Article Text

Original research
Analysis of sex differences in the clinical presentation, management and prognosis of infective endocarditis in Spain
  1. Laura Varela Barca1,
  2. Laura Vidal-Bonnet2,
  3. MC Fariñas3,
  4. Patricia Muñoz4,5,
  5. Maricela Valerio Minero4,
  6. Arístides de Alarcón6,
  7. Encarnacion Gutiérrez Carretero7,
  8. Manuel Gutiérrez Cuadra3,
  9. Asuncion Moreno Camacho8,
  10. Xabier Kortajarena Urkola9,
  11. Josune Goikoetxea Agirre10,
  12. Guillermo Ojeda Burgos11,
  13. Luis Eduardo López-Cortés12,
  14. JC Porres Azpiroz13,
  15. Jose Lopez-Menendez14
  16. GAMES Investigators
    1. 1 Cardiac Surgery, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain
    2. 2 Servicio de Cirugía Cardiaca, Hospital Universitari Son Espases, Palma de Mallorca, Illes Balears, Spain
    3. 3 Servicio de Enfermedades Infecciosas, Marques de Valdecilla Foundation, Santander, Cantabria, Spain
    4. 4 Servicio de Microbiología Clínica y Enfermedades Infecciosas, Gregorio Maranon General University Hospital Cardiology Service, Madrid, Spain
    5. 5 CIBER Enfermedades Respiratorias-CIBERES (CB06/06/0058), Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
    6. 6 Servicio de Enfermedades Infecciosas, Virgen del Rocio University Hospital, Sevilla, Spain
    7. 7 Cardiac Surgery, Virgen del Rocio University Hospital, Sevilla, Spain
    8. 8 Servicio de Enfermedades Infecciosas, Clinic Barcelona Hospital University, Barcelona, Spain
    9. 9 Servicio de Enfermedades Infecciosas, Donostia Ospitalea, San Sebastian, Spain
    10. 10 Servicio de Enfermedades Infecciosas, Cruces University Hospital, Barakaldo, País Vasco, Spain
    11. 11 Unidad de Gestión Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, University Hospital Virgen de la Victoria, Malaga, Spain
    12. 12 Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Complejo Hospitalario Virgen de la Macarena, Sevilla, Spain
    13. 13 Servicio de Cardiología, Miguel Servet University Hospital, Zaragoza, Spain
    14. 14 Cardiac Surgery, Hospital Universitario Ramon y Cajal, Madrid, Spain
    1. Correspondence to Dr Laura Varela Barca, Cardiac surgery, Hospital Universitario Fundacion Jimenez Diaz, 28034 Madrid, Spain; lauravarela21089{at}gmail.com

    Abstract

    Introduction Sex-dependent differences of infective endocarditis (IE) have been reported. Women suffer from IE less frequently than men and tend to present more severe manifestations. Our objective was to analyse the sex-based differences of IE in the clinical presentation, treatment, and prognosis.

    Material and methods We analysed the sex differences in the clinical presentation, modality of treatment and prognosis of IE in a national-level multicentric cohort between 2008 and 2018. All data were prospectively recorded by the GAMES cohort (Spanish Collaboration on Endocarditis).

    Results A total of 3451 patients were included, of whom 1105 were women (32.0%). Women were older than men (mean age, 68.4 vs 64.5). The most frequently affected valves were the aortic valve in men (50.6%) and mitral valve in women (48.7%). Staphylococcus aureus aetiology was more frequent in women (30.1% vs 23.1%; p<0.001).

    Surgery was performed in 38.3% of women and 50% of men. After propensity score (PS) matching for age and estimated surgical risk (European System for Cardiac Operative Risk Evaluation II (EuroSCORE II)), the analysis of the matched cohorts revealed that women were less likely to undergo surgery (OR 0.74; 95% CI 0.59 to 0.91; p=0.05).

    The observed overall in-hospital mortality was 32.8% in women and 25.7% in men (OR for the mortality of female sex 1.41; 95% CI 1.21 to 1.65; p<0.001). This statistical difference was not modified after adjusting for all possible confounders.

    Conclusions Female sex was an independent factor related to mortality after adjusting for confounders. In addition, women were less frequently referred for surgical treatment.

