The cardioprotective effects of estrogen in women have been well established.1,2 Specifically, men have a higher risk of cardiovascular disease and coronary heart disease than women, but those risks change following menopause.1,2 The age-specific and gender-specific influences on defibrillator lead failure have not been previously investigated. The purpose of this substudy was to determine whether age and gender influence defibrillator lead failure and patient mortality.
The Pacemaker and Implantable Defibrillator Lead Survival Study (“PAIDLESS”) is a large retrospective study of all pacemaker and defibrillator leads implanted at Winthrop University Hospital from February 1, 1996 to December 31, 2011.3 This study was approved by the Winthrop University Hospital Institutional Review Board. In the present substudy, defibrillator patients from PAIDLESS were analyzed with respect to age and gender. The impact of those two parameters was analyzed with regard to demographic data, follow-up status, lead-related complications, and survival as determined by the Social Security Death Index.4 These patients were included in a de-identified database in accordance with Health Insurance Portability and Accountability Act (HIPAA) regulations.5
Lead failure was defined previously in PAIDLESS and followed criteria used in the Medtronic System Longevity study.3,6 The criteria included failure to capture, failure to sense, increased pacing thresholds, abnormal pacing impedance and/or defibrillation impedance, failure of lead insulation, lead conductor fracture, cardiac perforation, extracardiac stimulation, lead dislodgment, and/or structural failure.3,6 The investigators reviewing lead failure data were blinded to patient identifiers and the implanting doctor.
Continuous data were presented as means ± standard deviations and the categorical data as proportions. The main endpoints were lead failures and mortality. Patient characteristics were compared between the genders using Wilcoxon rank-sum test and Fisher’s exact tests, as appropriate. The men and women were categorized by age decile, beginning at 15 years old (the youngest age in the study). Each subsequent age decile was analyzed with respect to gender and its impact on lead failure and mortality. No correction for multiple comparisons was performed. Survival estimates and accumulative event rates were compared with the Kaplan-Meier method using the time to event approach. The log-rank test was used to compare the Kaplan-Meier survival curves between men and women for overall data. This analysis was repeated for recalled and non-recalled leads group separately. Unadjusted Cox with regression analysis was performed on all appropriate clinical variables using time-dependent lead failure variables as the endpoint. All variables with unadjusted P-values of <.25 were considered for a multivariable model except for the co-linear variables, which were not included in the multivariable model. A stepwise multivariable Cox proportional hazard model was built to find risk factors of lead failures. Ties in the failure times were handled by the Exact method.
All calculations were performed using SAS version 9.3 for Windows (SAS Institute), and were also considered statistically significant when P was <.05.
Table 1 shows the patient characteristics of the men and women in this study. The study population included 2812 men (74%) and 990 women (26%) after exclusion of 44 patients with unknown status or lost to follow-up. The men and women had comparable mean ages (70 ± 13 years vs 71 ± 13 years, respectively; P=.048). The follow-up time was the same for both genders (4 ± 3 years; P=.05). Ejection fraction was also similar for men and women (29 ± 10% vs 30 ± 11%, respectively; P=.83). Coronary artery disease was more common in men vs women (75% vs 62%, respectively; P<.001). Similarly, myocardial infarction, coronary artery bypass graft surgery, ischemic cardiomyopathy, abdominal aortic aneurysm repair, and non-sustained and sustained ventricular tachycardia were more prevalent in men than women (overall P<.05).
On the other hand, mitral valve replacement, dilated cardiomyopathy, hypertrophic cardiomyopathy, cardiac arrest, hypertension, significant bradycardia, left ventricular hypertrophy, valve disease, atrioventricular junction ablation, supraventricular tachycardia including AVNRT, left bundle-branch block, long QT syndrome, and ventricular fibrillation were more common in women than men (overall P<.05). Baseline rhythms (sinus rhythm, atrial fibrillation and/or flutter, significant conduction disease) differed significantly between genders as well (P=.03). All other characteristics in Table 1 were not significantly different between the two genders.
Additionally, the numbers of recalled leads were compared between the genders. Across all ages, 1082 out of 2812 men (38%) and 373 out of 990 women (38%) received recalled leads (P=.68). Analyses of each age decile also revealed no gender differences in patients who received recalled leads. There were significantly more lead failures in women than men with recalled leads in the 45 to 54 years group (18% vs 5%; P=.046 via Fisher’s Exact test). A specific analysis of small-diameter leads (lead diameter ≤8 Fr; Riata, Riata ST, Sprint, Sprint Fidelis, Durata) across all ages was also performed, and demonstrated a slightly higher number of small-diameter leads in women (673/990 women [68%] vs 1815/2812 men [65%]; P=.05). In the 45 to 54 years group, there was no significant difference between the percentage of men who received small-diameter leads (166/255 men [65%] vs 51/79 women [65%]; P>.99).
