Early surgery for acute-onset infective endocarditis

Early surgery for acute-onset infective endocarditis Abstract OBJECTIVES: Acute onset of infective endocarditis has been previously linked to the development of septic shock and a worse prognosis. The purpose of this study was to analyse the clinical features and in-hospital evolution of patients with acute-onset endocarditis as well as the potential role of early surgery in the treatment of these patients. METHODS: From 1996 to 2014, 1053 consecutive patients with left-sided endocarditis were prospectively included. Patients were classified into 2 groups according to the clinical presentation: patients with acute-onset endocarditis (n = 491) and patients with non-acute endocarditis (n = 562). Acute-onset endocarditis was considered when the time between the appearance of symptoms and diagnosis was <15 days. RESULTS: At admission, acute renal failure, septic shock and cerebral embolism predominated among patients with acute-onset endocarditis. Staphylococcus aureus was more frequently isolated in patients with an acute onset (27.7% vs 7.8% P < 0.001). During hospitalization, patients with acute onset developed systemic embolism and septic shock more frequently. Death was much more common in this group (42.7 vs 30.1%, P < 0.001). Paravalvular complications, nosocomial infection, heart failure, S. aureus and septic shock were predictors of mortality. Acute-onset presentation of endocarditis was strongly associated with increased mortality. Among patients with acute-onset endocarditis, early surgery, performed within the first 2 days after diagnosis, was associated with a 64% of reduction in mortality. CONCLUSIONS: Patients with endocarditis and acute onset of symptoms are at high risk of septic in-hospital complications and mortality. Early surgery, performed within the first 2 days after diagnosis, plays a central role in the treatment of these patients. Endocarditis, Cardiac surgery, Prognosis INTRODUCTION Infective endocarditis (IE) is a serious disease associated with high mortality. Over the last years, surgical techniques and antibiotic therapies have improved significantly. Despite these advancements, IE-related mortality remains unacceptably high [1, 2]. The identification of prognostic markers of increased mortality, which deserve more intensive care or early surgery, is of paramount importance. Although surgical intervention is recommended in the current guidelines with the presence of heart failure, embolic events or septic complications, the timing of surgery is still an unresolved issue [3–6]. Acute onset of IE has been previously linked to the development of septic shock and a worse prognosis [7–9]. In this context, early surgery might improve the outcomes of patients. However, there are no specific studies focused on the evaluation of the potential role of early surgery in the prognosis of these patients. The purpose of this study was to analyse the clinical and echocardiographic features, microbiological profile, in-hospital evolution and prognosis of those patients with IE and acute onset of the disease. Furthermore, we aimed to assess the potential role of early surgery among these patients. METHODS This study was conducted at 3 tertiary care university hospitals with surgical facilities. All centres used standardized protocols, uniform data collection and identical diagnostic and therapeutic criteria. From 1996 to 2014, data from 1053 consecutive patients with left-sided IE were prospectively recorded on an ongoing multipurpose database. This registry was approved by the local ethical committees, and the study protocol was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Informed consent was obtained for participation in the study. For purposes of analysis and comparison, patients were classified into 2 groups according to the clinical presentation: patients with acute-onset IE (n = 491) and patients with non-acute IE (n = 562). Acute-onset IE was considered when the time between the appearance of symptoms and diagnosis was <15 days [10]. To ensure consecutive enrolment, all patients who underwent an echocardiogram to rule out IE were clinically followed until a final diagnosis was established. Duke criteria were applied until 2002 and modified Duke criteria thereafter [11]. Only definite cases of left-sided IE were included. Right-sided IE episodes were excluded due to their different epidemiology, clinical characteristics and prognosis. Data collection included detailed clinical history, standard physical examination, electrocardiography, chest X-ray, blood analysis, urinalysis, a set of 3 blood cultures at admission, 3 additional blood cultures 48–72 h later and at least one transthoracic and transoesophageal echocardiogram, as previously described [12]. For those patients already hospitalized at the time of infection (nosocomial IE), laboratory parameters were registered on the date of the first positive blood culture. Empiric antibiotic treatment was started after blood cultures were taken, and specific antibiotic therapy was initiated once the results of blood cultures were available. If blood cultures were negative after 72 h, specific serological tests for Chlamydia, Brucella, Coxiella burnetii, Bartonella, Mycoplasma and Legionella species were performed [12]. Definition of terms Nosocomial and community-acquired IE were defined according to the literature [3]. Previous antibiotic treatment was taken into account when it was administered within 15 days before extraction of blood cultures. Under the term of immunosuppression, patients with HIV and those who were on steroids or other immunosuppressive therapy were included. Persistent signs of infection were defined as persistent bacteraemia or fever after 7 days of appropriate antibiotic treatment once other possible foci of infection had been ruled out [8]. Septic shock was defined as the presence of an acute circulatory failure in sepsis, characterized by persistent arterial hypotension (systolic pressure <90 mmHg) despite adequate volume resuscitation [8]. The diagnosis of systemic embolism was based on clinical signs and data derived from imaging procedures. The echocardiographic criteria used for definition and measurement of vegetations, abscesses, pseudoaneurysms and fistulas have been described elsewhere [13]. Surgery was performed when any of the following occurred: heart failure, recurrent embolism with persistent vegetations in the echocardiogram, persistent signs of infection and fungal endocarditis. The initial presence of paravalvular complications in patients with a favourable clinical course was not an indication for surgery although enlargement of pseudoaneurysms and abscesses or progression to fistula were considered indications. When a patient meeting surgical criteria did not undergo surgery, the reason was either because of patient rejection, unacceptably high surgical risk or when the patient was too frail. The surgical indication and timing of operation were individualized for each patient. The decision for surgery was made by a multidisciplinary team, including cardiologists, cardiac surgeons, infectious disease specialists and a microbiologist, following the current guidelines for clinical practice in each case. Statistical analysis Continuous variables are described as mean value and standard deviation or median and interquartile range when appropriate. Levene’s test was used to assess the homogeneity of variances. A 2-tailed Student’s t-test was used to compare quantitative variables. In cases of inhomogeneity of variances, the Mann–Whitney U-test was used. Categorical variables are expressed as frequency and percentage, and they were compared with the χ2 test. Fisher’s exact test was used when at least 25% of the values in the 2 × 2 contingency table showed an absolute frequency of <5. This criterion was prespecified before the statistical analysis was performed. There was no variable with losses that exceeded 15%. A multivariable logistic regression analysis was performed to identify independent predictors of mortality. Variables which were found to be statistically significant in the univariable analysis as well as those previously known to be associated with prognosis were included in the model. The logistic regression model was built with the maximum likelihood method using stepwise selection. Inclusion and exclusion criteria were P < 0.05 and P > 0.10, respectively. Goodness of fit for each model was determined by the Hosmer–Lemershow test. To evaluate the role of time of surgery in patients with acute-onset IE, we performed a multivariable analysis in the model, including the variable ‘time to surgery’ classified into quartiles of time from IE diagnosis to surgical intervention. The adjusted odds ratios with 95% confidence intervals for each variable were calculated. All tests were 2-tailed, and differences were considered statistically significant at P-values <0.05. Statistical analysis was performed using the statistical package IBM SPSS Statistics V 22.0. RESULTS The mean age of our patient population (n = 1053) was 64.1 ± 14.6 years, and 670 (63.6%) patients were men. There were no differences in age and gender distribution between patients with acute and non-acute IE. Nosocomial infection was more common in the acute-onset group. Demographic characteristics, comorbidities, laboratory parameters and clinical presentation comparisons between patients with acute-onset IE and those with non-acute IE are summarized in Table 1. Table 1: Demographics and main clinical characteristics on admission in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491)  Non-acute-onset IE (n = 562)  P-value  Age (years)  64.7 (14.6)  63.4 (14.6)  0.156  Gender (male)  300 (61.1)  370 (65.8)  0.111  Community-acquired IE  287 (58.5)  432 (76.9)  <0.001  Prosthetic valve IE  219 (44.6)  200 (35.6)  0.003  Antibiotic therapy prior to admission  127 (29.5)  185 (37.8)  0.009  Centre 1  178 (36.3)  200 (35.6)  0.837  Centre 2  158 (32.2)  175 (31.1)  Centre 3  155 (31.6)  187 (33.3)  Comorbidities   Chronic anaemia  108 (22)  120 (21.4)  0.810   Chronic renal failure  73 (14.9)  66 (11.8)  0.141   Diabetes  123 (25.2)  117 (20.9)  0.098   COPD  42 (8.6)  44 (7.9)  0.666   Alcoholism  39 (8)  33 (5.9)  0.185   Malignant neoplasia  48 (9.8)  60 (10.7)  0.624   Immunosuppression  40 (8.2)  30 (5.4)  0.074  Clinical manifestations at admission   Fever  347 (71.4)  393 (70.3)  0.698   Heart failure  172 (35.2)  245 (43.9)  0.004   Acute renal failure  130 (26.6)  100 (17.9)  0.001   Septic shock  54 (11)  11 (2)  <0.001   Splenomegaly  22 (4.5)  59 (10.6)  <0.001   Confusional syndrome  75 (15.3)  43 (7.7)  <0.001   Coma  18 (3.7)  5 (0.9)  0.002   Stroke    Haemorrhagic  23 (4.7)  12 (2.1)  0.008    Ischaemic  69 (14.1)  57 (10.1)  0.008   Systemic embolism  97 (19.8)  103 (18.5)  0.572   Arthritis/spondylodiscitis  48 (9.8)  75 (13.3)  0.072  Laboratory parameters   C-reactive protein  12.9 (4.4–53.8)  9 (3.6–36.3)  0.033   Haemoglobin (gr/dl)  11.3 (2.2)  10.9 (1.9)  0.002   Platelet count (/μl)  175 × 103 (119–248) × 103  211 × 103 (156–280) × 103  <0.001    Acute-onset IE (n = 491)  Non-acute-onset IE (n = 562)  P-value  Age (years)  64.7 (14.6)  63.4 (14.6)  0.156  Gender (male)  300 (61.1)  370 (65.8)  0.111  Community-acquired IE  287 (58.5)  432 (76.9)  <0.001  Prosthetic valve IE  219 (44.6)  200 (35.6)  0.003  Antibiotic therapy prior to admission  127 (29.5)  185 (37.8)  0.009  Centre 1  178 (36.3)  200 (35.6)  0.837  Centre 2  158 (32.2)  175 (31.1)  Centre 3  155 (31.6)  187 (33.3)  Comorbidities   Chronic anaemia  108 (22)  120 (21.4)  0.810   Chronic renal failure  73 (14.9)  66 (11.8)  0.141   Diabetes  123 (25.2)  117 (20.9)  0.098   COPD  42 (8.6)  44 (7.9)  0.666   Alcoholism  39 (8)  33 (5.9)  0.185   Malignant neoplasia  48 (9.8)  60 (10.7)  0.624   Immunosuppression  40 (8.2)  30 (5.4)  0.074  Clinical manifestations at admission   Fever  347 (71.4)  393 (70.3)  0.698   Heart failure  172 (35.2)  245 (43.9)  0.004   Acute renal failure  130 (26.6)  100 (17.9)  0.001   Septic shock  54 (11)  11 (2)  <0.001   Splenomegaly  22 (4.5)  59 (10.6)  <0.001   Confusional syndrome  75 (15.3)  43 (7.7)  <0.001   Coma  18 (3.7)  5 (0.9)  0.002   Stroke    Haemorrhagic  23 (4.7)  12 (2.1)  0.008    Ischaemic  69 (14.1)  57 (10.1)  0.008   Systemic embolism  97 (19.8)  103 (18.5)  0.572   Arthritis/spondylodiscitis  48 (9.8)  75 (13.3)  0.072  Laboratory parameters   C-reactive protein  12.9 (4.4–53.8)  9 (3.6–36.3)  0.033   Haemoglobin (gr/dl)  11.3 (2.2)  10.9 (1.9)  0.002   Platelet count (/μl)  175 × 103 (119–248) × 103  211 × 103 (156–280) × 103  <0.001  Values are n (%) or mean (SD), except C-reactive protein and platelet count that are presented as median. COPD: chronic obstructive pulmonary disease; IE: infective endocarditis; SD: standard deviation. Boldface indicates statistically significant differences between groups. Table 1: Demographics and main clinical characteristics on admission in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491)  Non-acute-onset IE (n = 562)  P-value  Age (years)  64.7 (14.6)  63.4 (14.6)  0.156  Gender (male)  300 (61.1)  370 (65.8)  0.111  Community-acquired IE  287 (58.5)  432 (76.9)  <0.001  Prosthetic valve IE  219 (44.6)  200 (35.6)  0.003  Antibiotic therapy prior to admission  127 (29.5)  185 (37.8)  0.009  Centre 1  178 (36.3)  200 (35.6)  0.837  Centre 2  158 (32.2)  175 (31.1)  Centre 3  155 (31.6)  187 (33.3)  Comorbidities   Chronic anaemia  108 (22)  120 (21.4)  0.810   Chronic renal failure  73 (14.9)  66 (11.8)  0.141   Diabetes  123 (25.2)  117 (20.9)  0.098   COPD  42 (8.6)  44 (7.9)  0.666   Alcoholism  39 (8)  33 (5.9)  0.185   Malignant neoplasia  48 (9.8)  60 (10.7)  0.624   Immunosuppression  40 (8.2)  30 (5.4)  0.074  Clinical manifestations at admission   Fever  347 (71.4)  393 (70.3)  0.698   Heart failure  172 (35.2)  245 (43.9)  0.004   Acute renal failure  130 (26.6)  100 (17.9)  0.001   Septic shock  54 (11)  11 (2)  <0.001   Splenomegaly  22 (4.5)  59 (10.6)  <0.001   Confusional syndrome  75 (15.3)  43 (7.7)  <0.001   Coma  18 (3.7)  5 (0.9)  0.002   Stroke    Haemorrhagic  23 (4.7)  12 (2.1)  0.008    Ischaemic  69 (14.1)  57 (10.1)  0.008   Systemic embolism  97 (19.8)  103 (18.5)  0.572   Arthritis/spondylodiscitis  48 (9.8)  75 (13.3)  0.072  Laboratory parameters   C-reactive protein  12.9 (4.4–53.8)  9 (3.6–36.3)  0.033   Haemoglobin (gr/dl)  11.3 (2.2)  10.9 (1.9)  0.002   Platelet count (/μl)  175 × 103 (119–248) × 103  211 × 103 (156–280) × 103  <0.001    Acute-onset IE (n = 491)  Non-acute-onset IE (n = 562)  P-value  Age (years)  64.7 (14.6)  63.4 (14.6)  0.156  Gender (male)  300 (61.1)  370 (65.8)  0.111  Community-acquired IE  287 (58.5)  432 (76.9)  <0.001  Prosthetic valve IE  219 (44.6)  200 (35.6)  0.003  Antibiotic therapy prior to admission  127 (29.5)  185 (37.8)  0.009  Centre 1  178 (36.3)  200 (35.6)  0.837  Centre 2  158 (32.2)  175 (31.1)  Centre 3  155 (31.6)  187 (33.3)  Comorbidities   Chronic anaemia  108 (22)  120 (21.4)  0.810   Chronic renal failure  73 (14.9)  66 (11.8)  0.141   Diabetes  123 (25.2)  117 (20.9)  0.098   COPD  42 (8.6)  44 (7.9)  0.666   Alcoholism  39 (8)  33 (5.9)  0.185   Malignant neoplasia  48 (9.8)  60 (10.7)  0.624   Immunosuppression  40 (8.2)  30 (5.4)  0.074  Clinical manifestations at admission   Fever  347 (71.4)  393 (70.3)  0.698   Heart failure  172 (35.2)  245 (43.9)  0.004   Acute renal failure  130 (26.6)  100 (17.9)  0.001   Septic shock  54 (11)  11 (2)  <0.001   Splenomegaly  22 (4.5)  59 (10.6)  <0.001   Confusional syndrome  75 (15.3)  43 (7.7)  <0.001   Coma  18 (3.7)  5 (0.9)  0.002   Stroke    Haemorrhagic  23 (4.7)  12 (2.1)  0.008    Ischaemic  69 (14.1)  57 (10.1)  0.008   Systemic embolism  97 (19.8)  103 (18.5)  0.572   Arthritis/spondylodiscitis  48 (9.8)  75 (13.3)  0.072  Laboratory parameters   C-reactive protein  12.9 (4.4–53.8)  9 (3.6–36.3)  0.033   Haemoglobin (gr/dl)  11.3 (2.2)  10.9 (1.9)  0.002   Platelet count (/μl)  175 × 103 (119–248) × 103  211 × 103 (156–280) × 103  <0.001  Values are n (%) or mean (SD), except C-reactive protein and platelet count that are presented as median. COPD: chronic obstructive pulmonary disease; IE: infective endocarditis; SD: standard deviation. Boldface indicates statistically significant differences between groups. At admission, important clinical differences were found: presentation with acute renal failure, septic shock, confusional syndrome and central nervous system embolism predominated among patients with acute-onset IE. On the contrary, heart failure was more common in patients with non-acute onset of IE (Table 1). Microbiological profile Staphylococcus aureus was more frequently isolated in episodes with acute onset, whereas infections due to enterococci and streptococci (viridans, gallolyticus and other species) were more commonly present in those patients with non-acute presentation of IE (Table 2). Table 2: Microbiological profile in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Streptococcus gallolyticus  13 (2.6)  33 (5.9)  0.010  Streptococcus viridans  36 (7.3)  97 (17.3)  <0.001  Other estreptococci  40 (8.1)  29 (5.2)  0.052  Enterococci  35 (7.1)  78 (13.9)  <0.001  Staphylococcus aureus  136 (27.7)  94 (7.8)  <0.001  Coagulase-negative staphylococci  88 (17.9)  80 (14.3)  0.106  Gram-negative bacilli  19 (3.9)  16 (2.9)  0.359  Fungi  6 (1.2)  7 (1.2)  0.359  HACEK group  2 (0.4)  3 (0.5)  >0.999  Anaerobes  8 (1.6)  13 (2.3)  0.426  Polymicrobial  32 (6.5)  49 (8.7)  0.178  Others  10 (2)  29 (5.2)  0.007  Culture-negative  66 (13.4)  83 (14.8)  0.530    Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Streptococcus gallolyticus  13 (2.6)  33 (5.9)  0.010  Streptococcus viridans  36 (7.3)  97 (17.3)  <0.001  Other estreptococci  40 (8.1)  29 (5.2)  0.052  Enterococci  35 (7.1)  78 (13.9)  <0.001  Staphylococcus aureus  136 (27.7)  94 (7.8)  <0.001  Coagulase-negative staphylococci  88 (17.9)  80 (14.3)  0.106  Gram-negative bacilli  19 (3.9)  16 (2.9)  0.359  Fungi  6 (1.2)  7 (1.2)  0.359  HACEK group  2 (0.4)  3 (0.5)  >0.999  Anaerobes  8 (1.6)  13 (2.3)  0.426  Polymicrobial  32 (6.5)  49 (8.7)  0.178  Others  10 (2)  29 (5.2)  0.007  Culture-negative  66 (13.4)  83 (14.8)  0.530  HACEK: Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella spp.; IE: infective endocarditis. Boldface indicates statistically significant differences between groups. Table 2: Microbiological profile in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Streptococcus gallolyticus  13 (2.6)  33 (5.9)  0.010  Streptococcus viridans  36 (7.3)  97 (17.3)  <0.001  Other estreptococci  40 (8.1)  29 (5.2)  0.052  Enterococci  35 (7.1)  78 (13.9)  <0.001  Staphylococcus aureus  136 (27.7)  94 (7.8)  <0.001  Coagulase-negative staphylococci  88 (17.9)  80 (14.3)  0.106  Gram-negative bacilli  19 (3.9)  16 (2.9)  0.359  Fungi  6 (1.2)  7 (1.2)  0.359  HACEK group  2 (0.4)  3 (0.5)  >0.999  Anaerobes  8 (1.6)  13 (2.3)  0.426  Polymicrobial  32 (6.5)  49 (8.7)  0.178  Others  10 (2)  29 (5.2)  0.007  Culture-negative  66 (13.4)  83 (14.8)  0.530    Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Streptococcus gallolyticus  13 (2.6)  33 (5.9)  0.010  Streptococcus viridans  36 (7.3)  97 (17.3)  <0.001  Other estreptococci  40 (8.1)  29 (5.2)  0.052  Enterococci  35 (7.1)  78 (13.9)  <0.001  Staphylococcus aureus  136 (27.7)  94 (7.8)  <0.001  Coagulase-negative staphylococci  88 (17.9)  80 (14.3)  0.106  Gram-negative bacilli  19 (3.9)  16 (2.9)  0.359  Fungi  6 (1.2)  7 (1.2)  0.359  HACEK group  2 (0.4)  3 (0.5)  >0.999  Anaerobes  8 (1.6)  13 (2.3)  0.426  Polymicrobial  32 (6.5)  49 (8.7)  0.178  Others  10 (2)  29 (5.2)  0.007  Culture-negative  66 (13.4)  83 (14.8)  0.530  HACEK: Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella spp.; IE: infective endocarditis. Boldface indicates statistically significant differences between groups. Echocardiographic findings Echocardiographic data are shown in Table 2. Prosthetic valve infection was more frequent in patients with acute presentation. On the contrary, native valve infection, especially in the aortic location, was more common in non-acute IE. The detection of vegetations, their size and the presence of periannular complications were similar in both groups of patients. Moderate to severe valvular regurgitation was more common in patients with non-acute presentation (Table 3). Table 3: Echocardiographic findings   Acute-onset IE (n = 491)  Non-acute- onset IE (n = 562)  P-value  Location of the infection, n (%)   Aortic valve (native)  135 (27.5)  234 (41.6)  <0.001   Mitral valve (native)  185 (37.7)  225 (40)  0.434   Mechanical aortic prosthesis  66 (13.4)  66 (11.7)  0.406   Mechanical mitral prosthesis  118 (24)  100 (17.8)  0.013   Biological aortic prosthesis  46 (9.4)  41 (7.3)  0.223   Biological mitral prosthesis  10 (2)  12 (2.1)  0.911  Vegetation