Retrospective studies have suggested a beneficial effect of lipid-lowering treatment on the progression of aortic stenosis (AS) in milder stages of the disease. In the randomized, placebo-controlled Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, 4.3 years of combined treatment with simvastatin 40 mg and ezetimibe 10 mg did not reduce aortic valve events (AVEs), while ischemic cardiovascular events (ICEs) were significantly reduced in the overall study population. However, the impact of baseline AS severity on treatment effect has not been reported. Baseline and outcomes data in 1,763 SEAS patients (mean age 67 years, 39% women) were used. The study population was divided into tertiles of baseline peak aortic jet velocity (tertile 1: ≤2.8 m/s; tertile 2: >2.8 to 3.3 m/s; tertile 3: >3.3 m/s). Treatment effect and interaction were tested in Cox regression analyses. The rates of AVEs and ICEs increased with increasing baseline severity of AS. In Cox regression analyses, higher baseline peak aortic jet velocity predicted higher rates of AVEs and ICEs in all tertiles (all p values <0.05) and in the total study population (p <0.001). Simvastatin-ezetimibe treatment was not associated with a statistically significant reduction in AVEs in any individual tertile. A significant quantitative interaction between the severity of AS and simvastatin-ezetimibe treatment effect was demonstrated for ICEs (p <0.05) but not for AVEs (p = 0.10). In conclusion, the SEAS study results demonstrate a strong relation between baseline the severity of AS and the rate of cardiovascular events but no significant effect of lipid-lowering treatment on AVEs, even in the group with the mildest AS.
Epidemiologic and experimental studies have identified hypercholesterolemia as a possible risk factor for aortic stenosis (AS) and demonstrated cellular mechanisms involved in disease progression suggesting that lipid-lowering treatment might prevent the progression of AS and associated cardiovascular morbidity and mortality. Although several retrospective or small case-control studies have found statin treatment to reduce AS progression, results from 3 prospective treatment trials—the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE), the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, and the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) study—have all been disappointing. Despite the consistent finding from these 3 prospective treatment trials, retrospective analyses continue to suggest that lipid-lowering therapy may be effective in patients with the mildest degrees of aortic valve calcification. To follow up on this hypothesis, the present post hoc analysis was performed to assess the impact of the baseline severity of AS on lipid-lowering treatment effect in the SEAS study.
Methods
The study design, baseline characteristics, and main outcome results of the SEAS study have previously been published. In short, 1,873 healthy men and women aged 45 to 85 years, with asymptomatic mild to moderate AS having a peak aortic jet velocity of 2.5 to 4.0 m/s by echocardiography, were randomized to placebo or to combination treatment with simvastatin 40 mg and ezetimibe 10 mg daily. Core laboratory–read peak aortic jet velocity was available from baseline echocardiograms in 1,763 patients, who constituted the present study population. All patients gave written informed consent, and the study was approved by ethics committees in all participating countries.
Echocardiograms were performed at baseline, annually, and before planned aortic valve surgery following a standardized protocol at 173 study centers in 7 European countries and forwarded for blinded interpretation at the SEAS echocardiography core laboratory at Haukeland University Hospital (Bergen, Norway), as previously published. The severity of AS and left ventricular dimension and function were measured following current guidelines.
Statistical analysis was performed using SPSS version 15.0 (SPSS, Inc., Chicago, Illinois). Data are expressed as mean ± SD for continuous variables and as percentages for categorical variables. The study population was divided in tertiles of baseline peak aortic jet velocity (tertile 1: ≤2.8 m/s; tertile 2: >2.8 to 3.3 m/s; tertile 3: >3.3 m/s). Analysis of variance with post hoc tests and chi-square tests were used to compare variables among tertile groups. Predictors of the prespecified secondary composite end points of aortic valve events (AVEs; cardiovascular death, aortic valve replacement, and congestive heart failure because of progression of AS) and ischemic cardiovascular events (ICEs; cardiovascular death, nonfatal myocardial infarction, hospitalized unstable angina, coronary artery bypass surgery, percutaneous coronary intervention, and nonhemorrhagic stroke) in individual tertiles were identified by Cox regression analysis and presented as hazard ratios and 95% confidence intervals. The second model assessed treatment effect as a function of baseline AS severity as a continuous variable. A p value <0.05 was regarded as statistically significant.
Results
Clinical and biochemical characteristics did not differ among tertiles ( Table 1 ), nor did the use of concomitant medications. Despite the protocol requirement of recording aortic jet velocity from multiple windows, this was provided in only 40% of patients. Thus, baseline AS severity was based mainly on apical aortic jet velocity recordings. Higher baseline AS severity was associated with a higher prevalence of left ventricular hypertrophy ( Table 2 ).
| Variable | Tertile 1 | Tertile 2 | Tertile 3 |
|---|---|---|---|
| (n = 588) | (n = 597) | (n = 578) | |
| Age (years) | 67 ± 9 | 68 ± 10 | 67 ± 10 |
| Women | 40% | 38% | 37% |
| Systolic blood pressure (mm Hg) | 145 ± 20 | 145 ± 20 | 145 ± 21 |
| Diastolic blood pressure (mm Hg) | 82 ± 10 | 82 ± 10 | 82 ± 10 |
| Heart rate (beats/min) | 68 ± 10 | 68 ± 11 | 68 ± 10 |
| Height (cm) | 170 ± 9 | 171 ± 9 | 171 ± 9 |
| Weight (kg) | 78.2 ± 14.0 | 78.0 ± 14.8 | 79.0 ± 14.9 |
| Body surface area (m 2 ) | 1.89 ± 0.19 | 1.90 ± 0.20 | 1.91 ± 0.20 |
| History of hypertension | 54% | 52% | 49% |
| Smoking | 17% | 20% | 21% |
| Fasting glucose (mmol/L) | 5.3 ± 0.8 | 5.3 ± 0.8 | 5.3 ± 0.9 |
| Creatinine (μmol/L) | 94 ± 16 | 93 ± 15 | 94 ± 16 |
| Estimated GFR (ml/min/1.73 m 2 ) | 72 ± 21 | 72 ± 21 | 73 ± 23 |
| Total cholesterol (mmol/L [mg/dl]) | 5.8 ± 1.0 (222 ± 40) | 5.7 ± 1.0 (221 ± 38) | 5.7 ± 1.0 (219 ± 39) |
| LDL cholesterol (mmol/L [mg/dl]) | 3.6 ± 0.9 (138 ± 35) | 3.6 ± 0.9 (138 ± 34) | 3.5 ± 0.9 (137 ± 36) |
| HDL cholesterol (mmol/L [mg/dl]) | 1.5 ± 0.4 (58 ± 16) | 1.5 ± 0.5 (59 ± 18) | 1.5 ± 0.4 (58 ± 16) |
| Triglycerides (mmol/L [mg/dl]) | 1.5 ± 0.7 (130 ± 61) | 1.4 ± 0.7 (125 ± 64) | 1.4 ± 0.7 (121 ± 59) |
| Variable | Tertile 1 (n = 588) | Tertile 2 (n = 597) | Tertile 3 (n = 578) | |||
|---|---|---|---|---|---|---|
| Baseline | Study End | Baseline | Study End | Baseline | Study End | |
| LV end-diastolic diameter (cm) | 5.03 ± 0.65 | 4.69 ± 0.66 | 5.03 ± 0.62 | 4.70 ± 0.65 | 5.05 ± 0.62 | 4.82 ± 0.68 ⁎ , ‡ |
| LV end-systolic diameter (cm) | 3.20 ± 0.58 | 3.02 ± 0.57 | 3.20 ± 0.57 | 3.03 ± 0.61 | 3.18 ± 0.53 | 3.15 ± 0.62 ⁎ , ‡ |
| Interventricular septal thickness (cm) | 1.12 ± 0.27 | 1.31 ± 0.28 | 1.14 ± 0.27 | 1.38 ± 0.28 | 1.21 ± 0.29 ⁎ , ‡ | 1.44 ± 0.30 § |
| Posterior wall thickness (cm) | 0.86 ± 0.18 | 1.03 ± 0.19 | 0.88 ± 0.18 | 1.08 ± 0.21 | 0.92 ± 0.19 ⁎ , ‡ | 1.12 ± 0.21 § |
