Outcome of surgical intervention for aortic root abscess: a meta-analysis

Outcome of surgical intervention for aortic root abscess: a meta-analysis Abstract OBJECTIVES Aortic root abscess (ARA) is a catastrophic complication of aortic root endocarditis, involving both native and prosthetic valves, which often warrants surgical intervention. Currently, aortic valve replacement (AVR) and aortic root replacement (ARR) are the most widely employed techniques. However, evidence that directly compares these methods is scarce. In this meta-analysis, we aimed to describe the surgical outcome of ARA when using different surgical methods. METHODS In this meta-analysis, we performed literature searches in the EMBASE and PubMed databases and reviewed articles describing postoperative results of ARA that were published before 30 June 2016. After extracting the published data, we used a random-effects model to perform meta-analysis and compare the postoperative outcomes of ARA after management with AVR or ARR. RESULTS Seven published studies were included in this meta-analysis, which includes 781 episodes of infective endocarditis complicated with ARA. There was no significant difference in the 30-day postoperative mortality rate among patients receiving ARR [23.8%, 95% confidence interval (CI) 17.8–30.6] compared with AVR (19.1%, 95% CI 13.3–26.1%), with a relative risk ratio of 1.30 (95% CI 0.84–2.00). However, patients receiving ARR were associated with statistically significant lower rates of reoperation within 1 year (relative risk 0.50, 95% CI 0.26–0.94). CONCLUSIONS In our meta-analysis, ARR was associated with a 50% risk reduction of reoperation within 1 year among patients with ARA. There was no significant difference in the 30-day postoperative mortality rate between patients receiving ARR and patients receiving AVR; comparison of the long-term outcomes after these 2 procedures warrants further investigation. Infective endocarditis, Prosthetic valve endocarditis, Periannular abscess, Aortic valve replacement, Aortic root replacement INTRODUCTION Aortic root abscess (ARA) is a catastrophic complication of aortic valve endocarditis, which involves both native and prosthetic valves. In earlier reports, uncontrolled ARA could lead to severe valvular dysfunction, fistula formation, perforation of cusps, pseudoaneurysm, obstruction of coronary flow or fatal arrhythmia resulting from the involvement of the atrioventricular node. In addition to antimicrobial therapy, several retrospective cohorts demonstrated improved clinical outcomes among patients who received timely surgical interventions [1, 2]. Successful medical management without surgery had been reported after prolonged courses of antibiotics extending beyond 9–18 months [3, 4]. However, even with surgical debridement and proper antimicrobial therapy, the in-hospital mortality rate reported in the literature was still high, ranging from 12.2% to 30% [5, 6]. Reported risk factors associated with increased mortality include prosthetic valve endocarditis (PVE) and Staphylococcus aureus infection [1, 7]. Furthermore, recurrent infections after surgery were frequent [8]. Although surgical intervention is considered the cornerstone of successful treatment, the procedure of choice is still debatable [9, 10]. Since the 1970s, for patients with periannular spreading of infection and destruction of the surrounding tissue, successful treatment involved surgical debridement and the insertion of prosthetic aortic valves [11]. However, recurrence of infection was still a concern during the longitudinal follow-up of patients who survived surgery for ARA [12]. In the 1980s, Okita et al. [13] reported successful management of ARA by surgical excision and implantation of an antibiotic-sterilized aortic homograft, which theoretically provided a more radical debridement of the infected tissue. Initially, this technique had not been widely used due to limited access to aortic homografts and early calcification of the implants [14]. In recent decades, the use of biological or synthetic materials for replacement of infected aortic root also provided satisfactory results [10, 15–17]. Now, depending on the expertise of different surgeons and hospitals, aortic valve replacement (AVR) with patching of the aortic root and total aortic root replacement (ARR) are the 2 most widely used techniques. However, data comparing these 2 procedures are scarce and prone to bias due to a retrospective design and limited patient numbers. Moreover, the optimal timing for surgery is challenging; although an emergency operation might facilitate the early control of infection [10], delaying surgery until after clinical stabilization might minimize perioperative risk. Because of the rarity and often emergent settings of the diseases, conducting prospective clinical trials to compare short-term and long-term outcomes of these 2 procedures would be difficult. Therefore, we conducted this meta-analysis and systemic review to compare the clinical outcomes of patients who received ARR and patients who received AVR. MATERIALS AND METHODS Two authors (G.-J.C and S.-C.P) independently performed literature searches in the PubMed and EMBASE databases for articles concerning the treatment of ARA that were published before 30 June 2016. Keywords used in the literature search were ‘aortic root abscess’ and ‘periannular abscess’. We aimed to include studies that provided primary data from randomized trials and prospective and retrospective cohorts. Case reports, reviews, correspondences, editorials or conference proceedings were excluded from further analysis. After removing duplicate pieces, articles were screened by titles and abstracts for eligibility. Eligible articles were subsequently assessed based on the full text. Data describing the perioperative outcome and postoperative mortality among patients with a diagnosis of ARA or a periannular abscess of aortic valve endocarditis were included for further analysis. In case of any discrepant opinions related to article inclusion, the third author (W.-C.L) was consulted and the final decision was made after discussion. Data extraction and quality assessment We used a standardized form to extract primary data from eligible studies regarding patient characteristics and demographics (e.g. patient number, gender, mean or median age, comorbidities and history of previous operation), valve condition [native valve endocarditis (NVE) versus PVE], operative data (operative method and the timing of surgery), definite culture results and clinical outcomes (mortality and rate of reoperation). The definitions of mortality, rate of reoperation and timing of surgery were unified for comparison across different studies. Early mortality was defined as 30-day all-cause mortality, and mortality rates were calculated at 30 days, 1 year, 5 years and 10 years. One-year reoperation rate was defined as whether the patients had valvular operations again among the enrolled cohort, after excluding deceased patients and patients who were lost to follow-up. The reasons for reoperation were also recorded from each study using the definition from the American Association of Thoracic Surgery (AATS) [18]. Using the clinical management guidelines released by the European Society of Cardiology (ESC) [19], an emergent operation is defined as surgery performed for ARA within 24 h of diagnosis and an urgent operation is defined as surgery within 2 weeks of diagnosis. However, some of the enrolled studies did not differentiate from the original reports between emergent operations and urgent operations. Therefore, to evaluate the association of outcome and the timing of surgery for patients with ARA in this meta-analysis, ARA patients who had emergent operations and urgent operations were pooled together and compared with those who received delayed or elective operations. For each trial, missing outcome data for the patient who was lost to follow-up during the observation period were managed by a last observation carried forward approach. The methodological quality of the selected articles was assessed using the Newcastle–Ottawa Scale with selection, comparability, and outcome dimensions [20]. Statistical analysis In this meta-analysis, we considered all-cause mortality at 30 days, 1 year, 5 years and 10 years as the primary outcomes of interest. Random-effects meta-analysis was conducted using the STATA Metaprop command, which allows computation of 95% confidence intervals (CIs) using the score statistic and the exact binomial method and incorporates the Freeman–Tukey double arcsine transformation of proportions. The relationship between the within-study mortality rate and the year of study was assessed using a weighted least square regression. We also determined the pooled relative risks (RRs) to assess the effect of risk factors (NVE versus PVE and ARR versus AVR) on 30-day all-cause mortality across selected studies. Weighted least square