Methods

From 1999 to 2005, all 1,787 patients successfully implanted with biventricular pacing devices for CRT or CRT-D (Medtronic Inc., Minneapolis, Minnesota) were prospectively included in the InSync/InSync ICD Italian Registry. The registry enrolled patients with advanced symptomatic CHF, left ventricular ejection fraction (LVEF) ≤35%, and wide QRS complexe (≥130 ms). According to protocol, CRT or CRT-D should have been added to optimal medical therapy as recommended by the current guidelines for the diagnosis and treatment of CHF. The protocol of the InSync/InSync ICD Italian Registry, which complies with the Declaration of Helsinki, had been previously approved by the ethics committees of each participating center. At the time of enrollment, all patients gave their written informed consent to participate to the study. For each patient, demographic, history, and clinical variables were collected at baseline, before device implantation. The presence of chronic obstructive pulmonary disease, diabetes, hypertension, and renal failure was ascertained according to current guidelines. The stage of CHF was assessed according to New York Heart Association functional classification. Moreover, the number of hospitalizations due to CHF in the preceding 12 months was reported in the database. According to the design of the present study, we introduced only 2 variables to the original data set, the first associated with the presence of >2 co-morbid conditions in the same subject and the second for the age stratification of the population, which was consequently divided into 3 groups: <65, 65 to 74, and ≥75 years.

The echocardiographic evaluation of a patient was performed as previously reported. At all centers, all examinations of a subject were always made by the same physician, who had a specific competence in assessing the effects of CRT. Interventricular mechanical delay (the time interval between the onset of anterograde blood flow in the right and in the left ventricular outflow tracts) was used as the indicator of interventricular dyssynchrony. Optimization of CRT was recommended through echocardiography-guided programming of atrioventricular delay.

All patients underwent standard clinical visits at 1, 3, and 6 months and every 6 months thereafter; the study charts were always compiled by the physicians operating at the electrophysiology center. By protocol, a complete clinical and instrumental reassessment was performed at least 6 and 12 months after the implantation of the device. At 17 and 33 months, entire evaluations were available for 836 (47%) and 296 (17%) subjects of the original cohort. Patients showing reductions of left ventricular end-systolic volume >10% at the 6-month follow-up visit were defined as responders to CRT. For the purposes of this study, we reported only the results of the 6- and 12-month clinical and instrumental evaluations of patients. However, mortality data are related to the entire length of follow-up.

Statistical analysis was performed using SPSS for Windows version 18.0 (SPSS Inc., Chicago, Illinois). All analyses were carried out in the statistical laboratory of Medtronic Italy (Milan, Italy) on proposal of the chief investigators of the study. Continuous variables are expressed as mean ± SD. Categorical variables are expressed as percentages. Comparisons between groups of patients were performed using analysis of variance or chi-square tests for continuous or categorical variables, respectively. Changes in clinical and instrumental parameters during follow-up were evaluated using analysis of variance for repeated measures. Post hoc tests were applied to assess the existence of significant differences between each point of the follow-up and the baseline value.

All-cause mortality was studied using Kaplan-Meier curves and Cox regression analysis in univariate models. All significant clinical predictors were further introduced in a Cox multivariate regression model. In case of colinearity, only the variable that was more tightly associated with mortality was used. The results are reported also as hazard ratios with their related 95% confidence intervals. Assessing the influence of age on survival, the reference level (hazard ratio 1) was attributed to the group aged <65 years. For all analyses, a 2-tailed p value <0.05 was considered to indicate statistical significance.

Results

From 1999 to 2005, as previously mentioned, 1,787 consecutive subjects were enrolled in the InSync/InSync ICD Italian Registry. The oldest patients represented 27% (n = 476) of the entire cohort; the percentage of women significantly increased with age ( Table 1 ). Coronary artery disease, hypertension, and the coexistence of ≥3 co-morbid conditions were most represented in the 2 oldest groups. Baseline left ventricular diameters and volumes significantly decreased in an age-related fashion, while interventricular mechanical delay did not differ at all ( Table 1 ). The prevalence of atrial fibrillation (AF) was significantly higher in patients aged ≥65 years. The use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and of β blockers significantly decreased with age ( Table 1 ). CRT-D was progressively less often adopted with advancing age (<65 years, 48%; 65 to 74 years, 43%; ≥75 years, 29%; p <0.001).

