Collado-Lledó et al. BMC Cardiovascular Disorders (2020) 20:189 https://doi.org/10.1186/s12872-020-01467-4 RESEARCH ARTICLE Open Access Clinical picture, management and risk stratification in patients with cardiogenic shock: does gender matter? Elena Collado-Lledó1, Isaac Llaó1, Mercedes Rivas-Lasarte2, Victor González-Fernández3, Francisco J. Noriega4, Francisco José Hernández-Perez5, Oriol Alegre1, Alessandro Sionis2, Rosa M. Lidón3, Ana Viana-Tejedor4, Javier Segovia-Cubero5 and Albert Ariza-Solé1* Abstract Background: Early recognition and risk stratification are crucial in cardiogenic shock (CS). A lower adherence to recommendations has been described in women with cardiovascular diseases. Little information exists about disparities in clinical picture, management and performance of risk stratification tools according to gender in patients with CS. Methods: Data from the multicenter Red-Shock registry were used. All consecutive patients with CS were included. Both CardShock and IABP-SHOCK II risk scores were calculated. The primary end-point was in-hospital mortality. The discriminative ability of both scores according to gender was assessed by binary logistic regression, calculating Receiver operating characteristic (ROC) curves and the corresponding area under the curve (AUC). Results: A total of 793 patients were included, of whom 222 (28%) were female. Women were significantly older and had a lower proportion of chronic obstructive pulmonary disease and prior myocardial infarction. CS was less often related to acute coronary syndromes (ACS) in women. The use of vasoactive drugs, renal replacement therapy, invasive ventilation, therapeutic hypothermia and mechanical circulatory support was similar between both groups. In-hospital mortality was 346/793 (43.6%). Mortality was not significantly different according to gender (p = 0.194). Cardshock risk score showed a good ability for predicting in-hospital mortality both in man (AUC 0.69) and women (AUC 0.735). Likewise, the IABP-II successfully predicted in-hospital mortality in both groups (man: AUC 0.693; women: AUC 0.722). Conclusions: No significant differences were observed regarding management and in-hospital mortality according to gender. Both the CardShock and IABP-II risk scores depicted a good ability for predicting mortality also in women with CS. Keywords: Cardiogenic shock, Gender, Risk stratification, Prognosis * Correspondence: aariza@bellvitgehospital.cat 1 Intensive Cardiac Care Unit. Cardiology Department, Hospital Universitari de Bellvitge –IDIBELL, Feixa Llarga s/n. 08907. L’Hospitalet de Llobregat, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Collado-Lledó et al. BMC Cardiovascular Disorders (2020) 20:189 Page 2 of 8 Background was considered by default (0 points) in non ACS Cardiogenic shock (CS) is a severe clinical condition that patients. leads to a high mortality (40–59%) despite the treatment advances made in the last decade, including early myo- cardial reperfusion in myocardial infarction (MI) [1–3]. Outcomes Early recognition and risk stratification are crucial for Main outcome measured was in-hospital mortality ac- both patient allocation and selection of the optimal cording to gender status. treatment strategy [4]. The recently developed Card- Shock [1] and IABP-SHOCK II [5] risk scores contain Statistical analysis variables that can be easily obtained at the bedside or Baseline characteristics and clinical management were with routine laboratory tests, and have been recently val- assessed according to gender. Categorical variables were idated in a large cohort of non-selected patients with CS reported as frequencies and percentages, and statistical from a Spanish multicenter registry. differences were analysed by using the χ2 test. Continu- On the other hand, significant differences regarding ous variables were reported as the mean and standard clinical profile, management and prognosis according to deviation or the median and interquartile range; statis- gender have been previously described in patients with tical differences were analysed using the Student t test cardiovascular disease [6–9]. Importantly a significantly or Wilcoxon test, as appropriate. lower adherence to current recommendations has been The discriminative ability