Review
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
SALTIRE–RAAVE: targeting calcific aortic valve disease LDL-density-radius theory Expert Rev. Cardiovasc. Ther. 13(4), 355–367 (2015)
Nalini M Rajamannan*1,2, Anders M Greve3, Luis M Moura5, Patricia Best6 and Kristian Wachtell3,4 1 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA 2 Most Sacred Heart of Jesus Cardiology and Valvular Institute, Sheboygan, WI, USA 3 Department of Cardiology, Glostrup University Hospital, Copenhagen, Denmark 4 Department of Cardiology, Department Faculty of Health, O¨rebro University, O¨rebro, Sweden 5 University of Porto, Porto, Portugal 6 Division of Cardiology, Mayo Clinic, Rochester, MN, USA *Address for correspondence: Tel.: +507 284 4268 [email protected]
informahealthcare.com
SALTIRE and RAAVE were the first two studies to evaluate the use of statin therapy for impeding calcific aortic valve disease (CAVD). This review presents the findings of low-density lipoprotein (LDL)-density-radius theory as tested using the combined results from the SALTIRE and RAAVE studies. Patients who received statin therapy had a greater degree of LDL cholesterol lowering, seen as the % change in LDL (47 vs 2%, p = 0.012), which in itself was significantly associated with a lesser change in aortic valve area (AVA; p < 0.001 and R2 = 0.27). The percent change in the AVA for the treated patients was 5% and 15% for the nontreated patients (p = 0.579 and R2 = 0.03). In summary, these published findings suggest that when applying the LDL-density-radius theory, which combines the cellular biology and the hemodynamics as defined by the continuity equation for AVA, there may be a role for lipid-lowering therapy in contemporary patients with calcific aortic valve disease (CAVD). KEYWORDS: aortic valve stenosis . atherosclerosis . calcification . clinical trials . hemodynamics . statins
With the decline in the incidence of rheumatic carditis, calcific aortic valve disease (CAVD) [1] has become the most common indication for surgical valve replacement in the USA and in Europe [2]. For years, CAVD was thought to be due to a degenerative phenomenon. However, risk factors for CAVD are similar to those of vascular atherosclerosis, including smoking, male gender, body mass index, hypertension, elevated lipids and inflammatory markers, metabolic syndrome and renal failure [3–19]. During the past decade, seminal papers in the field have been recognized by the National Institutes of Health Heart, Lung and Blood Institute in a working group that published the first working group on the molecular biology of the heart valve, specifically the osteogenic activation of valve interstitial cells critical in the progression of CAVD [1]. Early stages of aortic valve disease, aortic valve sclerosis [20–24], is the initial valve abnormality important in the progression of CAVD in a younger patient population, which may be more responsive to medical therapy. For years, this lesion was thought to be a benign insignificant murmur. However, this benign innocent murmur may be the clinicians’ first
10.1586/14779072.2015.1025058
clue to early atherosclerosis and a 50% morbidity and mortality of coronary artery disease (CAD) [17]. Retrospective studies also demonstrate that aortic valve sclerosis and osteogenic markers critical in the progression of CAVD are also responsive to medical therapy and statin therapy [21,25]. The most compelling evidence for the role of low-density lipoprotein (LDL) is the genetic study, which used Mendelian genetics to determine the role of a weighted genetic risk score, which linked a higher incidence of aortic stenosis (AS) by 28% [26]. The understanding of calcification, as an active cellular process critical in CAVD that causes progression to severe stenosis and poor outcomes [27], led the way for randomized trials assessing the effectiveness of lipid-lowering therapy on impeding AS progression. However, to date, these trials, including the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE), Simvastatin Ezetimibe in Aortic Stenosis (SEAS), Aortic Stenosis Progression Observation: Measuring the Effects of Rosuvastatin (ASTRONOMER), have all been negative [28–31]. Notwithstanding, data from several studies have continued to confirm that all of the
