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Outcomes after transvenous defibrillator implantation in cardiac sarcoidosis: A systematic review

Abstract Introduction Sarcoidosis is a systemic inflammatory disorder associated with ventricular arrhythmias (VAs) and sudden death in the context of cardiac involvement. Guidelines advocate implantable cardioverter‐defibrillator (ICD) implantation in specific subcohorts, but there is a paucity of data on outcomes. Methods and Results A systematic review was performed to assess outcomes in patients with definite or probable cardiac sarcoidosis (CS) treated with ICD. Observational studies were identified from multiple databases from inception to 21st May 2021. Outcomes of interest included appropriate and inappropriate ICD therapies in addition to all‐cause mortality. Study quality was assessed individually using the Newcastle Ottawa Scale (NOS). Eight studies were identified comprising 530 patients, with follow‐up period of 24–66 months (weighted average 40 months). Mean age was 53.9 years with ejection fraction of 41.3%. Overall incidence of appropriate therapy was 38.1% during follow‐up. Left ventricular systolic dysfunction (LVSD) with ejection fraction <40% was a predictor of appropriate therapy in the majority of studies, as were sustained VAs during electrophysiological testing (EP) in one study. There was no interaction with device indication (i.e. primary or secondary). Where documented, inappropriate therapy was primarily driven by atrial arrhythmias. All‐cause mortality was 6.0% over a median follow‐up period of 42 months. Only three studies achieved good quality in the comparability domain of NOS. Conclusions Appropriate ICD therapy in patients with CS is commonly associated with LVSD, which can act as a surrogate for scar burden. The utility of EP testing in this setting remains unclear.


| INTRODUC TI ON
Sarcoidosis is a systemic, multi-system inflammatory disease characterised by the formation of non-caseating granulomas. 1 Whilst underlying aetiology has not been fully defined, it is hypothesised that the disorder manifests as a result of environmental triggers combined with underlying genetic susceptibility. [2][3][4] Prevalence of sarcoidosis is rare with estimates in the region of 20 per 100 000, with highest rates reported within the northern European and African-American populations. Granuloma deposition can occur within multiple organs but primarily affect the lungs, lymph nodes, skin and eyes. 5,6 Occurrence of clinically detectable cardiac sarcoidosis (CS) is as low as 5%, although studies have demonstrated cardiac involvement in up to 25% of autopsy specimens and as high as 55% in imaging studies of patients with extra-cardiac sarcoidosis. [7][8][9][10] CS is typified by the presence of myocardial inflammation, necrosis and granulomas, and is associated with significantly worse prognosis than sarcoidosis without cardiac involvement. 11 Early diagnosis is therefore paramount in order to initiate prompt therapy but is limited by the condition's typically insidious onset.
Confirmation of cardiac involvement can be achieved via endomyocardial biopsy but is of low sensitivity due to patchy involvement. 12 As such, non-invasive imaging modalities such as cardiac magnetic resonance imaging (MRI) have enabled earlier detection.
Computed tomography positron emission tomography (CT-PET) has also emerged as an effective imaging tool to assess myocardial perfusion and inflammation in CS, particularly if cardiac MRI is nondiagnostic or contraindicated. 13 Primary cardiac manifestations include conduction abnormalities, ventricular arrhythmias (VA), congestive heart failure (CHF) and sudden cardiac death (SCD). 14  However, there is a paucity of data on these cohorts which is traditionally limited to small sample sizes and single centres. This systematic review sought to appraise the contemporary literature to evaluate outcomes in patients with CS that undergo ICD implantation, including those with or without concurrent CRT.

| Data extraction and quality assessment
Data extraction was performed using a pre-specified template constructed on Microsoft Excel (Version 5.3.5, 2014). This was split and conducted independently by two authors (AT, OA), with subsequent verification by a separate author (AC) to ensure validity and accuracy. Relevant information pertaining to study designs, baseline characteristics, inclusion and exclusion criteria, follow-up period and outcomes was collated. The quality of each study was assessed independently by two authors (AT, OA) using the Newcastle Ottawa Scale (NOS). 17 A third author (RN) was consulted to resolve any discrepancies in interpretation.

| Data synthesis and analysis
Data extraction and synthesis was performed concurrently by two authors (AT, OA) using Microsoft Excel software (Version 5.3.5, 2014). All data were processed in accordance with the PRISMA statement. 18 Continuous data are presented as means (with associated standard deviations), unless otherwise stated, and categorical data as percentages. Where appropriate, subgroup analysis was performed to assess predictors of appropriate therapy. DerSimonian and Laird random effects models were fitted to accommodate for the expected inter-study variability in population characteristics. 19 Statistical significance was defined using two-sided p values and 95% confidence intervals (CIs) for all obtained pooled estimates. I 2 statistic was used to assess heterogeneity between studies and represents the proportion of variability amongst included studies that is not attributable to chance or random error, with threshold value >50% reflecting significance. All statistical analyses were conducted in R 4.1 using the meta package. AT and OA have full access to all the data in the study and take responsibility for its integrity and data analysis. identified through backward citation. An overview of the study selection process is depicted using a PRISMA flow diagram (see Figure 1).

