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Long‐term follow‐up of implantable cardioverter defibrillator patients with regard to appropriate therapy, complications, and mortality

Abstract Background An implantable cardioverter defibrillator (ICD) is recommended for patients with symptomatic heart failure with ejection fraction ≤35% despite optimal medical therapy. More recently, the benefits of ICDs have been questioned in nonischemic cardiomyopathy (CM). Aim To examine the incidence of appropriate therapy, complications, mortality, and cause of death among ICD patients in an unselected validated cohort. In primary prevention, appropriate therapy in ischemic versus nonischemic CM will be evaluated. Methods A retrospective observational study of patients in Region Gävleborg, Sweden, who underwent ICD implantation or replacement between 2007 and 2017. Results In total, 438 patients (mean age at implant: 65.9 ± 11.2 years, 82.0% males, mean follow‐up: 5.2 ± 4.0 years) were included. There were 108 (24.7%) deaths (49.1% due to heart failure) and 94.9% survived the first year. Cumulative incidence of appropriate therapy at 5‐year was 31.6%. Cumulative incidence of inappropriate shock at 5‐year was 9.1%. A total of 98 complications requiring surgical intervention occurred (annual rate: 4.3%). In total, 236 patients with primary prevention due to ischemic (61.9%) or nonischemic (38.1%) CM were included. During a mean follow‐up of 3.9 ± 2.5 years, for appropriate therapy, there was no significant difference (P = .985) between ischemic (cumulative incidence at 1, 3, and 5 years: 6.4%, 17.1%, and 19.6%) and nonischemic CM (cumulative incidence at 1, 3, and 5 years: 5.6%, 13.6%, and 24.4%). Conclusion Ischemic and nonischemic CM confer similar risk of ventricular arrhythmia. This supports current guidelines regarding primary‐prevention ICD. Short‐term survival is excellent but complications remain a problem.


BACKGROUND
In those deemed at increased risk of ventricular tachyarrhythmia, an implantable cardioverter defibrillator (ICD) is an effective way of preventing sudden cardiac death. 1 An ICD treats ventricular tachyarrhythmia by antitachycardia pacing (ATP) or cardioversion, but it also offers bradycardia pacing and can be combined with a cardiac This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
c 2019 The Authors. Pacing and Clinical Electrophysiology published by Wiley Periodicals, Inc.
resynchronization therapy system (CRTD). 1 In 1996, the Multicenter Automatic Defibrillator Implantation Trial (MADIT) showed a benefit of primary prophylactic ICD with a reduction in all-cause mortality in patients with heart failure, prior myocardial infarction, and nonsustained ventricular tachycardia. 2 The MADIT-II demonstrated this benefit in patients with prior myocardial infarction and heart failure even without documented nonsustained ventricular tachycardia. 3 In Pacing Clin Electrophysiol. 2020;43:245-253. wileyonlinelibrary.com/journal/pace the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), an ICD reduced mortality by 23% compared to optimal medical therapy alone in patients with heart failure and reduced left ventricular systolic ejection fraction (EF) either due to ischemic or nonischemic cardiomyopathy (CM); this result was notably driven by the reduction of sudden cardiac death in New York Heart Association (NYHA) functional class II patients. 4 In a smaller study, the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, ICDs reduced sudden cardiac death by 80.0% compared to optimal medical therapy alone, but the reduction in all-cause mortality in this nonischemic CM population was only borderline significant (hazard ratio (HR): 0.65, P = .08). 5

Definitions
Patients with a first ICD implant due to survival of documented ventricular fibrillation or ventricular tachycardia with hemodynamic compromise were classified as secondary prevention. Primary prevention implies a decision to implant an ICD based on some risk marker,

Type of device
ICDs were single chamber (ICD-VR, one right-ventricular lead), dual chamber (one right-atrial and one right-ventricular lead), or CRTD systems (leads pacing right and left ventricles and right atrium). There were no patients with subcutaneous ICDs.

Follow-up
Upgraded or downgraded devices were classified according to the initial ICD type. Patients were followed until loss to follow-up, ICD explant, downgrade to pacemaker, death, or the end of the study.

ICD therapy
Appropriate ICD therapies treated ventricular tachycardia/fibrillation with either ATP or cardioversion (shock). An episode of arrhythmia requiring therapy was counted as one event if it happened within 24 h, even if multiple therapies were delivered. Inappropriate therapy was defined as shock in the absence of ventricular tachycardia/ fibrillation.

