Outcomes of Concomitant Coronary Artery Bypass Grafting in Patients With Infective Endocarditis: A Systematic Review and Meta-Analysis

It is current practice to perform concomitant coronary artery bypass grafting (CABG) in patients with infective endocarditis who have relevant coronary artery disease. However, CABG may add complexity to the operation. We performed a systematic review and a meta-analysis of studies that presented outcomes from patients who underwent valve surgery because of infective endocarditis with or without concomitant CABG. Three databases were assessed. Perioperative mortality was the primary outcome. Long-term mortality and postoperative stroke were the secondary outcomes. Inverse variance method and random model were performed. Five studies with a total of 5,408 patients were included. Mean follow-up was 8.2 years. Just 1 study addressed exclusively patients with documented coronary artery disease. Perioperative mortality did not differ between patients with or without concomitant CABG (odds ratio 1.53, 95% confidence interval 0.52 to 4.48, p = 0.44). Long-term mortality did not differ between patients who received and those who did not receive concomitant CABG (odds ratio 1.79, confidence interval 0.88 to 3.65, p = 0.11). Only 1 study from a multicenter registry reported data on the occurrence of postoperative stroke, which demonstrated that its incidence after adjustment was 26% in patients with concomitant CABG versus 21% in patients without concomitant CABG (p = 0.003). The results suggest that in endocarditis patients, adding CABG to valve surgery does not affect perioperative or long-term mortality. Data available on the impact of concomitant CABG on neurologic outcomes are limited to a retrospective multicenter registry and suggest that concomitant CABG may be associated with higher postoperative stroke. It is current practice to perform concomitant coronary artery bypass grafting (CABG) in patients with infective endocarditis who have relevant coronary artery disease. However, CABG may add complexity to the operation. We performed a systematic review and a meta-analysis of studies that presented outcomes from patients who underwent valve surgery because of infective endocarditis with or without concomitant CABG. Three databases were assessed. Perioperative mortality was the primary outcome. Long-term mortality and postoperative stroke were the secondary outcomes. Inverse variance method and random model were performed. Five studies with a total of 5,408 patients were included. Mean follow-up was 8.2 years. Just 1 study addressed exclusively patients with documented coronary artery disease. Perioperative mortality did not differ between patients with or without concomitant CABG (odds ratio 1.53, 95% confidence interval 0.52 to 4.48, p = 0.44). Long-term mortality did not differ between patients who received and those who did not receive concomitant CABG (odds ratio 1.79, confidence interval 0.88 to 3.65, p = 0.11). Only 1 study from a multicenter registry reported data on the occurrence of postoperative stroke, which demonstrated that its incidence after adjustment was 26% in patients with concomitant CABG versus 21% in patients without concomitant CABG (p = 0.003). The results suggest that in endocarditis patients, adding CABG to valve surgery does not affect perioperative or long-term mortality. Data available on the impact of concomitant CABG on neurologic outcomes are limited to a retrospective multicenter registry and suggest that concomitant CABG may be associated with higher postoperative stroke. Infective endocarditis (IE) is a serious disease with high incidence of morbidity and mortality.1Murdoch DR Corey GR Hoen B Miró JM Fowler VG Bayer AS Karchmer AW Olaison L Pappas PA Moreillon P Chambers ST Chu VH Falcó V Holland DJ Jones P Klein JL Raymond NJ Read KM Tripodi MF Utili R Wang A Woods CW Cabell CH International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS) InvestigatorsClinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study.Arch Intern Med. 2009; 169: 463-473Crossref PubMed Scopus (1639) Google Scholar A fact that can accentuate the lethality of the disease is that cardiac surgery is most of the time indicated for patients with IE when the disease has already progressed locally or systemically which makes cardiac surgery for treatment of IE challenging.2Habib G Lancellotti P Antunes MJ Bongiorni MG Casalta JP Del Zotti F Dulgheru R El Khoury G Erba PA Iung B Miro JM Mulder BJ Plonska-Gosciniak E Price S Roos-Hesselink J Snygg-Martin U Thuny F Tornos Mas P Vilacosta I Zamorano JL ESC Scientific Document Group2015 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: 3075-3128Crossref