Age as a continuous variable and gender as a categorical variable were compared in the recalled and non-recalled groups. Within the recalled lead group, the average age of patients with lead failure was 66 ± 13 years, while the average age of patients with no lead failure was 71 ± 13 years (P<.001). Within the non-recalled lead group, the average age of patients with lead failure was 65 ± 14 years. This also differed significantly from the patients with no lead failure (70 ± 12 years; P=.01). Gender, however, made no difference in recalled or non-recalled categories (P=.59 and P>.99, respectively).
Figure 1 shows the percentage of men and women enrolled in the study within each age group. Figure 2 shows the ratio of men to women within each age group. Although the differences between men and women illustrated in Figure 1 seem insignificant, it is important to note that Figure 2 shows a peak in the male to female ratio of 3.2 in the 45 to 54 years decile, with a subsequent decline in the ratio with advancing age.
Figure 3 displays Kaplan-Meier lead survival curves by gender for all ages (P=.50). The curves demonstrate no significant difference in lead survival overall between men and women in this study. Figure 4 shows Kaplan-Meier lead survival curves by gender for patients between 45 and 54 years (P=.03). Specifically, defibrillator leads in those 45 to 54 years of age failed sooner in women than in men. Multivariable Cox regression models were built using important clinical and demographic variables to validate this finding; male gender was still found to be an independent protective factor of lead failures (for male gender: hazard ratio, 0.37; 95% confidence interval, 0.14-0.96; P=.04) in the 45 to 54 years group. The mean lead survival time for women between the ages of 45 and 54 years was 13.4 years (standard error, 0.6), while the mean lead survival time for men between the ages of 45 and 54 years was 14.7 years (standard error, 0.3). No other age decile had a significant difference in lead failure based on gender.
Figure 5 shows the Kaplan-Meier mortality curves between the genders for all ages (P=.87). This illustrates no significant differences in patient mortality rates between men and women in this study.
This study investigated the effects of gender and age on lead failure and survival. The largest percentage of men who received an implantable defibrillator in a specific age decile occurred in the group between 45 and 54 years of age. Subsequently, as age increased, the percentage of men referred for implantable defibrillators decreased and the percentage of women referred correspondingly increased. This correlates with Collins et al,13 who found that the incidence of cardiovascular events in women increased after age 45 to 54 years (perimenopausal group).
The current study found that the 45 to 54 years decile had the highest percentage of men; however, in a subanalysis, that particular decile also had a significantly higher rate of lead failure in women. The female patients in this age group were likely perimenopausal. There were no significant differences in lead failure between the genders in any other age decile.
Prior studies have reported that women who receive implantable defibrillators have more complications and receive fewer benefits.7-9 In addition, female gender and younger age have previously been implicated as factors associated with defibrillator lead failure.10-12 Birnie et al described the impact of gender, and specifically identified that women who received the recalled Medtronic Sprint Fidelis lead had an increased rate of lead failure following lead implantation compared with men who received the same lead.10 Hauser et al identified age and gender as significant factors with respect to the Medtronic recalled Sprint Fidelis lead, but not the non-recalled Sprint Quattro lead.11 Cheung et al found that female gender and younger age impacted lead failure in St. Jude Medical’s recalled Riata lead.12 This study performed a similar overall analysis of the impact of gender and age among the recalled and non-recalled leads. Our analysis examined all United States major manufacturers (Medtronic, Boston Scientific, and St. Jude Medical) and their recalled leads (Medtronic’s Sprint Fidelis and St. Jude Medical’s Riata and Riata ST leads). Our results differ in that only age, and not gender, had an impact on lead failure of the recalled leads.
The current study is the first to compare lead failure with gender at a single large implanting center within specific smaller subsets of age groups (deciles) in order to assess the impact of both age and gender on lead failure and mortality. In addition, we examined the impact of age and gender in those who received a recalled lead as compared with those who did not receive such a lead. There were significantly more lead failures in women than men with recalled leads in the 45 to 54 years group. This suggests that the etiology of the differences in lead failure found between men and women in the 45 to 54 years group was driven by the recalled status of the implanted lead. Interestingly, the women with failed recalled leads in this age group were implanted mostly with the Medtronic Sprint Fidelis leads. Previously, the PAIDLESS team found that recalled leads are more likely than non-recalled leads to fail.3 This new finding suggests that women in the perimenopausal age group are more adversely affected by the recalled leads than men in the 45 to 54 years decile.
