Mortality among ischemic and nonischemic heart failure patients with a primary implantable cardioverter‐defibrillator

Abstract Background The efficacy of implantable cardioverter defibrillators (ICDs) for primary prevention is controversial in patients with nonischemic heart failure (HF). We evaluated the mortality and predictors of mortality in patients with prophylactic ICD implantation for ischemic and nonischemic HF. Methods From 2008 to 2017, 1097 patients (667, nonischemic HF and 430, ischemic HF) who underwent prophylactic ICD implantation, were identified from the Korean National Health Insurance Service database. We used propensity score overlap weighting to correct the differences between two groups. Results Those with ischemic HF were older (67.0 ± 10.1 vs 61.8 ± 14.2 years), more often male (71.4% vs 63.7%), and had more comorbidities than patients with nonischemic HF. During a median follow‐up of 37.3 months (interquartile range [IQR], 14.2‐53.8 months), all‐cause mortality was higher in unweighted patients with ischemic HF than in those with nonischemic HF (10.9 vs 6.4 per 100 person‐years; hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.38‐2.20; P < .001). However, after weighting, the annual all‐cause mortality rate was similar in both groups (9.5 vs 8.8 per 100 person‐years), with no significant difference in the risk of all‐cause mortality (HR, 1.08; 95% CI, 0.68‐1.71; P = .755). Older age and chronic kidney disease were independent predictors of all‐cause mortality in both groups. There was no significant difference in cardiac and noncardiac mortality between the weighted nonischemic and ischemic HF groups. Conclusions The all‐cause, cardiac, and noncardiac mortality rates were similar between patients with nonischemic and ischemic HF who underwent prophylactic ICD implantation.


| INTRODUC TI ON
As implantable cardioverter defibrillators (ICDs) therapy reduces morbidity and mortality as a part of the primary prevention strategy in patients with heart failure with reduced left ventricular ejection fraction (HFrEF), [1][2][3][4] prophylactic ICD therapy for the primary prevention of sudden cardiac death (SCD) is recommended to reduce mortality in select patients with HFrEF with an left ventricular ejection fraction (LVEF) ≤35%. 5,6 Evidence for the benefit of prophylactic ICD therapy is much stronger for patients with ischemic heart failure (HF) than for patients with nonischemic HF. 2,7 No single study based exclusively on patients with HFrEF unrelated to coronary artery disease has demonstrated a reduction in mortality because of ICD implantation.
Moreover, many trials showing the benefit of prophylactic ICD therapy have been studied in patients enrolled more than 20 years ago, and might not reflect the current patient characteristics and current management of HFrEF. Indeed, recent advances have affected the risk profile of patients with HFrEF, leading to a 44% reduction in SCD risk over the past two decades. 8,9 Therefore, the beneficial prognostic effects of ICDs might be different because of the improved risk profile. The Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) trial questioned the efficacy of primary prophylactic ICD therapy in patients with nonischemic cardiomyopathy combined with contemporary treatments. 10 This trial showed that ICD implantation did not significantly decrease the rates of all-cause death in patients with nonischemic HF, even though the occurrence of SCD was effectively reduced. 10 The addition of cardiac resynchronization therapy (CRT) to ICD implantation (58% of patients in both arms of the DANISH trial carried CRT devices) not only modifies the possibility of improving left ventricular ejection fraction, especially in nonischemic cases but can also reduce the morbidity and mortality outcomes. [11][12][13][14] Pooled data from previous meta-analyses demonstrated that even after the elimination of CRT trials, ICD-only therapy accomplished a reduction in total mortality, ranging between 26% and 31% in patients with nonischemic HF. 15,16 The present study aimed to assess whether the rates of all-cause, cardiac, and noncardiac mortality differed between HFrEF patients with nonischemic and ischemic HF after ICD implantation as a primary prevention strategy. We aimed to identify the specific predictors of mortality in ischemic and nonischemic HF populations and to evaluate the rates of the other causes of death.

| Data source
The majority (97.1%) of the Korean population is mandatorily subscribed to the National Health Insurance Service (NHIS), a single insurer managed by the Korean government, with the remaining 3% categorized as medical aid subjects. As the database also includes information on the medical aid population, it can be considered to be representative of the entire Korean population. [17][18][19][20] All pertinent data, including patients' sociodemographic information, data on the use of inpatient and outpatient services, pharmacy-dispensing claims, and mortality rate data, can be accessed through this database. The NHIS database can be accessed only through the wired network at the designated analysis center, with formal payment according to the period of browsing and analyzing the data and applying strict regulations regarding data release (https://nhiss.nhis. or.kr/).

| Study population
The study cohort consisted of all admissions that included a procedure for ICDs (procedure codes: O2008, O0211, and O0212) from the entire Korean population in the Korean NHIS database. In accordance with the data provision policy of the Korea NHIS, 50% random sampling was performed when the study cohort was formed.

