Lead-related infective endocarditis: Factors influencing early and long-term survival in patients undergoing transvenous lead extraction

Author’s Accepted Manuscript Lead-related infective endocarditis – factors influencing early and long-term survival in patients undergoing transvenous lead extraction Anna Polewczyk, Wojciech Jacheć, Andrzej Tomaszewski, Wojciech Brzozowski, Marek Czajkowski, Grzegorz Opolski, Marcin Grabowski, Marianna Janion, Andrzej Kutarski

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S1547-5271(16)30887-6 http://dx.doi.org/10.1016/j.hrthm.2016.10.007 HRTHM6887

To appear in: Heart Rhythm Received date: 7 March 2016 Cite this article as: Anna Polewczyk, Wojciech Jacheć, Andrzej Tomaszewski, Wojciech Brzozowski, Marek Czajkowski, Grzegorz Opolski, Marcin Grabowski, Marianna Janion and Andrzej Kutarski, Lead-related infective endocarditis – factors influencing early and long-term survival in patients undergoing transvenous lead extraction, Heart Rhythm, http://dx.doi.org/10.1016/j.hrthm.2016.10.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Lead-related infective endocarditis – factors influencing early and long-term survival in patients undergoing transvenous lead extraction Brief running title: Survival of patients with lead related infective endocarditis Authors: Anna Polewczyk, MD, PhD 1,2, Wojciech Jacheć MD, PhD3, Andrzej Tomaszewski MD, PhD4, Wojciech Brzozowski MD, PhD4, Marek Czajkowski MD, PhD5, Grzegorz Opolski MD, PhD6, Marcin Grabowski MD, PhD6, Marianna Janion MD, PhD1,2 , Andrzej Kutarski MD, PhD4 1

The Jan Kochanowski University, Department of Medicine and Health Sciences Kielce,

Poland 2

2nd Department of Cardiology, Swietokrzyskie Cardiology Center, Kielce, Poland

3

2nd Department of Cardiology, Silesian Medical University, Zabrze, Poland

4

Department of Cardiology, Medical University, Lublin, Poland

5

Department of Cardiac Surgery, Medical University, Lublin, Poland

6

1st Department of Cardiology, Medical University of Warsaw, Poland

Corresponding author: Anna Polewczyk MD, PhD 2nd Department of Cardiology, Swietokrzyskie Cardiology Center 45, Grunwaldzka St. 25-736 Kielce [email protected] Phone number +48413671508, FAX number +48413671456

On behalf of all authors, the corresponding author states that there is no conflict of interest. 1

Abstract Background Lead-related infective endocarditis (LRIE) is a serious infectious disease with uncertain prognosis. Objective The purpose of the present study is to evaluate the factors that influence survival in patients with LRIE undergoing transvenous lead extraction (TLE). Methods Clinical data obtained from 500 consecutive patients with LRIE undergoing TLE in the Reference Center in the years 2006-2015 were retrospectively analyzed. We evaluated the effect of demographic, clinical and procedure-related factors on 30-day and long-term survival (mean 3-year follow-up). Results Analysis of 30-day survival after TLE revealed 19 deaths (3.8%), whereas long-term mortality (mean 3-year follow-up) was 29.3% (146 deaths). Multivariate analysis showed unfavorable effects of age: (hazard ratio-HR) 1.056; 95% CI [1.030-1.082], decreased LVEF: HR 0.687; 95% CI [0.545-0.866], renal failure: HR 3,099; 95% CI [1.865-5,150] and the presence of vegetation fragments remaining after TLE: HR 1,384; 95% CI [1.089-1,760]. The log rank test and the Kaplan-Meier survival curves demonstrated statistically worse prognosis in patients with large vegetations (>2 cm) and with vegetation remnants. Better prognosis was associated with LRIE coexisting with generator pocket infection (PI). Conclusions Long-term mortality in LRIE patients is still high. The factors that influence negatively prognosis include large cardiac vegetations and their remnants after TLE. Such 2

vegetations develop most frequently in patients with decreased LVEF and renal failure. Probably, early detection of LRIE would tend to limit the formation of large vegetations that invade the adjacent cardiac structures.