    • heart valve prosthesis implantation
    • endocarditis
    • risk factors

    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. The study included all consecutive patients included in the GAMES registry, maintained by 27 Spanish tertiary hospitals.

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    Introduction

    Sex-dependent differences in cardiovascular diseases have been previously recognised.1 There are several differences in clinical characteristics, treatment strategies, comorbidities and outcomes among men and women.2

    In the case of infective endocarditis (IE), these differences are also evident, and sex differences have been previously described.3 Although women suffer from IE less frequently than men, they tend to have more severe manifestations and are more prone to have worse outcomes.3–5 The location of IE was described to be different between sexes, probably because of the differences in predisposing lesions.6 In addition, in cases of sepsis7 and shock, sex differences have been demonstrated. Surgical outcomes have also been described to be worse in women after cardiac surgery,8 9 and female sex is generally considered an independent mortality risk factor after heart surgery.10

    Nevertheless, there is no clear understanding of the impact of sex on the prognosis of medically treated IE, surgical referral or surgical outcomes. Contradictory observations have been previously published, as some studies found a clear impact of sex on surgical outcome,11 12 whereas these sex differences were described as not being related to prognosis in others.13–15 Consequently, there is no clear understanding of the impact of these sex differences.

    We conducted an analysis of the sex differences in a large, national-level multicentric cohort of patients affected of IE (‘Spanish Collaboration on Endocarditis’ or GAMES cohort).

    The objectives of the present study were as follows: (1) describe the sex-related differences in the presentation of IE; (2) analyse the modality of treatment and surgical referral in men and women and (3) analyse the prognosis of IE between sexes through analysis of the differences in in-hospital mortality.

    Materials and methods

    Patients

    This was an observational, multicentric, prospective study based on a nationwide registry (GAMES registry) that included all consecutive patients with a diagnosis of definite IE according to the modified Duke criteria.16 17 A total of 3451 patients were included between January 2008 and December 2018. Patients with IE related to cardiac device infection without valvular involvement were excluded from the study because of the marked differences in the clinical approach. Patients with and without surgical treatment were included in this study.

    The local multidisciplinary teams completed standardised case report forms in each case regarding the active IE episode and follow-up data, which included clinical, microbiological and echocardiographic sections.

    All patients provided informed consent to be included in the registry.

    Definitions

    • GAMES stands for ‘Grupo de Apoyo al Manejo de la Endocarditis Infecciosa en España’ or ‘Spanish Collaboration on Endocarditis’. The GAMES prospectively enrolled patients in a nationwide registry in 32 tertiary hospitals across Spain. The characteristics of the GAMES cohort and its definitions are described elsewhere.18

    • Active IE was defined as endocarditis with at least one of the following: positive blood cultures, fever, leucocytosis, raised inflammation markers, or current antibiotic treatment.18

    • Hospital mortality was defined as death, regardless of the cause that occurred during hospital admission.

    • Renal insufficiency during the IE episode was defined as creatinine levels over 1.4 mg/dL or the exacerbation of baseline creatinine clearance by at least 25%.

    • Paravalvular abscess was considered an infection and necrosis with the formation of a purulent cavity.19

    • Shock was defined as septic or cardiogenic shock.

    • Previous cardiac surgery: previous surgical procedure with opening of the pericardium.

    • Functional class ≥III according to the New York Heart Association (NYHA) classification.

    • Prosthetic valve IE: IE affecting a previous prosthetic valve.

    • Surgical indication: every case of IE was discussed by the local expert panel, and recommendations for surgical treatment were evaluated by a multidisciplinary team at each centre. Indications were classified according to clinical guidelines17 into four groups: heart failure, uncontrolled infection (including locally uncontrolled infection, multiresistant organisms, etc), prevention of embolism and other causes. The final recommendation of the panel was recorded in the registry.

    Statistical analysis

    Statistical analysis was performed using Stata/IC V.14.2 (Stata Statistical Software: Release 14; StataCorp, College Station, Texas, USA). The statistical analysis conducted to answer the study questions was divided into three categories.

    To assess the sex-related differences in the presentation of IE

    Continuous variables are expressed as mean and SD if normally distributed or as median and IQR in the presence of marked asymmetries. Categorical variables are expressed as frequencies and proportions. Student’s t-test was used to compare continuous variables, and the Fisher’s exact test was used to compare proportions. Statistical significance was set at p<0.05.

