Introduction. CLINICAL RESEARCH Pacing and resynchronization therapy

CLINICAL RESEARCH Europace (2015) 17, 1092–1098 doi:10.1093/europace/euu293 Pacing and resynchronization therapy Preoperative skin antiseptics for ...
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CLINICAL RESEARCH

Europace (2015) 17, 1092–1098 doi:10.1093/europace/euu293

Pacing and resynchronization therapy

Preoperative skin antiseptics for prevention of cardiac implantable electronic device infections: a historical-controlled interventional trial comparing aqueous against alcoholic povidoneiodine solutions Antoine Da Costa 1*, Claire Tulane 1, Virginie Dauphinot 2, Je´re´my Terreaux 1, Ce´cile Romeyer-Bouchard1, Alexie Gate-Martinet 1, Marie Levallois 1, and Karl Isaaz 1 1

The Division of Cardiology, University Jean Monnet of Saint-Etienne, Saint-Etienne F-42000, France; and 2Neurology Unit D, Memory Research Centre, University Medical Hospital P.-Wertheimer, Lyon, France Received 13 June 2014; accepted after revision 25 September 2014; online publish-ahead-of-print 27 April 2015

Aims

Local skin antiseptic prevention against cardiac implantable electronic device (CIED) infections is not yet fully understood. This monocentre historical-controlled study sought to (i) conduct a prospective observational analysis comparing two antiseptic skin preparations over two similar consecutive periods of time, one conducted over a 1-year period using an aqueous povidone-iodine solution (Group I) and the other over the following with an alcoholic povidone-iodine solution (Group II); (ii) determine the predictive factors of CIED infection. ..................................................................................................................................................................................... Methods Cardiac implantable electronic device implantation was performed in 1326 patients (pts). A total of 32 pts (2.4%) developed a CIED infection. Long-term follow-up (26 + 3 months) revealed no significant difference between the groups: and results infections were observed in 14 of the 648 pts (2.2%) in Group I vs. 18 of the 678 pts (2.7%) in Group II (P ¼ 0.9). Single- and multiple-variable logistic regression analyses were performed to identify risk factors; adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. The occurrence of infection was positively correlated with re-intervention (aOR, 7.16; 95% CI, 2.56 –19.99; P , 0.0001), number of generator replacements, mean (aOR, 3.47; 95% CI, 2.22–5.44; P , 0.001), and haematoma (aOR, 48.4; 95% CI, 13.45–174.25; P , 0.0001). ..................................................................................................................................................................................... Conclusion This study found that aqueous and alcoholic povidone-iodine solutions displayed similar antiseptic effects regarding CIED infection prevention. Independent predictive factors of CIED infection were re-intervention, haematoma, and number of generator replacements.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Infection † Antiseptic agents † Risk factors † Aqueous povidone-iodine † Alcoholic povidone-iodine † Cardiac implantable electronic device † Implantation † Trial

Introduction Despite significant improvements in preoperative measures, surgical techniques, and antibiotic prophylaxis, cardiac implantable electronic device (CIED) infections still remain a serious and potentially lifethreatening complication of permanent pacemaker (PM) and implantable cardioverter-defibrillator (ICD) procedures.1 – 5 Incidence rates from 0.5 to 5.1% have been reported in retrospective and

prospective studies, with the current risk estimated at 1%.6 Virulent organisms, such as Staphylococcus aureus, cause infections closely following PM or ICD implantation, whereas coagulase-negative staphylococci, such as Staphylococcus epidermidis, are responsible for delayed infections.7 – 10 The increasing indications for PM and ICD have caused an increase in device implantation procedures,6 – 9,11 and our group revealed an apparently higher risk in patients benefiting from cardiac resynchronization therapy (CRT) devices.12

* Corresponding author. Tel: +33 4 77 82 81 13; fax: +33 477 82 81 64, E-mail address: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].

