Outcomes After Surgical Treatment of Native and Prosthetic Valve Infective Endocarditis

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1 Outcomes After Surgical Treatment of Native and Prosthetic Valve Infective Endocarditis Mahesh B. Manne, MD, MPH, Nabin K. Shrestha, MD, Bruce W. Lytle, MD, Edward R. Nowicki, MD, MS, Eugene Blackstone, MD, Steven M. Gordon, MD, Gosta Pettersson, MD, and Thomas G. Fraser, MD Departments of Internal Medicine and Infectious Disease, Medicine Institute, and Department of Cardiothoracic Surgery, Heart and Vascular Institute, The Cleveland Clinic, Cleveland, Ohio Background. The risk of death and complications of infective endocarditis (IE) treated medically has to be balanced against those from surgery in constructing a therapeutic approach. Recent literature has drawn conflicting conclusions on the benefit of surgery for IE. We reviewed patients treated surgically for IE at the Cleveland Clinic from 2003 to 2007 to examine their outcomes. Methods. A retrospective review of consecutive patients who underwent surgery for native and prosthetic valve endocarditis between January 1, 2003, and December 31, 2007, was conducted. Surgical outcomes were reviewed to include survival and postoperative complications. Survival was evaluated at end of hospital stay, 30 days, 1 year, and at last follow-up. Results. Four hundred twenty-eight patients underwent surgery for IE during the study period: 248 (58%) had native valve endocarditis and 180 (42%) had prosthetic valve endocarditis. Overall 90% of patients survived to hospital discharge. When compared with patients with native valve infection, patients with prosthetic infection had significantly higher 30-day mortality (13% versus 5.6%; p < 0.01), but long-term survival was not significantly different (35% versus 29%; p 0.19). Patients with IE caused by Staphylococcus aureus had significantly higher hospital mortality (15% versus 8.4%; p < 0.05), 6-month mortality (23% versus 15%; p 0.05), and 1-year mortality (28% versus 18%; p 0.02) compared with non S aureus IE. Conclusions. Surgical treatment of IE was associated with 90% hospital survival. Outcomes within the 30 days were better for native valve than for prosthetic valve endocarditis. Long-term outcomes were similar. Finally, S aureus was associated with significantly higher mortality compared with other pathogens. (Ann Thorac Surg 2012;93:489 94) 2012 by The Society of Thoracic Surgeons Infection of native and prosthetic heart valves still remains a disease associated with significant morbidity and mortality in the modern antibiotic era. Therefore evaluation for valve replacement surgery is recommended for severe valvular insufficiency, valvular perforation or dehiscence, decompensated heart failure, perivalvular or myocardial abscess, new heart block, or persistent fevers or bloodstream infection. Surgery for infective endocarditis (IE) has been considered to be potentially lifesaving and is indicated in 25% to 30% of cases during the acute phase ( active ) and in 20% to 40% during the convalescent phase ( inactive ) [1 3]. Publications from the last 10 years, however, have provided conflicting information regarding the mortality benefit of surgery for IE [4 6]. In this report we describe the morbidity and mortality associated with surgery for IE and compare differences in characteristics, pathogens, and outcomes for patients with native valve endocarditis (NVE) and prosthetic valve endocarditis (PVE) from a large surgery-minded tertiary referral center. Accepted for publication Oct 25, Address correspondence to Dr Manne, Desk G10, 9500 Euclid Ave, Cleveland, OH 44195; mannem@ccf.org. Patients and Methods This is a retrospective study that included consecutive patients who underwent open heart surgery for IE at the Cleveland Clinic between January 1, 2003, and December 31, Potential cases were identified from the Cardiovascular Information Registry (CVIR). The CVIR is a comprehensive registry that tracks all patients who undergo cardiac surgery at the Cleveland Clinic. The registry was queried for all cases with an IE descriptor. These charts were reviewed, and patients were classified by modified Duke criteria as having definite or possible endocarditis [7]. Only cases that met criteria for definite IE were included in the analysis. Patient characteristics and demographics to include state of residence and distance from their home to Cleveland Clinic were obtained from chart review and a query of the CVIR registry. The presence and severity of congestive heart failure before surgery was determined by application of New York Heart Association functional class. The presence and severity of valvular insufficiency was determined based on preoperative echocardiograms (transthoracic or transesophageal). These characteristics are captured prospectively as per routine