Gender differences in clinical outcome and primary prevention defibrillator benefit in patients with severe left ventricular dysfunction: A systematic review and meta-analysis

doi:10.1016/j.hrthm.2010.03.042

Heart Rhythm

Volume 7, Issue 7, July 2010, Pages 876-882

https://doi.org/10.1016/j.hrthm.2010.03.042 Get rights and content

Background

Women are underrepresented in primary prevention implantable cardioverter-defibrillator (ICD) trials, and data on the benefit of ICD therapy in this subgroup are controversial.

Objective

The purpose of this study was to better evaluate the benefit of prophylactic ICD in women by performing a meta-analysis of primary prevention ICD trials that assessed gender differences on the end-points of total mortality, appropriate ICD intervention, and survival benefit of ICD compared with placebo.

Methods

PubMed, CENTRAL, and other databases were searched in October 2009. Studies were included only if they examined gender differences in the specified end-points, providing the hazard ratio (HR) obtained in multiple Cox regression analyses, and adjusted for all confounding variables.

Results

We retrieved five studies (MADIT-II, MUSTT, SCD-HeFT, DEFINITE, COMPANION) that enrolled 7,229 patients (22% women) with dilated cardiomyopathy (74% ischemic). Compared to men, women had no significant difference in overall mortality (HR 0.96, 95% confidence interval [CI] 0.67–1.39, P = .84) but experienced significantly less appropriate ICD interventions (HR 0.63, 95% CI 0.49–0.82, P ≤.001). The benefit of ICD on mortality was significantly higher in men (HR 0.67, 95% CI 0.58–0.78, P <.001) but did not reach statistical significance in women (HR 0.78, 95% CI 0.57–1.05, P = .1).

Conclusion

Women enrolled in primary prevention ICD trials have the same mortality compared to men while experiencing significantly less appropriate ICD interventions, thus suggesting a smaller impact of sudden cardiac death on overall mortality in women with dilated cardiomyopathy. These findings may explain the smaller ICD survival benefit among women.

Introduction

Multiple randomized clinical trials have shown primary prevention of sudden cardiac death (SCD) with an implantable cardioverter-defibrillator (ICD) in patients with left ventricular dysfunction to be effective.¹ However, the real benefit of prophylactic ICD therapy in underrepresented subgroup of patients, such as women, has not been consistently demonstrated.2, 3, 4, 5 In fact, studies assessing gender differences in arrhythmic risk showed conflicting results,2, 3, 4, 5, 6, 7 and no clear-cut evidence supports the same benefit of prophylactic ICD therapy in the two genders.⁸

To better evaluate the presence and possible causes of gender differences in effectiveness of prophylactic ICD therapy in patients with left ventricular dysfunction, we performed a meta-analysis of primary prevention ICD studies on the end-points of total mortality, appropriate ICD intervention, and net ICD survival benefit in women compared to men.

Section snippets

Searching strategy and selection process

Two trained investigators (PS, GP) independently searched major web databases for all published studies that (1) had a prospective randomized design, (2) tested ICD therapy versus placebo in patients with dilated cardiomyopathy (DCM) who did not previously experience major arrhythmic events, and (3) reported an estimate of the risk for specified end-points for women compared to men, adjusted for all possible baseline confounders or covariates. Citations initially selected by systematic search

Search results and study selection

The search permitted retrieval of 3,467 citations. We identified nine eligible citations, which were assessed according to compliance to the inclusion criteria. Among the retrieved but excluded studies, DINAMIT (Defibrillator in Acute Myocardial Infarction Trial)¹² and IRIS (Immediate Risk Stratification Improves Survival)¹³ did not provide adjusted estimates of the risk of total mortality and appropriate ICD therapy in women compared to men and thus did not meet inclusion criteria.

Ultimately,

Discussion

This systematic review was designed to assess gender differences in outcome after prophylactic ICD placement and is based on the statistical pooling of five randomized studies, which enrolled more than 7,200 patients, and specifically compared women with men with regard to clinical outcome.

With more than 1,600 women, this meta-analysis includes the largest women cohort to date and shows that women enrolled in primary prevention ICD trials have the same overall mortality as compared to men,

Conclusion

This review presents a meta-analysis of data from five primary prevention randomized ICD studies that assessed gender differences in outcome and shows a smaller impact of SCD on overall mortality in women, which may explain their smaller and nonsignificant survival benefit from prophylactic ICD therapy.

