Intensive Lipid-Lowering Therapy for Patients WithAortic Stenosis

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Aofloyesecreqingtatthastatin therapy are of potential clinical relevance. This reportreviews these studies, as well as the Scottish Aortic Sten-osi(SAthe2 ovaMESteSEpro

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1996 to 1999 and had a mean follow-up period of 21months. Study inclusion criteria were mild to moderate

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000dois and Lipid Lowering Trial, Impact on RegressionLTIRE), which did not demonstrate an effect of statinrapy on the progression of aortic stenosis.5 I also discussngoing studies: the Aortic Stenosis Progression Obser-tion: Measuring Effects of Rosuvastatin (ASTRONO-R) study6 and the Simvastatin and Ezetimibe in Aorticnosis (SEAS) study.7 Particular attention is paid to theAS study, which has been designed and powered tovide definitiv information concerning the effect of in-

calcifi aortic stenosis with aortic valve area (AVA) of 1.0to 1.8 cm2, normal left ventricular function (ejection frac-tion 50%), and 2 transthoracic echocardiograms 12months apart.

In this study, approximately 33% of patients (57 of 174)received statin therapy, compared with 67% (117 of 174)who did not. The median serum low-density lipoprotein(LDL) cholesterol levels were 3.39 mmol/L (131 mg/dl) atbaseline in the non-statin-treated group and 3.32 mmol/L(128 mg/dl) in the statin group (p 0.49). Patients in thestatin group were generally older, with a higher frequencyof hypertension, diabetes mellitus, and coronary artery dis-ease, as well as higher triglyceride levels, but baselineechocardiographic parameters were similar in the 2 groups:the median AVA was 1.2 cm2 (range 1.0 to 1.4, p 0.71),and the mean gradient was 15 mm Hg (range 12 to 22, p 0.47). Statin doses were relatively low: 20 12 mg ofsimvastatin (n 21), 25 12 mg of lovastatin (n 18),14 5 mg of atorvastatin (n 8), 23 10 mg of prava-statin (n 8), and 25 21 mg of fluvastati (n 2) daily.3

The annualized decrease in AVA for the non-statin-treated group was 0.11 0.18 cm2, compared with 0.06

Centre for Preventive Medicine, Ullevl University Hospital, Oslo,rway. Manuscript received April 18, 2008; revised manuscript receivedaccepted July 29, 2008.*Corresponding author: Tel: 47-22-11-79-32; fax: 47-22-60-19-00.E-mail address: t.r.pedersen@medisin.uio.no (T.R. Pedersen).

Conflict of interest: Dr Pedersen has received research grants fromrck Sharp & Dohme, Norway; Merck/Schering-Plough, North Wales,nsylvania; and Pfizer Inc., New York, New York, and consultantoraria and speakers fees from Merck Sharp & Dohme; Merck/Scher--Plough; Pfizer Inc.; AstraZeneca, Wilmington, Delaware; and MerckaA, Darmstadt, Germany.

2-9149/08/$ see front matter 2008 Elsevier Inc. All rights reserved. www.AJConline.org:10.1016/j.amjcard.2008.07.028Terje R. Ped

It has been suggested by several retrospectipared with treatment with medications otherstenosis. Additional evidence for this has emRosuvastatin Affecting Aortic Valve Endotfindings of the randomized, double-blind ScotImpact on Regression (SALTIRE). Currentlyare in progress. These studies have longer duEzetimibe in Aortic Stenosis (SEAS) study, wlongest planned length of treatment (4 to 7therapy slows the progression of aortic stenthereby potentially reducing the urgency fosurgery, relieving adverse hemodynamic codecreasing mortality and morbidity in thesObservation: Measuring Effects of Rosuvastaprogression, involves 272 patients with aortic40 mg/d and placebo for 3 to 5 years. In conclwill help resolve the contradictory findingsintensive lipid-lowering treatment in aorticreserved. (Am J Cardiol 2008;102:15711576

rtic sclerosis without obstruction to left ventricular out-is present in approximately 25% of adults aged 65

ars.1,2 Valve replacement surgery for aortic stenosis is theond most frequent cardiac surgical procedure, and ituires considerable health care resources. Therefore, finds from studies by Novaro et al3 as well as the Rosuvas-in Affecting Aortic Valve Endothelium (RAAVE) study4

t the progression of aortic stenosis may be slowed byn, MD*

dies that lipid-lowering therapy (com-statins) retards the progression of aorticfrom the prospective (nonrandomized)(RAAVE) study, although not from

ortic Stenosis and Lipid Lowering Trial,ger randomized studies of aortic stenosiss than SALTIRE. The Simvastatin and73 patients, is the largest study with thethat will assess whether lipid-loweringnd the degradation of the aortic valve,gery or at least delaying the need forences of aortic stenosis, and possiblyients. The Aortic Stenosis ProgressionSTRONOMER) trial, a study of diseasesis, with treatment arms of rosuvastatin, the SEAS and ASTRONOMER studiesLTIRE and RAAVE on the benefit ofosis. 2008 Elsevier Inc. All rights

sive lipid-lowering therapy on the progression of aorticnosis.