    To analyse the modality of treatment and surgical referral in men and women

    The cohort was subdivided according to local expert panel recommendations for surgical treatment into three groups (figure 1): patients without surgical recommendation who finally did not undergo surgery (group 1), patients who underwent surgical treatment (group 2a) and patients who did not undergo surgical treatment (group 2b).

    Figure 1

    Stratification of the GAMES cohort according to surgical recommendation between sexes. Overall and stratified mortality is displayed in each group.

    In addition, we evaluated whether there were any sex-based differences in surgical referral after expert panel recommendations to proceed with surgery. We conducted a propensity score (PS) matching between males and females, considering the age and surgical risk (EuroSCORE II) as the independent variables for PS calculation, as the main reason for not proceeding with surgery usually is based on very old age, poor clinical condition, neurological involvement or kidney dysfunction. All these variables are reflected in the EuroSCORE II calculations. PS matching analysis was conducted using the STATA user-written command PSMATCH2 (Edwin Leuven, University of Oslo). The matching was performed using the nearest neighbour methodology without replacement, and the probability of undergoing surgery in patients with surgical recommendation by the expert panel consensus was analysed in the matched cohorts in men and women. After the development of PS score, the matched cohorts were analysed using paired analysis through conditional logistic regression, and the results were expressed as ORs, with their 95% CIs.

    To analyse the prognosis of IE between sexes

    The impact of sex on in-hospital mortality was analysed using logistic regression and expressed as ORs with their 95% CIs. Possible confounders, by definition,20 were considered as all those variables with a significant association with the primary outcome, which were also unevenly distributed between sex strata and were not an intermediate step between sex and mortality. All scientifically plausible variables that were recorded in the registry were evaluated as possible confounders, and those identified, especially those previously described as related to in-hospital mortality in IE, were analysed. The variables were considered as definite confounders if the adjusted logistic regression with the possible confounder as an independent term produced a variation in the OR of sex on the main event larger than 10%. Moreover, all possible models (derived from the maximal model with all possible confounders included) were analysed using the STATA user-written command ‘confound’ (V.1.1.7, Bellaterra: Universitat Autònoma de Barcelona, 2020) to estimate the possible confounding effects of the selected variables.

    Results

    A total of 3451 patients were included in the GAMES national cohort between 2008 and 2018. The mean age of the entire cohort was 65.7 (SD 14.6) years. The involved valves were a native valve in 67.9% and prosthetic valve in the remaining 32.9%. The cohort included a total of 2346 men (68%) and 1105 (32%) women.

    Sex-related differences in the presentation of IE

    We observed differences in baseline characteristics and clinical presentation of IE between sexes (table 1).

    Table 1

    Patient characteristics by gender

    Women were older and had a higher proportion of hypertension (HT) and previous valve diseases, whereas men had more chronic obstructive pulmonary disease (COPD), peripheral arteriopathy, liver disease, renal failure, ventricular dysfunction and conduction disturbances.

    Regarding IE location, it is important to note that the most affected valves were the aortic valve in men (50.6% vs 32.4% in women) and mitral valve in women (48.7% vs 29.5% in men).

    Sex-related differences in the modality of treatment

    We divided the cohort according to surgical recommendations, as suggested by the local GAMES expert consensus (figure 1).

    • Group 1: 904 patients without surgical recommendation who finally did not undergo surgery.

    • Group 2: 2574 patients with surgical recommendation, divided into the following:

      • Group 2a: patients who underwent surgical treatment (1598, 62%);

      • Group 2b: patients who did not undergo surgical treatment (949, 37%).

    A total of 1598 patients underwent surgical treatment, which represented 62% of the patients who had a recommendation for surgery by the local expert panel and 43% of the total sample. In the overall cohort, surgical treatment was performed in 38.3% of women and 50% of men.

    Baseline characteristics, clinical presentation and location were different among the three groups of treatment as expected regarding the different clinical profiles and prognoses (table 2). The indications for surgery were classified into four groups: 1272 patients had indication for cardiac surgery because of heart failure (49.9%), 852 because of uncontrolled infection (33.5%), 176 for prevention of embolism (6.9%) and 95 because of other non-codified causes (3.7%).

