Cox proportional hazards model weighted by the inverse probability of treatment.
NYHA I-IV indicates New York Heart Association class I to IV heart failure. aTransesophageal or transthoracic echocardiographic evidence of paravalvular abscess or fistula formation. bTransesophageal or transthoracic echocardiographic evidence of dehiscence or severe regurgitation.
Data are given as mortality point estimates; error bars indicate 95% CIs.aFisher exact P value.
eTable. Predictors of In-Hospital and 1-Year Mortality
eFigure. Flow Diagram of Study Patients From the ICE-PCS Database
Lalani T, Chu VH, Park LP, Cecchi E, Corey GR, Durante-Mangoni E, Fowler VG, Gordon D, Grossi P, Hannan M, Hoen B, Muñoz P, Rizk H, Kanj SS, Selton-Suty C, Sexton DJ, Spelman D, Ravasio V, Tripodi MF, Wang A, for the International Collaboration on Endocarditis–Prospective Cohort Study Investigators. In-Hospital and 1-Year Mortality in Patients Undergoing Early Surgery for Prosthetic Valve Endocarditis. JAMA Intern Med. 2013;173(16):1495-1504. doi:10.1001/jamainternmed.2013.8203
There are limited prospective, controlled data evaluating survival in patients receiving early surgery vs medical therapy for prosthetic valve endocarditis (PVE).
To determine the in-hospital and 1-year mortality in patients with PVE who undergo valve replacement during index hospitalization compared with patients who receive medical therapy alone, after controlling for survival and treatment selection bias.
Design, Setting, and Participants
Participants were enrolled between June 2000 and December 2006 in the International Collaboration on Endocarditis–Prospective Cohort Study (ICE-PCS), a prospective, multinational, observational cohort of patients with infective endocarditis. Patients hospitalized with definite right- or left-sided PVE were included in the analysis. We evaluated the effect of treatment assignment on mortality, after adjusting for biases using a Cox proportional hazards model that included inverse probability of treatment weighting and surgery as a time-dependent covariate. The cohort was stratified by probability (propensity) for surgery, and outcomes were compared between the treatment groups within each stratum.
Valve replacement during index hospitalization (early surgery) vs medical therapy.
Main Outcomes and Measures
In-hospital and 1-year mortality.
Of the 1025 patients with PVE, 490 patients (47.8%) underwent early surgery and 535 individuals (52.2%) received medical therapy alone. Compared with medical therapy, early surgery was associated with lower in-hospital mortality in the unadjusted analysis and after controlling for treatment selection bias (in-hospital mortality: hazard ratio [HR], 0.44 [95% CI, 0.38-0.52] and lower 1-year mortality: HR, 0.57 [95% CI, 0.49-0.67]). The lower mortality associated with surgery did not persist after adjustment for survivor bias (in-hospital mortality: HR, 0.90 [95% CI, 0.76-1.07] and 1-year mortality: HR, 1.04 [95% CI, 0.89-1.23]). Subgroup analysis indicated a lower in-hospital mortality with early surgery in the highest surgical propensity quintile (21.2% vs 37.5%; P = .03). At 1-year follow-up, the reduced mortality with surgery was observed in the fourth (24.8% vs 42.9%; P = .007) and fifth (27.9% vs 50.0%; P = .007) quintiles of surgical propensity.
Conclusions and Relevance
Prosthetic valve endocarditis remains associated with a high 1-year mortality rate. After adjustment for differences in clinical characteristics and survival bias, early valve replacement was not associated with lower mortality compared with medical therapy in the overall cohort. Further studies are needed to define the effect and timing of surgery in patients with PVE who have indications for surgery.
Prosthetic valve endocarditis (PVE) occurs in approximately 3% to 6% of patients within 5 years of valve implantation and is associated with significant morbidity and mortality.1- 4 Surgical intervention with debridement and valve replacement is recommended by consensus guidelines5,6 for patients with complications such as valve dysfunction, dehiscence, heart failure, cardiac abscesses, or persistent bacteremia. These guidelines are based largely on expert opinion and limited observational data.7 Studies8- 25 comparing survival between patients undergoing surgery vs medical therapy for PVE have reported conflicting results. In addition, retrospective data collection, single-center study design, and small sample sizes of these studies limit the ability to control for treatment selection and survivor bias.