evious Studiesveral studies evaluating the use of statins in patients withrtic stenosis have been completed and published or aregoing (Table 1812).Novaro et als3 study involved 174 patients studied from

Table 1Summary of c

Study

RetrospectiveNovaro et al

Pohle et al8

Aronow et a

Shavelle et a

Rosenhek et

Prospective, nstudies

Bellamy et a

RAAVE4

STOP-AS (o

Randomized, dplacebo-co

SALTIRE5

ASTRONOM(ongoing)

AORTICA 1

STAAT (ong

SEAS (ongo

* Values inEBT elec1572linical studies evaluating lipid-lowering management in patients with aortic stenosis

Follow-Up (mo)* Study Group Change in Mean Outcome VariableEchocardiography EBT of AorticValveAnnualizedCalcium Score (%)Annualized AVA

(cm2)Peak Gradient(mm Hg)

Mean Gradient(mm Hg)

Jet Velocity (m/s/yr)

studies3 21 (1240) No statin (n 117) 0.11 9.5 5.8

Statin users (n 57) 0.06 (p 0.03) 5.3 4.215 (1036) LDL-C 130 mg/dl (n 47) 43.2

LDL-C 130 mg/dl (n 57) 9.1 (p 0.001)l9 33 (24120) LDL-C 125 mg/dl, no statin (n 69) 6.3

LDL-C 125 mg/dl with statin (n 62) 3.4 (p 0.0001)LDL 125 mg/dl, no statin (n 49) 3.1 (p 0.0001)

l10 30 No statin (n 37) 32.0Statin users (n 28) 12.1

al11 24 (642) No statin (n 161) 0.39 0.42Statin users (n 50) 0.10 0.41 (p 0.0001)

onrandomized

l12 44 (28) No statin (n 118) 0.09 17Statin users (n 38) 0.04 (p 0.04) 9

17 (6) No statin (n 60) 0.10 0.24Rosuvastatin 20 mg/day (n 61) 0.05 (p 0.041) 0.04 (p 0.007)

ngoing)25 24 Historical controlsAtorvastatin 40 mg/day (n 59)

ouble-blind,ntrolled trials

25 (736) Placebo (n 78) 0.083 0.203 21.7Atorvastatin 80 mg/day (n 77) 0.079 (p 0.68) 0.199 (p 0.95) 22.3 (p 0.93)

ER6

48 PlaceboRosuvastatin 40 mg/day (total n 272)

(ongoing)23 12 PlaceboFluvastatin 80 mg/day (total n 164)

oing)24 24 PlaceboFluvastatin 4080 mg/day (total n 100)

ing)7 54 (4884) PlaceboSimvastatin 40 mg/day, ezetimibe10 mg/day (total n 1,873)

parentheses are ranges or SDs.tron-beam tomography; LDL-C LDL cholesterol.

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1573Review on Lipid Lowering for AS6 cm2 in the statin-treated group (p 0.03). Peak andan pressure gradients increased in the 2 groups during thedy, with a less pronounced increase in the statin groupording to multivariate analysis (p 0.02 and p 0.10peak and mean pressure increases, respectively).3

Commenting on these data, Novaro et al3 cautioned thaty were not able to adjust for all potential confounderst could have affected the benefit of therapy that wereserved. Furthermore, the studys exclusion criteria pre-ded generalization of the finding to all patients withrtic stenosis. The group also acknowledged that the ef-ts of statin treatment in the study could have been un-restimated because of the relatively low doses used andvariable treatment duration.