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What’s new? † First study evaluating two protocols of skin antiseptic prevention against cardiac implantable electronic device (CIED) infections. † Equivalence between aqueous povidone-iodine and alcoholic povidone-iodine solutions against CIED infections. † Identification of three independent predictive factors of CIED infection, namely haematoma requiring surgical revision, re-intervention, and number of generator replacements.

Since a patient’s skin is the primary source of pathogens, skin antiseptic preparation is a principal element of infection prophylaxis. Recently, Darouiche RO et al. 13 proved that chlorhexidine –alcohol was significantly more protective than aqueous povidone-iodine against superficial incisional infections, although not within the context of organ-space infections. It should however be noted that the Darouiche study was conducted in patients undergoing abdominal, thoracic, gynaecological, and urological surgery.13 Similarly, alcoholic solutions may provide higher protection against incisional infections, though no study has thus far been conducted in the setting of CIED infection.13 To our understanding, there are no established recommendations indicating the preferable antiseptic agent for preoperative use in CIED implantation, and no prospective studies have so far been published comparing alcoholic against aqueous solutions in this setting.14 This monocentre historical-controlled study sought to (i) conduct a prospective observational analysis using two antiseptic skin preparations over two similar consecutive time periods; in the first 1-year period (January 2010 to December 2010), an aqueous povidone-iodine solution (Group I) was used, while in the following year (January 2011 to December 2011), an alcoholic povidone-iodine solution (Group II) was used under the same conditions; (ii) determine the long-term predictive factors of CIED infections.

Methods Selection of patients and study design Overall 1326 consecutive patients who underwent PM, ICD, or CRT implantation procedures from January 2010 to December 2011 in our centre were included in this study. Written informed consent was obtained from all patients prior to enrollment. This investigator-initiated trial was designed by the first author (A.D.C.). We prospectively conducted a historical-controlled observational trial comparing two antiseptic skin preparation methods, using an aqueous povidone-iodine solution over a 1-year period (January 2010 to December 2010) (Group I; n ¼ 648), and an alcoholic povidone-iodine solution the following year (January 2011 to December 2011) (Group II; n ¼ 678) under the same conditions. All patients ≥18 years who underwent CIED implantation or replacement procedures were eligible for enrollment. The exclusion criteria were as follows: history of allergy to alcohol or iodophors; evidence of infection at or adjacent to operating site; perceived inability to follow-up the patient’s post-surgery evolution.

Implant procedure All patients were systematically shaved and subjected to an antiseptic shower with povidone-iodine 10% aqueous solution on the night prior

to the intervention. Antisepsis procedures were performed immediately before surgery, with two antiseptic solutions successively applied to the skin. In Group I, skin preparation was performed by a registered nurse (RN), applying first a povidone-iodine 4% aqueous solution, then a povidone-iodine 10% aqueous solution following rinsing and drying; lastly, a povidone-iodine 10% aqueous solution was applied twice by the surgeon. The same preparation was implemented in Group II, but aqueous povidone-iodine (Scrub Care Skin Prep Tray, Cardinal Health) was replaced by alcohol povidone-iodine 10% solution. All implant procedures were performed by the same experienced surgeons (A.D.C., C.R.B., and L.B.) under local anaesthesia and conscious sedation. All patients received the same antibiotic prophylaxis. Intravenous administration of prophylactic antibiotic was 60 – 90 min prior to the incision using one single dose of Cefazolin (1.5 g). No local antibiotic pocket wash was performed. In case of penicillin/cephalosporin allergy, intravenous vancomycin was used.

