Sudden cardiac death (SCD) constitutes about one-quarter of all coronary heart disease (CHD)-related major events and more than half of all CHD-related deaths. Ventricular arrhythmia is believed to be the most common direct cause (1). Coronary heart disease patients with left ventricular dysfunction have been shown to be at high risk for SCD, and in this population the implantable cardioverter-defibrillator (ICD) has been demonstrated to reduce mortality by 30% to 54% (2- 6) and the risk of SCD by 67% (7). The Coronary Artery Bypass Graft (CABG)-Patch trial, however, failed to show a benefit from ICD therapy in a similar population of high-risk cardiac patients who were undergoing CABG surgery (8). The lack of ICD benefit in this study may be related to the proximity of device implantation to the coronary revascularization (CR) procedure, compared with other primary prevention ICD trials (2- 5).

The present study was performed to evaluate the effect of elapsed time from CR on ICD benefit and the risk of SCD in high-risk CHD patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II.

The design and results of the MADIT-II study have been reported elsewhere (3). Briefly, 1,232 patients with documented prior myocardial infarction and a left ventricular ejection fraction of ≤30% were randomized to receive a prophylactic ICD or conventional medical therapy in a 3:2 ratio. Screened patients were excluded from enrollment if they had class IV congestive heart failure, CR within the previous three months, elapsed interval from most recent myocardial infarction of <1 month, or advanced medical comorbidity. After a mean follow-up of 20 months, the study was terminated by the Data Safety and Monitoring Board. Unadjusted mortality was 19.8% in the conventional therapy group and 14.2% in the ICD group, and the overall hazard ratio (HR) was 0.69 (95% confidence interval [CI] 0.51 to 0.93).

Nine hundred fifty-one patients who had CABG and/or percutaneous coronary intervention (PCI) before enrollment were included in the current analysis (time from last CR: mean 64.44 ± 58.22 months, median 48.89 months, interquartile range 82.50 months); 580 of the patients who had undergone CR were allocated to the ICD group, and 371 were allocated to the conventional therapy group. In 12 patients CR was performed three months or less before enrollment owing to authorized protocol deviations. Time-dependence of mortality and ICD benefit was examined by dividing times from most recent CR procedure to enrollment into an early post-CR period (6 months or less); an intermediate post-CR period (6 to 60 months); and a late post CR period (more than 60 months). Those time frames were chosen based upon current knowledge of the natural history of coronary artery disease progression after CR (9- 10). Accordingly, during the early period there is little progression in graft disease (9), and the process of restenosis after coronary stenting is usually complete, with little progression thereafter (10); during the intermediate period new stenoses develop in graft conduits and/or native vessels, but most (80%) of the post-CABG patients are free from angina (9); and during the late period there is accelerated graft stenosis and/or degeneration and progression of native coronary artery disease (9).

A modified Hinkle-Thaler system was used to classify deaths, as described previously (7).

Baseline characteristics of the patients within the post-CR subgroups were compared and contrasted using the chi-square test and Fisher exact test, as appropriate. Significant variables affecting outcome were incorporated into a Cox proportional-hazards regression model to determine covariate-adjusted hazard ratios for: 1) ICD benefit by time from CR; and 2) the mode of death by time from CR in conventionally treated patients. Kaplan-Meier estimates of all-cause mortality by treatment group, stratified according to time from CR, were estimated and graphically displayed according to the method of Kaplan and Meier, with comparison of cumulative events by the log-rank test. Analyses were performed with the use of SAS software (version 9.13, SAS Institute, Cary, North Carolina), and a two-sided probability value of <0.05 was used for declaring statistical significance.

Of the 951 patients who underwent CR, 130 patients had the procedure ≤6 months before enrollment in the study (early: mean ± SD 4 ± 1 months, median 4 months, interquartile range 3 to 5 months), 414 patients within 6 to 60 months (intermediate: mean ± SD 30 ± 16 months, median 27 months, interquartile range 15 to 44 months), and 404 patients >60 months (late: mean ± SD 119 ± 48 months, median 107 months, interquartile range 81 to 147 months). Seventy-four percent of the patients who underwent CR had CABG at any time in their past, 57% had PCI, and both procedures were performed in 31% of patients. Baseline characteristics of study patients in the post-CR subgroups are shown in (Table 1). Compared with the early and intermediate post-CR subgroups, the late post-CR subgroup had a higher proportion of older patients (≥65 years), a lower frequency of female patients, and a higher proportion of patients who had CABG as their last CR procedure before enrollment. The proportion of patients with diabetes mellitus, a low ejection fraction (<25%), and electrocardiographic abnormalities, including left bundle branch block and a QRS duration of >0.12 s, increased with increasing time after CR, whereas medical therapy with beta-blockers was administered less frequently with increasing time after CR. There were no significant differences between the conventional and ICD treatment groups with regard to baseline clinical characteristics within the post-CR subgroups (data not shown).

