Recent trials have failed to show that statin therapy halts the progression of calcific aortic stenosis (AS). We hypothesized that statin therapy in younger patients with congenital AS would be more beneficial, because the valve is less calcified. In the present double-blind, placebo-controlled trial, 63 patients with congenital AS (age 18 to 45 years) were randomly assigned to receive either 10 mg of rosuvastatin daily (n = 30) or matched placebo (n = 33). The primary end point was the progression of peak aortic valve velocity. The secondary end points were temporal changes in the left ventricular mass, ascending aortic diameter, and N-terminal pro-brain natriuretic peptide (NT-proBNP). The median follow-up was 2.4 years (interquartile range 1.9 to 3.0). The mean increase in peak velocity was 0.05 ± 0.21 m/s annually in the rosuvastatin group and 0.09 ± 0.24 m/s annually in the placebo group (p = 0.435). The annualized change in the ascending aorta diameter (0.4 ± 1.7 mm with rosuvastatin vs 0.5 ± 1.6 mm with placebo; p = 0.826) and left ventricular mass (1.1 ± 15.8 g with rosuvastatin vs −3.7 ± 30.9 g with placebo; p = 0.476) were not significantly different between the 2 groups. Within the statin group, the NT-proBNP level was 50 pg/ml (range 19 to 98) at baseline and 21 pg/ml (interquartile range 12 to 65) at follow-up (p = 0.638). NT-proBNP increased from 40 pg/ml (interquartile range 20 to 92) to 56 pg/ml (range 26 to 130) within the placebo group (p = 0.008). In conclusion, lipid-lowering therapy with rosuvastatin 10 mg did not reduce the progression of congenital AS in asymptomatic young adult patients. Interestingly, statins halted the increase in NT-proBNP, suggesting a potential positive effect of statins on cardiac function in young patients with congenital AS.
The Progression of Stenosis in Adult Patients With Congenital Aortic Stenosis (PROCAS) trial was designed to study the effect of long-term lipid-lowering therapy with daily use of rosuvastatin on the echocardiographic and neurohumoral outcomes in asymptomatic young adult patients with congenital aortic stenosis (AS). We hypothesized that statins prevent calcifications and halt the progression of congenital AS.
Methods
The PROCAS study was a prospective, double-blind, randomized, placebo-controlled, multicenter trial that evaluated the effect of rosuvastatin on the progression of asymptomatic congenital AS in young adult patients. The study was conducted at 6 tertiary referral centers for congenital heart disease in The Netherlands and Belgium. Enrollment occurred from December 2005 to December 2007. The intended follow-up duration was 3 years. Annually, patients underwent transthoracic echocardiography, laboratory testing, and electrocardiography. After the baseline assessment and randomization, the patients were scheduled for telephone interviews every 3 months to assess potential side effects and to emphasize the importance of compliance. For patients undergoing aortic valve replacement (AVR) during the study period, the findings from the last transthoracic echocardiogram, laboratory tests, and electrocardiogram before AVR were used in the present analysis. The medical ethics committee of each participating center approved the PROCAS study, and all patients gave written informed consent. The clinical trial registration number was ISRCTN56552248 (available at: www.controlled-trials.com/ ).
Eligible patients were selected from the CONgenital CORvitia (CONCOR) database, the Dutch registry for adult patients with congenital heart disease, and from the Leuven local congenital heart disease database. We included men and women 18 to 45 years old with native valvular congenital AS, with a peak aortic valve velocity >2.5 m/s. The patients who already used statins or had contraindications for the use of statins, such as known muscle disease, active liver disease, creatine kinase >600 U/L, or severe kidney dysfunction (creatinine >200 μmol/L) were excluded. Other exclusion criteria were previous AVR, a history of acute rheumatic fever, mitral valve stenosis or regurgitation, and severe aortic regurgitation. For young women, the wish to become pregnant within the next 5 years was also a contraindication. Eligible patients were randomized in a 1:1 fashion in blocks of 4 to receive either rosuvastatin 10 mg daily or a matching placebo. The randomization schedule was centralized and generated by a computer program at the Erasmus Medical University Center pharmacology department, which had no access to the rest of the data. When a center was ready to randomize a patient, the pharmacology department sent a randomization number to the site coordinator and the study medication to the patient. The patients, treating physicians, and investigators were all unaware of the treatment assignment.