Key words: lead related infective endocarditis, generator pocket infection, transvenous leads extraction, prognosis, vegetations remnants

Introduction Lead-related infective endocarditis (LRIE) is a serious systemic disease defined as an infection that affects the leads, valve leaflets and endocardium. There are two forms encountered in clinical practice: LRIE developing in patients with generator-pocket infection (PI) and isolated LRIE with an insidious course. Because of diagnostic difficulties and a multitude of statistical methods used in individual clinical studies it is hard to estimate the true incidence of LRIE. At present, the frequency of cardiac device infections (CDI) in the population of patients with cardiac implantable electronic devices (CIED) ranges from 0.5% to 2.2% [1]. It is even more difficult to estimate the true incidence of LRIE due to a small number of reports on isolated LRIE. The limited evidence shows that LRIE was diagnosed in 22% - 57% of patients with CDI [2,3,4,5,6], therefore the estimated incidence of lead-related infective endocarditis in the population of patients with CIED ranged from 0.1 to 1.3%. The cornerstone treatment for patients with LRIE is transvenous lead extraction (TLE) and prolonged 4 to 6-week antibiotic therapy [1,7]. LRIE is a relatively rare disease with established standards of care, however despite intensive therapy mortality is still high. The limited evidence shows that mortality at 1-5 years ranges from 31 to 44% [4,8,9]. Therefore,

3

in order to improve long-term survival it is extremely important to identify factors influencing prognosis in patients with LRIE. Methods Study population Clinical data from 500 patients with lead-related infective endocarditis were retrospectively analyzed. The study group was recruited from a population of 1840 consecutive patients undergoing TLE for infectious and non-infectious reasons in single high volume center in the years 2006-2015.

Definitions Lead-related infective endocarditis was diagnosed based on the modified Duke criteria for diagnosis of infective endocarditis on the leads in compliance with the ESC 2015 guidelines, taking into account generator pocket infection and pulmonary embolism as major criteria (referred to by the authors as modified Duke leads criteria – MDLC) [7,10]. The diagnosis of LRIE was definite in the presence of 2 major or one major and 3 minor criteria (in the present study none of the patients met 5 minor criteria of LRIE). Patients with possible LRIE meeting one major, one minor or 3 minor criteria also entered the study. Data from 11 patients with vegetations exceeding 4 cm in diameter were included in analysis, too. Because of a potentially high risk of periprocedural pulmonary embolism due to vegetations that might have become dislodged and migrate to the pulmonary vessels during TLE, the patients were initially considered for cardiac surgery. Eventually, 5 patients in this subgroup underwent TLE using special baskets to prevent vegetation dislodgement during the procedure. The remaining 6 patients underwent a hybrid procedure, namely the leads cut off at entry to the venous system up to the superior vena cava opening into the right atrium (RA) were freed via 4

the transvenous approach. In the second stage, during cardiac surgery, the proximal ends of the freed leads were pulled to the incision in the RA wall and then the entire lead with the vegetation was removed. Vegetations

were

detected

by

transthoracic

(TTE)

and/or

transesophageal

echocardiography (TEE). A vegetation was defined as a mobile, oscillating mass detected on the leads, valves or endocardium in at least two different echocardiographic planes [11,12]. According to the 2015 ESC guidelines, blood cultures were defined as positive if at least two different sets were positive for typical LRIE bacteria [7]. Local device infection was defined as an infection limited to the pocket of the cardiac device and was clinically suspected in the presence of local signs of inflammation at the generator pocket, including erythema, warmth, fluctuance, wound dehiscence, erosion, tenderness or purulent drainage [13]. Pulmonary embolism was diagnosed based on chest CT scanning, whereas recurrent pulmonary infections were considered as markers of septic pulmonary embolism.

Methods and effects of lead extraction The TLE procedure was performed only with the mechanical system based on cuttingrotation forces of telescopic polypropylene Byrd dilators of various lengths and sizes (Cook® Medical); no laser energy or radiofrequency wave technology were used. Procedural success and complication definitions were based on current TLE guidelines [14]. Radiological success was defined as removal of all targeted leads and lead material from the vascular space with the absence of any permanently disabling complication. Clinical success: removal of all targeted leads or retention of a small portion (<4cm) of the lead that did not negatively impact the outcome goals of the procedure (residual part did not increase

5

the risk of perforation, embolic events, perpetuation of infection or cause any undesired outcome). Major complications were defined as any of the outcomes related to the procedure which was life threatening or resulted in death, significant disability or any event that required significant surgical intervention [14].