Propensity score methods use an estimated probability of a treatment (ie, valve surgery) based on observed baseline characteristics to control for selection bias. This method has been used frequently in studies estimating treatment effects for patients with native valve endocarditis or including patients with either native valve endocarditis or PVE.26- 29 Important recommendations regarding performance of observational studies and use of propensity score–based methods were recently published.30- 33 The method of inverse probability of treatment weighting (IPTW) using the surgical propensity score in regression models for mortality is favored because of its superior performance in controlling for selection bias compared with stratification or propensity matching.32 Survivor bias can profoundly affect outcome estimates, and this bias should be addressed by matching or including treatment (surgery) as a time-dependent covariate.27,33
Although a small randomized trial of early surgery for native valve infective endocarditis (IE) has recently been reported,34 to our knowledge, no randomized studies of surgery for PVE have been performed. The objective of the present study was to assess in-hospital and 1-year mortality in patients with PVE who undergo valve replacement compared with patients who receive medical therapy alone using appropriate propensity score–based methods to provide adjusted estimates of treatment effect.
The International Collaboration on Endocarditis–Prospective Cohort Study (ICE-PCS) is a prospective, multicenter, international registry of patients with IE.35,36 Data based on standard definitions were collected prospectively between January 1, 2000, and December 31, 2006, from 64 sites in 28 countries. The study was approved by the institutional review boards or ethics committees at all participating sites.
Inclusion criteria for this study cohort were patients diagnosed with definite PVE based on the modified Duke criteria.37 Patients with the following characteristics were excluded: native and nonnative valve IE (eg, pacemaker IE), receipt of surgery before admission, and missing values for sex, receipt and/or date of surgery, length of initial hospitalization, in-hospital death, and death at 1-year follow-up. To preserve the assumption of independence of observations, only the first episode of IE recorded for an individual patient was used. For missing data in ICE-PCS, sites and their investigators were queried to complete data collection.
The definitions used in the ICE-PCS cohort have been reported.38Early surgery was defined as replacement or repair of the infected prosthetic valve during the initial hospitalization for PVE. Chronic illness was defined as the presence of chronic comorbidities, such as diabetes mellitus, cancer, immunosuppression, hemodialysis dependence, chronic obstructive pulmonary disease, and cirrhosis. Paravalvular complication was defined as the presence of an intracardiac abscess or fistula by transthoracic or transesophageal echocardiography. Prosthetic valvular complication was defined as evidence of dehiscence or severe regurgitation by transthoracic or transesophageal echocardiography. Systemic embolization was defined as embolism to any major arterial vessel, excluding stroke. Health care–associated endocarditis consisted of either nosocomial or nonnosocomial health care–associated infection.39
The association between early surgery and mortality was evaluated in a prospective, observational cohort. The primary outcomes were all-cause mortality during initial hospitalization and at 1-year follow-up. Analyses were expressed as hazard ratios (HRs) with 95% CIs; a 2-sided P value <.05 was considered significant. The unadjusted effect of early surgery on survival time was estimated using a univariate Cox proportional hazards model. Next, adjustment for measured confounders was performed using a multivariable Cox proportional hazards model with IPTW to address treatment selection bias. The cohort was also stratified by propensity score, and outcomes were compared between the treatment groups within each stratum using the Fisher exact test. A final Cox proportional hazards model included all relevant covariates as well as surgery as a time-dependent variable and IPTW to control for survival and treatment selection bias. All analyses were performed using commercial software (SAS, version 9.2; SAS Institute Inc).
Baseline characteristics and outcomes of patients with PVE who received early surgery were compared with those receiving medical therapy alone using the Wilcoxon rank sum test for continuous variables and the χ2 test for categorical variables. Unadjusted HRs were computed using a univariate Cox proportional hazards model. A multivariable Cox proportional hazards model with IPTW was performed to identify independent predictors of in-hospital and 1-year mortality (see the IPTW and Adjustment for Survivor Bias subsection below). This model included 19 clinically relevant variables (Supplement [eTable]). All of the variables used in the multivariable model had data collected for 97% or more of patients. Missing values for clinical outcomes were imputed with the negative category for categorical variables.
To account for treatment selection bias (ie, systematic differences in clinical characteristics between patients in the 2 treatment groups that may affect treatment selection), the propensity or probability for early surgery was calculated for each patient on the basis of a nonparsimonious multivariable logistic regression model. This model included 21 clinically relevant variables (Table 1) considered a priori by the investigators to contribute to surgical treatment. Odds ratios (ORs) and 95% CIs for early surgery were calculated for all predictors. The total cohort of 1025 patients was stratified into quintiles based on the probability of early surgery (and without regard to actual treatment received by the patient), and outcomes were estimated within each stratum.
