Infective endocarditis in patients with cardiac implantable electronic devices: a nationwide study

Abstract

Introduction

Infective endocarditis (IE) is a serious condition with high in-hospital mortality.¹ The epidemiology of IE has changed over the last decades. Due to an ageing population and the increasing use of cardiac implantable electronic devices (CIEDs), occurrence of IE is becoming more frequent in these patients.² The annual rate of CIED-related infection is estimated to be around 2–2.5%, and continues to increase.³ It is also higher in high-risk patients with specific baseline characteristics (e.g. renal failure, heart failure, diabetes, or anticoagulant treatment) or due to CIED-related factors (e.g. type of intervention and device, device manipulation, lack of antimicrobial prophylaxis).⁴ However, not all device-related infections are IE and IE in other locations can be found in patients with a CIED without a lead vegetation. There is little information on IE in patients with a CIED.

The purpose of our study is to describe the current profile of IE in patients with CIEDs and compare baseline characteristics and comorbidities of patients with IE and CIEDs against those without CIEDs. Furthermore, a comparison between patients with CIEDs will be performed considering the time and location of the IE.

Methods

The Spanish Collaboration on Endocarditis—GAMES (Grupo de Apoyo al Manejo de la Endocarditis Infecciosa en España) is a national observational registry, described previously.^4,5 Multidisciplinary teams that compose this group, including infectious disease physicians, cardiologists, cardiac surgeons, microbiologists, echocardiographers, and other imaging specialists, prospectively completed standardized case report forms with information regarding IE episodes and follow-up data. A complete list of GAMES members is available as a Supplementary material online, Appendix. Infective endocarditis patients were consecutively included at 36 Spanish hospitals between January 2008 and November 2017. Inclusion criterion was diagnosis of definite IE as per the modified Duke criteria.⁶ Infective endocarditis management, including the decision to perform surgery and type of surgery, was done by the local medical team following the European Society of Cardiology recommendations.⁷ This study complies with the principles outlined in the Declaration of Helsinki and was approved by the ethics committee of the participating centres.

Definitions

We considered the following IE-related complications: heart failure, peripheral artery embolism, embolic stroke, persistent bacteraemia (>7 days), and intracardiac complications. Heart failure was defined according to the guidelines of the European Society of Cardiology. The involvement of the central nervous system was considered to be present in patients who had undergone transient ischaemic attack or stroke. An intracardiac complication was considered to be present in patients with heart structure disruption: valvular perforation/rupture, pseudoaneurysm, abscess, or intracardiac fistula.

Existence of CIED-related IE was considered when a vegetation was located on the CIED lead at echocardiography or after lead extraction. Early IE was defined as occurring within the first year of device implantation. Surgery refers to any type of cardiac intervention, including valve repair or replacement, and total CIED system extraction with open heart surgery or transvenous lead extraction.

Statistical methods

Continuous variables are summarized as means ± standard deviations or medians, and interquartile ranges when data when a normal distribution was not observed as per the Kolmogorov–Smirnov goodness-of-fit test; categorical variables are expressed as frequencies and percentages. Categorical variables were compared using the χ² test or Fisher’s exact test. The Student’s t-test, the Mann–Whitney U test or the paired t-test were used to compare continuous variables. We performed multivariable logistic regression and Cox regression analyses (backward selection) to determine the predictors of in-hospital mortality and mortality during follow-up. All variables with P-value <0.10 in univariate analyses were included in the multivariable analyses. Statistical analysis was performed using SPSS, version 22.0 (IBM, Armonk, NY, USA).