in the CVIR. The etiology of each infection was determined by review of microbiologic laboratory results as well as infectious 2012 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 490 MANNE ET AL Ann Thorac Surg ENDOCARDITIS SURGERY OUTCOMES 2012;93: disease serologies. The surgical pathologic diagnosis was obtained from individual chart review. Histopathology results were divided into three categories: active, healed, and no evidence for IE. The histopathologic type was considered to be active if there were vegetations, microorganisms seen on staining, or valvular inflammation with a predominance of polymorphonuclear cells; healed if there was only a nonspecific valvular inflammation without organisms; and no evidence if there was a complete absence of inflammation and microorganisms. The involved valve was obtained through chart review and was determined by echocardiographic findings or submission of operative specimens for culture or histopathologic examination. The number and type of valve procedures, the type of prostheses used, and the number of coronary artery bypass graft procedures done was determined by query of the CVIR. Patient comorbidities and postoperative complications were defined according to The Society of Thoracic Surgeons Adult Cardiac Surgery Database ( STSWebRiskCalc261/support_definitions.html). A procedure was defined as emergent if it was in response to acute cardiac compromise unresponsive to medical therapy. Hospital length of stay was defined as the interval from date of admission to date of discharge, and postoperative length of stay was the interval from date of surgery to date of discharge. Hospital death was considered to have occurred if a patient did not survive the same hospitalization as the index surgery. Thirty-day and 1-year survival and patients alive at last follow-up were determined using the Social Security Death Index. The study was approved by the Cleveland Clinic Institutional Review Board (09-045). Overall surgical principles at the Cleveland Clinic for patients with IE are based on the belief that the key to success is radical debridement of all infected tissue and foreign material. Debridement is followed by generous irrigation. Local antiseptics and antibiotics are used sparingly. Allografts are preferred for aortic root reconstruction in cases with annulus destruction and periannular invasion. When the annulus is preserved the choice of valve does not differ from other patients with valve disease. If additional material is necessary to buttress the suture line of a prosthetic valve autologous pericardium is preferred. Reconstruction is required for double valve endocarditis with destruction of the intravalvular fibrosa. Use of foreign material is kept to a minimum, and glue is not used. Descriptive statistics were used to summarize the data. Continuous variables are presented as mean standard deviation. Pairwise comparisons were made using the Wilcoxon rank-sum test. Categorical variables are described using frequencies and percentages; comparisons were made using the 2 test. All analyses were performed using SAS statistical software (SAS v9.1; SAS, Inc, Cary, NC). Overall nonparametric survival estimates were obtained by the Kaplan-Meier method with comparisons between curves based on the log-rank 2 statistic. Results Five hundred nine patients were identified with an IE descriptor in the CVIR registry during the 5-year study period. Eighty-one patients (16%) were excluded from the study because (1) 45 patients (8.8%) did not meet modified Duke criteria for definite or possible IE, (2) 27 patients (5.3%) had possible IE, and (3) records were not available for 9 patients (1.7%). The remaining 428 patients (84%) met criteria for definite IE and made up the final cohort. Forty-two percent of patients resided within a 50-mile straight line distance of the Cleveland Clinic, and 54% resided within a 100-mile straight line distance. Sixty-two percent were residents of Ohio, 14% were residents of either New York, Pennsylvania, or Indiana, and 24% were residents of either another state or a foreign country. Twenty-four patients (5.6%) were actively using intravenous drugs at the time of IE onset. An additional 8 patients had a history of intravenous drug use. Baseline characteristics of the 428 patients can be found in Table 1. There were 248 patients (57.9%) with NVE and 180 patients (42.1%) with PVE. The aortic valve was most commonly involved, but the mitral valve was the most common to have moderate to severe valvular insufficiency. Men were predominant in both NVE and PVE groups. Patients with PVE were significantly older (58.7 years versus 54.3 years; p 0.001). Moderate to severe heart failure (New York Heart Association class III or IV) was present in 31% of patients with NVE and 25% of patients with PVE at the time of operation. Moderate to