regression was used to observe the association between the timing of the operation and mortality. Heterogeneity was assessed using the Q statistic and the I2 statistic. Publication bias was examined using funnel plots and Egger tests. All of the statistical analysis was conducted with STATA software (12th edition, StataCorp, College Station, TX, USA). RESULTS Literature search Using a keyword search with ‘aortic root abscess’ or ‘periannular abscess’, 884 articles were found from EMBASE and PubMed that were published before 30 June 2016. After removing duplicate articles, 646 records were screened via their titles and abstracts. Twelve records were retrieved to check eligibility by assessing the full text. Two additional articles were found during full-text assessment and were screened. Eight articles were included in a qualitative synthesis [1, 5, 6, 21–25]. Additionally, 1 study included patients who did not undergo aortic surgery; this study was excluded from quantitative analysis [1]. Finally, a total of 7 records were included in the data extraction and meta-analysis (Fig. 1). Figure 1: View largeDownload slide Flow chart of literature search and enrolled studies. Figure 1: View largeDownload slide Flow chart of literature search and enrolled studies. From the 7 included studies, 781 episodes of infective endocarditis were reported. All of these episodes had complications with ARA or periannular abscess. Summaries of each study are shown in Table 1. All of the included articles were retrospective observational studies, with various follow-up periods ranging from 30 days to 10 years. The methodological assessment of all enrolled studies used the Newcastle–Ottawa Quality Assessment Scale for cohort studies; the results are shown in Table 2. Using funnel plots and an Egger test, no implication of publication bias was suspected (P-value of Egger test = 0.82, Supplementary Material, Fig. S3). Table 1: Summary of studies enrolled for data extraction and meta-analysisa References  Duration of enrolment  Total cases (n)  Age (years), mean (SD)  Duration of follow-up (months), mean (SD, range)  Male gender, n (%)  Overall 30-day mortality, % (95% CI)  Patients who underwent different procedures   Proportion of emergent/ urgent operations  ARR material  AVR (n)  ARR (n)  Glazier et al. [6]  1972–1989  30  42 (18)  66 (42, 9–144)  20 (67)  19 (13–27)  0b  30  100  H  Choussat et al. [21]  1989–1993  175  51 (15)  6 (1, 1–58)  105 (60)  22 (9–42)  161  14    Prosthetic material, pericardium  Yankah et al. [22]  1986–2001  161  53 (17)  60 (52, —c)  127 (79)  12 (5–25)  78  83  100  H  Musci et al. [23]  1986–2007  189        22 (17–29)  0b  189    H  Lee et al. [5]  1999–2012  49  50 (14)  69 (40, 2–159)  36 (73)  24 (17–31)  42  7  31  A, B, D  Leontyev et al. [25]  1999–2012  150  62 (15)  84 (6, 1–151)  130 (87)  17 (11–23)  59  91  91  A, B, D  Kirali et al. [24]  1998–2013  27  37 (13)  82 (44, —c)  20 (74)  23 (10–42)  20  7  26  Biological or prosthetic  References  Duration of enrolment  Total cases (n)  Age (years), mean (SD)  Duration of follow-up (months), mean (SD, range)  Male gender, n (%)  Overall 30-day mortality, % (95% CI)  Patients who underwent different procedures   Proportion of emergent/ urgent operations  ARR material  AVR (n)  ARR (n)  Glazier et al. [6]  1972–1989  30  42 (18)  66 (42, 9–144)  20 (67)  19 (13–27)  0b  30  100  H  Choussat et al. [21]  1989–1993  175  51 (15)  6 (1, 1–58)  105 (60)  22 (9–42)  161  14    Prosthetic material, pericardium  Yankah et al. [22]  1986–2001  161  53 (17)  60 (52, —c)  127 (79)  12 (5–25)  78  83  100  H  Musci et al. [23]  1986–2007  189        22 (17–29)  0b  189    H  Lee et al. [5]  1999–2012  49  50 (14)  69 (40, 2–159)  36 (73)  24 (17–31)  42  7  31  A, B, D  Leontyev et al. [25]  1999–2012  150  62 (15)  84 (6, 1–151)  130 (87)  17 (11–23)  59  91  91  A, B, D  Kirali et al. [24]  1998–2013  27  37 (13)  82 (44, —c)  20 (74)  23 (10–42)  20  7  26  Biological or prosthetic  a All included studies were retrospective observational cohort studies. b National Heart Hospital, London [6] and Deutsches Herzzentrum Berlin [23] had a policy that preferred ARR for aortic root abscess and only enrolled patients with ARR procedures. c Not provided in original articles. A: autologous pericardium; ARR: aortic root replacement; AVR: aortic valve replacement; B: bovine pericardium; CI: confidence interval; D: Dacron; H: homologous pericardium; SD: standard deviation. Table 2: Quality assessment of enrolled studies using the Newcastle-Ottawa Quality Assessment Scale (NOS) References  Selection   Comparability  Outcomes   Quality score  Representativeness of the exposed cohort  Selection of the non-exposed cohort  Ascertainment of exposure  Outcome of interest was not present at the start of study  Comparability of cohorts based on the design or analysis  Assessment of outcomes  Enough follow-up length  Adequacy of follow-up of cohorts  Glazier et al. [6]  ★  O  ★  ★  N/A  ★  ★  ★  6  Choussat et al. [21]  ★  ★  ★  ★  N/A  O  O  ★  5  Yankah et al. [22]  ★  ★  ★  ★  N/A  ★  ★  ★  7  Musci et al. [23]  ★  O  ★  ★  N/A  ★  ★  ★  6  Lee et al. [5]  ★  ★  ★  ★  O  O  ★  ★  6  Leontyev et al. [25]  ★  ★  ★  ★  ★  ★  ★  ★  8  Kirali et al. [24]  ★  ★  ★  ★  O  ★  ★  ★  7  References  Selection   Comparability  Outcomes   Quality score  Representativeness of the exposed cohort  Selection of the non-exposed cohort  Ascertainment of exposure  Outcome of interest was not present at the start of study  Comparability of cohorts based on the design or analysis  Assessment of outcomes  Enough follow-up length  Adequacy of follow-up of cohorts  Glazier et al. [6]  ★  O  ★  ★  N/A  ★  ★  ★  6  Choussat et al. [21]  ★  ★  ★  ★  N/A  O  O  ★  5  Yankah et al. [22]  ★  ★  ★  ★  N/A  ★  ★  ★  7  Musci et al. [23]  ★  O  ★  ★  N/A  ★  ★  ★  6  Lee et al. [5]  ★  ★  ★  ★  O  O  ★  ★  6  Leontyev et al. [25]  ★  ★  ★  ★  ★  ★  ★  ★  8  Kirali et al. [24]  ★  ★  ★  ★  O  ★  ★  ★  7  ★: one point attributed in the NOS; O: zero point attributed in the NOS; N/A: not applicable. Postoperative outcomes and risk factors In this meta-analysis, the 30-day, 1-year, 5-year and 10-year pooled mortality rates after surgery were 20% (95% CI 17–23%), 28% (95% CI 22–34%), 34% (95% CI 24–44%) and 36% (95% CI 25–48%), respectively (Fig. 2). The time of enrolment of the included studies varied significantly from 1972 to 2013; however, using a weighted least square regression, there was no statistically significant change of 30-day mortality across the time periods (P = 0.40, Supplementary Material, Fig. S1). Of all the included cohorts, 3 reported reoperation rates during follow-up, and 43 redo valvular surgeries were reported after the index operation for ARA [22, 24, 25]. The longest duration to reoperation reported in these 3 cohorts was 8 years after the index surgery. The overall rate of reoperation within 1 year, after excluding deceased patients, was 5.2% (95% CI 2.9–8.7%). The leading indications for repeat surgery were recurrence of infection and non-structural deterioration, which accounted for 53% and 42% of reoperated patients, respectively (data not shown). Figure 2: View largeDownload slide Pooled overall 30-day, 1-year, 5-year and 10-year mortality of patients with aortic root abscess. CI: confidence interval. Figure 2: View largeDownload slide Pooled overall 30-day, 1-year, 5-year and 10-year mortality of patients with aortic root abscess. CI: confidence interval. The pooled 30-day postoperative mortality rate was 19.1% (95% CI 13.3–26.1) among patients who received AVR and 23.8% (95% CI 17.8–30.6) among patients who received ARR. When compared with patients who underwent AVR, ARR was associated with a trend of increased 30-day postoperative mortality, although this correlation was not statistically significant (RR 1.30, 95% CI 0.84–2.00) (Fig. 3). However, ARR was associated with a lower rate of 1-year reoperation when compared with the AVR technique (RR 0.50, 95% CI 0.26–0.94) (Fig. 4). Furthermore, among patients with PVE, the 30-day mortality rate after operation was significantly higher than patients who received a diagnosis of NVE (RR 1.72, 95% CI 1.24–2.37) (Fig. 3). Figure 3: View largeDownload slide (A) Comparison of 30-day mortality among patients receiving ARR versus AVR technique. (B) Comparison of 30-day mortality among patients with PVE versus NVE. ARR: aortic root replacement; AVR: aortic valve replacement; CI: confidence interval; NVE: native valve endocarditis; PVE: prosthetic valve endocarditis. Figure 3: View largeDownload slide (A) Comparison of 30-day mortality among patients receiving ARR versus AVR technique. (B) Comparison of 30-day mortality among patients with PVE versus NVE. ARR: aortic root replacement; AVR: aortic valve replacement; CI: confidence interval; NVE: native valve endocarditis; PVE: prosthetic valve endocarditis. Figure 4: View largeDownload slide Comparison of 1-year reoperation rate