? Gender differences in geometric remodeling, myocyte cell loss, and gene expression have been reported JACC 2009

19. Cattedra di Cardiologia Università di Catania SCD in Women JACC 2009 CAD is the most common urderlying cardiovascular disease in patients with SCD

20. Cattedra di Cardiologia Università di Catania Portland, Oregon, Metropolitan Area, Feb 2002 to Jan 2007 (n 1,568) Demographics and Cardiac Arrest Circumstances in Men and Women Age >35 Years With SCA

21. Cattedra di Cardiologia Università di Catania Conclusions Since fewer women may be eligible for ICD implantation based on LVEF criteria alone, the identification of novel SCA risk predictors for women becomes an important priority. JACC 2009

22. Cattedra di Cardiologia Università di Catania ICD in Women Community-based studies reported that only 25% to 30% of SCAs occur in subjects who have severely reduced LV systolic function Women account for only 10%-29% of the study populations in ICD clinical trials Men are significantly more likely to undergo ICD implantion for both primary and secondary prevention of SCA

23. Cattedra di Cardiologia Università di Catania Women represent 27% of patients receiving ICD for primary prevention in clinical practice in USA. Possible explanations: - Selection criteria are applied more stringently to women - Trial criteria are being applied more stringently among older women than older men with no significant gender differences among younger patients - Women are less commonly referred for invasive cardiac procedures - Older women have more coexisting illnesses and higher complication rates and are therefore viewed as less likely to benefit from therapy - Older women may be more likely to refuse ICD therapy compared to men - Higher complications rates of ICD implantation in women Am Heart J 2009

24. Cattedra di Cardiologia Università di Catania 2009 161.470 pts, 27% women

25. Cattedra di Cardiologia Università di Catania 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 Ghanbari et al. Arch Int Med 2009 Redberg RF. Arch Int Med 2009 Conclusions

26. Cattedra di Cardiologia Università di Catania 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.

27. Cattedra di Cardiologia Università di Catania Lingiustizia di sempre…