Contemporary benefit‐harm profile over two decades in primary prophylactic ICD‐therapy

Abstract Background Implantable cardioverter defibrillator (ICD) was implemented into clinical routine more than 20 years ago. Since then, ICD therapy became standard therapy for primary and secondary prevention of sudden cardiac death in clinical practice. Objectives Aim of the study was to evaluate the benefit‐harm profile of contemporary primary prophylactic ICD therapy. Methods A total of 1222 consecutive patients of a prospective single‐center ICD‐registry were analyzed who underwent primary prophylactic ICD implantation between 2000 and 2017. Patients were divided into two groups according to the implantation year: 2010‐2017 (group 1, n = 579) and 2000‐2009 (group 2, n = 643). Results The rate of estimated appropriate ICD therapy after 8 years was 51% in the 2000s and 42% in the 2010s (P < .001). The complication rate changed slightly from 53% to 47% (P = .005). This decline was mainly driven by the reduction of inappropriate ICD shocks (30% vs 14%, P < .001) whereas the rate of ICD shock lead malfunction and device/ lead infection remained unchanged over time. Nonischemic cardiomyopathy was an independent predictor for ICD complications without benefit of ICD therapy (HR 1.37, 95% CI 1.07‐1.77). Conclusion The ICD therapy rate for ventricular arrhythmias in patients with primary prophylactic ICD implantation is decreasing over the last two decades. Complication rate remains high due to an unchanged rate of ICD shock malfunctions and device infections. Nonischemic cardiomyopathy is an independent predictor for ICD complications without benefit of ICD therapy in primary prophylactic ICD‐therapy.


| INTRODUCTION
The implantable cardioverter defibrillator (ICD) therapy was implemented into clinical routine more than 20 years ago. Since then it became standard therapy for primary and secondary prevention of sudden cardiac death in clinical practice. Randomized studies like the Multicenter Automatic Defibrillator Implantation Trial (MADIT) or Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) which introduced the ICD therapy for primary prophylactic indication to standard heart failure treatment were conducted in the 90s or beginning of the 2000s. 1,2 Treatment of heart failure patients in these trials are not comparable with today's clinical state of optimized heart failure treatment. In MADIT or SCD-HeFT patient's prescription rate of beta-blocker was 70% and spironolactone 20%, which is low compared to today's expected optimized heart failure treatment. [1][2][3] Cardiac resynchronization therapy (CRT) which is indicated for up to 50% of ICD patients in registries were not included into the early primary prophylactic prevention studies. 4 The DANISH trial, a recently published randomized study dealing with the beneficial effect of ICD therapy in nonischemic cardiomyopathy, had a nearly 50% CRT therapy and could not show a benefit of ICD therapy compared to optimized medical treatment. 5 With the implementation of optimized heart failure therapy in daily clinical practice patients with heart failure today have a higher life expectancy than in the 2000s. 3,6,7 ICD shock lead performance becomes more relevant with longer patient's life as the ICD shock lead failure increases up to 20% after 8 years of ICD therapy. 8 Device recalls or lead performance alerts can force the patient to undergo additional revision surgeries that implicates further risks for the patient. For a potential ICD patient in the late 2010s the benefit and harm of ICD therapy might have changed over time during the last decades. Therefore, the present study evaluates the contemporary benefit-harm profile in patients undergoing primary prophylactic ICD therapy.

| Patient characteristics and follow-up
A total of 1222 of 2378 (51%) patients of the prospective singlecenter ICD-registry Ludwigshafen who underwent ICD implantation between 2000 and 2017 and had a primary prophylactic ICD indication with an ejection fraction (EF) ≤ 40% were included into the present study. The prospective single center ICD-registry Ludwigshafen has been previously described in detail. 8   Kaplan-Meier curves were calculated to compare the different endpoints. Differences were compared by using the log rank test. Cox regression analysis was performed to find independent predictors for benefit or harm from ICD therapy. The following parameters were included into the multivariate analysis: age > 70 years, female gender, EF < 30%, nonischemic heart disease, diabetes, atrial fibrillation, CRT, Riata ICD lead and implantation decade. All P-values were two-tailed.