Results

We identified 3966 cases of IE; 708 (17.7%) had a CIED and 424 (60%) had a CIED-related IE (Figure 1). The comparison between patients with and without a CIED is shown in Table 1. Patients with a CIED were older and had a higher prevalence of comorbidities. In-hospital (40.6% vs. 27.1%; P ≤ 0.01) and healthcare-related IE (7.9% vs. 10.4%, P = 0.035) were more frequent in subjects with a CIED. The main aetiologies in patients with a CIED were coagulase-negative staphylococci (CoNS) in 188 patients (26.6%) and Staphylococcus aureus in 179 (25.3%). Coagulase-negative staphylococci were more frequent among patients with a CIED than in those without (26.6% vs. 15.5%, respectively, P < 0.001). Gram-negative bacilli (GNB) were also more frequent among patients with a CIED than in those without (6.8% vs. 3.7%, respectively, P < 0.001). Gram-negative bacilli included 25 different species, the most frequent being Escherichia coli (24.0%), Pseudomonas aeruginosa (19.0%), Haemophilus aphrophilus (12.5%), and HACEK (Haemophilus spp., Actinobacillus actinomycetemcomitans, Cryptosporidium hominis, Eikenella corrodens, and Kingella spp.—5.4%). Patients with a CIED had fewer intracardiac complications, vascular phenomena, and involvement of the central nervous system than patients without a CIED. Surgery was more frequently performed in subjects with a CIED than in patients without a CIED (58.3% vs. 42.5%, P < 0.001). In CIED patients, surgery included complete removal of the system in 363 cases (89%): 170 underwent open-heart surgery and 193 transvenous traction. Regarding mortality, no relevant differences were found between patients with or without CIED (Table 1).

Figure 1

Study overview. CIED, cardiac implanted electronic devices; IE, infective endocarditis.

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Focusing on patients with a CIED, 171 (24.2%) died while in the hospital and 216 (30.5%) during the first year. Table 2 shows the variables associated with mortality in these patients. Comorbidity, heart failure, and septic shock were associated with in-hospital mortality. CIED-related IE was associated with a better prognosis. One hundred and five patients (14.8%) had IE at multiple sites.

Table 3 compares CIED-related IE against valve IE and no CIED lead involvement. Nosocomial infections, Gram-positive microorganism, and better prognoses were more frequently observed in patients with CIED-related IE in comparison to valve IE and no CIED lead involvement. In CIED-related IE patients, surgery was more frequently indicated than in patients with valve IE or no CIED lead involvement (83.5% vs. 65.1%, P ≤ 0.001); this difference was even more remarkable in the case of patients who underwent surgery (77.8% vs. 29.3%, P ≤ 0.001). In the group of patients with CIED-related IE, surgery was performed in 330 (77.8%) subjects to whom complete removal of the system was performed [146 (44.3%) with open-heart surgery and 184 (55.7%) with transvenous lead extraction], and 26 (7.9%) with associated valve repair/replacement. There were 185 patients with valve IE and no CIED lead involvement and indication of surgery. The latter was performed in 83 subjects, from which 34 underwent complete system extraction (25 with open-heart system and nine transvenous lead extractions).

Surgery did not improve the prognosis of patients with valve IE and no CIED lead involvement, in-hospital mortality [32 (38.6%) vs. 77 (38.5%), P = 0.99], 1-year mortality [38 (45.8%) vs. 93 (46.5%), P = 0.91]. In-hospital mortality tended to be higher in patients with surgical indication managed conservatively in comparison to those treated with surgery [56 (54.9%) vs. 32 (38.6%), P = 0.04]. However, this was mainly associated to a high-risk profile. In fact, the main reasons for not performing surgery were poor prognosis (67.7%), surgeon’s refusal (35.2%), and technical difficulties (23.5%).

In CIED-related IE cases, surgery was associated with lower in-hospital mortality [37 (11.3%) vs. 25 (25.8%), P < 0.001] and lower 1-year mortality [53 (16.2%) vs. 32 (33%), P < 0.001]. Surgery was independently associated with in-hospital survival in CIED-related IE but not with valve IE and no CIED lead involvement (Table 4). In CIED-related IE, similar outcomes were observed for complete system removal with open-heart surgery and transvenous lead extraction: intracardiac complication (2.7% vs. 1.6%, P = 0.74), heart failure (19.8% vs. 13.0%, P = 0.13), in-hospital mortality (11.6% vs. 9.8%, P = 0.59), and days of hospital stay [35 (22–54) vs. 36 (24–54), P = 0.45].

We compared early [289 (68.2%)] and late [135 (31.8%)] CIED-related IE. No relevant differences in the aetiology and clinical complications were found. Heart failure [80 (59.3%) vs. 118 (40.8%), P < 0.001] and in-hospital acquisition [92 (68.1%) vs. 100 (34.6%); P < 0.001] were more common in patients with early CIED-related IE.

Discussion

We found that over a sixth of patients with IE have a CIED. These subjects were older and had more comorbidities; however, they developed fewer complications in comparison to patients without a CIED. Surgery was associated with lower mortality in patients with CIED-related IE. No relationship was found between surgery and survival in CIED patients with valve IE and no CIED lead involvement.

