Appropriate time for ejection fraction reassessment after revascularization in patients with left ventricular dysfunction for risk stratification of sudden cardiac death

Abstract Background Appropriate time for ejection fraction (EF) reassessment after revascularization in patients with left ventricular dysfunction has not been investigated comprehensively, although 3 months after revascularization is recommended to stratify the risk of sudden cardiac death (SCD). Hypothesis EF reassessed within different timeframe after revascularization may have incosistent contribution for risk stratification of SCD. Methods Patients who had EF ≤ 40% before revascularization and had EF reassessment at least once during follow‐up were included. The role of early (<3 months) versus late (3–12 months) EF measurements in prediction of all‐cause mortality and SCD were compared. Results A total of 1589 patients were identified. EF reassessed <3 months was lower than EF reassessed within 3–12 months (42.1 ± 9.7% vs. 45.8 ± 10.8%; p < .01). Among 1069 patients who had EF reassessed <3 months, EF ≤ 35% was associated with a higher risk of all‐cause mortality (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.22–2.29; p < .01), but had no association with the risk of SCD (HR, 1.44; 95% CI, 0.84–2.48; p = .18). By contrast, among 595 patients who had EF reassessed within 3–12 months, EF ≤ 35% was associated with higher risks of both all‐cause death (HR, 1.81; 95% CI, 1.06–3.10; p = .03) and SCD (HR, 2.71; 95% CI, 1.31–5.61; p < .01). The relative contribution of SCD to all‐cause death was higher in patients with EF ≤ 35% than patients with EF > 35% when EF was reassessed within 3–12 months (p = .04). However, when EF was reassessed <3 months, the mode of death was similar in patients with EF ≤ 35% versus >35% (p = .85). Conclusions 3 to 12 months after revascularization may be appropriate for cardiac function reassessment and SCD risk stratification.


| INTRODUCTION
Ejection fraction (EF) has already been accepted as a critical factor for risk stratification for sudden cardiac death (SCD), and one of the criteria for placement of implantable cardioverter defibrillator (ICD) for primary or secondary SCD prevention. 1,2][5][6][7][8][9][10][11] Persistent LV dysfunction with EF ≤ 35% after coronary artery bypass graft (CABG) has been reported ranging from 25% to 74%. 7,8One explanation is the difference in baseline characteristics of patient cohorts, such as the myocardial viability 4,6 and preoperative EF. 10 Another potential explanation that has not yet been addressed clearly is the timing of EF reassessment following revascularization.The reassessment time for EF comparison was diverse from predischarge 5 to 24 months 10 after revascularization.The EF might change over time after revascularization in patients with LV dysfunction. 5,9rrent guideline recommends that patients with LV dysfunction undergo a reassessment of EF 3 months after revascularization to evaluate the necessity for ICD placement. 12,13The rationale for waiting 90 days after revascularization is based upon the premise that LV function can be improved sufficiently to raise the EF to above 35% and the clinical trials 14,15 which enrolled patients with a 3-month waiting period after CABG before the implantation of an ICD.However, this time point for EF reassessment is not supported by solid evidence, as the guideline document 13 said "the 3-month term was chosen because it was used in some randomized clinical trials related to timing for device implantation," "the waiting period of 3 months after diagnosis of a new cardiomyopathy or revascularization procedure is arbitrary."Yet, some trials [16][17][18] recorded EF measurement before the completion of 3 months after revascularization and had ICD implanted in patients with a higher risk of ventricular arrhythmia.
However, the trials failed to indicate a clear benefit of ICD in overall mortality reduction.The potential reasons were controversial. 19,20As revascularization may have an important timedependent effect on EF evolution, we hypothesize that EF