detection, n (%)  413 (85.7)  454 (82.7)  0.190  Vegetation size (mm), median (IQR)  12 (7.5–17)  12 (8–18)  0.800  Moderate-severe valvular regurgitation, n (%)  290 (60.2)  420 (76.5)  <0.001  Paravalvular complications, n (%)  126 (26.1)  153 (27.9)  0.533   Abscess  78 (16.2)  79 (14.4)  0.424   Pseudoaneurysm  60 (12.4)  95 (17.3)  0.030    Acute-onset IE (n = 491)  Non-acute- onset IE (n = 562)  P-value  Location of the infection, n (%)   Aortic valve (native)  135 (27.5)  234 (41.6)  <0.001   Mitral valve (native)  185 (37.7)  225 (40)  0.434   Mechanical aortic prosthesis  66 (13.4)  66 (11.7)  0.406   Mechanical mitral prosthesis  118 (24)  100 (17.8)  0.013   Biological aortic prosthesis  46 (9.4)  41 (7.3)  0.223   Biological mitral prosthesis  10 (2)  12 (2.1)  0.911  Vegetation detection, n (%)  413 (85.7)  454 (82.7)  0.190  Vegetation size (mm), median (IQR)  12 (7.5–17)  12 (8–18)  0.800  Moderate-severe valvular regurgitation, n (%)  290 (60.2)  420 (76.5)  <0.001  Paravalvular complications, n (%)  126 (26.1)  153 (27.9)  0.533   Abscess  78 (16.2)  79 (14.4)  0.424   Pseudoaneurysm  60 (12.4)  95 (17.3)  0.030  IE: infective endocarditis; IQR: interquartile range. Boldface indicates statistically significant differences between groups. Table 3: Echocardiographic findings   Acute-onset IE (n = 491)  Non-acute- onset IE (n = 562)  P-value  Location of the infection, n (%)   Aortic valve (native)  135 (27.5)  234 (41.6)  <0.001   Mitral valve (native)  185 (37.7)  225 (40)  0.434   Mechanical aortic prosthesis  66 (13.4)  66 (11.7)  0.406   Mechanical mitral prosthesis  118 (24)  100 (17.8)  0.013   Biological aortic prosthesis  46 (9.4)  41 (7.3)  0.223   Biological mitral prosthesis  10 (2)  12 (2.1)  0.911  Vegetation detection, n (%)  413 (85.7)  454 (82.7)  0.190  Vegetation size (mm), median (IQR)  12 (7.5–17)  12 (8–18)  0.800  Moderate-severe valvular regurgitation, n (%)  290 (60.2)  420 (76.5)  <0.001  Paravalvular complications, n (%)  126 (26.1)  153 (27.9)  0.533   Abscess  78 (16.2)  79 (14.4)  0.424   Pseudoaneurysm  60 (12.4)  95 (17.3)  0.030    Acute-onset IE (n = 491)  Non-acute- onset IE (n = 562)  P-value  Location of the infection, n (%)   Aortic valve (native)  135 (27.5)  234 (41.6)  <0.001   Mitral valve (native)  185 (37.7)  225 (40)  0.434   Mechanical aortic prosthesis  66 (13.4)  66 (11.7)  0.406   Mechanical mitral prosthesis  118 (24)  100 (17.8)  0.013   Biological aortic prosthesis  46 (9.4)  41 (7.3)  0.223   Biological mitral prosthesis  10 (2)  12 (2.1)  0.911  Vegetation detection, n (%)  413 (85.7)  454 (82.7)  0.190  Vegetation size (mm), median (IQR)  12 (7.5–17)  12 (8–18)  0.800  Moderate-severe valvular regurgitation, n (%)  290 (60.2)  420 (76.5)  <0.001  Paravalvular complications, n (%)  126 (26.1)  153 (27.9)  0.533   Abscess  78 (16.2)  79 (14.4)  0.424   Pseudoaneurysm  60 (12.4)  95 (17.3)  0.030  IE: infective endocarditis; IQR: interquartile range. Boldface indicates statistically significant differences between groups. In-hospital evolution During hospitalization, the development of heart failure was similar between groups. Patients with acute-onset IE showed more persistent fever and developed systemic embolism and septic shock during hospitalization more frequently (Table 4). Patients with acute-onset IE underwent surgery less frequently than those with non-acute-onset IE (Table 4). The surgical risk according to the logistic EuroSCORE was higher in patients with acute-onset IE [30% (14.9–50.1) vs 20% (9–38.9), P = 0.011]. Table 4: Clinical events during in-hospital evolution in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Fever  107 (21.8)  55 (9.8)  0.007  Heart failure  111 (22.6)  110 (19.6)  0.228  CNS embolism  29 (5.9)  24 (4.3)  0.226  Systemic embolism  68 (13.8)  55 (9.8)  0.041  Acute renal failure  103 (21)  99 (17.6)  0.167  AV block  26 (5.3)  33 (5.9)  0.685  Septic shock  58 (11.8)  38 (6.8)  0.005  Surgery  251 (51.1)  360 (64.2)  <0.001  Death  208 (42.7)  168 (30.1)  <0.001    Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Fever  107 (21.8)  55 (9.8)  0.007  Heart failure  111 (22.6)  110 (19.6)  0.228  CNS embolism  29 (5.9)  24 (4.3)  0.226  Systemic embolism  68 (13.8)  55 (9.8)  0.041  Acute renal failure  103 (21)  99 (17.6)  0.167  AV block  26 (5.3)  33 (5.9)  0.685  Septic shock  58 (11.8)  38 (6.8)  0.005  Surgery  251 (51.1)  360 (64.2)  <0.001  Death  208 (42.7)  168 (30.1)  <0.001  Events that were already present at admission to the hospital have not been included in this table. AV block: atrioventricular block; CNS: central nervous system; IE: infective endocarditis. Boldface indicates statistically significant differences between groups. Table 4: Clinical events during in-hospital evolution in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Fever  107 (21.8)  55 (9.8)  0.007  Heart failure  111 (22.6)  110 (19.6)  0.228  CNS embolism  29 (5.9)  24 (4.3)  0.226  Systemic embolism  68 (13.8)  55 (9.8)  0.041  Acute renal failure  103 (21)  99 (17.6)  0.167  AV block  26 (5.3)  33 (5.9)  0.685  Septic shock  58 (11.8)  38 (6.8)  0.005  Surgery  251 (51.1)  360 (64.2)  <0.001  Death  208 (42.7)  168 (30.1)  <0.001    Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Fever  107 (21.8)  55 (9.8)  0.007  Heart failure  111 (22.6)  110 (19.6)  0.228  CNS embolism  29 (5.9)  24 (4.3)  0.226  Systemic embolism  68 (13.8)  55 (9.8)  0.041  Acute renal failure  103 (21)  99 (17.6)  0.167  AV block  26 (5.3)  33 (5.9)  0.685  Septic shock  58 (11.8)  38 (6.8)  0.005  Surgery  251 (51.1)  360 (64.2)  <0.001  Death  208 (42.7)  168 (30.1)  <0.001  Events that were already present at admission to the hospital have not been included in this table. AV block: atrioventricular block; CNS: central nervous system; IE: infective endocarditis. Boldface indicates statistically significant differences between groups. There were 376 deaths (35.7%); 208 of 491 (42.7%) patients with acute-onset IE died. Death was much more common in patients with acute-onset IE than in those with non-acute IE (42.7% vs 30.1%, P < 0.001) (Table 4). Differences between survivors and non-survivors among patients who did undergo surgery and those treated medically were analysed (Supplementary Material, Tables S1–S4). In both groups, older patients with more comorbidities, prosthetic valve carriers, non-community acquired infections, S. aureus IE, as well as those who developed septic shock during hospitalization had higher mortality. In addition, among patients who did not undergo surgery, those with heart failure had a worse outcome. To assess the potential impact of time span on the results, the patient population was divided into 2 groups of approximately equal size: patients included between 1996 and 2006 (n = 508) and those included between 2007 and 2014 (n = 543). There was no significant difference in mortality between the 2 periods of time (38.6% vs 33.7%, P = 0.100). Multivariable analysis for mortality We performed a multivariable analysis to predict mortality with the information obtained at admission or during the 1st week of hospitalization. We found that periannular complications, nosocomial infection, heart failure, S. aureus infection and septic shock were predictors of mortality. Acute-onset presentation of IE was strongly associated with increased mortality after adjustment for other variables (Fig. 1). Figure 1: View largeDownload slide Multivariable analysis to predict mortality in the whole cohort of 1053 patients with left-sided infective endocarditis. OR and 95% confidence intervals are represented in the graph. IE: infective endocarditis; OR: odds ratio. Figure 1: View largeDownload slide Multivariable analysis to predict mortality in the whole cohort of 1053 patients with left-sided infective endocarditis. OR and 95% confidence intervals are represented in the graph. IE: infective endocarditis; OR: odds ratio. Evaluation of the potential influence of surgical timing in mortality Focusing on patients with acute-onset IE, a multivariable logistic regression analysis for prediction of mortality was performed. We aimed to explore the potential impact of surgical timing over mortality among this high-risk population. Thus, time from diagnosis to surgery was included in the model and was classified into quartiles. In addition, we included in the model those variables previously known to be associated with increased mortality and those which resulted statistically significant in the univariable analysis. To avoid potential sources of bias, those patients with an indication for surgery who did not undergo surgery due to high surgical risk were not included in the model (48 patients). Nosocomial infection, presence of paravalvular complications, cerebral embolism, heart failure and septic shock were independently associated with increased mortality (Table 5). On the contrary, early surgery [performed within the 1st quartile of time (<2 days)] was associated with a 64% reduction in mortality in patients with acute-onset IE. As expected, surgery performed within the 4th quartile (>18 days) was also associated with a lower mortality. However, when the previous multivariable analysis was performed in patients with non-acute-onset IE, surgical timing was not an independent predictor of lower mortality (Supplementary Material, Table S5). Table 5: Multivariable analysis for prediction of mortality in patients with acute-onset infective endocarditis (n = 443) Variables  OR  95% CI  P-value  Time to surgery         Quartile 1  0.36  0.18–0.73  0.005   Quartile 2  0.69  0.33–1.44  0.323   Quartile 3  0.52  0.26–1.05  0.066   Quartile 4  0.31  0.14–0.67  0.003  Age  1.01  0.99–1.03  0.298  Acute renal failure  1.16  0.70–1.92  0.561  Vegetation  1.35  0.69–2.63  0.377  Staphylococcus aureus  1.40  0.83–2.35  0.208  Paravalvular complications  1.78  1.05–3.01  0.031  Nosocomial origin  2.06  1.26–3.34  0.004  CNS embolism  2.08  1.08–4.01  0.030  Heart failure  2.55  1.55–4.19  <0.001  Septic shock  7.74  4.42–13.57  <0.001  Variables  OR  95% CI  P-value  Time to surgery         Quartile 1  0.36  0.18–0.73  0.005   Quartile 2  0.69  0.33–1.44  0.323   Quartile 3  0.52  0.26–1.05  0.066   Quartile 4  0.31  0.14–0.67  0.003  Age  1.01  0.99–1.03  0.298  Acute renal failure  1.16  0.70–1.92  0.561  Vegetation  1.35  0.69–2.63  0.377  Staphylococcus aureus  1.40  0.83–2.35  0.208  Paravalvular complications  1.78  1.05–3.01  0.031  Nosocomial origin  2.06  1.26–3.34  0.004  