editorials

3. Hacke W, Donnan G, Fieschi C, et al. Association of outcome
with early stroke treatment: pooled analysis of ATLANTIS,
ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-
74.
4. Marler JR, Tilley BC, Lu M, et al. Early stroke treatment as-
sociated with better outcome: the NINDS rt-PA Stroke Study.
Neurology 2000;55:1649-55.
5. Saver JL. Time is brain — quantified. Stroke 2006;37:263-6.
6. Sattin JA, Olson SE, Liu L, Raman R, Lyden PD. An expedited
code stroke protocol is feasible and safe. Stroke 2006;37:2935-9.
7. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for
the early management of adults with ischemic stroke: a guide-
line from the American Heart Association/American Stroke
­Association Stroke Council, Clinical Cardiology Council, Cardio-
vascular Radiology and Intervention Council, and the Athero-
sclerotic Peripheral Vascular Disease and Quality of Care Out-
comes in Research Interdisciplinary Working Groups: the
American Academy of Neurology affirms the value of this guide-
line as an educational tool for neurologists. Stroke 2007;38:1655-
711. [Errata, Stroke 2007;38(6):e38, 38(9):e96.]
8. Generalized efficacy of t-PA for acute stroke: subgroup analy-
sis of the NINDS t-PA Stroke Trial. Stroke 1997;28:2119-25.
9. Graham GD. Tissue plasminogen activator for acute ische-
mic stroke in clinical practice: a meta-analysis of safety data.
Stroke 2003;34:2847-50.
10. Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with
alteplase for acute ischaemic stroke in the Safe Implementation
of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an ob-
servational study. Lancet 2007;369:275-82. [Erratum, Lancet 2007;
369:826.]
11. Lyden PD. Thrombolytic therapy for acute stroke. 2nd ed.
Totowa, NJ: Humana Press, 2005.
12. Alexandrov AV, Grotta JC. Arterial reocclusion in stroke
patients treated with intravenous tissue plasminogen activator.
Neurology 2002;59:862-7.
13. Tilley BC, Marler J, Geller NL, et al. Use of a global test for
multiple outcomes in stroke trials with application to the Na-
tional Institute of Neurological Disorders and Stroke t-PA Stroke
Trial. Stroke 1996;27:2136-42.
14. Adams HP Jr, Kenton EJ III, Scheiber SC, Juul D. Vascular
neurology: a new neurologic subspecialty. Neurology 2004;63:
774-6.
15. Barber PA, Zhang J, Demchuk A, Hill MD, Buchan AM. Why
are stroke patients excluded from TPA therapy? An analysis of
patient eligibility. Neurology 2001;56:1015-20.
16. California Acute Stroke Pilot Registry (CASPR) Investiga-
tors. Prioritizing interventions to improve rates of thrombolysis
for ischemic stroke. Neurology 2005;64:654-9.
17. Alberts MJ, Hademenos G, Latchaw RE, et al. Recommenda-
tions for the establishment of primary stroke centers. JAMA
2000;283:3102-9.
Copyright © 2008 Massachusetts Medical Society.

Calcific Aortic Stenosis — Time to Look More Closely at the Valve

Catherine M. Otto, M.D.
Calcific aortic stenosis is a progressive disease The presence of mild valve changes, even in the
that results in stiff valve leaflets with eventual ob- absence of obstruction to blood flow, is associ-
struction to left ventricular outflow. Once symp- ated with an increase of 50% in the risk of myo-
toms occur, valve replacement is the only effec- cardial infarction and death from cardiovascular
tive treatment, and there are no known therapies causes during the next 5 years. Genetic factors
to prevent disease progression. However, several are difficult to study in a disease that often is not
lines of evidence suggest that calcific valve dis- evident until the sixth or seventh decade of life.
ease is not simply due to age-related degenera- However, in a subgroup of families, a bicuspid
tion but, rather, is an active disease process with valve appears to be inherited in an autosomal
identifiable initiating factors, clinical and genetic dominant pattern. In one study in France, famil-
risk factors, and cellular and molecular pathways ial clustering of calcific disease in trileaflet valves
that mediate disease progression. also was shown. Mutations in the signaling and
The key initiating factor in the development transcriptional regulator NOTCH1 gene have been
of calcific aortic stenosis appears to be mechan- identified in families with bicuspid aortic valves
ical stress. Specifically, a congenitally bicuspid and leaflet calcification.3 Case–control studies
valve, which is present in about 0.5 to 0.8% of have suggested an association between calcific
the population, is the underlying anatomy in the aortic stenosis and genetic polymorphisms in
majority of valve replacements for aortic steno- the vitamin D receptor, estrogen receptor, apo-
sis.1 Blood-flow dynamics may also play a role, lipoprotein E4, and interleukin-10 alleles.
since early lesions are located on the aortic side Our understanding of disease progression at
of the valve in regions with low shear stress. the tissue level is based on human valve studies
Clinical factors that are associated with the of either early lesions or end-stage disease, with
presence of calcific valve disease include older the assumption that these processes represent
age, male sex, elevated serum levels of low-densi- the ends of a disease spectrum (Fig. 1).4,5 Experi-
ty lipoprotein and lipoprotein(a), smoking, hyper­ mental models support this assumption, with
tension, diabetes, and the metabolic syndrome.2 the demonstration that valve lesions occur in the