Survival analysis Based on the clinical database and data obtained from the Ministry of Internal Affairs regarding mortality in the study population, we analyzed the factors influencing early (30day) and long-term survival (mean follow-up period of 3.0 ± 2.14 years). Comparative analysis between survivors and those who died during the study included demographic, clinical and procedural factors was performed (Table I). The study was approved by the local Bioethics Committee.

Statistical analysis Continuous variables were expressed as arithmetic means and standard deviations, whereas dichotomous variables were expressed as a number and percentage. The MannWhitney U test was used to compare differences between group 1 and 2 for continuous variables, whereas the Chi2 test incorporating Yates correction was used for dichotomous variables. The likelihood of vegetation fragments remaining after TLE depending on the mass size prior to TLE was calculated using the ANOVA Kruskal-Wallis test and graphically depicted. Parameters reaching a significance level of p <0.05 in the univariate analysis were entered into a multivariate regression model, including those patients who underwent TEE 6

after TLE. Complete data and cut-off points were considered in univariate and multivariate regression models. Results were presented as hazard ratios (HR) with a 95% confidence interval. Complete data and cut-off points were considered in the log rank test, similar to Cox regression analysis. The presence of vegetations before and after TLE and their relation with prognosis was graphically depicted as Kaplan-Meier survival curves. The log rank test was used to compare survival in both groups. Differences between groups were deemed significant if the p value was <0.05 or when the 95% confidence interval did not include the null value. If the 95% confidence interval was between 0.5 and 0.1 its value was provided with three digits after the decimal point. The p value ≥ 0.1 was considered to be not significant (NS).

Results Demographic and clinical data The mean age of patients with LRIE was 66.96±13.90 years, males made up 68.6% of the population. 146 (29,3%) patients died in the mean 3-years follow up period. According to Duke criteria 400 (80%) patients had definite LRIE, the remaining 100 patients (20%) were diagnosed as having possible LRIE. Generator pocket infection concomitantly with LRIE was present in 300 (60%) patients, with PI being more common approaching the borderline of significance in those showing better survival rates (p=0.057). The mean LVEF was 49.15±14.47 % in patients with the mean NYHA functional class 1.66±0.75, with both parameters being significantly better in patients with longer survival. Vegetations were detected in 352 (70.4%) patients (TEE prior to TLE was performed in 90% of patients), including 195 (39%) patients with large vegetative lesions, exceeding 2 cm in diameter. In 37 7

(7.2%) patients vegetations were clearly invading the myocardial walls. The presence of large masses infiltrating the cardiac structures was significantly more common in patients with worse prognosis. Vegetation fragments remaining after TLE were detected in 63 (15.6%) patients out of 404 subjects undergoing TEE after TLE and also significantly more commonly in those who died during the study. Recurrent pulmonary infections were diagnosed in 177 (35.3%) patients, with a tendency towards being less common in the group of survivors (p=0.068) (Table I). Permanent atrial fibrillation, diabetes mellitus and renal failure were significantly more frequent in the group of non-survivors. Laboratory tests in surviving patients with LRIE revealed higher levels of hemoglobin, lower leukocyte level approaching the borderline of significance (p=0.059) (with lower neutrophil to lymphocyte ratio and neutrophil to blood platelet ratio) and significantly lower CRP levels. Cultures from blood and extracted leads (incomplete data because of logistic difficulties) yielding the commonest pathogens (Staphylococcus epidermidis and Staphylococcus aureus) did not show statistically significant differences between the survivors and non-survivors. Duration of hospitalization was longer in non-survivors (p=0,01). In the present study the patients with LRIE did not differ significantly in procedure-related factors (the number of extracted leads, pacemaker type, procedure duration, major TLE complications and the need of periprocedural temporary pacing) between those with good and bad prognosis. Similarly, there were no differences in the immediate outcomes of TLE: radiological and clinical success, and presence of periprocedural complications (Table I). 30-days mortality after TLE Analysis of 30-day survival after TLE revealed 19 deaths (3.8%), Clinical data of 19 patients who died within 30 days following the procedure was presented in the table in supplementary file. 8