PubMed Scopus (3345) Google Scholar Despite these technical challenges, valve surgery is an independent predictor for better short-term and long-term survival in patients with IE.3Bannay A Hoen B Duval X Obadia JF Selton-Suty C Le Moing V Tattevin P Iung B Delahaye F Alla F AEPEI Study GroupThe impact of valve surgery on short- and long-term mortality in left-sided infective endocarditis: do differences in methodological approaches explain previous conflicting results?.Eur Heart J. 2011; 32: 2003-2015Crossref PubMed Scopus (146) Google Scholar Around 13% to 40% of patients with IE can also present with coronary artery disease (CAD), which has been identified as an independent predictor of long-term mortality.4Sims JR Anavekar NS Chandrasekaran K Steckelberg JM Wilson WR Gersh BJ Baddour LM DeSimone DC Utility of cardiac computed tomography scanning in the diagnosis and pre-operative evaluation of patients with infective endocarditis.Int J Cardiovasc Imaging. 2018; 34: 1155-1163Crossref PubMed Scopus (27) Google Scholar The current guidelines for patients who underwent aortic valve replacement) for non-IE pathologies recommend performing coronary artery bypass grafting (CABG) to all significant coronary stenoses.5Neumann FJ Sousa-Uva M Ahlsson A Alfonso F Banning AP Benedetto U Byrne RA Collet JP Falk V Head SJ Jüni P Kastrati A Koller A Kristensen SD Niebauer J Richter DJ Seferovic PM Sibbing D Stefanini GG Windecker S Yadav R Zembala MO ESC Scientific Document Group2018 ESC/EACTS Guidelines on myocardial revascularization [published correction appears in Eur Heart J 2019;40:3096].Eur Heart J. 2019; 40: 87-165Crossref PubMed Scopus (4401) Google Scholar In some cases, this logic is also applied in patients with IE. However, cardiac surgery for IE is associated with more exaggerated inflammatory response than for non-IE pathologies6Diab M Tasar R Sponholz C Lehmann T Pletz MW Bauer M Brunkhorst FM Doenst T Changes in inflammatory and vasoactive mediator profiles during valvular surgery with or without infective endocarditis: a case control pilot study.PLoS One. 2020; 15e0228286Crossref Google Scholar and therefore, may require different strategies to achieve optimal results. Adding CABG to valve surgery prolongs the duration of the cardiopulmonary bypass (CPB) and aortic cross-clamping.7Doenst T Borger MA Weisel RD Yau TM Maganti M Rao V Relation between aortic cross-clamp time and mortality–not as straightforward as expected.Eur J Cardiothorac Surg. 2008; 33: 660-665Crossref PubMed Scopus (94) Google Scholar,8Kumar A Anstey C Tesar P Shekar K Risk factors for mortality in patients undergoing cardiothoracic surgery for infective endocarditis.Ann Thorac Surg. 2019; 108: 1101-1106Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar These 2 factors are responsible for amplifying the inflammatory status of the already infected patient, resulting in increased sepsis incidence and consequently accentuated multi-organ failure, the main cause of death in patients with IE.2Habib G Lancellotti P Antunes MJ Bongiorni MG Casalta JP Del Zotti F Dulgheru R El Khoury G Erba PA Iung B Miro JM Mulder BJ Plonska-Gosciniak E Price S Roos-Hesselink J Snygg-Martin U Thuny F Tornos Mas P Vilacosta I Zamorano JL ESC Scientific Document Group2015 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: 3075-3128Crossref PubMed Scopus (3345) Google Scholar,9Mirabel M Sonneville R Hajage D Novy E Tubach F Vignon P Perez P Lavoué S Kouatchet A Pajot O Mekontso-Dessap A Tonnelier JM Bollaert PE Frat JP Navellou JC Hyvernat H Hssain AA Timsit JF Megarbane B Wolff M Trouillet JL ENDOREA Study GroupLong-term outcomes and cardiac surgery in critically ill patients with infective endocarditis.Eur Heart J. 2014; 35: 1195-1204Crossref PubMed Scopus (62) Google Scholar,10Diab M Lehmann T Bothe W Akhyari P Platzer S Wendt D Deppe AC Strauch J Hagel S Günther A Faerber G Sponholz C Franz M Scherag A Velichkov I Silaschi M Fassl J Hofmann B Lehmann S Schramm R Fritz G Szabo G Wahlers T Matschke K Lichtenberg A Pletz MW Gummert JF Beyersdorf F Hagl C Borger MA Bauer M Brunkhorst FM Doenst T REMOVE Trial Investigators*Cytokine hemoadsorption during cardiac surgery versus standard surgical care for infective endocarditis (REMOVE): results from a multicenter randomized controlled trial.Circulation. 