among patients receiving ARR versus AVR technique. ARR: aortic root replacement; AVR: aortic valve replacement; CI: confidence interval. Figure 4: View largeDownload slide Comparison of 1-year reoperation rate among patients receiving ARR versus AVR technique. ARR: aortic root replacement; AVR: aortic valve replacement; CI: confidence interval. Timing of surgical intervention The optimal timing of ARA was also debatable; some specialists favoured emergent or urgent operation to obtain better control of infection, while others delayed surgery until after clinical stabilization to minimize perioperative morbidity and mortality. Five of the enrolled trials reported the timing of the operation [5, 6, 22, 24, 25]. We depicted the proportion of emergent operation and postoperative mortality rate from each cohort. There was no correlation between the timing of operation and mortality when using a weighted least square regression (P = 0.27, Supplementary Material, Fig. S2). Causative microorganism and mortality Five of the enrolled studies provided details concerning the causative pathogens associated with ARA (Table 3) [5, 6, 22, 24, 25]. Among patients with identifiable pathogens, staphylococci remained the most common pathogen and accounted for 28.1% of all ARA. Streptococci were the second most common micro-organism followed by enterococci, which accounted for 23.3% and 10.3% of all infections, respectively. In 1 cohort describing 67 patients with periannular abscesses, Anguera et al. [1] identified S.aureus infection as an independent risk for mortality. However, the correlation between postoperative mortality and causative microorganism was not discussed in other included studies. Table 3: Reported pathogens associated with aortic root abscess across different studies Pathogens  Glazier et al. [6] (n = 30), n (%)  Yankah et al. [22], (n = 161), n (%)  Lee et al. [5] (n = 49), n (%)  Leontyev et al. [25] (n = 150), n (%)  Kirali et al. [24] (n = 27), n (%)  Total (n = 417), n (%)  All staphylococci  14 (46.7)  47 (29.2)  6 (12.2)  40 (26.7)  10 (37.0)  117 (28.1)   Staphylococcus aureus  5 (16.7)  13 (8.1)  4 (8.2)  12 (8.0)  8 (29.6)  42 (10.1)   Coagulase-negative staphylococci  9 (30.0)  34 (21.1)  2 (4.1)  28 (18.7)  2 (7.4)  75 (18.0)  Streptococci  11 (36.7)  39 (24.2)  21 (42.9)  22 (14.7)  4 (14.8)  97 (23.3)  Enterococci  1 (3.3)  23 (14.3)  3 (6.1)  13 (8.7)  3 (11.1)  43 (10.3)  Gram-negative bacilli  1 (3.3)  NR  3 (6.1)  NR  0 (0)  a  Candida spp.  0 (0)  NR  1 (2.0)  1 (0.7)  1 (3.7)  a  Not identified, culture-negative  3 (10.0)  NR  15 (30.6)  63 (42.0)  9 (33.3)  a  Pathogens  Glazier et al. [6] (n = 30), n (%)  Yankah et al. [22], (n = 161), n (%)  Lee et al. [5] (n = 49), n (%)  Leontyev et al. [25] (n = 150), n (%)  Kirali et al. [24] (n = 27), n (%)  Total (n = 417), n (%)  All staphylococci  14 (46.7)  47 (29.2)  6 (12.2)  40 (26.7)  10 (37.0)  117 (28.1)   Staphylococcus aureus  5 (16.7)  13 (8.1)  4 (8.2)  12 (8.0)  8 (29.6)  42 (10.1)   Coagulase-negative staphylococci  9 (30.0)  34 (21.1)  2 (4.1)  28 (18.7)  2 (7.4)  75 (18.0)  Streptococci  11 (36.7)  39 (24.2)  21 (42.9)  22 (14.7)  4 (14.8)  97 (23.3)  Enterococci  1 (3.3)  23 (14.3)  3 (6.1)  13 (8.7)  3 (11.1)  43 (10.3)  Gram-negative bacilli  1 (3.3)  NR  3 (6.1)  NR  0 (0)  a  Candida spp.  0 (0)  NR  1 (2.0)  1 (0.7)  1 (3.7)  a  Not identified, culture-negative  3 (10.0)  NR  15 (30.6)  63 (42.0)  9 (33.3)  a  a The actual frequency of some pathogen was not reported and calculation of overall proportion was not possible. NR: not reported. DISCUSSION In this meta-analysis, including 7 clinical studies with 781 episodes of ARA, we found that patients who received ARR for management of ARA carried a 50% lower risk for repeat operation when compared with those who underwent AVR. There is a trend of an increased 30-day mortality rate among patients who underwent ARR compared with the AVR technique, although this is not statistically significant. Emergent or urgent operation was not associated with improved clinical outcomes in our meta-analysis. The only risk factor associated with increased mortality was PVE, which carries a 1.7-fold elevation of RR when compared with NVE. Postoperative outcomes ARA mortality remained high even with revolutionary techniques and novel materials. In our meta-analysis, the 30-day mortality remained as high as 20%, which saw no significant improvement during the past 3 decades (Supplementary Material, Fig. S1). We also found a trend for higher mortality among patients who received ARR rather than AVR. In another cohort of 100 patients with active aortic valve endocarditis and an unknown proportion of ARA, Mayer et al. [26] found a trend of increased mortality in patients who received ARR. However, the mortality among ARA patients is multifactorial, and many confounding factors must be balanced before directly comparing these 2 techniques. Due to the scarcity of enrolled clinical studies, meta-regression was not performed to stratify possible confounding factors such as age, gender, New York Heart Association functional classification, pathogens, perioperative clinical status and concurrent sepsis. Additionally, the preoperative risk assessment score was not universally available, as only Leontyev et al. [25] reported a logistic EuroSCORE as high as 62 ± 14% among all the ARA patients. The trend of increased mortality among the ARR group might be attributed to confounding by indication, as patients with more severe disease and more extensive destruction might tend to receive ARR and eventually carry a higher mortality rate. When choosing between these 2 procedures, both the National Heart Hospital, London (enrolled cases with PVE only) [6] and the Deutsches Herzzentrum Berlin (enrolled groups with NVE and PVE) [23] had a policy that preferred to remove infected tissues for patients with ARA and only included patients with ARR procedures. In other studies, the operation method was mainly chosen depending on the anatomical conditions [22, 24, 25]. Studies from Lee et al. [5] and Choussat et al. [21] did not provide clear indications for operation method selection. Thus, whether ARR can lead to lesser short-term or long-term mortality may need further investigation and would need to be stratified by valvular condition (NVE versus PVE) and other possible confounding factors. In our meta-analysis, 5.2% (95% CI 2.9–8.7%) of patients required repeat cardiac surgery after receiving surgery for ARA within the 1st postoperative year. By assessing the available data from the included studies in this meta-analysis, most of these reoperated patients received a second surgery due to recurrent infection and non-structural deterioration of the aortic valves. Extensive removal of the infected tissue followed by surgical reconstruction was favoured by some experts due to the destructive nature of the disease [10]. ARR had been suggested as an eradicative operation method to remove the most infectious tissue and provide a better reconstruction of the aortic root, which probably prevents a reoperation due to infection recurrence or non-structural deterioration [13, 27]. Our finding was in line with this assumption and demonstrated a reduced rate of repeat operations among the ARR group, with the RR being 0.43 (95% CI 0.24–0.62). To the best of our knowledge, this is the first meta-analysis to summarize the limited ARA cohort and confirm that there is a significantly lower risk for reoperation among ARR patients compared with AVR patients. Five of the 7 enrolled studies reported their data concerning patients with PVE versus NVE [5, 21–24], while only 1 of them was able to demonstrate an increased mortality rate among patients with PVE compared with NVE [23]. After pooling the data in our meta-analysis, PVE was associated with a 1.7-fold increase in 30-day postoperative mortality. The difference in clinical characteristics between NVE and PVE was well documented in previous studies. In these earlier reports, patients with PVE were associated with more periannular abscesses [28], more haemodynamic dysfunction, higher mortality and higher incidence of recurrence [7, 29]. However, most of these trials described patients with endocarditis rather than focusing on patients who had ARA complications. Our report was the first meta-analysis to describe the different clinical outcomes in patients with ARA that arose from PVE versus NVE and clearly demonstrated a higher risk of mortality in patients with PVE compared with NVE (RR 1.65, 95% CI 1.20–2.25). In several observational cohorts focusing on patients with PVE with or without ARA, there was a higher rate of preoperative haemodynamic instability that likely affected the perioperative outcome [7]. However, further studies are required to identify which risk factors contribute to the increased risk of mortality among PVE patient who have ARA complications. Timing of surgical procedure Despite being considered a surgical