Gender Equality in Primary Prevention ICD Benefit

By Cara Pellegrini, MD

Assistant Professor of Medicine, University of California San Francisco; Cardiology Division, Electrophysiology Section, San Francisco VA Medical Center

Dr. Pellegrini reports no financial relationships relevant to this field of study.

SYNOPSIS: In a propensity-matched study, women who received a primary prevention implantable cardioverter defibrillator had a significant survival advantage, which was similar to that observed among men.

SOURCE: Zeitler EP, et al. Comparative effectiveness of implantable cardioverter defibrillators for primary prevention in women. Circ Heart Fail 2016;9:e002630.

The benefit of primary prevention implantable cardioverter defibrillators (ICDs) in women is controversial. As women constituted only 10-30% of enrolled subjects in the randomized, controlled trials that established efficacy of primary prevention devices, these trials were underpowered to show benefit in this subgroup. Subsequently, two meta-analyses have examined this issue with conflicting results, and other post-hoc and observational analyses of primary prevention ICDs in women have had similarly mixed results. National guidelines are sex neutral in their recommendations, yet the actual use of primary prevention ICDs is lower in women than men, possibly reflecting residual concern regarding the paucity of current data.

To address this void, Zeitler et al used data from the Get With The Guidelines for Heart Failure (GWTG-HF) registry, linked with data from the Centers for Medicare and Medicaid Services, to compare outcomes in women who were hospitalized for heart failure and who did or did not receive an ICD. They collected patient demographic and medical history variables, medication and laboratory data, and hospital characteristics. As the population was not randomized to determine receipt of the intervention, the collected variables were used to create a propensity model for ICD implantation to make the groups more comparable — that is, to minimize confounding. Researchers repeated a similar process for men. All-cause mortality was the primary outcome.

In this group of older women with heart failure and reduced left ventricular ejection fraction (LVEF), implantation of an ICD (or prescription for implantation shortly after discharge) was associated with improved survival over a median follow-up of about 3 years (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.66-0.92; P = 0.003). The benefit was similar to that observed in men (HR, 0.76; 95% CI, 0.67-0.87; P < 0.001). There was no significant sex-based interaction. Notably, the benefit in the ICD group was immediately apparent, with early separation of the survival curves. The authors concluded that among patients with heart failure with a reduced LVEF, a primary prevention ICD was associated with a significant survival advantage among both women and men, supporting guideline-directed use of primary prevention ICDs.

COMMENTARY

The observed mortality benefit in both sexes in this registry study was similar to the observed mortality benefit of ICD vs placebo in SCD-HeFT, the landmark randomized clinical trial of primary prevention ICDs with the most similar population (HR, 0.77). By controlling for hospital characteristics, this study goes beyond previous observational studies in addressing likely sources of confounding. Notably, aside from age and LVEF, the biggest discrepancies between the groups who did and did not receive an ICD were site-related factors. Patients admitted to teaching hospitals in the Northeast with a large number of beds and a capacity for on-site cardiac procedures were far more likely to receive an ICD.

Yet, there are a number of limitations to this study. First and foremost, it is not a randomized, controlled trial, and residual confounding can still be present, despite the authors’ great efforts to account for it with propensity matching. All practicing clinicians can appreciate that nothing can substitute for examining a patient to determine appropriateness for an elective procedure, or lack thereof. It is hard to fully capture with a collection of variables all that goes into judgment of likely outcomes. Indeed, neither New York Heart Association class nor a characterization of functional status, two factors that clearly would enter into a clinical thought process, could be included in this analysis. The very act of performing a propensity match by its nature excludes the sickest patients with a high burden of disease who are too dissimilar to find a match. Conversely, generalization to heart failure patients who are healthy enough to avoid hospitalization, or simply younger than this population, could be specious.

Nonetheless, this study is critical. A clear signal of benefit is particularly warranted in women, who suffer disproportionately from procedural complications related to primary prevention ICD implantation. Should a study firmly establish benefit, a greater push for correction of the current underutilization of primary prevention ICDs by women will be needed. Even among institutions that have chosen to participate in GWTG-HF, a voluntary quality improvement program, only 11% of eligible women and 16% of eligible men received an ICD or prescription for one at time of heart failure hospitalization discharge. Finally, despite the current study’s limitations, the data likely provide the most definitive answer we will receive, given that there is no longer sufficient equipoise to allow for a specific randomized, controlled trial of primary prevention ICD use in women.