severe aortic insufficiency (54.8% versus 39.4%; p 0.002) and mitral insufficiency (62.5% versus 42.8%; p 0.001) were more common in NVE than PVE. The most common valve procedure in both NVE and PVE was isolated aortic valve replacement, 54% and 83%, respectively. Among the total cohort, 282 patients required aortic valve replacements. An aortic allograft was used for 173, a pulmonary autograft (Ross procedure) for 1, a bioprosthesis for 84, and a mechanical prosthesis for 24. There were 12 aortic valve repairs. One hundred twenty-four patients underwent mitral valve replacement. A bioprosthesis was used for 103 and a mechanical prosthesis for 21. Overall there were 102 mitral valve repairs performed among the cohort. Ten patients required tricuspid valve replacement, all with a bioprosthesis, and there were 76 tricuspid valve repairs. Concomitant coronary artery bypass grafting was performed in 92 patients, 20% of patients with NVE and 24% of patients with PVE. Seventeen patients underwent 22 reoperations with the indication in 9 patients being endocarditis. There were 2 patients who had a total of three surgeries for reinfections. Seven patients required reoperation for persistent infection or relapse: 3 patients with two additional surgeries and 4 patients with one additional surgery each. Table 2 lists the pathogens responsible for the infection in the cohort. A microbiologic diagnosis was made in 92% of patients. Three hundred sixty-three patients (84.8%)

3 Ann Thorac Surg MANNE ET AL 2012;93: ENDOCARDITIS SURGERY OUTCOMES 491 Table 1. Baseline Characteristics of Patients Treated Surgically for Infective Endocarditis a Variable All (n 428) NVE (n 248) PVE (n 180) p Value Age (mean SD) Male 305 (71.3) 171 (69) 134 (74) 0.22 NYHA class III or IV 122 (28.5) 77 (31) 45 (25) Valve involved Aortic 213 (49.8) 97 (39.1) 116 (64.4) Mitral 113 (26.4) 86 (34.7) 27 (15) Right-sided 20 (4.7) 17 (6.8) 3 (1.7) Multivalvular 82 (19.1) 48 (19.4) 34 (18.9) Moderate to severe valvular insufficiency Aortic 207 (48.4) 136 (54.8) 71 (39.4) Mitral 232 (54.2) 155 (62.5) 77 (42.8) Tricuspid 152 (35.5) 85 (34.3) 67 (37.2) a Values reported are number with percentage in parentheses, except for age. NVE native valve endocarditis; NYHA New York Heart Association; PVE prosthetic valve endocarditis; SD standard deviation. had specimens from the explanted valves sent for culture, and the cultures were positive in 124 (34%); 39.9% of those with PVE and 29.8% of those with NVE had a positive culture. Staphylococcus aureus was the most common pathogen, accounting for 25.1% of identified pathogens. Staphylococcus aureus was the most commonly identified cause of NVE (27.6%) and the second most common cause of PVE (22.1%). Propionibacterium acnes (5% versus 0.8%; p 0.01) and fungi (7.8% versus 1.2%; p 0.01) were significantly more common in PVE than NVE. Overall, 90% of patients survived to hospital discharge (Table 3). Patients with NVE had better hospital (93.5% versus 84%; p 0.01) and 30-day survival (94.4% versus 87%; p 0.01). Long-term survival for patients who underwent surgery for NVE was not significantly different from that of PVE patients (Fig 1). Patients with S aureus IE had significantly worse survival, including higher hospital (15% versus 8.4%; p 0.05), 6-month (23% versus 15%; p 0.05), and 1-year (28% versus 18%; p 0.02) mortality compared with patients with non S aureus IE (Fig 2). Patients with PVE had longer intensive care unit length of stay ( days versus days; p 0.05) and hospital length of stay ( days versus days; p 0.05). Three percent of patients in both groups had postoperative cerebrovascular accidents. Postoperative acute kidney injury was more common in patients with PVE than NVE (11% versus 4.4%; p 0.01). Return to the operating room for bleeding, Table 2. Microbiologic Etiology of Infective Endocarditis in Surgically Treated Patients a Microorganism All (n 482) b NVE (n 283) b PVE (n 199) b Staphylococcus aureus 121 (25.1) 78 (27.6) 43 (22.1) Coagulase-negative Staphylococcus 84 (17.4) 36 (12.7) 48(24.1) Enterococcus 53 (11.0) 31 (10.9) 22 (11.0) Viridans Streptococcus 69 (14.4) 55 (19.4) 14 (7.0) Abiotrophia species 6 (1.2) 5 (1.8) 1 (0.5) Streptococcus agalactiae 8 (1.7) 6 (2.1) 2(1.0) Streptococcus bovis 3 (0.6) 3 (1.1) 0 Streptococcus pneumoniae 5 (1) 5 (1.8) 0 Yeast 17 (3.5) 3 (1) 14 (7.0) Mold 3 (0.6) 0 3 (1.5) Propionibacterium 11 (2.3) 2 (0.7) 9 (4.5) Culture negative 39 (8.1) 23 (8.1) 16 (8.0) Bartonella 3 (0.6) 1 (0.4) 2 (1.0) HACEK 4 (0.8) 2 (0.7) 2 (1.0) Others 56 (11.7) 33 (11.7) 23 (11.6) a Values reported are number with percentage in parentheses. b In a few cases more than one pathogen was isolated. HACEK Haemophilus parainfluenzae, H aphrophilus, and H paraphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae; NVE native valve endocarditis; PVE prosthetic valve endocarditis.

