Same Support, Different Outcomes

Corresponding Author

Dr Bernadine Healy, the first woman to lead the National Institutes of Health, published an editorial on the “Yentl Syndrome” in 1991, deriving from Nobel Prize Winner Isaac Bashevis Singer’s classic story of a Jewish girl who disguised herself as a boy to study the Torah. Dr Healy pointed out the decades of sex-exclusive research focusing on normalizing outcomes to men as the standard and the inherent biases and undertreatment of women that comes with this.¹ Unfortunately, decades later, this continues to hold true.

In this timely piece by Kalaba et al.² the authors retrospectively evaluated sex-specific in-hospital and 1-year outcomes among patients undergoing complex percutaneous coronary intervention (PCI) with mechanical circulatory support (MCS), including Impella in roughly two-thirds of the patients, or intra-aortic balloon pump (IABP) in the remainder. Women made up 24% of the patient cohort, and at 1 year, the primary composite outcome of major adverse cardiovascular events was significantly higher in women compared with men (25.5% vs 13.8%; P = 0.002), largely driven by higher mortality in women (20.8% vs 10.2%, P = 0.003). When adjusted for baseline comorbidities, the difference in the composite major adverse cardiovascular events risk was no longer statistically significant. Women also had higher rates of in-hospital complications including higher rates of bleeding (27.6% vs 14.3%) and death (8.3% vs 3.9%), with adjusted bleeding risk remaining significantly higher at 1 year in women. The authors concluded that fewer women received MCS for complex PCI and compared with men, had higher comorbidity and acuity burden, resulting in worse in-hospital and 1-year outcomes. The limitations of this study, as pointed out by the authors, include its observational retrospective design, risk for residual confounding, and inability to access granular data related to access site management such as sheaths size, closure device selection, and access-management, which influences bleeding complications. Furthermore, Impella devices (that is Impella Cardiac Power and Impella 5.5) were assessed as 1 group despite inherent device related differences. Despite the above limitations, these contemporary findings from a large tertiary academic center are informative on the real-world sex differences in short- and medium-term outcomes that challenge front-line clinicians considering the utilization of MCS to support complex or high-risk PCI.

Interestingly, the authors observed no significant heterogeneity in outcomes between patients receiving different types of MCS (IABP vs Impella). The IMPRESS trial was the first trial to compare Impella vs IABP, but women accounted for just 25% of those patients receiving Impella and just 17% of the IABP group. The study found similar mortality at 30 days in both MCS groups, reaching 50% at 6 months, although the sample size of the trial was only 48 participants.³ The PROTECT II trial randomized patients to IABP vs Impella 2.5 for hemodynamic support for nonemergent high risk PCI, with women comprising 19% of the patient population. Although the trial was stopped early for futility related to the 30-day primary endpoint after an interim analysis, the intention-to-treat analysis for the prespecified 30- and 90-day primary analyses showed that Impella was not superior to IABP; however, per-protocol and later analyses suggested improved 90-day outcomes and more complete revascularization with Impella 2.5.⁴ Most recently, the PROTECT III trial,⁵ a single-arm prospective registry of Impella-supported high risk PCI, evaluated the outcomes of protected high risk PCI comparing against historical controls from PROTECT II rather than against a concurrent randomized arm. In “PROTECT II-like” patients of this registry, the use of Impella Cardiac Power/2.5 resulted in more complete revascularization and lower 90-day major adverse events compared with the PROTECT II Impella arm (≈15% vs 21.9%; P ≈ 0.035) and PROTECT II IABP arm (∼31%). Women represented 27% of the registry, and similar to the current analysis by Kalaba et al.,² female patients were older and had higher burden of baseline comorbidities such as anemia and low glomerular filtration rate, prior history of peripheral vascular disease and transient ischemic attack/stroke, and were more likely to present with acute myocardial infarction. Despite these differences, there were no sex differences in 90-day or major adverse events or major bleeding in women compared to men.

In the setting of acute ST-segment elevation with cardiogenic shock, DanGer Shock trial (Danish-German Shock) demonstrated that the use of Impella in treatment of select patients reduced the risk of all-cause death at 180 days compared to the standard care alone.⁶ A prespecified secondary sex-specific analysis of the trial demonstrated higher 180-day mortality in women, who made up 20.8% of the trial population. Compared with men, women were significantly older (75 years vs 67 years), and had a 2.2-fold longer time from symptom onset to randomization. It was noted that 25.7% of screened patients were women, with women being excluded more frequently than men because of access-site issues precluding Impella placement. Women had significantly higher unadjusted 180-day all-cause mortality (primary endpoint), as well as higher unadjusted early mortality and increased hazard for the secondary composite cardiac endpoint.⁷ With a similar pattern to that seen in the current analysis, after adjustment for age, time from symptom onset to randomization, left ventricular ejection fraction and baseline lactate, none of the aforementioned outcomes remained significant.

The present data from Kalaba et al,² when viewed alongside a broader body of observational and randomized evidence summarized above, highlight a persistent and concerning signal for sex differences in in-hospital and 1-year outcomes following MCS-supported PCI. Across multiple registries and trials, women remain both under-represented and highly selected for an older and more comorbid cohort, who face delays in care. These imbalances contribute to worse early outcomes, including bleeding and mortality, that may mask or mitigate the potential benefits of MCS in this population. However, the evidence base remains fragmented, consisting of retrospective data, subgroup analyses, and small-sample trials underpowered for sex-specific insights. What urgently needed are prospective, adequately powered randomized studies that intentionally enroll representative female cohorts and incorporate sex-specific analyses from the outset. Moreover, future work must go beyond binary sex comparisons to disentangle the anatomical, biological, procedural, and systemic contributors that disproportionately affect women. Until then, clinicians must remain vigilant in recognizing the ways care pathways may inadvertently disadvantage women. As Dr Healy warned more than 3 decades ago, women continue to be treated equitably only when they present like men. The Yentl Syndrome is far from resolved and its implications remain life-threatening.

Funding support and author disclosures

Dr Nanna has received research support from the American College of Cardiology Foundation supported by the George F. and Ann Harris Bellows Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the Yale Claude D. Pepper Older Americans Independence Center (P30AG021342), and the National Institute on Aging (K76AG088428); and is a consultant for Novo Nordisk, Heartflow, Novartis, and Merck. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.