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Sex Disparities in the Use and Outcomes of Temporary Mechanical Circulatory Support for Acute Myocardial Infarction-Cardiogenic Shock

Background There are limited sex-specific data on patients receiving temporary mechanical circulatory support (MCS) for acute myocardial infarction-cardiogenic shock (AMI-CS). Methods All admissions with AMI-CS with MCS use were identified using the National Inpatient Sample from 2005 to 2016. Outcomes of interest included in-hospital mortality, discharge disposition, use of palliative care and do-not-resuscitate (DNR) status, and receipt of durable left ventricular assist device (LVAD) and cardiac transplantation. Results In AMI-CS admissions during this 12-year period, MCS was used more frequently in men—50.4% vs 39.5%; P < 0.001. Of the 173,473 who received MCS (32% women), intra-aortic balloon pumps, percutaneous LVAD, extracorporeal membrane oxygenation, and ≥ 2 MCS devices were used in 92%, 4%, 1%, and 3%, respectively. Women were on average older (69 ± 12 vs 64 ± 13 years), of black race (10% vs 6%), and had more comorbidity (mean Charlson comorbidity index 5.0 ± 2.0 vs 4.5 ± 2.1). Women had higher in-hospital mortality than men (34% vs 29%, adjusted odds ratio [OR]: 1.19, 95% confidence interval [CI]: 1.16-1.23; P < 0.001) overall, in intra-aortic balloon pumps users (OR: 1.20 [95% CI: 1.16-1.23]; P < 0.001), and percutaneous LVAD users (OR: 1.75 [95% CI: 1.49-2.06]; P < 0.001), but not in extracorporeal membrane oxygenation or ≥ 2 MCS device users (P > 0.05). Women had higher use of palliative care, DNR status, and discharges to skilled nursing facilities. Conclusions There are persistent sex disparities in the outcomes of AMI-CS admissions receiving MCS support. Women have higher in-hospital mortality, palliative care consultation, and use of DNR status.

Cardiogenic shock (CS) is defined as a critical state of endorgan hypoperfusion due to primary pump failure, nearly 80% of which is due to acute myocardial infarction (AMI). 1 In addition to the primary pump failure, these patients also have systemic inflammation and hypoxemia further worsening end-organ failure. [2][3][4][5] Temporary mechanical circulatory support (MCS) devices, such as intra-aortic balloon pump (IABP), percutaneous left ventricular assist device (pLVAD) (Impella or TandemHeart), and extracorporeal membrane oxygenation (ECMO), can be used to support cardiovascular function in selected patients. [6][7][8][9][10] However, there are conflicting data on the clinical management and outcomes of men and women who received temporary MCS for AMI-CS. 11,12 Prior data suggest that men and women differ at baseline in terms of etiology of CS and AMI, prognosis, and the treatment strategies they receive. 13 Alternatively, in a substudy from the Intra-Aortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial, despite having a worse clinical profile, women had comparable clinical outcomes with men. 14 Prior work from national databases has shown persistent sex disparities in the management and outcomes of durable LVAD admissions. 15 It is unclear if similar disparities exist in the clinical profile and outcomes of men and women receiving temporary MCS for AMI-CS in the United States. [16][17][18] In light of these conflicting data, this study sought to assess sex differences in the use and outcomes of MCS in a 12-year nationally representative AMI-CS population. We hypothesized that women would receive MCS less frequently and have higher in-hospital mortality compared with men. We also sought to evaluate the sex differences in demographics, clinical course, and management strategies of these cohorts to better inform clinical care for these patients.

Study population, variables, and outcomes
The National (Nationwide) Inpatient Sample (NIS) is the largest all-payer database of hospital inpatient stays in the United States. NIS contains discharge data from a 20% stratified sample of community hospitals and is a part of the Healthcare Quality and Utilization Project (HCUP), sponsored by the Agency for Healthcare Research and Quality. 19 Information regarding each discharge includes patient demographics, primary payer, hospital characteristics, principal diagnosis, up to 24 secondary diagnoses, and procedural diagnoses. The HCUP-NIS does not capture individual patients but captures all information for a given admission. Institutional review board approval was not sought due to the publicly available nature of this deidentified database. These data are available to other authors via the HCUP-NIS database with the Agency for Healthcare Research and Quality.
The primary outcome was in-hospital mortality in men and women with AMI-CS supported by MCS. Temporal trends in the use of MCS in AMI-CS, type of MCS devices, and in-hospital mortality over the study period, stratified by sex, were evaluated. Secondary outcomes included length of stay, hospitalization costs, discharge disposition, use of donot-resuscitate (DNR) status, use of palliative care consultation, receipt of durable LVAD, and cardiac transplantation.