disease, the proper timing for operations among patients with ARA was not previously well studied. Although some centres performed emergent operations, such as the report by Leontyev et al. [25] in Germany, the study by Kirali et al. [24] in Turkey suggested that delayed-urgent surgery was feasible after stabilizing the infection and haemodynamic status. In the report by Yankah et al. [22], patients who received emergent operations had a 30-day mortality of 14.3%, which was not statistically different to the 9.3% 30-day mortality among non-emergent patients. The method of diagnosis may also influence the timing of the surgery. ARA diagnosis was based on echocardiography prior to surgery for studies published after 2000. However, in studies published before 2000, the decision to operate was mainly based on progressive cardiac failure and ongoing sepsis [6, 21], and most ARA cases were diagnosed based on macroscopic inspection or histological examination during surgery [21]. Our meta-analysis did not reveal a correlation between the proportion of emergent or urgent operations and postoperative mortality. It is worth noting that the individual data of timing of operation and mortality were not available for all enrolled studies; thus, we adopted an ecological study method in this study. Therefore, further investigation is needed to determine whether an emergent or an urgent operation improves the clinical outcomes of ARA. Surgery versus medical treatment In this meta-analysis, we focused on the outcomes of surgical patients, and thus, cohorts including patients who were ineligible for surgery were excluded. When considering the report by Anguera et al. [1], which included 67 patients with 11 (16%) of them ineligible for surgery, there was a trend for lower mortality in patients who had received surgery. In another report by Chan et al. [2], surgery was also associated with lower post-operative mortality (surgical patients versus non-surgical patients 51.6% vs 66.6%). Even though the results of both the aforementioned studies were not statistically significant, the studies may be underpowered by their limited case numbers. Among the 12 patients who were ineligible for surgery in the study by Chan et al. [2], only 3 (25%) of them survived more than 2 years without symptomatic heart failure, valvular deterioration or infection recurrence. Some authors reported successful medical treatment alone with a prolonged course of antibiotics for up to 9–18 months. Limitations Our study had several limitations, and thus interpretations of our results should be cautious. First, only 7 studies were included in our meta-analysis, and all of them were retrospective cohorts. However, our meta-analysis is the first attempt to gather sparse data related to ARA. We suggest that high-quality prospective clinical studies are warranted to confirm our findings related to clinical outcomes, especially the long-term reoperation rate after ARR and AVR. For this purpose, international multicentre initiatives, such as the International Cooperation on Endocarditis (http://www.endocarditis.org/ice/index.html), may provide useful information from prospectively enrolled cohorts. Second, the length of follow-up period in each study varied considerably (Table 1), and the completeness of each study’s follow-up could not be assessed with the original data. Outcomes from the 1st postoperative year were provided for comparison because we believed that the risk of loss to follow-up would be smaller. However, the use of last observation carried forward method in managing the missing data might lead to underestimation of the clinical event rate, especially the 5-year and 10-year mortality. We believe that the underestimation of mortality or reoperation rate because of missing data would be no different in ARR versus AVR or NVE versus PVE. Finally, several clinically relevant questions could not be answered by this meta-analysis and still warrant further study. We did not find associations between emergent or urgent operations and mortality, and thus the optimal timing for surgery is still debatable. The duration of antimicrobial treatment after operation cannot be assessed in our meta-analysis because of the limitations of the original data. Furthermore, the optimal treatment strategy for patients who were ineligible for surgery was discussed rarely in the past and remains unclear. CONCLUSION This meta-analysis revealed that ARA still carries a high risk for mortality even after a surgical intervention. There was no statistically significant difference in 30-day mortality among patients who received ARR versus AVR. However, when compared with AVR, ARR was associated with fewer repeated operations within 1 year. Further study is needed to evaluate the long-term mortality and reoperation rates between the 2 operation methods and to clarify the effects caused by other possible risk factors. SUPPLEMENTARY MATERIAL Supplementary material is available at EJCTS online. Conflict of interest: none declared. REFERENCES 1 Anguera I, Miro JM, Cabell CH, Abrutyn E, Fowler VGJr, Hoen B et al.   Clinical characteristics and outcome of aortic endocarditis with periannular abscess in the International Collaboration on Endocarditis Merged Database. Am J Cardiol  2005; 96: 976– 81. Google Scholar CrossRef Search ADS PubMed  2 Chan K-L. Early clinical course and long-term outcome of patients with infective endocarditis complicated by perivalvular abscess. CMAJ  2002; 167: 19– 24. Google Scholar PubMed  3 Tucker KJ, Johnson JA, Ong T, Mullen WL, Mailhot J. Medical management of prosthetic aortic valve endocarditis and aortic root abscess. Am Heart J  1993; 125: 1195– 7. Google Scholar CrossRef Search ADS PubMed  4 Enoch DA, Phillimore N, Karas JA, Horswill L, Mlangeni DA. Relapse of enterococcal prosthetic valve endocarditis with aortic root abscess following treatment with daptomycin in a patient not fit for surgery. J Med Microbiol  2010; 59: 482– 5. Google Scholar CrossRef Search ADS PubMed  5 Lee S, Chang BC, Park HK. Surgical experience with infective endocarditis and aortic root abscess. Yonsei Med J  2014; 55: 1253– 9. Google Scholar CrossRef Search ADS PubMed  6 Glazier JJ, Verwilghen J, Donaldson RM, Ross DN. Treatment of complicated prosthetic aortic valve endocarditis with annular abscess formation by homograft aortic root replacement. J Am Coll Cardiol  1991; 17: 1177– 82. Google Scholar CrossRef Search ADS PubMed  7 Romano G, Carozza A, Della Corte A, De Santo LS, Amarelli C, Torella M et al.   Native versus primary prosthetic valve endocarditis: comparison of clinical features and long-term outcome in 353 patients. J Heart Valve Dis  2004; 13: 200– 8; discussion 208–9. Google Scholar PubMed  8 Lytle BW, Priest BP, Taylor PC, Loop FD, Sapp SK, Stewart RW et al.   Surgical treatment of prosthetic valve endocarditis. J Thorac Cardiovasc Surg  1996; 111: 198– 207; discussion 207–10. Google Scholar CrossRef Search ADS PubMed  9 Yao Z, Hua Z, Jun X, Chan W, Xiao-Jun M. Lack of response in severe pneumocystis pneumonia to combined caspofungin and clindamycin treatment: a case report. Chin Med Sci J  2011; 26: 246– 8. Google Scholar CrossRef Search ADS PubMed  10 Okada K, Okita Y. Surgical treatment for aortic periannular abscess/pseudoaneurysm caused by infective endocarditis. Gen Thorac Cardiovasc Surg  2013; 61: 175– 81. Google Scholar CrossRef Search ADS PubMed  11 Danielson GK, Titus JL, DuShane JW. Successful treatment of aortic valve endocarditis and aortic root abscesses by insertion of prosthetic valve in ascending aorta and placement of bypass grafts to coronary arteries. J Thorac Cardiovasc Surg  1974; 67: 443– 9. Google Scholar PubMed  12 D’Udekem Y, David TE, Feindel CM, Armstrong S, Sun Z. Long-term results of surgery for active infective endocarditis. Eur J Cardiothorac Surg  1997; 11: 46– 52. Google Scholar CrossRef Search ADS PubMed  13 Okita Y, Franciosi G, Matsuki O, Robles A, Ross DN. Early and late results of aortic root replacement with antibiotic-sterilized aortic homograft. J Thorac Cardiovasc Surg  1988; 95: 696– 704. Google Scholar PubMed  14 Nottin R, Al-Attar N, Ramadan R, Azmoun A, Therasse A, Kortas C et al.   Aortic valve translocation for severe prosthetic valve endocarditis: early results and long-term follow-up. Ann Thorac Surg  2005; 79: 1486– 90. Google Scholar CrossRef Search ADS PubMed  15 Jassar AS, Bavaria JE, Szeto WY, Moeller PJ, Maniaci J, Milewski RK et al.   Graft selection for aortic root replacement in complex active endocarditis: does it matter? Ann Thorac Surg  2012; 93: 480– 7. Google Scholar CrossRef Search ADS PubMed  16 Muller LC, Chevtchik O, Bonatti JO, Muller S, Fille M, Laufer G. Treatment of destructive aortic valve endocarditis with the Freestyle Aortic Root Bioprosthesis. Ann Thorac Surg  2003; 75: 453– 6. Google Scholar CrossRef Search ADS PubMed  17 Leyh RG, Knobloch K, Hagl C, Ruhparwar A, Fischer S, Kofidis T et al.   