Statistics
Data are described as frequencies, percentages, and means including standard deviations. The annualized rate was calculated as the proportion of patients experiencing at least one event divided by the followup time calculated as the sum of follow-up time until first episode or censoring event (loss to follow-up, death, downgrade to pacemaker, or device explant). A single patient could account for more than one episode (note that several ATP/cardioversion during the same day were counted as one episode) or complication. The cumulative incidence was calculated using time to first event as the censoring event; otherwise, total time of follow-up for patients without an event was counted as long as they had an active ICD.

t-test was used for comparisons of continuous variables and 2 test
for categorical variables. Kaplan-Meier methods were used to describe time to event and the log-rank test was used to test for differences.
The HR for death was estimated for a risk marker using both univariable and multivariable Cox proportional hazard regression. Two-sided P-values <.05 were considered as statistically significant.

Appropriate therapy
In our study, the cumulative incidence of appropriate therapy after 5 years was 31.6%. This is comparable to a recently published American study, including patients with both primary and secondary indication, where patients at inclusion had their ICD for on average 4.6 years and 33.1% had experienced appropriate therapy. 7

Appropriate therapy in primary-prevention ICD due to ischemic and nonischemic CM
In the DEFINITE trial (mean follow-up: 29 months), the risk of sudden cardiac death was reduced, but the reduction of overall mortality was not statistically significant. 5 Recently, the DANISH trial showed a reduction in sudden cardiac death but no significant reduction in overall mortality. 6 However, a meta-analysis of six trials of primaryprevention ICD in nonischemic CM, including DANISH, showed a sig-nificant reduction in all-cause mortality (HR: 0.76, 95% confidence interval (CI) 0.64 to 0.90, P = .001). 8 In a propensity-score matched analysis of the Swedish Heart Failure Registry, ICD was associated with a 27% reduction in 1-year all-cause mortality and this was consistent across subgroups including ischemic CM and nonischemic CM. 9 Our results show that in a modern unselected cohort with CRTDs and medical therapy according to guidelines, ischemic and nonischemic CM patients experience appropriate therapy at the same rate. 10 Notably, in SCD-HeFT, ischemic CM was associated with an increased risk of death following appropriate therapy. 4,11 It thus appears that nonischemic CM patients in our study had at least similar benefit from their ICD as ischemic CM patients.

Inappropriate shock and complications requiring surgery
The proportion of patients who underwent surgery due to complications was 17.6% in this observational study of a regional cohort, without tertiary center bias. In a validation study of the nationwide Danish register of both pacemakers and ICDs, 9.5% of the patients experienced a complication at 6-month follow-up but this also included minor complications not requiring surgery. 12 Notably, our cohort was followed for a considerably longer time, which increases the number of lead-related complications because leads are the weakest link of the system. 13 17 However, registries seem to underestimate the true rate of complications, which emphasizes the importance of validation work. 16 The cumulative incidence of an inappropriate shock (not ATP) at 2-year follow-up was 3.3% in our study compared to 13% in the MADIT II, but 2.2% over a mean follow-up of 1.4 years in the subsequent MADIT-RIT. 18,19 This is likely attributable to differences in programming, pharmaceutical agents, device algorithms, and possibly home monitoring. [19][20][21] The most common reason for inappropriate shock was atrial arrhythmia, which is consistent with several other studies. 19

Mortality and cause of death
An ICD effectively terminates ventricular arrhythmias and improves survival in patients with reduced EF as a primary prevention indication. [3][4][5] This has been confirmed in extended follow-up of randomized controlled trials. 23 It is standard treatment after lifethreatening ventricular arrhythmias and miscellaneous diseases with specific criteria. 1 CRT has beneficial effects on the underlying heart failure and improves survival. [24][25][26] Furthermore, CRTD as compared with CRTP reduces all-cause mortality by reducing sudden cardiac death. 27 Altogether, this may alter the mode of death. In the current study, the most common cause of death was deteriorated heart failure. Notably, sudden cardiac death occurred in 9% of cases, which is comparable to another retrospective study. 28 Death often involves the interplay of several contributing causes and these are not always easily discernable. Nevertheless, our data highlight the importance of following the progression of heart failure and its optimal management. The prediction of death is difficult, but crucial especially in primary preven-

LIMITATIONS
We assume that appropriate therapy was life-saving, but this is not necessarily always the case, because ventricular tachycardia may selfterminate. This is a limitation that we share with other similar studies. Moreover, the programming may affect the occurrence of ICD therapy. 30 The ICD implantation rate is lower in Sweden than in many comparable countries, which should be kept in mind when applying these findings to different contexts. 31 While offering validated realworld data, this is a smaller study, which increases the risk of type 2 errors. Risk stratification for sudden cardiac death remains a challenge and more observational studies with long-term follow-up are needed to further elucidate this important topic.

CONCLUSIONS
Primary-prevention ICD patients with ischemic and nonischemic CM are at similar risk of life-threatening ventricular arrhythmias. This supports current guidelines regarding risk stratification for sudden cardiac death. Inappropriate shock is still a non-negligible problem in ICD patients. A considerable amount of patients undergo surgical intervention due to device-related complications. Half of patients with ICD/CRTD die from heart failure.