2022; 145: 959-968Crossref PubMed Scopus (47) Google Scholar To date, there is no randomized clinical trial investigating the impact of concomitant CABG during cardiac surgery in this specific population. Recently, a multicenter study with almost 5,000 patients showed that in patients with IE with CAD, adding CABG to valve surgery may be associated with a higher likelihood of postoperative stroke without adding long-term survival benefits.11Diab M Lehmann T Weber C Petrov G Luehr M Akhyari P Tugtekin SM Schulze PC Franz M Misfeld M Borger MA Matschke K Wahlers T Lichtenberg A Hagl C Doenst T Role of concomitant coronary artery bypass grafting in valve surgery for infective endocarditis.J Clin Med. 2021; 10: 2867Crossref PubMed Scopus (2) Google Scholar In the face of this argumentation contrast and the absence of a randomized setup, we aimed to review the entire literature and perform systematic research and meta-analysis to evaluate the impact of concomitant CABG with IE valve surgery on clinical outcomes. Ethical approval of this analysis was not required as no human or animal subjects were involved. This review was registered with the National Institute for Health Research International Registry of Systematic Reviews (PROSPERO, CRD42022353509). We performed a comprehensive literature search to identify contemporary studies reporting short-term and long-term outcomes from patients who underwent valve surgery because of IE with populations divided by the presence or absence of concomitant CABG. Searches were run in May 2022, in the following databases: Ovid MEDLINE, Web of Science, and The Cochrane Library (Wiley). The search strategy for Ovid MEDLINE is listed in Supplementary Table 1. The study selection followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) strategy. After de-duplication, records were screened by 2 independent reviewers (TC and HK). Any discrepancies and disagreements were resolved by a third author (MD). Titles and abstracts were reviewed against predefined inclusion and exclusion criteria. Studies were considered for inclusion if they were written in English and reported direct comparison between isolated valve surgery and concomitant CABG in patients with IE. Animal studies, abstracts, case reports, commentaries, editorials, expert opinions, conference presentations, and studies not reporting the outcomes of interest were excluded. The full text was pulled for the selected studies for a second round of eligibility screening. References for articles selected were also reviewed for relevant studies not captured by the original search. The quality of the included studies was assessed using the Newcastle-Ottawa Scale for observational studies (Supplementary Table 2). Two reviewers (TC and HK) independently performed data extraction. Accuracy was verified by a third author (MD). The extracted variables included study characteristics (publication year, country, sample size, study design, mean follow-up, and presence or absence of population adjustment) and the outcomes data. Primary outcome was perioperative mortality (30-day/inhospital). The secondary outcome was long-term all-cause mortality defined by studies with follow-up >2 years and postoperative stroke. Short-term binary outcomes were reported as odds ratios (ORs) with 95% confidence intervals (CIs) using the generic inverse variance method. For mid-term and long-term outcomes, hazard ratio (HR) with its 95% CIs was reported using generic inverse variance method. When HRs were provided, the natural logarithm of the HR was used, otherwise, HR was estimated through the reported events and accumulated group-specific person-years of follow-up. Random and fixed effect meta-analysis was performed using “metafor” and “meta” packages. Publication bias was assessed by funnel plot (using the trim and fill method) and Egger test. Heterogeneity was reported as low (I2 = 0−25%), moderate (I2 = 26% to 50%), or high (I2 > 50%). Leave-one-out analyses for the primary outcome were performed to assess the robustness of the obtained estimate. p Value for interaction was used to ascertain subgroup differences. All statistical analyses were performed using R (version 3.3.3, R Project for Statistical Computing) within RStudio (The R Foundation for Statistical Computing, Vienna, Austria). A total of 1,486 studies were retrieved from the systematic search, of which 5 met the criteria for inclusion in the final analysis. Figure 1 shows the PRISMA flowchart for study selection. Included studies were published between 2011 and 2021, all studies were observational cohorts, and 1 was multicentric. Two studies originated from Germany and 1 each from Belgium, the United States, and Turkey. Table 1 lists the details of the included studies. Three studies were based on risk-adjusted populations. A total of 5,408 patients were included in the final analysis. The number of patients in each study ranged from 19 to 4,917.Table 1Summary of included studies (references are reported in the supplementary material)AuthorYear of PublicationCountryN° of patientsStudy DesignMean Follow-up (years)Population