CRT produced significant and similar left ventricular reverse remodeling in the 3 age groups ( Table 2 ), which showed the same prevalence of responders (<65 years, 58%; 65 to 74 years, 60%; ≥75 years, 62%; p = 0.419). CRT significantly improved functional capacity independent of age ( Figure 1 ).

CRT-induced changes in New York Heart Association (NYHA) class between baseline and the 12-month evaluation, by age group.

After 12 months, the proportion of patients with ≥1 readmission for CHF was not statistically different among the 3 groups (<65 years, 10%; 65 to 74 years, 12%; ≥75 years, 13%; p = 0.509).

At the end of the follow-up period (mean 19 ± 13 months), all-cause mortality was 10% (n = 60), 12% (n = 86), and 14% (n = 65) in patients aged <65, 65 to 74, and ≥75 years, respectively. Kaplan-Meier analysis revealed a lower survival rate in the oldest group compared to the youngest group ( Figure 2 ). Among patients with known causes of mortality (n = 177/211 [84%]), no age-related differences in sudden (<65 years, 2.3%; 65 to 74 years, 2.3%; ≥75 years, 2.1%; p = 0.870) and nonsudden cardiac death (<65 years, 5.3%; 65 to 74 years, 4.7%; ≥75 years, 5.9%; p = 0.378) were observed, while the proportion of noncardiac death was highest in the oldest group (<65 years, 1.1%; 65 to 74 years, 3.0%; ≥75 years, 3.4%; p = 0.006). The complete results of univariate survival analysis are listed in Table 3 . The responder condition to CRT was associated with longer survival in the whole series of patients and in each age group when independently studied (survival hazard ratio for nonresponder vs responder condition: <65 years, 0.46, p = 0.003; 65 to 74 years, 0.34, p <0.001; ≥75 years, 0.38, p <0.001; Figure 3 ). The use of CRT-D was not associated with a significant reduction in mortality.

Kaplan-Meier analysis of overall survival in the InSync population by age group. Only the comparison between the trends observed in patients aged ≥75 and <65 years showed a statistically significant difference.

Table 3

Results of univariate Cox regression analyses exploring the association between clinical and instrumental variables and all-cause follow-up mortality in the entire InSync/InSync ICD Italian Registry population

Variable	HR	95% CI	p Value
Age group (years)
<65	1
65–74	0.99	0.76–1.31	0.976
≥75	1.47	1.10–1.98	0.010
Men vs women	1.67	1.12–2.49	0.012
Chronic obstructive pulmonary disease (+ vs −)	1.53	0.90–2.60	0.113
Diabetes mellitus (+ vs −)	0.93	0.55–1.57	0.775
Hypertension (+ vs −)	1.14	0.80–1.62	0.483
Renal failure (+ vs −)	1.94	1.24–3.05	0.004
≥3 co-morbidities (+ vs −)	1.75	1.13–2.73	0.013
Coronary artery disease (+ vs −)	1.34	1.02–1.76	0.033
LV end-diastolic diameter (mm)	1.01	0.99–1.02	0.592
LV end-systolic diameter (mm)	1.01	0.98–1.02	0.887
LVEF (%)	0.98	0.96–0.99	0.025
QRS length (ms)	1.00	0.99–1.01	0.605
New York Heart Association class	1.07	0.84–1.36	0.596
Permanent atrial fibrillation (+ vs −)	1.62	1.18–2.22	0.003
Atrioventricular node ablation (+ vs −)	0.96	0.57–1.63	0.890
Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (+ vs −)	0.64	0.48–0.85	0.002
β blockers (+ vs −)	0.46	0.35–0.62	<0.001
CRT responder (+ vs −)	0.40	0.30–0.52	<0.001
CRT-D (+ vs −)	0.94	0.70–1.25	0.664

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