Annually, a complete Doppler transthoracic echocardiogram was performed by trained echocardiographers. Randomly selected studies were reviewed to ensure that the studies and measurements were performed in accordance with the protocol. The recommended parameters for the clinical evaluation of AS severity are the peak velocity, mean gradient, and aortic valve area. We used the peak aortic velocity as the primary end point, because it is the most reproducible measurement of the severity of AS and left ventricular (LV) function was normal in all patients. The ascending aorta diameter was measured at 4 levels: the annulus, sinus of Valsalva, sinotubular junction, and proximal ascending aorta. We considered the aorta dilated if the value was 2 standard deviations greater than the normal value, according to gender, in the guidelines. The LV mass was calculated using the Devereux-modified formula. LV hypertrophy was defined by a body surface area-indexed threshold of >134 g/m 2 for men and >110 g/m 2 for women. We defined the aortic valve as calcified if thickening was present combined with increased echogenicity of the leaflets in the parasternal long- or short-axis views. Annual laboratory tests included high-sensitivity C-reactive protein, N-terminal pro-brain natriuretic peptide (NT-proBNP), lipid profile, creatine kinase, and creatinine. After a patient had rested for 30 minutes, venous blood samples were collected and stored at −80°C until the end of the study. Kits to determine the NT-proBNP levels were offered by Roche Diagnostics (Basel, Switzerland), with a cutoff value for elevation of 125 pg/ml. Creatine kinase was considered elevated at >200 U/L in men and 170 U/L in women.
For the statistical analyses, the Statistical Package for Social Sciences, version 15.0 (SPSS, Chicago, Illinois) and R (version 2.11.1, available at: www.r-project.org ) were used. All statistical tests were 2-sided; p <0.05 was considered statistically significant. The primary end point was the annual peak aortic valve velocity progression. The secondary end points were progression of the LV mass, ascending aorta diameter, and NT-proBNP. The data were analyzed according to an intention-to-treat analysis. To account for different follow-up durations, the annualized changes were calculated by dividing the change by the follow-up duration. On the basis of a standard deviation of 0.15 m/s annually, we calculated that a sample size of 90 patients in each treatment group would give the study 80% power at a 5% significance level to detect a difference in the primary end point of 0.06 m/s annually in the peak velocity. Group differences were assessed using the 2-sample t test, chi-square test, or Mann-Whitney U test. Normally distributed continuous variables were summarized using the mean ± SD. Non-normally distributed continuous variables were summarized using the median and interquantile range. The categorical variables were summarized using the frequency and percentage. The treatment groups were compared through the use of the 2-sample t test or Mann-Whitney U test. A subgroup analysis was performed in patients with less severe AS (peak aortic velocity <3.0 m/s) and in patients without aortic valve calcifications. To compare the changes in cholesterol and high-sensitivity C-reactive protein levels within the groups over time, the repeated measurements analysis of variance test and Friedman test were used for comparison. Intervention-free survival analysis to detect differences between the treatment groups was performed using the Kaplan-Meier survival analysis. Cox regression analysis was used to evaluate the prognostic significance of variables that potentially could predict intervention-free survival. A correlation analysis of the NT-proBNP level with age and AS severity parameters was performed using the Pearson correlation test or Spearman correlation test.
Results
From December 2005 to December 2007, 242 patients were assessed for eligibility to participate in the PROCAS trial ( Figure 1 ). The main reason for refusal was the burden of taking medication for 3 years. The main reasons for not meeting the inclusion criteria were young women considering pregnancy, previous AVR, and severe aortic regurgitation. The median follow-up was 2.4 years (interquartile range 1.9 to 3.0). The baseline characteristics of the 2 treatment groups were well balanced ( Table 1 ), without significant differences between the treatment groups at baseline.