    Table 2

    Patient characteristics by groups of treatment

    Despite the fact that the recommendation of the local GAMES expert panel was surgical treatment, only 68.7% of the women with surgical recommendation actually did undergo surgery compared with 74.3% of men.

    In patients with recommendations to proceed with surgery according to the GAMES expert panel, women were less likely to be finally accepted for surgery (OR for not proceeding with surgery despite recommendation 1.59; 95% CI 1.34 to 1.89; p<0.001). Characteristics of patients who did not undergo surgery and patients who underwent surgery are shown in table 3 and table 4.

    Table 3

    Characteristics of patients who underwent surgery by gender

    Table 4

    Characteristics of patients who did not undergo surgery by gender

    PS matching was conducted to analyse differences in the final performance of surgical treatment between men and women. After matching, 1398 patients with the recommendation of surgical treatment were divided by sex into two cohorts of 714 patients, matched by age and estimated surgical risk by EuroSCORE II. The differences in age and surgical risk were effectively neutralised after matching: mean age (67.73% vs 67.74%; p=0.98) and EuroSCORE II (13.0% vs 12.1%; p=0.43). In the analysis of the matched cohorts, women were less likely to undergo surgery than men (OR for not proceeding with surgery 1.35; 95% CI 1.09 to 1.69; p=0.05).

    Prognosis of IE between sexes

    The observed in-hospital mortality was 27.9%, with remarkable differences between sexes: mortality was 32.8% in women and 25.7% in men (OR for the mortality of female sex 1.41; 95% CI 1.21 to 1.65; p<0.001).

    Analysis of the impact of sex corrected for possible confounders through a multivariate logistic regression was conducted. We identified 10 variables that fulfilled the definition as possible confounders of the effect of sex on mortality: age, COPD, HT, diabetes mellitus (DM), ventricular dysfunction, renal failure, S. aureus as causal agent, conduction disorders, peripheral arteriopathy and surgical treatment. The only variable that produced a variation larger than 10% in the adjusted OR was age, but the age-adjusted OR remained statistically significant (age-adjusted OR for the mortality of female sex 1.25; 95% CI 1.07 to 1.47; p<0.01). No differences were found in the OR after adjusting for all the previously mentioned factors. The change in the adjusted OR of the maximal model was <0.06%.

    Sex differences in mortality were also observed when the affected valves were considered. Mortality was significantly higher in women with aortic valve IE (33.1% vs 25.1%; p<0.001) and mitral valve IE (35.2% vs 25.4%; p<0.001). Moreover, mortality was higher in women with native valve IE (30.4% vs 24.0%; p<0.001) and prosthetic valve IE (37.4% vs 29.3%; p<0.001).

    See online supplemental file 1 for the graphical abstract.

    Supplemental material

    Discussion

    The main findings of our study are as follows: (1) there were sex-related differences in the clinical presentation and location of IE, as women were older and had a higher proportion of mitral valve IE; (2) in cases where surgical treatment was recommended by multidisciplinary team evaluation, women were less likely to undergo surgery; (3) differences in in-hospital mortality showed a worse prognosis for active IE in women than in men.

    Regarding the clinical presentation, the protective role of oestrogens against endothelial damage has been proven through animal experiments.21 22 Hormonal differences protect young women from cardiovascular disease; therefore, women tend to develop heart disease later in life. This was confirmed in our analysis, as we found a significant difference in the age of presentation of the IE episode between sexes: the mean ages of women and men were 68.4 (SD 14.9) and 64.5 (SD 14.4) years, respectively. In addition, as reported in previously published studies,3–5 we found a ratio between men and women of 2.12 to 1, despite the fact that in Spain, females represent 51% of the overall population (data from the National Statistics Institutea; www.ine.es).

    There were several differences in the clinical presentations of IE in our study. The most affected valve in men was the aortic valve, whereas women presented a mitral valve affectation in 48.7% of the cases. This finding agrees with previously published results, since IE location was described to be different between sexes because of the differences in the predisposing lesions.6

    We also confirmed that the prognosis of IE episodes varies between sexes.

    Some previously published studies reported that the higher mortality rate in women than in men to be associated with worse baseline characteristics in women.5 6 We also found differences in preoperative characteristics, however, we found that the increased in-hospital mortality of women was independent of these clinical characteristics, as the estimated OR for the mortality of female sex was 1.41 (95% CI 1.21 to 1.65; p<0.001) after adjustment for possible confounders.