| LV ejection fraction (%) | 66 ± 7 | 65 ± 6 | 66 ± 7 | 65 ± 7 | 67 ± 6 | 64 ± 7 ⁎ , † |
| LV mass (g) | 186 ± 66 | 209 ± 71 | 191 ± 65 | 223 ± 72 | 206 ± 71 ⁎ , ‡ | 247 ± 77 § |
| LV hypertrophy | 26% | 44% | 31% | 51% | 40% § | 71% § |
| Peak transaortic jet velocity (m/s) | 2.51 ± 0.21 | 3.09 ± 0.58 | 3.06 ± 0.16 | 3.72 ± 0.64 | 3.72 ± 0.29 | 4.21 ± 0.64 |
| Peak transaortic gradient (mm Hg) | 25 ± 4 | 40 ± 15 | 38 ± 4 | 57 ± 20 | 56 ± 9 | 73 ± 22 |
| Mean transaortic gradient (mm Hg) | 14 ± 3 | 22 ± 10 | 22 ± 3 | 33 ± 13 | 33 ± 6 | 43 ± 13 |
| Aortic valve area (cm 2 ) | 1.53 ± 0.52 | 1.38 ± 0.50 | 1.24 ± 0.40 | 1.10 ± 0.41 | 1.07 ± 0.36 ⁎ , ‡ | 0.98 ± 0.39 ⁎ , ‡ |
| Aortic valve area index (cm 2 /m 2 ) | 0.81 ± 0.25 | 0.73 ± 0.25 | 0.65 ± 0.20 | 0.58 ± 0.20 | 0.56 ± 0.18 ⁎ , ‡ | 0.52 ± 0.19 ⁎ , ‡ |
| Aortic regurgitation | 55.3% | 64.4% | 63.8% ⁎ | 68.1% | 63.1% ⁎ | 71.9% ⁎ |
During the 4.3-year median study duration, annualized progression of AS was 0.16 ± 0.28 m/s/year in the lowest tertile, 0.19 ± 0.18 m/s/year in the middle tertile, and 0.19 ± 0.27 m/s/year in the highest tertile (p = 0.113). The incidence of AVEs (particularly aortic valve replacement and congestive heart failure due to AS progression) and ICEs increased with higher baseline aortic jet velocity ( Figure 1 , Table 3 ). The principal component of AVEs was aortic valve replacement (86%). Higher baseline severity of AS predicted higher rates of AVEs and ICEs in each tertile in Cox regression analyses ( Table 4 ). Simvastatin-ezetimibe treatment was not associated with a statistically significant reduction in AVEs in any individual tertile in Cox regression analyses including baseline aortic jet velocity and randomized study treatment as covariates ( Table 4 ). In the total study population, quantitative interactions between the severity of AS and simvastatin-ezetimibe treatment effect were demonstrated for ICEs (p <0.05) but not significantly for AVEs (p = 0.10) ( Figure 2 ).
| Variable | Tertile 1 (n = 588) | Tertile 2 (n = 587) | Tertile 3 (n = 578) | |||
|---|---|---|---|---|---|---|
| AVEs | ICEs | AVEs | ICEs | AVEs | ICEs | |
| Simvastatin-ezetimibe treatment group | 13% | 9% | 27% | 12% | 56% | 26% |
| Placebo group | 16% | 17% | 32% | 17% | 56% | 24% |
| p value | 0.348 | 0.005 | 0.249 | 0.073 | 0.633 | 0.601 |
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