of the CardShock score and consistently described in other clinical scenarios, espe- the IABP-II score were assessed by a binary regression cially in patients with Acute Coronary Syndromes (ACS) logistic model, calculating Receiver operating character- [10, 11]. Little information exists about clinical picture, istic (ROC) curves and the corresponding area under the management and prognosis according to gender in pa- curve (AUC). For the performance of this analysis only tients with CS. patients with available Cardshock and IABP-II scores Therefore, the aim of this study was to describe the values were included (n = 696). Comparison between clinical picture, management and the predictive ability of AUCs was performed by the DeLong method [13]. Cali- the Cardshock and IABP-II risk scores according to gen- bration of the scores was assessed by the Hosmer- der in patients with CS from routine clinical practice. Lemeshow test. A P-value < 0.05 was considered signifi- cant and all statistical analyses were performed using Methods STATA software, version 13.1 (Stata Corp, College Sta- Study design and inclusion criteria tion, TX, USA). Red-Shock registry [12] is an observational, retrospect- ive, cohort study. The design has been previously de- scribed [12]. Consecutive patients aged 18 years or older Ethics statement with cardiogenic shock ((a) systolic blood pressure < 90 All procedures performed in this study were in accord- mmHg (after adequate fluid challenge) for 30 min or ance with the ethical standards of the institutional re- need for vasopressor therapy to maintain systolic blood search committee and with the 1964 Helsinki pressure > 90 mmHg, and b) signs of hypoperfusion) declaration and its later amendments or comparable eth- were included. Patients with shock after cardiac or non- ical standards. This study was approved by the reference cardiac surgery or ongoing haemodynamically significant institutional ethics comittee). arrhythmia as the cause of hypotension were excluded. The study was approved by the reference research eth- ics committee and was conducted in accordance with Results the Declaration of Helsinki. Because the study was retro- A total of 793 patients with CS were included from 6 spective, informed consent was not required. Patients centers, of whom 222 (28%) were female. Mean age was were treated according to the current practice of each 65.1 ± 15 years. A high proportion of comorbidities was center. observed, such as hypertension (58.8%) diabetes mellitus (39.6%), prior MI (20.1%) or previous heart failure Data collection (26.9%). In most cases (501/793, 63.2%) CS was related Demographic characteristics, clinical profile at admission to ACS. (within 6 h after the onset of CS) and treatments admin- Patients had a high risk profile, with a severely de- istered were recorded. pressed left ventricular function, high proportion of con- Both the CardShock [1] and the IABP-SHOCK II [5] fusion at presentation, elevated lactate values and low risk scores were calculated in the study cohort. An opti- values of estimated glomerular filtration (eGFR) mal thrombolysis in myocardial infarction (TIMI) flow (Table 1). Collado-Lledó et al. BMC Cardiovascular Disorders (2020) 20:189 Page 3 of 8 Table 1 Clinical characteristics according to gender status Whole cohort (n = 793) Male (n = 571) Female (n = 222) P value Age 65.1 (15) 64.2 (14) 67.3 (16) 0,013 BMI 26.9 (5) 27 (4) 26.7 (6) 0.537 Diabetes mellitus 314 (39.6) 226 (39.6) 88 (39.6) 0.988 Hypertension 466 (58.8) 331 (58) 135 (61.1) 0.424 Dyslipidemia 446 (56.2) 329 (57.6) 117 (52.7) 0.210 Active smoker 219 (27.7) 190 (33.4) 29 (13.1) 0.001 COPD 130 (16.4) 108 (18.9) 22 (9.9) 0.002 Prior stroke 69 (8.7) 54 (9.5) 15 (6.8) 0.226 PAD 90 (11.3) 71 (12.4) 19 (8.6) 0.122 Prior MI 159 (20.1) 126 (22.1) 33 (14.9) 0.023 Prior PCI 96 (12.1) 74 (13) 22 (9.9) 0.485 Prior CABG 33 (4.2) 24 (4.2) 9 (4.1) 0.789 Renal failure 134 (16.9) 104 (18.2) 30 (13.5) 0.113 Previous heart failure 213 (26.9) 150 (26.3) 63 (28.5) 0.524 ACS-related cardiogenic shock 501 (63.2) 373 (65.3) 128 (57.7) 0.044 Systolic blood pressure 81 (16) 81 (16) 80 (15) 0.969 Heart rate 94 (28) 94 (29) 93 (27) 0.459 Cardiac arrest 176 (22.2) 132 (23.1) 44 (19.9) 0.330 Sinus rythm 565 (72.3) 404 (71.6) 161 (74.2) 0.473 