Univariate and multivariate analysis of long-term survival (mean follow-up 3.0 ± 2.14 years) In patients with LRIE univariate analysis revealed a negative effect of older age, lower LVEF and higher functional NYHA class, atrial fibrillation, diabetes mellitus, renal failure and pulmonary infections on survival. There was a relationship between higher mortality and lower hemoglobin levels, higher leukocyte levels and CRP. The presence of large vegetations (>2 cm) in the cardiac structures and vegetation fragments remaining after transvenous lead extraction was markedly associated with worse survival. Patients who underwent removal of their ICD had also worse survival, whereas those with local pocket infection showed better prognosis. The mortality of patients with a reimplanted system after TLE was lower. Greater remnant size was correlated with worse outcome.(Table II). Multivariate analysis revealed a relationship between worse survival and older age, lower LVEF, renal failure and vegetation remnants after TLE. Prognosis of patients undergoing reimplantation was better, but only during the first 3 months after TLE (Figure 1) (Supplementary file). Kaplan-Meier analysis revealed that the probability of survival was significantly lower in patients with large vegetations (Figure 2) and vegetation remnants in the heart (Figure 3), in contrast to those with LRIE and PI (Figure 4).

Limitations The limitation of the present study is incompleteness of microbiological material and missing TEE after TLE in 20% of patients. Long-run causes of death in patients with LRIE are unknown, either.

9

Discussion The factors influencing long-term survival in patients with lead-related infective endocarditis are rarely evaluated in the literature. The present study probably describing the largest population of subjects with LRIE demonstrated that 30% of potentially correctly treated patients died within 3 years after transvenous lead extraction. In spite of the fact that the patients were already at increased risk because of the presence of large >2 cm vegetations, periprocedural mortality - 4 deaths (0.8%) and the number of major complications - 9 (1.8%) were very low in 39% of them. Also, 30-day mortality rate of 3.8% was relatively low. A meta-analysis of TLE effectiveness (36 studies in a total of 9272 patients , >60% of infectious indications) demonstrated that the rate of overall periprocedural deaths and major complications was 1.7%, 95% CI 91.2-2.2), whereas 30-day mortality in the same metaanalysis based on 12 studies (2094 patients) was 3.0%, 95% CI (1.5-5.0) [15]. According to one of the few studies in a relatively large population of patients with LRIE undergoing TLE (100 patients with vegetations on the leads) major periprocedural complications were absent, whereas 30-day mortality was 10% [16]. The present study revealed that deaths at 30 days after TLE occurred in patients with multiple risk factors: decreased LVEF, renal failure and large vegetations. Moreover, these patients more frequently had isolated LRIE with an insidious course. It is worth noticing that the commonest direct cause of 30-day death was decompensated cardiac failure, not the procedure-related factors. These findings are consistent with data obtained in the above mentioned analysis of short-term mortality in 100 patients with LRIE [16]. The available evidence shows that the following factors most commonly influence long-term survival in patients with LRIE: age, heart failure, cardiac resynchronization therapy,

renal

failure,

Staphylococcus

aureus 10

infection,

chronic

steroid

therapy,

thrombocytopenia, diffuse neoplastic process, chronic anticoagulation, bleeding requiring transfusion, multi-organ infection and dementia [4,8,17]. The current study confirmed the effect of age, decreased LVEF and renal failure on long-term survival. Moreover, univariate analysis revealed higher mortality in patients with diabetes mellitus, atrial fibrillation, pulmonary infections, and a constellation of laboratory findings (anemia, high white blood cell count and CRP) reflecting a severe, septic course of LRIE. In this study we analyzed the neutrophil to lymphocyte and blood platelet ratio, and despite insignificant differences, there was a tendency towards worse survival in patients with the higher ratio. There are several reports in the literature describing the effect of high neutrophil to lymphocyte and blood platelet ratio on mortality in patients with endocarditis [18], further studies in patients with LRIE will need to be undertaken. The results of this study show that large vegetations on the cardiac structures have an unfavorable impact on long-term prognosis. Previous studies provide conflicting data on mortality in patients with vegetations. According to some investigators the presence of vegetations, especially large masses had a negative effect on long-term survival [11,18]. However, other studies did not detect any evidence for the existence of this relationship [4,8,19]. The most important finding in the current study was that vegetation fragments retained after TLE, not the vegetation itself, had the effect on survival. In the available literature there are single reports on vegetation remnants detected by echocardiography in patients undergoing TLE both for infectious and non-infectious reasons. Out of 212 patients undergoing transvenous lead extraction (88 patients with LRIE, 59 with PI) post-procedure echocardiography revealed additional “ghost” structures in the right heart chambers in 17 patients (8%). Such remnants were detected only in patients with infectious complications and were thought to have a potentially negative effect on long-term prognosis, although the 11