    Finally, we analysed the sex-based differences when surgical treatment was recommended. Although female sex is considered a risk factor in the majority of cardiac surgery scores, it is only present in half of the IE-specific scores.23 Women who underwent surgery tend to be older and have a higher incidence of DM and renal failure, which may alter surgical outcomes.24 25

    One interesting finding of our analysis is that women were less likely to undergo surgery than men (OR for proceeding with surgery 0.74; 95% CI 0.59 to 0.91; p=0.05), despite the adjustment for age and estimated surgical risk. Although previously published studies described the worse prognosis in women to be related to a lower proportion of surgical treatment,3 26 our results showed that women were less likely to be finally accepted for surgery6 26 27 after a PS-matching analysis. We do not have a clear understanding of this finding, but surgical teams are less prone to proceed with surgery in females, which could be produced by a higher perceived risk of female patients by the surgical team (more mitral involvement, advanced age), although this perceived increased risk is not adequately reflected by the traditional risk estimation scores. We previously published a meta-analysis of the prognostic factors of IE and found that sex was an independent predictor of worse surgical outcomes in IE, with a pooled OR of 1.56.4 Therefore, we strongly recommend the use of specific IE risk scores in the preoperative evaluation to help guide clinicians involved in the multidisciplinary evaluation. Nevertheless, despite the increased surgical risk of female patients, mortality of the patients who did not undergo surgery when it was recommended by the multidisciplinary team was the highest of all analysed groups. Female patients should be carefully evaluated when surgical treatment is recommended, and despite their increased surgical risk, the denial of surgical treatment may imply a dismal prognosis.

    Study limitations

    Some limitations may have affected our study. On the one hand, selection bias could not be discarded, as most of the institutions participating in the GAMES registry are tertiary university hospitals that receive critically ill patients referred from other smaller centres, which could explain the high mortality rate. Regarding missing data, the estimated percentage of that in the GAMES cohort is considered to be <1%. We did not know how many patients did not present surgical indications on admission and developed surgical indications during hospitalisation. Regarding surgical recommendations, although surgical indications were established according to guidelines,17 those were made by a local multidisciplinary team at each centre, with the subsequent possible heterogeneity.

    Observational studies are an accepted way to establish relations between variables, despite the fact that this type of study could not confirm causality. The observed differences between sexes in our study may have been caused by other variables; therefore, confounders were also analysed. Nevertheless, sex-based differences persisted after this further analysis; therefore, there is a highly plausible association between sex and the observed differences, but the influence of other variables that were not recorded in the registry could not be ruled out.

    Another limitation was the heterogeneity between the centres and patients. Although the heterogeneity between centres was sufficient to have a significant influence on our results, some of the groups presented several biases because of heterogeneity. This is the case for group 2b in the modality of treatment analysis, which presented significant differences in terms of setting surgical indication.

    Another limitation was that the main reason for precluding surgery in a patient with surgical indication was not recorded in the GAMES database. Nevertheless, it is usually caused by a prohibitive surgical risk, despite indications by the surgical team.

    Nonetheless, regarding our results, there is evidence of sex-dependent differences in IE that affect the outcomes, causing a worse expected prognosis, which could be partially explained because women received less surgical treatment despite indication.

    Conclusions

    Female patients showed marked differences in the clinical presentation of IE compared with male patients. We observed sex differences in mortality that could not be completely explained by the differences in clinical presentation, as female sex was an independent factor related to mortality after adjustment for confounders.

    In addition, women were referred less to surgical treatment despite expert panel recommendation.

    Key messages

    What is already known on this subject?

    • Women suffer from infective endocarditis (IE) less frequently than men.

    • Women tend to have more severe manifestations and are more likely to have worse outcomes.

    • The observed differences in the postoperative outcomes between women and men who undergo cardiac surgery have been reported to be confounded by marked differences in comorbidities.

    What might this study add?

    • Female patients showed marked differences in the clinical presentation of IE compared with male patients.

    • Women were older, and the most affected valves were the aortic valve in men and mitral valve in women.

    • Female sex was an independent factor related to in-hospital mortality after adjusting for confounders.