| Outcomes
The primary clinical outcome was all-cause mortality. Data on vital status and date of death were confirmed from the National Population Registry of the Korea National Statistical Office using a unique personal identification number, in which central registration of death was conducted on the basis of the death certificates. [17][18][19][20][21][22] This approach provides a complete event ascertainment given that the NHIS and National Statistical Office are national organizations that cover all Korean subjects.
We also assessed cardiac death, noncardiac death, and arrhythmic death as secondary outcomes. Cause-specific mortality was analyzed based on the causes of death confirmed by the Korea National Statistical Office. Cardiac death included death related to HF and coronary disease, sudden and other cardiac deaths, and noncardiac death included death related to cancer, cerebrovascular disease, and other causes. The definitions of the clinical outcomes are presented in Table S1.

| Statistical analysis
The baseline characteristics of participants with nonischemic and ischemic HF were compared using the Student's t test and Pearson's chi-square test. Simple between-group analyses were conducted using the Student's t test. Categorical variables were compared using Fisher's exact test.
We used an overlap weighting approach based on propensity scores to allow an unbiased comparison in the main analyses.
Propensity scores were calculated using the following variables: age; gender; economic status; history of atrial fibrillation; hypertension; peripheral artery disease; chronic kidney disease; chronic obstructive pulmonary disease; liver disease; cancer; and treatment with aspirin, P 2 Y 12 inhibitors, oral anticoagulants, aldosterone antagonists, furosemide, beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and the anti-arrhythmic drugs digoxin and statin. The overlap weight was calculated as 1 minus the propensity score for the ischemic HF patients, and the propensity score for the nonischemic HF patients. 23 The balance between the populations was evaluated by standardized differences of all baseline covariates using a threshold of 0.1 to indicate imbalance.
The incidence of events was calculated by dividing the number of events by the person-times at risk, with 95% confidence intervals (CI) estimated by exact Poisson distributions. The incidence of death was compared using the weighted log-rank test, and the weighted failure curves were plotted. Cox proportional hazards regression was used to compare the nonischemic and ischemic HF groups.
Kaplan-Meier curves were constructed to estimate the eventfree outcomes in the two study groups using the log-rank test.
A Cox proportional hazards regression model was used to estimate the hazard ratios (HRs) for clinical events. All covariates that reached a significance level of P < .1 were included in the multivariate regression model. Statistical significance was set at P < .05.
Statistical analyses were conducted using SAS version 9.4 (SAS Institute) and R version 4.0.1 (The R Foundation, www.R-proje ct.org).

| Patient characteristics
From 2008 to 2017, 1097 patients aged 19 years or older who underwent prophylactic ICD implantation were identified from the Korean NHIS database. Those with ischemic HF were older (67.0 ± 10.1 years vs 61.8 ± 14.2), more often male (71.4% vs 63.7%), and had more comorbidities, including hypertension, diabetes, and atrial fibrillation, than patients with nonischemic HF.
Moreover, antiplatelet agents, diuretics, beta-blockers, ACEIs/ ARBs, and statins were more frequently used in patients with ischemic HF than in those with nonischemic HF. CRT-D was implanted in 45.6% and 40.0% of the nonischemic and ischemic HF populations, respectively. The median follow-up duration was slightly shorter in patients with ischemic HF than in those with nonischemic HF (29.2 months vs 33.0 months, P = .010). After weighting, all baseline characteristics were similar between the two groups (Table 1).  Table S2. There were no significant differences in the proportions of cardiac death and noncardiac death between the nonischemic HF and ischemic HF groups. The mortality rate was higher in patients with ischemic HF than in those with nonischemic HF (P < .001), with annualized allcause mortality rates of 10.9 and 6.4 per 100 person-years, respectively. Ischemic HF was associated with a 74% higher risk of all-cause death compared with nonischemic HF (HR, 1.74; 95% CI, 1.38-2.20, P < .001) ( Table 2). The Kaplan-Meier estimate of survival free from all-cause death was significantly lower in patients with ischemic HF than in those with nonischemic HF (log-rank P < .001; Figure 1A).