Objectives The primary study objective was to compare CIED infection prevalence with two antiseptic skin preparations over two similar consecutive periods of time. Infections were defined following criteria previously described by our group and others.7 – 9,12,15 Clinical evidence included local signs of inflammation at the generator pocket, such as erythema, warmth, fluctuance, wound dehiscence, tenderness, purulent drainage, or frank erosion caused by the generator or lead puncturing the skin. Device-related endocarditis was clinically confirmed on the detection of valvular or lead vegetations by means of echocardiography, or if the modified Duke criteria for infective endocarditis were met.2,15 Cardiac implantable electronic device infection was microbiologically confirmed based on positive culture results from samples of the generator pocket, leads, or blood, in the presence of local inflammatory signs at the generator pocket, absence of another source of bacteraemia, and resolution of bloodstream infection following device explantation. Cardiac implantable electronic device infection was defined according to the time of occurrence as early (within 30 days), late (after 30 days), or delayed (after 364 days).1 The secondary study objective was to determine the predictive factors of device-related infection.

Re-intervention Surgical re-intervention was defined as a surgical procedure required for management of non-infectious complication of the implant device. A pocket haematoma was evacuated only if tense swelling caused poor capillary perfusion of the affected skin or severe pain, or alternatively if the haematoma progressively enlarged. Surgical re-intervention was systematically performed in cases of lead dislodgement.

Follow-up Prospective data included (i) patient demographic and clinical characteristics; (ii) preoperative risk factors, such as anticoagulant or antiplatelet regimen, cutaneous lesions, or signs of infection; (iii) device characteristics, such as PM or defibrillator implantation, primo-implants, or replacement or system upgrade of pulse generators or leads; (iv) type of device implanted and number of leads; and (v) complications requiring re-intervention. Infectious complications were prospectively defined in the study protocol. Patient follow-up was performed by three cardiologists (A.D.C., C.R.B., and L.B.) and five specialized registry nurses (RNs). Electrocardiograms and implant device control were performed the day following the procedure (Day 1) and on Day 3, prior to discharge. Patients, including scars and sutures, were monitored in our outpatient clinic on Day 10.

1094 Patient follow-up comprised physical examination, device interrogation until the last follow-up, and CIED infection detection, or death. Follow-up visits took place at Months 3 and 6, and at 6-month intervals thereafter. In the event of any complications requiring surgical re-intervention, followup periods were decreased to 3-month intervals. For each patient group, follow-up was censored at 30 + 3 months in order to obtain similar follow-up for both groups.

Statistical analysis Baseline patient characteristics were compared between the aqueous and alcoholic povidone-iodine solution groups using Fisher’s exact test for categorical variables and two-sample t-test for continuous variables, as appropriate. Summary values were expressed as proportions and means + standard deviation (SD). For all time-to-event analyses, the Kaplan–Meier method was used to provide rate estimates, which were compared by the log-rank test. Patient data were recorded at the last contact, study withdrawal, or time of death. All the risk factors included in the analysis were assessed at the time of device implantation. Comparisons between patients with or without CIED infections were made using continuous variables by means of unpaired Student’s t-test or Mann–Whitney test, as appropriate. The prognostic power of each covariate was analysed based on a Cox regression model, and the covariates found to be significant in crude models were included in the multivariate analysis. Variables associated with a value of P , 0.05 in the single-variable analysis were entered into a multiple-variable logistic regression analysis. The strength of the relationships between predictor variables and the occurrence of infection was assessed by the odds ratio (OR) calculated by logistic regression modelling. Odds ratio were adjusted for all other variables that reached statistical significance. Crude and adjusted ORs with their 95% confidence intervals (CIs) were presented. All analyses were conducted using StatVieww 5.0 (StatView IV, Abacus Concept). All the authors had full access to the data, took responsibility for its integrity, read the manuscript, and provided final approval.

Results Baseline population characteristics Between January 2010 and December 2011, CIED implantation was performed on 1326 patients (pts) (416 women, 31.4%). Group I and Group II characteristics were compared and baseline characteristic population did not differ (Table 1). Both groups were followed during the same period of time (Table 1). Eleven patients (0.08%) were lost to follow-up.