Among patients enrolled during the early post-CR period, the two-year Kaplan-Meier estimates of all-cause mortality in the ICD and conventional therapy groups were similar (Figure 1A); whereas among patients enrolled after the early post-CR period, all-cause mortality rates were lower in the ICD group than in the conventional therapy group ((Figure 1)B and Figure 1C).

In multivariate analysis (Table 2), ICD therapy was associated with an overall 30% reduction in the risk of all-cause mortality (p = 0.01). There was a significant 36% reduction in the risk of all-cause mortality among patients who had CR >6 months before enrollment, corresponding to a significant 45% and a marginally significant 33% reduction in the risk of all-cause mortality among patients enrolled during the intermediate and late post-CR periods, respectively. No survival benefit with ICD therapy was shown among patients in whom the device was implanted during the early post-CR period. The benefit of ICD therapy after the early post-CR period was consistent when narrower post-CR time intervals were analyzed (Figure 2).

Defibrillator therapy was associated with an overall significant 63% reduction in the risk of SCD (p < 0.001). When analyzed by elapsed time from CR, treatment with an ICD was associated with a significant reduction in the risk of SCD in each CR period >6 months before enrollment (7 to 60 months: 73% reduction; p = 0.004; >60 months: 60% reduction; p = 0.03; corresponding to a 66% reduction in the risk of SCD among patients enrolled during the overall >6 months post-CR period; p < 0.001). Defibrillator therapy did not reduce SCD risk in patients enrolled during the early post-CR period, and a trend to an interaction between the ≤6 months and >6 months post-CR periods was observed when the efficacy of ICD for reducing SCD risk was analyzed (p value for treatment-time interaction = 0.16). Kaplan-Meier estimates of the cumulative probability of SCD 1 and 2 years after enrollment demonstrated very low, and similar, SCD rates in the ICD and conventional therapy groups among patients in whom CR was performed ≤6 months before enrollment (Figure 3A). The rate of SCD was increased in patients in whom CR was performed after this time period in the two treatment groups; and one- and two-year rates of SCD were significantly lower in the ICD group than in the conventional therapy group in patients who enrolled in the intermediate (Figure 3B) and late (Figure 3C) post-CR periods.

Although subgroup analysis of CABG surgery or PCI was associated with too few events to carry out a separate Cox analysis, Kaplan-Meier estimates of the cumulative rate of all-cause mortality and SCD at two years among patients who had CABG as an isolated procedure, PCI as an isolated procedure, or multiple revascularization procedures before enrollment demonstrated consistent results. Each therapeutic modality was associated with similar survival rates in the ICD and conventional therapy groups among patients in whom the procedure was performed ≤6 months before enrollment and with improved survival in ICD-allocated patients in whom the procedure was performed >6 months before enrollment (Table 3).

Mortality rates in conventionally treated patients increased as a function of time from the most recent CR to enrollment (unadjusted all-cause mortality rates: 10%, 15%, and 25% in the respective early, intermediate, and late post-CR subgroups; p = 0.01). Cox regression analysis (Table 4) showed a significant increase in the risk of all-cause mortality and cardiac death with increasing time from CR (p for trend = 0.01 and 0.009, respectively). The increase in risk of cardiac death >6 months after CR was related mainly to a six-fold increase in the risk of SCD among patients enrolled during this time period as compared with patients enrolled ≤6 months after CR (p for trend = 0.07), whereas the risk of non-SCD was not significantly different among the three post-CR subgroups (p for trend = 0.56). Although the number of deaths was small, the proportion of sudden cardiac deaths to total deaths was 17% among patients enrolled during the early post-CR period and 60% among patients enrolled after this time period (p = 0.04) (Figure 4).

We have shown that in patients with ischemic left ventricular dysfunction, the benefit of ICD therapy after CR is time dependent. There was a significant 36% and 68% reduction in the risk of all-cause mortality and SCD, respectively, in patients who had undergone CR more than six months before enrollment, whereas no such benefit was demonstrated in patients enrolled within six months after CR. The change in ICD efficacy corresponded to a significant increase in the risk of cardiac death more than six months after CR in conventionally treated patients, attributed mainly to a six-fold increase in the risk of SCD, whereas no change in the risk of non-SCD was observed with increasing time after CR. Thus, the lack of ICD benefit when implanted early after CR may be related to the relatively low risk of arrhythmic mortality during this time period.