RAAVE study: The RAAVE study4 was a prospective,en-label study that enrolled 121 consecutive patientsean age 73.7 8.9 years; 57 men, 64 women) presentingth asymptomatic, moderate to severe aortic stenosisVA 1.0 to 1.5 cm2). Those with coronary artery disease,vious statin therapy, or metabolic and serious diseasesre excluded. The investigators used echocardiography toess valve changes over a mean follow-up period of 73 weeks.Patients (n 61 [50.4%]) with elevated LDL cholesterolean 4.14 0.87 mmol/L [159.7 33.4 mg/dl]) receiveduvastatin 20 mg/day; the control group, which consistedpatients (n 60 [49.6%]) without profoundly abnormalL cholesterol levels (3.07 0.97 mmol/L [118.6 37.4/dl]), received no statin. At baseline, the mean peak jetlocity and AVA were closely matched in the 2 groups; forrosuvastatin and control groups, they were, respectively,5 0.64 and 3.62 0.61 m/s and 1.23 0.42 and0 0.35 cm2.The annual decrease in AVA was significantl lower instatin group (0.05 0.12 cm2) compared with the

ntrol group (0.10 0.09 cm2) (p 0.041). The annualrease in peak aortic jet valve velocity was also signifitly less pronounced in patients receiving statins (0.04 8 m/s) compared with controls (0.24 0.30 m/s) (p 07). Significan improvements in mean and peak aorticlve gradients, as well as serum lipid levels, were alsoserved in the statin group compared with the controlup.According to the investigators, this was the firs studymonstrating the potential of targeted therapy in asymp-atic aortic stenosis, although its open-label, observa-nal nature precluded its ability to confir rather thannerate hypotheses.4

Randomized studies: Unfortunately, previous double-nd, randomized, controlled studies of statins for theatment of cardiovascular conditions other than aorticnosis have not imparted detailed information concern-the effects of statins in patients with aortic stenosis.

me of these trials have prohibited participation bytients with valvular heart disease (e.g., Treating to Newrgets [TNT] and Pravastatin or Atorvastatin Evaluation

d Infection TherapyThrombolysis In Myocardial In-ction 22 [PROVE-ITTIMI 22])1315; others have not

grovided any specifi information about aortic stenosis intients in the trials.1622 In light of this relative paucityinformation, there is a need for well-designed prospec-e, randomized, double-blind, controlled trials concern-lipid-lowering therapy in the management of aortic

nosis.SALTIRE: This randomized, double-blind, placebo-con-lled trial included 155 patients with calcifi aortic steno-and aortic jet velocities 2.5 m/s who were treated withher atorvastatin 80 mg/day (n 77) or placebo (n 78),th a median follow-up period of 25 months (range 7 to). Exclusion criteria included severe mitral valve stenosis,ere mitral or aortic regurgitation, an ejection fraction5%, or total cholesterol 3.89 mmol/L (150 mg/dl).5

ppler echocardiography was used to evaluate aortic ste-sis, whereas helical computed tomography was used toaluate calcification The primary end points of the studyre change in aortic jet velocity and aortic valve calciumre. Secondary end points were a composite of death fromdiovascular causes, aortic valve replacement, or hospi-ization attributable to severe aortic stenosis; aortic valvelacement; death from any cause; hospitalization for anyse; and hospitalization for cardiovascular causes.Baseline values for the atorvastatin group were as fol-s: age 68 11 years, LDL cholesterol 3.55 0.88ol/L (137 34 mg/dl), aortic jet velocity 3.39 0.62s, peak gradient 47.8 17.4 mm Hg, AVA 1.03 0.42, and aortic valve median calcium score 5,424. Corre-nding baseline values for the placebo group were aslows: age 68 10 years, LDL cholesterol 3.44 0.78ol/L (133 30 mg/dl), aortic jet velocity 3.45 0.67s, peak gradient 49.5 19.5 mm Hg, AVA 1.02 0.412, and aortic valve median calcium score 6,221.5

Atorvastatin significantl decreased serum LDL choles-ol to 1.63 0.60 mmol/L (63 23 mg/dl); LDL cho-terol remained near the baseline value (3.37 0.78ol/L [130 30 mg/dl]) in the placebo group (p.001). Aortic jet velocity increased annually by 0.199 10 m/s in the atorvastatin group and 0.203 0.208 m/sthe placebo group (adjusted mean difference 0.002, 95%nfidenc interval 0.066 to 0.070 m/s/year, p 0.95).5

Progression in valvular calcificatio was 22.3 21.0%/ar in the atorvastatin group and 21.7 19.8%/year in thecebo group (ratio of post-treatment aortic valve calciumre 0.998, 95% confidenc interval 0.947 to 1.050, p 3). Proportions of patients reaching secondary clinicald points were somewhat lower in the atorvastatin group,t none of the differences between groups achieved statis-al significance There were slightly lower, but not statis-ally significantl different, incidences of all secondaryd points except death from cardiovascular causes in thervastatin group compared with the placebo group.5

On the basis of their assessment of these data, the inves-ators concluded that intensive lipid-lowering therapy didt halt the progression (or induce a regression) of aorticnosis. However, they could not exclude a modest decel-tion in disease progression or a significan decrease injor clinical end points. Finally, nearly 25% of patients (n