Follow-up and complications Mean follow-up time for the entire population was 26 + 3 months (ranging from 1 to 30 months). Non-infectious complications Large haematoma requiring surgical revision was reported in 16 pts (1.2%). Other complications included lead dislodgement in 27 pts (2%), pericarditis reaction requiring anti-inflammatory agents in 6 pts (0.4%), phrenic nerve stimulations with no possibility of CRT re-programming in 5 pts (0.3%), pneumothorax in 3 pts (0.2%), pericardial effusion with tamponade requiring peri-cardiocentesis in 1 pt, haemothorax in 1 pt, and Twiddler syndrome in 1 pt. A total of 62 pts

A. Da Costa et al.

Table 1 Group comparison characteristics Group I (n 5 648)

Group II (n 5 678)

P

0.1

................................................................................ Age (year)

73 + 12

72 + 13

Gender (% women)

29%

33%

0.1

Diabetes mellitus Dialysis

21% 1.80%

24% 1.50%

0.2 0.9 0.6

Atrial fibrillation

37%

38%

Device type Single chamber PM

68

72

Dual-chamber PM

276

278

CRT-P Single ICD

39 38

46 66

Dual-chamber ICD

49

55

CRT-D Cardiomyopathy

178 56%

160 45%

0.6

LVEF (%)

47 + 16

49 + 17

0.2

Primo implantation Generator replacement Follow-up (months)

439 209

448 230

0.6 0.6

26 + 4

26 + 5

0.5

0.1

LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

required re-intervention (4.6%), due to lead dislodgement in 27 (2%), lead revision because of Sprint Fidelis defect in 9 (0.6%), haematoma size in 16 (1.2%), phrenic nerve stimulation requiring lead revision in five (0.4%), and LV up-grading in 5 (0.4%). Infectious complications A total of 32 patients (2.4%) developed CIED infection (18 early and 14 late) within a mean delay of 7 + 7 months (ranging from 1 to 28 months). Endocarditis was reported in four, pocket erosion in two, pocket infection or abscess in 21, and septicaemia in 5. The cumulative risk of CIED infection was interpreted by applying Kaplan –Meier curves and compared by means of the log-rank test. Long-term follow-up revealed no significant difference between the groups, with infections observed in 14 out of 648 pts (2.2%) in Group I and in 18 of 660 (2.7%) in Group II (P ¼ 0.9). Cardiac implantable electronic device infection prevalence was 2.4% (1% per year incidence). Microorganisms responsible for the infection were isolated from blood cultures or in the case of negative blood cultures, from the device pocket or the lead. The following microorganisms were involved: methicillin-susceptible S. aureus in 13 pts, Staphylococcus coagulase-negative in 10 pts, methicillin-resistant S. aureus in two pts, methicillin-resistant Staphylococcus coagulase-negative in one pt. Cultures were negative in six pts. No patients required open heart surgery for lead extraction; early-infection required a simple extraction process with no specific tools; late-infections required a locking stylet (Spectranetics, Inc.) or the Liberator beacon tip locking stylet (Cook vascular incorporated 1186 Montgomery Lane Vandergrift). A 12 Fr., 14 Fr., or 16 Fr. laser-powered sheath system (Spectranetics Inc.) was used depending on the lead size and the operator’s choice. All CIEDs were extracted, including the device and the leads.

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Univariate and multivariate analysis As shown by univariate analysis, predictive factors of CIED infection were: re-intervention (25 vs. 4.2%; P , 0.0001), haematoma (25 vs. 0.5% P ¼ 0.01), dialysis (6.25 vs. 1.4%; P ¼ 0.04), diabetes mellitus (35.5 vs. 22.2%; P ¼ 0.03), generator replacement (75 vs. 32%; P , 0.001), number of generator replacements (1.2 + 09 vs. 0.4 + 0.6; P , 0.0001), ICD vs. PM (62.5 vs. 40.6%; P ¼ 0.01), and procedure type [with CRT (53.1%) vs. no CRT (31.3%); P ¼ 0.01] (Table 2). Single- and multiple-variable logistic regression analyses were performed to identify risk factors; adjusted odds ratios (aORs) and 95% CIs were calculated (Table 3). The occurrence of infection was positively correlated with re-intervention (aOR, 7.16; 95% CI, 2.56– 19.99; P , 0.0001), number of generator replacements, mean (aOR, 3.47; 95% CI, 2.22–5.44; P , 0.001), and haematoma (aOR, 48.4; 95% CI, 13.45–174.25; P , 0.0001) (Table 3).