ComparabilityReported OutcomesLeontyev2011Germany152Prospective, single center6.5Multivariate regression analysesPerioperative mortalityCaes2014Belgium186Retrospective, single center4.3Multivariate regression analysesPerioperative and long-term mortalityNeragi-Miandoab2014United States134Retrospective, single center2.3Not adjustedLong-term mortalityDiab2021Germany4,917Retrospective, multicenter1.2Inverse probability weightingPerioperative mortality, long-term mortality and postoperative strokeGüner2021Turkey19Retrospective, single centerIn-hospital outcomesNot adjustedPerioperative mortality Open table in a new tab Figure 2 shows the forest plot for perioperative all-cause mortality. There was no difference in perioperative mortality between patients with and without concomitant CABG during IE valve surgery (OR 1.53, 95% CI 0.52 to 4.48, p = 0.44). Figure 3 shows the leave-one-out analysis, which confirmed the robustness of the main analysis. Figure 4 shows the forest plot for long-term all-cause mortality. There was no difference between patients with and without concomitant CABG during IE valve surgery (OR 1.79, 95% CI 0.88 to 3.65, p = 0.11). Only 1 study from a multicenter registry reported data on the occurrence of postoperative stroke, which demonstrated that its incidence after adjustment was 26% in patients with concomitant CABG versus 21% in patients without concomitant CABG (p = 0.003).11Diab M Lehmann T Weber C Petrov G Luehr M Akhyari P Tugtekin SM Schulze PC Franz M Misfeld M Borger MA Matschke K Wahlers T Lichtenberg A Hagl C Doenst T Role of concomitant coronary artery bypass grafting in valve surgery for infective endocarditis.J Clin Med. 2021; 10: 2867Crossref PubMed Scopus (2) Google Scholar Factors that can influence the stroke rate like IE localization, Staphylococcus aureus infection, multi-valve surgery, and previous stroke were adjusted in the described study. The results suggest that in patients with endocarditis, adding CABG to valve surgery did not affect perioperative or long-term mortality. Data available on the impact of concomitant CABG on neurological outcomes are limited to a retrospective multicenter registry and suggest that concomitant CABG may be associated with higher postoperative stroke. Our results are relevant as they affect a significant number of patients and provide important information for clinical decision-making. Globally, the number of IE cases has been increasing over the last 3 decades, accounting for more than 1 million/year.12Chen H Zhan Y Zhang K Gao Y Chen L Zhan J Chen Z Zeng Z The global, regional, and national burden and trends of infective endocarditis from 1990 to 2019: results from the global burden of disease Study 2019.Front Med (Lausanne). 2022; 9774224Google Scholar In Europe, IE incidence has been rising with an average of 4.1% per year, amounting to a compound increase in incidence of 106% over 18 years, with the highest estimated yearly increase for Germany.13Talha KM Baddour LM Thornhill MH Arshad V Tariq W Tleyjeh IM Scott CG Hyun MC Bailey KR Anavekar NS Palraj R Sohail MR DeSimone DC Dayer MJ Escalating incidence of infective endocarditis in Europe in the 21st century.Open Heart. 2021; 8e001846Crossref PubMed Scopus (29) Google Scholar At the same time, ischemic heart disease affects around 126 million patients worldwide, or approximately 1.7% of the world with a rising MA MJ H R of ischemic heart results from the global burden of disease 2020; Google Scholar guidelines for patients without IE with who underwent aortic valve recommend performing CABG in all significant coronary stenoses.5Neumann FJ Sousa-Uva M Ahlsson A Alfonso F Banning AP Benedetto U Byrne RA Collet JP Falk V Head SJ Jüni P Kastrati A Koller A Kristensen SD Niebauer J Richter DJ Seferovic PM Sibbing D Stefanini GG Windecker S Yadav R Zembala MO ESC Scientific Document Group2018 ESC/EACTS Guidelines on myocardial revascularization [published correction appears in Eur Heart J 2019;40:3096].Eur Heart J. 2019; 40: 87-165Crossref PubMed Scopus (4401) Google Scholar However, has been that the survival of CABG may be because of an most coronary and to the myocardial by or of that were not the time of T A P P Falk V E A H and CABG for coronary artery review of the 2019; PubMed Scopus Google T Falk V M to coronary artery review of the 2021; PubMed Scopus Google Scholar This provide an of no mortality difference in perioperative or long-term outcomes when an as IE. to the for patients without results 2 important for clinical a concomitant CABG during IE surgery does not better long-term if by the concomitant CABG be and does not increase perioperative mortality. 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