An additional Cox proportional hazards model was created to estimate the effect of surgery on mortality while controlling for treatment selection and survivor bias. Survivor bias was considered important, since the likelihood of receiving early surgery may be influenced by longer survival (or, in other words, patients who die early during hospitalization may be considered as deaths associated with medical therapy despite surgical indications). To adjust for treatment selection bias, each patient was assigned a “weight” or influence when estimating the effect of treatment on mortality, which was inversely proportional to the probability of receiving the treatment to which they were assigned in reality (IPTW). To reduce survivor bias, early surgery was included as a time-dependent covariate, that is, surgical patients were included in the medical therapy group until the date of surgery and in the surgical group thereafter.
A total of 4166 patients with definite left- or right-sided IE were enrolled in the ICE-PCS cohort between January 1, 2000, and December 31, 2006. Of these, 1025 patients had definite PVE and met the eligibility criteria for this study (Supplement [eFigure]). A prosthetic aortic valve was present in 719 (70.1%) patients (mechanical valve: 349 [48.5%]; bioprosthetic valve: 353 [49.1%]; repair: 17 [2.4%]), and a prosthetic mitral valve or ring was present in 473 (46.1%) patients (mechanical valve: 303 [64.1%]; bioprosthetic valve: 86 [18.2%]; repair: 84 [17.8%]) patients. Staphylococcus aureus was the most common cause of PVE. Among the PVE cases, 490 of 1025 patients (47.8%) underwent early surgery and 535 patients (52.2%) received medical therapy alone during the index hospitalization (Table 1). There was no significant difference in the time interval between valve insertion and PVE diagnosis between the 2 treatment groups among the 408 patients for whom this variable was collected (the variable was removed from case report forms in August 2005). The median time from admission to surgery was 8 days (quintile 1 to quintile 3, 4-20 days).
Patients who received early surgery were significantly younger, had a shorter duration of symptoms, and were more likely to have been transferred from another facility. Prosthetic valve endocarditis caused by S aureus and enterococci was associated with receiving medical therapy, while coagulase-negative Staphylococcus was associated with higher use of surgery. As expected, a significantly higher proportion of the surgical group compared with the medical group had complications of PVE, such as mitral valve regurgitation (28.8% vs 19.60%; OR, 1.64 [95% CI, 1.16-2.31]), paravalvular complications (43.5% vs 20.2%; OR, 2.62 [95% CI, 1.92-3.58]), or prosthetic valve complications (41.6% vs 24.1%; OR, 1.63 [95% CI, 1.17-2.27]). Early surgery was associated with lower in-hospital mortality (22.0% vs 26.7%; HR, 0.68 [95% CI, 0.53-0.87]) and 1-year mortality (27.1% vs 36.6%; HR, 0.68 [95% CI, 0.55-0.85]) in the unadjusted Cox proportional hazards model.
To control for treatment selection bias, the probability of surgery by propensity score was calculated for each patient. The propensity score model had a concordance index of 0.74 and a Hosmer-Lemeshow test statistic of 7.78 (P = .45), indicating good discriminative and predictive ability. The predicted probability of surgery for the total cohort ranged from 5.2% to 98.2%. An adjusted Cox proportional hazards model, including IPTW and controlling for other measured covariates, was performed. Early surgery remained strongly associated with lower mortality after adjusting for treatment selection bias (in-hospital mortality: HR, 0.44 [95% CI, 0.38-0.52] and 1-year mortality: HR, 0.57 [95% CI, 0.49-0.67]) (Table 2, Figure 1, and Supplement [eTable]).
The cohort was then divided into 5 subgroups (ie, quintiles) based on the predicted probability of surgery (and without regard to actual treatment received by the patient). Thus, each quintile had 205 patients who were comparable in clinical characteristics and probability of surgery but differed by the treatment received (a process similar to randomization). In addition, patients in the fifth quintile had a higher predicted probability of surgery (range, 68.5%-98.2%) vs those in the first quintile (range, 5.2%-27.5%). Figure 2 shows the frequency of PVE complications that may indicate a clinical indication for surgery across the quintiles of propensity. Patients in quintile 5 had a higher frequency of new mitral or aortic valve regurgitation, prosthetic valve/paravalvular complications, and New York Heart Association class I to IV congestive heart failure compared with patients in the lower quintiles and therefore had a higher probability of receiving surgical treatment. We then compared the outcomes between patients who underwent valve surgery with those who received medical therapy alone within each quintile. A lower in-hospital mortality incidence for surgery was observed only in the highest surgical propensity quintile (21.2% vs 37.5%, respectively; P = .03) (Figure 3). At the 1-year follow-up, lower mortality associated with surgery was observed in the fourth (24.8% vs 42.9%; P = .007) and fifth (28% vs 50%; P = .007) quintiles (Figure 4).