Discussion Major findings This study revealed that the prevalence of CIED infection remains unaltered whether using an alcoholic or aqueous povidone-iodine solution, at almost 2.5% at the 2.5-year time point, with a per

annum incidence of 1%. Three independent predictive factors of CIED were identified: re-intervention, haematoma, and number of generator replacements.

Cardiac implantable electronic device infection prevalence In comparison, the estimated infection rate following standard PM or ICD implantation was assessed in a large French prospective study.7 Infection incidence was 0.68% at 1 year, with an observed discrepancy between de novo implantation (0.56%) and replacement implants (0.99%).7 The authors stressed that the incidence was almost 1.2% per year after inclusion of impending or frank erosions, with a yearly rate of 1.77% in the CRT patient subgroup.7 In both our study and recent publications, CRT device infection incidence was higher, at 1.7% at 1 year, with a prevalence of 4.3% at 2.6 years compared with a single device.7,12 We reported that the risk of CRT device infection was doubled when compared with the standard PM or ICD implant risk.12 Our present study produced similar results, with 1% per annum incidence, 0.65% for PM, 1.5% for ICD, and 1.7% for CRT. In conclusion, despite surgical team experience and several preventive measures, CIED infections remain a significant complication with significant morbidity and mortality, in addition to

Table 2 Comparison of patient characteristics according to CIED in the overall population Device-related infection (n 5 32)

No infection group (n 5 1294)

P value

............................................................................................................................................................................... Age (year)

73 + 12

73 + 12

0.9

Gender (% female) Diabetes mellitus

9/32 (28%) 12/32 (37.5%)

407/1294 (31.4%) 288/1294 (22.2%)

0.7 0.038

Dialysis

2/32 (6.25%)

19/1294 (1.4%)

0.049

Atrial fibrillation Dilated cardiomyopathy

16/32 (47%) 8/32 (23.5%)

479/1294 (37%) 209/1294 (16.2%)

0.1 0.6

Ischaemic cardiomyopathy

8/32 (23.6%)

348/1294 (27%)

0.6

LVEF Antithrombotic agent

46 + 20

48 + 17

0.6

Aspirin

8/32 (23.5%)

393/1294 (30%)

0.6

Vitamin K antagonists Vitamin K antagonists + aspirin

14/32 (43.7%) 5/32 (15.6%)

415/1294 (32%) 113/1294 (8.7%)

Clopidogrel

3/32 (9.3%)

130/1294 (10%)

Haematoma Re-intervention

8/32 (25%) 8/32 (25%)

80/1294 (0.5%) 54/1294 (4.2%)

,0.001 ,0.0001

Generator replacement

24/32 (75%)

415/1294 (32%)

,0.001

Number of generator replacements Procedure type:

1.12 + 0.9

0.4 + 0.6

,0.0001

Single-PM

3/32 (9.4%)

137/1294 (6%)

Dual PM CRT-P

8/32 (25%) 1/32 (3.1%)

547/1294 (42%) 84/290 (3.6%)

Single-ICD

2/32 (6.25%)

102/1294 (4.4%)

Dual ICD CRT-D

2/32 (6.25%) 16/32 (50%)

102/1294 (4.4%) 322/1294 (24.5%)

ICD vs. PM

20/32 (62.5%)

525/1294 (40.6%)

0.01

CRT vs. no CRT

17/32 (53.1%)

406/1294 (31.3%)

0.01

CRT, cardiac resynchronization therapy; PM, pacemaker; ICD, defibrillator.

0.08

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Table 3 Risk factors of CIED infection Variables

Unadjusted analysis

................................................ Crude OR

95% CI

P value

Multivariate analysisa

....................................................