| Data collection and definitions
Baseline characteristics including demographics, comorbidities, EF, angiographic results, and medicines at discharge were captured from patients' medical records.Left main disease was defined as at least 50% diameter stenosis in the left main vessel.Multivessel disease was defined as the presence of coronary luminal diameter stenosis ≥70% in more than one of the three major epicardial vessels.
Complete revascularization was defined as successful PCI of all angiographically significant lesions (≥70% diameter stenosis) in three coronary arteries and their major branches.For CABG procedures, grafting to every primary coronary artery with ≥70% diameter stenosis was accepted as complete revascularization.
All EF measurements were assessed by echocardiography in Beijing Anzhen Hospital.The initial EF was defined as being measured within 30 days before the index PCI or CABG.During the follow-up, EF values were recorded and separated into the following time intervals: <3, 3-6, 6-9, 9-12, and the last measurement (>12 months).For patients who had multiple echocardiography measurements within each time interval of <3, 3-6, 6-9, and 9-12 months, the first available measurement was used.For patients with multiple measurements in the last interval (>12 months), the last available measurement was used.For patients defined as having EF reassessed within 3-12 months, the first available measurement was used if the patients had multiple measurements within 3-12 months.
Outcome data were obtained from both medical records at Beijing Anzhen Hospital as well as through phone contact.Death was categorized as cardiac and noncardiac death.Cardiac death was further categorized SCD and non-SCD. 21Death with insufficient information to make a reasonable decision as to the cause of death was classified as death due to unknown causes.According to a modified Hinkle-Thaler system, 22 SCD was defined as a sudden, unexpected cardiac death, which included those who: (1) died suddenly and unexpectedly within 1 h of cardiac symptoms in the absence of progressive cardiac deterioration; (2) died unexpectedly in bed during sleep; and (3) died unexpectedly within 24 h after last being seen alive.

| Statistical analysis
Categorical variables were summarized as frequencies, with percentages and continuous variables were expressed as mean ± SD.Correspondingly, patients (n = 595) who had EF reassessed within 3-12 months were included in the analysis of the association between EF reassessed within 3-12 months and the risk of allcause death and SCD.The follow-up for these patients started on the day of their EF reassessment.Patients in these two cohorts were all categorized as their reassessed EF being of ≤35% or >35%. 12,13Cumulative incidences were estimated by the Kaplan-Meier method and compared by log-rank test.The risk of all-cause death was analyzed using a Cox proportional hazard regression model.To identify factors associated with the risk of SCD, a Cox proportional hazard model by treating deaths from other causes as a competing risk was used. 23All variables that had marginal association in univariate analysis (p < .10)were adopted as independent variables in the multivariate model.For

| Improvement of EF over time
In total, 2852 patients had preoperative EF ≤ 40% who underwent either PCI or CABG.Patients who had concomitant non-CABG surgery (n = 306), and who died in hospital during the index procedure (n = 104), and who were lost to follow-up (n = 229), and who had no EF reassessment after revascularization (n = 624) were excluded.A total of 1589 patients were finally included in the study, of whom 632 (39.8%) underwent PCI and 957 (60.2%) underwent CABG (Table 1).All the patients had EF reassessed at least once during the follow-up.The mean age was 65.6 years with a mean initial EF of 35.9%.

| Change of causes of death
Among patients with EF reassessed <3 months, the percentage of overall death accounted for SCD was similar regardless of whether the EF was ≤35% or >35% (36% vs. 35%, p = .85)(Figure 4).However, when the was reassessed within 3-12 months after revascularization, 58% of deaths were SCD in group with EF ≤35%, whereas only 33% of deaths were SCD in group of EF >35% (p = .04).

| DISCUSSION
In the present study of CAD patients with reduced EF (≤40%), we found that (1) EF after revascularization changed over time.However, EF reassessment taken within 3-12 months remained relatively stable indicating that this time period may be more appropriate for According to the EF assessed <3 months, patients who had EF ≤ 35% had a similar risk of SCD compared to patients with EF > 35%, though EF ≤ 35% was associated with a higher risk of mortality.This implied that EF ≤ 35% as a traditional risk factor of SCD, when it was reassessed <3 months, may not be predictive enough to discriminate high-risk population that was prone to suffer SCD.Moreover, it did not appear to influence the cause of death (SCD vs. all-cause).Thus, the survival benefit of ICD therapy on this patient cohort with EF ≤ 35% would be lacking because the proportion of patients who benefit from ICD is less.In the trials of DINAMIT 17 and IRIS, 18 according to the EF assessed <3 months, ICD therapy was associated with a reduction in the rate of death due to arrhythmia, but did not reduce overall mortality in patients with recent MI.Our data provided another potential explanation and supported the rationale for waiting 90 days after revascularization to a decision making of ICD therapy.