Next, we evaluated the effect of early surgery on mortality after controlling for treatment selection and survivor bias. The survival benefit was no longer evident after adjusting for survivor bias by including surgery as a time-dependent variable in the Cox proportional hazards model (in-hospital mortality: HR, 0.90 [95% CI, 0.76-1.07] and 1-year mortality: HR, 1.04 [0.89-1.23]). Variables independently associated with in-hospital and 1-year mortality in this model included chronic illness, S aureus infection, health care–associated infection, and PVE complications of stroke, congestive heart failure, intracardiac abscess, and paravalvular complications (Table 3).
Our study compared the clinical characteristics and outcome of patients with PVE treated with early surgery or medical therapy during the index hospitalization. Our main findings were (1) a high percentage of patients with PVE (48%), particularly those with complications related to endocarditis, underwent surgery during the index hospitalization; (2) although early surgery was associated with a mortality benefit in the unadjusted analysis and after controlling for treatment selection bias, this mortality benefit was neutralized after controlling for survivor bias in the overall cohort; (3) surgery in subgroups of patients who had strong indications for surgery (eg, valve regurgitation, vegetation, and dehiscence or paravalvular abscess/fistula) was associated with lower 1-year mortality. To our knowledge, this is the largest study of PVE in the medical literature with strengths of prospectively collected data from multinational centers with an expertise in IE and in a contemporary era of surgical therapy.
The rate of valve surgery in our cohort (48%) is similar to surgical rates for PVE reported in the literature.8- 25 This is a reflection of the guidelines from the American Heart Association/American College of Cardiology and the European Society of Cardiology that recommend consideration of surgery for all patients with PVE, particularly those with complications unlikely to be treated effectively by medical therapy alone, such as heart failure, prosthetic valve dysfunction, and intracardiac abscess.5,6 Nevertheless, operative (in-hospital) mortality remains high for surgical patients and not less than the rates in previous eras,25 and patients with complicated PVE in our cohort had similar in-hospital and longer-term mortality compared with patients with a lower-risk clinical profile treated with medical therapy alone. A recent study reported in the Society of Thoracic Surgery database40 showed a low operative mortality in IE (8%), but the study did not specifically evaluate PVE, and surgery during the active stage of IE was associated with a 2-fold higher operative mortality.
In our study, early surgery was not associated with a mortality benefit in the overall cohort after adjusting for treatment selection and survivor bias. The findings of our subgroup analysis support the American Heart Association guidelines because patients with the highest predicted probability of surgery (ie, those with the surgical indications mentioned above) had lower mortality rates when they received surgery vs medical therapy. However, these findings should be interpreted cautiously as results of a post hoc subgroup analysis that did not adjust for survivor bias.
Previous studies of PVE have found conflicting results regarding the effect of surgery. In a previous study by the International Collaboration on Endocarditis Investigators41 of retrospectively merged IE databases with propensity matching, surgery and medical therapy had similar in-hospital mortality rates, but longer-term outcome was not evaluated. In planning the present study, we had hypothesized that a survival benefit of surgery may not be apparent during the initial hospitalization given the higher operative risk of patients with PVE. However, after adjusting for selection and survivor bias in the surgical group, mortality rates remained similar even at 1 year after PVE for both treatment groups and were strongly related to host factors, pathogen, and particularly complications of PVE (heart failure, stroke, and paravalvular complications). Of note, heart failure was the strongest predictor of both in-hospital and 1-year mortality, confirming the significance of this complication even with a high rate of surgical intervention.42 Several other factors reflecting changes in the epidemiology of PVE, such as the higher patient age, cause of S aureus, and health care–associated infection, may contribute to the persistently high in-hospital and 1-year mortality compared with earlier studies.25,41
Recently, a small, randomized study34 of surgery for native valve endocarditis was reported. In that study, patients treated with surgery within 48 hours of diagnosis had a lower rate of embolic events but similar survival at 6 months compared with patients treated with usual care (yet 77% of patients receiving usual care underwent surgery).34 No randomized studies of surgery for PVE have been performed. Based on the differing survival estimates between the propensity-adjusted and Cox proportional hazards model, our results emphasize that survival bias and timing of surgery should be considered when evaluating the treatment effect on mortality. Although patients underwent surgery at a median of 8 days after admission, the potential benefit of earlier intervention was not evaluated and may influence outcome.