2015 Informa UK Ltd
ISSN 1477-9072
355
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Review
Rajamannan, Greve, Moura, Best & Wachtell
traditional risk factors, including metabolic syndrome [13] and renal failure [14], which are important in the development of vascular atherosclerosis, are also implicated in the development of CAVD [3–19]. Thus, although there is no overall effect of lipid-lowering therapy on impeding AS, these recent findings provide the foundation to study targeted strategies for medical therapy, including, for example, medications for hyperlipidemia, hypertension and diabetes in patients with AS. As such, there are a growing number of experimental in vivo models of calcific AS, which demonstrate primarily that lipids [32–38], diabetes [38] and renal failure [39] are important in the development of this disease. There is also increasing evidence that these cells undergo specific differentiation steps toward the development of this bone phenotype as shown in in vitro and in vivo studies [32,40–48]. In addition, there are a growing number of retrospective [49–52] and large-scale prospective clinical trials [28–30] testing the hypothesis that atherosclerotic CAVD may be targeted with medical therapy. The pioneers in valve clinical trials designed studies prior to the publication of many of the experimental models [43,46,48,53], which confirm that statins attenuate the atherosclerotic lesion in the valve. As such, the only clinical trial to date to show an effect of lipid-lowering on AS progression: The Rosuvastatin Affecting Aortic Valve Endothelium to Slow the Progression of Aortic Stenosis trial (RAAVE), tested the hypothesis that treating elevated LDL compared to normal LDL patients, slows progression of CAVD [28]. This study was hypothesis driven and targeted specifically the hypothesis that elevated LDL is a significant risk factor for the progression of CAVD. Furthermore, the initial trials, SALTIRE, ASTRONOMER and SEAS, were designed with the traditional CAD trial design for lipid lowering, using combined vascular and valvular endpoints. The aim of this review is, therefore, to relate recent evidence [54] regarding the findings in the published trials on lipid-lowering therapy in AS, and how an improved biological understanding of valve calcification, namely the LDL-density-radius theory, may play a role in the design of future randomized clinical trials of medical therapy for CAVD. Randomized clinical trials of lipid lowering in AS SALTIRE
The first randomized prospective study testing the effects of statins in CAVD, SALTIRE, was published in 2005 [31]. In this double-blind, placebo-controlled trial, patients with calcific AS were randomly assigned to receive either 80 mg of atorvastatin daily or a matched placebo. Aortic valve stenosis and calcification were assessed with the use of Doppler echocardiography and helical computed tomography, respectively. The primary endpoints were change in aortic jet velocity and aortic valve calcium score; secondary endpoints were traditional vascular endpoints. The SALTIRE investigators demonstrated no statistically significant primary endpoints for the study. The clinical characteristics of the SALTIRE patient population are shown in TABLE 1. The vascular endpoints demonstrated 356
statistically significant improvement. The SALTIRE investigators concluded that intensive lipid-lowering therapy does not halt the progression of calcific AS or induce its regression [31] and the reason for this negative trial is the timing of therapy as shown in FIGURE 1 [31]. The study had full Institutional Review Board and informed consent, but no ClinicalTrials.gov registration due to the initiation of the trial prior to the International Committee of Journal Medical Editors requirements. RAAVE