| All-cause death and predictors associated with mortality
However, in overlap weighted nonischemic and ischemic HF groups, the annual mortality rate was 8.8 and 9.5 per 100 person-years, respectively, with no significant difference in the risk of all-cause death (HR, 1.08; 95% CI, 0.68-1.71; P = .755) ( Table 2). The Kaplan-Meier estimate of survival free from all-cause death also showed no significant difference between patients with ischemic HF and those with nonischemic HF (log-rank P = .622, Figure 1B); this trend was consistently observed at 1-and 5-year follow-ups (

| Cardiac, noncardiac, and arrhythmic death
Among the causes of death, 140 (48.8%) patients died from cardiovascular causes, and 83 (28.9%) died from noncardiovascular causes.  (Table 4). Moreover, the Kaplan-Meier estimate of survival free from cardiac and noncardiac death was significantly lower in patients with ischemic HF than in those with nonischemic HF (all log-rank P < .05; Figure 2A). However, there was no significant difference in cardiac (4.1 and 4.6 per 100 person-years) and noncardiac mortality (2.4 and 3.1 per 100 person-years) between the weighted nonischemic and ischemic HF groups. Furthermore, the rate of arrhythmic death did not differ significantly between the two groups before and after weighting ( Table 4). The Kaplan-Meier estimate of survival free from cardiac, noncardiac, and arrhythmic death also TA B L E 1 Baseline characteristics of patients with nonischemic and ischemic HF who underwent prophylactic ICD implantation Abbreviation: AAD, Anti-arrhythmic drugs; ACEI, Angiotensin-converting enzyme inhibitor; ARB, Angiotensin II receptor blocker; COPD, Chronic obstructive pulmonary disease; CRT-D, Cardiac resynchronization therapy with defibrillator; HF, Heart failure; ICD, Implantable cardioverter defibrillator; SD, Standard deviation; SMD, Standardized mean difference. showed no significant difference between the weighted ischemic HF and nonischemic HF groups ( Figure 2B).

| D ISCUSS I ON
The main findings of this study were as follows. In HF patients who underwent prophylactic ICD therapy, patients with ischemic HF were older and had more comorbidities than those with nonischemic HF. All-cause, cardiac, and noncardiac mortality rates were higher in unweighted patients with ischemic HF than in those with nonischemic HF; however, these rates were similar between the two groups after weighting. The predictors of all-cause mortality were older age and chronic kidney disease for both ischemic and nonischemic HF patients, whereas hypertension was only associated with death in patients with nonischemic HF. Furthermore, the rates of arrhythmic death were similar between patients with ischemic and nonischemic HF after weighting.

| Primary prophylactic ICD therapy in contemporary patients with HFrEF
In recent years, the long-term prognosis of patients with HF has improved with advances in evidence-based therapy for HFrEF, such TA B L E 2 Incidence rate of all-cause death in patients with nonischemic and ischemic HF who underwent prophylactic ICD implantation    26 Younger patients may be more susceptible to ventricular tachycardia, while older patients are more likely to die from pump failure or noncardiovascular problems. 26 In the post hoc analysis of the DANISH study, ICD implantation was consistently associated with a reduction in all-cause mortality in patients aged ≤70 years. Furthermore, the benefit of ICD implantation decreased with age and was not apparent in patients aged >70 years. Older patients were more likely to die from causes other than SCD than younger patients, which might explain why the association between ICD transplantation and all-cause death decreased with increasing age. 27

| Mortality in patients with nonischemic and ischemic HF who underwent prophylactic ICD therapy
In this study, the mortality rate was similar in patients with nonischemic and ischemic HF who underwent prophylactic ICD therapy after weighting. Therefore, the benefit of prophylactic ICD therapy in HF patients should not be restricted to ischemic patients.
The use of prophylactic ICD therapy for the primary prevention of SCD in patients with nonischemic HF has been debated in recent years. In the SCD-HeFT trial, ICD implantation reduced mortality by 21% and 27% in patients with ischemic HF and those with nonischemic HF, respectively. which may have lowered the overall mortality as a result of disease modification. 28 Therefore, the chance of observing any effect of ICD implantation in addition to that of CRT in the DANISH trial may have been limited a priori. Meta-analyses incorporating data from all randomized controlled trials testing primary prophylactic ICDs, including the DANISH trial, have confirmed a significant reduction in all-cause mortality associated with ICD use in patients with nonischemic HF. 10,29,30 This may suggest that the DANISH trial was not sufficiently powered to test its primary endpoint over an extended follow-up period, which might have led to a late alignment of the Kaplan-Meier curves. 10

| CON CLUS IONS
In contemporary HF patients undergoing prophylactic ICD implantation in Korea, all-cause, cardiac, and noncardiac mortality rates were similar between patients with nonischemic and ischemic HF when weighting is performed to account for differences in patient characteristics. Therefore, the benefit of prophylactic ICD therapy in HF patients should not be restricted to ischemic patients. We identified a higher overall mortality in HF patients who underwent ICD implantation in Korea compared to that in recently published DANISH trial, with a lower usage of beta-blockers, ACEI/ARBs, and aldosterone antagonists. So, our findings support the current guidelines recommendation for primary-prevention ICD in HFrEF patients with ischemic or nonischemic HF and call for better implementation of medical therapy in clinical practice.

ACK N OWLED G M ENTS
Access to the National Health Information Database was provided by the NHIS of Korea. The authors would like to thank the NHIS for their cooperation.