Postimplantation pocket hematoma increases risk of cardiac implantable electronic device infection: A meta‐analysis

Abstract Introduction Several studies have shown an inconsistent relationship between postimplantation pocket hematoma and cardiac implantable electronic device (CIED) infection. In this study, we performed a systematic review and meta‐analysis to explore the effect of postimplantation hematoma and the risk of CIED infection. Methods We searched the databases of MEDLINE and EMBASE from inception to March 2020. Included studies were cohort studies, case‐control studies, cross‐sectional studies, and randomized controlled trials that reported incidence of postimplantation pocket hematoma and CIED infection during the follow‐up period. CIED infection was defined as either a device‐related local or systemic infection. Data from each study were combined using the random effects, generic inverse variance method of Der Simonian and Laird to calculate odds ratios (OR) and 95% confidence intervals (CI). Results Fourteen studies were included in final analysis, involving a total of 28 319 participants. In random‐effect model, we found that postimplantation pocket hematoma significantly increases the risk of overall CIED infection (OR = 6.30, 95% CI: 3.87‐10.24, I 2 = 49.3%). There was no publication bias observed in the funnel plot as well as no small‐study effect observed in Egger’s test. Conclusions Our meta‐analysis demonstrated that postimplantation pocket hematoma significantly increases the risk of CIED infection. Precaution should be taken during device implantation to reduce postimplantation hematoma and subsequent CIED infection.


| INTRODUC TI ON
Approximately 1.5 million people receive cardiovascular implantable electronic devices (CIEDs) worldwide per year. 1 The use of CIEDs by cardiologists has been increasing because of the expansion of the eligibility criteria for CIEDs in recent guidelines of cardiac arrhythmias. 2,3 Even though CIED implantation has been shown to improve outcomes in the selected population, the procedure carries risk of complications, such as CIED infection, which is associated with increased morbidity, mortality, hospital length of stay, and substantial financial burden. [4][5][6] The clinical manifestations of CIED infection can vary from local pocket infection to systemic infection such as endocarditis, bacteremia, or lead infection. The overall incidence of CIED infection ranges from 0.68% to 5.7%, 7 with increased rate in patients who have comorbidities including diabetes mellitus, end-stage renal disease, chronic obstructive pulmonary disease, corticosteroid use, malignancy, and heart failure. 8 Postimplantation pocket hematoma is another common complication after CIED implantation, reported occurring around 1.04% to 16.67%. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] However, the results from previous studies exploring the effect of postimplantation hematoma on the risk of CIED infection have been inconsistent. Several studies showed that postimplantation hematoma increased the risk of CIED infection after device implantation, 10,12,13,[15][16][17]19,20,22 while others failed to demonstrate such a relationship. 9,11,14,18,21 Thus, the primary objective of this study was to evaluate the association between postimplantation hematoma and the risk of CIED infection following cardiac implantable electronic device implantation via the systematic review and meta-analysis.

| Search strategy
Two investigators (CK and ST) independently searched for published studies indexed in the MEDLINE and EMBASE databases from inception to March 2020 using a search strategy including the terms "hematoma," "cardiac implantable electronic device," and "infection" as described in Data S1. Only full articles in English were included. A manual search for additional pertinent studies using references from retrieved articles was also completed.

| Inclusion criteria
The eligibility criteria included the following: 1. Cohort studies (prospective or retrospective), case-control studies, cross-sectional studies, and randomized control trials (RCT) reporting incidence of CIED infection following the implantation, comparing between patients with postimplantation hematoma and without postimplantation hematoma 2. Relative risk (RR), odds ratio (OR), hazard ratio (HR) with 95% confidence interval (CI), or sufficient raw data to perform the above calculations were provided. Patients without documented postimplantation hematoma were used as controls Study eligibility was independently determined by two investigators (CK and ST) and differences were resolved by mutual consensus. The Newcastle-Ottawa quality assessment scale (NOS) was used. The Newcastle-Ottawa Scale uses a star system (0 to 9) to evaluate included studies on three domains: recruitment and selection of the participants, similarity and comparability between the groups, and ascertainment of the outcome of interest among cohort and case-control studies. 23 Higher scores represent higher quality studies.

| Data extraction
A standardized data collection form was used to obtain the following information from each study: title of study, name of the first author, year of publication, country of origin, prevalence and diagnostic method of CIED infection, device type, time of outcome measurement, definition of postimplantation hematoma, and pathogen.
Two investigators (CK and ST) independently performed this data extraction process to ensure accurate data extraction. Any data discrepancy was resolved by reviewing the primary data from the original articles.