In the RAAVE trial [28], performed a prospective trial of AS with Rosuvastatin targeting serum LDL slowed progression of echo hemodynamic measurements, and improved inflammatory biomarkers providing the first clinical evidence for targeted therapy in patients with asymptomatic AS. The aim of the study was to assess the effect of Rosuvastatin on hemodynamic progression and inflammatory markers of AS by treating LDL in patients with AS according to the NCEP-ATPIII guidelines for 1 year. The clinical characteristics of the RAAVE trial are shown in TABLE 2. Prospective treatment of moderate AS with Rosuvastatin targeting serum LDL did slow progression of echocardiographic parameters of AS compared with control that were not on statin therapy, improved inflammatory biomarkers and vascular endpoints demonstrating the first clinical evidence for targeted therapy in asymptomatic moderate-to-severe AS as shown in FIGURE 2 [28]. The RAAVE trial [28] had full Institutional Review Board informed consent and ClinicalTrials.gov registration [55]. SEAS
The largest clinical trial was the SEAS trial [29]. This trial is a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic AS. Again, similar to SALTIRE, there were fewer patients with ischemic cardiovascular events in the Simvastatin–Ezetimibe group (148 patients) than in the placebo group (187 patients); the authors noted that this was mainly because of the smaller number of patients who underwent coronary artery bypass grafting. Cancer occurred more frequently in the Simvastatin–Ezetimibe group (105 vs 70; p = 0.01). The investigators concluded that the medication did not reduce the composite outcome of combined aortic valve events in patients with AS, including echo progression and vascular endpoints. ASTRONOMER
ASTRONOMER [40], the most recent trial, also demonstrated negative randomized clinical results and included patients with bicuspid aortic valve disease. This was a randomized, doubleblind, placebo-controlled trial in asymptomatic patients with mild-to-moderate AS and no clinical indications for cholesterol lowering. The patients were randomized to receive either placebo or Rosuvastatin 40 mg daily. A total of 269 patients were randomized: 134 patients to Rosuvastatin 40 mg daily and 135 patients to placebo. Annual echocardiograms were performed to assess AS progression, which was the primary outcome; the median follow-up was 3.5 years. The peak AS gradient Expert Rev. Cardiovasc. Ther. 13(4), (2015)
Clinical trials in aortic valve disease
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Table 1. Clinical characteristics of the SALTIRE reprinted with permission from
Review
[31].
Characteristic
Atorvastatin (n = 77)
Placebo (n = 78)
Age-yr
68 + 11
68 + 10
Male sex – %
68
72
Hypertension – no.
48
54
Hyperlipidemia – no.
8
5
Diabetes mellitus – no.
3
4
Current smoker – no.
21
22
Coronary heart disease – no.
18
21
Cerebrovascular disease – no.
9
11
Peripheral vascular disease – no.
5
13
–Aspirin
43
40
–AVE inhibitor
12
14
–Beta-blocker
21
27
–Warfarin
8
12
Height-cm
168 ± 9
169 ± 8
Weight-kg
79 ± 15
80 ± 15
Heart rate – bpm
68 ± 11
66 ± 12
Systolic blood pressure – mmHg
144 ± 18
144 ± 21
Diastolic blood pressure – mmHg
82 ± 10
81 ± 12
– Total cholesterol – mg/dl
220 ± 38
127 ± 34
– LDL cholestero. – mg/dl
137 ± 34
133 ± 30
– Cholesterol HDL ratio
4.1 ± 1.1
4.1 ± 1.4
– Urea-mg/dl
38 ± 13
43 ± 13
– Creatinine – mg/dl
1.07 ± 0.25
1.08 ± 0.26
– Glucose – mg/dl
91 ± 19
95 ± 21
Sinus rhythm – %
94
92
Atrial fibrillation – %
6
8
Romhilt-Estes score – median (interquartile range)
1(0 – 3)
2(1 – 4)
Tricuspid aortic valve – %
96
97
Bicuspid aortic valve – %
4
3
Aortic jet velocity – m/sec
3.39 ± 0.62
3.45 ± 0.67
Peak gradient – mmHg
47.8 ± 17.4
49.5 ± 19.5
Aortic valve area – cm
1.03 ± 0.4
1.02 ± 0.41
Aortic valve calcium score – median AU (interquartile range)
5424 (2750 – 9689)
6221 (3037 – 9575)
Log aortic-valve calcium score – Log AU
3.7 ± 0.5
3.7 ± 0.6
Drug history – no.