    • Women were less referred to surgical treatment despite expert panel recommendation.

    How might this impact on clinical practice?

    • We observed differences in terms of clinical presentation, outcomes and prognosis between sexes, which should be taken into consideration in clinical practice.

    • Risk estimation in women should be performed carefully.

    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. The study included all consecutive patients included in the GAMES registry, maintained by 27 Spanish tertiary hospitals.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The study was approved by the regional and local ethics committees of the participating hospitals.

    Acknowledgments

    We would like to thank Editage (www.editage.com) for English language editing.

    References

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Collaborators Members of GAMES: Hospital Costa del Sol, (Marbella): Fernando Fernández Sánchez, Mariam Noureddine, Gabriel Rosas, Javier de la Torre Lima Hospital Universitario de Cruces, (Bilbao): Elena Bereciartua, Roberto Blanco, María Victoria Boado, Marta Campaña Lázaro, Alejandro Crespo, Laura Guio Carrión, Mikel Del Álamo Martínez de Lagos, Gorane Euba Ugarte, Josune Goikoetxea, Marta Ibarrola Hierro, José Ramón Iruretagoyena, Josu Irurzun Zuazabal, Leire López-Soria, Miguel Montejo, Javier Nieto, David Rodrigo, Regino Rodríguez, Yolanda Vitoria, Roberto Voces. Hospital Universitario Virgen de la Victoria, (Málaga): Ma Victoria García López, Radka Ivanova Georgieva, Guillermo Ojeda, Isabel Rodríguez Bailón, Josefa Ruiz Morales. Hospital Universitario Donostia-Poliklínica Gipuzkoa-IIS Biodonostia, (San Sebastián): Harkaitz Azkune Galparsoro, Elisa Berritu Boronat, Ma Jesús Bustinduy Odriozola, Cristina del Bosque Martín, Tomás Echeverría, Alberto Eizaguirre Yarza, Ana Fuentes, Miguel Ángel Goenaga, Muskilda Goyeneche del Río, Ángela Granda Bauza, José Antonio Iribarren, Xabier Kortajarena Urkola, José Ignacio Pérez-Moreiras López, Ainhoa Rengel Jiménez, Karlos Reviejo, Alberto Sáez Berbejillo, Elou Sánchez Haza, Rosa Sebastián Alda, Itziar Solla Ruiz, Irati Unamuno Ugartemendia, Diego Vicente Anza, Iñaki Villanueva Benito, Mar Zabalo Arrieta. Hospital General Universitario de Alicante, (Alicante): Rafael Carrasco, Vicente Climent, Patricio Llamas, Esperanza Merino, Joaquín Plazas, Sergio Reus Complejo Hospitalario Universitario A Coruña, (A Coruña): Nemesio Álvarez, José María Bravo-Ferrer, Laura Castelo, José Cuenca, Pedro Llinares, Enrique Miguez Rey, María Rodríguez Mayo, Efrén Sánchez, Dolores Sousa Regueiro. Complejo Hospitalario Universitario de Huelva, (Huelva): Francisco Javier Martínez Hospital Universitario de Canarias, (Canarias): Ma del Mar Alonso, Beatriz Castro, Teresa Delgado Melian, Javier Fernández Sarabia, Dácil García Rosado, Julia González González, Juan Lacalzada, Lissete Lorenzo de la Peña, Alina Pérez Ramírez, Pablo Prada Arrondo, Fermín Rodríguez Moreno. Hospital Regional Universitario de Málaga, (Málaga): Antonio Plata Ciezar, José Ma Reguera Iglesias. Hospital Universitario Central Asturias, (Oviedo): Víctor Asensi Álvarez, Carlos Costas, Jesús de la Hera, Jonnathan Fernández Suárez, Lisardo Iglesias Fraile, Víctor León Arguero, José López Menéndez, Pilar Mencia Bajo, Carlos Morales, Alfonso Moreno