Replacement of the aortic root for acute prosthetic valve endocarditis: prosthetic composite versus aortic allograft root replacement. J Thorac Cardiovasc Surg  2004; 127: 1416– 20. Google Scholar CrossRef Search ADS PubMed  18 Akins CW, Miller DC, Turina MI, Kouchoukos NT, Blackstone EH, Grunkemeier GL et al.   Guidelines for reporting mortality and morbidity after cardiac valve interventions. Ann Thorac Surg  2008; 85: 1490– 5. Google Scholar CrossRef Search ADS PubMed  19 Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F et al.   2015 ESC Guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J  2015; 36: 3075– 128. Google Scholar CrossRef Search ADS PubMed  20 Margulis AV, Pladevall M, Riera-Guardia N, Varas-Lorenzo C, Hazell L, Berkman ND et al.   Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank. Clin Epidemiol  2014; 6: 359– 68. Google Scholar CrossRef Search ADS PubMed  21 Choussat R, Thomas D, Isnard R, Michel PL, Iung B, Hanania G et al.   Perivalvular abscesses associated with endocarditis; clinical features and prognostic factors of overall survival in a series of 233 cases. Perivalvular Abscesses French Multicentre Study. Eur Heart J  1999; 20: 232– 41. Google Scholar CrossRef Search ADS PubMed  22 Yankah AC, Pasic M, Klose H, Siniawski H, Weng Y, Hetzer R. Homograft reconstruction of the aortic root for endocarditis with periannular abscess: a 17-year study. Eur J Cardiothorac Surg  2005; 28: 69– 75. Google Scholar CrossRef Search ADS PubMed  23 Musci M, Weng Y, Hubler M, Amiri A, Pasic M, Kosky S et al.   Homograft aortic root replacement in native or prosthetic active infective endocarditis: twenty-year single-center experience. J Thorac Cardiovasc Surg  2010; 139: 665– 73. Google Scholar CrossRef Search ADS PubMed  24 Kirali K, Sarikaya S, Ozen Y, Sacli H, Basaran E, Yerlikhan OA et al.   Surgery for aortic root abscess: a 15-year experience. Tex Heart Inst J  2016; 43: 20– 8. Google Scholar CrossRef Search ADS PubMed  25 Leontyev S, Davierwala PM, Krogh G, Feder S, Oberbach A, Bakhtiary F et al.   Early and late outcomes of complex aortic root surgery in patients with aortic root abscesses. Eur J Cardiothorac Surg  2016; 49: 447– 54; discussion 454–5. Google Scholar CrossRef Search ADS PubMed  26 Mayer K, Aicher D, Feldner S, Kunihara T, Schafers HJ. Repair versus replacement of the aortic valve in active infective endocarditis. Eur J Cardiothorac Surg  2012; 42: 122– 7. Google Scholar CrossRef Search ADS PubMed  27 David TE, Regesta T, Gavra G, Armstrong S, Maganti MD. Surgical treatment of paravalvular abscess: long-term results. Eur J Cardiothorac Surg  2007; 31: 43– 8. Google Scholar CrossRef Search ADS PubMed  28 Daniel WG, Mugge A, Martin RP, Lindert O, Hausmann D, Nonnast-Daniel B et al.   Improvement in the diagnosis of abscesses associated with endocarditis by transesophageal echocardiography. N Engl J Med  1991; 324: 795– 800. Google Scholar CrossRef Search ADS PubMed  29 Marcacci C, Trezzi M, Dreyfus GD. Recurrent aortic prosthetic valve endocarditis: a radical additional anatomical solution. Ann Thorac Surg  2016; 102: e577– 79. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Cardio-Thoracic Surgery Oxford University Press

Outcome of surgical intervention for aortic root abscess: a meta-analysis

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Oxford University Press
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1010-7940
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1873-734X
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10.1093/ejcts/ezx421
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Abstract

Abstract OBJECTIVES Aortic root abscess (ARA) is a catastrophic complication of aortic root endocarditis, involving both native and prosthetic valves, which often warrants surgical intervention. Currently, aortic valve replacement (AVR) and aortic root replacement (ARR) are the most widely employed techniques. However, evidence that directly compares these methods is scarce. In this meta-analysis, we aimed to describe the surgical outcome of ARA when using different surgical methods. METHODS In this meta-analysis, we performed literature searches in the EMBASE and PubMed databases and reviewed articles describing postoperative results of ARA that were published before 30 June 2016. After extracting the published data, we used a random-effects model to perform meta-analysis and compare the postoperative outcomes of ARA after management with AVR or ARR. RESULTS Seven published studies were included in this meta-analysis, which includes 781 episodes of infective endocarditis complicated with ARA. There was no significant difference in the 30-day postoperative mortality rate among patients receiving ARR [23.8%, 95% confidence interval (CI) 17.8–30.6] compared with AVR (19.1%, 95% CI 13.3–26.1%), with a relative risk ratio of 1.30 (95% CI 0.84–2.00). However, patients receiving ARR were associated with statistically significant lower rates of reoperation within 1 year (relative risk 0.50, 95% CI 0.26–0.94). CONCLUSIONS In our meta-analysis, ARR was associated with a 50% risk reduction of reoperation within 1 year among patients with ARA. There was no significant difference in the 30-day postoperative mortality rate between patients receiving ARR and patients receiving AVR; comparison of the long-term outcomes after these 2 procedures warrants further investigation. Infective endocarditis, Prosthetic valve endocarditis, Periannular abscess, Aortic valve replacement, Aortic root replacement INTRODUCTION Aortic root abscess (ARA) is a catastrophic complication of aortic valve endocarditis, which involves both native and prosthetic valves. In earlier reports, uncontrolled ARA could lead to severe valvular dysfunction, fistula formation, perforation of cusps, pseudoaneurysm, obstruction of coronary flow or fatal arrhythmia resulting from the involvement of the atrioventricular node. In addition to antimicrobial therapy, several retrospective cohorts demonstrated improved clinical outcomes among patients who received timely surgical interventions [1, 2]. Successful medical management without surgery had been reported after prolonged courses of antibiotics extending beyond 9–18 months [3, 4]. However, even with surgical debridement and proper antimicrobial therapy, the in-hospital mortality rate reported in the literature was still high, ranging from 12.2% to 30% [5, 6]. Reported risk factors associated with increased mortality include prosthetic valve endocarditis (PVE) and Staphylococcus aureus infection [1, 7]. Furthermore, recurrent infections after surgery were frequent [8]. Although surgical intervention is considered the cornerstone of successful treatment, the procedure of choice is still debatable [9, 10]. Since the 1970s, for patients with periannular spreading of infection and destruction of the surrounding tissue, successful treatment involved surgical debridement and the insertion of prosthetic aortic valves [11]. However, recurrence of infection was still a concern during the longitudinal follow-up of patients who survived surgery for ARA [12]. In the 1980s, Okita et al. [13] reported successful management of ARA by surgical excision and implantation of an antibiotic-sterilized aortic homograft, which theoretically provided a more radical debridement of the infected tissue. Initially, this technique had not been widely used due to limited access to aortic homografts and early calcification of the implants [14]. In recent decades, the use of biological or synthetic materials for replacement of infected aortic root also provided satisfactory results [10, 15–17]. Now, depending on the expertise of different surgeons and hospitals, aortic valve replacement (AVR) with patching of the aortic root and total aortic root replacement (ARR) are the 2 most widely used techniques. However, data comparing these 2 procedures are scarce and prone to bias due to a retrospective design and limited patient numbers. Moreover, the optimal timing for surgery is challenging; although an emergency operation might facilitate the early control of infection [10], delaying surgery until after clinical stabilization might minimize perioperative risk. Because of the rarity and often emergent settings of the diseases, conducting prospective clinical trials to compare short-term and long-term outcomes of these 2 procedures would be difficult. Therefore, we conducted this meta-analysis and systemic review to compare the clinical outcomes of patients who received ARR and patients who received AVR. MATERIALS AND METHODS Two authors (G.-J.C and S.