Ezetimibe and in Aortic Stenosis

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The n e w e ng l a n d j o u r na l of m e dic i n e original article Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis 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
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  The  new england journal of  medicine n engl j med 359;13 www.nejm.org september 25, 2008 1343 srcinal article Intensive Lipid Lowering with Simvastatinand Ezetimibe in Aortic Stenosis 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* The authors’ affiliations are listed in theAppendix. Address reprint requests toDr. Rossebø at the Division of Cardiology,Aker University Hospital, Trondheims-veien 235, N-0514 Oslo, Norway, or atanne@rossebo.net.*Members of the Simvastatin andEzetimibe in Aortic Stenosis (SEAS)study committees and other investiga-tors are listed in the Appendix.This article (10.1056/NEJMoa0804602)was published at www.nejm.org on Sep-tember 2, 2008.N Engl J Med 2008;359:1343-56. Copyright © 2008 Massachusetts Medical Society. 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 sim- vastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a com-posite of major cardiovascular events, including death from cardiovascular causes,aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstableangina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related toaortic-valve stenosis and ischemic cardiovascular events. Results During a median follow-up of 52.2 months, the primary outcome occurred in 333patients (35.3%) in the simvastatin–ezetimibe group and in 355 patients (38.2%) in theplacebo group (hazard ratio in the simvastatin–ezetimibe group, 0.96; 95% confi-dence interval [CI], 0.83 to 1.12; P = 0.59). Aortic-valve replacement was performed in267 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 pa-tients had ischemic cardiovascular events in the simvastatin–ezetimibe group (148patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63to 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 reducedthe incidence of ischemic cardiovascular events but not events related to aortic-valvestenosis. (ClinicalTrials.gov number, NCT00092677.) Copyright © 2008 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on October 13, 2009 . For personal use only. No other uses without permission.  The  new england journal of  medicine n engl j med 359;13 www.nejm.org september 25, 2008 1344 A ortic-valve stenosis is common   in  elderly persons, with a prevalence of 3 to5% in the population over 75 years of age. 1,2  The condition has been shown to be an inflam-matory process associated with cardiovascular risk factors, with histopathological changes in the valveleaflets that are similar to those in other athero-sclerotic diseases. 2-19 Changes in the aortic valveare associated with an increased risk of deathfrom cardiovascular causes and myocardial infarc-tion, even in the absence of hemodynamic obstruc-tion and signs of coronary disease. 20-22 The stan-dard treatment is surgical replacement when the valve becomes severely stenotic. 23,24 Epidemiologic 2 and genetic 25,26 studies haveidentified risk factors for the development of aortic-valve stenosis, and experimental work haselucidated the cellular mechanisms involved indisease progression, many of which resembleatherosclerosis. 27-30 One interpretation of thesefindings is that lipid-lowering treatment might prevent progression of aortic-valve stenosis andthus reduce the need for aortic-valve replacement.The effect of statin treatment on aortic-valvestenosis has been assessed in several retrospectiveor small case–control studies. 27,31-33 Most stud-ies have suggested a beneficial effect of statins, whereas one prospective, randomized study didnot find any effect of lipid-lowering therapy onthe progression of aortic-valve stenosis. 34 The Simvastatin and Ezetimibe in Aortic Steno-sis (SEAS) trial was designed to study the effectsof long-term, intensive cholesterol lowering withdaily use of simvastatin and ezetimibe on clinicaland echocardiographic outcomes in patients withasymptomatic, mild-to-moderate aortic-valve sten-osis and no other indication for lipid-loweringtreatment. Methods Patient Population The study design and baseline characteristics of the patients have been reported previously. 35 Menand 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 sec-ond, were eligible for the study. Patients were ex-cluded if they had received a diagnosis or hadsymptoms of coronary artery disease, peripheralarterial disease, cerebrovascular disease, or dia-betes mellitus or if they had any other conditionrequiring lipid-lowering therapy. The study was ap-proved by all relevant institutional ethics commit-tees or by ethics committees in each country, andall patients provided written informed consent. Study Protocol The study was initiated by the investigators and wasdesigned by the steering committee on the basis of a protocol developed for the Simvastatin in AorticStenosis (SAS) study, 35 which evaluated the effect of lipid-lowering therapy with simvastatin (at a doseof 40 to 80 mg) as compared with placebo on clin-ical and echocardiographic outcomes in patients with aortic stenosis. The SAS study was sponsoredby Merck but was otherwise managed by the SASstudy steering committee.From March 2001 through December 2002,a total of 196 patients underwent randomization.To improve the lipid-lowering effect while decreas-ing the risk of myopathy, the steering committeedecided 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 forthe logistics of the SEAS trial was transferred tothe sponsor, but the scientific responsibility re-mained with the independent steering committee, which included two nonvoting members of thesponsor. 