This study had several other limitations. The ICE cohort may be influenced by referral bias because most institutions are tertiary care centers with voluntary participation. Thus, the results of the present study may not be generalizable to the global epidemiology, treatment, and outcomes of PVE. Despite the use of propensity score adjustment to reduce selection bias for surgical treatment and Cox proportional hazards modeling to reduce survival bias, other variables not evaluated may confound the results of this analysis. The timing of PVE diagnosis relative to the date of prosthetic valve implantation was not evaluated because of missing data. Data regarding the presence of surgical indications in medically treated patients and the reason for not undergoing valve surgery were also unavailable for most patients in the cohort. However, other variables included in these analyses, such as health care–associated infection and causative organism (staphylococcal), correlate with early PVE characteristics. Data regarding surgery after hospital discharge were not routinely collected; among 252 of 392 patients (64%) who received medical therapy and survived to hospital discharge, only 24 of 252 patients (10%) had undergone surgery at 1-year follow-up.
In conclusion, approximately one-third of patients with PVE die within 1 year after diagnosis, with mortality strongly associated with other chronic illness, health care–associated infection, S aureus, and complications of PVE. Surgical treatment was not associated with a lower mortality at 1-year in the overall PVE cohort after controlling for treatment selection and survivor bias. Further studies are needed to define the effect and timing of surgery in patients with PVE who have indications for surgery.
Corresponding Author: Tahaniyat Lalani, MD, MHS, Naval Medical Center Portsmouth, Bldg 3, First Floor, 620 John Paul Jones Cir, Portsmouth, VA 23708 (email@example.com).
Accepted for Publication: April 14, 2013.
Published Online: July 15, 2013. doi:10.1001/jamainternmed.2013.8203.
Author Contributions:Study concept and design: Lalani, Fowler, Hoen, Wang.
Acquisition of data: Chu, Cecchi, Corey, Durante-Mangoni, Fowler, Gordon, Grossi, Hannan, Hoen, Muñoz, Rizk, Kanj, Selton-Suty, Sexton, Spelman, Ravasio, Tripodi.
Analysis and interpretation of data: Lalani, Park, Cecchi, Durante-Mangoni, Gordon, Hannan, Hoen, Spelman, Wang.
Drafting of the manuscript: Lalani, Hannan, Sexton, Wang.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Lalani, Park, Grossi, Rizk, Spelman.
Obtained funding: Chu, Hannan, Muñoz, Wang.
Administrative, technical, and material support: Chu, Fowler, Gordon, Hoen, Muñoz, Rizk, Wang.
Study supervision: Cecchi, Corey, Hoen, Sexton, Wang.
Conflict of Interest Disclosures: None reported.
Funding/Support: Dr Andrew Wang is supported in part by American Heart Association Mid-Atlantic Affiliate Grant in Aid 12GRNT12030071 for this study.
Disclaimer: Dr Lalani is an employee of the US government. As such, this work was prepared as part of official duties. Title 17 USC 105 provides that “copyright protection under this title is not available for any work of the United States Government.” Title 17 USC 101 defines a US government work as “a work prepared by a military service member or employee of the US government as part of that person’s official duties.” The content of this publication is the sole responsibility of the authors and does not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US government.
