Clinical trials have not provided evidence for a role of statin therapy in reducing aortic valve stenosis (AVS) severity in patients with documented AVS. However, whether statin therapy could prevent the onset of AVS is unknown. Our objectives were (1) to compare the incidence rates of AVS among patients treated with high-dose versus usual-dose statin or placebo and (2) to identify clinical risk factors associated with the development of AVS. We conducted post hoc analyses in 23,508 participants from 3 large-scale multicenter atorvastatin randomized blinded clinical trials: Treating to New Targets, the Incremental Decrease in End Points Through Aggressive Lipid Lowering, and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels. The main outcome measure was the incidence of clinical AVS over a median follow-up of 4.9 years (82 cases). Among patients who developed AVS, 39 (47.6%) were treated with atorvastatin 80 mg and 43 (52.4%) were treated with lower dose statin (atorvastatin 10 mg in Treating to New Targets, simvastatin 20 to 40 mg in Incremental Decrease in End Points Through Aggressive Lipid Lowering, or placebo in Stroke Prevention by Aggressive Reduction in Cholesterol Levels; hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.59 to 1.41, p = 0.67). In multivariate analyses forcing treatment, sex, and race into the model, factors that were significantly associated with AVS included age (HR 2.17, 95% CI 1.61 to 2.93, p <0.0001 per 1-SD increment), diabetes (HR 1.67, 95% CI 1.00 to 2.80, p = 0.05), vitamin K antagonist use (HR 3.25, 95% CI 2.06 to 5.16, p <0.0001), and previous statin use (HR 2.65, 95% CI 1.54 to 4.60, p = 0.0008). In conclusion, random allocation to high-dose versus usual-dose statin therapy or placebo did not impact the incidence of AVS among patients without known AVS. Age, diabetes, vitamin K antagonists, and previous statin use were significant predictors of incident AVS in these high-risk patients.
Aortic valve stenosis (AVS) is a complex disorder that is present in more than 2% patients aged >65 years, and it is the most frequent indication for surgical heart valve replacement. Despite a body of evidence suggesting that statins were beneficial in animal models of AVS and in early observational studies, at least 3 clinical trials have failed to show efficacy of statin therapy in delaying the progression of AVS among asymptomatic patients with documented mild-to-moderate AVS. Therefore, there is no sufficient evidence to support the use of statins to delay the progression of AVS. After the publication of the results of these trials, the National Heart and Lung and Blood Institute Aortic Stenosis Working group recommended that studies be performed to test the impact of statin therapy before the onset of AVS in patients without known AVS but at high risk. The objectives of the present study were twofold. First, we sought to compare the incidence rates of AVS among patients without known AVS who were treated with atorvastatin 80 mg/day versus usual dose or placebo in 3 large-scale statin trials. Second, we aimed to identify clinical risk factors associated with the risk of incident AVS in patients with documented cardiovascular disease.
Methods
The study protocol and results of the Treating to New Targets (TNT) trial have been published previously. In brief, patients with clinically manifest coronary heart disease commenced 8 weeks of open-label treatment with atorvastatin 10 mg/day. After this run-in period, 10,001 patients with low-density lipoprotein cholesterol levels <3.4 mmol/L (<130 mg/dl) on atorvastatin 10 mg/day were randomized in a double-blind design to therapy with either 10 or 80 mg of atorvastatin per day. Patients were followed up for a median of 4.9 years. The study protocol and results of the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial have been published previously. In IDEAL, atorvastatin 80 mg was compared with simvastatin 20 mg/day in 8,888 patients with postmyocardial infarction. Patients were eligible for the IDEAL trial if they were 80 years of age or less, had experienced a definite myocardial infarction, and had qualified for statin therapy according to their national guidelines at the time of recruitment. Twenty-eight patients developed AVS during the course of the trial. The study protocol and results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial have also been published previously. In SPARCL, 80 mg/day of atorvastatin was compared with placebo in 4,731 patients with a recent stroke or transient ischemic attack. Eligibility criteria for the SPARCL trial included a stroke or transient ischemic attack 1 to 6 months before the study, no known coronary disease, and low-density lipoprotein cholesterol of 2.6 to 4.9 mmol/L (100 to 190 mg/dl). Nine patients developed AVS during the course of the trial. In these 3 studies, patients with known AVS and were excluded from this analysis (n = 73 for TNT, n = 30 for IDEAL, and n = 9 for SPARCL). Patients with a clinical diagnosis of AVS during follow-up were identified through careful screening of the list of potential adverse events as AVS was not a prespecified outcome in any of these trials.