4 492 MANNE ET AL Ann Thorac Surg ENDOCARDITIS SURGERY OUTCOMES 2012;93: Table 3. Mortality and Postoperative Outcomes for Patients With Infective Endocarditis a Variable All (n 428) NVE (n 248) PVE (n 180) p Value Survival Hospital death (%) 44 (10.3) 16 (6.5) 28 (16) day mortality (%) 38 (8.9) 14 (5.6) 24 (13) year mortality (%) 87 (20.3) 45 (18) 42 (23) 0.19 Death at the end of follow up (%) 135 (31.5) 72 (29) 63 (35) 0.19 Postoperative complications Cerebrovascular accident (%) 14 (3.3) 8 (3.2) 6 (3.3) 0.95 Renal failure (%) 31 (7.2) 11 (4.4) 20 (11) Return to OR for bleeding (%) 32 (7.5) 15 (6) 17 (9.4) 0.19 Respiratory insufficiency (%) 75 (17.5) 42 (17) 33 (18) 0.71 Septicemia/sepsis (%) 55 (12.9) 31 (13) 24 (13) 0.80 Length of stay Total days in ICU b Operative length of stay (days) Hospital length of stay (days) a Values reported are number with percentage in parentheses, except for lengths of stay values, which are mean SD. b n 424. ICU intensive care unit; NVE native valve endocarditis; OR operating room; PVE prosthetic valve endocarditis. respiratory insufficiency, and sepsis were similar in both groups. Comment The diagnosis and management of IE remain one of the great challenges of clinical medicine. Similar to patients with other valvular disease, the limitations of medical treatment of IE often necessitate surgery. This report summarizes the review we undertook of clinical outcomes of a large cohort of surgically treated patients with both NVE and PVE during a 5-year period. Ninety percent of patients survived to hospital discharge, a survival rate that is in keeping with the previously published literature on this topic [4, 5]. More patients with NVE were alive at discharge and at 30 days than patients with PVE. Interestingly, long-term survival was the same for both groups, suggesting that the differences in early survival may be attributable to the patient s ability to sustain the stress of the surgery and Fig 1. Survival estimates of patients with infective endocarditis treated surgically are stratified by prosthetic valve endocarditis versus native valve endocarditis. Each symbol represents a death positioned on the vertical axis by Kaplan-Meier estimator, vertical bars are confidence limits equal to one standard error of the mean, and numbers in parentheses are patients still alive and traced at 6 months and 1, 2, 3, and 5 years. Filled circles ( ) on the dashed line are prosthetic valve endocarditis (n 180) and open circles (X) on the solid line are native valve endocarditis (n 248). There is no statistically significant difference in survival (log-rank p 0.16). Fig 2. Survival estimates stratified by Staphylococcus aureus infective endocarditis versus all other pathogens. Each symbol represents a death positioned on the vertical axis by Kaplan-Meier estimator, vertical bars are confidence limits equal to one standard error of the mean, and numbers in parentheses are patients still alive and traced at 6 months and 1, 2, 3, and 5 years. Filled circles ( ) on the dashed line are S aureus (n 120) and open circles (X) on the solid line are non S aureus (n 308). There is a significant difference in survival (log-rank p 0.003).