measurement 3
months earlier after revascularization does not predict the risk of SCD.This study aimed to investigate (1) the change of EF over time after revascularization; (2) association between EF reassessed <3 months and the risk of long-term mortality and SCD; (3) association between EF reassessed within 3-12 months and the risk of long-term mortality and SCD; (4) change in the composition of mortality risk (SCD vs. non-SCD deaths) stratified by EF reassessed <3 months and within 3-12 months. 2 | MATERIAL AND METHODS 2.1 | Patient selection This was a real-world cohort study that used data from Beijing Anzhen Hospital.The study was registered in the Chinese Clinical Trial Registry (No. ChiCTR2100044378).The study protocol was approved by the hospital's ethics committee.Patients with initial EF ≤ 40% who underwent either percutaneous coronary intervention (PCI) with drug-eluting stent or CABG due to CAD between January 2005 to December 2014 were screened.If patients had multiple PCI or CABG during the follow-up, the first qualifying procedure was used.Patients who had EF reassessment at least once after revascularization were enrolled.
Comparison of EF at each time period was by one-way ANOVA followed by Bonferroni multiple-comparison tests.A repeated measures mixed model was used to analyze changes in EF over time between the PCI and CABG groups.Patient characteristics among cohorts with EF reassessment at least once, with EF reassessed <3 months and with EF reassessed within 3-12 months were compared by one-way ANOVA for continuous variables and chi-square test for categorical variables.Patients (n = 1069) who had EF reassessed <3 months were included in the analysis of the association between EF reassessed <3 months and the risk of all-cause mortality and SCD.
study purposes only, EF reassessed <3 or 3-12 months after revascularization was locked in the model and was not subjected to the selection criteria.All statistical analyses were based on two-tailed tests.Values of p < .05were considered statistically significant.Statistical analyses were performed with Stata version 14.0 (College Station).
evaluating cardiac function recovery; (2) EF reassessed within 3-12 months after revascularization had a predictive role for the risk of SCD but not EF reassessed <3 months; (3) EF reassessed within 3-12 months influenced the cause of death but not EF reassessed <3 months.Evolution of EF over time after myocardial revascularization in patients with LV dysfunction has not yet been addressed comprehensively.In the present study, all patients had initial EF ≤ 40% and underwent either PCI or CABG.There was no statistically significant difference in EF reassessed among the time intervals of 3-6, 6-9, and 9-12 months.However, EF reassessed <3 months after revascularization was significantly less than EF reassessed during each of the above three time intervals.

F I G U R E 1
Ejection fraction (EF) improvement over time after revascularization by either coronary bypass grafting (CABG) or percutaneous coronary intervention (PCI).The error bar indicated 95% confidence intervals.measurements by hospitals other than the index hospital (Anzhen) echocardiography were excluded.This restriction improved the accuracy of the EF measurements, but increased the number of patients who were lost to follow-up.Studies that have used retrospective death certificate-based methodology to identify cases of SCD are likely to overestimate the SCD mortality rate. 27Only 13 patients had ICD therapy during the follow-up.But the data on ICD shocks or aborted sudden cardiac arrest were lacking.However, it was unlikely to have affected current findings because of their uses were minimal in this study population.

F I G U R E 2
Ejection fraction (EF) ≤ 35% versus EF > 35% for risks of all-cause death (left) and sudden cardiac death (right).EF was reassessed <3 months after revascularization.F I G U R E 3 Ejection fraction (EF) ≤ 35% versus EF > 35% for risk of all-cause death (left) and sudden cardiac death (right).EF was reassessed within 3-12 months after revascularization.EF changed over time after revascularization in patients with LV dysfunction.When EF was reassessed early (<3 months) after revascularization, EF of 35% or less did not discriminate against the risk of SCD and had no influence in the mode of death as it did when EF was reassessed later (3-12 months).Our data suggested that 3-12 months after revascularization may be more appropriate for cardiac function reassessment than the usual reassessment at <3 months.A prospective study should be performed to determine what is the optimal time of EF reassessment to optimize ICD utilization.
T A B L E 1 Baseline characteristics.