Patient characteristics at randomization were compared between patients who did develop AVS versus those who did not develop AVS during the study follow-up using a chi-square test for categorical variables and a Wilcoxon rank-sum test for continuous variables with either normal or non-normal distribution. Candidate variables that could be related to AVS risk were selected a priori based on the previous literature and known risk factors and included sex, race, smoking status, age, body mass index, systolic and diastolic blood pressure, diabetes, metabolic syndrome, detailed cardiovascular history (previous myocardial infarction, angina, cerebrovascular disease, peripheral vascular disease, congestive heart failure, arrhythmia, angioplasty, and/or coronary artery bypass grafting), concomitant medication, estimated glomerular filtration rate, and plasma lipoprotein-lipid levels including apolipoprotein B and A-1, glucose, log-transformed white blood cell count, uric acid, lactate dehydrogenase levels, and blood urea nitrogen. The association of each of the candidate variables with the risk of AVS was assessed by univariable Cox proportional hazard models to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Next, statistically significant variables that were associated with AVS risk at a p value of <0.05 in the univariable analyses were then entered into the multivariable model before and after forcing age, sex, and treatment into the model.
Results
Baseline characteristics of all study participants are listed in Table 1 . Baseline characteristics of study participants for all trials separately are listed in Supplementary Tables 1.1 to 1.3 .
| Baseline Characteristics | AVS Cases (n = 82) | Controls (n = 23,426) | p Value |
|---|---|---|---|
| Atorvastatin 80 mg | 39 (48) | 11,698 (50) | 0.67 |
| Male gender | 65 (79) | 17,964 (77) | 0.58 |
| Caucasians | 80 (98) | 22,458 (96) | 0.44 |
| Age (yrs) | 67.5 (7.4) | 61.6 (9.6) | <0.0001 |
| Height (cm) | 78.79 (84.7) | 99.82 (84.3) | 0.02 |
| Weight (kg) | 85.73 (16.3) | 82.45 (14.9) | 0.14 |
| Body mass index (kg/m 2 ) | 29.09 (5.2) | 27.84 (4.3) | 0.04 |
| Systolic blood pressure (mm Hg) | 137.49 (20.3) | 134.59 (18.9) | 0.16 |
| Diastolic blood pressure (mm Hg) | 77.89 (10.5) | 79.64 (10.1) | 0.11 |
| Smoker | |||
| Current | 12 (15) | 4,058 (17) | 0.52 |
| Previous | 48 (59) | 13,287 (57) | 0.74 |
| Never | 22 (27) | 6,077 (26) | 0.85 |
| Myocardial infarction | 49 (60) | 14,604 (62) | 0.63 |
| Angina pectoris | 56 (68) | 12,396 (53) | 0.005 |
| Cerebrovascular disease | 2 (2) | 1,166 (5) | 0.29 |
| Peripheral vascular disease | 11 (13) | 1,581 (7) | 0.02 |
| Congestive heart failure | 5 (6) | 1,312 (6) | 0.85 |
| Arrhythmia | 11 (13) | 1,842 (8) | 0.06 |
| Angioplasty | 29 (35) | 7,393 (32) | 0.46 |
| Coronary artery bypass grafting | 36 (44) | 6,332 (27) | 0.0006 |
| Diabetes mellitus | 21 (26) | 3,317 (14) | 0.003 |
| Hypertension | 47 (57) | 11,150 (48) | 0.08 |
| Metabolic syndrome | 30 (37) | 6,990 (30) | 0.18 |
| eGFR (ml/min/1.73 m 2 ) | 64.45 (12.3) | 66.49 (13.7) | 0.18 |
| Baseline lipids (mg/dl) | |||
| Total cholesterol | 186.96 (30.4) | 190.30 (34.7) | 0.46 |
| LDL cholesterol | 108.07 (24.8) | 113.63 (30.1) | 0.24 |
| HDL cholesterol | 48.07 (11.3) | 47.36 (12.0) | 0.54 |
| Triglycerides | 155.18 (74.4) | 148.58 (76.2) | 0.35 |
| Apolipoprotein A-1 | 145.93 (21.4) | 144.19 (25.0) | 0.28 |
| Apolipoprotein B | 115.74 (21.6) | 118.65 (26.8) | 0.42 |
| White blood cells (10 3 /mm 3 ) | 6.67 (1.8) | 6.54 (1.9) | 0.63 |
| Glucose (mg/dl) | 113.40 (36.7) | 107.33 (30.8) | 0.15 |
| Uric acid (mmol/L) | 6.08 (1.4) | 6.16 (1.4) | 0.52 |
| Blood urea nitrogen (mg/dl) | 17.74 (4.8) | 17.01 (5.0) | 0.12 |
| Lactate dehydrogenase (mg/dl) | 178.62 (120.7) | 192.29 (124.1) | 0.79 |
| Medications | |||
| ACE inhibitors | 39 (48) | 10,037 (43) | 0.39 |
| Angiotensin II receptor blockers | 16 (20) | 2,884 (12) | 0.05 |
| β Blockers | 59 (72) | 15,585 (67) | 0.30 |
| Calcium channel blockers | 40 (49) | 7,246 (31) | 0.0005 |
| Antiplatelets | 14 (17) | 3,709 (16) | 0.76 |
| Vitamin K antagonists | 33 (40) | 3,084 (13) | <0.0001 |
| Other anticoagulants | 3 (4) | 864 (4) | 0.99 |
| Aspirin | 66 (80) | 16,691 (72) | 0.06 |
| Statin use prerandomization | 64 (78) | 13,024 (56) | <0.0001 |
In univariable analyses ( Table 2 ), treatment with atorvastatin 80 mg was not significantly associated with incident AVS compared with treatment with usual-dose statin/placebo (HR 0.91, 95% CI 0.59 to 1.41, p = 0.67). In contrast, older age and higher body mass index (weight directly and height inversely), and the categorical variables including previous angina, peripheral vascular disease, coronary artery bypass grafting, and diabetes were significantly (p ≤0.05 for each) associated with incident AVS. Previous use of calcium channel blockers, vitamin K antagonists, and statins was also significantly associated with increased risk of AVS. Supplementary Tables 2.1 to 2.3 list the results for each trial separately.