CNS embolism  2.08  1.08–4.01  0.030  Heart failure  2.55  1.55–4.19  <0.001  Septic shock  7.74  4.42–13.57  <0.001  Time from diagnosis to surgery (days): quartile 1 (<2), quartile 2 (2–8), quartile 3 (8–18) and quartile 4 (>18). CI: confidence interval; CNS: central nervous system; OR: odds ratio. Boldface indicates statistically significant differences between groups. Table 5: Multivariable analysis for prediction of mortality in patients with acute-onset infective endocarditis (n = 443) Variables  OR  95% CI  P-value  Time to surgery         Quartile 1  0.36  0.18–0.73  0.005   Quartile 2  0.69  0.33–1.44  0.323   Quartile 3  0.52  0.26–1.05  0.066   Quartile 4  0.31  0.14–0.67  0.003  Age  1.01  0.99–1.03  0.298  Acute renal failure  1.16  0.70–1.92  0.561  Vegetation  1.35  0.69–2.63  0.377  Staphylococcus aureus  1.40  0.83–2.35  0.208  Paravalvular complications  1.78  1.05–3.01  0.031  Nosocomial origin  2.06  1.26–3.34  0.004  CNS embolism  2.08  1.08–4.01  0.030  Heart failure  2.55  1.55–4.19  <0.001  Septic shock  7.74  4.42–13.57  <0.001  Variables  OR  95% CI  P-value  Time to surgery         Quartile 1  0.36  0.18–0.73  0.005   Quartile 2  0.69  0.33–1.44  0.323   Quartile 3  0.52  0.26–1.05  0.066   Quartile 4  0.31  0.14–0.67  0.003  Age  1.01  0.99–1.03  0.298  Acute renal failure  1.16  0.70–1.92  0.561  Vegetation  1.35  0.69–2.63  0.377  Staphylococcus aureus  1.40  0.83–2.35  0.208  Paravalvular complications  1.78  1.05–3.01  0.031  Nosocomial origin  2.06  1.26–3.34  0.004  CNS embolism  2.08  1.08–4.01  0.030  Heart failure  2.55  1.55–4.19  <0.001  Septic shock  7.74  4.42–13.57  <0.001  Time from diagnosis to surgery (days): quartile 1 (<2), quartile 2 (2–8), quartile 3 (8–18) and quartile 4 (>18). CI: confidence interval; CNS: central nervous system; OR: odds ratio. Boldface indicates statistically significant differences between groups. We analysed the profiles of patients across the different quartiles of time from diagnosis to surgery and found some differences which deserve consideration. Patients who did not undergo surgery were older than those who had surgery. Patients who underwent surgery within the first 2 days had heart failure and septic shock at admission more frequently. Central nervous system embolism was more frequent among patients in the 3rd quartile. Development of heart failure and periannular extension of infection during hospitalization were more common in patients in the 3rd quartile, whereas a higher proportion of those who underwent surgery later in the 4th quartile, developed acute renal failure. New onset of septic shock during hospitalization was observed more frequently among patients in the 2nd quartile. Regarding the microbiological profile, those patients from the 1st quartile had negative cultures more frequently. In-hospital mortality of patients who underwent early surgery was 33%, significantly lower than those who did not undergo surgery (43.8%) or when the surgery was performed in the 2nd (46.2%) or the 3rd quartile (39.7%) of time. As previously mentioned, surgery performed within the 4th quartile (>18 days) was also associated with a lower mortality (22.4%) (Supplementary Material, Tables S6–S9). DISCUSSION To determine the appropriate treatment of patients with IE and the timing of surgery, it is important to be able to detect those patients who are at higher risk. The results of the current study show that acute clinical presentation is a risk marker in patients with IE. In fact, acute-onset IE was associated with a 4.5-fold increased risk of mortality after multivariable adjustment. According to our results, patients with acute-onset IE are a subgroup of patients in whom manifestations of sepsis at admission as well as during hospitalization are more prominently displayed (fever, septic shock, acute renal failure, confusional syndrome, stroke, etc.). Staphylococcus aureus is the microorganism most probably involved in this clinical scenario. Other studies, although scarce, have analysed the prognosis of patients with IE according to the temporality from the onset of symptoms to diagnosis with similar results [9, 14]. Surgery was performed in 58% of patients in this study. Surgical indications are fairly well established in the main guidelines and can be summarized in 3 categories: heart failure, uncontrolled infection and prevention of embolism [3, 15]. However, for certain patients, this is not always so clear-cut and there is often debate, for example, in cases of mild heart failure or regarding the vegetation size to consider high embolic risk. In addition, the optimal timing of surgery is also a contentious issue. Some advocate for early surgery [16], whereas others prefer delaying surgery with a longer duration of antibiotic therapy to achieve better control of sepsis and stabilization of haemodynamics, which does not always occur. According to Tornos et al. [17], up to 28–47% of patients with native valve IE who initially received medical therapy alone will eventually require surgery for valve replacement, mostly during the 2 years following the index episode. In our study, after adjustment for other important prognostic variables, early surgery (performed within 48 h after diagnosis) was associated with a 64% relative reduction of mortality in patients with acute-onset IE compared to medical therapy alone. To date, just one randomized clinical trial has evaluated the potential role of early surgery (undertaken within 48 h of randomization) in the prognosis of IE patients [16]. In that study, the population included was at a lower risk than ours. Mostly young patients (mean age 47 years) with infected native valves predominantly due to streptococci were included. Early surgery was associated with a significant reduction in the composite end point of in-hospital death or embolism, mainly due to the reduction of embolism. On the contrary, several studies by the ICE-PCS registry have shown conflicting results [4, 18, 19]. Here, we could be facing an issue of definition, i.e. in these studies, early surgery was defined as one undertaken within the course of the initial hospitalization for IE. In fact, there is no universal definition for early surgery. The recent European Society of Cardiology (ESC) guidelines distinguish emergency surgery (performed within 24 h) and urgent surgery (within a few days) from elective surgery (after 1–2 weeks of antibiotics), whereas the American Heart Association (AHA) guidelines define early surgery when it is performed during initial hospitalization and before completion of a full course of antibiotics. Thus, a single universal definition of early surgery should be pursued. When considering the profiles of patients across the different quartiles of time from diagnosis to surgery, we found that patients who underwent surgery within the 1st quartile of time showed a higher risk profile as they had heart failure and septic shock more often on admission. In this high-risk group, very early surgery achieved a relative reduction in mortality of 64%. On the contrary, those patients operated later (4th quartile, after 18 days) showed a more benign presentation at diagnosis. In this subgroup, surgery was also associated with a reduction in mortality. Besides, patients with acute-onset IE in whom surgery was deferred due to high risk but who have survived more than 18 days had a higher chance of surviving after surgery. Surgical benefit was lower among patients who underwent surgery between the 2nd and 18th days after diagnosis (quartiles 2 and 3). Patients operated during this time frame had more central nervous system embolism at admission. This fact most probably influenced the post-surgical evolution and prognosis of these patients. In summary, the results of this study highlight a 2-fold message: first, patients with IE and acute onset of symptoms are at a high risk of septic in-hospital complications and mortality; second, early surgery (performed during the first 48 h) plays a central role in the treatment of these patients. Therefore, based on our results, it follows that once the surgical indication has been established, surgery needs to be performed as soon as possible. Limitations This study has several limitations that should be considered when interpreting the results. Although it is a multicentre study including a large number of patients, it has potential referral bias because all the participants are tertiary care centres. Besides, this is an observational study with limitations inherent to this type of studies. Information in regards intraoperative procedures, such as time of cardiopulmonary bypass or cross clamping time, was not available. The onset of symptoms was inevitably determined retrospectively by patients and the treating physician, although included prospectively in our database. Therefore, it could be affected by recall bias. Moreover, many of the IE-related symptoms were non-specific, and sometimes it was difficult to determine with certainty if they were related to IE. CONCLUSION Acute-onset IE is independently associated with a higher risk of in-hospital complications and a higher mortality. Early surgery, performed within the first 2 days after diagnosis, was associated with lower in-hospital mortality in patients with acute-onset IE. Randomized studies would be needed to adequately assess the impact of surgical timing over mortality in this high-risk population. SUPPLEMENTARY MATERIAL Supplementary material is available at EJCTS online. Conflict of interest: none declared. REFERENCES 1 Fernández-Hidalgo N, Almirante B, Tornos P, González-Alujas MT, Planes AM, Galiñanes M et al.   Immediate and long-term outcome of left-sided infective endocarditis. A 12-year prospective study from acontemporary cohort in a referral hospital. Clin Microbiol Infect  2012; 18: E522– 30. Google Scholar CrossRef Search ADS PubMed  2 Fernández-Hidalgo N, Tornos Mas P. Epidemiology of infective endocarditis in Spain in the last 20 years. 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Impact of early valve surgery on outcome of Staphylococcus aureus prosthetic valve infective endocarditis: analysis in the International Collaboration of Endocarditis-Prospective Cohort Study. Clin Infect Dis  2015; 60: 741– 9. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Cardio-Thoracic Surgery Oxford University Press

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1010-7940
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1873-734X