†
Biochemistry
2
*Plus-minus values are means ± SD. † To convert values for cholesterol to millimoles per liter, multiply by 0,02586. To convert values for urea to millimoles per liter, multiply by 0.357. To convert values for creatinine to micromoles per liter by 88.4. ACE: Denotes angiotensin-converting enzyme; AU: Arbitrary units; HDL: High-density lipoprotein; LDL: Low-density lipoprotein.
informahealthcare.com
357
Review
Rajamannan, Greve, Moura, Best & Wachtell
A
B Log CT aortic-valve calcium score (AU)
4.5
Placebo Atorvastatin
4.0 3.5 3.0 2.5
5.0 4.5
Placebo Atorvastatin
4.0 3.5 3.0 2.5
0
0 0
12
24
0
36
12
77 77
36
No. of patients
No. of patients Placebo Atorvastatin
24 Months
Months
69 65
55 60
Placebo Atorvastatin
30 34
76 77
69 64
56 60
29 34
C p < 0.001
200 Serum LDL cholesterol concentration (mg/dl)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Aortic-jet velocity (m/sec)
5.0
150
100 50 Placebo Atorvastatin 0 0
12
24
36
Months No. of patients Placebo Atorvastatin
78 77
70 65
54 58
31 35
Figure 1. Clinical Results of the SALTIRE reprinted with permission from [31].
increased in patients receiving Rosuvastatin from a baseline of 40.8 ± 11.1–57.8 ± 22.7 mmHg at the end of follow-up and in patients with placebo from 41.6 ± 10.9 mmHg at baseline to 54.8 ± 19.8 mmHg at the end of follow-up. The annual increase in the peak AS gradient was 6.3 ± 6.9 mmHg in the Rosuvastatin group compared with 6.1 ± 8.2 mmHg in the placebo group (p = 0.83). Patients with metabolic syndrome had increased propensity to progress in this clinical study, indicating the importance of this risk factor in the disease progression and that the effect of metabolic syndrome [56] needs to be targeted as well as lowering LDL levels in patients with CAVD. Translating experimental evidence to randomized clinical trials
These three clinical trials have different results. TABLE 2 demonstrates the results from the SALTIRE study, and FIGURE 2 demonstrates the results from the RAAVE trial. This review evaluates two different trial designs, which measure the effect 358
of statins in aortic valve disease in different patient populations. Combining evidence from the published clinical trials and novel experimental evidence, we propose that from a translational perspective, the testing of the role of medical therapy for CAVD and design of the clinical trials can be improved with the application of the LDL-density-radius hypothesis [57]. The theory, as previously published [57] hypothesis, is related to two fundamental issues for these two similar but very different disease processes: first is the LDL effect and second is the difference in the radius between the aortic valve and that of the vessel. The theory refers to the concentration of the LDL as a density and the concept that the effect of LDL accumulates over time across the valve leaflet and also within the interior of the circumference of the artery. The understanding of the molecular biology of LDL, the effect of the accumulation of the lipids over time on the anatomic tissue, is critical for the future analysis of published trials Expert Rev. Cardiovasc. Ther. 13(4), (2015)
Clinical trials in aortic valve disease
Table 2. Clinical characteristics of the RAAVE reprinted with permission from Characteristic
Review
[28].
All patients (n = 121)
Statin-treated group (n = 61)
Untreated group (n = 60)
p-value
Age (yrs)
73.7 ± 8.9
73.4 ± 8.5
73.9 ± 9.4
0.749
Men, n (%)
57 (47.1)
21 (34.4)
36 (60.0)
0.006
Arterial hypertension, n (%)
77 (63.6)
45 (73.8)
32 (53.3)
0.024
Diabetes, n (%)
39 (32.2)
26 (42.6) 1
3 (21.7)
0.019
Smokers, n (%)
4 (3.3)
0 (0)
4 (6.7)
0.057
Sinus rhythm, n (%)
106 (87.6)
56 (91.8)
50 (83.3)
0.179
Diastolic blood pressure (mm Hg)
75.9 ± 12.9
78.4 ± 13.6
73.4 ± 13.6
0.033
Systolic blood pressure (mm Hg)
150.6 ± 22.9
154.4 ± 18.6
146.6 ± 26.2
0.060
Cardiac frequency (beats/min)
72.8 ± 13.0
73.8 ± 13.1
71.8 ± 12.8
0.379
Total cholesterol level (mg/dl)
217.7 ± 50.1
243.0 ± 40.5
192.0 ± 45.8