| Definition
Cardiac implantable electronic device infection was defined as either local/wound infection or systemic infection (bacteremia or infective endocarditis or lead infection/vegetation) or both. 24

| Statistical analysis
We performed a meta-analysis of the included studies using a random-effect model. Studies were excluded if they did not report an outcome in each group or did not have enough information available to calculate the OR or RR. We pooled the point estimates of HR, RR, and OR from each study, separately for each type of parameters, using the generic inverse-variance method of Der Simonian and Laird. 25 The heterogeneity of effect size estimated across these studies was quantified using the I 2 statistic. The I 2 statistic ranges in value from 0% to 100% (I 2 < 25%, low heterogeneity; I 2 = 25%-50%, moderate heterogeneity; and I 2 ≥ 50%, substantial heterogeneity). 26 A sensitivity analysis was performed to assess the influence of the individual studies on the overall results. Publication bias was assessed using a funnel plot and the Egger's regression test, 27 with a P < .05 being considered significant. All data analyses were performed using STATA SE version 14.2.

| Sensitivity analysis
We used a sequential exclusion strategy, as described by Patsopoulos et al, to examine whether overall estimates were influenced by the substantial heterogeneity observed. 28 We sequentially and cumulatively excluded studies that accounted for the largest share of heterogeneity until I 2 was less than 50%. We then examined whether OR estimates were consistent.

| Search results
Our search strategy yielded 329 potentially relevant articles (294 articles from EMBASE and 35 articles from MEDLINE). After the exclusion of 193 duplicated articles, 136 articles underwent title and abstract review. At this stage, 90 articles were excluded as they were not conducted in patients with cardiac device, not study design of interests, or not relevant to our objective. This left 46 articles for full-length review. Further 32 studies were excluded as they did not report outcome of interests of device infection, relevant data were not available, or full article was not available. No additional studies were added through the manual search. Therefore, a total of 14 studies were included in the meta-analysis. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] The PRISMA flow diagram is demonstrated in Figure 1.

| Quality assessment of included studies
The NOS of included studies are described in Data S2.

| Sensitivity analysis
To assess the stability of the results of the meta-analysis, we conducted a sensitivity analysis for each outcome by excluding one study at a time. For every outcome, none of the results were significantly altered, as the results after removing one study at a time were similar to that of the main meta-analysis, indicating that our results were robust.

| Publication bias
To investigate the effect of potential publication bias on the main outcome, we examined a funnel plot generated from the included studies ( Figure 5). The vertical axis represents study size (standard error) while the horizontal axis represents effect size (log odds ratio).
From this plot, no bias was observed, as the distribution of studies is symmetrical on both sides of the mean. Egger's test was not significant. 29,30

| D ISCUSS I ON
The main result from our meta-analysis showed that postimplantation pocket hematoma is associated with an increased risk of CIED infection up to 6.3-folds.
Recent systematic review suggested that there is an association between pocket hematoma and risk of wound infection among patients with a CIED. 31 However, this study mainly focused on pocket infection rather than systemic infection. Additionally, meta-analysis was not performed and only OR from included studies were reported. This is the first study to explore the association There has been conflicting data regarding the association between pocket hematoma and the risk of CIED infection. Among the included studies in our systematic review, nine from 14 studies revealed a significant association between postimplantation pocket hematoma and an increased risk of CIED infection. 10,12,13,[15][16][17]19,20,22 Four studies suggested positive correlation, but the results did not reach statistical significance. 9,11,14,21 Only one study did not demonstrate positive correlation, although the study had a small number of CIED infection events. 18 In subgroup analysis, there is a slightly The mechanism of postimplantation hematoma leading to CIED infection has been proposed. Although up to 60 to 80% of CIED infections were caused by staphylococcal species, virtually any pathogen can cause the infection, including normal flora. 39 Hematoma can separate the incision, making the wound vulnerable to bacterial migration through the superficial tissue and into a subsequent deeper layer. 40 Conversely, compromised wound closure could also lead to hematoma development as well. 41 Moreover hematoma itself can act as a culture medium for bacterial growth. 42 There is evidence describing risk factors for pocket hematoma following CIED implantation including heart failure, renal failure, coagulopathy. 36,37 As these are similar risk factors for CIED infection, it is possible that these populations simply just possess risk profiles for both hematoma and CIED infection rather than having a causal association.

| Limitation
Our meta-analysis is not without limitations. First, despite the significant association we found on the main analysis, a causal relationship F I G U R E 5 Funnel plot evaluating publication bias of the metaanalysis [Colour figure can be viewed at wileyonlinelibrary.com] cannot be inferred. As mentioned earlier, certain patients may be at risk for both hematoma and CIED infection. Second, most data extracted from the included studies were not adjusted for confounders known to be associated with CIED infections, including diabetes mellitus, heart failure, renal dysfunction, oral anticoagulant, or longterm corticosteroid use. In studies reported adjusted ratios, these factors were not uniformly addressed in addition to other factors such as definition of postimplantation hematoma, follow-up duration, device type (pacemaker, defibrillator, biventricular defibrillator), and device revision/new implantation. There is also not enough sufficient data to perform subgroup analysis for these factors.
Third, data from studies included in this meta-analysis was obtained

| CON CLUS ION
Our study suggested a statistically significant association between postimplantation hematoma and an increased risk of CIED infection following the implantation. This correlation should not be overlooked and extra steps to detect or prevent hematoma are needed to reduce CIED infection.