Infective endocarditis remains a severe condition with high morbidity and mortality, particularly among subjects with CIED.⁸ Previous studies^2,9–13 have focused on its epidemiological description and the infection- or mortality-risk factors. These studies are limited by the small number of patients included^9,10 or by the fact that only specific devices as pacemakers² or implantable cardiac defibrillators¹¹ are considered. Moreover, in most cases, there is no clear differentiation between CIED-related infection and IE. Furthermore, no information is provided regarding IE in sites unrelated to CIED lead, which is frequently not included. Our work provides a detailed description of a large population of IE cases in subjects with CIEDs, distinguishing between those with CIED-related IE and those without.

Our study confirms changes in the clinical profile of patients with IE that is now mainly seen in patients with advanced age and frequent comorbidities. Comorbidities such as diabetes, pulmonary disease, renal insufficiency, or coronary artery disease are more frequently found in subjects with a CIED in comparison to patients without a CIED, correlating with a greater age. The opposite occurs with cancer, hepatic dysfunction, HIV infection, congenital heart diseases, and intravenous drug use. This may also be associated, at least in part, to the above-mentioned age difference, due to the poor prognosis in patients affected by these conditions. We also found that nosocomial and healthcare-associated IE are more common in subjects with a CIED, probably reflecting more frequent hospital stays and contacts.¹⁴ Regarding the aetiology, recent registries describe a progressive increase in the rate of microbiological isolation of S. aureus, CoNS, and enterococci.¹⁵ Moreover, an increased rate of S. aureus and CoNS microbiological isolation has been shown in previous series of patients with CIEDs and device infections.^16,17 This high proportion of Gram-positive, S. aureus and CoNS may be related to common cutaneous Gram-positive bacterial colonization and subsequent contamination during device implantation. Our results confirm that subjects with a CIED are more frequently infected by S. aureus and CoNS, although not as high as that reported in previous series.^16,17 Furthermore, we found that Gram-positive aetiology remains low even in patients with CIED and device-related IE. The higher proportion of GNB may be due to the high rate of different comorbidities, which is associated to more frequent invasive diagnosis or treatment measures. We found no differences regarding aetiology between early and late CIED-related IE.

With respect to the prognosis of these patients, our study confirms some previously reported risk factors, such as involvement of the central nervous system, kidneys, and heart.^4,14,18 Interestingly, we found a lower rate of clinical events and complications in subjects with a CIED. However, and probably due to the previously mentioned prognostic influence of age and comorbidities, in-hospital and 1-year mortality were similar in patients with and without CIED.

Surgery was associated with lower in-hospital and 1-year mortality in CIED-related IE patients. Complete CIED system removal in case of IE, with or without CIED-related IE, is recommended.^17,19,20,21In subjects with a CIED, valve IE and no CIED lead involvement, surgery was not associated with better survival. However, this is not a randomized study and subgroup differences may explain these findings.

Limitations

Our study has some limitations. The data were mainly obtained from large academic hospitals and might not represent the clinical practice in less complex centres with lower level of specialization. We only considered CIED patients to have CIED-related IE when a lead vegetation was present. Tricuspid IE was not included as CIED-related IE, although sometimes it is not easy to differentiate between lead and tricuspid vegetation. However, the location of the tricuspid valve was only reported in approximately 5% of the patients with a CIED. Finally, local medical teams were responsible of IE management, including deciding on surgery and the removal of the CIED system, and any judgements may have been influenced by factors not registered in this study.

Conclusion

Over a sixth of IE patients have a CIED. They are older, have more comorbidities and fewer IE-related complications in comparison to subjects without a CIED. In-hospital mortality is similar in patients with and without CIED. In CIED subjects, surgery was associated with lower mortality in those with CIED-related IE, but not in subjects with IE exclusively in the valves. The existence of confounders justifies the need for future research to elucidate the role of surgery in valve IE with no CIED lead involvement.

Supplementary material

Supplementary material is available at Europace online.

Acknowledgements

The authors would like to thank the Spanish Collaboration on Endocarditis (GAMES) and all the authors indicated for their important and continuous scientific labour.

Funding

MHM held a Rio Hortega Research Grant (CM17/00062) from ‘Instituto de Salud Carlos III’ and the ‘Ministerio de Economia y Competitividad’, Madrid (Spain) in 2018–20.

Conflict of interest: none declared.

References