follow-up period in the study was relatively short i.e. 3 to 15 months [20]. In the current study analysis was performed only in patients with documented LRIE, moreover echocardiograms were obtained by experienced operators who differentiated the presence of connective tissue fragments retained after lead extraction based on their morphology, mobility, and first of all location with respect to the earlier detected vegetations. Additional structures detected by TEE after transvenous lead extraction were not “ghost” structures, but remnants of the earlier visualized vegetations. In the light of the documented significant impact of vegetation remnants in the heart on survival in patients with LRIE it is interesting that no such effect could be found in patients with fragments of the leads that were unable to be completely removed during the transvenous procedure. It was a small group (3.8% of the study population) which was characterized by a slightly higher mortality (37%) as compared with the subjects in whom radiological success had been achieved. It seems also that LRIE patients with lead remnants in the heart should be placed under close clinical supervision. It is undoubtedly worthwhile considering in what way the findings of the current study could influence long-term survival in patients with LRIE. Due to the important role of vegetation remnants periprocedural transesophageal echocardiography should be the standard procedure in each patient, not only before transvenous lead extraction but also prior to discharge or transfer to another hospital for continuation of antibiotic therapy. If post-TLE echocardiography reveals the presence of vegetations the clinical status of the patient, including size of vegetation remnants and inflammatory parameters, should be closely monitored. The current British guidelines for the diagnosis, prevention and management of implantable cardiac electronic device infection suggest that antibiotic treatment in patients with vegetations on the leads can be shortened, however 4-week regimen should be maintained in patients with documented endocardial infiltration [1]. The ESC 2015 guidelines 12

propose a similar approach to post-discharge follow-up of patients with infective endocarditis at one, 3, 6 and 12 months [7]. It is also very important to detect LRIE sufficiently early to prevent the formation of large vegetations invading the heart. In the current study we did not find any significant differences in survival depending on the time elapsed between onset of symptoms and diagnosis, however it should be remembered that generally it was a long time interval, exceeding 6 months. Another important finding in the current study was better survival in patients with the concomitant presence of LRIE and PI as compared with those diagnosed with isolated lead-related infective endocarditis. These results match those observed in earlier studies. According to a multicenter MEDIC registry patients with the presence of PI more frequently had smaller <1 cm vegetations as compared with those diagnosed with isolated lead-related infective endocarditis [19]. It appears that generator pocket infection is a warning sign that is useful for early diagnosis, which confirms that early detection of the disease improves survival.

Conclusions: Lead-related infective endocarditis is a relatively rare infectious disease, but associated with a high mortality rate. Progress in transvenous removal techniques and use of transvenous lead extraction as the standard procedure in patients with lead-related infections have undoubtedly resulted in improved survival in this group of patients. The findings of the current study confirm the very high efficacy and safety of the procedure also in highest-risk patients i.e. with >2 cm vegetations. However, long-term mortality is still high with 30% of patients dying within 3 years after successful TLE and appropriate antibiotic therapy. An important factor that influences long-term prognosis is the presence of vegetations remnants on the cardiac structures. Prevention of the development of large vegetations invading the 13

myocardial wall through improved diagnosis and close clinical supervision of patients with vegetations remaining after TLE should improve survival of patients with lead-related infective endocarditis a serious disease.

References 1. Sandoe JA, Barlow G, Chambers JB, et al. Guidelines for the diagnosis, prevention and management of implantable cardiac electronic device infection. J Antimicrob Chemother. 2015;70:325-359 2. LE KY, Sohail MR, Friedman PA, Uslan DZ, Cha SS, Hayes DL, Wilson WR, Steckelberg JM, Baddour LM; Mayo Cardiovascular Infections Study Group. Clinical predictors

of

cardiovascular

implantable

electronic

device-related

infective

endocarditis. Pacing Clin Electrophysiol 2011;34:450–459 3.