Adjusted OR

95% CI

P value

............................................................................................................................................................................... Age

0.99

0.97–1.03

0.87

...

...

...

Gender (ref. categoryb: male)

0.85

0.39–1.86

0.69

...

...

...

Diabetes mellitus Dialysis

2.20 4.47

1.05–4.58 0.99–20.08

0.036 0.05

2.10 5.74

0.87– 5.07 0.69– 47.94

0.10 0.11

Atrial fibrillation

1.80

0.87–3.72

0.11

...

...

...

Dilated cardiomyopathy (ref. category: others or none)

1.73

0.77–3.90

0.19

...

...

...

Ischaemic cardiomyopathy (ref. category: others or none) LVEF, mean

0.91 0.99

0.40–2.04 0.98–1.01

0.81 0.58

... ...

... ...

... ...

Aspirin Vitamin K antagonists

0.76 1.65

0.34–1.72 0.81–3.34

0.52 0.17

... ...

... ...

... ...

Vitamin K antagonists + aspirin

...

...

...

Antithrombotic agent:

a

1.94

0.73–5.12

0.18

Clopidogrel Haematoma

0.61 71.33

0.18–2.02 22.98–221.47

0.42 ,0.0001

... 48.40

... 13.45– 174.25

... ,0.0001

Re-intervention

7.65

3.28–17.81

,0.0001

7.16

2.56– 19.99

,0.0001

Generator replacement Number of generator replacement, mean

6.35 3.28

2.83–14.26 2.22–4.85

,0.0001 ,0.0001

1.11 3.47

0.31– 3.98 2.22– 5.44

0.88 ,0.001

Adjusted for the other variables in the table. Reference category.

b

the risk pertaining to infected device extraction. Consequently, we conclude that further investigation is necessary into how to prevent CIED infection.

Cardiac implantable electronic device infection prevention Though systemic antibioprophylaxis has been well-defined and proven in the literature,7,11,16,17 only few studies have been published concerning local skin infection prevention when implanting a device, and the results are typically extrapolated from those produced with other surgical approaches.13,18 For example, recent publications on the subject provided no clear evidence of benefits of preoperative showering or bathing with chlorhexidine in comparison with other wash products (bar soap) in terms of reducing surgical site infection.19 Efforts to reduce the incidence of nosocomial surgical site infection should focus on interventions that have been proven effective. It is believed that the effectiveness of preoperative skin preparation depends on both the antiseptic and application methods used, although it is unclear whether preoperative skin antisepsis really does reduce postoperative wound infection, and, if so, which antiseptic is most effective. In standard clinical practice, strict aseptic surgical techniques and microbicidal skin solutions are employed in combination with systemic antibiotic prophylaxis for CIED infection prevention. Povidone-iodine (Betadinew) is a commonly used microbicide skin preparation in device implantation procedures due to its broad-spectrum antiseptic, and it is applied for sterilizing skin, wounds, and mucous membranes. For over 150 years now, iodine has been used in infection prevention as well as wound treatment,19 and newer derivatives, such as iodophors, have proven highly effective microbicides in a wide range of

medical applications. They demonstrated a wide antimicrobial spectrum, and their efficacy has been fully tested and proven against serious pathogens like the methicillin-resistant S. aureus and Enterococcus species. Though excellent local tolerability was observed with povidone-iodine, there is still controversy surrounding the effects it produces on wound healing and the product’s strength. In a recent European survey, 57.8% of centres reported using povidone-iodine solution as a skin antiseptic, while the use of chlorhexidine was reported in 42.2% of centres. In general, the majority use or recommend the use of alcoholic solutions, composed of either povidone-iodine or chlorhexidine.19 To our knowledge, no study has yet been conducted comparing aqueous against alcoholic povidone-iodine solutions in the setting of CIED infection prevention. Despite general recommendations, some surgeons use aqueous povidone-iodine solutions, and there have been several suggestions in the literature that the ‘active ingredient′ of skin antiseptics could potentially be the alcohol solution due to its antimicrobial properties.13 Our study was the first to present an assessment of two povidone-iodine skin solution protocols designed to prevent CIED infection, and we found the CIED infection risk to be similar in both the aqueous and alcoholic povidone-iodine groups (2.2 vs. 2.6%; ns). This result thus backs the theory of povidone-iodine having a predominant antiseptic effect, rather than the alcoholic component. Even though alcohol-based skin preparation in large incisional surgeries seems to make a difference, the same does not seem to translate into smaller incision based surgeries like cardiac device placement. Moreover, commercially available products containing chlorhexidine have not always been available in all countries. Until this becomes available across the board, CIED infection could be prevented by both the aqueous and alcoholic povidone-iodine solutions.