| Study designs
Eligible studies were conducted between 2005 and 2017, with all being retrospective and non-randomised in design. All were conducted primarily in the United States of America (USA), aside from the most contemporary report which was performed in Japan. 26 There was patient overlap between three studies, 22   specified to be unique. 20,27 One study subcategorised participants based on use of radiofrequency ablation (RFA) with or without concurrent ICD versus ICD alone. 20 As it was not possible to delineate those in the RFA arm that had undergone device implant, only the latter cohort were included for the purposes of this analysis.
The criteria used to diagnosis CS for each included study is detailed in 2-Selection of the non-exposed cohort ☆ (drawn from the same community of the exposed cohort) ☆ (drawn from the same community of the exposed cohort) ☆ (drawn from the same community of the exposed cohort)

| Quality assessment
Assessment of the quality of included studies as per the NOS is summarised in  ☆ (drawn from the same community of the exposed cohort)

| Appropriate therapies
☆ (drawn from the same community of the exposed cohort) ☆ (drawn from the same community of the exposed cohort) ☆ (drawn from the same community of the exposed cohort) ☆ (drawn from the same community of the exposed cohort) In the subgroup of those without spontaneous, sustained VAs, PVS positivity remained a significant predictor (p = 0.01).
Two studies specifically explored non-predictors of appropriate therapy. In one study of 33 participants, this included extent of cardiac involvement on CT-PET and pre-procedure VA burden. 21 The other study found non-predictors to be age >60 years, New York Heart Association (NYHA) class III/IV, LVEF <35%, non-sustained VT, paroxysmal atrial fibrillation (AF), QRS interval >150 ms, QTc interval >470 ms and concurrent amiodarone therapy. 26

| Inappropriate therapies
Occurrence of inappropriate therapy during the follow-up period was reported in all studies apart from two, 20,21 with a weighted average of 19.4% (range 0-63%). Two studies highlighted incidence due to either SVT, T wave over-sensing or lead noise but did not provide details of the split. 25,26 In one study of 45 patients, there were six discrete events of which five were due to SVT (mostly AF) and one due to lead fracture. 22 In another, incidence was 30% (9/30) and driven by atrial arrhythmia, with 3 cases due to SVT, 3 due to AF and 3 due to atrial tachycardia (AT) or sinus tachycardia. 24 In the largest study, occurrence was 24.3% (57/235) with the majority (30%, 17/57) deemed secondary to AF. 23

| All-cause mortality
All-cause mortality was reported in six studies, [20][21][22]24,25,27 with         Appropriate therapy occurred with an overall incidence of 39% during the follow-up period. This is comparatively higher than other non-ischaemic aetiologies such as dilated cardiomyopathy (DCM). For instance, one study found that incidence was 56% in patients with definite CS, 68% if suspected CS but only 32% in those with DCM. 26 The original indication for device therapy did not appear to be a significant risk modifier (42% if primary, 53% if secondary), and this finding is consistent with that derived from a recent meta-analysis. 29 Notably, LVSD was observed to predict likelihood of appropriate therapy in five studies with three identifying this association when EF <40%. However, a retrospective study of registry data found significant risk of SCD with or without LVSD over a follow-up period of 2.8 years, albeit all had concomitant AV block at time of presentation. 30 Assessment for scar burden via late gadolinium enhancement (LGE) on cardiac MRI may be a more prudent strategy. In a multivariate analysis of 155 patients, LGE was shown to be the best independent predictor of potentially lethal events and superior to functional parameters including LVEF. 31 45 During a median follow-up of 6.6 years, 9.1% succumbed to a cardiac cause, 10% underwent transplantation and another 10% suffered an aborted SCD. Kaplan-Meier estimates for transplantationfree survival at 10 years was 83%, which is broadly lower than occurrence in cohorts with ischaemic and non-ischaemic cardiomyopathies. 46,47 Unfortunately, no extensive details on mode of death were available in our review to inform our understanding of pathogenesis, though most events appeared to arise from refractory CHF or VT.
There are two other systematic reviews in the literature that have assessed outcomes in patients with CS after ICD implantation. One differs in only including five studies that exclusively reviewed factors associated with appropriate ICD therapies rather than generalised outcomes. As per our study, LVSD was found to be an independent predictor. 48 The other was a meta-analysis of 10 studies, but with less stringent inclusion criteria; notably, one was a conference paper and another solely reported modulators of inappropriate therapy. 29 Appropriate therapy was reported to be 39% with all-cause mortality of 8% over a mean follow-up period of 25 months, results that are broadly consistent with our analysis.

| Limitations
This systematic review has notable limitations. All included studies were retrospective and observational which carries the risk of selection bias, though each reported clear inclusion criterion for CS diagnosis to mitigate this risk. There was study heterogeneity pertaining to participant characteristics, particularly with regards to timing, nature and specification of AMD regimen, although age, steroid use and baseline EF were broadly similar. No consistent details were available on baseline scar burden and concurrent biologic therapy which could both conceivably modulate occurrence of device therapies. Data was absent on device programming settings which are likely to be dependent upon manufacturer used and local provisions. Moreover, details on lCD lead position (i.e. apical or septal) were lacking which may theoretically have pro-arrhythmic tendency if placed at site of scar.

| CON CLUS ION
LVSD with ejection fraction <40% appears to be a predictor of appropriate therapy in patients with CS after ICD implantation, which may act as a surrogate for scar burden. The utility of EP testing in this setting remains undefined. Large-scale, prospective trials are warranted to accurately define factors that modify occurrence of adverse outcomes in the context of CS.

ACK N OWLED G M ENTS
PAP conceived the study and provided senior mentorship for the project. AT and OA performed the initial searches, extracted and collated data, and wrote the manuscript as joint first authors. RN assisted with adjudication and performed statistical analyses. AC, RN and PAP provided critical review. All authors have approved the final manuscript prior to submission.

FU N D I N G I N FO R M ATI O N
None.

CO N FLI C T O F I NTE R E S T
All authors have no conflicts of interest to declare.