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10.1093/ejcts/ezy208
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Abstract

Abstract OBJECTIVES: Acute onset of infective endocarditis has been previously linked to the development of septic shock and a worse prognosis. The purpose of this study was to analyse the clinical features and in-hospital evolution of patients with acute-onset endocarditis as well as the potential role of early surgery in the treatment of these patients. METHODS: From 1996 to 2014, 1053 consecutive patients with left-sided endocarditis were prospectively included. Patients were classified into 2 groups according to the clinical presentation: patients with acute-onset endocarditis (n = 491) and patients with non-acute endocarditis (n = 562). Acute-onset endocarditis was considered when the time between the appearance of symptoms and diagnosis was <15 days. RESULTS: At admission, acute renal failure, septic shock and cerebral embolism predominated among patients with acute-onset endocarditis. Staphylococcus aureus was more frequently isolated in patients with an acute onset (27.7% vs 7.8% P < 0.001). During hospitalization, patients with acute onset developed systemic embolism and septic shock more frequently. Death was much more common in this group (42.7 vs 30.1%, P < 0.001). Paravalvular complications, nosocomial infection, heart failure, S. aureus and septic shock were predictors of mortality. Acute-onset presentation of endocarditis was strongly associated with increased mortality. Among patients with acute-onset endocarditis, early surgery, performed within the first 2 days after diagnosis, was associated with a 64% of reduction in mortality. CONCLUSIONS: Patients with endocarditis and acute onset of symptoms are at high risk of septic in-hospital complications and mortality. Early surgery, performed within the first 2 days after diagnosis, plays a central role in the treatment of these patients. Endocarditis, Cardiac surgery, Prognosis INTRODUCTION Infective endocarditis (IE) is a serious disease associated with high mortality. Over the last years, surgical techniques and antibiotic therapies have improved significantly. Despite these advancements, IE-related mortality remains unacceptably high [1, 2]. The identification of prognostic markers of increased mortality, which deserve more intensive care or early surgery, is of paramount importance. Although surgical intervention is recommended in the current guidelines with the presence of heart failure, embolic events or septic complications, the timing of surgery is still an unresolved issue [3–6]. Acute onset of IE has been previously linked to the development of septic shock and a worse prognosis [7–9]. In this context, early surgery might improve the outcomes of patients. However, there are no specific studies focused on the evaluation of the potential role of early surgery in the prognosis of these patients. The purpose of this study was to analyse the clinical and echocardiographic features, microbiological profile, in-hospital evolution and prognosis of those patients with IE and acute onset of the disease. Furthermore, we aimed to assess the potential role of early surgery among these patients. METHODS This study was conducted at 3 tertiary care university hospitals with surgical facilities. All centres used standardized protocols, uniform data collection and identical diagnostic and therapeutic criteria. From 1996 to 2014, data from 1053 consecutive patients with left-sided IE were prospectively recorded on an ongoing multipurpose database. This registry was approved by the local ethical committees, and the study protocol was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Informed consent was obtained for participation in the study. For purposes of analysis and comparison, patients were classified into 2 groups according to the clinical presentation: patients with acute-onset IE (n = 491) and patients with non-acute IE (n = 562). Acute-onset IE was considered when the time between the appearance of symptoms and diagnosis was <15 days [10]. To ensure consecutive enrolment, all patients who underwent an echocardiogram to rule out IE were clinically followed until a final diagnosis was established. Duke criteria were applied until 2002 and modified Duke criteria thereafter [11]. Only definite cases of left-sided IE were included. Right-sided IE episodes were excluded due to their different epidemiology, clinical characteristics and prognosis. Data collection included detailed clinical history, standard physical examination, electrocardiography, chest X-ray, blood analysis, urinalysis, a set of 3 blood cultures at admission, 3 additional blood cultures 48–72 h later and at least one transthoracic and transoesophageal echocardiogram, as previously described [12]. For those patients already hospitalized at the time of infection (nosocomial IE), laboratory parameters were registered on the date of the first positive blood culture. Empiric antibiotic treatment was started after blood cultures were taken, and specific antibiotic therapy was initiated once the results of blood cultures were available. If blood cultures were negative after 72 h, specific serological tests for Chlamydia, Brucella, Coxiella burnetii, Bartonella, Mycoplasma and Legionella species were performed [12]. Definition of terms Nosocomial and community-acquired IE were defined according to the literature [3]. Previous antibiotic treatment was taken into account when it was administered within 15 days before extraction of blood cultures. Under the term of immunosuppression, patients with HIV and those who were on steroids or other immunosuppressive therapy were included. Persistent signs of infection were defined as persistent bacteraemia or fever after 7 days of appropriate antibiotic treatment once other possible foci of infection had been ruled out [8]. Septic shock was defined as the presence of an acute circulatory failure in sepsis, characterized by persistent arterial hypotension (systolic pressure <90 mmHg) despite adequate volume resuscitation [8]. The diagnosis of systemic embolism was based on clinical signs and data derived from imaging procedures. The echocardiographic criteria used for definition and measurement of vegetations, abscesses, pseudoaneurysms and fistulas have been described elsewhere [13]. Surgery was performed when any of the following occurred: heart failure, recurrent embolism with persistent vegetations in the echocardiogram, persistent signs of infection and fungal endocarditis. The initial presence of paravalvular complications in patients with a favourable clinical course was not an indication for surgery although enlargement of pseudoaneurysms and abscesses or progression to fistula were considered indications. When a patient meeting surgical criteria did not undergo surgery, the reason was either because of patient rejection, unacceptably high surgical risk or when the patient was too frail. The surgical indication and timing of operation were individualized for each patient. The decision for surgery was made by a multidisciplinary team, including cardiologists, cardiac surgeons, infectious disease specialists and a microbiologist, following the current guidelines for clinical practice in each case. Statistical analysis Continuous variables are described as mean value and standard deviation or median and interquartile range when appropriate. Levene’s test was used to assess the homogeneity of variances. A 2-tailed Student’s t-test was used to compare quantitative variables. In cases of inhomogeneity of variances, the Mann–Whitney U-test was used. Categorical variables are expressed as frequency and percentage, and they were compared with the χ2 test. Fisher’s exact test was used when at least 25% of the values in the 2 × 2 contingency table showed an absolute frequency of <5. This criterion was prespecified before the statistical analysis was performed. There was no variable with losses that exceeded 15%. A multivariable logistic regression analysis was performed to identify independent predictors of mortality. Variables which were found to be statistically significant in the univariable analysis as well as those previously known to be associated with prognosis were included in the model. The logistic regression model was built with the maximum likelihood method using stepwise selection. Inclusion and exclusion criteria were P < 0.05 and P > 0.10, respectively. Goodness of fit for each model was determined by the Hosmer–Lemershow test. To evaluate the role of time of surgery in patients with acute-onset IE, we performed a multivariable analysis in the model, including the variable ‘time to surgery’ classified into quartiles of time from IE diagnosis to surgical intervention. The adjusted odds ratios with 95% confidence intervals for each variable were calculated. All tests were 2-tailed, and differences were considered statistically significant at P-values <0.05. Statistical analysis was performed using the statistical package IBM SPSS Statistics V 22.0. RESULTS The mean age of our patient population (n = 1053) was 64.1 ± 14.6 years, and 670 (63.6%) patients were men. There were no differences in age and gender distribution between patients with acute and non-acute IE. Nosocomial infection was more common in the acute-onset group. Demographic characteristics, comorbidities, laboratory parameters and clinical presentation comparisons between patients with acute-onset IE and those with non-acute IE are summarized in Table 1. Table 1: Demographics and main clinical characteristics on admission in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491)  Non-acute-onset IE (n = 562)  P-value  Age (years)  64.7 (14.6)  63.4 (14.6)  0.156  Gender (male)  300 (61.1)  370 (65.8)  0.111  Community-acquired IE  287 (58.5)  432 (76.9)  <0.001  Prosthetic valve IE  219 (44.6)  200 (35.6)  0.003  Antibiotic therapy prior to admission  127 (29.5)  185 (37.8)  0.009  Centre 1  178 (36.3)  200 (35.6)  0.837  Centre 2  158 (32.2)  175 (31.1)  Centre 3  155 (31.6)  187 (33.3)  Comorbidities   Chronic anaemia  108 (22)  120 (21.4)  0.810   Chronic renal failure  73 (14.9)  66 (11.8)  0.141   Diabetes  123 (25.2)  117 (20.9)  0.098   COPD  42 (8.6)  44 (7.9)  0.666   Alcoholism  39 (8)  33 (5.9)  0.185   Malignant neoplasia  48 (9.8)  60 (10.7)  0.624   Immunosuppression  40 (8.2)  30 (5.4)  0.074  Clinical manifestations at admission   Fever  347 (71.4)  393 (70.3)  