-C.P) independently performed literature searches in the PubMed and EMBASE databases for articles concerning the treatment of ARA that were published before 30 June 2016. Keywords used in the literature search were ‘aortic root abscess’ and ‘periannular abscess’. We aimed to include studies that provided primary data from randomized trials and prospective and retrospective cohorts. Case reports, reviews, correspondences, editorials or conference proceedings were excluded from further analysis. After removing duplicate pieces, articles were screened by titles and abstracts for eligibility. Eligible articles were subsequently assessed based on the full text. Data describing the perioperative outcome and postoperative mortality among patients with a diagnosis of ARA or a periannular abscess of aortic valve endocarditis were included for further analysis. In case of any discrepant opinions related to article inclusion, the third author (W.-C.L) was consulted and the final decision was made after discussion. Data extraction and quality assessment We used a standardized form to extract primary data from eligible studies regarding patient characteristics and demographics (e.g. patient number, gender, mean or median age, comorbidities and history of previous operation), valve condition [native valve endocarditis (NVE) versus PVE], operative data (operative method and the timing of surgery), definite culture results and clinical outcomes (mortality and rate of reoperation). The definitions of mortality, rate of reoperation and timing of surgery were unified for comparison across different studies. Early mortality was defined as 30-day all-cause mortality, and mortality rates were calculated at 30 days, 1 year, 5 years and 10 years. One-year reoperation rate was defined as whether the patients had valvular operations again among the enrolled cohort, after excluding deceased patients and patients who were lost to follow-up. The reasons for reoperation were also recorded from each study using the definition from the American Association of Thoracic Surgery (AATS) [18]. Using the clinical management guidelines released by the European Society of Cardiology (ESC) [19], an emergent operation is defined as surgery performed for ARA within 24 h of diagnosis and an urgent operation is defined as surgery within 2 weeks of diagnosis. However, some of the enrolled studies did not differentiate from the original reports between emergent operations and urgent operations. Therefore, to evaluate the association of outcome and the timing of surgery for patients with ARA in this meta-analysis, ARA patients who had emergent operations and urgent operations were pooled together and compared with those who received delayed or elective operations. For each trial, missing outcome data for the patient who was lost to follow-up during the observation period were managed by a last observation carried forward approach. The methodological quality of the selected articles was assessed using the Newcastle–Ottawa Scale with selection, comparability, and outcome dimensions [20]. Statistical analysis In this meta-analysis, we considered all-cause mortality at 30 days, 1 year, 5 years and 10 years as the primary outcomes of interest. Random-effects meta-analysis was conducted using the STATA Metaprop command, which allows computation of 95% confidence intervals (CIs) using the score statistic and the exact binomial method and incorporates the Freeman–Tukey double arcsine transformation of proportions. The relationship between the within-study mortality rate and the year of study was assessed using a weighted least square regression. We also determined the pooled relative risks (RRs) to assess the effect of risk factors (NVE versus PVE and ARR versus AVR) on 30-day all-cause mortality across selected studies. Weighted least square regression was used to observe the association between the timing of the operation and mortality. Heterogeneity was assessed using the Q statistic and the I2 statistic. Publication bias was examined using funnel plots and Egger tests. All of the statistical analysis was conducted with STATA software (12th edition, StataCorp, College Station, TX, USA). RESULTS Literature search Using a keyword search with ‘aortic root abscess’ or ‘periannular abscess’, 884 articles were found from EMBASE and PubMed that were published before 30 June 2016. After removing duplicate articles, 646 records were screened via their titles and abstracts. Twelve records were retrieved to check eligibility by assessing the full text. Two additional articles were found during full-text assessment and were screened. Eight articles were included in a qualitative synthesis [1, 5, 6, 21–25]. Additionally, 1 study included patients who did not undergo aortic surgery; this study was excluded from quantitative analysis [1]. Finally, a total of 7 records were included in the data extraction and meta-analysis (Fig. 1). Figure 1: View largeDownload slide Flow chart of literature search and enrolled studies. Figure 1: View largeDownload slide Flow chart of literature search and enrolled studies. From the 7 included studies, 781 episodes of infective endocarditis were reported. All of these episodes had complications with ARA or periannular abscess. Summaries of each study are shown in Table 1. All of the included articles were retrospective observational studies, with various follow-up periods ranging from 30 days to 10 years. The methodological assessment of all enrolled studies used the Newcastle–Ottawa Quality Assessment Scale for cohort studies; the results are shown in Table 2. Using funnel plots and an Egger test, no implication of publication bias was suspected (P-value of Egger test = 0.82, Supplementary Material, Fig. S3). Table 1: Summary of studies enrolled for data extraction and meta-analysisa References  Duration of enrolment  Total cases (n)  Age (years), mean (SD)  Duration of follow-up (months), mean (SD, range)  Male gender, n (%)  Overall 30-day mortality, % (95% CI)  Patients who underwent different procedures   Proportion of emergent/ urgent operations  ARR material  AVR (n)  ARR (n)  Glazier et al. [6]  1972–1989  30  42 (18)  66 (42, 9–144)  20 (67)  19 (13–27)  0b  30  100  H  Choussat et al. [21]  1989–1993  175  51 (15)  6 (1, 1–58)  105 (60)  22 (9–42)  161  14    Prosthetic material, pericardium  Yankah et al. [22]  1986–2001  161  53 (17)  60 (52, —c)  127 (79)  12 (5–25)  78  83  100  H  Musci et al. [23]  1986–2007  189        22 (17–29)  0b  189    H  Lee et al. [5]  1999–2012  49  50 (14)  69 (40, 2–159)  36 (73)  24 (17–31)  42  7  31  A, B, D  Leontyev et al. [25]  1999–2012  150  62 (15)  84 (6, 1–151)  130 (87)  17 (11–23)  59  91  91  A, B, D  Kirali et al. [24]  1998–2013  27  37 (13)  82 (44, —c)  20 (74)  23 (10–42)  20  7  26  Biological or prosthetic  References  Duration of enrolment  Total cases (n)  Age (years), mean (SD)  Duration of follow-up (months), mean (SD, range)  Male gender, n (%)  Overall 30-day mortality, % (95% CI)  Patients who underwent different procedures   Proportion of emergent/ urgent operations  ARR material  AVR (n)  ARR (n)  Glazier et al. [6]  1972–1989  30  42 (18)  66 (42, 9–144)  20 (67)  19 (13–27)  0b  30  100  H  Choussat et al. [21]  1989–1993  175  51 (15)  6 (1, 1–58)  105 (60)  22 (9–42)  161  14    Prosthetic material, pericardium  Yankah et al. [22]  1986–2001  161  53 (17)  60 (52, —c)  127 (79)  12 (5–25)  78  83  100  H  Musci et al. [23]  1986–2007  189        22 (17–29)  0b  189    H  Lee et al. [5]  1999–2012  49  50 (14)  69 (40, 2–159)  36 (73)  24 (17–31)  42  7  31  A, B, D  Leontyev et al. [25]  1999–2012  150  62 (15)  84 (6, 1–151)  130 (87)  17 (11–23)  59  91  91  A, B, D  Kirali et al. [24]  1998–2013  27  37 (13)  82 (44, —c)  20 (74)  23 (10–42)  20  7  26  Biological or prosthetic  a All included studies were retrospective observational cohort studies. b National Heart Hospital, London [6] and Deutsches Herzzentrum Berlin [23] had a policy that preferred ARR for aortic root abscess and only enrolled patients with ARR procedures. c Not provided in original articles. A: autologous pericardium; ARR: aortic root replacement; AVR: aortic valve replacement; B: bovine pericardium; CI: confidence interval; D: Dacron; H: homologous pericardium; SD: standard deviation. Table 2: Quality assessment of enrolled studies using the Newcastle-Ottawa Quality Assessment Scale (NOS) References  Selection   Comparability  Outcomes   Quality score  Representativeness of the exposed cohort  Selection of the non-exposed cohort  Ascertainment of exposure  Outcome of interest was not present at the start of study  Comparability of cohorts based on the design or analysis  Assessment of outcomes  Enough follow-up length  Adequacy of follow-up of cohorts  Glazier et al. [6]  ★  O  ★  ★  N/A  ★  ★  ★  6  Choussat et al. [21]  ★  ★  ★  ★  N/A  O  O  ★  5  Yankah et al. [22]  ★  ★  ★  ★  N/A  ★  ★  ★  7  Musci et al. [23]  ★  O  ★  ★  N/A  ★  ★  ★  6  Lee et al. [5]  ★  ★  ★  ★  O  O  ★  ★  6  Leontyev et al. [25]  ★  ★  ★  ★  ★  ★  ★  ★  8  Kirali et al. [24]  ★  ★  ★  ★  O  ★  ★  ★  7  References  Selection   Comparability  Outcomes   Quality score  Representativeness of the exposed cohort  Selection of the non-exposed cohort  Ascertainment of exposure  Outcome of interest was not present at the start of study  Comparability