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
SALTIRE–RAAVE: targeting calcific aortic valve disease LDL-density-radius theory Expert Rev. Cardiovasc. Ther. 13(4), 355–367 (2015)
Nalini M Rajamannan*1,2, Anders M Greve3, Luis M Moura5, Patricia Best6 and Kristian Wachtell3,4 1 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA 2 Most Sacred Heart of Jesus Cardiology and Valvular Institute, Sheboygan, WI, USA 3 Department of Cardiology, Glostrup University Hospital, Copenhagen, Denmark 4 Department of Cardiology, Department Faculty of Health, O¨rebro University, O¨rebro, Sweden 5 University of Porto, Porto, Portugal 6 Division of Cardiology, Mayo Clinic, Rochester, MN, USA *Address for correspondence: Tel.: +507 284 4268 [email protected]
informahealthcare.com
SALTIRE and RAAVE were the first two studies to evaluate the use of statin therapy for impeding calcific aortic valve disease (CAVD). This review presents the findings of low-density lipoprotein (LDL)-density-radius theory as tested using the combined results from the SALTIRE and RAAVE studies. Patients who received statin therapy had a greater degree of LDL cholesterol lowering, seen as the % change in LDL (47 vs 2%, p = 0.012), which in itself was significantly associated with a lesser change in aortic valve area (AVA; p < 0.001 and R2 = 0.27). The percent change in the AVA for the treated patients was 5% and 15% for the nontreated patients (p = 0.579 and R2 = 0.03). In summary, these published findings suggest that when applying the LDL-density-radius theory, which combines the cellular biology and the hemodynamics as defined by the continuity equation for AVA, there may be a role for lipid-lowering therapy in contemporary patients with calcific aortic valve disease (CAVD). KEYWORDS: aortic valve stenosis . atherosclerosis . calcification . clinical trials . hemodynamics . statins
With the decline in the incidence of rheumatic carditis, calcific aortic valve disease (CAVD) [1] has become the most common indication for surgical valve replacement in the USA and in Europe [2]. For years, CAVD was thought to be due to a degenerative phenomenon. However, risk factors for CAVD are similar to those of vascular atherosclerosis, including smoking, male gender, body mass index, hypertension, elevated lipids and inflammatory markers, metabolic syndrome and renal failure [3–19]. During the past decade, seminal papers in the field have been recognized by the National Institutes of Health Heart, Lung and Blood Institute in a working group that published the first working group on the molecular biology of the heart valve, specifically the osteogenic activation of valve interstitial cells critical in the progression of CAVD [1]. Early stages of aortic valve disease, aortic valve sclerosis [20–24], is the initial valve abnormality important in the progression of CAVD in a younger patient population, which may be more responsive to medical therapy. For years, this lesion was thought to be a benign insignificant murmur. However, this benign innocent murmur may be the clinicians’ first
10.1586/14779072.2015.1025058
clue to early atherosclerosis and a 50% morbidity and mortality of coronary artery disease (CAD) [17]. Retrospective studies also demonstrate that aortic valve sclerosis and osteogenic markers critical in the progression of CAVD are also responsive to medical therapy and statin therapy [21,25]. The most compelling evidence for the role of low-density lipoprotein (LDL) is the genetic study, which used Mendelian genetics to determine the role of a weighted genetic risk score, which linked a higher incidence of aortic stenosis (AS) by 28% [26]. The understanding of calcification, as an active cellular process critical in CAVD that causes progression to severe stenosis and poor outcomes [27], led the way for randomized trials assessing the effectiveness of lipid-lowering therapy on impeding AS progression. However, to date, these trials, including the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE), Simvastatin Ezetimibe in Aortic Stenosis (SEAS), Aortic Stenosis Progression Observation: Measuring the Effects of Rosuvastatin (ASTRONOMER), have all been negative [28–31]. Notwithstanding, data from several studies have continued to confirm that all of the
