key: cord-0683373-6he6dy4k authors: Quesada, Odayme; Van Hon, Logan; Yildiz, Mehmet; Madan, Mina; Sanina, Cristina; Davidson, Laura; Htun, Wah Wah; Saw, Jacqueline; Garcia, Santiago; Deghani, Payam; Stanberry, Larissa; Bortnick, Anna; Henry, Timothy D.; Grines, Cindy L.; Benziger, Catherine title: Sex Differences in Clinical Characteristics, Management Strategies, and Outcomes of STEMI With COVID-19: NACMI Registry date: 2022-05-19 journal: nan DOI: 10.1016/j.jscai.2022.100360 sha: e3921cdc2a484fea1177ba3d98aa79419c3860f3 doc_id: 683373 cord_uid: 6he6dy4k Background Women with ST-segment elevation myocardial infarction (STEMI) are known to have worse outcomes than men prior to the COVID-19 pandemic. Although concomitant COVID-19 infection increases mortality risk in STEMI patients, no studies have evaluated sex differences in this context. Methods The North American COVID-19 STEMI registry is a prospective, multicenter registry of hospitalized STEMI patients with COVID-19 infection. We compared sex differences in clinical characteristics, presentation, management strategies, and outcomes, including in-hospital mortality as the primary outcome. Results Among 585 patients with STEMI and COVID-19 infection, 154 (26.3%) were women. Compared to men, women were significantly older, had a higher prevalence of diabetes and stroke/transient ischemic attack, and were more likely to be on a statin on presentation. Men more frequently presented with chest pain, whereas women presented with dyspnea. Women more often had STEMI without an identified culprit lesion than men (33% vs 18%, P ​< ​.001). The use of percutaneous coronary intervention was significantly higher in men, whereas medical therapy was higher in women. In-hospital mortality was 33% for women and 27% for men (P ​= ​.22). There were no significant sex differences for in-hospital stroke, reinfarction, or composite endpoint. Conclusions In the North American COVID-19 STEMI registry of patients presenting with STEMI in the context of COVID-19, the in-hospital mortality rate was 30% and similar for men and women. Lack of an identifiable culprit lesion was common in the setting of COVID-19 for both sexes but more likely in women (1/3 women vs 1/5 men). Evaluation of specific underlying etiologies is underway to better define the full impact of COVID-19 on STEMI outcomes and better understand the observed sex differences. COVID-19 significantly increases the risk of arterial and venous thromboembolic events up to 2-fold, including the risk of myocardial infarction (MI) in the 7 days after COVID-19 diagnosis. [1] [2] [3] Patients in the early phase of the COVID-19 pandemic who developed ST-segment elevation MI (STEMI) were reported to be at higher risk of mortality (up to 36%), 4-7 partly due to the higher prevalence of cardiovascular 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 risks, higher risk of pre-percutaneous coronary intervention (PCI) cardiogenic shock in COVID-19 patients with STEMI, and lower likelihood of undergoing invasive angiography and mechanical circulatory support. 5, 8 Prior studies in patients with STEMI without COVID-19 infection have shown sex disparities in STEMI care and outcomes, with some studies reporting a significantly higher risk of mortality in women. The higher mortality in women, particularly young women (<60 years of age), was predominantly related to late presentation, delayed diagnosis, and underutilization of evidence-based therapies, including revascularization with primary PCI. [9] [10] [11] [12] [13] [14] [15] Although men have been reported to have more severe disease and higher mortality with COVID-19 infection, 16, 17 the risk of MI with COVID-19 infection is no different in men compared with women. 18 Sex differences in patients with COVID-19 infection and MI are limited to only 1 small, single-center study (n ¼ 57) in Iran predominantly composed of patients with NSTEMI Q4 that reported no sex difference in in-hospital mortality risk. 19 This prespecified analysis aims to describe sex differences in clinical characteristics, management strategies, and outcomes of STEMI patients with COVID-19 infection using the North American COVID-19 STEMI (NACMI) registry. NACMI is a multicenter, prospective, investigator-initiated, observational registry of hospitalized STEMI patients in North America with confirmed or suspected COVID-19 infection, as previously described. 