Additionally, the current study analyzed the implantation of small-diameter leads (which included the recalled Riata, Riata ST, and Sprint Fidelis leads, as well as the non-recalled Sprint and Durata leads). This was to test the hypothesis that women in particular may have received more small-diameter leads and therefore potentially more recalled leads based on operator preference to implant smaller leads in women vs men because of their general smaller body size and skeleton. No significant differences were found, although women of all ages received small-diameter leads almost significantly more than men. This suggests that there are some differences in the implantation of small-diameter leads, but within the 45 to 54 year age group, women did not receive a higher number of small-diameter or recalled leads.
Study limitations. A significant limitation of this study relates to the fact that it is retrospective and observational in design. In addition, the subgroup analyses were limited by their small sample size. The findings in this study raise new questions, which the investigators hope will be answered in the future with a larger, prospective series.
The results of the large, single-center PAIDLESS trial do not completely correlate with previous trials. At the least, this study emphasizes the complex interplay between gender and age with respect to defibrillator lead failure and mortality. In addition, these results highlight the need for additional prospective, controlled studies to further elucidate the true impact of both age and gender on these important outcomes.
Acknowledgment. We acknowledge the support and encouragement of the Winthrop University Hospital Administration, including John Collins, CEO; Palmira Cataliotti, CFO; and Solomon Torres, Vice President of Cardiology. In addition, we appreciate the statistical support of the Winthrop University Hospital Research Institute and are grateful for the financial support of our research coordinators by Medtronic as well as Boston Scientific.
Funding: This study was submitted to each of the manufacturers listed in the manuscript (Medtronic, Boston Scientific, and St. Jude Medical); however, the study was only partially funded by grants from Medtronic and Boston Scientific.
Disclosure: The authors report no conflicts of interest regarding the content herein.
Published with permission from the Journal of Invasive Cardiology. 2015;27(12):530-534.
- Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med. 1976;85:447-452.
- Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease. The Framingham Study. Ann Intern Med. 1978;89:157-161.
- Cohen TJ, Asheld WJ, Germano J, Islam S, Patel D. A comparative study of defibrillator leads at a large volume implanting hospital: results from the Pacemaker and Implantable Defibrillator Leads Survival Study (“PAIDLESS”). J Invasive Cardiol. 2015;27:292-300.
- Social Security Death Index cross-referenced with manufacturer-supplied data to ensure up-to-date status of Out of Service leads that are due to the death of the patient (OOS-D) Social Security Death Index. http://www.genealogybank.com/gbnk/ssdi/
- The United States Human and Health Services. Guidance regarding methods for de-identification of protected health information in accordance with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule. Washington, DC: Government Printing Office, 2012.
- Medtronic Criteria for Cardiac Rhythm Disease Management (CRDM) and System Longevity Study. http://wwwp.medtronic.com/productperformance/content/method_for_estimating_leads.html
- MacFadden DR, Crystal E, Krahn AD, et al. Sex differences in implantable cardioverter-defibrillator outcomes: findings from a prospective defibrillator database. Ann Intern Med. 2012;156:195-203.
- Hsu JC, Varosy PD, Bao H, Dewland TA, Curtis JP, Marcus GM. Cardiac perforation from implantable cardioverter-defibrillator lead placement: insights from the National Cardiovascular Data Registry. Circ Cardiovasc Qual Outcomes. 2013;6:582-590.
- Peterson PN, Daugherty SL, Wang Y, et al; National Cardiovascular Data Registry. Gender differences in procedure-related adverse events in patients receiving implantable cardioverter-defibrillator therapy. Circulation. 2009;119:1078-1084.
- Birnie DH, Parkash R, Exner DV, et al. Clinical predictors of Fidelis lead failure: report from the Canadian Heart Rhythm Society Device Committee. Circulation. 2012;125:1217-1225.
- Hauser RG, Maisel WH, Friedman PA, et al. Longevity of Sprint Fidelis implantable cardioverter-defibrillator leads and risk factors for failure: implications for patient management. Circulation. 2011;123:358-333.
- Cheung JW, Al-Kazaz M, Thomas G, et al. Mechanisms, predictors, and trends of electrical failure of Riata leads. Heart Rhythm. 2013;10:1453-1459.
- Collins P, Rosano G, Casey C, et al. Management of cardiovascular risk in the peri-menopausal woman: a consensus statement of European cardiologists and gynaecologists. Eur Heart J. 2007;28:2028-2040.