Group Information: International Collaboration on Endocarditis–Prospective Cohort Study (ICE-PCS) Investigators and Sites: Argentina: Liliana Clara, MD, and Marisa Sanchez, MD (Hospital Italiano); José Casabé, MD, PhD, and Claudia Cortes, MD (Hospital Universitario de la Fundaciòn Favaloro); Francisco Nacinovich, MD, Pablo Fernandez Oses, MD, Ricardo Ronderos, MD, Adriana Sucari, MD, and Jorge Thierer, MD (Instituto Cardiovascular); and Javier Altclas, MD, and Silvia Kogan, MD (Sanatorio de la Trinidad Mitre). Australia: Denis Spelman, MD (Alfred Hospital); Eugene Athan, MD, and Owen Harris, MBBS (Barwon Health); Karina Kennedy, MBBS, and Ren Tan, MBBS (Canberra Hospital); David Gordon, MBBS, PhD, and Lito Papanicolas, MBBS (Flinders Medical Centre); Damon Eisen, MBBS, MD, Leeanne Grigg, MBBS, and Alan Street, MBBS (Royal Melbourne Hospital); Tony Korman, MD, and Despina Kotsanas, BSc (Hons) (Southern Health); Robyn Dever, MD, Phillip Jones, MD, Pam Konecny, MD, Richard Lawrence, MD, David Rees, MD, and Suzanne Ryan, MHSc (St. George Hospital); Michael P. Feneley, MD, John Harkness, MD, Phillip Jones, MD, and Suzanne Ryan, MHSc (St. Vincent’s); Phillip Jones, MD, and Suzanne Ryan, MHSc (Sutherland); and Phillip Jones, MD, Jeffrey Post, MD, Porl Reinbott, and Suzanne Ryan, MHSc (The University of New South Wales). Austria: Rainer Gattringer, MD, and Franz Wiesbauer, MD (Vienna General Hospital). Brazil: Adriana Ribas Andrade, MD, Ana Cláudia Passos de Brito, MD, and Armenio Costa Guimarães, MD (Ana Neri Hospital); Max Grinberg, MD, PhD, Alfredo José Mansur, MD, PhD, Rinaldo Focaccia Siciliano, MD, Tania Mara Varejao Strabelli, MD, and Marcelo Luiz Campos Vieira, MD (Heart Institute [Incor], University of Sao Paulo Medical School); Regina Aparecida de Medeiros Tranchesi, MD, and Marcelo Goulart Paiva, MD (Hospital 9 de Julho); Claudio Querido Fortes, MD, PhD (Hospital Universitario Clementino Fraga Filho/Universidade Federal do Rio de Janeiro); Auristela de Oliveira Ramos, MD (Instituto Dante Pazzanese de Cardiologia); and Giovanna Ferraiuoli, MD, PhD, Wilma Golebiovski, MD, Cristiane Lamas, MD, Clara Weksler, MD, and Marisa Santos, MD, PhD (Instituto Nacional de Cardiologia, Rio de Janerio). Canada: James A. Karlowsky, MD, Yoav Keynan, MD, Andrew M. Morris, MD, and Ethan Rubinstein, MD, LLB (University of Manitoba). Chile: Sandra Braun Jones, MD, and Patricia Garcia, MD (Hospital Clínico Pont, Universidad Católica de Chile); and M. Cereceda, MD, Alberto Fica, MD, and Rodrigo Montagna Mella, MD (Hospital Clinico Universidad de Chile). Columbia: Ricardo Fernandez, MD, Liliana Franco, MD, Javier Gonzalez, MD, and Astrid Natalia Jaramillo, MD (Clinica Cardiovascular Medellín). Croatia: Bruno Barsic, MD, PhD, Suzana Bukovski, MD, PhD, Vladimir Krajinovic, MD, Ana Pangercic, MD, Igor Rudez, MD, and Josip Vincelj, MD, PhD (University Hospital for Infectious Diseases). Czech Republic: Tomas Freiberger, MD, PhD, Jiri Pol, MD, and Barbora Zaloudikova, MSc (Centre for Cardiovascular Surgery and Transplantation). Egypt: Zainab Ashour, MD, Amani El Kholy, MD, Marwa Mishaal, MD, Dina Osama, MD, and Hussien Rizk, MD (Cairo University Medical School). France: Neijla Aissa, MD, Corentine Alauzet, MD, Francois Alla, MD, PhD, Catherine Campagnac, RN, Thanh Doco-Lecompte, MD, and Christine Selton-Suty, MD (CHU Nancy-Brabois); Jean-Paul Casalta, MD, Pierre-Edouard Fournier, MD, Gilbert Habib, MD, Didier Raoult, MD, PhD, and Franck Thuny, MD (Faculté de Médecine de Marseille); Francois Delahaye, MD, PhD, Armelle Delahaye, RN, and Francois Vandenesch, MD (Hospital Louis Pradel); Erwan Donal, MD, Pierre Yves Donnio, PhD, Erwan Flecher, MD, PhD, Christian Michelet, MD, PhD, Matthieu Revest, MD, and Pierre Tattevin, MD, PhD (Pontchaillou University); Florent Chevalier, MD, Antoine Jeu, MD, Jean Paul Rémadi, MD, Dan Rusinaru, MD, and