Results
Out of 14 656 patients with AS undergoing transthoracic echocardiography, 9558 were excluded for AVA >1 cm, 2231 excluded for reduced EF, 1156 excluded for concomitant moderate valvular lesions and 1299 excluded for mean gradient ≥40 mm Hg. Of 405 patients with LG severe AS and preserved EF, 90 (22%) had SVI <38 mL/m, 105 (26%) had SVI 38–43 mL/m, 104 (26%) had SVI 43–48 mL/m and 106 (26%) had SVI ≥48 mL/m. There were 53 (13%) patients with SVI <35 mL/m. More patients in groups 1 (n=61, 68%) and 2 (n=72, 69%) were symptomatic at the time of initial presentation compared with groups 3 (n=46, 44%) and 4 (n=50, 47%), (p<0.001). Patients with BMI ≥30 kg/m were more often symptomatic compared with patients with BMI <30 kg/m (65% vs. 53%, p=0.03).
Age was similar among groups, and there was a higher prevalence of women in group 4 compared with the other groups (Table 1). Body size was smaller in group 4, with more obesity present in group 1. Hypertension was common in all groups, but most prevalent in group 3. Atrial fibrillation was more common in low SVI groups (1 and 2). There was no difference in the prevalence of other comorbidities between groups including coronary artery disease, chronic pulmonary disease, renal dysfunction, anaemia, heart failure and history of stroke. Diuretic and ACE inhibitor use was more common in groups 1 and 2 compared with other groups.
Resting heart rate was higher in groups with lower SVI, but there were no significant differences in blood pressure (Table 2). EF was consistently lower and relative wall thickness higher with decreasing SVI, but there were no differences in LV dimensions. Indexed AVA was consistently smaller in the low SVI groups. Peak aortic velocity and mean gradient were lower with decreasing SVI. There were no differences in LV outflow tract diameter, medial E/e' or estimated right ventricular systolic pressure between groups.
Outcomes
Mean follow-up duration was 2.55±1.87 years and 305 (75%) had >1 year of follow-up. During the follow-up period, AVR was performed in 42 patients in group 1, 48 patients in group 2, 45 patients in group 3 and 41 patients in group 4 (2-year estimates: 44%, 39%, 49% and 56%, p=0.17 for AVR among groups). Concomitant coronary artery bypass grafting was performed at the time of AVR in 19 (45%) patients in group 1, 22 (46%) in group 2, 20 (44%) in group 3 and 14 (34%) in group 4 (p=0.42). Death occurred in 34 patients in group 1, 31 patients in group 2, 17 patients in group 3 and 22 patients in group 4 (2-year estimates: 56%, 71%, 82% and 85%, p=0.002).
Examination of the residuals from the proportional hazards model showed that SVI as a continuous variable was linearly associated with the risk of death (HR 0.94, 95% CI 0.92 to 0.97, p<0.0001 for every 1 mL/m increase in SVI). Overall survival was lowest in group 1 (3-year estimate 54%), followed by group 2 (3-year estimate 70%), group 4 (3-year estimate 80%) and group 3 (3-year estimate 86%) (p=0.002). Compared with an age and sex-matched expected population, group 1 had the poorest survival (3-year estimate 54% vs. 84% expected, p<0.001), group 2 also had reduced survival (3-year estimate 70% vs. 81% expected, p=0.02), and groups 3 and 4 had survival similar to an age and sex-matched group (3-year estimate 86% vs. 80% expected, p=0.33; and 80% vs. 76%, p=0.48, respectively). Adjusted survival is shown in figure 1. To evaluate whether BMI influenced survival in the SVI <43 group, an interaction between BMI and SVI was tested and found to be non-significant (p=0.49). We also noted that the subgroup of patients with BMI <25 kg/m and SVI <43 (n=52) had significantly reduced survival compared with that of age and sex-matched controls (3-year estimate 44% vs. 76% expected, p<0.001).
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Figure 1.
Stroke volume index (SVI) quartiles and adjusted survival. Group 1 (SVI <38 mL/m) had the lowest survival (3-year estimate 49%), followed by group 2 (SVI 38–43 mL/m; 3-year estimate 70%), group 4 (SVI >48 mL/m; 3-year estimate 85%) and group 3 (SVI 43–48 mL/m; 3-year estimate 86%) (p<0.001). Groups 1 and 2 had reduced survival compared with expected (p<0.001). Survival estimates were computed at the mean of variables in the multivariable model: age (80 years), body mass index (28.3 kg/m) and right ventricular systolic pressure (39.3 mm Hg).
c-Statistics for SVI <35, SVI <38 and SVI <43 mL/m in predicting all-cause mortality were 0.56 (0.52 to 0.61), 0.58 (0.53 to 0.63) and 0.61 (0.56 to 0.66), respectively (Table 3). SVI as a continuous variable yielded a c-statistic value of 0.61 (0.55 to 0.67).
Groups 1 and 2 had the poorest survival with medical management (censored at AVR) compared with groups 3 and 4 (3-year estimate 46% and 67% vs. 78% and 73%, respectively, p=0.002) although referral rate for AVR was similar among groups (53%–62% underwent AVR, p=0.57). Thirty-day survival after AVR was excellent in all groups (98±2% in groups 1, 2 and 3, respectively, and 97±3% in group 4, p>0.99).
Univariable and multivariable analysis
Univariable age-adjusted predictors of mortality are shown in table 4. After multivariable analysis, age, BMI, right ventricular systolic pressure and SVI were independent predictors of all-cause mortality (Table 4). Using the cube formula-derived SVI, SVI remained predictive of all-cause mortality (HR 0.98 (0.96 to 0.99) p=0.03) and remained a significant predictor of outcome after multivariable analysis (HR 0.98 (0.96 to 0.99) p=0.02). For the secondary endpoint of mortality censored at AVR, multivariable analysis yielded the same independent predictors: age, BMI, right ventricular systolic pressure and SVI (Table 5). On comparing the new proposed multivariable model (age, BMI, SVI and RVSP) with a model composed of variables previously shown to be predictive of mortality in AS (age, heart rate, peak aortic velocity, EF and creatine), the c-statistic for the new model was 0.74 (0.68 to 0.79) while the 'traditional model' c-statistic was 0.63 (0.57 to 0.70) (difference in c-statistics: 0.096 (0.030 to 0.161), p=0.004).
SVI was inversely associated with mortality (HR 1.28 (1.11 to 1.46) per every 5 mL/m decrease in SVI). Annualised mortality rates according to SVI in 5 mL/m increments are shown in figure 2. Using different SVI cut off points, SVI <35 was associated with highest mortality (HR 2.36 (1.49 to 3.73) p<0.001), followed by SVI <38 (HR 2.09 (1.39 to 3.16) p<0.001) and SVI <43 (HR 2.05 (1.38 to 3.05), p<0.001).
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Figure 2.
Annualised mortality rate according to stroke volume index (SVI). Annualised mortality rate was progressively higher with lower SVI (p<0.001), with highest mortality seen in patients with SVI <35 mL/m.