RESULTS
The main clinical characteristics, R2I2 and PERS values, for the 50 study and 29 control subjects are summarised in Table 1. Controls had higher LVEF than study patients. R2I2 was significantly higher in study than in control patients both as a continuous and binary variable (0.99±0.05 vs. 0.63±0.04, <0.001). PERS showed a non-significant trend to higher values in the study group, particularly when used as a continuous variable (1.18[0.63] vs. 1.09[0.54], p=0.07). Moderate positive correlation was seen between R2I2 and PERS in controls (Figure 2; r=0.71, p<0.01). No correlation was seen between R2I2 and PERS in study patients (r=0.20, p=0.17).
Median follow up in the study group was 5.6 years [IQR 1.9 years] during which 9 patients reached the endpoint of VA/death: 6 VA and 5 deaths (2 patients had successful ICD therapy for VA and subsequently died). ICDs were implanted in 16/50 study patients. Three endpoints occurred in the 34 study group patients who did not have ICDs, 1 patient survived a VF arrest and 2 died. Characteristics of the study patients partitioned on the basis of the primary endpoint of VA/death are shown in Table 2. Patients who experienced VA/death showed non-significant trends to higher mean R2I2 (1.14±0.07 vs. 0.95±0.05, p=0.12) and PERS (1.46[0.49] vs. 1.13[0.62], p=0.22) than those that did not. Combined R2I2+PERS was a significant predictor of the primary endpoint (p=0.01). Comparison of primary endpoint prediction in patients positive for both R2I2 and PERS with patients negative for both R2I2 and PERS gave sensitivity 100%, specificity 74%, positive predictive value 40% and negative predictive value 100%.
Kaplan-Meier survival curves were constructed using the pre-defined R2I2 value of 1.03, the predefined PERS value of 1.21 and combined R2I2+PERS to partition patients into high and low risk groups as shown in Figure 3.11 Individually a trend to higher rates of VA/death was seen in patients positive for R2I2≥1.03 (p=0.08) and PERS≥1.21 (p=0.06) compared to negative patients. In combination, patients positive for either/both R2I2≥1.03+PERS≥1.21 had significantly higher rates of VA/death than negative patients (7% annual incidence vs. 0% annual incidence, p<0.05). A receiver operating characteristic analysis found that R2I2 significantly discriminated between those experiencing VA/death and those not during follow up (area under curve of 0.70, Figure 4). Further receiver operating characteristic analysis of PERS found a trend to discrimination of patients experiencing VA/death from those without (area under curve of 0.61) and no significant additional benefit from combination of R2I2 and PERS (area under curve of 0.71).
Cox proportional hazards analysis found trends to higher rates of VA/death in patients with R2I2≥1.03 (hazard ratio 3.3, p=0.09) and PERS≥1.21 (hazard ratio 4.0, p=0.08) compared to those with negative values. In a Cox proportional hazards model combined R2I2+PERS significantly predicted VA/death (p=0.02) with a hazard ratio per positive component (i.e. R2I2 positive / PERS positive) of 3.2 (95% confidence interval 1.2 to 8.8). Aetiology other than DCM compared with DCM was also associated with VA/death (hazard ratio 4.5, p=0.04). In multivariate analysis using a Cox proportional hazards model of combined R2I2+PERS and aetiology, only R2I2+PERS remained independently predictive of VA/death (hazard ratio 2.7, p=0.04).
Characteristics of the study patients partitioned on the basis of the aetiology are shown in Table 3. There were significant differences in in age, left ventricular ejection fraction and medications usage between the cohort of patients with dilated cardiomyopathy compared with those with other diagnoses. R2I2 was higher in DCM patients versus controls (1.00±0.06 vs. 0.63± 0.04, p<0.001) and ‘other conditions’ versus controls (0.96±0.08 vs. 0.63±0.04, p<0.001). PERS showed a trend to higher values in DCM patients versus controls (1.25±0.10 vs. 1.06±0.09, p=0.18) and in ‘other conditions’ versus controls (1.36±0.14 vs. 1.06±0.09, p=0.07). Study aetiology subgroup analysis of VA/death showed non-significant trends to higher R2I2/PERS values in patients reaching the endpoint of VA/death compared with those not. A preponderance of endpoints occurred in the ‘other conditions’ subgroup (6/17 patients) compared to the dilated cardiomyopathy subgroup (3/33 patients, p=0.05).