Statistical analysis
As recommended by the HCUP-NIS, survey procedures using discharge weights provided with the HCUP-NIS database were used to generate national estimates. Using the trend weights provided by the HCUP-NIS, samples from 2005 to 2011 were reweighted to adjust for the 2012 HCUP-NIS redesign. 26 c 2 and t-tests were used to compare categorical and continuous variables by sex, respectively. Logistic regression was used to compare the risk of outcomes over time by sex, with results presented as odds ratios (OR) with 95% confidence intervals (CI). To evaluate temporal trends, the risk of the outcome in each year of the study was compared with the year 2005. The inherent restrictions of the HCUP-NIS database related to research design, data interpretation, and data analysis were reviewed and addressed. 26 Pertinent considerations include not assessing individual hospital-level volumes (due to changes to sampling design detailed above), treating each entry as an "admission" as opposed to individual patients, restricting the study details to inpatient factors because the HCUP-NIS does not include outpatient data, and limiting administrative codes to those previously validated and used for similar studies. Multivariable logistic regression analysis incorporating age, race, primary payer status, socioeconomic stratum, hospital characteristics, comorbidities, acute organ failure, AMI-type, cardiac procedures, and noncardiac procedures was performed for temporal trends analyses and in-hospital mortality. For the multivariable modelling, regression analysis with purposeful selection of statistically (liberal threshold of P < 0.20 in univariate analysis) and clinically relevant variables was conducted. A priori subgroup analyses were performed stratifying admissions by race, concomitant cardiac arrest, AMI-CS type, early (hospital day zero) vs delayed (! hospital day 1) MCS placement, and receipt of percutaneous coronary intervention (PCI). Two-tailed P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS v25.0 (IBM Corp, Armonk, NY).

Results
In the period between January 1, 2005, and December 31, 2016, there were 374,920 admissions with AMI-CS, of which MCS was used in 173,473 (46.3%). Men received more frequent MCS support than women (50.4% vs 39.5%; P < 0.001). Of the included population, women constituted 31.7%. Compared with men, women were on average older, of black race, bearing Medicare insurance, from a lower  1B).
Of those receiving MCS support, the IABP, pLVAD, ECMO, and ! 2 MCS devices were used in 159,240 (91.8%), 7516 (4.3%), 1469 (0.8%), and 5248 (3.0%), respectively. The temporal trends in the use of IABP, pLVAD, and ECMO stratified by sex were similar in men and women (Fig. 2). Women who received any of these MCS devices were    Table S2). Women had higher unadjusted in-hospital mortality over the entire 12-year period (Fig. 3A). The adjusted mortality shows a steady decrease in the in-hospital mortality in 2016 as compared with 2000 in both groups (Fig. 3B). The increased risk of in-hospital mortality in women vs men extended to all racial and ethnic groups, those with and without concomitant cardiac arrest, both types of AMI-CS, patients with early and delayed MCS placement, and those who did and did not receive PCI (Fig. 4). Women had comparable length of hospital stay, lower hospitalization costs, and were less often discharged to home and more often discharged to skilled nursing facilities compared with men (Table 3). Although women and men had comparable rates of durable LVAD placement and cardiac transplantation during the AMI-CS hospitalization, women had higher use of DNR status and palliative care consultation (Table 3). Women had higher all-cause unadjusted in-hospital mortality across all MCS devices except in those using ECMO (  (Table 4).