Ipek EG, Guray U, Demirkan B Guray Y, Aksu T. Infections of implantable cardiac rhythm devices: predisposing factors and outcome. Acta Cardiol 2012; 67:303–310

4. Deharo JC, Quatre A, Mancini J, et al. Long-term outcomes following infection of cardiac implantable electronic devices: a prospective matched cohort study. Heart 2012:98:724–773 5. Rodriguez Y, Garisto J, Carrillo RG. Management of cardiac device-related infections: a review of protocol-driven care. Int J Cardiol 2013;166:55–60 6. Le KY, Sohail MR, Friedman PA, Uslan DZ, Cha SS, Hayes DL, Wilson WR, Steckelberg JM, Baddour LM; Mayo Cardiovascular Infections Study Group. Impact of timing of device removal on mortality in patients with cardiovascular implantable electronic device infections. Heart Rhythm 2011; 8: 1678–1685

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7. Habib G, Lancellotti P, Antunes MJ, et al. Guidelines for the management of infective endocarditis.. Eur Heart J. 2015; 21;36:3075-3128. 8. Tarakji KG, Wazni OM, Harb S, Hsu A, Saliba W, Wilkoff BL. Risk factors for 1year mortality among patients with cardiac implantable electronic device infection undergoing transvenous lead extraction: the impact of the infection type and the presence of vegetation on survival. Europace. 2014;16:1490-1495 9. Henrikson CA, Zhang K, Brinker JA. High mid-term mortality following successful lead extraction for infection. Pacing Clin Electrophysiol. 2011;34:32-36 10. Polewczyk A, Jacheć W, Janion M, Podlaski R, Kutarski A. Lead-Dependent Infective Endocarditis: The Role of Factors Predisposing to Its Development in an Analysis of 414 Clinical Cases. Pacing Clin Electrophysiol. 2015;38:846-856. 11. Golzio PG, Fanelli AL, Vinci M Pelissero E, Morello M, Grosso Marra W, Gaita F. Lead vegetations in patients with local and systemic cardiac device infections: prevalence, risk factors, and therapeutic effects. Europace. 2013;15:89-100 12. Greenspon AJ, Prutkin JM, Sohail MR et al. Timing of the most recent device procedure influences the clinical outcome of lead-associated endocarditis results of the MEDIC (Multicenter Electrophysiologic Device Infection Cohort). J Am Coll Cardiol. 2012,14;59:681-687 13. Sohail MR, Uslan DZ, Khan AH, Friedman PA, Hayes DL, Wilson WR, Steckelberg JM, Stoner S, Baddour LM. Management and outcome of permanent pacemaker and implantable cardioverter-defibrillator infections. J Am Coll Cardiol 2007;49:1851– 1859 14. Wilkoff BL, Love CJ, Byrd CL, et al. Transvenous lead extraction: Heart Rhythm Society expert consensus on facilities, training, indications, and patient management: 15

this document was endorsed by the American Heart Association (AHA). Heart Rhythm. 2009;6:1085-1104 15. Di Monaco A, Pelargonio G, Narducci M, et al. Safety of transvenous lead extraction according to centre volume: a systematic review and meta-analysis. Europace. 2014 ;16:1496-1507 16. Grammes JA, Schulze CM, Al-Bataineh M, Yesenosky GA, Saari CS, Vrabel MJ, Horrow J, Chowdhury M, Fontaine JM, Kutalek SP. Percutaneous pacemaker and implantable cardioverter-defibrillator lead extraction in 100 patients with intracardiac vegetations defined by transesophageal echocardiogram. J Am Coll Cardiol. 2010 2;55:886-894 17. Habib A, Le KY, Baddour LM Friedman PA, Hayes DL, Lohse CM, Wilson WR, Steckelberg JM, Sohail MR; Mayo Cardiovascular Infections Study Group. Predictors of mortality in patients with cardiovascular implantable electronic device infections. Am J Cardiol 2013; 111: 874–879 18. Turak O1, Özcan F, Işleyen A, Başar FN, Gül M, Yilmaz S, Sökmen E, Yüzgeçer H, Lafçi G, Topaloğlu S, Aydoğdu S. Usefulness of neutrophil-to-lymphocyte ratio to predict in-hospital outcomes in infective endocarditis. Can J Cardiol. 2013;29:16721678 19. Greenspon AJ, Le KY, Prutkin JM, et al. Influence of vegetation size on the clinical presentation and outcome of lead-associated endocarditis: results from the MEDIC registry. JACC Cardiovasc Imaging. 2014;7:541-549 20. Baman TS, Gupta SK, Valle JA, Yamada E. Risk factors for mortality in patients with cardiac device-related infection. Circ Arrhythm Electrophysiol. 2009; 2:129-134