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Risk factors of cardiac implantable electronic device infections Identifying CIED infection risk factors would enable preventive measures to be designed. Previous studies have identified several CIED infection risks in standard procedures (PM and ICD implantation).7,8,12 The largest prospective study to date identified five independent predictive factors that included fever and temporary pacing before implantation, re-intervention, device replacement or revision, and absence of antibiotic prophylaxis.7 We prospectively reported that the factors independently involved in CIED CRT patients were re-intervention, procedure time, dialysis, and primo CRT-ICD implantation.12 Our study reconfirms the main CIED infection risks to be re-intervention, haematoma requiring surgical revision, and the number of device replacements. Our study results once again underline the risk inherent to re-intervention procedures, and patients requiring re-intervention for haematoma or lead dislodgement should therefore be considered to be at a higher risk. It is not surprising to find this factor present in the CRT population because of the high lead dislodgment rates of this group (ranging from 4 to 10%). Anticoagulant therapy management for patients who are scheduled to undergo surgical device interventions should include oral anticoagulant agents without heparin and drainage systems.20 In current clinical practice, it is clearly proven that maintaining vitamin K (AVK) or new anticoagulant agents presents less risk of haematoma in comparison with heparin bridging.20 For our trial series, the new clinical factor that independently predicted CIED infection was the number of pulse generator replacement procedures. This element could enable a patient subgroup to be identified as those who would potentially benefit from specific strategies of both minimizing the risk of infection and detecting infection onset. To date, significant data have been uncovered in support of the premise that device replacement and/or pocket reoperation represent the strongest independent risk factors for CIED infection, as this report itself confirms. This should be taken into account when assessing patients who may require reoperation within an old generator pocket.

Study limitations Despite including all cases corresponding to CIED definitions, the rate of infection may nevertheless have been underestimated, although the rigorous nature of our long-term patient follow-up probably reduced this risk to the lower end of the range. Secondly, all devices were implanted subcutaneously, which may have impacted the incidence of infection. Yet this type of risk factor has not been identified in the literature, and all patients were implanted with the same subcutaneous procedure. In addition, a monocentre trial clearly constitutes a limitation for this kind of assessment. It should be noted, however, that our overall infection rate was similar to that reported in a French multicentre study.7 Moreover, a randomized study would be required to confirm our results; yet, on the other hand, this case –control study was conducted by the same group, under the same operating conditions, and with the same experienced surgical team. Further research should be dedicated to developing strategies aimed at minimizing modifiable risk variables and determining which local antiseptic protocol should definitively be used. To continue investigation in this area, we have set up the Chlovis study, aimed at testing chlorhexidine against povidone-iodine

for CIED infection prevention (NCT01841242). The French multicentre Chlovis study (NCT01841242) was designed and has enrolled 350 patients.

Conclusion This study clearly showed that the antiseptic effect produced by both aqueous and alcoholic povidone-iodine solutions for preventing CIED infection was equivalent. Predictive factors of CIED infection were re-intervention, haematoma, and the number of generator replacements. These parameters should henceforth constitute an integral part of the risk-benefit evaluation in patients selected for device implantation. Conflicts of interest: None declared.

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