Discussion
In the largest study evaluating the use of temporary MCS in AMI-CS, there were significant sex disparities in the use of MCS, patient characteristics, and outcomes. Women with AMI-CS received MCS devices less frequently, had higher comorbidity, and higher rates of respiratory failure and mechanical ventilation use. Over the 12-year study period, there was a decrease in the use of IABP with increases in the use of pLVAD and ECMO in both men and women. Women had higher in-hospital mortality, more frequent use of DNR status and palliative care consultation, and higher postacute care resource utilization. Women receiving IABP or pLVAD support, but not ECMO support, had higher in-hospital mortality in AMI-CS. Although the overall mortality from AMI-CS has decreased over the last few decades, there remain significant challenges and opportunities for improvement in the care of these patients. 4 As noted previously, patient-and hospitalspecific demographic factors continue to be associated with  Multivariate logistic regression analysis for in-hospital mortality in women with AMI-CS receiving MCS compared with men. Multivariable adjusted odds ratios (95% confidence intervals)* for in-hospital mortality in women compared with men stratified by race, presence of cardiac arrest, type of AMI, timing of MCS placement, and receipt of PCI; all P < 0.001. *Adjusted for age, race, year of admission, primary payer, socioeconomic status, hospital location/teaching status, hospital bed size, hospital region, year of admission, comorbidity, type of AMI-CS, acute organ failure, cardiac arrest, coronary angiography, PCI, pulmonary artery catheterization, mechanical ventilation, and hemodialysis. AMI, acute myocardial infarction; CS, cardiogenic shock; MCS, mechanical circulatory support; NSTEMI, noneST-elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction. differences in clinical outcomes in this population. [27][28][29] In this study, there were significant sex differences in the outcomes for patients receiving MCS for AMI-CS. The results are consistent with prior research that has shown pervasive sex disparities in acute cardiovascular care. 29,30 Compared with men, women experiencing an AMI are often older, present with delayed and atypical symptoms, often have longer total ischemic time, and are revascularized less often. 30 Furthermore, women have higher comorbidity, higher rates of heart failure, were less likely to undergo primary reperfusion, and had higher rates of in-hospital complications. 31 Similar results were also noted in prior studies from the HCUP-NIS database. 32 In our study, despite noting that women were older and had greater comorbidity, there were no differences in the use of angiography and PCI between the sexes. This observation could be related to a selection bias because all admissions in this study had received MCS devices. It is conceivable that given the concerns with large bore access-related complications, women were considered for MCS further along their "hemo-metabolic" cascade compared with men. 4,31 Prior data have shown that clinicians worry about higher complications with largebore MCS in women due to smaller calibre of femoral vessels, lower body surface area, and higher rates of bleeding. 18,30,33 Prior studies have shown that sex disparities in ST-segment elevation AMI-CS have less pronounced sex differences. 34 Therefore, it is conceivable that the worse outcomes in women in this study may be related to the higher prevalence of noneST-segment elevation AMI-CS. Further dedicated studies of noneST-segment AMI-CS are needed to better understand this phenomenon. Lastly, women had higher rates of respiratory failure and mechanical ventilation use, which might reflect higher severity of heart failure. The lower rates of angiography and PCI in this population are consistent with prior real-world literature that reflects reluctance to perform angiography in higher risk cohorts despite robust guideline recommendations. 35 As compared with AMI, there are limited data on the sex disparities in AMI-CS. In the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) registry, women had higher comorbidity and higher rates of mechanical complications. 11 In a population study from Ontario including 9750 patients, female sex was associated with lower rates of revascularization and less frequent transfers to PCI-capable centres. 36 However, these studies did not show any differences in mortality despite the significant differences in the clinical profiles between men and women. In AMI-CS, reports of higher mortality in women are often confounded by small sample sizes, inadequate adjustment for delays since symptom onset and incomplete accounting for race, age, and socioeconomic status. 11,30 In this large study using administrative data, these limitations were circumvented. Importantly, the study added to the sex-specific outcomes in AMI-CS literature in the contemporary MCS era. [16][17][18]29 In 600 patients with AMI-CS from the IABP-SHOCK II study, although women had higher comorbidity and greater hemodynamic instability, they did not experience higher short-or long-term mortality compared with men. 14 Using the catheter-based ventricular assist device registry (Impella 2.5 or CP), Alraies et al. 16 did not note any sex-specific differences in clinical outcomes in Impellasupported PCI, including in 303 patients with AMI. In a retrospective registry of 81 patients with AMI-CS receiving Impella 2.5 or CP support, Doshi et al. 17 did not note any differences in in-hospital and 30-day mortality between women and men.
In contrast, an older study of 180 patients with AMI-CS receiving Impella 2.5 support for AMI-CS showed that women had lower in-hospital mortality compared with men. 18 In contrast to these smaller studies, the present study of 173,473 AMI-CS admissions shows persistent sex-specific disparities in clinical outcomes across the total cohort of MCS users and in the cohorts receiving the IABP and pLVAD. Although both sexes showed a temporal decrease in in-hospital mortality, female sex was an independent predictor of in-hospital mortality. These disparities persisted in the stratified analyses. Importantly, women have lower use of guideline-directed therapy after AMI complicated by heart failure/CS and have higher in-hospital mortality after durable LVAD placement, suggestive of a systematic bias along the spectrum of care of these patients. 15 As evidenced in our study, women had higher rates of palliative care referrals, higher use of DNR status, and higher discharges to skilled nursing facilities. Prior data have demonstrated that women with AMI discharged to skilled nursing facilities have higher in-hospital mortality. 37 Taken in aggregate, these findings may suggest that women have a poorer social support system and potentially face earlier withdrawal of care. In this administrative database, it was not possible to quantify these qualitative measures including marital status, presence of advanced directives, and the outcomes from palliative care consultation. It is conceivable that we may note a similar picture as a consequence of higher severity of illness; however, the lower rates of end-organ perfusion and overall lower use of MCS support argue otherwise. Greater recognition of subconscious biases, sex-specific therapeutic strategies, and involvement of multidisciplinary teams for shared decision making are potential avenues to address these health care disparities. 7,28 Lastly, in an exploratory subgroup analysis, we identified multiple subgroups wherein female sex was associated with worse in-hospital mortality. Consistent with similar literature from other AMI studies, non-white women had higher in-hospital mortality. 38 The worse outcomes of female and racial minorities, in addition to insurance status, are closely related to social, economic, and environmental factors that need to be considered in future qualitative studies.