20 NACMI included a total of 64 sites (12 Canadian and 52 US sites). Institutional review board approval was required at the coordinating center (Minneapolis Heart Institute Foundation) and at each enrolling site. Patients were enrolled from March 1, 2020, to December 31, 2021. This registry included adult patients (!18 years) with (1) ST-segment elevation in at least 2 contiguous leads (or new-onset left bundle branch block); (2) a clinical correlate of myocardial ischemia; and (3) confirmed or suspected COVID-19 infection. This analysis only included confirmed COVID-19 cases based on positivity by any commercially available test during or 4 weeks prior to the index STEMI hospitalization regardless of treatment strategy. Also included were patients with in-hospital STEMI presentations with confirmed COVID-19 irrespective of the admission reason. The primary endpoint was in-hospital mortality. Secondary endpoints included stroke, reinfarction, and the composite of mortality, stroke, or reinfarction. Nonfatal events were defined using National Cardiovascular Data Registry (NCDR) CathPCI Registry v4.4 definitions. Standardized data-collection forms were used, designed using the American College of Cardiology NCDR definitions. Data were collected at the sites and entered into a REDCap database; statistical analysis was performed by the coordinating center (Minneapolis Heart Institute Foundation). Continuous variables are summarized by mean AE standard deviation if normally distributed or as median and interquartile range (25th percentile, 75th percentile) if skewed; categorical variables are summarized by count and percentage. For categorical data, the Pearson χ 2 or the Fisher exact test was used; for continuous variables, the t test or Wilcoxon rank-sum test was used, as appropriate. Given a relatively short hospital length of stay, in-hospital mortality is modeled as a binary variable, and relative risk of mortality is estimated from a multivariate robust Poisson regression with a canonical log-link and a robust sandwich estimator of variance to allow for overdispersion in the data. Model covariates included sex, body mass index, abnormal chest x-ray findings, indicator variables for age <66 years, White race, current smoker, coronary artery disease, signs of congestive heart failure, diabetes, previous MI, stroke or transient ischemic attack (TIA), PCI or coronary artery bypass grafting, and shock before PCI. The choice of the variables and categories in the model is informed by existing literature, exploratory data analysis, sample size, and the number of adverse events. Model parameters are estimated from imputed data, with missing values approximated by sample medians. Model estimates are reported with their 95% confidence intervals and P values. A P value of <.05 is considered statistically significant without adjustment for multiplicity. Data were analyzed using R version 4.1.2 (R Foundation for Statistical Computing) in RStudio environment version 2021.09.1 (RStudio, PBC). A total of 585 COVID-19-positive patients with STEMI were included in the present analysis, of which 154 (26.3%) were women. Among women, 46% were White, 21% Black, 17% Hispanic, and 9.3% Asian, with similar rates in men. Compared with men, women were older, and more of them had diabetes (53% vs 41%) and stroke/TIA (14% vs 7.4%). There was no other difference in risk factors between sexes including hypertension, dyslipidemia, smoking, body mass index, previous coronary artery disease, and previous MI. Women also had higher statin use prior to presentation (49% vs 32%). Men more frequently presented with chest pain (59% vs 47%), whereas women more frequently presented with dyspnea (56% vs 45%). There was no significant sex-based difference in pre-PCI cardiac arrest, cardiogenic shock, or left ventricular ejection fraction (Table 1) . Angiography was not performed in 18% of women and 17% of men. Among those who underwent angiography, women had fewer identifiable culprit lesions than men (67% vs 82%), with one-third presenting with no culprit lesion. Women were more often treated with medical therapy, and men more frequently had primary PCI. In addition, there was no between-group differences in length of stay (Table 2) . In-hospital mortality was 33% for women and 27% for men. There were no significant sex differences in stroke, reinfarction, or the composite endpoint (Table 3 ). In the multivariable model, age !66 years, history of stroke/TIA, pulmonary infiltrates on presentation, and cardiogenic shock (pre-PCI) were independent predictors of in-hospital mortality ( Figure 1 and Supplemental Table S1 ). In-hospital mortality was not significantly different in women and men who (1) did not undergo angiography (60% vs 44%%, P ¼ .20); (2) had a culprit lesion (25% vs 18%, P ¼ .19); (3) had no culprit lesion (34% vs 46%, P ¼ .23); (4) were treated medically (29% vs 48%, P ¼ .06); (5) underwent primary/rescue PCI (26% vs 18%, P ¼ .13); or (6) were intubated (61% vs 61%, P ¼ .96). Among the 165 patients enrolled in 2021 (at which point vaccines were widely available in the United States and Canada), none of the 22 vaccinated patients expired in hospital. Based on this prospective, multicenter registry, patients presenting with STEMI in the setting of COVID-19 had a poor prognosis, with a 30% overall mortality rate affecting men and women equally. Absence of an identifiable culprit on angiography appears to be more common in the setting of STEMI in COVID-19 but was more likely in women, along with 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 other sex-based differences in risk factors, presentation, and treatment (Central Illustration). Prior to COVID-19, mortality rates for STEMI had significantly improved in the past decade, with rates as low as 5%. 