35 The patients who were assigned to re-ceive simvastatin in the SAS study remained in theactive-treatment group in the SEAS trial, in whichezetimibe was added to simvastatin, and the pa-tients in the SAS placebo group remained in theSEAS placebo group. During this process, neitherthe patients nor the investigators were aware of study-group assignments. After a 4-week run-inperiod in which all patients were given single-blind placebo tablets and were instructed to fol-low a lipid-lowering diet according to the recom-mendations of the National Cholesterol EducationProgram, 36 eligible patients underwent random-ization in a 1:1 fashion in blocks of two to receiveeither simvastatin–ezetimibe or placebo (Fig. 1).Open-label lipid-lowering therapy, which in-cluded up to 40 mg of simvastatin or an equipo-tent dose of another lipid-lowering drug, could beadministered in addition to the study drug at thediscretion of each treating physician, althoughpatients and investigators remained unaware of study-group assignments. The numbers of pa-tients receiving open-label therapy are shownin Figure 1. Copyright © 2008 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on October 13, 2009 . For personal use only. No other uses without permission.  Intensive Lipid Lowering with Simvastatin and Ezetimibe n engl j med 359;13 www.nejm.org september 25, 2008 1345 The study was completed according to the pro-tocol when all patients had been followed for aminimum of 4 years after randomization, at whichpoint the primary outcome had occurred in at least 464 patients. 35 The SEAS steering committee designed thestudy and vouches for the accuracy and complete-ness of the data and the analysis. The sponsorgathered the data; the Echocardiography CoreLaboratory read the locally recorded echocardio-grams. The statistical analysis was performed by Merck, according to a predefined protocol. In ad-dition, parallel statistical analysis with the use of SPSS software (version 15.0) was performed on raw data by an independent statistician, a processthat generated identical results. The first draft of the manuscript was written by the lead academicauthor. Efficacy Outcomes The primary outcome of the study was major car-diovascular events, a composite consisting of deathfrom cardiovascular causes, aortic-valve replace-ment, congestive heart failure as a result of pro-gression of aortic-valve stenosis, nonfatal myocar-dial infarction, hospitalization for unstable angina,coronary-artery bypass grafting (CABG), percuta-neous coronary intervention (PCI), or nonhemor- 1873 Underwent randomization2010 Patients were assessedfor eligibility (startedon run-in placebo)196 Were included fromSAS study333 Were excluded in the run-in period273 Did not meet inclusion criteria34 Declined to participate26 Had other reason944 Were assigned to receivesimvastatin plus ezetimibe943 Received the study drugs929 Were assigned to receiveplacebo929 Received placebo5 Discontinued the study0 Were lost to follow-up5 Had other reason198 Discontinued study drugs,followed per protocol105 Died11 Discontinued the study2 Were lost to follow-up9 Had other reason170 Discontinued placebo,followed per protocol100 Died939 Were followed for end pointsuntil end of study or death69 Had open-label statin added30 Had open-label statin alone918 Were followed for end pointsuntil end of study or death134 Had open-label statin added24 Had open-label statin alone944 Were included in the primaryanalysis943 Were included in the safetyanalysis859 Were included in the echo-cardiographic analysis929 Were included in the primaryanalysis929 Were included in the safetyanalysis834 Were included in the echo-cardiographic analysis       Figure 1.Enrollment and Outcomes. SAS denotes the Simvastatin in Aortic Stenosis Study. Copyright © 2008 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on October 13, 2009 . For personal use only. No other uses without permission.  The  new england journal of  medicine n engl j med 359;13 www.nejm.org september 25, 2008 1346 rhagic stroke. The primary composite outcomeincluded aortic-valve–related clinical events andischemic events to account for possible cardiovas-cular 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 aorticstenosis, or death from cardiovascular causes) andischemic events (which were defined as death fromcardiovascular causes, nonfatal myocardial infarc-tion, hospitalization for unstable angina, CABG,PCI, or nonhemorrhagic stroke). Other secondary objectives were progression of aortic stenosis, asseen on echocardiography, and the safety of thestudy drugs. Table 1.Baseline Characteristics of the Patients.*CharacteristicPlacebo(N = 929)Simvastatin–Ezetimibe(N = 944)P Value† Age — yr67.4±9.767.7±9.40.46Female sex — no. (%)360 (38.8)363 (38.5)0.92White race — no. (%)‡928 (99.9)940 (99.6)NABlood pressure — mm HgSystolic 144.0±20.0145.6±20.40.08Diastolic82.0±10.082.0±10.60.98Hypertension — no. (%)476 (51.2)489 (51.8)0.82Smoking status — no. (%)0.59Current 171 (18.4)189 (20.0)Former344 (37.0)333 (35.3)Never414 (44.6)422 (44.7)Body-mass index26.8±4.326.9±4.30.58Atrial fibrillation — no. (%)§90 (9.7)87 (9.2)0.75Atrioventricular block — no. (%)23 (2.5)21 (2.2)0.76Benign prostatic hyperplasia — no. of men (%)63 (11.1)74 (12.7)0.47Neoplasm (benign, malignant, or unspecified) — no. (%) 103 (11.1)79 (8.4)0.05Drug therapy — no. (%)Angiotensin-converting–enzyme inhibitor149 (16.0)139 (14.7)0.44Angiotensin-receptor blocker98 (10.5)95 (10.1)0.76Calcium antagonist160 (17.2)157 (16.6)0.76Beta-blocker268 (28.8)242 (25.6)0.12Aspirin or other platelet inhibitor260 (28.0)236 (25.0)0.16Anticoagulant agent49 (5.3)58 (6.1)0.43Diuretic (including spironolactone)229 (24.7)209 (22.1)0.21Digitalis glycoside22 (2.4)28 (3.0)0.47Laboratory valuesGlucose — mg/dl96.2±15.596.3±14.70.95Creatinine — mg/dl1.06±0.171.06±0.180.82Estimated glomerular filtration rate — ml/min per 1.73 m 2 ¶68.2±12.068.5±12.60.54High-sensitivity C-reactive protein — mg/liter0.76Median2.202.10Interquartile range0.90–4.900.90–4.10 Copyright © 2008 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on October 13, 2009 . For personal use only. No other uses without permission.
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