Limitations
This study has several limitations, some of which are inherent to the analysis of a large administrative database. Coding errors, misrepresentation of procedural volumes, and underreporting of comorbidities are potential limitations of using administrative codes. The HCUP-NIS attempts to mitigate potential errors by using internal and external quality control measures. The administrative codes for AMI, CS, and MCS have been previously validated that reduces the inherent errors in the study. Although adjustments were made for differences in characteristics using multivariable analysis, it is possible that the observed outcomes could have been influenced, to some extent, by other unidentified confounders because of the inherent limitations of a retrospective study. Concomitant use of MCS with other devices/procedures was defined as those performed on the same procedure day. However, because further granularity in timing is unavailable and AMI-CS often evolves dynamically, the exact sequence of events cannot be discerned. The HCUP-NIS does not record duration of support or explantation of organ support; this study did not evaluate duration of MCS support alone or in combination with other MCS devices. The lack of universal health care, individual institutional practices, and patient preferences might impact the use and outcomes associated with the MCS devices and need a careful study in the future. The angiographic data, such as PCI location, lesion classification, presence of multivessel disease, and revascularization failure, that may significantly influence outcomes were not available in this database. From a CS standpoint, the database does not record echocardiographic, hemodynamic, and physiological data, which may limit the ability to risk-stratify the CS in these patients. 39 It is conceivable that similar to the long-term outcomes of an all-comer AMI population, these sex disparities may be less pervasive in the long term. 40 However, further data are needed to study this high-risk population, that is, those with CS and receiving MCS therapy. The strengths of this analysis include the large sample size, the ability to provide longitudinal data across the 12-year study period, and the identification of sex-specific disparities in this complex population.  AMA, against medical advice; AMI, acute myocardial infarction; CS, cardiogenic shock; ECMO, extracorporeal membrane oxygenation; HHC, home health care; IABP, intra-aortic balloon pump; LVAD, left ventricular assist device; MCS, mechanical circulatory support; pLVAD, percutaneous left ventricular assist device; SNF, skilled nursing facility; USD, United States Dollars.

Conclusions
In this retrospective, observational, and administrative database study, persistent sex disparities in care and outcomes of AMI-CS admissions supported with temporary MCS were noted. Women who received MCS had higher in-hospital mortality and posthospitalization resource utilization. Further dedicated research into the pathobiology of AMI-CS and MCS use with a sex-specific focus is needed to improve care and ensure equitable outcomes between men and women.