LVEF (%) 32 (13) 31 (13) 34 (13) 0.003 Confusion at presentation 486 (61.4) 352 (61.8) 134 (60.4) 0.717 Lactate 0.056 < 2 mmol/L 169 (23.8) 128 (24.9) 41 (21) 2–4 mmol/L 213 (30) 162 (31.5) 51 (26.2) > 4 mmol/L 328 (46.2) 225 (43.7) 103 (52.8) Glucose > 191 mg/dL 357 (46.9) 252 (45.8) 105 (49.8) 0,329 eGFR (ml/min/1.73 m2) 0.027 < 30 146 (24.3) 90 (20.9) 56 (32.7) 30–60 271 (45) 205 (47.6) 66 (38.6) > 60 185 (30.7) 136 (31.6) 49 (28.7) CardShock score value 4.7 (1.7) 4.7 (1.7) 4.8 (1.8) 0.501 IABP II score value 2.5 (1.8) 2.5 (1.8) 2.6 (1.8) 0.525 BMI Body mass index, COPD Chronic obstructive pulmonary disease, PAD Peripheral artery disease, MI Myocardial infarction, PCI percutaneous coronary intervention, CABG Coronary artery bypass grafting, ACS Acute Coronary Syndrome, LVEF Left Ventricle Ejection Fraction, eGFR estimated glomerular filtration rate Clinical characteristics according to gender status Clinical management according to gender status Women were significantly older, were less often active The proportion of use of vasoactive drugs was not smokers and had a significantly lower proportion of co- significantly different in both groups, except for a morbidities such as chronic obstructive pulmonary dis- less common utilisation of dobutamine and a higher ease (COPD) and prior MI (Fig. 1). CS was less often prescription of milrinone in women. Likewise, the related to ACS in women. A slightly better left ventricu- rate of utilisation of in-hospital invasive procedures lar function was observed in this group, as well as lower (renal replacement therapy, invasive ventilation, values of lactate at admission and higher values of eGFR. therapeutic hypothermia) was similar between both No significant differences were observed regading the groups. Mechanical circulatory support was also used CardShock and IABP II risk scores values according to with a similar proportion in men and women gender status. (Table 2). Collado-Lledó et al. BMC Cardiovascular Disorders (2020) 20:189 Page 4 of 8 predicted in-hospital mortality in both groups (AUC in man 0.693, 95% CI 0.647–0.739; women AUC 0.722, 95% CI 0.649–0.795). The predictive ability of both scores was not significantly different according to gender. Calibration was also acceptable for both scores in both groups (supplementary Table 1). Figure 2 shows the ROC curves for the prediction of in-hospital mortality of the Cardshock score in man (2a) and women (2b). Fig- ure 3 shows the ROC curves for the prediction of in- Fig. 1 Baseline clinical characteristics according to gender status hospital mortality of the IABP-II risk score in men (3a) and women (3b). In-hospital mortality and predictive ability of Cardshock Contribution of each components of the Cardshock and and IABP-II risk scores according to gender IABP-II scores to in-hospital mortality according to gender In-hospital mortality for the overall cohort was 346/793 In man, the components of the Cardshock with a stron- (43.6%). Mortality was not significantly different accord- ger association with mortality were confusion at presen- ing to gender (47.3% vs 42.2%, p = 0.194). Mortality was tation, lactate levels and glomerular filtration. Left more commonly due to cardiac causes (76.2%, vs 61.4%) ventricular disfunction was also significantly associated and less commonly due to severe neurologic damage in with mortality, while the association between age > 75 men (4.8% vs 12%, p = 0.027). years and mortality had a non-significant trend. In con- Cardshock risk score showed a good ability for pre- trast, the association between previous MI or coronary dicting in-hospital mortality both in man (AUC 0.69, artery bypass surgery and ACS etiology with mortality 95% CI 0.6547–0.739) and women (AUC 0.735, 95% CI was clearly not significant (supplementary Table 2). In 0.663–0.806). Likewise, the IABP-II successfully contrast, in women only lactate levels and glomerular Table 2 Clinical management according to gender status Whole cohort (n = 793) Male (n = 571) Female (n = 222) P value Vasoactive drugs Dobutamine 716 (90.3) 530 (92.8) 186 (83.8) 0.001 Dopamine 62 (7.8) 42 (7.4) 20 (9) 0.435 Adrenaline 132 (16.6) 95 (16.6) 37 (16.7) 0.992 Noradrenaline 620 (78.2) 444 (77.8) 176 (79.3) 0.436 Levosimendan 75 (9.5) 59 (10.3) 16 (7.2) 0.177 