| ICD programming
A P-value <.05 was considered to be statistically significant. The tests were performed using SPSS. The authors had full access to the data and take complete responsibility for the integrity of the data. All authors have read and agreed to the manuscript as written.

| Patient characteristics
Baseline clinical data of the patients stratified according to the implantation decade are summarized in Table 1. Patients with ICD-implantation between 2010 and 2017 (group 1) were more often female, had less often atrial fibrillation or renal failure (Table 1). They were less often treated with digoxin or amiodarone but more often received spironolactone than patients with ICD implantation between 2000 and 2009 (group 2, Table 1). No differences were observed between both groups with regard to age, EF or the underlying cardiac disease.

| Benefit and harm of ICD therapy during follow-up
Patients with implantation between 2010 and 2017 (group 1) had a 12% lower 8 year mortality than patients implanted in the 2000s (27% vs 39%, P < .001). The rate of estimated appropriate ICD therapy after 8 years was 51% in the 2000s and 42% in the 2010s (P < .001, Figure 1). This decline was observed in all subgroups: VT/VF shocks, VF shocks, VT shocks and ATP for VT.
The overall complication rate changed slightly from 53% to 47% (P = .004, Figure 2). This decline was mainly driven by the reduction of inappropriate ICD shocks (30% vs 14%, P < .001, Figure 3). The perioperative complications of the index ICD implantation procedure remained similar with 4.8% in group 1 and 6.2% in group 2. The rate of ICD lead malfunction rate after 8 years remained high and unchanged (29% in 2010s vs 28% in 2000s, P = n.s., Figure 4). Causes for ICD malfunction were structural defects (isolation failure or fracture) in 75%, sensing or pacing problems in 14% and perforation/ dis-  decades. The complication rate has slightly reduced due to a substantial decrease of inappropriate ICD shocks whereas ICD shock lead problems and device infection remain a major issue in ICD therapy.
Nearly a quarter of primary prophylactic ICD patients has only ICD complications without receiving appropriate ICD therapy. The presence of nonischemic cardiomyopathy is an independent predictor for ICD complications without benefit of ICD therapy.

| Benefit of ICD therapy during follow-up
The rate of appropriate ICD therapy decreased over the last two decades. This reduction included ICD shocks, and ATP therapy as well as VT and VF episodes. One important reason might be attributed to the temporal trend of a less aggressive programming of the VT/VF zones. Several studies showed that change of ICD programming to less aggressive therapy resulted in lower mortality rates. 9 problems. [18][19][20] The most serious ICD complication is the device infection which remained unchanged during the two decades. Standard guidelines for prevention of device infection were applied as accurate as possible. 21 One of the strongest known predictors for device infection is a revision procedure as bacterial colonization can exacerbate during a revision procedure. 22 Therefore revision interventions should be avoided as much as possible. Longer battery longevity, less ICD lead revisions due to lead failure and conservative management of device recalls should reduce the revision rate and consecutively the infection rate.
Other forms like the use of antibacterial envelope might further reduce the infection rate. 23

| Study limitations
As the current study is a single-center registry, our observations and conclusions may not be necessarily generalized. ICD related complications might dependent from local conditions like operation technique, choice of manufacturer or device programming. Especially the rate of ICD shock lead malfunctions might be influenced by certain leads having higher rates of malfunction like the Riata lead. 16

| CONCLUSIONS
The rate of ICD therapy for ventricular arrhythmias is decreasing while the complication rates remain high due to an unchanged elevated malfunction rate of ICD shock leads after 8 years and an unchanged device infection rate. Future efforts should focus on improving the long-term performance of ICD shock leads and reduction of device infections. Careful selection and detailed informed consent of patients is necessary before implantation of primary prophylactic ICD implantation.