Torrico, Carmen Palomo, Begoña Paya Martínez, Ángeles Rodríguez Esteban, Raquel Rodríguez García, Mauricio Telenti Asensio. Hospital Clínic-IDIBAPS, Universidad de Barcelona, (Barcelona): Manuel Almela, Juan Ambrosioni, Manuel Azqueta, Mercè Brunet, Marta Bodro, Ramón Cartañá, Carlos Falces, Guillermina Fita, David Fuster, Cristina García de la Mària, Delia García-Pares, Marta Hernández-Meneses, Jaume Llopis Pérez, Francesc Marco, José M. Miró, Asunción Moreno, David Nicolás, Salvador Ninot, Eduardo Quintana, Carlos Paré, Daniel Pereda, Juan M. Pericás, José L. Pomar, José Ramírez, Irene Rovira, Elena Sandoval, Marta Sitges, Dolors Soy, Adrián Téllez, José M. Tolosana, Bárbara Vidal, Jordi Vila. Hospital General Universitario Gregorio Marañón, (Madrid): Iván Adán, Juan Carlos Alonso, Ana Álvarez-Uría, Javier Bermejo, Emilio Bouza, Gregorio Cuerpo Caballero, Antonia Delgado Montero, Ana García Mansilla, Ma Eugenia García Leoni, Esther Gargallo, Víctor González Ramallo, Martha Kestler Hernández, Amaia Mari Hualde, Marina Machado, Mercedes Marín, Manuel Martínez-Sellés, Patricia Muñoz, María Olmedo, Blanca Pinilla, Ángel Pinto, Cristina Rincón, Hugo Rodríguez-Abella, Marta Rodríguez-Créixems, Antonio Segado, Neera Toledo, Maricela Valerio, Pilar Vázquez, Eduardo Verde Moreno Hospital Universitario La Paz, (Madrid): Isabel Antorrena, Belén Loeches, Mar Moreno, Ulises Ramírez, Verónica Rial Bastón, María Romero, Sandra Rosillo. Hospital Universitario Marqués de Valdecilla, (Santander): Jesús Agüero Balbín, Cristina Amado, Carlos Armiñanzas Castillo, Ana Arnaiz, Francisco Arnaiz de las Revillas, Manuel Cobo Belaustegui, María Carmen Fariñas, Concepción Fariñas-Álvarez, Marta Fernández Sampedro, Iván García, Claudia González Rico, Laura Gutierrez-Fernandez, Manuel Gutiérrez-Cuadra, José Gutiérrez Díez, Marcos Pajarón, José Antonio Parra, Ramón Teira, Jesús Zarauza. Hospital Universitario Puerta de Hierro, (Madrid): Jorge Calderón Parra, Marta Cobo, Fernando Domínguez, Alberto Fortaleza, Pablo García Pavía, Jesús González, Ana Fernández Cruz, Elena Múñez, Antonio Ramos, Isabel Sánchez Romero. Hospital Universitario Ramón y Cajal, (Madrid): Tomasa Centella, José Manuel Hermida, José Luis Moya, Pilar Martín-Dávila, Enrique Navas, Enrique Oliva, Alejandro del Río, Jorge Rodríguez-Roda Stuart, Soledad Ruiz. Hospital Universitario Virgen de las Nieves, (Granada): Carmen Hidalgo Tenorio Hospital Universitario Virgen Macarena, (Sevilla): Manuel Almendro Delia, Omar Araji, José Miguel Barquero, Román Calvo Jambrina, Marina de Cueto, Juan Gálvez Acebal, Irene Méndez, Isabel Morales, Luis Eduardo López-Cortés Hospital Universitario Virgen del Rocío, (Sevilla): Arístides de Alarcón, Emilio García, Juan Luis Haro, José Antonio Lepe, Francisco López, Rafael Luque. Hospital San Pedro, (Logroño): Luis Javier Alonso, Pedro Azcárate, José Manuel Azcona Gutiérrez, José Ramón Blanco, Antonio Cabrera Villegas, Lara García-Álvarez, Concepción García García, José Antonio Oteo. Hospital de la Santa Creu i Sant Pau, (Barcelona): Natividad de Benito, Mercé Gurguí, Cristina Pacho, Roser Pericas, Guillem Pons Complejo Hospitalario Universitario de Santiago de Compostela, (A Coruña): M. Álvarez, A. L. Fernández, Amparo Martínez, A. Prieto, Benito Regueiro, E. Tijeira, Marino Vega. Hospital Santiago Apóstol, (Vitoria): Andrés Canut