Milrinone 16 (2) 6 (1.1) 10 (4.5) 0.004 Invasive procedures Renal replacement therapy 150 (19) 105 (18.5) 45 (20.3) 0.558 Invasive mechanical ventilation 489 (61.7) 358 (62.7) 131 (59) 0.617 Non invasive mechanical ventilation 77 (9.7) 53 (9.3) 24 (10.8) 0.597 Therapeutic hypothermia 43 (5.4) 35 (6.1) 8 (3.6) 0.158 Swan-Ganz catheter 273 (34.4) 191 (33.5) 82 (36.9) 0.353 Intraaortic counterpulsation 370 (46.7) 274 (48) 96 (43.2) 0.229 ECMO 67 (8.4) 53 (9.3) 14 (6.3) 0.176 Impella® 30 (3.8) 23 (4) 7 (3.2) 0.562 Levitronix centrimag® 55 (6.9) 40 (7) 15 (6.8) 0.902 Revascularization 0.426 None 334 (42.1) 233 (40.8) 101 (45.5) PCI 433 (54.6) 320 (56) 113 (50.9) Surgical 26 (3.3) 18 (3.2) 8 (3.6) PCI Percutaneous coronary intervention Collado-Lledó et al. BMC Cardiovascular Disorders (2020) 20:189 Page 5 of 8 Fig. 2 ROC curves for the prediction of in-hospital mortality of the Cardshock score in man (a) and women (b) filtration were significantly associated with mortality associated to in-hospital mortality, in women this associ- (supplementary Table 2). ation with mortality was observed only for creatinine Likewise, significant differences were observed regard- and lactate levels (supplementary Table 3). ing the specific contribution of each of the components of the IABP-II score for predicting mortality according Discussion to gender. While in man age, creatinine, lactate levels Main findings from this study are: a) around one of each and TIMI flow grade in culprit lesion were significantly three of these patients with CS from routine clinical Fig. 3 ROC curves for the prediction of in-hospital mortality of the IABP-II risk score in men (a) and women (b) Collado-Lledó et al. BMC Cardiovascular Disorders (2020) 20:189 Page 6 of 8 practice were women; b) female patients with CS were Women from this series were significantly older, but older, and CS was less commonly ACS-related in this the proportion of important comorbidities such as dia- group; c) both clinical management and in-hospital mor- betes, prior stroke or peripheral artery disease was not tality were similar regardless gender status, and d) both significantly different between both groups. Indeed, the the CardShock and IABP-II risk scores depicted a good proportion of comorbidities such as COPD and prior MI ability for predicting mortality in both sexes. was lower in women. Interestingly, the proportion of CS is a severe clinical condition with a very high mor- ACS-related CS was significantly lower in women. tality despite continuous therapeutic advances. Clinical A significant concern exists about the lower adherence evidence regarding the optimal management in these to recommendations in women with cardiovascular complex patients is scarce. The few randomized trials [3, disease, especially in ACS. Likewise, in women with 14, 15] addressing patients with CS showed negative re- acute heart failure intensive medical and interventional sults, and literature is mostly base in heterogeneous ob- therapies are also underutilized [25]. Information about servational studies addressing ACS-related CS [16–21]. management disparities in women with CS is scarce. The proportion of women in these series ranges between Abdel-Qadir et al. [20] assessed a series of 9750 patients 25 and 45%, with mean ages ranging between 65 and 80 with ACS-related CS from the Ontario Myocardial In- years [16–22]. farction Database. The authors described that women This series included one of the youngest populations with CS were less likely to present to revascularization- of CS patients, with a relatively low proportion of capable sites, were less often revascularized and less women as compared to previous data. This could be re- likely to be transferred when they presented to non- lated to the fact that this study included highly selected revascularization sites. patients from high complexity centers, with consolidated Improving this gender related disparities is one of the heart transplantation and advanced heart failure pro- major challenges for the upcoming years. In this sense, grams in most cases. Importantly, almost 40% of patients the implementation of standardized ST segment eleva- had non-ACS related CS, in contrast to most published tion myocardial infarction (STEMI) protocol and CS series [16–22]. Systems has been associated to a reduction of health Women with cardiovascular disease have been clearly care differences and mortality in women with ACS [26]. under represented in clinical trials, and the evidence re- On the other hand, management at high volume special- garding their optimal clinical management in different ized centers has been associated to a better adherence to clinical scenarios is scarce, especially in patients with recommendations and lower mortality in patients with ACS. Most data come from observational studies show- CS [27]. In an interesting study, Iantorno et al. [21] ing that women are usually older, have a high degree of assessed a series of 8845 consecutive adult patients ad- comorbidities, a lower adherence to current recommen- mitted to a tertiary coronary care unit, of whom 42.1% dations and a higher mortality [10, 11]. Information were women. A similar pulmonary artery catheter (PAC) about differences in clinical characteristics, management use according to gender was observed (11.3% in women and outcomes according to gender in CS patients is and 11.5% in men). In CS patients, PAC use rates in scarce. Most of the few series show that women with CS women and men were also similar (50.3% vs 49.1%) The are usually older [1, 16–22]. However, differences re- authors concluded that full-time intensivist staffing garding the proportion of comorbidities between men might contribute to reduce gender-based treatment and women are not so evident as compared to patients disparities. with ACS. This is especially remarkable in series of pa- As stated before, management disparities seem to be tients undergoing advanced therapies at high complexity lower in highly selected patients requiring advanced sup- centers, probably because of a likely selection bias. port measures. Joseph et al. [18] described a series of In an interesting contribution, Hayıroğlu et al. [23] 180 patients from the cVAD Registry who underwent assessed predictors of in-hospital mortality in 319 pa- percutaneous coronary intervention (PCI) and Impella tients with MI complicated with CS. Despite a trend to a 2.5 support for CS complicating an acute MI, of whom higher proportion of women was observed among non- 49 (27.2%) were women. Despite women were older, the survivors, gender showed no significant association with proportion of important comorbidities such as diabetes, mortality in the multivariate analysis. Likewise, in a prior MI, PAD or renal dysfunction was not significantly series of 544 patients with STEMI with CS undergoing different according to gender. No differences in timing primary PCI, Cheng et al. [24] described a significant as- to intervention were found between men and women. sociation between female gender and mortality in uni- The number of inotropes and the proportion of mechan- variable analysis. However, only age, baseline lactate ical ventilation and intraaortic counterpulsation were creatinine levels remained independent predictors of 30- not significantly different in both groups. There was no day mortality in the multivariable analysis. difference in survival to discharge (p = 0.3). Interestingly, Collado-Lledó et al. BMC Cardiovascular Disorders (2020) 20:189 Page 7 of 8 the magnitude of the survival benefit was significantly stratification of patients with CS according to gender. greater in women who received the Impella pre-PCI as Improving clinical outcomes of these complex patients compared to men. may lead to potential important social and economic Consistently with these data, we did not observe in consequences. our patients significant differences regarding vasoactive drugs prescription and use of in-hospital invasive proce- Conclusions dures according to gender. In our opinion, this might be About one of each three of these patients with CS from mostly related to the high degree of selection of CS pa- routine clinical practice were women. Female patients tients from this series (especially women with CS), as with CS were older, and CS was less commonly ACS- well as the fact of being treated at high complexity aca- related in this group. No significant differences were ob- demic hospitals. This similar management patterns ac- served regarding management and in-hospital mortality cording to gender