Our findings challenge current LVEF-based prophylactic ICD recommendations, raising concerns about the appropriateness of generalizing such recommendations to subgroups of patients

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Cited by (132)

Disparities in Referral and Utilization of Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Cardiac Death
2023, Canadian Journal of Cardiology
Implantable cardioverter-defibrillators (ICDs) reduce mortality in patients with reduced left ventricular ejection fraction (LVEF). We investigated sex disparities in a contemporary Canadian population for utilization of primary prevention ICDs.
This was a retrospective cohort study on patients with reduced LVEF admitted to hospitals from 2010 to 2020 in Nova Scotia (population = 971,935).
There were 4406 patients eligible for ICDs: 3108 (71%) men and 1298 (29%) women. The mean follow-up time was 3.9 ± 3.0 years. Rates of coronary disease were similar between men and women (45.8% vs 44.0%; P = 0.28), but men had lower LVEF (26.6 ± 5.9% vs 27.2 ± 5.8%; P = 0.0017). The referral rate for ICD was 11% (n = 487), with 13% of men (n = 403) and 6.5% of women (n = 84) referred (P < 0.001). The ICD implantation rate in the population was 8% (n = 358), with 9.5% of men (n = 296) and 4.8% of women (n = 62) (P < 0.001) receiving the device. Men were more likely than women to receive an ICD (odds ratio 2.08, 95% confidence interval 1.61-2.70; P < 0.0001)). There was no significant difference in mortality between men and women (P = 0.2764). There was no significant difference in device therapies between men and women (43.8% vs 31.1%; P = 0.0685).
A significant disparity exists in the utilization of primary prevention ICDs between men and women in a contemporary Canadian population.
Les défibrillateurs cardioverteurs implantables (DCI) réduisent la mortalité chez les patients présentant une fraction d’éjection du ventricule gauche (FEVG) réduite. Nous avons analysé les différences entre les sexes dans la population canadienne contemporaine en ce qui a trait à l’utilisation des DCI en prévention primaire.
Il s’agissait d’une étude de cohorte rétrospective portant sur les patients qui présentaient une FEVG réduite et qui ont été admis à l’hôpital entre 2010 et 2020 en Nouvelle-Écosse (population : 971 935).
Au total, 4 406 patients étaient admissibles à un DCI : 3 108 hommes (71 %) et 1 298 femmes (29 %). La durée de suivi médian était de 3,9 ± 3,0 ans. Le taux de maladie coronarienne était similaire chez les hommes et les femmes (45,8 % vs 44,0 %; p = 0,28), mais les hommes présentaient une FEVG inférieure (26,6 ± 5,9 % vs 27,2 % ± 5,8 %; p = 0,0017). Le taux d’orientation pour un DCI était de 11 % (n = 487), soit 13 % pour les hommes (n = 403) et 6,5 % pour les femmes (n = 84) (p < 0,001), et le taux d’implantation de DCI dans la population était de 8 % (n = 358), soit 9,5 % pour les hommes (n = 296) et 4,8 % pour les femmes (n = 62) (p < 0,001). Les hommes étaient plus susceptibles que les femmes de recevoir un DCI (rapport de cotes : 2,08; intervalle de confiance à 95 % : 1,61 à 2,70; p < 0,0001). Il n’y avait aucune différence significative entre les deux groupes quant au taux de décès (p = 0,2764). Il n’y avait pas non plus de différence significative entre les deux groupes quant aux traitements à l'aide de dispositifs (43,8 % vs 31,1 %; p = 0,0685).
Il existe une disparité importante dans l’utilisation des DCI en prévention primaire entre les hommes et les femmes dans la population canadienne contemporaine.
Age, Sex, and Outcomes in Heart Failure With Reduced EF: Insights From the VICTORIA Trial
2023, JACC: Heart Failure
Age and sex influence treatment and outcomes in patients with heart failure (HF).
The authors examined the associations of age and sex with clinical characteristics, background therapies, outcomes, and response to vericiguat in this post hoc analysis of 5,050 VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) patients with HF and reduced ejection fraction; 1,568 (31%) were ≥75 years of age, of whom 445 (24%) were women.
Clinical characteristics were compared across age (<65, 65 to <75, and ≥75 years) and sex. The treatment effect of vericiguat was estimated by age and sex on the primary composite outcome (time to first HF hospitalization or cardiovascular death) using Cox proportional hazards regression.
Compared with younger patients, those ≥75 years of age had more class III and IV symptoms, higher N-terminal pro–B-type natriuretic peptide levels, and worse kidney function but had the lowest use of triple therapy. No sex differences in triple therapy existed by age, but achieving target doses of triple therapy was less likely in older patients. Men ≥75 years of age were more than twice as likely to receive defibrillators and 65% more likely to undergo cardiac resynchronization than women. The primary composite outcome was nominally lower in women than men across all age groups. Vericiguat dosing did not differ between sexes in each age group, and its beneficial effect on the primary endpoint was not modified by age (continuous age, P_interaction = 0.169; categorical age, P_interaction = 0.189); and sex (3-way interaction; P = 0.847).
Although elderly women received less intense background HF therapy than men, their prognosis was nominally better. The benefit of vericiguat was independent of age and sex. (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534)
Gender and race-related disparities in the management of ventricular arrhythmias
2023, Trends in Cardiovascular Medicine
Modern studies have revealed gender and race-related disparities in the management and outcomes of cardiac arrhythmias, but few studies have focused on outcomes for ventricular arrhythmias (VAs) such as ventricular tachycardia (VT) or ventricular fibrillation (VF). The aim of this article is to review relevant studies and identify outcome differences in the management of VA among Black and female patients. We found that female patients typically present younger for VA, are more likely to have recurrent VA after catheter ablation, are less likely to be prescribed antiarrhythmic medication, and are less likely to receive primary prevention ICD placement as compared to male patients. Additionally, female patients appear to derive similar overall mortality benefit from primary prevention ICD placement as compared to male patients, but they may have an increased risk of acute post-procedural complications. We also found that Black patients presenting with VA are less likely to undergo catheter ablation, receive appropriate primary prevention ICD placement, and have significantly higher risk-adjusted 1-year mortality rates after hospital discharge as compared to White patients. Black female patients appear to have the worst outcomes out of any demographic subgroup.