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21. Le Dolley Y, Thuny F, Mancini J, et al. Diagnosis of cardiac device-related infective endocarditis after device removal. JACC Cardiovasc Imaging. 2010;3:673-678

Legend to tables and figures Table I Comparative analysis of the clinical data of 500 patients with LRIE depending on survival at a mean follow-up period of 3.00 ±2.14 years Table II Univariate Cox regression model to predict mean 3-year mortality after TLE for LRIE Figure 1 Multivariate Cox regression model to predict mean 3-year mortality after TLE for LRIE Figure 2 Kaplan-Meier survival probability in patients with small and large (>2 cm) vegetations Figure 3 Kaplan-Meier survival probability in patients with remnants of vegetations after TLE Figure 4 Kaplan-Meier survival probability in patients with LRIE and concomitant PI

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Table I

Number of patients Gender (male) (n %) Age [years] SD BMI kg/m2 SD NYHA class SD EF [%] DM2 (n %) RF(n %) AF (n %) Malignancy (n %) Cardioimplant (n %) OAC (n %) A/PTL (n %) Hemoglobin (g/dl) SD CRP mg% SD WBC (103) SD Neutr/limf ratio SD Neutr / pł II ratio SD Staph. Epidermidis (blood) (n %) 349 cultures Staph epidermidis (lead) (n %) 428 cultures Staph. aureus (blood) (n %) 349 cultures Staph aureus (lead) (n %) 428 cultures Pulmonary infections (n %) Vegetations presence (n %) Vegetations size (2-4 vs 0-1) (n %) Vegetations connected with heart’s wall (n %) Multiple vegetations presence (n %) Pocket infection (n %) LRIE sure / likely (n %) Duration from onset symptoms to recognition [months]SD Duration of hospitalization (days)

All 500 343 (68,6) 66,96±13,90 27,14±4,83 1,66±0,75 49,15±14,47 116 (23,2) 50 (10,0) 107 (21,0) 12 (2,4) 31 (6,2) 143 (28,6) 209 (41,2) 12,09±2,03 52,03±66,71 9,64±4,88 6,31±14,59 2,36±15,47

Death 146 100 (68,5) 71,95±11,36 27,11±4,58 1,93±0,82 44,64±14,71 46 (31,5) 29 (19,9) 46 (31,5) 6 (4,11) 14 (9,59) 46 31,5) 61 (41,8) 11,50±2,10 61,47±75,26 10,45±5,47 8,03±16,99 2,93±17,25

Alive 354 243 (68,6) 64,90±14,33 27,15±4,93 1,55±0,69 51,01±13,82 70 (19,8) 21 (5,93) 61 (17,2) 6 (1,69) 17 (4,80) 97 (27,4) 148 (41,8) 12,33±1,95 48,16±62,57 9,31±4,58 5,60±13,44 2,12±14,70

58 (16,61)

20/111 (18,02)

38/238 (15,97)

NS

126 (29,44)

32/119 (26,89) 13/111 (11,72) 14/119 (11,76) 61 (41,8) 107 (73,3)

94/309 (30,42) 30/238 (9,15) 31/309 (7,95) 116 (32,8) 245 (69,2)

NS

NS 0,068 NS

68 (46,6)

127 (35,9)

0,028

37 (7,2)

19 (13,0)

18 (5,08)

0,007 NS

168 (33,6) 300 (60,0) 400 (80,0)

54 (37,0) 77 (52,7) 119 (81,5)

114 (32,2) 223 (63,0) 281 (79,4)

6,64±11,97

6,56±8,86

6,68±12,75

11,84±12,79

13,48±14,01

11,17±12,21

43 (12,23) 45 (10,51) 177 (35,4) 352 (70,4) 195 (39,0)

18

p NS 0,000 NS 0,000 0,000 0,005 0,000 0,000 NS 0,069 NS NS 0,000 0,003 0,059 0,000 0,004

NS

0,057 NS NS 0,01

Number of extracted leeds SD ICD extraction (n %) CRT extraction (n %) Time of procedure [min] SD Necessity of pacing during and after TLE (n %) Reimplantation during follow-up Without reimplantation Vegetations remnants after TLE (n %) 406 TEE Errors in the proceeding before TLE (n %) False diagnosis during discharge (n %) Full radiological success(n %) Full clinical success(n %) Major complcations (n %)