might have contributed to the similar according to gender. Both the CardShock and IABP-II mortality observed in both groups. risk scores depicted a good ability for predicting mortal- Patients with stablished shock criteria and high lactate ity also in women with CS. levels have a significantly higher mortality. Therefore, early risk stratification is crucial step in order to select Supplementary information the optimal clinical management. Recently two risk Supplementary information accompanies this paper at https://doi.org/10. scores have been published to predict short-term mor- 1186/s12872-020-01467-4. tality in patients with CS: the CardShock risk score [1], Additional file 1: Table S1. Predictive contribution to in-hospital mor- derived from a multicentre cohort of ACS and non-ACS tality of each of the components of the CardShock score according to patients, and the IABP-SHOCK II risk score [5], derived gender status Table S2. Predictive contribution to in-hospital mortality from a clinical trial performed in acute MI patients of each of the components of the IABP-II score according to gender sta- tus Table S3. Discrimination and calibration of the CardShock and IABP II undergoing percutaneous coronary intervention (PCI). scores for predicting in-hospital mortality according to gender status. Both scores have shown good discrimination for short- term mortality. It is important to note that gender is not Abbreviations a component in either CardShock or IABP-SHOCK risk CS: Cardiogenic shock; MI: Myocardial infarction; ACS: Acute coronary scores. To our knowledge no study addressed the poten- syndromes; TIMI flow: Thrombolysis in myocardial infarction; ROC curves: Receiver operating characteristic; AUC: Area under the curve; tial disparities of risk stratification according to gender eGFR: Estimated glomerular filtration; COPD: Chronic obstructive pulmonary in patients with CS. This is an interesting point, since disease; STEMI: ST segment elevation myocardial infarction; PAC: Pulmonary women were under represented in the populations form artery catheter; PCI: Percutaneous coronary intervention whom both scores were derived. Data from this study Acknowledgements showed a good ability for predicting in-hospital mortality We thank CERCA Programme / Generalitat de Catalunya for institutional from both scores in both women and men. Therefore, support. both the Cardshock and the IABP-II scores should be Authors’ contributions considered useful tools also in women with CS. IL, MPRL, VGF, FJN and FJHP researched data. ECL and AAS wrote the Other predictive factors have been described in pa- manuscript and researched data. OA reviewed/edited the manuscript. AS, tients with CS. Information for the coronary anatomy RML, AVT and JS contributed to the discussion and reviewed/edited the manuscript. All authors have read and approved the manuscript. can also contribute to predict outcomes in CS pa- tients. In this sense, recently a combination of clinical Funding and angiographic factors by the SYNTAX score II None. showed also a significant predictive ability for predict- Availability of data and materials ing mortality in STEMI patients with CS undergoing The datasets used and/or analyzed during the current study are available primary PCI [28]. from the corresponding author on reasonable request. This study has some limitations, such as its moderate sample size and its observational nature, so we cannot Ethics approval and consent to participate This study was approved by the reference institutional ethics comittee. Since rule the effect of unmeasured confounding. Patients this was a retrospective observational registry, written informed consent was were mostly admitted to high complexity hospitals with not available in most patients and was not required for being included in heart transplantation and advanced heart failure pro- this registry. Information of patients was protected according to national normative, and no other administratve permissions were considered. grams, which may lead to a significant selection bias. Therefore, our findings should be validated in larger Consent for publication series of non-selected CS patients admitted to other type not applicable. of centers. 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