Differences in mode of death between men and women receiving implantable cardioverter-defibrillators or cardiac resynchronization therapy in the MADIT trials
2023, Heart Rhythm
Studies have reported sex differences in outcomes following implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy–defibrillator (CRT-D) implantation. However, little is known about sex differences with regard to mode of death or device efficacy following ICD or CRT-D implantation.
The purpose of this study was to investigate whether sex influenced mode of death or device efficacy in ICD and CRT-D subjects enrolled in the MADIT (Multicenter Automatic Defibrillator Implantation Trial) studies (MADIT-II, MADIT-CRT, and MADIT-RIT).
The combined MADIT cohort consisted of 3038 men and 1000 women with ischemic cardiomyopathy (ICM) or nonischemic cardiomyopathy (NICM), left ventricular ejection fraction ≤30%; New York Heart Association functional class I–III heart failure who received ICD or CRT-D. Mode of death was divided into cardiac and noncardiac causes, reviewed by independent adjudication committees.
A total of 295 men and 66 women died (9.7% vs 6.6%; P =.003) during 26 months. The most common cause of death was nonarrhythmic cardiac death in men (n = 121 [41%]) and noncardiac death in women (n = 22 [33%]). All-cause mortality and cardiac deaths were 1.5- to 2.0-fold higher in men vs women with ICM but similar for those with NICM after adjustment for covariates. ICD efficacy was similar in men and women, resulting in a 50% reduction in all-cause mortality. CRT-D was more effective at reducing all-cause and cardiac death in women than men.
Mode of death differs between sex and is dependent on the underlying cardiac substrate. Compared to women, cardiac death is higher in men with ICM but similar in those with NICM. ICDs are equally effective at reducing mortality in both men and women. However, CRT-D may be more effective at reducing mortality in women.
Sex differences on outcomes of catheter ablation of ventricular tachycardia in patients with structural heart disease: A real-world systematic review and meta-analysis
2022, Heart Rhythm O2
Sex differences have diversely affected cardiac diseases. Little is known whether these differences impact outcomes of catheter ablation of ventricular tachycardia (VT).
To assess the impact of sex differences on outcomes of catheter ablation of VT.
Databases were searched from inception through December 2021. Effect estimates from individual studies were extracted and combined using the random-effects, generic inverse variance method of DerSimonian and Laird. The outcomes of interest included VT recurrence rates, all-cause mortality, and composite outcomes of mortality, left ventricular assistant device use, and heart transplantation following VT ablation.
Our analysis included 22 observational studies. There were 10,206 patients, of which 12.8% were women. We found no statistical difference between sexes for VT recurrence rate (pooled hazard ratio [HR] 1.04, P = .57, I² = 14.9%). Similarly, there was statistical difference in neither all-cause mortality nor composite outcomes (pooled HR 0.93, P = .75, I² = 59.1% and pooled HR 0.9, P = .33, I² = 0%, respectively). There was a trend toward an increase in women undergoing VT ablation in the recent registries (P = .071).
Our contemporary analysis suggests that sex may have no impact on clinical outcomes of catheter ablation of VT in patients with structural heart disease, though women are the underrepresented. However, recent VT ablation registries have involved more women in their studies. Future studies with a higher proportion of women are encouraged to verify the current perception.
Ventricular Arrhythmias and Implantable Cardioverter-Defibrillator Therapy in Women: A Propensity Score-Matched Analysis
2022, JACC: Clinical Electrophysiology
Citation Excerpt :
Also, anatomical differences between women and men are well known at the cardiac level. The left ventricular size is significantly smaller in women, with a reduced number of re-entrant propagating electrical waves and a less susceptible substrate.19 Finally, other less-quantifiable factors, including adherence to a low-risk lifestyle, psychological factors, and patient care decisions may also play roles.
Causes of sex differences in incidence of sustained ventricular arrhythmias (SVAs) are poorly understood.
This study aims to investigate sex-specific risk of SVAs and device therapies by balancing sex groups in relation to several baseline characteristics with the propensity score (PS).
We used a large remote monitoring dataset from implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy defibrillators (CRT-Ds). Study endpoints were time to the first appropriate SVA, time to the first device therapy for SVA, and time to the first ICD shock. Results were compared between females and a PS-matched male subgroup.
In a cohort of 2,532 patients with an ICD or CRT-D (median age, 70 years), 488 patients (19.3%) were women. After selecting 488 men PS-matched for 19 variables relative to baseline demographics, implant indications, principal comorbidities, and concomitant therapy, yet the SVA rate at the 2.1-year median follow-up was significantly lower in women than in man (adjusted HR: 0.65; 95% CI: 0.51-0.81; P < 0.001). Women also showed a reduced risk of any device therapy (HR: 0.59; 95% CI: 0.45-0.76; P < 0.001) and shocks (HR: 0.66; 95% CI: 0.47-0.94; P = 0.021). Differences in sex-specific SVA risk profile were not confirmed in CRT-D patients (HR: 0.78; 95% CI: 0.55-1.09; P = 0.14) nor in those with an ejection fraction <30% (HR: 0.80; 95% CI: 0.52-1.23; P = 0.31).
After matching demographics, indications, principal comorbidities, and concomitant therapy, women still exhibited a lower SVA risk profile than men, except in the subgroups of CRT-D or/and ejection fraction <30%.

