We reported baseline demographics and clinical data of the 2136 patients in STICH (3, 11, 23). Baseline echocardiography was performed within 90 days of randomization and prior to initiating study treatment in 2009 (94% of 2136) patients, of which 498 (24.7% of 2009) were excluded due to technically inadequate E/A ratio measurement or absent A wave due to atrial fibrillation, the remaining 1511 patients comprised our cohort. The primary outcome was the rate of death from any cause. There were 604 deaths over a median follow-up of 56 months. Median age was 60 years (25th percentile; 54, 75th percentile; 68) and 84.6% were male. The median E/A ratio was 1.0 (25th percentile; 0.67, 75th percentile; 1.67) with no difference between the H1 and H2 populations with respect to the distribution of this variable (3). At least moderate MR (≥grade 2) was present in 24.1% (344 of 1426 patients in whom MR was characterized) in the cohort, at least moderate MR was also present in 29.4% (p = 0.033 between groups) in the 498 patients excluded due to absent E/A ratio (118 of 402)
Median values for the eleven echocardiographic variables are shown (Table 1). By study design, E/A ratio was the most complete dataset, whereas E/e’ ratio had the most missing values.
Univariable modeling of prognostic variables with the original dataset
Each of the eleven variables, when considered without imputation, was associated with all- cause mortality. LVESVI had a strong relationship with mortality (χ2 = 57.5, p<0.001) even with a large number of missing values (350 patients), as did EF (χ2 = 43.5, p <0.001) and E/A ratio (χ2 =41.1, p <0.001). However, due to the degree and variation of missing data, a meaningful comparison of the strength of the relationship of each variable to mortality required the use of imputation.
Mortality increased with increasing LVESVI and decreasing EF in a non-linear fashion. For example, mortality was lowest for LVESVI <65 cc/m2 with minimal increase in risk up to a LVESVI of 65 cc/m2. Beyond this, mortality increased linearly with increasing LVESVI. Similarly, there was modest effect on mortality with decreasing EF down to 30%. For EF ≤30%, mortality increased in a linear fashion as EF decreased.
E/A ratio had a u-shaped relationship with mortality (Figure 1). Mortality was higher for small (E/A <0.6) and large (>1.0) values than intermediate (0.6-1.0) values, and was lowest for E/A ≈ 0.8. However, the higher mortality for E/A <0.6 was not significantly different from mortality with E/A 0.6-1.0 (HR 1.16, 95% CI 0.88-1.53, p=0.28). In contrast, mortality was highest for large E/A ratios (>1.0 up to approximately 2.3, beyond which there was no further increase in risk) compared to E/A <0.6 (HR 1.35, 95% CI 1.04-1.75, p= 0.02) and E/A 0.6-1.0 (HR 1.58, 95% CI 1.30-1.92, p<0.001).
Of the 1511 patients, 273 had E/A ratio ≤0.6, 1010 had E/A >0.6-2.3 (n= 622 with E/A 0.6-1.0), and 228 had E/A > 2.3. Differences in baseline characteristics for each E/A group are shown (Table 2). The E/A ratio > 2.3 group had worse renal function, lower EF, larger LVESVI, more spherical LV, worse RV function, lower systolic blood pressure, higher heart rate and RAR mortality index compared to the other groups. The E/A ≤0.6 and E/A >0.6-2.3 groups were similar, except that those with E/A ≤0.6 were older, and more often female. Cardiac index was similar across the three groups.
Univariable modeling of prognostic variables with imputed datasets
Univariable modeling using the combined 25 imputed datasets are shown (Table 3). LVEDVI was excluded due to its high correlation with LVESVI (r=0.96). E/A ratio was a significant predictor of all-cause mortality (χ2 41.1, p <0.001). Only LVEF (χ2 43.1, p <0.001; HR 0.94, 95% CI 0.93-0.96) and LVESVI (χ2 41.1, p <0.001; HR 1.11, 95% CI 1.07- 1.14) were more significant predictors of mortality than E/A ratio.
Multivariable modeling of prognostic variables with imputed datasets
Multivariable models in which each echocardiographic variable was considered together with the eight clinical variables are shown in Table 4. Each echocardiographic variable provided incremental prognostic value to the combined set of eight clinical variables. E/A ratio was the third most significant echo variable (χ2 =29.1, p<0.001), following LVESVI (χ2=44.3, p<0.001) and LVEF (χ2 =31.9, p<0.001).
The combined clinical and echocardiographic multivariable mortality model is shown in table 5. Creatinine (χ2 =30.0, p <0.001; HR 3.21 95% CI 2.11-4.86), LVESVI (χ2 =27.3, p<0.001; HR 1.09 95% CI 1.06- 1.13), age, and E/A ratio (χ2 =12.4, p<0.001) combined accounted for 74% of the prognostic information for predicting risk. Increasing E/A ratio (χ2 = 12.4, p<0.001) was the 5th most important variable after age and treatment strategy (MED vs CABG or CABG +SVR).
Interaction with Treatment Strategy
Hypothesis 1 (MED vs. CABG)
Of the 1511 patients included in this analysis, 845 were enrolled in H1 (60 were enrolled in both H1 and H2) (9, 23). Only E/A ratio had a significant treatment interaction (p= 0.033). While the medical treatment arm displayed a u-shaped relationship with mortality (Figure 2A), in the CABG arm, mortality increased in a more linear fashion as E/A increased. Compared to the medical arm, mortality was lower for CABG with smaller E/A ratio ≤ 0.6 (HR 0.64 95% CI 0.36, 1.14, p= 0.13) and higher E/A ratio >1.4 (HR 0.78, 95% CI 0.54, 1.12, p= 0.17), although this difference was not statistically significant. Mortality risk was similar for CABG and medical therapy when E/A ratio approached 0.8 (HR 1.05, 95% CI 0.75, 1.47, p= 0.79).
Hypothesis 2 (CABG vs. CABG +SVR)
The remaining 726 patients in our study cohort had sufficient anterior and apical dyskinesia to be eligible for SVR and were enrolled in H2 (9, 11). In H2, only RV dysfunction (p= 0.038) had a significant treatment interaction. With normal RV function (680 patients), there was no difference in mortality with CABG versus CABG +SVR. With mild RV dysfunction (100 patients), there was a trend towards increased mortality with CABG+SVR versus CABG alone (HR 1.47 95% CI 0.71-3.04, p = 0.301). However, with moderate or severe RV dysfunction (76 patients), mortality was significantly higher with CABG +SVR compared to CABG alone (HR 3.05 95% CI 1.29-7.22, p= 0.008). LVESVI, EF, MR severity, and E/A ratio did not have a significant treatment interaction in H2. E/A ratio exhibited a u-shaped relationship with mortality for CABG and CABG + SVR without any significant difference in mortality between the two groups (Figure 2B).