Christophe Tribouilloy, MD, PhD (South Hospital Amiens); and Yvette Bernard, MD, Catherine Chirouze, MD, Bruno Hoen, MD, PhD, Joel Leroy, MD, and Patrick Plesiat, MD (University Medical Center of Besançon). Germany: Christoph Naber, MD, PhD, and Carl Neuerburg (Universitaetskliniken Bergmannsheil Bochum); and Bahram Mazaheri, PhD, Christoph Naber, MD, PhD, and Carl Neuerburg (University Essen). Greece: Tsaganos Thomas, MD, and Efthymia Giannitsioti, MD (Attikon University General Hospital); and Elena Mylona, MD, Olga Paniara, MD, PhD, Konstantinos Papanikolaou, MD, John Pyros, MD, and Athanasios Skoutelis, MD, PhD (Evangelismos General Hospital of Athens). India: Gautam Sharma, MD (All India Institute of Medical Sciences); and Johnson Francis, MD, DM, Lathi Nair, MD, DM, Vinod Thomas, MD, DM, and Krishnan Venugopal, MD, DM (Medical College Calicut). Ireland: Margaret Hannan, MB, BCh, BAO, MSc, and John Hurley, MB, BCh (Mater Hospitals). Israel: Amos Cahan, MD, Dan Gilon, MD, Sarah Israel, MD, Maya Korem, MD, and Jacob Strahilevitz, MD (Hadassah-Hebrew University); and Ethan Rubinstein, MD, LLB, and Jacob Strahilevitz, MD (Tel Aviv University School of Medicine). Italy: Emanuele Durante-Mangoni, MD, PhD, Irene Mattucci, MD, Daniela Pinto, MD, Federica Agrusta, MD, Alessandra Senese, MD, Enrico Ragone, MD, PhD, and Riccardo Utili, MD, PhD (II Università di Napoli); Enrico Cecchi, MD, Francesco De Rosa, MD, Davide Forno, MD, Massimo Imazio, MD, and Rita Trinchero, MD (Maria Vittoria Hospital); Alessandro Tebini, MD, Paolo Grossi, MD, PhD, Mariangela Lattanzio, MD, and Antonio Toniolo, MD (Ospedale di Circolo Varese); Antonio Goglio, MD, Annibale Raglio, MD, DTM&H, Veronica Ravasio, MD, Marco Rizzi, MD, and Fredy Suter, MD (Ospedali Riuniti di Bergamo); and Giampiero Carosi, MD, Silvia Magri, MD, and Liana Signorini, MD (Spedali Civili–Università di Brescia). Lebanon: Khalil Anouti, MD, Jad Chahoud, MD, Zeina Kanafani, MD, MS, and Souha S. Kanj, MD (American University of Beirut Medical Center). Malaysia: Imran Abidin, MD (University of Malaya Medical Center); and Syahidah Syed Tamin, MD (National Heart Institute). Mexico: Eduardo Rivera Martínez, MD, and Gabriel Israel Soto Nieto, MD (Instituto Nacional de Cardiología Ignacio Chávez). Netherlands: Jan T. M. van der Meer, MD, PhD (University of Amsterdam). New Zealand: Stephen Chambers, MD, MSc (University of Otago); David Holland, MB, ChB, PhD (Middlemore Hospital); Arthur Morris, MD (Diagnostic Medlab); Nigel Raymond, MB, ChB (Wellington Hospital); Kerry Read, MB, ChB (North Shore Hospital); and David R. Murdoch, MD, MSc, DTM&H (University of Otago). Romania: Stefan Dragulescu, MD, PhD, Adina Ionac, MD, PhD, and Cristian Mornos, MD (Victor Babes University of Medicine and Pharmacy). Russia: O. M. Butkevich, PhD (Learning-Scientific Centre of Medical Centre of Russian Presidential Affairs Government Medical Centre of Russia); and Natalia Chipigina, PhD, Ozerecky Kirill, MD, Kulichenko Vadim, PhD, and Tatiana Vinogradova, MD, PhD (Russian Medical State University). Saudi Arabia: Jameela Edathodu, MBBS, and Magid Halim, MBBS (King Faisal Specialist Hospital & Research Center). Singapore: Yee-Yun Liew, and Ru-San Tan, MBBS (National Heart Centre). Slovenia: Tatjana Lejko-Zupanc, MD, PhD, Mateja Logar, MD, PhD, and Manica Mueller-Premru, MD, PhD (Medical Center Ljublijana). South Africa: Patrick Commerford, MD, Anita Commerford, MD, Eduan Deetlefs, MD, Cass Hansa, MD, and Mpiko Ntsekhe, MD (University of Cape Town and Groote Schuur Hospital). Spain: Manuel Almela, MD, Yolanda Armero, MD, Manuel Azqueta, MD, Ximena Castañeda, MD, Carlos Cervera, MD, PhD, Ana del Rio, MD, PhD, Carlos