Gender Differences in Clinical Outcome After Catheter Ablation or Implantation of Cardiac Device

In recent years, it has been increasingly reported that there are gender-related differences in the presentation and clinical course of many cardiovascular disorders. Clinical cardiac electrophysiology is not a stranger to such differences, which involve both basic electrophysiology and the clinical course of many arrhythmias. Clinical electrophysiologists must be aware of such differences in order to provide optimal care for their patients. In fact, most of the available evidence supporting the use of invasive electrophysiological procedures has been derived from studies enrolling predominantly males. That has been the case for studies evaluating the role of catheter ablation of atrial fibrillation (AF), and for those testing implantable cardioverter-defibrillator (ICD) therapy for the prevention of sudden cardiac death, and cardiac resynchronization therapy (CRT) for the treatment of heart failure. The purpose of this article is to provide an overview of gender-related differences that can be encountered in the everyday practice of clinical cardiac electrophysiology, with a particular focus on catheter ablation of AF, and on the clinical outcome after implantation of cardiac devices, such as ICD and CRT. Gender Differences in Catheter Ablation of Atrial Fibrillation The curative catheter ablation of AF has made important advances during the last few years towards a reproducible and effective procedure, thus leading to more patients being offered this treatment option.1 Several studies have reported a gender difference with AF, which may significantly affect both the baseline characteristics, and thus the results of catheter ablation in the two genders. In the Framingham Heart Study, men had an overall higher risk of developing AF compared to women.2 On the other hand, in the older age groups, the absolute number of women with AF outweighed the number of men, mainly due to the greater longevity of females.2 In addition to epidemiological differences, several studies support also the presence of significant gender-related differences in clinical presentation and prognosis of AF.1,3-5 Symptoms of AF are more frequent in women, with higher mean heart rates and longer episodes compared to men.5 Furthermore, the prognostic impact of AF in females seems greater compared to their male counterpart, with women having a higher risk of death,1,4 and cardio-embolic strokes.3,4 Therefore, the bulk of the available evidence supports an aggressive treatment approach for AF in women, although the best treatment strategy to accomplish this is still debated. The early choice of a curative catheter ablation approach seems reasonable, especially considering the reported significant impact of AF on quality of life and prognosis in this subgroup.1,3,5 In addition, the older age of most women with AF and the competing risk of thrombosis and bleeding from anticoagulation make the management of thromboembolic risk difficult,3,6 and the choice to prescribe antiarrhythmic drugs in women should be balanced with the greater risk for QT prolongation consistently reported in several studies.7-9 On the other hand, studies on catheter ablation of AF in females have suggested a lower success rate as compared to males, which may reflect significant differences in baseline clinical characteristics between the two genders.10,11 To this regard, we recently reported the results of pulmonary vein antrum isolation (PVAI) according to gender in 3,265 consecutive patients referred to our institutions from January 2005 to May 2008 for highly symptomatic and drug-refractory AF.10 Overall, although the catheter ablation referral rate for women tended to increase over years (Figure 1), women accounted for only 15.8% of the final study population and were referred for catheter ablation after having failed more antiarrhythmic drugs than men (4±1 vs. 2±3, P =0.04). Our data are in line with previous reports, which showed that women are significantly under-referred for costly invasive procedures.11-14 Moreover, our population of females undergoing PVAI was older (59±13 vs. 56±19 years, P Gender Differences in Clinical Outcome After Implantation of Cardiac Devices Implantable Cardioverter-Defibrillator Randomized clinical trials have demonstrated the efficacy of prophylactic ICD placement in reducing mortality in patients at high risk of sudden cardiac death.17 Further observations have raised serious concerns regarding the benefit of prophylactic ICD therapy among subgroups underrepresented in guideline-concluding trials.18 In particular, the benefit of prophylactic ICD therapy in women has not yet been demonstrated, and studies on this topic have shown very conflicting results.16,19-21 Subgroup analyses of the Multicenter Unsustained Tachycardia Trial (MUSTT)20 and of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II)21 reported no significant gender-related difference on the benefit of ICD therapy on mortality. However, the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) investigators found a significantly lower survival benefit of prophylactic ICD therapy among women,19 a finding confirmed in other studies.16 Therefore, the real benefit of prophylactic ICD therapy in women is a matter of controversy, and further studies are certainly warranted to appropriately address this issue. Interestingly, a consistent finding among all these studies is that women undergoing prophylactic ICD therapy suffer from more advanced forms of congestive heart failure, present with more comorbidities, and are significantly undertreated compared to their male counterpart.16,19-21 Again, the later referral for prophylactic ICD therapy may play a significant role in the benefit of ICD therapy in females, as is the case for AF catheter ablation. Accordingly, a “real-world” analysis from a Medicare population revealed that women were much less likely to receive an ICD than men, and that among patients with a left ventricular ejection fraction of Cardiac Resynchronization Therapy Cardiac resynchronization therapy has consistently proven to decrease mortality and improve symptoms, quality of life, and exercise tolerance in patients with a severely depressed left ventricular ejection fraction.26,27 As is the case for primary prevention ICD trials, women were significantly underrepresented also in CRT trials, being approximately one-third of the total population enrolled.26-28 However, at variance with ICD studies, subgroup analyses of CRT trials suggest that women may have a better response to CRT, although different studies showed conflicting results.29-31 In a post-hoc analysis of the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial, Woo and associates reported significant differences in outcome based on gender, with women randomized to CRT having a significantly lower incidence of the combined endpoint of first heart failure hospitalization or death compared to women allocated to the placebo arm; no difference was reported among men for the same endpoint.31 In line with these findings are the data from the observational registry by Lilli and colleagues.30 The authors reported the clinical and echocardiographic one-year follow-up in a cohort of 195 patients who underwent CRT implantation. Overall, female gender was independently associated with a better response to CRT, defined as degree of left ventricular reverse remodeling as assessed by the echocardiographic reduction of left ventricular end systolic volume. Accordingly, Di Biase et al found that female gender was an independent predictor of favorable left ventricular reverse remodeling following CRT, analyzing data from a prospective registry of 398 consecutive patients (25% female) undergoing CRT.32 Conversely, Bleeker et al investigated the gender difference in response to CRT in 173 patients undergoing CRT implantation according to the selection criteria of earlier trials.29 In this study, no significant gender-related difference in the clinical response to CRT was demonstrated, with both genders improving symptoms and exercise tolerance equally. These findings were largely confirmatory of what emerged from the Cardiac Resynchronization-Heart Failure (CARE-HF)27 and Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION)26 trials, which failed to show significant gender differences in clinical response to CRT. Putting together these results, it appears logical to conclude that both genders benefit from CRT, with no significant difference in survival.