Myocardial ischemia has been suggested to be an important trigger for development of ventricular tachyarrhythmias (11). Therefore, CR may attenuate subsequent SCD risk. The Coronary Artery Surgery Study (12) and European Coronary Surgery Study (13) demonstrated reductions in SCD with surgical revascularization versus medical therapy in a population of patients with normal, or mildly reduced, left ventricular function. A subsequent analysis of the Studies of Left Ventricular Dysfunction trials (14) showed that in patients with an ejection fraction of ≤35%, prior CABG was independently associated with a significant 25% reduction in risk of death and a 46% reduction in risk of SCD. This study, however, did not analyze the effect of elapsed time from CR on mortality risk. We have shown, in a similar population of patients with left ventricular dysfunction, that risk reduction conferred by CR was confined mainly to the early (six months or less) post-CR period.

Our findings are consistent with those of the CABG-Patch trial, in which no evidence of improved survival was shown among patients with CHD, a depressed left ventricular ejection fraction, and an abnormal signal-averaged electrocardiogram in whom an ICD was implanted prophylactically at the time of CABG (8). Notably, the hazard ratio for ICD benefit in the CABG-Patch trial (1.07; p = 0.64) was very similar to that demonstrated among patients in whom the ICD was implanted during the early post-CR period in the MADIT-II study (1.19; p = 0.76). Further analysis of the CABG-Patch trial, revealed that most of the deaths (71%) in the study were nonarrhythmic in nature (15). In the current study, we have similarly shown that the mode of death among patients enrolled during the early post-CR period was dominated by nonarrhythmic mortality (83%), whereas after this early time period the proportion of deaths that were nonsudden in nature was reduced to 40%. Thus, it appears that both in MADIT-II study and the CABG-Patch trial, the lack of defibrillator benefit when implanted in proximity to a CR procedure, was related to the fact that most of deaths during this time period were nonarrhythmic in nature.

A previous analysis of the MADIT-II study (16) has demonstrated that a significant decrease in the risk of SCD with ICD therapy was apparent within one year after enrollment, whereas during this time period the rate of non-SCD was significantly higher in the ICD group than in the conventional therapy group, leading to an overall significant survival benefit with ICD therapy only after the first year of the trial. In the present study we have consistently shown that among patients enrolled more than six months after CR the rates of SCD were significantly lower in the ICD group than in the conventional therapy group within both one and two years after enrollment, leading to an overall survival benefit with ICD therapy at two years in patients who enrolled in the intermediate and late post-CR periods. In contrast, SCD rates in patients enrolled in the early post-CR period were similar in the two treatment arms throughout the study, leading to a neutral effect of ICD therapy on all-cause mortality at two years in this subgroup of patients.

Coronary revascularization was not a randomized event in the MADIT-II study; therefore, there were significant differences in the baseline characteristics among the post-CR subgroups. However, adjusting for those differences did not explain the differences in outcome among the post-CR subgroups.

Patients were excluded from enrollment in the MADIT-II study if their most recent CR procedure was performed within three months before enrollment (only 12 patients were included within this time period owing to authorized protocol deviations). Therefore, the current results do not include sufficient data on the immediate post-CR period in which an even lower risk of SCD may exist, corresponding to a further reduction in ICD benefit during this time period.

As compared with PCI, CABG provides a more complete revascularization of the coronary arteries. Therefore, the latter revascularization modality may afford better protection against arrhythmic mortality than the former. Data on the completeness of revascularization were not available in the current study. Thus, the effect of this important factor was not analyzed. The consistent trends among patients who underwent PCI as an isolated procedure suggest that recent revascularization, limited to the target vessel, may also reduce the risk of arrhythmic mortality.

We have shown that ICD therapy is associated with a significant survival benefit and reduction in SCD risk after CR. This life-saving benefit, however, is time dependent, and in the current analysis of the MADIT-II study, improved survival was apparent when the ICD was implanted more than six months after CR. Our findings suggest that the early post-CR period is dominated by nonarrhythmic mortality and may explain the lack of defibrillator benefit in the CABG-Patch trial. Further prospective studies are needed to delineate the optimal timing of device implantation after CR. At present, the relatively low risk of arrhythmic mortality during the early period after successful CR should be considered when planning ICD implantation for the primary prevention of SCD in CHD patients with advanced left ventricular dysfunction.