4 This is in stark contrast to the very poor prognosis observed in our registry of patients with STEMI and COVID-19 infection where in-hospital mortality was 33% for women and 27% for men. These findings align with earlier observations that reported in-hospital mortality in STEMI patients with COVID-19 infection ranging from 15% to 36%. [4] [5] [6] [7] Possible causes of this excess mortality in STEMI associated with COVID-19 include the higher incidence of cardiogenic shock and the presence of pulmonary infiltrates on presentation, suggestive of amore severe COVID-19 infection, which carried a 2-fold higher risk of in-hospital mortality in our study. The combination of direct effects of the virus, higher risk of thrombotic lesions and microthrombi, delays in patient presentation, deviations from evidence-based STEMI protocol during the early phase of the pandemic resulting in delays, and reduced access to angiography likely contributed to the poor observed prognosis. Further research is needed to understand the impact that COVID-19 vaccinations will have on the incidence and prognosis of STEMI in COVID-19 patients. 21 No culprit lesion was identified on angiography in 33% of women and 18% of men with STEMI and COVID-19 infection. This is a startling difference to the 3.5%-6.5% rates of MI with nonobstructive CAD Q5 (MINOCA) reported in patients without COVID infection. [22] [23] [24] [25] Potential mechanisms for STEMI in patients with COVID-19 infection and no culprit lesion on angiography include microvascular thrombosis/embolization, given that COVID-19 has been described as a state of inflammation and hypercoagulability, 2 myocarditis, which has been associated with worse prognosis in COVID-19 patients, 26 stress cardiomyopathy in the setting of severe illness, 27 demand ischemia in the setting of severe hypoxia, 28 and electrolyte imbalances common in critically ill patients with COVID-19 infection. Other causes of MINOCA include coronary artery plaque disruption, epicardial coronary spasm, spontaneous coronary artery dissection, and nonischemic cardiomyopathy. 29 Evaluation of specific underlying etiologies is underway to better define the mechanisms of STEMI in COVID-19 infection. Similarly, MI studies in patients without COVID-19 infection consistently reported predominance of MINOCA in women; however, the reason for this remains unknown. [22] [23] [24] [25] In-hospital Values are n (%), mean AE standard deviation, or median (interquartile range). PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; TIA, transient ischemic attack. Values are n (%) or median (interquartile range). PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction. a For patients undergoing coronary angiography. Values are n (%). STEMI, ST-segment elevation myocardial infarction. 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 mortality was not significantly different in women vs men that did not have angiography performed, had a culprit lesion on angiography, or in those without a culprit lesion on angiography. Other important sex differences were observed in this study. Women were older and had a significantly higher prevalence of pre-existing diabetes and stroke/TIA. Men presenting with STEMI and COVID-19 more frequently presented with chest pain, whereas women presented more often with atypical symptoms such as dyspnea in the current study, 30, 31 likely due to the different underlying sex-based mechanisms of STEMI. Similarly, the difference in treatment strategies with more PCI in men and more medical treatment in women likely reflects the higher rates of MINOCA in women than in men; however, differences in STEMI treatment have been shown to contribute to worse outcomes in women. Therefore, further investigation into the impact of treatment on outcomes is warranted. 