No Woman Left Behind | Circulation: Heart Failure

See Article by Vallabhajosyula et al

For many clinicians, the acute myocardial infarction (AMI) presentation invokes classic imagery of an older man clutching his chest with anginal pains, as skillfully depicted by Dr Frank H. Netter. However, the patient profile of AMI is evolving. In the setting of an overall temporal decline in AMI, young women have unexpectedly increased as a proportion of patients with AMI.^1,2 Almost 10% of patients presenting with AMI in the United States are now women aged 18 to 59 years.³ These women are more often of Black race and have higher rates of diabetes mellitus and obesity compared with men.¹ Women with AMI may present with less classic biomarker, ECG, and chest pain findings.⁴ Younger women with ST-segment–elevation myocardial infarction are known to receive less coronary revascularization,^3–5 and the disparity may be widening over time¹; women are also less likely to meet the 90-minute door-to-balloon time threshold, suggesting delays in AMI recognition by providers or patients.⁶ Inpatient mortality for younger women with AMI has been variously described as higher or equivalent to that of younger men.^1,3,5

The highest risk patients with AMI are those who develop cardiogenic shock (CS), characterized by clinical and biochemical evidence of tissue hypoperfusion. AMI is the commonest cause of CS, with an in-hospital mortality of ≈35%.⁷ Women with AMI-CS typically present later in life—in one contemporary CS trial, the median age was 75 years (interquartile range, 68–81) for women versus 67 years (58–77) for men⁸—and with higher comorbidity burden, but less is known about younger women with AMI-CS. Early revascularization reduces progression to CS and mortality in AMI-CS. Compared with men, women with CS are less likely to receive early percutaneous coronary intervention (PCI; 38.9% of women versus 45.2% of men with ST-segment–elevation myocardial infarction in the National Inpatient Sample; P<0.001) and also intra-aortic balloon pump (IABP) support (43% versus 55.1%; P<0.001).⁷ Some prior studies of temporary mechanical circulatory support (MCS) deployment in CS have shown poorer survival for women,⁹ although several indicate equivalent outcomes between sexes.^8,10 However, prior reports have not specifically described AMI-CS in younger women or revascularization and MCS deployment in young women as compared with young men.

In this issue of Circulation: Heart Failure, Vallabhajosyula et al¹¹ use the National Inpatient Sample between 2000 and 2017 to build upon the limited sex-specific data for patients with AMI-CS, focusing on those aged 18 to 55 years. They deliver an important message that young women not only experience AMIs but also progress into CS with similar frequency as young men: 3.5% of younger women admitted with AMI were diagnosed with CS, comparable to 3.6% of younger men. As anticipated, women with AMI-CS were more frequently of Black race, had Medicare/Medicaid as the primary payor, resided in lower income zip codes, and had higher comorbidity burdens, as compared with men. However, sex-specific prevalence of diabetes mellitus and obesity was not provided in the article. Consistent with prior literature, young women were less likely to receive coronary angiography, PCI, and MCS.

Despite presenting with a lower prevalence of ST-segment elevation and fewer cardiac arrests, women were marginally more likely than men to die, with an in-hospital mortality of 23.0% versus 21.7% (P<0.001). Female sex remained associated with greater in-hospital mortality after adjustment, although residual confounding could be present due to the lack of granular adjustment for comorbidities, for example, continuous variables for renal function and body mass. Furthermore, the adjusted odds ratio was small in magnitude and the excess risk concentrated in earlier years of the study period, with the gap narrowing more recently. Mortality rates improved over time for both sexes, but conversely, there was no temporal improvement in the sex-specific gap for PCI and MCS, possibly indicating that medical critical care CS management was the predominant area of improvement for women. Notably, women who did not receive PCI or did not receive MCS were significantly more likely to have in-hospital mortality.

Thus young women with AMI-CS tend to present with a lower acuity AMI profile, receive fewer interventions including mechanical support, and yet experience at least as high—possibly higher—in-hospital mortality as their male counterparts. This sex-specific disconnect between acuity, interventions, and survival raises important questions about both female AMI-CS pathophysiology and the quality of care delivered: (1) Do women present with different AMI phenotypes from that typically seen in men? (2) Is the AMI-CS clinical care delivered to women less effective than that received by men?