2,20±0,88 121 (24,14) 97 (19,52) 108,4±51,0

2,30±1,00 42 (28,8) 35 (24,0) 113,0±57,1

2,16±0,83 79 (22,3) 62 (17,5) 106,5±48,3

NS NS NS NS

102 (20,4) 294 (64,5) 162 (35,5) 63/406 (15,59)

32 (21,9) 77 (58,8) 54 (41,2) 26/78 (33,33)

70 (19,8) 217 (66,8) 108 (33,2) 37/265 (13,96)

NS NS NS

170 (34,0)

49 (33,6)

121 (34,2)

102 (20,4) 473 (94,6) 487 (97,4) 9 (1,8)

24 (16,4) 133 (91,1) 140 (95,9) 3 (2,05)

78 (22,0) 340 (96,0) 347 (98,0) 6 (1,69)

0,003 NS NS NS NS NS

Abbreviations: AF- atrial fibrillation, A/PTL – antiplatelet therapy, DM- diabetes, EF- ejection fraction, NS- non significant, RF- renal failure. OAC- oral anticoagulation

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Table II Univariable Cox regression model Gender (male) Age [years] BMI NYHA class EF DM2 RF AF (yes / no) Cancer (yes / no) Cardioimplant (yes / no) OAK (yes / no) a/PTL (yes / no) Hemoglobin concentration (g/dl) Max CRP concentration Max WBC level Neutrophiles/limfocytes ratio Neutrophiles / platelet II ratio Staph. epidermidis (blood) Staph epidermidis (lead) Staph aureus (blood) Staph aureus (lead) Pulmonary infections (yes / no) Vegetations presence (yes / no) Vegetations presence (2-4 vs 0-1) Vegetations presence (no / with lead / with heart’s wall) Vegetations connected wit heart’s wall (yes / no) Vegetations presence (single / multiple) (yes / no) Pocket infection LRIE sure / likely Number of extracted leads ICD extraction (yes / no) CRT extraction (yes / no) Time of procedure [min] Major complcations Necessity of pacing during and after TLE Reimplantation during follow-up Vegetations remnants after TLE TEE (n=404; yes no) Vegetations remnants after TLE [by 1cm] Errors in the proceeding before TLE False diagnosis during discharge Full radiological success Full clinical success 20

p 0,683 0,000 0,988 0,000 0,000 0,001 0,000 0,000 0,461 0,111 0,202 0,496 0,000 0,037 0,008 0,153 0,629 0,934 0,396 0,732 0,641 0,017 0,067 0,004 0,013 0,004 0,101 0,047 0,230 0,353 0,028 0,120 0,346 0,681 0,147 0,030 0,000 0,001 0,955 0,384 0,177 0,416

HR 95%CI 0,929 0,653-1,322 1,040 1,025-1,055 1,000 0,956-1,045 1,746 1,446-2,108 0,743 0,667-0,828 1,827 1,282-2,603 2,900 2,069-4,064 1,950 1,372-2,771 1,158 0,785-1,708 1,566 0,901-2,721 1,259 0,884-1,792 1,122 0,805-1,564 0,837 0,772-0,907 1,002 1,000-1,004 1,038 1,010-1,067 1,006 0,998-1,015 1,002 0,993-1,012 0,978 0,580-1,648 0,822 0,523-1,292 1,113 0,605-2,047 1,154 0,633-2,104 1,502 1,075-2,098 1,414 0,975-2,050 1,612 1,160-2,240 1,440 1,080-1,920 1,506 1,136-1,997 1,326 0,945-1,859 0,717 0,517-0,995 1,297 0,848-1,984 1,088 0,911-1,298 1,508 1,046-2,174 1,353 0,924-1,979 1,001 0,998-1,004 1,273 0,403-4,028 1,339 0,902-1,988 0,629 0,413-0,956 2,298 1,461-3,615 1,381 1,133-1,682 0,990 0,701-1,398 0,992 0,973-1,010 0,665 0,367-1,203 0,689 0,281-1,690

Abbreviations: AF- atrial fibrillation, A/PTL – antiplatelet therapy, DM- diabetes, EF- ejection fraction, RF- renal failure. OAC- oral anticoagulation

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