19 in the atorvastatin group [25%], n 17 in the placeboup [22%]) had severe aortic stenosis, which may have

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1574 The American Journal of Cardiology (www.AJConline.org)en too advanced to respond to statin treatment within thedys treatment interval.5

dies in Progresse ASTRONOMER trial6 and the SEAS study7 (both withdy designs and baseline data published to date) mayprove understanding of the relations (if any) betweenid-lowering therapy and aortic stenosis progression,en the contradictions inherent in previously reporteddings Three unpublished, ongoing studies are the Ran-mized Study to Evaluate the Efficac of Fluvastatin onlammator Markers in the Haemodynamic Progression ofgenerative Aortic Stenosis (AORTICA 1), at UniversitySalamanca in Spain (scheduled completion November08)23; the Statin Therapy in Asymptomatic Aortic Steno-(STAAT) study, at the University of Leipzig Heartnter (scheduled completion December 2008)24; and thefect of Statin Therapy (Atorvastatin) on the ProgressionCalcifi Valvular Aortic Stenosis (STOP-AS) trial, at theeveland Clinic (estimated completion June 2008).25

RTICA 1 and STAAT have relatively few patients en-led to date. The STOP-AS prospective study also has fewtients enrolled and is also an open-label rather than auble-blind study that uses historical versus concurrentntrols, which are inherent weaknesses of this trial.

ASTRONOMER trial: A Canadian randomized, dou--blind, placebo-controlled trial with a 3- to 5-year fol--up period, ASTRONOMER is being conducted totermine whether patients with mild to moderate asymp-atic aortic stenosis randomized to rosuvastatin 40 mg/

le 2ary and secondary end points of the Simvastatin and Ezetimibe in

rtic Stenosis study

mary: Major cardiovascular eventsardiovascular deathVR surgeryHF as a result of the progression of ASonfatal MIABGCIospitalized unstable anginaonhemorrhagic strokeondary. Aortic valve eventsCardiovascular deathAVR surgeryCHF as a result of progression of AS. Ischemic cardiovascular eventsCardiovascular deathNonfatal MICABG or PCIHospitalized unstable anginaNonhemorrhagic stroke. Progression of aortic valve stenosis as measured by Dopplerechocardiography

VR aortic valve replacement; CABG coronary artery bypassfting; CHF congestive heart failure; MI myocardial infarction;I percutaneous coronary intervention.y (compared with placebo) will experience less aorticnosis progression.6 Those with clinical indications for the

hahaof cholesterol-lowering agents were excluded. A total272 patients from 23 Canadian sites were recruitedough December 2005, and results are expected in 2009.tients in the ASTRONOMER trial are younger (meane 58.1 13.6 years), have mild to moderate aortic ste-sis (mean peak transaortic jet velocity 3.2 0.4 m/s), andlude a larger proportion of patients (48.9%) with bicus-aortic valves compared with patients with aortic stenosispreviously published trials. The primary end point isgression in aortic stenosis severity (measured by aorticnsvalvular gradients and AVA). Secondary end pointslude rates of cardiac death and aortic valve replacement,well as time to reaching an end point.

SEAS study: A multicenter, double-blind, placebo-con-lled trial with a minimum follow-up duration of 4 years,SEAS study is the largest study undertaken to evaluateeffects of lipid-lowering therapy in patients with aorticnosis.7 The trials aims are to determine the effects oftimibe coadministered with simvastatin on (1) aorticlve events (including aortic valve replacement), (2) peakvelocity and other hemodynamic and anatomic features

the aortic valve by echocardiography, and (3) ischemicents. The study is powered to detect clinically significanects of therapy on the primary and secondary end pointsted in Table 2.In the SEAS study, patients are being treated once dailyth simvastatin 40 mg, together with the cholesterol ab-ption inhibitor ezetimibe 10 mg, or placebo after aeek open-label placebo and diet run-in. The study is

aluating the effects of intensive lipid-lowering therapy onrtic valve degradation and the need for surgery, adversemodynamic consequences of aortic stenosis progression, heart failure), and morbidity and mortality due to isch-ic disease in patients with asymptomatic mild to moder-aortic stenosis.A total of 1,873 men and women aged 45 to 85 years

le 3eline characteristics of patients in the Simvastatin and Ezetimibe inrtic Stenosis study (n 1,873)

iable Value

e (yrs) 68 10an maximum velocity ataseline (m/s) (n 1,760)