0.698   Heart failure  172 (35.2)  245 (43.9)  0.004   Acute renal failure  130 (26.6)  100 (17.9)  0.001   Septic shock  54 (11)  11 (2)  <0.001   Splenomegaly  22 (4.5)  59 (10.6)  <0.001   Confusional syndrome  75 (15.3)  43 (7.7)  <0.001   Coma  18 (3.7)  5 (0.9)  0.002   Stroke    Haemorrhagic  23 (4.7)  12 (2.1)  0.008    Ischaemic  69 (14.1)  57 (10.1)  0.008   Systemic embolism  97 (19.8)  103 (18.5)  0.572   Arthritis/spondylodiscitis  48 (9.8)  75 (13.3)  0.072  Laboratory parameters   C-reactive protein  12.9 (4.4–53.8)  9 (3.6–36.3)  0.033   Haemoglobin (gr/dl)  11.3 (2.2)  10.9 (1.9)  0.002   Platelet count (/μl)  175 × 103 (119–248) × 103  211 × 103 (156–280) × 103  <0.001    Acute-onset IE (n = 491)  Non-acute-onset IE (n = 562)  P-value  Age (years)  64.7 (14.6)  63.4 (14.6)  0.156  Gender (male)  300 (61.1)  370 (65.8)  0.111  Community-acquired IE  287 (58.5)  432 (76.9)  <0.001  Prosthetic valve IE  219 (44.6)  200 (35.6)  0.003  Antibiotic therapy prior to admission  127 (29.5)  185 (37.8)  0.009  Centre 1  178 (36.3)  200 (35.6)  0.837  Centre 2  158 (32.2)  175 (31.1)  Centre 3  155 (31.6)  187 (33.3)  Comorbidities   Chronic anaemia  108 (22)  120 (21.4)  0.810   Chronic renal failure  73 (14.9)  66 (11.8)  0.141   Diabetes  123 (25.2)  117 (20.9)  0.098   COPD  42 (8.6)  44 (7.9)  0.666   Alcoholism  39 (8)  33 (5.9)  0.185   Malignant neoplasia  48 (9.8)  60 (10.7)  0.624   Immunosuppression  40 (8.2)  30 (5.4)  0.074  Clinical manifestations at admission   Fever  347 (71.4)  393 (70.3)  0.698   Heart failure  172 (35.2)  245 (43.9)  0.004   Acute renal failure  130 (26.6)  100 (17.9)  0.001   Septic shock  54 (11)  11 (2)  <0.001   Splenomegaly  22 (4.5)  59 (10.6)  <0.001   Confusional syndrome  75 (15.3)  43 (7.7)  <0.001   Coma  18 (3.7)  5 (0.9)  0.002   Stroke    Haemorrhagic  23 (4.7)  12 (2.1)  0.008    Ischaemic  69 (14.1)  57 (10.1)  0.008   Systemic embolism  97 (19.8)  103 (18.5)  0.572   Arthritis/spondylodiscitis  48 (9.8)  75 (13.3)  0.072  Laboratory parameters   C-reactive protein  12.9 (4.4–53.8)  9 (3.6–36.3)  0.033   Haemoglobin (gr/dl)  11.3 (2.2)  10.9 (1.9)  0.002   Platelet count (/μl)  175 × 103 (119–248) × 103  211 × 103 (156–280) × 103  <0.001  Values are n (%) or mean (SD), except C-reactive protein and platelet count that are presented as median. COPD: chronic obstructive pulmonary disease; IE: infective endocarditis; SD: standard deviation. Boldface indicates statistically significant differences between groups. Table 1: Demographics and main clinical characteristics on admission in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491)  Non-acute-onset IE (n = 562)  P-value  Age (years)  64.7 (14.6)  63.4 (14.6)  0.156  Gender (male)  300 (61.1)  370 (65.8)  0.111  Community-acquired IE  287 (58.5)  432 (76.9)  <0.001  Prosthetic valve IE  219 (44.6)  200 (35.6)  0.003  Antibiotic therapy prior to admission  127 (29.5)  185 (37.8)  0.009  Centre 1  178 (36.3)  200 (35.6)  0.837  Centre 2  158 (32.2)  175 (31.1)  Centre 3  155 (31.6)  187 (33.3)  Comorbidities   Chronic anaemia  108 (22)  120 (21.4)  0.810   Chronic renal failure  73 (14.9)  66 (11.8)  0.141   Diabetes  123 (25.2)  117 (20.9)  0.098   COPD  42 (8.6)  44 (7.9)  0.666   Alcoholism  39 (8)  33 (5.9)  0.185   Malignant neoplasia  48 (9.8)  60 (10.7)  0.624   Immunosuppression  40 (8.2)  30 (5.4)  0.074  Clinical manifestations at admission   Fever  347 (71.4)  393 (70.3)  0.698   Heart failure  172 (35.2)  245 (43.9)  0.004   Acute renal failure  130 (26.6)  100 (17.9)  0.001   Septic shock  54 (11)  11 (2)  <0.001   Splenomegaly  22 (4.5)  59 (10.6)  <0.001   Confusional syndrome  75 (15.3)  43 (7.7)  <0.001   Coma  18 (3.7)  5 (0.9)  0.002   Stroke    Haemorrhagic  23 (4.7)  12 (2.1)  0.008    Ischaemic  69 (14.1)  57 (10.1)  0.008   Systemic embolism  97 (19.8)  103 (18.5)  0.572   Arthritis/spondylodiscitis  48 (9.8)  75 (13.3)  0.072  Laboratory parameters   C-reactive protein  12.9 (4.4–53.8)  9 (3.6–36.3)  0.033   Haemoglobin (gr/dl)  11.3 (2.2)  10.9 (1.9)  0.002   Platelet count (/μl)  175 × 103 (119–248) × 103  211 × 103 (156–280) × 103  <0.001    Acute-onset IE (n = 491)  Non-acute-onset IE (n = 562)  P-value  Age (years)  64.7 (14.6)  63.4 (14.6)  0.156  Gender (male)  300 (61.1)  370 (65.8)  0.111  Community-acquired IE  287 (58.5)  432 (76.9)  <0.001  Prosthetic valve IE  219 (44.6)  200 (35.6)  0.003  Antibiotic therapy prior to admission  127 (29.5)  185 (37.8)  0.009  Centre 1  178 (36.3)  200 (35.6)  0.837  Centre 2  158 (32.2)  175 (31.1)  Centre 3  155 (31.6)  187 (33.3)  Comorbidities   Chronic anaemia  108 (22)  120 (21.4)  0.810   Chronic renal failure  73 (14.9)  66 (11.8)  0.141   Diabetes  123 (25.2)  117 (20.9)  0.098   COPD  42 (8.6)  44 (7.9)  0.666   Alcoholism  39 (8)  33 (5.9)  0.185   Malignant neoplasia  48 (9.8)  60 (10.7)  0.624   Immunosuppression  40 (8.2)  30 (5.4)  0.074  Clinical manifestations at admission   Fever  347 (71.4)  393 (70.3)  0.698   Heart failure  172 (35.2)  245 (43.9)  0.004   Acute renal failure  130 (26.6)  100 (17.9)  0.001   Septic shock  54 (11)  11 (2)  <0.001   Splenomegaly  22 (4.5)  59 (10.6)  <0.001   Confusional syndrome  75 (15.3)  43 (7.7)  <0.001   Coma  18 (3.7)  5 (0.9)  0.002   Stroke    Haemorrhagic  23 (4.7)  12 (2.1)  0.008    Ischaemic  69 (14.1)  57 (10.1)  0.008   Systemic embolism  97 (19.8)  103 (18.5)  0.572   Arthritis/spondylodiscitis  48 (9.8)  75 (13.3)  0.072  Laboratory parameters   C-reactive protein  12.9 (4.4–53.8)  9 (3.6–36.3)  0.033   Haemoglobin (gr/dl)  11.3 (2.2)  10.9 (1.9)  0.002   Platelet count (/μl)  175 × 103 (119–248) × 103  211 × 103 (156–280) × 103  <0.001  Values are n (%) or mean (SD), except C-reactive protein and platelet count that are presented as median. COPD: chronic obstructive pulmonary disease; IE: infective endocarditis; SD: standard deviation. Boldface indicates statistically significant differences between groups. At admission, important clinical differences were found: presentation with acute renal failure, septic shock, confusional syndrome and central nervous system embolism predominated among patients with acute-onset IE. On the contrary, heart failure was more common in patients with non-acute onset of IE (Table 1). Microbiological profile Staphylococcus aureus was more frequently isolated in episodes with acute onset, whereas infections due to enterococci and streptococci (viridans, gallolyticus and other species) were more commonly present in those patients with non-acute presentation of IE (Table 2). Table 2: Microbiological profile in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Streptococcus gallolyticus  13 (2.6)  33 (5.9)  0.010  Streptococcus viridans  36 (7.3)  97 (17.3)  <0.001  Other estreptococci  40 (8.1)  29 (5.2)  0.052  Enterococci  35 (7.1)  78 (13.9)  <0.001  Staphylococcus aureus  136 (27.7)  94 (7.8)  <0.001  Coagulase-negative staphylococci  88 (17.9)  80 (14.3)  0.106  Gram-negative bacilli  19 (3.9)  16 (2.9)  0.359  Fungi  6 (1.2)  7 (1.2)  0.359  HACEK group  2 (0.4)  3 (0.5)  >0.999  Anaerobes  8 (1.6)  13 (2.3)  0.426  Polymicrobial  32 (6.5)  49 (8.7)  0.178  Others  10 (2)  29 (5.2)  0.007  Culture-negative  66 (13.4)  83 (14.8)  0.530    Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Streptococcus gallolyticus  13 (2.6)  33 (5.9)  0.010  Streptococcus viridans  36 (7.3)  97 (17.3)  <0.001  Other estreptococci  40 (8.1)  29 (5.2)  0.052  Enterococci  35 (7.1)  78 (13.9)  <0.001  Staphylococcus aureus  136 (27.7)  94 (7.8)  <0.001  Coagulase-negative staphylococci  88 (17.9)  80 (14.3)  0.106  Gram-negative bacilli  19 (3.9)  16 (2.9)  0.359  Fungi  6 (1.2)  7 (1.2)  0.359  HACEK group  2 (0.4)  3 (0.5)  >0.999  Anaerobes  8 (1.6)  13 (2.3)  0.426  Polymicrobial  32 (6.5)  49 (8.7)  0.178  Others  10 (2)  29 (5.2)  0.007  Culture-negative  66 (13.4)  83 (14.8)  0.530  HACEK: Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella spp.; IE: infective endocarditis. Boldface indicates statistically significant differences between groups. Table 2: Microbiological profile in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Streptococcus gallolyticus  13 (2.6)  33 (5.9)  0.010  Streptococcus viridans  36 (7.3)  97 (17.3)  <0.001  Other estreptococci  40 (8.1)  29 (5.2)  0.052  Enterococci  35 (7.1)  78 (13.9)  <0.001  Staphylococcus aureus  136 (27.7)  94 (7.8)  <0.001  Coagulase-negative staphylococci  88 (17.9)  80 (14.3)  0.106  Gram-negative bacilli  19 (3.9)  16 (2.9)  0.359  Fungi  6 (1.2)  7 (1.2)  0.359  HACEK group  2 (0.4)  3 (0.5)  >0.999  Anaerobes  8 (1.6)  13 (2.3)  0.426  Polymicrobial  32 (6.5)  49 (8.7)  0.178  Others  10 (2)  29 (5.2)  0.007  Culture-negative  66 (13.4)  83 (14.8)  0.530    Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Streptococcus gallolyticus  13 (2.6)  33 (5.9)  0.010  Streptococcus viridans  36 (7.3)  97 (17.3)  <0.001  Other estreptococci  40 (8.1)  29 (5.2)  0.052  Enterococci  35 (7.1)  78 (13.9)  <0.001  Staphylococcus aureus  136 (27.7)  94 (7.8)  <0.001  Coagulase-negative staphylococci  88 (17.9)  80 (14.3)  0.106  Gram-negative bacilli  19 (3.9)  16 (2.9)  0.359  Fungi  6 (1.2)  7 (1.2)  0.359  HACEK group  2 (0.4)  3 (0.5)  >0.999  Anaerobes  8 (1.6)  13 (2.3)  0.426  Polymicrobial  32 (6.5)  49 (8.7)  0.178  Others  10 (2)  29 (5.2)  0.007  Culture-negative  66 (13.4)  83 (14.8)  0.530  HACEK: Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella spp.; IE: infective endocarditis. Boldface indicates statistically significant differences between groups. Echocardiographic findings Echocardiographic data are shown in Table 2. Prosthetic valve infection was more frequent in patients with acute presentation. On the contrary, native valve infection, especially in the aortic location, was more common in non-acute IE. The detection of vegetations, their size and the presence of periannular complications were similar in both groups of patients. Moderate to severe valvular regurgitation was more common in patients with non-acute presentation (Table 3). Table 3: Echocardiographic findings   Acute-onset IE (n = 491)  Non-acute- onset IE (n = 562)  P-value  Location of the infection, n (%)   Aortic valve (native)  135 (27.5)  234 (41.6)  <0.001   Mitral valve (native)  185 (37.7)  225 (40)  0.434   Mechanical aortic prosthesis  66 (13.4)  66 (11.7)  0.406   Mechanical mitral prosthesis  118 (24)  100 (17.8)  0.013   Biological aortic prosthesis  46 (9.4)  41 (7.3)  0.223   Biological mitral prosthesis  10 (2)  12 (2.1)  0.911  Vegetation detection, n (%)  413 (85.7)  454 (82.7)  0.190  Vegetation size (mm), median (IQR)  12 (7.5–17)  12 (8–18)  0.800  Moderate-severe valvular regurgitation, n (%)  290 (60.2)  420 (76.5)  <0.001  Paravalvular complications, n (%)  126 (26.1)  153 (27.9)  0.533   Abscess  78 (16.2)  79 (14.4)  0.424   Pseudoaneurysm  60 (12.4)  95 (17.3)  0.030    Acute-onset IE (n = 491)  Non-acute- onset IE (n = 562)  P-value  Location of the infection, n (%)   Aortic valve (native)  135 (27.5)  234 (41.6)  <0.001   Mitral valve (native)  185 (37.7)  225 (40)  0.434   Mechanical aortic prosthesis  66 (13.4)  66 (11.7)  0.406   Mechanical mitral prosthesis  118 (24)  100 (17.8)  0.013   Biological aortic prosthesis  46 (9.4)  41 (7.3)  0.223   Biological mitral prosthesis  10 (2)  12 (2.1)  0.911  Vegetation detection, n (%)  413 (85.7)  454 (82.7)  0.190  Vegetation size (mm), median (IQR)  12 (7.5–17)  12 (8–18)  0.800  Moderate-severe valvular regurgitation, n (%)  290 (60.2)  420 (76.5)  <0.001  Paravalvular complications, n (%)  126 (26.1)  153 (27.9)  0.533   Abscess  78 (16.2)  79 (14.4)  0.424   Pseudoaneurysm  60 (12.4)  95 (17.3)  0.030  IE: infective endocarditis; IQR: interquartile range. Boldface indicates statistically significant differences between groups. Table 3: Echocardiographic findings   Acute-onset IE (n = 491)  Non-acute- onset IE (n = 562)  P-value  Location of the infection, n (%)   Aortic valve (native)  135 (27.5)  234 (41.6)  <0.001   Mitral valve (native)  185 (37.7)  225 (40)  0.434   Mechanical aortic prosthesis  66 (13.4)  66 (11.7)  0.406   Mechanical mitral prosthesis  118 (24)  100 (17.8)  0.013   Biological aortic prosthesis  46 (9.4)  41 (7.3)  0.223   Biological mitral prosthesis  10 (2)  12 (2.1)  0.911  Vegetation detection, n (%)  413 (85.7)  454 (82.7)  0.190  Vegetation size (mm), median (IQR)  12 (7.5–17)  12 (8–18)  0.800  Moderate-severe valvular regurgitation, n (%)  290 (60.2)  420 (76.5)  <0.001  Paravalvular complications, n (%)  126 (26.1)  153 (27.9)  0.533   Abscess  78 (16.2)  79 (14.4)  0.424   Pseudoaneurysm  60 (12.4)  95 (17.3)  0.030    Acute-onset IE (n = 491)  Non-acute- onset IE (n = 562)  P-value  Location of the infection, n (%)   Aortic valve (native)  135 (27.5)  234 (41.6)  <0.001   Mitral valve (native)  185 (37.7)  225 (40)  0.434   Mechanical aortic prosthesis  66 (13.4)  66 (11.7)  0.406   Mechanical mitral prosthesis  118 (24)  100 (17.8)  0.013   Biological aortic prosthesis  46 (9.4)  41 (7.3)  0.223   Biological mitral prosthesis  10 (2)  12 (2.1)  0.911  Vegetation detection, n (%)  413 (85.7)  454 (82.7)  0.190  Vegetation size (mm), median (IQR)  12 (7.5–17)  12 (8–18)  0.800  Moderate-severe valvular regurgitation, n (%)  290 (60.2)  420 (76.5)  <0.001  Paravalvular complications, n (%)  126 (26.1)  153 (27.9)  0.533   Abscess  78 (16.2)  79 (14.4)  0.424   Pseudoaneurysm  60 (12.4)  95 (17.3)  0.030  IE: infective endocarditis; IQR: interquartile range. Boldface indicates statistically significant differences between groups. In-hospital evolution During hospitalization, the development of heart failure was similar between groups. Patients with acute-onset IE showed more persistent fever and developed systemic embolism and septic shock during hospitalization more frequently (Table 4). Patients with acute-onset IE underwent surgery less frequently than those with non-acute-onset IE (Table 4). The surgical risk according to the logistic EuroSCORE was higher in patients with acute-onset IE [30% (14.9–50.1) vs 20% (9–38.9), P = 0.011]. Table 4: Clinical events during in-hospital evolution in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Fever  107 (21.8)  55 (9.8)  0.007  Heart failure  111 (22.6)  110 (19.6)  0.228  CNS embolism  29 (5.9)  24 (4.3)  0.226  Systemic embolism  68 (13.8)  55 (9.8)  0.041  Acute renal failure  103 (21)  99 (17.6)  0.167  AV block  26 (5.3)  33 (5.9)  0.685  Septic shock  58 (11.8)  38 (6.8)  0.005  Surgery  251 (51.1)  360 (64.2)  <0.001  Death  208 (42.7)  168 (30.1)  <0.001    Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Fever  107 (21.8)  55 (9.8)  0.007  Heart failure  111 (22.6)  110 (19.6)  0.228  CNS embolism  29 (5.9)  24 (4.3)  0.226  Systemic embolism  68 (13.8)  55 (9.8)  0.041  Acute renal failure  103 (21)  99 (17.6)  0.167  AV block  26 (5.3)  33 (5.9)  0.685  Septic shock  58 (11.8)  38 (6.8)  0.005  Surgery  251 (51.1)  360 (64.2)  <0.001  Death  208 (42.7)  168 (30.1)  <0.001  Events that were already present at admission to the hospital have not been included in this table. AV block: atrioventricular block; CNS: central nervous system; IE: infective endocarditis. Boldface indicates statistically significant differences between groups. Table 4: Clinical events during in-hospital evolution in 1053 episodes of left-sided infective endocarditis   Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Fever  107 (21.8)  55 (9.8)  0.007  Heart failure  111 (22.6)  110 (19.6)  0.228  CNS embolism  29 (5.9)  24 (4.3)  0.226  Systemic embolism  68 (13.8)  55 (9.8)  0.041  Acute renal failure  103 (21)  99 (17.6)  0.167  AV block  26 (5.3)  33 (5.9)  0.685  Septic shock  58 (11.8)  38 (6.8)  0.005  Surgery  251 (51.1)  360 (64.2)  <0.001  Death  208 (42.7)  168 (30.1)  <0.001    Acute-onset IE (n = 491), n (%)  Non-acute- onset IE (n = 562), n (%)  P-value  Fever  107 (21.8)  55 (9.8)  0.007  Heart failure  111 (22.6)  110 (19.6)  0.228  CNS embolism  29 (5.9)  24 (4.3)  0.226  Systemic embolism  68 (13.8)  55 (9.8)  0.041  Acute renal failure  103 (21)  99 (17.6)  0.167  AV block  26 (5.3)  33 (5.9)  0.685  Septic shock  58 (11.8)  38 (6.8)  0.005  Surgery  251 (51.1)  360 (64.2)  <0.001  Death  208 (42.7)  168 (30.1)  <0.001  Events that were already present at admission to the hospital have not been included in this table. AV block: atrioventricular block; CNS: central nervous system; IE: infective endocarditis. Boldface indicates statistically significant differences between groups. There were 376 deaths (35.7%); 208 of 491 (42.7%) patients with acute-onset IE died. Death was much more common in patients with acute-onset IE than in those with non-acute IE (42.7% vs 30.1%, P < 0.001) (Table 4). Differences between survivors and non-survivors among patients who did undergo surgery and those treated medically were analysed (Supplementary Material, Tables S1–S4). In both groups, older patients with more comorbidities, prosthetic valve carriers, non-community acquired infections, S. aureus IE, as well as those who developed septic shock during hospitalization had higher mortality. In addition, among patients who did not undergo surgery, those with heart failure had a worse outcome. To assess the potential impact of time span on the results, the patient population was divided into 2 groups of approximately equal size: patients included between 1996 and 2006 (n = 508) and those included between 2007 and 2014 (n = 543). There was no significant difference in mortality between the 2 periods of time (38.6% vs 33.7%, P = 0.100). Multivariable analysis for mortality We performed a multivariable analysis to predict mortality with the information obtained at admission or during the 1st week of hospitalization. We found that periannular complications, nosocomial infection, heart failure, S. aureus infection and septic shock were predictors of mortality. Acute-onset presentation of IE was strongly associated with increased mortality after adjustment for other variables (Fig. 1). Figure 1: View largeDownload slide Multivariable analysis to predict mortality in the whole cohort of 1053 patients with left-sided infective endocarditis. OR and 95% confidence intervals are represented in the graph. IE: infective endocarditis; OR: odds ratio. Figure 1: View largeDownload slide Multivariable analysis to predict mortality in the whole cohort of 1053 patients with left-sided infective endocarditis. OR and 95% confidence intervals are represented in the graph. IE: infective endocarditis; OR: odds ratio. Evaluation of the potential influence of surgical timing in mortality Focusing on patients with acute-onset IE, a multivariable logistic regression analysis for prediction of mortality was performed. We aimed to explore the potential impact of surgical timing over mortality among this high-risk population. Thus, time from diagnosis to surgery was included in the model and was classified into quartiles. In addition, we included in the model those variables previously known to be associated with increased mortality and those which resulted statistically significant in the univariable analysis. To avoid potential sources of bias, those patients with an indication for surgery who did not undergo surgery due to high surgical risk were not included in the model (48 patients). Nosocomial infection, presence of paravalvular complications, cerebral embolism, heart failure and septic shock were independently associated with increased mortality (Table 5). On the contrary, early surgery [performed within the 1st quartile of time (<2 days)] was associated with a 64% reduction in mortality in patients with acute-onset IE. As expected, surgery performed within the 4th quartile (>18 days) was also associated with a lower mortality. However, when the previous multivariable analysis was performed in patients with non-acute-onset IE, surgical timing was not an independent predictor of lower mortality (Supplementary Material, Table S5). Table 5: Multivariable analysis for prediction of mortality in patients with acute-onset infective endocarditis (n = 443) Variables  OR  95% CI  P-value  Time to surgery         Quartile 1  0.36  0.18–0.73  0.005   Quartile 2  0.69  0.33–1.44  0.323   Quartile 3  0.52  0.26–1.05  0.066   Quartile 4  0.31  0.14–0.67  0.003  Age  1.01  0.99–1.03  0.298  Acute renal failure  1.16  0.70–1.92  0.561  Vegetation  1.35  0.69–2.63  0.377  Staphylococcus aureus  1.40  0.83–2.35  0.208  Paravalvular complications  1.78  1.05–3.01  0.031  Nosocomial origin  2.06  1.26–3.34  0.004  CNS embolism  2.08  1.08–4.01  0.030  Heart failure  2.55  1.55–4.19  <0.001  Septic shock  7.74  4.42–13.57  <0.001  Variables  OR  95% CI  P-value  Time to surgery         Quartile 1  0.36  0.18–0.73  0.005   Quartile 2  0.69  0.33–1.44  0.323   Quartile 3  0.52  0.26–1.05  0.066   Quartile 4  0.31  0.14–0.67  0.003  Age  1.01  0.99–1.03  0.298  Acute renal failure  1.16  0.70–1.92  0.561  Vegetation  1.35  0.69–2.63  0.377  Staphylococcus aureus  1.40  