For the first question, it has been proposed that both traditional (diabetes mellitus, obesity, hypertension) and nontraditional (anxiety/depression, caregiver stress, low household income, preeclampsia, polycystic ovary syndrome, early menopause, autoimmune disease) risk factors strongly contribute toward AMI in young women. Diabetes mellitus is acknowledged in the present study within the Charlson Comorbidity Index but obesity is not; a more detailed exploration of comorbidities—particularly type 1 and 2 diabetes mellitus—would enhance the understanding of sex-specific risk factors because diabetes mellitus is known to serve as a stronger atherosclerotic risk factor in women than men. Furthermore, a proportion of AMI in women was likely secondary to spontaneous coronary artery dissection, coronary spasm, coronary embolism in the setting of autoimmune disease, or breast cancer radiation-induced coronary disease, each with strong female predominance. Although these diverse coronary etiologies could contribute toward the lower revascularization rates for women, they would not account for disparate use of angiography or MCS. Unfortunately a major limitation of administrative databases is that these phenotypic nuances are not decipherable,¹² and thus, detailed prospective registries are necessary to unravel the mysteries of why young women experience AMI-CS. Such registries should also record prior hypertension during pregnancy, which is increasingly recognized as predictive of future cardiovascular events, and may invoke opportunities for risk factor modification.¹³

For the second question, the current article amplifies concerns that our modern strategies for managing CS may be underutilized among young women with AMI-CS. Sex-specific disparities in rates of revascularization and MCS deployment have previously been attributed to the older age at which women generally present with CS, potentially limiting their candidacy for invasive procedures. However, this report does raise the uncomfortable possibility that even young women might experience less access to potentially life-saving interventions. In the absence of hemodynamic and inotrope/pressor data, the lower rates of IABP, percutaneous ventricular assist device, and extracorporeal membrane oxygenation support observed for women could potentially be appropriate for the lower rates of ST-segment–elevation myocardial infarction, cardiac arrest, and renal/hepatic failure among women. However the mortality odds ratio for women who did not receive MCS implies there were women who might have survived if appropriately recognized as mechanical support candidates.

Potential explanations for a lack of MCS deployment in women are multilayered and connect with the lower rates of angiography/PCI, including lack of timely AMI recognition, lack of timely CS recognition, underappreciation of CS severity, and concerns around vascular access safety or MCS safety profile for women, for example, related to bleeding complications. Women have historically been underrepresented in MCS device trials, and so sex-specific safety and efficacy data are sparse, with reliance on retrospective observations.^14,15 For MCS device trials, sex-specific data are currently recommended but not mandated by the Food and Drug Administration. Adequately powered sex-specific analyses are essential to either refute concerns about device safety in women or identify sex-specific complications, such as those related to smaller body size and arterial caliber, and develop devices that mitigate these risks. A clinical trial structured around clear hemodynamic eligibility criteria, randomizing participants with severe CS to percutaneous ventricular assist device versus extracorporeal membrane oxygenation support and powered for analysis by sex subgroups, would answer the question of whether men and women of equivalent CS severity experience equivalent benefits and complications from these MCS strategies. Similarly in routine clinical care, CS management protocols with clear hemodynamic and biochemical criteria may help minimize subjectivity around angiography and MCS decision-making. It is essential also to actively engage diverse female clinicians and researchers within the AMI-CS medical field to ensure the right questions about CS in women continue to be asked.

Vallabhajosyula et al demonstrate not only that young women with AMI are at similar risk as young men for developing CS but that young women of Black race and lower income groups are disproportionately affected by this high acuity condition. Furthermore, their work generates the hypothesis that underrecognition and undertreatment of younger women with AMI-CS may have mortality consequences, given that mortality for women was particularly high among those who did not receive MCS. This strengthens the call for detailed registries to further investigate the phenomenon of CS in young women and highlights the importance of conscious efforts to ensure that MCS devices meet the needs of female patients. The evolution of the Cardiogenic Shock Team and a host of clinical innovations in MCS devices over the past decade represent major advances within cardiology, but we have a responsibility to achieve parity in this progress. Ensuring that young women, especially socially or economically disadvantaged women, are not left behind during these critical care advances is a challenge that must be embraced throughout the AMI-CS clinical and research community.

Footnotes