| Variable | Rosuvastatin (n = 30) | Placebo (n = 33) |
|---|---|---|
| Age (years) | 33 ± 9 | 32 ± 10 |
| Men | 21 (70%) | 24 (73%) |
| Body mass index (kg/m 2 ) | 25 ± 3 | 25 ± 4 |
| Blood pressure (mm Hg) | ||
| Systolic | 129 ± 16 | 131 ± 16 |
| Diastolic | 76 ± 10 | 78 ± 9 |
| Smoker | ||
| Current | 7 (23%) | 10 (30%) |
| Former | 1 (3%) | 1 (3%) |
| Never | 22 (73%) | 22 (67%) |
| Previous intervention (surgical valvulotomy or balloon valvuloplasty) | 22 (73%) | 26 (79%) |
| Bicuspid valve | 28 (93%) | 29 (88%) |
| Aortic regurgitation | ||
| Non/grade 1 | 21 (70%) | 18 (55%) |
| Grade 2 | 6 (20%) | 10 (30%) |
| Grade 3 | 3 (10%) | 5 (15%) |
| Aortic valve calcium | 12 (40%) | 12 (36%) |
| Measurements of aortic stenosis | ||
| Peak aortic valve velocity (m/s) | 3.4 ± 0.7 | 3.6 ± 0.9 |
| Peak aortic gradient (mmHg) | 48 ± 18 | 56 ± 28 |
| Mean aortic gradient (mmHg) | 27 ± 10 | 32 ± 17 |
| Aortic valve area (cm 2 ) | 1.3 ± 0.4 | 1.3 ± 0.5 |
| Aortic diameter at 4 levels (mm) | ||
| Annulus | 24 ± 5 | 25 ± 5 |
| Sinus of Valsalva | 32 ± 6 | 32 ± 6 |
| Sinotubular junction | 27 ± 6 | 28 ± 6 |
| Proximal ascending aorta | 36 ± 6 | 37 ± 8 |
| Fractional shortening (%) | 39 ± 8 | 39 ± 7 |
| Left ventricular mass (g) | 214 ± 59 | 212 ± 77 |
| Left ventricular hypertrophy | 6 (20.0%) | 11 (33.3%) |
| Lipid concentrations | ||
| Total cholesterol (mg/dl) | 177 ± 36 | 176 ± 39 |
| Total cholesterol (mmol/L) | 4.6 ± 0.9 | 4.6 ± 1.0 |
| Low-density lipoprotein cholesterol (mg/dl) | 106 ± 31 | 104 ± 35 |
| Low-density lipoprotein cholesterol (mmol/L) | 2.8 ± 0.8 | 2.7 ± 0.9 |
| High-density lipoprotein cholesterol (mg/dl) | 46 ± 13 | 48 ± 15 |
| High-density lipoprotein cholesterol (mmol/L) | 1.2 ± 0.3 | 1.3 ± 0.4 |
| Triglycerides (mg/dl) | 49 ± 28 | 52 ± 29 |
| Triglycerides (mmol/L) | 1.3 ± 0.7 | 1.3 ± 0.7 |
| High-sensitivity C-reactive protein (mg/L) | 1.4 (0.8–5.3) | 1.3 (0.5–2.9) |
| N-terminal pro-brain natriuretic peptide (pg/ml) | 50 (19–98) | 40 (20–92) |
| Creatinine (μmol/L) | 69 ± 15 | 73 ± 11 |
| Creatine kinase (U/L) | 96 (65–110) | 92 (68–124) |
No significant differences were found between the rosuvastatin and placebo group in the annual change in the primary and secondary end points ( Table 2 ). The subgroup analyses did not show interaction effects for the annual progression of peak aortic velocity in patients with less severe AS (p = 0.864) or in patients without baseline aortic valve calcification (p = 0.316). Figure 2 shows the comparison data for AS progression at 0, 1, 2, and 3 years of treatment. The numerical values for the echocardiographic parameters at baseline and at the end of the study are listed in Table 3 . The median NT-proBNP in the rosuvastatin group at baseline was 50 pg/ml (interquartile range 19 to 98) and 21 pg/ml (interquartile range 12 to 65) at the end of the follow-up period (p = 0.638). The median NT-proBNP in the placebo group at baseline was 40 pg/ml (interquartile range 20 to 92) and increased with time to 56 pg/ml (interquartile range 26 to 153; p = 0.008). The NT-proBNP level showed weak correlations with the peak velocity ( r = 0.311; p = 0.020), peak gradient ( r = 0.291; p = 0.029), mean gradient ( r = 0.297; p = 0.026), aortic valve area ( r = −0.338; p = 0.011), and age ( r = 0.320; p = 0.016). The prevalence of aortic root dilation was high: 33% at the annulus level, 27% at the sinus of Valsalva level, 79% at the sinotubular junction level, and 78% at the proximal ascending aorta level. Dilation of the ascending aorta at any of the 4 levels occurred in 84% of the patients.