Blasco, José Cordo Mollar, Juan Carlos Gainzarain Arana, Oscar García Uriarte, Alejandro Martín López, Zuriñe Ortiz de Zárate, José Antonio Urturi Matos. Hospital SAS Línea de la Concepción, (Cádiz): Sánchez-Porto Antonio, Úbeda Iglesias Alejandro. Hospital Clínico Universitario Virgen de la Arrixaca (Murcia): José Ma Arribas Leal, Elisa García Vázquez, Alicia Hernández Torres, Ana Blázquez, Gonzalo de la Morena Valenzuela. Hospital de Txagorritxu, (Vitoria): Ángel Alonso, Javier Aramburu, Felicitas Elena Calvo, Anai Moreno Rodríguez, Paola Tarabini-Castellani. Hospital Virgen de la Salud, (Toledo): Eva Heredero Gálvez, Carolina Maicas Bellido, José Largo Pau, Ma Antonia Sepúlveda, Pilar Toledano Sierra, Sadaf Zafar Iqbal-Mirza. Hospital Rafael Méndez, (Lorca-Murcia):, Eva Cascales Alcolea, Ivan Keituqwa Yañez, Julián Navarro Martínez, Ana Peláez Ballesta. Hospital Universitario San Cecilio (Granada): Eduardo Moreno Escobar, Alejandro Peña Monje, Valme Sánchez Cabrera, David Vinuesa García. Hospital Son Llátzer (Palma de Mallorca): María Arrizabalaga Asenjo, Carmen Cifuentes Luna, Juana Núñez Morcillo, Ma Cruz Pérez Seco, Aroa Villoslada Gelabert Hospital Universitario Miguel Servet (Zaragoza): Carmen Aured Guallar, Nuria Fernández Abad, Pilar García Mangas, Marta Matamala Adell, Ma Pilar Palacián Ruiz, Juan Carlos Porres. Hospital General Universitario Santa Lucía (Cartagena): Begoña Alcaraz Vidal, Nazaret Cobos Trigueros, María Jesús Del Amor Espín, José Antonio Giner Caro, Roberto Jiménez Sánchez, Amaya Jimeno Almazán, Alejandro Ortín Freire, Monserrat Viqueira González. Hospital Universitario Son Espases (Palma de Mallorca): Pere Pericás Ramis, Ma Ángels Ribas Blanco, Enrique Ruiz de Gopegui Bordes, Laura Vidal Bonet Complejo Hospitalario Universitario de Albacete (Albacete): Ma Carmen Bellón Munera, Elena Escribano Garaizabal, Antonia Tercero Martínez, Juan Carlos Segura Luque Hospital Universitario Terrassa: Cristina Badía, Lucía Boix Palop, Mariona Xercavins, Sónia Ibars. Hospital Universitario Dr. Negrín (Gran Canaria): Eloy Gómez Nebreda, Ibalia Horcajada Herrera, Irene Menduiña Gallego. Complejo Hospitalario Universitario Insular Materno Infantil (Las Palmas de Gran Canaria): Héctor Marrero Santiago, Isabel de Miguel Martínez, Elena Pisos Álamo. Hospital Universitario 12 de Octubre (Madrid): Eva Ma Aguilar Blanco, Mercedes Catalán González, María Angélica Corres Peiretti, Andrea Eixerés Esteve, Laura Domínguez Pérez, Santiago de Cossío Tejido, Francisco Galván Román, José Antonio García Robles, Francisco López Medrano, Ma Jesús López Gude, Ma Ángeles Orellana Miguel, Patrick Pilkington, Yolanda Revilla Ostalaza, Juan Ruiz Morales, Sebastián Ruiz Solís, Ana Sabín Collado, Marcos Sánchez Fernández, Javier Solera Rallo, Jorge Solís Martín. Hospital Universitari Bellvitge (Barcelona): Carmen Ardanuy, Guillermo Cuervo Requena, Sara Grillo, Alejandro Ruiz Majoral. Hospital Universitario Fundación Jiménez Díaz (Madrid): Beatriz Álvarez, Alfonso Cabello Úbeda, Ricardo Fernández Roblas, Miguel Ángel Navas Lobato, Ana María Pello.

    • Contributors All authors listed have contributed sufficiently to the project in order to be included as authors. This work has been accepted by the GAMES group.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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