3.09 0.54

rs since diagnosis 5 6men 38.6%y mass index (kg/m2) 26.9 4.3pertension 50.9%okers 19.2%smokers 36.1%er smokers 44.7%ids/lipoprotein (mmol/L [mg/dl])al cholesterol 5.74 1.02 (222 39)L cholesterol 3.60 0.92 (139 36)h-density lipoprotein cholesterol 1.49 0.43 (58 17)glycerides 1.42 0.69 (126 61)olipoprotein B (g/L) 1.31 0.28

ata are expressed as mean SD or as percentages.ve been enrolled. To be eligible, patients were required tove asymptomatic mild to moderate aortic stenosis, de-

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1575Review on Lipid Lowering for ASe as aortic valve thickening by echocardiographic eval-tion accompanied by aortic peak flo velocity 2.5 and.0 m/s on Doppler echocardiography, LDL cholesterolmmol/L (232 mg/dl) (or less than local guidelines for

id-lowering therapy), and triglycerides 4.5 mmol/L8 mg/dl). Patients have been enrolled from Ireland (n7), the United Kingdom (n 187), Germany (n 292),rway (n 425), Sweden (n 401), Finland (n 221),d Denmark (n 330). Patients already receiving statinrapy or with indications for such treatment were ex-ded, as were patients with coronary artery disease, im-rtant valvular disease (other than aortic stenosis), diabetesllitus, or other conditions precluding participation.7

Patients baseline characteristics are listed in Table 3. Atdy entry, patients had less advanced aortic stenosis com-red with subjects in SALTIRE, as evidenced by meanrtic jet velocities of 3.09 and 3.39 m/s, respectively.seline mean lipid and lipoprotein levels are also listed inble 3.7

POWER CONSIDERATIONS: The initial estimate of thember of patients needed to be randomly assigned (about00) was obtained on the basis of a projected 4-year evente of 40% in the placebo group, assuming a baseline meanlue of jet velocity (a strong predictor of clinical out-mes) of 3.6 m/s.7 In January 2004, toward the end of theruitment period, a review of entry data showed that thean jet velocity was approximately 3.2 m/s. This findingested that patients were entering the study with lessvanced disease than originally projected and that it woulde 4.5 years from the date of firs patient entry toserve the projected 464 patients with primary events. Tontrol the study duration, it was therefore decided to in-ase the sample size to approximately 1,800 patients.cording to an annual deterioration of 0.3 m/s in jet ve-ity, revised assumptions were used to assess the impactlarger sample sizes on expected study duration. In theing of 2006, the investigators decided to prolong thelow-up to a minimum of 4 years (and a maximum of 7ars), to account for the sooner than projected number ofmary end points reached. As of 2007, the SEAS studyd a much larger number of patients eligible for echocar-graphy and for a longer follow-up interval than did theLTIRE study (Table 4).7

inical Implications From Ongoing Studiesall probability, ongoing randomized placebo-controlled

le 4ients eligible for echocardiography

SALTIRE (Final)5 SEAS (as of 2007)

eline 154 1,873riskyr 134 1,848yrs 115 1,731yrs 64 1,551yrs 0 1,187yrs 0 115dies will resolve the question of the potential benefit ofensive lipid-lowering therapy for patients with aortic ste-sis because these studies are well controlled, adequatelywered, and of relatively long treatment durations. If it candemonstrated that intensive lipid-lowering therapy re-ces the progression of aortic stenosis, such therapy isely to be used at earlier stages of the disease, and in-ased screening of patients at these susceptible ages shoulddiscussed. Negative outcomes of the studies would besistent with the conclusion that lipid-lowering therapy doest significantl decelerate aortic stenosis progression, reducedefer the need for valve surgery, or improve echocardio-phic parameters. Such outcomes would reinforce the initialding of SALTIRE5 and potentially heighten interest iner treatment modalities to retard the progression of degen-tive aortic stenosis.

knowledgment: Assistance in manuscript preparations provided by Stephen W. Gutkin of Rete Biomedicalmmunications Corp. (Wyckoff, New Jersey).

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25. ClinicalTrials.gov. The Effect of Lipitor on Aortic Stenosis. Availableat: http://www.clinicaltrials.gov/ct2/show/NCT00590135?termclevelandaorticstenosis&rank1. Accessed February 2, 2008.

1576 The American Journal of Cardiology (www.AJConline.org)

Intensive Lipid-Lowering Therapy for Patients With Aortic StenosisPrevious StudiesRAAVE studyRandomized studiesSALTIRE

Studies in ProgressASTRONOMER trialSEAS studyPOWER CONSIDERATIONS

Clinical Implications From Ongoing StudiesAcknowledgmentReferences