2015 Informa UK Ltd
ISSN 1477-9072
355
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Review
Rajamannan, Greve, Moura, Best & Wachtell
traditional risk factors, including metabolic syndrome [13] and renal failure [14], which are important in the development of vascular atherosclerosis, are also implicated in the development of CAVD [3–19]. Thus, although there is no overall effect of lipid-lowering therapy on impeding AS, these recent findings provide the foundation to study targeted strategies for medical therapy, including, for example, medications for hyperlipidemia, hypertension and diabetes in patients with AS. As such, there are a growing number of experimental in vivo models of calcific AS, which demonstrate primarily that lipids [32–38], diabetes [38] and renal failure [39] are important in the development of this disease. There is also increasing evidence that these cells undergo specific differentiation steps toward the development of this bone phenotype as shown in in vitro and in vivo studies [32,40–48]. In addition, there are a growing number of retrospective [49–52] and large-scale prospective clinical trials [28–30] testing the hypothesis that atherosclerotic CAVD may be targeted with medical therapy. The pioneers in valve clinical trials designed studies prior to the publication of many of the experimental models [43,46,48,53], which confirm that statins attenuate the atherosclerotic lesion in the valve. As such, the only clinical trial to date to show an effect of lipid-lowering on AS progression: The Rosuvastatin Affecting Aortic Valve Endothelium to Slow the Progression of Aortic Stenosis trial (RAAVE), tested the hypothesis that treating elevated LDL compared to normal LDL patients, slows progression of CAVD [28]. This study was hypothesis driven and targeted specifically the hypothesis that elevated LDL is a significant risk factor for the progression of CAVD. Furthermore, the initial trials, SALTIRE, ASTRONOMER and SEAS, were designed with the traditional CAD trial design for lipid lowering, using combined vascular and valvular endpoints. The aim of this review is, therefore, to relate recent evidence [54] regarding the findings in the published trials on lipid-lowering therapy in AS, and how an improved biological understanding of valve calcification, namely the LDL-density-radius theory, may play a role in the design of future randomized clinical trials of medical therapy for CAVD. Randomized clinical trials of lipid lowering in AS SALTIRE
The first randomized prospective study testing the effects of statins in CAVD, SALTIRE, was published in 2005 [31]. In this double-blind, placebo-controlled trial, patients with calcific AS were randomly assigned to receive either 80 mg of atorvastatin daily or a matched placebo. Aortic valve stenosis and calcification were assessed with the use of Doppler echocardiography and helical computed tomography, respectively. The primary endpoints were change in aortic jet velocity and aortic valve calcium score; secondary endpoints were traditional vascular endpoints. The SALTIRE investigators demonstrated no statistically significant primary endpoints for the study. The clinical characteristics of the SALTIRE patient population are shown in TABLE 1. The vascular endpoints demonstrated 356
statistically significant improvement. The SALTIRE investigators concluded that intensive lipid-lowering therapy does not halt the progression of calcific AS or induce its regression [31] and the reason for this negative trial is the timing of therapy as shown in FIGURE 1 [31]. The study had full Institutional Review Board and informed consent, but no ClinicalTrials.gov registration due to the initiation of the trial prior to the International Committee of Journal Medical Editors requirements. RAAVE
