Tenth International Symposium HEART FAILURE & Co. CARDIOLOGY SCIENCE UPDATE

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. ICD Trials

3. 2004

4. Survival Free From Arrhythmic Death or Cardiac Arrest Overall Survival 2004

5. 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. 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 2005

7. 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. 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. 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. 2008

11. 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. 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. Mortality among women with systolic dysfunction randomized to ICD implantation vs medical therapy for the primary prevention of SCD Mortality among men with systolic dysfunction randomized to ICD implantation vs medical therapy for the primary prevention of SCD

15. 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. Am Heart J 1998

17. JACC 2009 • 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

18. SCD in Women CAD is the most common urderlying cardiovascular disease in patients with SCD JACC 2009

19. Demographics and Cardiac Arrest Circumstancesin Men and Women Age >35 Years With SCA (n 1,568) Portland, Oregon, Metropolitan Area, Feb 2002 to Jan 2007

20. 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

21. ICD in Women Men are significantly more likely to undergo ICD implantion for both primary and secondary prevention of SCA • 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

22. 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

23. 2009 161.470 pts, 27% women

24. 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 Ghanbari et al. Arch Int Med 2009 Redberg RF. Arch Int Med 2009

25. 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.

26. L’ingiustizia di sempre…