**6. Conclusions**

ferent age groups. Subgroup analyses of CRT trials have reported a similar degree of CRT benefit in elderly and younger patients [86-88]. Taken together, these findings support that CRT alone may be the best device therapy in elderly persons with severe left ventricular

This upward drift in age representation in the real world not substantiated by trial data is concerning, not only on scientific grounds but from an ethic and philosophic viewpoint.

Different studies suggest that the incidences of various types of cardiac arrhythmia are dif‐ ferent for women and men, although in many cases we still do not know why this should be. Two principle mechanisms have been proposed to explain these differences between the sexes differential: hormonal effects on the expression or function of ion channels or, con‐ versely, differences in autonomic tone. It is also possible that a combination of these 2 mech‐ anisms may be involved. A combined mechanism would lead to greater sympathetic activity and a lower baroreflex response in men of any age as well as to more pronounced parasympathetic or vagal activity in women. Experimental animal models studies, that used ovariectomized females treated with different gonadal steroids, suggest that the gonadal ste‐ roids are responsible for the differences, thanks to their effects on the ion channels of the cell membrane. These differences between sexes have some clinical implications, particularly for the therapeutic approach and clinical treatment of arrhythmias in women [89]. Differences in ventricular tachycardia and sudden death between the sexes were also reported in the Framingham study [90]. After a follow-up of 26 years, the incidence of sudden death in‐ creased with the age of the population, with a predominance in men in all age groups and an overall ratio in the incidence of approximately 3:1 compared to woman. This difference was explained by the epidemiology of the heart disease (in women, it appears 10 years to 20 years later). An analysis of survival in the VALIANT study, conducted in 14.703 patients with heart failure and ventricular dysfunction after myocardial infarction, revealed that 1067 cases of sudden death were reported during follow-up. Of these, 67% occurred in men and 33% in women [91]. The presence of gender differences in sudden cardiac death substrates and mechanisms has been reported also in epidemiological studies evaluating out-of-hospi‐ tal cardiac arrest, which showed that women present more commonly with asystole and pulseless electrical activity, whereas men usually have ventricular tachycardia and ventricu‐ lar fibrillation [92]. Subgroup analysis in several primary prevention trials revealed that the reduction of overall mortality achieved by ICD was more pronounced in male patients and it did not reach statistically significant levels in women [49,58,59]. In addition, a meta-analy‐ sis of 4 major primary prevention trials [93] found no mortality benefit of ICDs in women. After prophylactic ICD implantation, the mortality reduce significantly in men (HR 0,67, 95% CI 0,58-0,78, p<0,001), whereas in women the mortality reduction was inconclusive (HR 0,78, 95% CI 0,57-1,05, p=0,1) [94]. These data confirm that EF is not a reliable sudden death risk factor in women. At variance with ICD studies subgroup analyses of CRT trials suggest

dysfunction.

68 Cardiac Defibrillation

**5.5. Gender**

The existing evidence does not support recommendations for ICD implantation by current guidelines on several occasions. We may over treat certain patients. As current guidelines have been broadened to include lower-risks groups with lower event rates, the cost-effec‐ tiveness of ICD therapy has become even less favorable. Implantable cardioverter-defibrilla‐ tors are life-saving in high-risk population that, however, cannot be defined simply by the EF. The ICD does not confer immortality. It is most likely to result in meaningful prolonga‐ tion of life in patients who are at high risk for lethal arrhythmias but low risk of death from hemodynamic failure or other organ system disease [98]. Further studies are necessary for identifying the most appropriately "at-risk" population for ICD therapies and the guidelines should be re-evaluated and updated. Serious comorbidities that limit the life expectancy of the patient, as well as gender and age should also be taken into account. The adoption of strict criteria for ICD implantation is a necessary step toward a rational use of our limited resources, particularly in an era of economic uncertainty and financial crises [31]. Finally, the ICD implantation should be preceded by a careful analysis of risk/benefit balance, shared with the patient and his family. Comunication with these patients focused on a hori‐ zon of 5 years, during which for every 100 patients receiving devices, approximately 30 pa‐ tients are predicted to die with or without an ICD, while 7 to 8 lives may be saved with the ICD. These estimates are presented in the context of adverse events, including unnecessary shocks, and the possibility that circumstances may arise for which the defibrillator may be inactivated to allow natural death [99]. Considerations of an individual's age comordibity, and remaining life expectancy have a vital place not only in decision-making regarding ex‐ pensive and invasive procedures such as ICD implantation, but also for "routine" health screenings. Many questions still remain open.