In the RAAVE trial [28], performed a prospective trial of AS with Rosuvastatin targeting serum LDL slowed progression of echo hemodynamic measurements, and improved inflammatory biomarkers providing the first clinical evidence for targeted therapy in patients with asymptomatic AS. The aim of the study was to assess the effect of Rosuvastatin on hemodynamic progression and inflammatory markers of AS by treating LDL in patients with AS according to the NCEP-ATPIII guidelines for 1 year. The clinical characteristics of the RAAVE trial are shown in TABLE 2. Prospective treatment of moderate AS with Rosuvastatin targeting serum LDL did slow progression of echocardiographic parameters of AS compared with control that were not on statin therapy, improved inflammatory biomarkers and vascular endpoints demonstrating the first clinical evidence for targeted therapy in asymptomatic moderate-to-severe AS as shown in FIGURE 2 [28]. The RAAVE trial [28] had full Institutional Review Board informed consent and ClinicalTrials.gov registration [55]. SEAS
The largest clinical trial was the SEAS trial [29]. This trial is a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic AS. Again, similar to SALTIRE, there were fewer patients with ischemic cardiovascular events in the Simvastatin–Ezetimibe group (148 patients) than in the placebo group (187 patients); the authors noted that this was mainly because of the smaller number of patients who underwent coronary artery bypass grafting. Cancer occurred more frequently in the Simvastatin–Ezetimibe group (105 vs 70; p = 0.01). The investigators concluded that the medication did not reduce the composite outcome of combined aortic valve events in patients with AS, including echo progression and vascular endpoints. ASTRONOMER
ASTRONOMER [40], the most recent trial, also demonstrated negative randomized clinical results and included patients with bicuspid aortic valve disease. This was a randomized, doubleblind, placebo-controlled trial in asymptomatic patients with mild-to-moderate AS and no clinical indications for cholesterol lowering. The patients were randomized to receive either placebo or Rosuvastatin 40 mg daily. A total of 269 patients were randomized: 134 patients to Rosuvastatin 40 mg daily and 135 patients to placebo. Annual echocardiograms were performed to assess AS progression, which was the primary outcome; the median follow-up was 3.5 years. The peak AS gradient Expert Rev. Cardiovasc. Ther. 13(4), (2015)
Clinical trials in aortic valve disease
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Table 1. Clinical characteristics of the SALTIRE reprinted with permission from
Review
[31].
Characteristic
Atorvastatin (n = 77)
Placebo (n = 78)
Age-yr
68 + 11
68 + 10
Male sex – %
68
72
Hypertension – no.
48
54
Hyperlipidemia – no.
8
5
Diabetes mellitus – no.
3
4
Current smoker – no.
21
22
Coronary heart disease – no.
18
21
Cerebrovascular disease – no.
9
11
Peripheral vascular disease – no.
5
13
–Aspirin
43
40
–AVE inhibitor
12
14
–Beta-blocker
21
27
–Warfarin
8
12
Height-cm
168 ± 9
169 ± 8
Weight-kg
79 ± 15
80 ± 15
Heart rate – bpm
68 ± 11
66 ± 12
Systolic blood pressure – mmHg
144 ± 18
144 ± 21
Diastolic blood pressure – mmHg
82 ± 10
81 ± 12
– Total cholesterol – mg/dl
220 ± 38
127 ± 34
– LDL cholestero. – mg/dl
137 ± 34
133 ± 30
– Cholesterol HDL ratio
4.1 ± 1.1
4.1 ± 1.4
– Urea-mg/dl
38 ± 13
43 ± 13
– Creatinine – mg/dl
1.07 ± 0.25
1.08 ± 0.26
– Glucose – mg/dl
91 ± 19
95 ± 21
Sinus rhythm – %
94
92
Atrial fibrillation – %
6
8
Romhilt-Estes score – median (interquartile range)
1(0 – 3)
2(1 – 4)
Tricuspid aortic valve – %
96
97
Bicuspid aortic valve – %
4
3
Aortic jet velocity – m/sec
3.39 ± 0.62
3.45 ± 0.67
Peak gradient – mmHg
47.8 ± 17.4
49.5 ± 19.5
Aortic valve area – cm
1.03 ± 0.4
1.02 ± 0.41
Aortic valve calcium score – median AU (interquartile range)
5424 (2750 – 9689)
6221 (3037 – 9575)
Log aortic-valve calcium score – Log AU
3.7 ± 0.5
3.7 ± 0.6
Drug history – no.