Falces, MD, PhD, Cristina Garcia-de-la-Maria, PhD, Guillermina Fita, MD, Jose M. Gatell, MD, PhD, Magda Heras MD, PhD, Jaime Llopis, MD, PhD, Francesc Marco, MD, PhD, Carlos A. Mestres, MD, PhD, José M. Miró, MD, PhD, Asuncion Moreno, MD, PhD, Salvador Ninot, MD, Carlos Paré, MD, PhD, Joan M. Pericas, MD, Jose Ramirez, MD, PhD, Irene Rovira, MD, and Marta Sitges, MD, PhD (Hospital Clinic–IDIBAPS, University of Barcelona); Ignasi Anguera, MD, PhD, Bernat Font, MD, and Joan Raimon Guma, MD (Hospitál de Sabadell); Javier Bermejo, MD, PhD, Emilio Bouza, MD, PhD, Miguel Angel Garcia Fernández, MD, Victor Gonzalez-Ramallo, MD, Mercedes Marín, MD, Patricia Muñoz, MD, PhD, Miguel Pedromingo, MD, Jorge Roda, MD, Marta Rodríguez-Créixems, MD, PhD, and Jorge Solis, MD (Hospital General Universitario Gregorio Marañón); Benito Almirante, MD, Nuria Fernandez-Hidalgo, MD, and Pilar Tornos, MD (Hospital Universitari Vall d’Hebron); and Arístides de Alarcón, MD, PhD, and Ricardo Parra (Hospital Universitario Virgen del Rocío). Sweden: Eric Alestig, MD, Magnus Johansson, MD, PhD, Lars Olaison, MD, PhD, and Ulrika Snygg-Martin, MD (Sahlgrenska Universitetssjukhuset/Östra). Thailand: Orathai Pachirat, MD, Pimchitra Pachirat, MD, Burabha Pussadhamma, MD, and Vichai Senthong, MD (Khon Kaen University). United Kingdom: Anna Casey, MBBS, Tom Elliott, PhD, DSc, Peter Lambert, BSc, PhD, DSc, and Richard Watkin, MBBS (Queen Elizabeth Hospital); and Christina Eyton, and John L. Klein, MD (St. Thomas’ Hospital). United States: Suzanne Bradley, MD, and Carol Kauffman, MD (Ann Arbor Veterans Affairs Medical Center); Roger Bedimo, MD, MS (Dallas Veterans Affairs Medical Center); Vivian H. Chu, MD, MHS, G. Ralph Corey, MD, Anna Lisa Crowley, MD, MHS, Pamela Douglas, MD, Laura Drew, RN, BSN, Vance G. Fowler, MD, MHS, Thomas Holland, MD, Tahaniyat Lalani, MD, MHS, Daniel Mudrick, MD, Zaniab Samad, MD, MHS, Daniel Sexton, MD, Martin Stryjewski, MD, MHS, Andrew Wang, MD, and Christopher W. Woods, MD, MPH (Duke University Medical Center); Stamatios Lerakis, MD (Emory University); Robert Cantey, MD, Lisa Steed, PhD, and Dannah Wray, MD, MHS (Medical University of South Carolina); Stuart A. Dickerman, MD (New York University Medical Center); Hector Bonilla, MD, Joseph DiPersio, MD, PhD, and Sara-Jane Salstrom, RN (Summa Health System); John Baddley, MD, and Mukesh Patel, MD (University of Alabama at Birmingham); Gail Peterson, MD, and Amy Stancoven, MD (The University of Texas-Southwestern Medical Center); Donald Levine, MD, Jonathan Riddle, and Michael Rybak, PharmD, MPH (Wayne State University); and Christopher H. Cabell, MD, MHS (Quintiles). ICE Coordinating Center: Khaula Baloch, MPH, Vivian H. Chu, MD, MHS, G. Ralph Corey, MD, Christy C. Dixon, Vance G. Fowler, Jr, MD, MHS, Tina Harding, RN, BSN, Marian Jones-Richmond, Paul Pappas, MS, Lawrence P. Park, PhD, Bob Sanderford, and Judy Stafford, MS. ICE Publications Committee: Kevin Anstrom, PhD, Eugene Athan, MD, Arnold S. Bayer, MD, Christopher H. Cabell, MD, MHS, Vivian H. Chu, MD, MHS, G. Ralph Corey, MD, Vance G. Fowler Jr, MD, MHS, Bruno Hoen, MD, PhD, A. W. Karchmer, MD, José M. Miró, MD, PhD, David R. Murdoch, MD, MSc, DTM&H, Daniel J. Sexton, MD, and Andrew Wang, MD. ICE Steering Committee: Arnold S. Bayer, MD, Christopher H. Cabell, MD, MHS, Vivian Chu, MD, MHS, G. Ralph Corey, MD, David T. Durack, MD, D Phil, Susannah Eykyn, MD, Vance G. Fowler, Jr, MD, MHS, Bruno Hoen, MD, PhD, José M. Miró, MD, PhD, Phillipe Moreillon, MD, PhD, Lars Olaison, MD, PhD, Didier Raoult, MD, PhD, Ethan Rubinstein MD, LLB, and Daniel J. Sexton, MD.
Correction: This article was corrected on September 30, 2013, for errors in Figure 3.