| Variable | All Patients (n = 59) | Rosuvastatin (n = 27) | Placebo (n = 32) | p Value |
|---|---|---|---|---|
| Aortic stenosis progression | ||||
| Peak aortic velocity (m/s) | 0.07 ± 0.23 | 0.05 ± 0.21 | 0.09 ± 0.24 | 0.435 |
| Peak aortic gradient (mm Hg) | 3.0 ± 7.7 | 2.5 ± 5.7 | 3.5 ± 9.2 | 0.638 |
| Mean aortic gradient (mm Hg | 1.6 ± 4.2 | 1.2 ± 3.3 | 1.9 ± 4.8 | 0.515 |
| Aortic valve area (cm 2 ) | −0.03 ± 0.15 | −0.03 ± 0.11 | −0.03 ± 0.18 | 0.999 |
| Aortic diameter progression | ||||
| Annulus (mm) | 0.4 ± 2.2 | 0.1 ± 1.9 | 0.7 ± 2.5 | 0.330 |
| Sinus of Valsalva (mm) | 0.2 ± 1.6 | 0.2 ± 1.2 | 0.1 ± 1.7 | 0.802 |
| Sinotubular junction (mm) ⁎ | 0.2 ± 2.1 | −0.1 ± 1.4 | 0.5 ± 2.5 | 0.332 |
| Proximal ascending aorta (mm) ⁎ | 0.4 ± 1.6 | 0.4 ± 1.7 | 0.5 ± 1.6 | 0.826 |
| Left ventricular mass (gram) | −1.6 ± 25.2 | 1.1 ± 15.8 | −3.7 ± 30.9 | 0.476 |
| N-terminal pro-brain natriuretic peptide (pg/ml) † | 0.4 (−8.0–8.7) | −0.9 (−8.0–6.3) | 4.1 (−6.9–13.4) | 0.187 |
⁎ Rosuvastatin group, n = 26; placebo group, n = 31, total, n = 57.
† Rosuvastatin group, n = 24; placebo group, n = 24; total, n = 48.
| Characteristics | Rosuvastatin (n = 30) | Placebo (n = 32) | ||||
|---|---|---|---|---|---|---|
| Baseline | Follow-up | p-value | Baseline | Follow-up | p-value | |
| Peak aortic valve velocity (m/s) | 3.4 ± 0.6 | 3.5 ± 0.7 | 0.410 | 3.6 ± 0.9 | 3.7 ± 1.1 | 0.046 |
| Peak aortic gradient (mmHg) | 46 ± 16 | 51 ± 18 | 0.042 | 55 ± 28 | 60 ± 35 | 0.034 |
| Mean aortic gradient (mmHg) | 26 ± 8 | 29 ± 11 | 0.082 | 31 ± 17 | 35 ± 22 | 0.038 |
| Aortic valve area (cm 2 ) | 1.3 ± 0.4 | 1.3 ± 0.5 | 0.251 | 1.3 ± 0.5 | 1.3 ± 0.5 | 0.260 |
| Annulus (mm) | 24 ± 5 | 24 ± 4 | 0.904 | 25 ± 5 | 26 ± 6 | 0.294 |
| Sinus of Valsalva (mm) | 31 ± 5 | 32 ± 5 | 0.441 | 32 ± 6 | 32 ± 6 | 0.948 |
| Sinotubular junction (mm) ⁎ | 27 ± 6 | 27 ± 5 | 0.665 | 28 ± 5 | 29 ± 6 | 0.508 |
| Proximal ascending aorta (mm) ⁎ | 35 ± 6 | 36 ± 6 | 0.229 | 37 ± 8 | 38 ± 8 | 0.110 |
| Left ventricular mass (gram) | 212 ± 56 | 212 ± 75 | 0.947 | 209 ± 77 | 203 ± 77 | 0.456 |
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