0.83–2.35  0.208  Paravalvular complications  1.78  1.05–3.01  0.031  Nosocomial origin  2.06  1.26–3.34  0.004  CNS embolism  2.08  1.08–4.01  0.030  Heart failure  2.55  1.55–4.19  <0.001  Septic shock  7.74  4.42–13.57  <0.001  Time from diagnosis to surgery (days): quartile 1 (<2), quartile 2 (2–8), quartile 3 (8–18) and quartile 4 (>18). CI: confidence interval; CNS: central nervous system; OR: odds ratio. Boldface indicates statistically significant differences between groups. Table 5: Multivariable analysis for prediction of mortality in patients with acute-onset infective endocarditis (n = 443) Variables  OR  95% CI  P-value  Time to surgery         Quartile 1  0.36  0.18–0.73  0.005   Quartile 2  0.69  0.33–1.44  0.323   Quartile 3  0.52  0.26–1.05  0.066   Quartile 4  0.31  0.14–0.67  0.003  Age  1.01  0.99–1.03  0.298  Acute renal failure  1.16  0.70–1.92  0.561  Vegetation  1.35  0.69–2.63  0.377  Staphylococcus aureus  1.40  0.83–2.35  0.208  Paravalvular complications  1.78  1.05–3.01  0.031  Nosocomial origin  2.06  1.26–3.34  0.004  CNS embolism  2.08  1.08–4.01  0.030  Heart failure  2.55  1.55–4.19  <0.001  Septic shock  7.74  4.42–13.57  <0.001  Variables  OR  95% CI  P-value  Time to surgery         Quartile 1  0.36  0.18–0.73  0.005   Quartile 2  0.69  0.33–1.44  0.323   Quartile 3  0.52  0.26–1.05  0.066   Quartile 4  0.31  0.14–0.67  0.003  Age  1.01  0.99–1.03  0.298  Acute renal failure  1.16  0.70–1.92  0.561  Vegetation  1.35  0.69–2.63  0.377  Staphylococcus aureus  1.40  0.83–2.35  0.208  Paravalvular complications  1.78  1.05–3.01  0.031  Nosocomial origin  2.06  1.26–3.34  0.004  CNS embolism  2.08  1.08–4.01  0.030  Heart failure  2.55  1.55–4.19  <0.001  Septic shock  7.74  4.42–13.57  <0.001  Time from diagnosis to surgery (days): quartile 1 (<2), quartile 2 (2–8), quartile 3 (8–18) and quartile 4 (>18). CI: confidence interval; CNS: central nervous system; OR: odds ratio. Boldface indicates statistically significant differences between groups. We analysed the profiles of patients across the different quartiles of time from diagnosis to surgery and found some differences which deserve consideration. Patients who did not undergo surgery were older than those who had surgery. Patients who underwent surgery within the first 2 days had heart failure and septic shock at admission more frequently. Central nervous system embolism was more frequent among patients in the 3rd quartile. Development of heart failure and periannular extension of infection during hospitalization were more common in patients in the 3rd quartile, whereas a higher proportion of those who underwent surgery later in the 4th quartile, developed acute renal failure. New onset of septic shock during hospitalization was observed more frequently among patients in the 2nd quartile. Regarding the microbiological profile, those patients from the 1st quartile had negative cultures more frequently. In-hospital mortality of patients who underwent early surgery was 33%, significantly lower than those who did not undergo surgery (43.8%) or when the surgery was performed in the 2nd (46.2%) or the 3rd quartile (39.7%) of time. As previously mentioned, surgery performed within the 4th quartile (>18 days) was also associated with a lower mortality (22.4%) (Supplementary Material, Tables S6–S9). DISCUSSION To determine the appropriate treatment of patients with IE and the timing of surgery, it is important to be able to detect those patients who are at higher risk. The results of the current study show that acute clinical presentation is a risk marker in patients with IE. In fact, acute-onset IE was associated with a 4.5-fold increased risk of mortality after multivariable adjustment. According to our results, patients with acute-onset IE are a subgroup of patients in whom manifestations of sepsis at admission as well as during hospitalization are more prominently displayed (fever, septic shock, acute renal failure, confusional syndrome, stroke, etc.). Staphylococcus aureus is the microorganism most probably involved in this clinical scenario. Other studies, although scarce, have analysed the prognosis of patients with IE according to the temporality from the onset of symptoms to diagnosis with similar results [9, 14]. Surgery was performed in 58% of patients in this study. Surgical indications are fairly well established in the main guidelines and can be summarized in 3 categories: heart failure, uncontrolled infection and prevention of embolism [3, 15]. However, for certain patients, this is not always so clear-cut and there is often debate, for example, in cases of mild heart failure or regarding the vegetation size to consider high embolic risk. In addition, the optimal timing of surgery is also a contentious issue. Some advocate for early surgery [16], whereas others prefer delaying surgery with a longer duration of antibiotic therapy to achieve better control of sepsis and stabilization of haemodynamics, which does not always occur. According to Tornos et al. [17], up to 28–47% of patients with native valve IE who initially received medical therapy alone will eventually require surgery for valve replacement, mostly during the 2 years following the index episode. In our study, after adjustment for other important prognostic variables, early surgery (performed within 48 h after diagnosis) was associated with a 64% relative reduction of mortality in patients with acute-onset IE compared to medical therapy alone. To date, just one randomized clinical trial has evaluated the potential role of early surgery (undertaken within 48 h of randomization) in the prognosis of IE patients [16]. In that study, the population included was at a lower risk than ours. Mostly young patients (mean age 47 years) with infected native valves predominantly due to streptococci were included. Early surgery was associated with a significant reduction in the composite end point of in-hospital death or embolism, mainly due to the reduction of embolism. On the contrary, several studies by the ICE-PCS registry have shown conflicting results [4, 18, 19]. Here, we could be facing an issue of definition, i.e. in these studies, early surgery was defined as one undertaken within the course of the initial hospitalization for IE. In fact, there is no universal definition for early surgery. The recent European Society of Cardiology (ESC) guidelines distinguish emergency surgery (performed within 24 h) and urgent surgery (within a few days) from elective surgery (after 1–2 weeks of antibiotics), whereas the American Heart Association (AHA) guidelines define early surgery when it is performed during initial hospitalization and before completion of a full course of antibiotics. Thus, a single universal definition of early surgery should be pursued. When considering the profiles of patients across the different quartiles of time from diagnosis to surgery, we found that patients who underwent surgery within the 1st quartile of time showed a higher risk profile as they had heart failure and septic shock more often on admission. In this high-risk group, very early surgery achieved a relative reduction in mortality of 64%. On the contrary, those patients operated later (4th quartile, after 18 days) showed a more benign presentation at diagnosis. In this subgroup, surgery was also associated with a reduction in mortality. Besides, patients with acute-onset IE in whom surgery was deferred due to high risk but who have survived more than 18 days had a higher chance of surviving after surgery. Surgical benefit was lower among patients who underwent surgery between the 2nd and 18th days after diagnosis (quartiles 2 and 3). Patients operated during this time frame had more central nervous system embolism at admission. This fact most probably influenced the post-surgical evolution and prognosis of these patients. In summary, the results of this study highlight a 2-fold message: first, patients with IE and acute onset of symptoms are at a high risk of septic in-hospital complications and mortality; second, early surgery (performed during the first 48 h) plays a central role in the treatment of these patients. Therefore, based on our results, it follows that once the surgical indication has been established, surgery needs to be performed as soon as possible. Limitations This study has several limitations that should be considered when interpreting the results. Although it is a multicentre study including a large number of patients, it has potential referral bias because all the participants are tertiary care centres. Besides, this is an observational study with limitations inherent to this type of studies. Information in regards intraoperative procedures, such as time of cardiopulmonary bypass or cross clamping time, was not available. The onset of symptoms was inevitably determined retrospectively by patients and the treating physician, although included prospectively in our database. Therefore, it could be affected by recall bias. Moreover, many of the IE-related symptoms were non-specific, and sometimes it was difficult to determine with certainty if they were related to IE. CONCLUSION Acute-onset IE is independently associated with a higher risk of in-hospital complications and a higher mortality. Early surgery, performed within the first 2 days after diagnosis, was associated with lower in-hospital mortality in patients with acute-onset IE. Randomized studies would be needed to adequately assess the impact of surgical timing over mortality in this high-risk population. SUPPLEMENTARY MATERIAL Supplementary material is available at EJCTS online. Conflict of interest: none declared. REFERENCES 1 Fernández-Hidalgo N, Almirante B, Tornos P, González-Alujas MT, Planes AM, Galiñanes M et al.   Immediate and long-term outcome of left-sided infective endocarditis. A 12-year prospective study from acontemporary cohort in a referral hospital. Clin Microbiol Infect  2012; 18: E522– 30. Google Scholar CrossRef Search ADS PubMed  2 Fernández-Hidalgo N, Tornos Mas P. Epidemiology of infective endocarditis in Spain in the last 20 years. 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Impact of early valve surgery on outcome of Staphylococcus aureus prosthetic valve infective endocarditis: analysis in the International Collaboration of Endocarditis-Prospective Cohort Study. Clin Infect Dis  2015; 60: 741– 9. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Jun 4, 2018

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