†
Biochemistry
2
*Plus-minus values are means ± SD. † To convert values for cholesterol to millimoles per liter, multiply by 0,02586. To convert values for urea to millimoles per liter, multiply by 0.357. To convert values for creatinine to micromoles per liter by 88.4. ACE: Denotes angiotensin-converting enzyme; AU: Arbitrary units; HDL: High-density lipoprotein; LDL: Low-density lipoprotein.
informahealthcare.com
357
Review
Rajamannan, Greve, Moura, Best & Wachtell
A
B Log CT aortic-valve calcium score (AU)
4.5
Placebo Atorvastatin
4.0 3.5 3.0 2.5
5.0 4.5
Placebo Atorvastatin
4.0 3.5 3.0 2.5
0
0 0
12
24
0
36
12
77 77
36
No. of patients
No. of patients Placebo Atorvastatin
24 Months
Months
69 65
55 60
Placebo Atorvastatin
30 34
76 77
69 64
56 60
29 34
C p < 0.001
200 Serum LDL cholesterol concentration (mg/dl)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Aortic-jet velocity (m/sec)
5.0
150
100 50 Placebo Atorvastatin 0 0
12
24
36
Months No. of patients Placebo Atorvastatin
78 77
70 65
54 58
31 35
Figure 1. Clinical Results of the SALTIRE reprinted with permission from [31].
increased in patients receiving Rosuvastatin from a baseline of 40.8 ± 11.1–57.8 ± 22.7 mmHg at the end of follow-up and in patients with placebo from 41.6 ± 10.9 mmHg at baseline to 54.8 ± 19.8 mmHg at the end of follow-up. The annual increase in the peak AS gradient was 6.3 ± 6.9 mmHg in the Rosuvastatin group compared with 6.1 ± 8.2 mmHg in the placebo group (p = 0.83). Patients with metabolic syndrome had increased propensity to progress in this clinical study, indicating the importance of this risk factor in the disease progression and that the effect of metabolic syndrome [56] needs to be targeted as well as lowering LDL levels in patients with CAVD. Translating experimental evidence to randomized clinical trials
These three clinical trials have different results. TABLE 2 demonstrates the results from the SALTIRE study, and FIGURE 2 demonstrates the results from the RAAVE trial. This review evaluates two different trial designs, which measure the effect 358
of statins in aortic valve disease in different patient populations. Combining evidence from the published clinical trials and novel experimental evidence, we propose that from a translational perspective, the testing of the role of medical therapy for CAVD and design of the clinical trials can be improved with the application of the LDL-density-radius hypothesis [57]. The theory, as previously published [57] hypothesis, is related to two fundamental issues for these two similar but very different disease processes: first is the LDL effect and second is the difference in the radius between the aortic valve and that of the vessel. The theory refers to the concentration of the LDL as a density and the concept that the effect of LDL accumulates over time across the valve leaflet and also within the interior of the circumference of the artery. The understanding of the molecular biology of LDL, the effect of the accumulation of the lipids over time on the anatomic tissue, is critical for the future analysis of published trials Expert Rev. Cardiovasc. Ther. 13(4), (2015)
Clinical trials in aortic valve disease
Table 2. Clinical characteristics of the RAAVE reprinted with permission from Characteristic
Review
[28].
All patients (n = 121)
Statin-treated group (n = 61)
Untreated group (n = 60)
p-value
Age (yrs)
73.7 ± 8.9
73.4 ± 8.5
73.9 ± 9.4
0.749
Men, n (%)
57 (47.1)
21 (34.4)
36 (60.0)
0.006
Arterial hypertension, n (%)
77 (63.6)
45 (73.8)
32 (53.3)
0.024
Diabetes, n (%)
39 (32.2)
26 (42.6) 1
3 (21.7)
0.019
Smokers, n (%)
4 (3.3)
0 (0)
4 (6.7)
0.057
Sinus rhythm, n (%)
106 (87.6)
56 (91.8)
50 (83.3)
0.179
Diastolic blood pressure (mm Hg)
75.9 ± 12.9
78.4 ± 13.6
73.4 ± 13.6
0.033
Systolic blood pressure (mm Hg)
150.6 ± 22.9
154.4 ± 18.6
146.6 ± 26.2
0.060
Cardiac frequency (beats/min)
72.8 ± 13.0
73.8 ± 13.1
71.8 ± 12.8
0.379
Total cholesterol level (mg/dl)
217.7 ± 50.1
243.0 ± 40.5
192.0 ± 45.8