View all citing articles on Scopus

: Dr. Natale has received compensation for belonging to the speakers' bureau for St. Jude Medical, Boston Scientific, Medtronic, and Biosense Webster and has received a research grant from St. Jude Medical.

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ClinicalDeviceGender differences in clinical outcome and primary prevention defibrillator benefit in patients with severe left ventricular dysfunction: A systematic review and meta-analysis

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Searching strategy and selection process

Search results and study selection

Discussion

Conclusion

Am Heart J

Lancet

J Am Coll Cardiol

Am J Cardiol

Am Heart J

Am J Cardiol

J Am Coll Cardiol

Circulation

Primary prevention with defibrillator therapy in women: results from the Sudden Cardiac Death in Heart Failure Trial

J Cardiovasc Electrophysiol

Influence of gender on arrhythmia characteristics and outcome in the Multicenter UnSustained Tachycardia Trial

J Cardiovasc Electrophysiol

Clinical course and implantable cardioverter defibrillator therapy in postinfarction women with severe left ventricular dysfunction

J Cardiovasc Electrophysiol

Sex differences in the use of implantable cardioverter-defibrillators for primary and secondary prevention of sudden cardiac death

JAMA

Implantable cardioverter defibrillators: do women fare worse than men?Gender comparison in the INTRINSIC RV trial

J Cardiovasc Electrophysiol

Effectiveness of implantable cardioverter-defibrillators for the primary prevention of sudden cardiac death in women with advanced heart failure: a meta-analysis of randomized controlled trials

Arch Intern Med

Clinical
Device
Gender differences in clinical outcome and primary prevention defibrillator benefit in patients with severe left ventricular dysfunction: A systematic review and meta-analysis