5 Ann Thorac Surg MANNE ET AL 2012;93: ENDOCARDITIS SURGERY OUTCOMES 493 hospitalization. This possibility is supported by the fact that PVE patients in our cohort were older, more likely to experience acute kidney injury, and had longer intensive care unit and hospital lengths of stay. Alternatively, patients with PVE may have had more severe valvular infection, although the degree of valve dysfunction and heart failure, two markers for extent of infection, were not worse in this group. Staphylococcus aureus was the most common pathogen causing IE in our patients and also was associated with significantly decreased survival as compared with non S aureus IE. Staphylococcus aureus is increasingly recognized as the most common cause of IE and has been shown to be an independent predictor of mortality from IE [8, 9]. Similar to our experience, Fowler and colleagues [8] have found infection attributable to S aureus to be significantly associated with decreased survival as compared with non S aureus infection in a cohort wherein 40% of the population was treated surgically. Although more than 90% of the cohort survived to 30 days after surgery, only 80% survived to 1 year, 82% of those with NVE and 77% of those with PVE. The scope of this work does not allow us to understand this change. As mentioned previously, S aureus infection was a substantial portion of our cohort. The significance of bacteremic events attributable to S aureus on long-term survival is increasingly being recognized. Previous work from our institution has shown 1-year mortality of 40% in patients with S aureus bacteremia from any source with the attributable mortality ranging between 8% and 16% [10]. The strengths of this paper are that it is a comprehensive review of a large cohort that includes the pathogens responsible for disease. We have evaluated both NVE and PVE and have short-term and long-term follow-up. A further strength of this report is that it has allowed us to critically look at our outcomes so that we can identify areas in which the delivery of care can be improved. The limitations of this work include the fact that this is a retrospective report of patients referred to a specialized cardiac surgery center wherein 75% of patients with a diagnosis of IE are treated surgically, thereby potentially limiting the application of our findings to all settings. Although the plurality of patients in this cohort reside within 100 miles of our hospital or are Ohio residents, a substantial number do live in other states or other countries. Those coming from the greatest distance usually have had some amount of prior antibiotic therapy. However, referral to our center may also be a marker for advanced disease that was deemed by outside treating physicians to require surgical intervention. Also, intravenous drug users, a population at risk for IE, made up a minority of this cohort, again representing a potential selection bias limiting generalizability. Work by other authors has shown that those who use intravenous drugs have similar outcomes to nonaddicts even though they tend to have IE at a younger age [11]. Further limitations include the fact that we were unable to capture the prevalence and type of underlying valve lesion if present. This is often difficult to accurately determine even on histopathologic review of explanted valves given the destructive changes that occur owing to endocarditis. Also this paper does not include a medically treated cohort whose outcomes can be compared with the observed survival for this surgical cohort. We are currently undertaking a similar review of medically treated patients with IE to understand whether they truly did not require surgery for their valve infection or whether they were deemed not operable. We thank Sarah Williams, Tanya Ashinhurst, and Jiansheng Zhong for their statistical support in preparing this manuscript. We also thank Alan Taege, MD, for mentoring the early stages of this project. References 1. Olaison L, Pettersson G. Current best practices and guidelines indications for surgical intervention in infective endocarditis. Infect Dis Clin North Am 2002;16:453 75, xi. 2. Jault F, Gandjbakhch I, Rama A, et al. Active native valve endocarditis: determinants of operative death and late mortality. Ann Thorac Surg 1997;63: Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med 2001;345: Vikram HR, Buenconsejo J, Hasbun R, Quagliarello VJ. Impact of valve surgery on 6-month mortality in adults with complicated, left-sided native valve endocarditis: a propensity analysis. JAMA 2003;290: Aksoy O, Sexton DJ, Wang A, et al. Early surgery in patients with infective endocarditis: a propensity score analysis. Clin Infect Dis 2007;44: Tleyjeh IM, Ghomrawi HM, Steckelberg JM, et al. The impact of valve surgery on 6-month mortality in left-sided infective endocarditis. Circulation 2007;115: Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30: Fowler VG Jr, Miro JM, Hoen B, et al. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 2005;293: Cabell CH, Jollis JG, Peterson GE, et al. Changing patient characteristics and the effect on mortality in endocarditis. Arch Intern Med 2002;162: Van Duin D, Fraser T, Jain A, Gordon S, Shrestha N. Attributable mortality after S. aureus bacteremia. Annual Meeting of the Society for Healthcare Epidemiology of America, Dallas, TX; March Kaiser SP, Melby SJ, Zierer A, et al. Long-term outcomes in valve replacement surgery for infective endocarditis. Ann Thorac Surg 2007;83:30 5. INVITED COMMENTARY This retrospective review from the Cleveland Clinic details the outcomes of 428 patients surgically treated for native (58%) and prosthetic valve (42%) endocarditis over a 5-year period [1]. Two thirds of the patients lived in Ohio and one third came from other states or countries. Only 24 patients (5.6%) were active intravenous drug 2012 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur