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Original Article

Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis

List of authors.
  • Anne B. Rossebø, M.D.,
  • Terje R. Pedersen, M.D., Ph.D.,
  • Kurt Boman, M.D., Ph.D.,
  • Philippe Brudi, M.D.,
  • John B. Chambers, M.D.,
  • Kenneth Egstrup, M.D., Ph.D.,
  • Eva Gerdts, M.D., Ph.D.,
  • Christa Gohlke-Bärwolf, M.D.,
  • Ingar Holme, Ph.D.,
  • Y. Antero Kesäniemi, M.D., Ph.D.,
  • William Malbecq, Ph.D.,
  • Christoph A. Nienaber, M.D., Ph.D.,
  • Simon Ray, M.D.,
  • Terje Skjærpe, M.D., Ph.D.,
  • Kristian Wachtell, M.D., Ph.D.,
  • and Ronnie Willenheimer, M.D., Ph.D.
  • for the SEAS Investigators*

Abstract

Background

Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results.

Methods

We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events.

Results

During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin–ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin–ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin–ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97). Fewer patients had ischemic cardiovascular events in the simvastatin–ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), 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).

Conclusions

Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic-valve events and ischemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. (ClinicalTrials.gov number, NCT00092677.)

Introduction

Aortic-valve stenosis is common in elderly persons, with a prevalence of 3 to 5% in the population over 75 years of age. 1,2 The condition has been shown to be an inflammatory process associated with cardiovascular risk factors, with histopathological changes in the valve leaflets that are similar to those in other atherosclerotic diseases. 2-19 Changes in the aortic valve are associated with an increased risk of death from cardiovascular causes and myocardial infarction, even in the absence of hemodynamic obstruction and signs of coronary disease. 20-22 The standard treatment is surgical replacement when the valve becomes severely stenotic.23,24

Epidemiologic2 and genetic25,26 studies have identified risk factors for the development of aortic-valve stenosis, and experimental work has elucidated the cellular mechanisms involved in disease progression, many of which resemble atherosclerosis.27-30 One interpretation of these findings is that lipid-lowering treatment might prevent progression of aortic-valve stenosis and thus reduce the need for aortic-valve replacement.

The effect of statin treatment on aortic-valve stenosis has been assessed in several retrospective or small case–control studies.27,31-33 Most studies have suggested a beneficial effect of statins, whereas one prospective, randomized study did not find any effect of lipid-lowering therapy on the progression of aortic-valve stenosis.34

The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial was designed to study the effects of long-term, intensive cholesterol lowering with daily use of simvastatin and ezetimibe on clinical and echocardiographic outcomes in patients with asymptomatic, mild-to-moderate aortic-valve stenosis and no other indication for lipid-lowering treatment.

Methods

Patient Population

The study design and baseline characteristics of the patients have been reported previously.35 Men and women between the ages of 45 and 85 years who had asymptomatic, mild-to-moderate aortic-valve stenosis, as assessed on echocardiography, with a peak aortic-jet velocity of 2.5 to 4 m per second, were eligible for the study. Patients were excluded if they had received a diagnosis or had symptoms of coronary artery disease, peripheral arterial disease, cerebrovascular disease, or diabetes mellitus or if they had any other condition requiring lipid-lowering therapy. The study was approved by all relevant institutional ethics committees or by ethics committees in each country, and all patients provided written informed consent.

Study Protocol

The study was initiated by the investigators and was designed by the steering committee on the basis of a protocol developed for the Simvastatin in Aortic Stenosis (SAS) study,35 which evaluated the effect of lipid-lowering therapy with simvastatin (at a dose of 40 to 80 mg) as compared with placebo on clinical and echocardiographic outcomes in patients with aortic stenosis. The SAS study was sponsored by Merck but was otherwise managed by the SAS study steering committee.

Figure 1. Figure 1. Enrollment and Outcomes.

SAS denotes the Simvastatin in Aortic Stenosis Study.

From March 2001 through December 2002, a total of 196 patients underwent randomization. To improve the lipid-lowering effect while decreasing the risk of myopathy, the steering committee decided to add ezetimibe (at a dose of 10 mg daily) to 40 mg of simvastatin in the larger SEAS trial, as suggested by the sponsor. The responsibility for the logistics of the SEAS trial was transferred to the sponsor, but the scientific responsibility remained with the independent steering committee, which included two nonvoting members of the sponsor.35 The patients who were assigned to receive simvastatin in the SAS study remained in the active-treatment group in the SEAS trial, in which ezetimibe was added to simvastatin, and the patients in the SAS placebo group remained in the SEAS placebo group. During this process, neither the patients nor the investigators were aware of study-group assignments. After a 4-week run-in period in which all patients were given single-blind placebo tablets and were instructed to follow a lipid-lowering diet according to the recommendations of the National Cholesterol Education Program,36 eligible patients underwent randomization in a 1:1 fashion in blocks of two to receive either simvastatin–ezetimibe or placebo (Figure 1).

Open-label lipid-lowering therapy, which included up to 40 mg of simvastatin or an equipotent dose of another lipid-lowering drug, could be administered in addition to the study drug at the discretion of each treating physician, although patients and investigators remained unaware of study-group assignments. The numbers of patients receiving open-label therapy are shown in Figure 1.

The study was completed according to the protocol when all patients had been followed for a minimum of 4 years after randomization, at which point the primary outcome had occurred in at least 464 patients.35

The SEAS steering committee designed the study and vouches for the accuracy and completeness of the data and the analysis. The sponsor gathered the data; the Echocardiography Core Laboratory read the locally recorded echocardiograms. The statistical analysis was performed by Merck, according to a predefined protocol. In addition, parallel statistical analysis with the use of SPSS software (version 15.0) was performed on raw data by an independent statistician, a process that generated identical results. The first draft of the manuscript was written by the lead academic author.

Efficacy Outcomes

The primary outcome of the study was major cardiovascular events, a composite consisting of death from cardiovascular causes, aortic-valve replacement, congestive heart failure as a result of progression of aortic-valve stenosis, nonfatal myocardial infarction, hospitalization for unstable angina, coronary-artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or nonhemorrhagic stroke. The primary composite outcome included aortic-valve–related clinical events and ischemic events to account for possible cardiovascular symptoms and events occurring in patients with aortic-valve stenosis.21

Key secondary outcomes were aortic-valve events (which were defined as aortic-valve replacement surgery, congestive heart failure due to aortic stenosis, or death from cardiovascular causes) and ischemic events (which were defined as death from cardiovascular causes, nonfatal myocardial infarction, hospitalization for unstable angina, CABG, PCI, or nonhemorrhagic stroke). Other secondary objectives were progression of aortic stenosis, as seen on echocardiography, and the safety of the study drugs.

All outcomes were classified by an independent end-point classification committee whose members were unaware of study-group assignments. The data and safety monitoring board performed four preplanned interim analyses of efficacy and safety,35 as well as two extra analyses of safety.

Echocardiography was performed at baseline and then annually and before valve surgery, according to a standardized echocardiographic protocol.37 All images were recorded on Video Home System videotape or digitally in Digital Imaging and Communications in Medicine format on compact disk or magneto-optical disk and were forwarded to the SEAS Echocardiography Core Laboratory at Haukeland University Hospital in Bergen, Norway. All readings were performed according to the American Society of Echocardiography guidelines38 with the use of an off-line digital computerized review system on workstations with Image Arena software (TomTec Imaging Systems). The readers were unaware of the sequence and site in order to minimize bias.

Statistical Analysis

The study outcomes were analyzed according to the intention-to-treat principle. The study had a power of 90% to detect a reduction of 22% in the relative risk of the primary outcome. For all time-to-event outcomes, survival analytic methods were used, with analyses based on a Cox proportional-hazards model.

Analyses were performed with the use of SAS software, version 8.2. For aortic-stenosis progression, the analysis included data from all patients with at least one baseline and one follow-up measurement. For analyses of adverse events, confidence intervals for differences in proportions of patients were computed with the method of Miettinen and Nurminen and with Fisher's exact test, when appropriate. Tests were generally performed at a two-sided significance level of 0.05, except that for the primary outcome, which was performed at a significance level of 0.0490 to account for interim analyses.

Data on adverse events were collected from all patients who underwent follow-up and analysis, with the exception of nonfatal events that did not require hospitalization and that occurred at least 15 days after the discontinuation of study drug or placebo, according to the protocol.

Results

Patients

Table 1. Table 1. Baseline Characteristics of the Patients.

A total of 1873 patients underwent randomization at 173 study sites in seven European countries.35 Of these patients, 944 were assigned to receive 40 mg of simvastatin and 10 mg of ezetimibe daily, and 929 were assigned to receive placebo. Baseline demographic, laboratory, and echocardiographic data for the two study groups are shown in Table 1. The median follow-up period was 52.2 months.

Lipids

Figure 2. Figure 2. Serum Low-Density Lipoprotein (LDL) Cholesterol Levels (Panel A) and the Change from Baseline in Peak Aortic-Jet Velocity (Panel B).

The I bars represent standard errors. In Panel A, the first data points correspond to results at the 8-week visit.

The mean serum level of low-density lipoprotein (LDL) cholesterol remained unchanged in the placebo group and decreased by 61.3%, to a mean (±SD) level of 53±23 mg per deciliter (1.36±0.60 mmol per liter) at 8 weeks, in the simvastatin–ezetimibe group. During the entire follow-up period, the mean percent reduction in LDL cholesterol was 53.8% in the simvastatin–ezetimibe group and 3.8% in the placebo group (Figure 2A).

Outcome Measures

Table 2. Table 2. Prespecified Primary and Secondary Composite Outcomes and Death. Figure 3. Figure 3. Kaplan–Meier Curves for Primary and Secondary Outcomes and Death.

The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke (Panel A). Secondary outcomes were events related to aortic-valve stenosis (Panel B) and ischemic cardiovascular events (Panel C). There was no difference between the study groups in overall mortality (Panel D).

The primary composite outcome occurred in 333 patients (35.3%) in the simvastatin–ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin–ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59) (Table 2 and Figure 3A).

There was no significant difference between the two study groups in the secondary outcome of aortic-valve–related events, including aortic-valve replacement, death from cardiovascular causes, and hospitalization for heart failure as a consequence of progression of aortic stenosis (hazard ratio, 0.97; 95% CI, 0.83 to 1.14; P=0.73) (Figure 3B). The principal component of this secondary composite outcome was aortic-valve replacement, which occurred in 267 patients (28.3%) in the simvastatin–ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97).

There were fewer patients with the secondary composite outcome of ischemic cardiovascular events in the simvastatin–ezetimibe group (148 patients, or 15.7%) than in the placebo group (187 patients, or 20.1%) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02) (Table 2 and Figure 3C). The treatment effect was dominated by a significant reduction in the need for CABG, with 69 patients (7.3%) in the simvastatin–ezetimibe group, as compared with 100 patients (10.8%) in the placebo group, undergoing the procedure (hazard ratio, 0.68; 95% CI, 0.50 to 0.93; P=0.02). All but one of the CABG procedures were performed together with aortic-valve replacement.

Effect on Progression

In the placebo group, the mean (±SD) peak aortic-jet velocity was 3.71±0.76 m per second at the end of the study, an increase of 0.62±0.61 m per second. This change was similar to that in the simvastatin–ezetimibe group, in which the velocity was 3.69±0.78 m per second at the end of the study, an increase of 0.61±0.59 m per second (95% CI, −0.06 to 0.05; P=0.83) (Figure 2B). This was the predefined key echocardiographic measure for the evaluation of progression of aortic stenosis. In the placebo group, the mean pressure gradient was 22.5±8.5 mm Hg at baseline and increased to 34.4±14.9 mm Hg at the end of the study, as compared with a value of 22.2±8.5 mm Hg at baseline with an increase to 34.0±15.1 mm Hg in the simvastatin–ezetimibe group. Neither the difference between the two groups at either time point nor the difference in the change from baseline in the aortic-valve area was significant. Annualized changes in the mean (±SE) peak aortic-jet velocity were 0.15±0.01 m per second per year in the simvastatin–ezetimibe group and 0.16±0.01 m per second per year in the placebo group. The mean transaortic pressure gradient increased by 2.7±0.1 mm Hg per year in the simvastatin–ezetimibe group and by 2.8±0.1 mm Hg per year in the placebo group. There was an annualized reduction in the aortic-valve area of 0.03±0.01 cm2 per year in each of the two groups.

Mortality

There was no significant difference between the study groups in overall mortality (Table 2 and Figure 3D). The composite outcome of death from cardiovascular causes and the components of this composite outcome also did not differ significantly between the two groups.

Deaths from noncardiovascular causes occurred in 56 patients (5.9%) in the simvastatin–ezetimibe group and in 44 patients (4.7%) in the placebo group (hazard ratio in the simvastatin–ezetimibe group, 1.26; 95% CI, 0.85 to 1.86; P=0.26). The numbers of fatal cancers were 39 (4.1%) in the simvastatin–ezetimibe group and 23 (2.5%) in the placebo group (hazard ratio, 1.67; 95% CI, 1.00 to 2.79; P=0.05 according to the prespecified data-analysis plan; P=0.06 with Yates' continuity correction) (Table 2). Of these patients, one in the simvastatin–ezetimibe group and three in the placebo group died from recurrent cancers, plus one patient in the simvastatin–ezetimibe group died from cancer that was diagnosed in the SAS trial, before entry into the SEAS trial.

Adverse Events

Table 3. Table 3. Adverse Events (Safety Population).

There was a significant increase in the number of patients with elevated liver enzyme levels in the simvastatin–ezetimibe group, as compared with the placebo group, during the study period (Table 3). There were no differences in clinical, organ-related adverse events, except for significantly higher incident cancers in the simvastatin–ezetimibe group (Table 3).

Cancer

Table 4. Table 4. Incident Cancer (Safety Population). Figure 4. Figure 4. Kaplan–Meier Curves for Cancer-Related Mortality.

P=0.06 as calculated with log-rank continuity correction.

In the simvastatin–ezetimibe group, incident cancer was diagnosed in 105 patients (11.1%), as compared with 70 patients (7.5%) in the placebo group (P=0.01). Cancers that had been diagnosed before randomization recurred in eight of these patients (three in the simvastatin–ezetimibe group and five in the placebo group), and one patient had a cancer that developed during the SAS trial, before enrollment in the SEAS trial. The excess cancers in the simvastatin–ezetimibe group were not clustered at any particular site (Table 4). In addition, the risk of incident cancer was not associated with the degree of LDL-cholesterol lowering. Figure 4 shows Kaplan–Meier curves for cancer-related mortality in the two study groups.

Discussion

The combination of simvastatin and ezetimibe resulted in an average reduction in LDL cholesterol of at least 50%, as compared with placebo. Despite this favorable effect over a minimum period of 4 years, there was no overall effect on aortic-valve stenosis and no significant overall effect on the composite primary outcome. The lack of any effect on the progression of aortic stenosis as seen on echocardiography supports the conclusion that the lack of effect on clinical valve-related events was real and not due to a lack of statistical power. The finding of increased numbers of incident and fatal cancers in the simvastatin–ezetimibe group, as compared with the placebo group, was unexpected and requires further exploration in trials of simvastatin and ezetimibe.

The lack of effect on aortic-valve stenosis is in agreement with the findings of the smaller Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) study, in which atorvastatin was used.34 The results of the Rosuvastatin Affecting Aortic Valve Endothelium (RAAVE) study (ClinicalTrials.gov number, NCT00114491) indicated a favorable effect on aortic stenosis, but the study had a nonrandomized and open-label design, with comparisons of various categories of patients with aortic stenosis.39

Our study population did not represent all patients with aortic-valve stenosis, since high-risk patients with severe hyperlipidemia requiring active lipid-lowering treatment, known atherosclerotic disease, or diabetes mellitus were not included in order to allow for placebo treatment. This factor may explain the relatively low rate of progression of aortic-valve stenosis in our study, as compared with that in other studies.34,40 Otherwise, the patients in our study had characteristics that are typical of patients with aortic stenosis. It is possible that treatment in our study was initiated too late in the course of the disease to affect further progression, but it is also possible that high levels of LDL cholesterol are just a marker for progression of stenosis.

Therapy with simvastatin and ezetimibe resulted in a significant reduction in the risk of ischemic cardiovascular events, mainly through fewer CABG procedures. Since nearly all coronary surgery was performed as a combined procedure with aortic-valve replacement, the study-drug regimen may have had a substantial effect on atherosclerosis, as shown on coronary angiography. However, the reduction in the risk of other components of the secondary ischemic outcome was smaller than expected on the basis of the large reduction in LDL cholesterol levels.41 There was a weaker relationship between baseline LDL cholesterol levels and any ischemic event in the placebo group than was seen in studies in high-risk populations, suggesting less potential for risk reduction with lipid-lowering therapy.

Long-term statin therapy has not been associated with an increased risk of cancer. Analysis of data from 14 statin trials involving approximately 90,000 patients showed no evidence of an increased incidence of or death from cancer.41 However, ezetimibe has been studied less extensively than statins, and the finding of a significant difference between the two study groups in the numbers of patients with new and fatal cancers is a concern. In this issue of the Journal, Peto et al.42 describe the results of an independent analysis of preliminary data on cancer from two large, ongoing studies, the Study of Heart and Renal Protection (SHARP) (NCT00125593) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878).42 Both trials tested the same study-drug combination that we used in our study, though in other patient populations and with a combined study population of nearly 20,000 patients. Cancer was one of a very large number of safety indicators analyzed in the SEAS trial, and the observed difference in cancer rates in the study may have been the result of chance, but this possibility requires further study.

We conclude that in patients with mild-to-moderate, asymptomatic aortic-valve stenosis and no traditional indications for lipid-lowering therapy at baseline, long-term, intensive lipid-lowering therapy with simvastatin and ezetimibe had no overall effect on the course of aortic-valve stenosis. However, lipid-lowering therapy reduced the risk of ischemic cardiovascular events, especially the need for CABG. The higher incidence of cancer in the simvastatin–ezetimibe group requires further exploration in ongoing and future trials.

Funding and Disclosures

Supported by Merck and Schering-Plough Pharmaceuticals.

Drs. Rossebø and Wachtell report receiving consulting fees from Merck and research support from Merck and Schering-Plough; Dr. Pedersen, receiving consulting fees from Merck and Schering-Plough and lecture fees from Pfizer and AstraZeneca; Dr. Boman, receiving lecture fees from AstraZeneca, Merck, and Schering-Plough and consulting fees from Merck; Drs. Brudi and Malbecq, being employees of Merck and having an equity interest in the company; Dr. Chambers, receiving consulting and lecture fees from St. Jude Medical; Dr. Egstrup, receiving consulting and lecture fees from Merck and Pfizer and lecture fees from AstraZeneca; Dr. Gerdts, receiving grant support and consulting fees from Merck; Dr. Gohlke-Bärwolf, receiving consulting and lecture fees from Merck; Dr. Holme, receiving consulting fees from Merck and lecture fees from Merck and Pfizer; Dr. Kesäniemi, receiving consulting fees from AstraZeneca, Merck, Pfizer, and Schering-Plough, lecture fees from AstraZeneca, Merck, and Schering-Plough, and research support from Merck, Novartis, and Schering-Plough and having an equity interest in Orion Pharma; Dr. Nienaber, receiving lecture fees from Merck, Pfizer, and Essex; Dr. Skjærpe, receiving consulting fees from Merck; Dr. Ray, receiving lecture fees from Merck; and Dr. Willenheimer, receiving lecture fees from Merck and Schering-Plough and consulting fees from Merck. No other potential conflict of interest relevant to this article was reported.

This article (10.1056/NEJMoa0804602) was published at www.nejm.org on September 2, 2008.

Author Affiliations

The authors' affiliations are listed in the Appendix.

Address reprint requests to Dr. Rossebø at the Division of Cardiology, Aker University Hospital, Trondheimsveien 235, N-0514 Oslo, Norway, or at .

Members of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study committees and other investigators are listed in the Appendix.

Appendix

The authors' affiliations are as follows: Aker University Hospital (A.B.R.); Center for Preventive Medicine, Ullevål University Hospital (T.R.P., I.H.); and Faculty of Medicine, University of Oslo (T.R.P.) — all in Oslo; Skellefteå Hospital, Skellefteå, and the Institution of Public Health and Clinical Medicine, Umeå University, Umeå — both in Sweden (K.B.); Merck−Schering-Plough, Whitehouse Station, NJ (P.B.); Guy's and St. Thomas' Hospitals, London (J.B.C.); Svendborg Hospital, Svendborg, Denmark (K.E.); University of Bergen and Haukeland University Hospital, Bergen, Norway (E.G.); Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany (C.G.-B.); University of Oulu, Biocenter Oulu, Oulu, Finland (Y.A.K.); MSD Europe, Brussels (W.M.); Universitätsklinikum Rostock, Rostock, Germany (C.A.N.); University Hospitals of South Manchester, Manchester, United Kingdom (S.R.); St. Olavs Hospital, Trondheim, Norway (T.S.); the Heart Center, Rigshospitalet, Copenhagen (K.W.); and Lund University and Heart Health Group, Malmö, Sweden (R.W.).

The following committee members and primary investigators from clinical centers participated in the study: Steering Committee: Norway: T.R. Pedersen (chair), A.B. Rossebø (coordinator), E. Gerdts (head of Echocardiography Core Laboratory), T. Skjærpe, I. Holme (statistician); Sweden: R. Willenheimer, K. Boman; Denmark: K. Wachtell, K. Egstrup; Finland: Y.A. Kesäniemi; Germany: C. Gohlke-Bärwolf, C. Nienaber; United Kingdom and Ireland: J. Chambers, S. Ray; nonvoting members: P. Brudi, W. Malbecq. End-Point Classification Committee: Denmark: C. Hassager; Norway: T. Gundersen. Data and Safety Monitoring Board: United Kingdom: D. Julian (chair), S.J. Pocock; Norway: J. Kjekshus. Merck Monitoring Offices: Norway: G. Karlsen; United States: G. McPeters. National Project Leaders: Denmark: G.S. Andersen; Finland: P. Koskinen, I. Puhakainen; Germany: A. Ketter, H. Ansari Esfahani, M. Meergans; Ireland: N. Farrelly, C. Parish; Norway: V. Larsen; Sweden: H. Boström, L. Bergvall; United Kingdom: K. Wincott. Investigators: Denmark (330 patients): J. Abdulla, F. Akrawi, J. Berning, K.L. Christensen, P. Clemmensen, D. Dalsgaard, F.J. Davidsen, U. Dixen, A. Dorph-Petersen, K.K. Dodt, K. Egstrup, H. Elming, B. Engby, G. Espersen, H.K.B. Franow, M. Frederiksen, E. Friis, T.K. Glud, P. Grande, O. Gøtzsche, D. Haar, D. Hansen, J.F. Hansen, M.G. Hansen, C. Hassager, D.E. Høfsten, N. Høst, L. Iemming, G. Jensen, J. Jensen, J. Jeppesen, J. Kjærgaard, L. Kjøller-Hansen, I.C. Klausen, E. Korup, J.E.H. Kristensen, K. Kristensen, J. Larsen, K. Lindvig, O. May, T. Melchior, A. McNair, E.S. Nielsen, H. Nielsen, J.E.R. Nielsen, T. Niemann, J.F. Olsen, M.E. Olsen, M. Ottesen, A.T. Pedersen, S.H. Poulsen, N. Ralskiær, B. Rasmussen, H. Rasmussen, J. Rasmussen, S.L. Rasmussen, J. Rosenberg, N. Roseva-Nielsen, M. Scheibel, E.B. Schmidt, M. Schou, K. Schultz, M. Seibæk, H. Sortsøe, S.E. Stentebjerg, T.L. Svendsen, R. Sykulski, E.V. Sørensen, K.K. Thomsen, J. Thorsen, C. Tuxen, C. Tveskov, H. Ulriksen. Finland (221 patients): J. Ahonen, E. Engblom, K. Groundstroem, J. Haapanen, T. Jerkkola, T. Jääskeläinen, E. Kanniainen, H. Kervinen, K. Kervinen, A.Y. Kesäniemi, P. Kettunen, R. Kettunen, K. Kiilavuori, J. Kuusisto, J. Lilleberg, A. Seppälä-Lindroos, J. Melin, J.N. Mustonen, M. Nikkilä, J. Nurminen, R. Pajari, K. Peuhkurinen, P. Raasakka, T. Terho, T. Tiensuu, A. Turpeinen, S.O. Utriainen, P. Uusimaa, T. Vihinen, A. Ylitalo. Germany (292 patients): J. Arenz, E. Bahlmann, M. Bangert, C. Bauknecht, F. Bea, L. Berchem, P. Berhardt, E. Blessing, L.-H. Boldt, A.C. Borges, D. Boscher, R. Brandt, G. Breithardt, T. Böhmeke, M. Baar, C. Diefenbach, R. Doliva, S. Drawert, K. Droese, H.-D. Düngen, F. Edelmann, O. Franzen, M. Freyland, J. Gadow, S. Gehlhar, U. Gerk, K. Giokoglu, H. Gohlke, C. Gohlke-Bärwolf, M. Guha, L. Görnand, A. Hafer, C. Hamm, F. Hartmann, C. Hegeler, T. Heitzer, D. Horstkotte, N. Jander, F. Kaden, B. Keweloh, A. Kilkowski, F. Knebel, G. Kober, N. Kokott, N.O. Krekel, J. Kreuzer, I. Kruck, S. Kuhls, R. Lange, S.A. Lange, H.-M. Lorenz, J. Lüdecke, D. Mathey, B. Mayer, K.-P. Mellwig, R. Moebes, T. Münzel, C. Nienaber, H. Omran, K.J. Osterziel, J.-W. Park, M. Petzsch, P. Pinick, T. Pomykaj, M. Preusch, N. Proskynitopoulos, B. Rauch, T. Rehders, U. Reichert, S. Reichl, H. Reinicke, I. Richter, H. Sachs, F. Salzer, W. Sanad, A. Schmidt, H. Schmidt, A. Schnabel, C. Schneider, J. Schofer, A. Schramm, A. Schreckenberg, A. Schumacher, H. Schunkert, J. Schäfer, K. Stangl, D. Steven, R. Strasser, C. Tack, F. Thuneke, C. Troatz, G. Tsogias, T. Tübler, K. von Olshausen, C. Vahlhaus, C. Viedt, C. Weiler, M. Werle, T. Wichter, R. Winkler, H. Worth, J. Wunderlich, Z. Zagoric. Ireland (17 patients): N. Colwell, P.A. Crean, J. Crowley, D.P. Foley, D.P. Moore, C.J. Vaughan. Norway (425 patients): A. Al-Ani, K. Andersen, K.-H. Arntzen, R. Bjørnerheim, V.V.S. Bonarjee, E. Bøhmer, E.S. Davidsen, G.D.W. Eveborn, J.E. Falang, D. Fausa, G. Frøland, E. Gerdts, G. Gradek, T. Graven, M. Grundtvig, T. Grønvold, T. Gundersen, B.A. Halvorsen, B.K. Haug, A. Heskestad, K.A. Hofsøy, T. Hole, G. Høgalmen, H. Ihlen, T.O. Klemsdal, B. Klykken, K.M. Knutsen, A. Koss, P. Lem, A. Lied, E.S.P. Myhre, T. Nerdrum, A. Ose, T.R. Pedersen, A.B. Rossebø, R. Rød, S. Samstad, A.G. Semb, P.A. Sirnes, G.K. Skjelvan, T. Skjærpe, T.R. Snaprud, T.I. Stakkevold, K. Steine, H.A. Tjønndal, D. Torvik, T.P. Ugelstad, B. Undheim, J.Å. Vegsundvåg, A. von der Lippe, M. von Rosen, E. Vaage, N. Walde, L. Woie, K. Waage, S. Aakhus, E. Aaser. Sweden (401 patients): G. Agert, G. Ahlberg, P. Ahlström, K. Andersson, L. Andersson, T. Aronsson, B. Atmer, U. Axelsson, C. Backman, S. Bandh, S.-E. Bartfay, H. Bastani, O. Bech-Hanssen, S. Berglund, A. Bergström, Ö. Bjuhr, J. Blomgren, K. Boman, M. Broqvist, R. Carlsson, P. Cherfan, K. deSilva, E. Diderholm, C. Digerfeldt, A. Dilan, A. Ebrahimi, J. Ellström, V. Ercegovac, J. Eskilsson, L. Falk, O. Fredholm, B.-O. Fredlund, B. Fredriksson, M. Frisk, G. Gustafsson, P.-E. Gustafsson, C. Hammar, A. Henriksson, P. Henriksson, J. Herlitz, L. Hjelmaeus, C. Höglund, L. Illés, J.-H. Jansson, M. Jensen-Urstad, J. Johansson, L. Johansson, T. Jonson, T. Juhlin, A. Juhlin-Dannfelt, L. Juntti-Larsson, F. Karlsson, L. Klintberg, T. Kronvall, P. Kvidal, A. Kåregren, A.-C. Larsson, S. Liljedahl, R. Lindberg, B. Linde, M. Lycksell, P. Löfdahl, I. Lönnberg, A. Martinsson, A. Modica, T. Mooe, P.-Å. Moström, N.E. Nielsen, O. Nilsson, F. Noberius, U. Näslund, P. Nyman, Å. Ohlsson-Önerud, S.-E. Olsson, K. Pedersen, B. Persson, F. Randers, M. Risenfors, K. Rodmar, A. Roijer, E. Rydberg, G. Rüter, S. Sandgren, M. Schaufelberger, D. Serban, B. Shams, L. Svennberg, K. Svensson, O. Svensson, P. Szecsödy, J. Thollander, D. Ticic, K. Tolagen, Z. Trivic, H. Tygesen, G. Ulvenstam, J. Viklund, U. Wedén, S. Wiberg, R. Willenheimer, P. Wodlin, M.-L. Zethson-Halldén, R. Zlatewa, H. Öhlin, J. Åberg. United Kingdom (187 patients): P. Adams, B. Anantharam, M. Behan, N. Boon, C. Brookes, N. Campbell, N. Capps, N. Chalal, J. Chambers, G. Clesham, C. Davidson, D. Dutka, I. Findlay, A.G. Fraser, J. Glover, N. Goodfield, J. Grapsa, I. Haq, D. Hildick-Smith, B. Howarth, P. Howarth, H. Kadr, B. Kneale, P. Kumar, P.S. Lewis, M. Liodakis, G. Lloyd, P. McKeown, A. McLeod, J. McMurray, P. Nihoyannopoulos, S. Ray, R. Senior, W. Taggu, R. Veasey, D. Walker.

References (42)

  1. 1. Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol 1993;21:1220-1225

  2. 2. Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease: Cardiovascular Health Study. J Am Coll Cardiol 1997;29:630-634

  3. 3. Agmon Y, Khandheria BK, Meissner I, et al. Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? Insights from a population-based study. J Am Coll Cardiol 2001;38:827-834

  4. 4. Aronow WS, Schwartz KS, Koenigsberg M. Correlation of serum lipids, calcium, and phosphorus, diabetes mellitus and history of systemic hypertension with presence or absence of calcified or thickened aortic cusps or root in elderly patients. Am J Cardiol 1987;59:998-999

  5. 5. Deutscher S, Rockette HE, Krishnaswami V. Diabetes and hypercholesterolemia among patients with calcific aortic stenosis. J Chronic Dis 1984;37:407-415

  6. 6. Hoagland PM, Cook EF, Flatley M, Walker C, Goldman L. Case-control analysis of risk factors for presence of aortic stenosis in adults (age 50 years or older). Am J Cardiol 1985;55:744-747

  7. 7. Lindroos M, Kupari M, Valvanne J, Strandberg T, Heikkila J, Tilvis R. Factors associated with calcific aortic valve degeneration in the elderly. Eur Heart J 1994;15:865-870

  8. 8. Mautner GC, Mautner SL, Cannon RO III, Hunsberger SA, Roberts WC. Clinical factors useful in predicting aortic valve structure in patients >40 years of age with isolated valvular aortic stenosis. Am J Cardiol 1993;72:194-198

  9. 9. Mohler ER, Sheridan MJ, Nichols R, Harvey WP, Waller BF. Development and progression of aortic valve stenosis: atherosclerosis risk factors -- a causal relationship? A clinical morphologic study. Clin Cardiol 1991;14:995-999

  10. 10. Novaro GM, Pearce GL, Sprecher DL, Griffin BP. Comparison of cardiovascular risk and lipid profiles in patients undergoing aortic valve surgery versus those undergoing coronary artery bypass grafting. J Heart Valve Dis 2001;10:19-24

  11. 11. Novaro GM, Sachar R, Pearce GL, Sprecher DL, Griffin BP. Association between apolipoprotein E alleles and calcific valvular heart disease. Circulation 2003;108:1804-1808

  12. 12. O'Brien KD, Kuusisto J, Reichenbach DD, et al. Osteopontin is expressed in human aortic valvular lesions. Circulation 1995;92:2163-2168

  13. 13. O'Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of `degenerative' valvular aortic stenosis. Arterioscler Thromb Vasc Biol 1996;16:523-532

  14. 14. Olsson M, Rosenqvist M, Nilsson J. Expression of HLA-DR antigen and smooth muscle cell differentiation markers by valvular fibroblasts in degenerative aortic stenosis. J Am Coll Cardiol 1994;24:1664-1671

  15. 15. Olsson M, Dalsgaard CJ, Haegerstrand A, Rosenqvist M, Ryden L, Nilsson J. Accumulation of T lymphocytes and expression of interleukin-2 receptors in nonrheumatic stenotic aortic valves. J Am Coll Cardiol 1994;23:1162-1170

  16. 16. Olsson M, Thyberg J, Nilsson J. Presence of oxidized low density lipoprotein in nonrheumatic stenotic aortic valves. Arterioscler Thromb Vasc Biol 1999;19:1218-1222

  17. 17. Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O'Brien KD. Characterization of the early lesion of `degenerative' valvular aortic stenosis: histological and immunohistochemical studies. Circulation 1994;90:844-853

  18. 18. Palta S, Pai AM, Gill KS, Pai RG. New insights into the progression of aortic stenosis: implications for secondary prevention. Circulation 2000;101:2497-2502

  19. 19. Pohle K, Otte M, Maffert R, et al. Association of cardiovascular risk factors to aortic valve calcification as quantified by electron beam computed tomography. Mayo Clin Proc 2004;79:1242-1246

  20. 20. Cosmi JE, Kort S, Tunick PA, et al. The risk of the development of aortic stenosis in patients with “benign” aortic valve thickening. Arch Intern Med 2002;162:2345-2347

  21. 21. Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med 1999;341:142-147

  22. 22. Otto CM. Aortic stenosis: even mild disease is significant. Eur Heart J 2004;25:185-187

  23. 23. Bonow RO, Carabello BA, Chatterjee K, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48:e1-e148[Erratum, J Am Coll Cardiol 2007;49:1014.]

  24. 24. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart disease. Eur Heart J 2007;28:230-268

  25. 25. Bosse Y, Mathieu P, Pibarot P. Genomics: the next step to elucidate the etiology of calcific aortic valve stenosis. J Am Coll Cardiol 2008;51:1327-1336

  26. 26. Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature 2005;437:270-274

  27. 27. Rajamannan NM, Subramaniam M, Springett M, et al. Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation 2002;105:2660-2665

  28. 28. Rajamannan NM, Subramaniam M, Rickard D, et al. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation 2003;107:2181-2184

  29. 29. Rajamannan NM, Nealis TB, Subramaniam M, et al. Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation. Circulation 2005;111:3296-3301

  30. 30. Rajamannan NM, Bonow RO, Rahimtoola SH. Calcific aortic stenosis: an update. Nat Clin Pract Cardiovasc Med 2007;4:254-262

  31. 31. Novaro GM, Tiong IY, Pearce GL, Lauer MS, Sprecher DL, Griffin BP. Effect of hydroxymethylglutaryl coenzyme A reductase inhibitors on the progression of calcific aortic stenosis. Circulation 2001;104:2205-2209

  32. 32. Rosenhek R, Rader F, Loho N, et al. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004;110:1291-1295

  33. 33. Shavelle DM, Takasu J, Budoff MJ, Mao S, Zhao XQ, O'Brien KD. HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet 2002;359:1125-1126

  34. 34. Cowell SJ, Newby DE, Prescott RJ, et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389-2397

  35. 35. Rossebo AB, Pedersen TR, Allen C, et al. Design and baseline characteristics of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Am J Cardiol 2007;99:970-973

  36. 36. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497

  37. 37. Cramariuc D, Rieck AE, Staal EM, et al. Factors influencing left ventricular structure and stress-corrected systolic function in men and women with asymptomatic aortic valve stenosis (a SEAS substudy). Am J Cardiol 2008;101:510-515

  38. 38. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440-1463

  39. 39. Moura LM, Ramos SF, Zamorano JL, et al. Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. J Am Coll Cardiol 2007;49:554-561

  40. 40. Otto CM, Pearlman AS, Gardner CL. Hemodynamic progression of aortic stenosis in adults assessed by Doppler echocardiography. J Am Coll Cardiol 1989;13:545-550

  41. 41. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-1278[Erratum, Lancet 2005:366:1358, 2008;371:2084.]

  42. 42. Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008;359:1357-1366

Citing Articles (1099)

Only the 1000 most recent citing articles are listed here.

    Letters

    Figures/Media

    1. Figure 1. Enrollment and Outcomes.
      Figure 1. Enrollment and Outcomes.

      SAS denotes the Simvastatin in Aortic Stenosis Study.

    2. Table 1. Baseline Characteristics of the Patients.
      Table 1. Baseline Characteristics of the Patients.
    3. Figure 2. Serum Low-Density Lipoprotein (LDL) Cholesterol Levels (Panel A) and the Change from Baseline in Peak Aortic-Jet Velocity (Panel B).
      Figure 2. Serum Low-Density Lipoprotein (LDL) Cholesterol Levels (Panel A) and the Change from Baseline in Peak Aortic-Jet Velocity (Panel B).

      The I bars represent standard errors. In Panel A, the first data points correspond to results at the 8-week visit.

    4. Table 2. Prespecified Primary and Secondary Composite Outcomes and Death.
      Table 2. Prespecified Primary and Secondary Composite Outcomes and Death.
    5. Figure 3. Kaplan–Meier Curves for Primary and Secondary Outcomes and Death.
      Figure 3. Kaplan–Meier Curves for Primary and Secondary Outcomes and Death.

      The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke (Panel A). Secondary outcomes were events related to aortic-valve stenosis (Panel B) and ischemic cardiovascular events (Panel C). There was no difference between the study groups in overall mortality (Panel D).

    6. Table 3. Adverse Events (Safety Population).
      Table 3. Adverse Events (Safety Population).
    7. Table 4. Incident Cancer (Safety Population).
      Table 4. Incident Cancer (Safety Population).
    8. Figure 4. Kaplan–Meier Curves for Cancer-Related Mortality.
      Figure 4. Kaplan–Meier Curves for Cancer-Related Mortality.

      P=0.06 as calculated with log-rank continuity correction.

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