11, 13 Limitations The NACMI registry has important limitations common to observational studies when comparing outcomes of subgroups, including measured and unmeasured confounders. Furthermore, clinical events and cause of death were not independently adjudicated, there was no independent angiographic analysis to determine the underlying mechanism of STEMI, and the samples size was limited to detect differences in mortality. Total ischemic time and transfer times for patients presenting to non-PCI hospitals, the reason for not performing angiography, and detailed laboratory data including hypercoagulable biomarkers were not collected. Finally, our study did not capture information regarding COVID-19 variation or vaccination status; therefore, association with outcomes is not possible. In the prospective NACMI registry of patients presenting with STEMI and COVID-19, the in-hospital mortality rate was 30% and similar for men and women. Lack of an identifiable culprit lesion was common in the setting of COVID-19 for both sexes but more likely in women. Evaluation of the underlying mechanisms of STEMI is underway. Dr Quesada reports financial support was provided by Medtronic Inc, Abbott Cardiovascular Structural Heart Division, American College of Cardiology Accreditation, and Saskatchewan Health Research Foundation. NIHK23HL151867. Dr Quesada declares receiving institutional research grants from Edwards Lifesciences, BSCI, Medtronic, and Abbott Vascular. Dr Quesada is a consultant for American College of Cardiology, Medtronic, and BSCI. Dr Garcia is a proctor for Edwards Lifesciences. The remaining authors have nothing to disclose. The authors would like to thank the administrative and scientific personnel of the Society for Cardiovascular Angiography and Interventions 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 and Minneapolis Heart Institute Foundation for their support of North American COVID-19 ST-Segment-Elevation Myocardial Infarction. Medtronic and Abbott Vascular, American College of Cardiology Accreditation Grant, and Saskatchewan Health Research Foundation. 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 COVID-19 can affect the heart COVID-19 for the cardiologist: basic virology, epidemiology, cardiac manifestations, and potential therapeutic strategies Thromboembolic risk in hospitalized and nonhospitalized COVID-19 patients Initial findings from The North American COVID-19 Myocardial Infarction Registry Association between COVID-19 diagnosis and in-hospital mortality in patients hospitalized with ST-segment elevation myocardial infarction International prospective registry of acute coronary syndromes in patients with COVID-19 Impact of SARS-CoV-2 positivity on clinical outcome among STEMI patients undergoing mechanical reperfusion: insights from the ISACS STEMI COVID 19 registry Myocardial infarction during the COVID-19 pandemic Sex differences in outcomes after STEMI Sex differences in reperfusion in young patients with ST-segment-elevation myocardial infarction Temporal trends and sex differences in revascularization and outcomes of ST-segment elevation myocardial infarction in younger adults in the United States A gender perspective on shortand long term mortality in ST-elevation myocardial infarction -a report from the SWEDEHEART register Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention Sex differences in short-term and long-term all-cause mortality among patients with ST-segment elevation myocardial infarction treated by primary percutaneous intervention Delayed care and mortality among women and men with myocardial infarction Considering how biological sex impacts immune responses and COVID-19 outcomes Factors associated with COVID-19-related death using OpenSAFELY The role of sex and inflammation in cardiovascular outcomes and mortality in COVID-19 Clinical implications and indicators of mortality among patients hospitalized with concurrent COVID-19 and myocardial infarction North American COVID-19 ST-Segment-Elevation Myocardial Infarction (NACMI) registry: rationale, design, and implications BNT162b2 vaccine booster and mortality due to Covid-19 Long-term prognosis of patients presenting with ST-segment elevation myocardial infarction with no significant coronary artery disease (from the HORIZONS-AMI trial) MINOCA presenting with STEMI: incidence, aetiology and outcome in a contemporaneous cohort Long-term survival and causes of death in patients with ST-elevation acute coronary syndrome without obstructive coronary artery disease Prevalence, clinical factors, and outcomes associated with myocardial infarction with nonobstructive coronary artery Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection Incidence of stress cardiomyopathy during the coronavirus disease 2019 pandemic Myocardial injury in severe COVID-19 compared with non-COVID-19 acute respiratory distress syndrome Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the Symptoms and type of symptom onset in acute coronary syndrome in relation to ST elevation, sex, age, and a history of diabetes Gender differences in symptom presentation of ST-elevation myocardial infarctionan observational multicenter survey study