of cohorts based on the design or analysis  Assessment of outcomes  Enough follow-up length  Adequacy of follow-up of cohorts  Glazier et al. [6]  ★  O  ★  ★  N/A  ★  ★  ★  6  Choussat et al. [21]  ★  ★  ★  ★  N/A  O  O  ★  5  Yankah et al. [22]  ★  ★  ★  ★  N/A  ★  ★  ★  7  Musci et al. [23]  ★  O  ★  ★  N/A  ★  ★  ★  6  Lee et al. [5]  ★  ★  ★  ★  O  O  ★  ★  6  Leontyev et al. [25]  ★  ★  ★  ★  ★  ★  ★  ★  8  Kirali et al. [24]  ★  ★  ★  ★  O  ★  ★  ★  7  ★: one point attributed in the NOS; O: zero point attributed in the NOS; N/A: not applicable. Postoperative outcomes and risk factors In this meta-analysis, the 30-day, 1-year, 5-year and 10-year pooled mortality rates after surgery were 20% (95% CI 17–23%), 28% (95% CI 22–34%), 34% (95% CI 24–44%) and 36% (95% CI 25–48%), respectively (Fig. 2). The time of enrolment of the included studies varied significantly from 1972 to 2013; however, using a weighted least square regression, there was no statistically significant change of 30-day mortality across the time periods (P = 0.40, Supplementary Material, Fig. S1). Of all the included cohorts, 3 reported reoperation rates during follow-up, and 43 redo valvular surgeries were reported after the index operation for ARA [22, 24, 25]. The longest duration to reoperation reported in these 3 cohorts was 8 years after the index surgery. The overall rate of reoperation within 1 year, after excluding deceased patients, was 5.2% (95% CI 2.9–8.7%). The leading indications for repeat surgery were recurrence of infection and non-structural deterioration, which accounted for 53% and 42% of reoperated patients, respectively (data not shown). Figure 2: View largeDownload slide Pooled overall 30-day, 1-year, 5-year and 10-year mortality of patients with aortic root abscess. CI: confidence interval. Figure 2: View largeDownload slide Pooled overall 30-day, 1-year, 5-year and 10-year mortality of patients with aortic root abscess. CI: confidence interval. The pooled 30-day postoperative mortality rate was 19.1% (95% CI 13.3–26.1) among patients who received AVR and 23.8% (95% CI 17.8–30.6) among patients who received ARR. When compared with patients who underwent AVR, ARR was associated with a trend of increased 30-day postoperative mortality, although this correlation was not statistically significant (RR 1.30, 95% CI 0.84–2.00) (Fig. 3). However, ARR was associated with a lower rate of 1-year reoperation when compared with the AVR technique (RR 0.50, 95% CI 0.26–0.94) (Fig. 4). Furthermore, among patients with PVE, the 30-day mortality rate after operation was significantly higher than patients who received a diagnosis of NVE (RR 1.72, 95% CI 1.24–2.37) (Fig. 3). Figure 3: View largeDownload slide (A) Comparison of 30-day mortality among patients receiving ARR versus AVR technique. (B) Comparison of 30-day mortality among patients with PVE versus NVE. ARR: aortic root replacement; AVR: aortic valve replacement; CI: confidence interval; NVE: native valve endocarditis; PVE: prosthetic valve endocarditis. Figure 3: View largeDownload slide (A) Comparison of 30-day mortality among patients receiving ARR versus AVR technique. (B) Comparison of 30-day mortality among patients with PVE versus NVE. ARR: aortic root replacement; AVR: aortic valve replacement; CI: confidence interval; NVE: native valve endocarditis; PVE: prosthetic valve endocarditis. Figure 4: View largeDownload slide Comparison of 1-year reoperation rate among patients receiving ARR versus AVR technique. ARR: aortic root replacement; AVR: aortic valve replacement; CI: confidence interval. Figure 4: View largeDownload slide Comparison of 1-year reoperation rate among patients receiving ARR versus AVR technique. ARR: aortic root replacement; AVR: aortic valve replacement; CI: confidence interval. Timing of surgical intervention The optimal timing of ARA was also debatable; some specialists favoured emergent or urgent operation to obtain better control of infection, while others delayed surgery until after clinical stabilization to minimize perioperative morbidity and mortality. Five of the enrolled trials reported the timing of the operation [5, 6, 22, 24, 25]. We depicted the proportion of emergent operation and postoperative mortality rate from each cohort. There was no correlation between the timing of operation and mortality when using a weighted least square regression (P = 0.27, Supplementary Material, Fig. S2). Causative microorganism and mortality Five of the enrolled studies provided details concerning the causative pathogens associated with ARA (Table 3) [5, 6, 22, 24, 25]. Among patients with identifiable pathogens, staphylococci remained the most common pathogen and accounted for 28.1% of all ARA. Streptococci were the second most common micro-organism followed by enterococci, which accounted for 23.3% and 10.3% of all infections, respectively. In 1 cohort describing 67 patients with periannular abscesses, Anguera et al. [1] identified S.aureus infection as an independent risk for mortality. However, the correlation between postoperative mortality and causative microorganism was not discussed in other included studies. Table 3: Reported pathogens associated with aortic root abscess across different studies Pathogens  Glazier et al. [6] (n = 30), n (%)  Yankah et al. [22], (n = 161), n (%)  Lee et al. [5] (n = 49), n (%)  Leontyev et al. [25] (n = 150), n (%)  Kirali et al. [24] (n = 27), n (%)  Total (n = 417), n (%)  All staphylococci  14 (46.7)  47 (29.2)  6 (12.2)  40 (26.7)  10 (37.0)  117 (28.1)   Staphylococcus aureus  5 (16.7)  13 (8.1)  4 (8.2)  12 (8.0)  8 (29.6)  42 (10.1)   Coagulase-negative staphylococci  9 (30.0)  34 (21.1)  2 (4.1)  28 (18.7)  2 (7.4)  75 (18.0)  Streptococci  11 (36.7)  39 (24.2)  21 (42.9)  22 (14.7)  4 (14.8)  97 (23.3)  Enterococci  1 (3.3)  23 (14.3)  3 (6.1)  13 (8.7)  3 (11.1)  43 (10.3)  Gram-negative bacilli  1 (3.3)  NR  3 (6.1)  NR  0 (0)  a  Candida spp.  0 (0)  NR  1 (2.0)  1 (0.7)  1 (3.7)  a  Not identified, culture-negative  3 (10.0)  NR  15 (30.6)  63 (42.0)  9 (33.3)  a  Pathogens  Glazier et al. [6] (n = 30), n (%)  Yankah et al. [22], (n = 161), n (%)  Lee et al. [5] (n = 49), n (%)  Leontyev et al. [25] (n = 150), n (%)  Kirali et al. [24] (n = 27), n (%)  Total (n = 417), n (%)  All staphylococci  14 (46.7)  47 (29.2)  6 (12.2)  40 (26.7)  10 (37.0)  117 (28.1)   Staphylococcus aureus  5 (16.7)  13 (8.1)  4 (8.2)  12 (8.0)  8 (29.6)  42 (10.1)   Coagulase-negative staphylococci  9 (30.0)  34 (21.1)  2 (4.1)  28 (18.7)  2 (7.4)  75 (18.0)  Streptococci  11 (36.7)  39 (24.2)  21 (42.9)  22 (14.7)  4 (14.8)  97 (23.3)  Enterococci  1 (3.3)  23 (14.3)  3 (6.1)  13 (8.7)  3 (11.1)  43 (10.3)  Gram-negative bacilli  1 (3.3)  NR  3 (6.1)  NR  0 (0)  a  Candida spp.  0 (0)  NR  1 (2.0)  1 (0.7)  1 (3.7)  a  Not identified, culture-negative  3 (10.0)  NR  15 (30.6)  63 (42.0)  9 (33.3)  a  a The actual frequency of some pathogen was not reported and calculation of overall proportion was not possible. NR: not reported. DISCUSSION In this meta-analysis, including 7 clinical studies with 781 episodes of ARA, we found that patients who received ARR for management of ARA carried a 50% lower risk for repeat operation when compared with those who underwent AVR. There is a trend of an increased 30-day mortality rate among patients who underwent ARR compared with the AVR technique, although this is not statistically significant. Emergent or urgent operation was not associated with improved clinical outcomes in our meta-analysis. The only risk factor associated with increased mortality was PVE, which carries a 1.7-fold elevation of RR when compared with NVE. Postoperative outcomes ARA mortality remained high even with revolutionary techniques and novel materials. In our meta-analysis, the 30-day mortality remained as high as 20%, which saw no significant improvement during the past 3 decades (Supplementary Material, Fig. S1). We also found a trend for higher mortality among patients who received ARR rather than AVR. In another cohort of 100 patients with active aortic valve endocarditis and an unknown proportion of ARA, Mayer et al. [26] found a trend of increased mortality in patients who received ARR. However, the mortality among ARA patients is multifactorial, and many confounding factors must be balanced before directly comparing these 2 techniques. Due to the scarcity of enrolled clinical studies, meta-regression was not performed to stratify possible confounding factors such as age, gender, New York Heart Association functional classification, pathogens, perioperative clinical status and concurrent sepsis. Additionally, the preoperative risk assessment score was not universally available, as only Leontyev et al. [25] reported a logistic EuroSCORE as high as 62 ± 14% among all the ARA patients. The trend of increased mortality among the ARR group might be attributed to confounding by indication, as patients with more severe disease and more extensive