| Baseline Characteristics | HR | 95% CI | p Value |
|---|---|---|---|
| Atorvastatin 80 mg | 0.91 | 0.59–1.41 | 0.67 |
| Male gender | 1.17 | 0.69–2.00 | 0.56 |
| Caucasians | 1.73 | 0.42–7.02 | 0.45 |
| Age (yrs) | 2.05 | 1.59–2.63 | <0.0001 |
| Height (cm) | 0.80 | 0.65–1.00 | 0.05 |
| Weight (kg) | 1.22 | 1.00–1.50 | 0.05 |
| Body mass index (kg/m 2 ) | 1.26 | 1.06–1.51 | 0.009 |
| Systolic blood pressure (mm Hg) | 1.16 | 0.95–1.43 | 0.15 |
| Diastolic blood pressure (mm Hg) | 0.83 | 0.67–1.04 | 0.11 |
| Smoker | |||
| Current | 0.83 | 0.45–1.54 | 0.56 |
| Previous | 1.08 | 0.69–1.67 | 0.75 |
| Never | 1.04 | 0.64–1.69 | 0.89 |
| Cardiovascular history | |||
| Myocardial infarction | 0.94 | 0.60–1.46 | 0.78 |
| Angina pectoris | 1.92 | 1.20–3.05 | 0.006 |
| Cerebrovascular disease | 0.50 | 0.12–2.05 | 0.34 |
| Peripheral vascular disease | 2.18 | 1.16–4.12 | 0.02 |
| Congestive heart failure | 1.15 | 0.47–2.85 | 0.76 |
| Arrhythmia | 1.80 | 0.95–3.40 | 0.07 |
| Angioplasty | 1.16 | 0.74–1.83 | 0.52 |
| Coronary artery bypass grafting | 2.12 | 1.37–3.28 | 0.0008 |
| Diabetes mellitus | 2.12 | 1.29–3.49 | 0.003 |
| Hypertension | 1.47 | 0.95–2.27 | 0.09 |
| Metabolic syndrome | 1.36 | 0.87–2.13 | 0.18 |
| eGFR (ml/min/1.73 m 2 ) | 0.83 | 0.65–1.06 | 0.13 |
| Baseline lipids (mg/dl) | |||
| Total cholesterol | 0.91 | 0.73–1.14 | 0.40 |
| LDL cholesterol | 0.82 | 0.65–1.04 | 0.11 |
| HDL cholesterol | 1.05 | 0.85–1.30 | 0.65 |
| Triglycerides | 1.08 | 0.91–1.27 | 0.39 |
| Apolipoprotein A-1 | 1.06 | 0.86–1.31 | 0.61 |
| Apolipoprotein B | 0.89 | 0.71–1.12 | 0.33 |
| ln white blood cells (10 3 /mm 3 ) | 1.10 | 0.89–1.37 | 0.38 |
| Glucose (mg/dl) | 1.17 | 0.99–1.37 | 0.06 |
| Uric acid (mmol/L) | 0.96 | 0.77–1.19 | 0.68 |
| Blood urea nitrogen (mg/dl) | 1.15 | 0.96–1.38 | 0.13 |
| Lactate dehydrogenase (mg/dl) | 0.92 | 0.73–1.17 | 0.49 |
| Medications | |||
| ACE inhibitors | 1.20 | 0.78–1.85 | 0.42 |
| Angiotensin II receptor blockers | 1.66 | 0.96–2.87 | 0.07 |
| β Blockers | 1.30 | 0.80–2.10 | 0.29 |
| Calcium channel blockers | 2.11 | 1.37–3.25 | 0.0008 |
| Aspirin | 1.68 | 0.97–2.90 | 0.07 |
| Other antiplatelet agents | 1.07 | 0.60–1.90 | 0.83 |
| Vitamin K antagonists | 4.49 | 2.89–6.98 | <0.0001 |
| Other anticoagulants | 1.03 | 0.33–3.26 | 0.96 |
| Statin use prerandomization | 2.92 | 1.73–4.93 | <0.0001 |
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