destruction might tend to receive ARR and eventually carry a higher mortality rate. When choosing between these 2 procedures, both the National Heart Hospital, London (enrolled cases with PVE only) [6] and the Deutsches Herzzentrum Berlin (enrolled groups with NVE and PVE) [23] had a policy that preferred to remove infected tissues for patients with ARA and only included patients with ARR procedures. In other studies, the operation method was mainly chosen depending on the anatomical conditions [22, 24, 25]. Studies from Lee et al. [5] and Choussat et al. [21] did not provide clear indications for operation method selection. Thus, whether ARR can lead to lesser short-term or long-term mortality may need further investigation and would need to be stratified by valvular condition (NVE versus PVE) and other possible confounding factors. In our meta-analysis, 5.2% (95% CI 2.9–8.7%) of patients required repeat cardiac surgery after receiving surgery for ARA within the 1st postoperative year. By assessing the available data from the included studies in this meta-analysis, most of these reoperated patients received a second surgery due to recurrent infection and non-structural deterioration of the aortic valves. Extensive removal of the infected tissue followed by surgical reconstruction was favoured by some experts due to the destructive nature of the disease [10]. ARR had been suggested as an eradicative operation method to remove the most infectious tissue and provide a better reconstruction of the aortic root, which probably prevents a reoperation due to infection recurrence or non-structural deterioration [13, 27]. Our finding was in line with this assumption and demonstrated a reduced rate of repeat operations among the ARR group, with the RR being 0.43 (95% CI 0.24–0.62). To the best of our knowledge, this is the first meta-analysis to summarize the limited ARA cohort and confirm that there is a significantly lower risk for reoperation among ARR patients compared with AVR patients. Five of the 7 enrolled studies reported their data concerning patients with PVE versus NVE [5, 21–24], while only 1 of them was able to demonstrate an increased mortality rate among patients with PVE compared with NVE [23]. After pooling the data in our meta-analysis, PVE was associated with a 1.7-fold increase in 30-day postoperative mortality. The difference in clinical characteristics between NVE and PVE was well documented in previous studies. In these earlier reports, patients with PVE were associated with more periannular abscesses [28], more haemodynamic dysfunction, higher mortality and higher incidence of recurrence [7, 29]. However, most of these trials described patients with endocarditis rather than focusing on patients who had ARA complications. Our report was the first meta-analysis to describe the different clinical outcomes in patients with ARA that arose from PVE versus NVE and clearly demonstrated a higher risk of mortality in patients with PVE compared with NVE (RR 1.65, 95% CI 1.20–2.25). In several observational cohorts focusing on patients with PVE with or without ARA, there was a higher rate of preoperative haemodynamic instability that likely affected the perioperative outcome [7]. However, further studies are required to identify which risk factors contribute to the increased risk of mortality among PVE patient who have ARA complications. Timing of surgical procedure Despite being considered a surgical disease, the proper timing for operations among patients with ARA was not previously well studied. Although some centres performed emergent operations, such as the report by Leontyev et al. [25] in Germany, the study by Kirali et al. [24] in Turkey suggested that delayed-urgent surgery was feasible after stabilizing the infection and haemodynamic status. In the report by Yankah et al. [22], patients who received emergent operations had a 30-day mortality of 14.3%, which was not statistically different to the 9.3% 30-day mortality among non-emergent patients. The method of diagnosis may also influence the timing of the surgery. ARA diagnosis was based on echocardiography prior to surgery for studies published after 2000. However, in studies published before 2000, the decision to operate was mainly based on progressive cardiac failure and ongoing sepsis [6, 21], and most ARA cases were diagnosed based on macroscopic inspection or histological examination during surgery [21]. Our meta-analysis did not reveal a correlation between the proportion of emergent or urgent operations and postoperative mortality. It is worth noting that the individual data of timing of operation and mortality were not available for all enrolled studies; thus, we adopted an ecological study method in this study. Therefore, further investigation is needed to determine whether an emergent or an urgent operation improves the clinical outcomes of ARA. Surgery versus medical treatment In this meta-analysis, we focused on the outcomes of surgical patients, and thus, cohorts including patients who were ineligible for surgery were excluded. When considering the report by Anguera et al. [1], which included 67 patients with 11 (16%) of them ineligible for surgery, there was a trend for lower mortality in patients who had received surgery. In another report by Chan et al. [2], surgery was also associated with lower post-operative mortality (surgical patients versus non-surgical patients 51.6% vs 66.6%). Even though the results of both the aforementioned studies were not statistically significant, the studies may be underpowered by their limited case numbers. Among the 12 patients who were ineligible for surgery in the study by Chan et al. [2], only 3 (25%) of them survived more than 2 years without symptomatic heart failure, valvular deterioration or infection recurrence. Some authors reported successful medical treatment alone with a prolonged course of antibiotics for up to 9–18 months. Limitations Our study had several limitations, and thus interpretations of our results should be cautious. First, only 7 studies were included in our meta-analysis, and all of them were retrospective cohorts. However, our meta-analysis is the first attempt to gather sparse data related to ARA. We suggest that high-quality prospective clinical studies are warranted to confirm our findings related to clinical outcomes, especially the long-term reoperation rate after ARR and AVR. For this purpose, international multicentre initiatives, such as the International Cooperation on Endocarditis (http://www.endocarditis.org/ice/index.html), may provide useful information from prospectively enrolled cohorts. Second, the length of follow-up period in each study varied considerably (Table 1), and the completeness of each study’s follow-up could not be assessed with the original data. Outcomes from the 1st postoperative year were provided for comparison because we believed that the risk of loss to follow-up would be smaller. However, the use of last observation carried forward method in managing the missing data might lead to underestimation of the clinical event rate, especially the 5-year and 10-year mortality. We believe that the underestimation of mortality or reoperation rate because of missing data would be no different in ARR versus AVR or NVE versus PVE. Finally, several clinically relevant questions could not be answered by this meta-analysis and still warrant further study. We did not find associations between emergent or urgent operations and mortality, and thus the optimal timing for surgery is still debatable. The duration of antimicrobial treatment after operation cannot be assessed in our meta-analysis because of the limitations of the original data. Furthermore, the optimal treatment strategy for patients who were ineligible for surgery was discussed rarely in the past and remains unclear. CONCLUSION This meta-analysis revealed that ARA still carries a high risk for mortality even after a surgical intervention. There was no statistically significant difference in 30-day mortality among patients who received ARR versus AVR. However, when compared with AVR, ARR was associated with fewer repeated operations within 1 year. Further study is needed to evaluate the long-term mortality and reoperation rates between the 2 operation methods and to clarify the effects caused by other possible risk factors. SUPPLEMENTARY MATERIAL Supplementary material is available at EJCTS online. Conflict of interest: none declared. REFERENCES 1 Anguera I, Miro JM, Cabell CH, Abrutyn E, Fowler VGJr, Hoen B et al.   Clinical characteristics and outcome of aortic endocarditis with periannular abscess in the International Collaboration on Endocarditis Merged Database. Am J Cardiol  2005; 96: 976– 81. Google Scholar CrossRef Search ADS PubMed  2 Chan K-L. 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European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Apr 1, 2018

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