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Copyright © 2008 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

A Valve Histology Showing Progression of the Disease

Initiating factors: Disease Progression: End-Stage Disease
Bicuspid valve Age and sex
Genetic factors Increased serum lipids
Shear stress Increased blood pressure
Diabetes and metabolic syndrome
Smoking
Early Lesion
T cell Monocyte
LDL

Aorta

Endothelium

Ca2+ Phenotypic transformation

Wnt3, Lrp5, and β catenin

Oxidized LDL Macrophage
Fibrosa Calcification
Ang II Increased alkaline phosphatase
TGF-β
Fibroblast Increased BMP-2
TNF-α Osteoblast
Osteopontin Increased osteocalcin
Interleukin 1β
Ventricularis
Left ventricle

B Aortic-Valve Anatomy

Normal Aortic sclerosis Mild-to-moderate aortic stenosis Severe aortic stenosis

C Doppler Aortic-Jet Velocity

0 0 0 0

1 1 1 1

2 2 2 2
m/sec

3 3 3 3

4 4 4 4

5 5 5 5
Mild-to-moderate
Normal Aortic sclerosis aortic stenosis Severe aortic stenosis
<2.5 m/sec 2.5–4.0 m/sec >4 m/sec

Figure 1. Disease Progression in Calcific Aortic Stenosis, Showing Changes in Aortic-Valve Histologic Features, Leaflet Opening in Systole,
and Doppler Velocities. COLOR FIGURE

In Panel A, the histology of the early lesion is characterized by a subendothelial accumulation of oxidized low-density lipoprotein (LDL),
Rev4 09/03/08
production of angiotensin (Ang) II, and inflammation with T lymphocytes and macrophages. Disease progression occurs by several
Author Dr.
mechanisms, including local production of proteins, such as osteopontin, osteocalcin, and bone morphogenic protein 2 (BMP-2), whichOtto
mediate tissue calcification; activation of inflammatory signaling pathways, including tumor necrosis factor Fig # α (TNF-α),1 tumor growth
Title including the accumulation
factor β (TGF-β), the complement system, C-reactive protein, and interleukin-1β; and changes in tissue matrix,
ME
of tenascin C, and up-regulation of matrix metalloproteinase 2 and alkaline phosphatase activity. In addition, leaflet fibroblasts undergo
phenotypic transformation into osteoblasts, regulated by the Wnt3–Lrp5–β catenin signaling pathway.DE MicroscopicCurfmanaccumulations of
­extracellular calcification (Ca2+) are present early in the disease process, with progressive calcification Artist
as the disease progresses
Daniel Mullerand
areas of frank bone formation in end-stage disease. The corresponding changes in aortic-valve anatomy are viewed AUTHOR from the aortic
PLEASE NOTE:side
with the valve open in systole (Panel B) and in Doppler aortic-jet velocity (Panel C). Figure has been redrawn and type has been reset
Please check carefully

Issue date 09-25-2008

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Copyright © 2008 Massachusetts Medical Society. All rights reserved.
 editorials
presence of hypercholesterolemia, resulting in
leaflet calcification and valve obstruction.6 Taken
together, the association of calcific aortic steno-
sis with elevated serum lipid levels, the presence
of lipid accumulation in the leaflets, and the in-
creased risk of atherosclerotic clinical end points
all lead to the hypothesis that lipid-lowering
therapy might slow or prevent disease progres-
sion. This hypothesis was supported by several
retrospective clinical studies indicating slower
hemodynamic progression or leaflet calcification
in patients who were receiving lipid-lowering
medications than in control subjects and by ex-
perimental models showing that lipid-lowering
therapy blocks the development of valve lesions.7
Thus, the results of the Simvastatin and Ezeti­
mibe in Aortic Stenosis (SEAS) study (ClinicalTrials.
gov number, NCT00092677) that are report­ed in
this issue of the Journal8 are disappointing. In this
large, randomized, prospective clinical trial,
Rossebø et al. convincingly show that aggressive
lipid lowering does not affect either hemodynam-
ic progression or the time to valve replacement in
adults with aortic stenosis.8 Although it is pos-
sible that treatment even earlier in the disease
process might have some benefit, the study pa-
tients had only mild-to-moderate disease. Other
than those with a bicuspid valve or specific ge-
netic markers, earlier identification of patients
at risk would be problematic. The reduction in
atherosclerotic clinical end points in this study
is encouraging. However, the clinical effect was
small, given that benefit was primarily due to a
reduced rate of coronary bypass grafting at the
time of valve replacement.
If intensive lipid-lowering therapy is not the
answer to the prevention of aortic stenosis pro-
gression, where do we go from here? Many adults
with calcific valve disease meet current indica-
tions for lipid-lowering therapy, and the SEAS
study certainly supports the evaluation and re-
duction of risk factors in patients with aortic
stenosis, as recommended for all adults by estab-
lished guidelines. However, we can no longer re-
assure ourselves that either the lipid-lowering or
pleiotropic effects of potent agents such as statins
and ezetimibe might change the disease process
in the valve leaflets. We need to explore other
potential therapeutic targets, especially the path-
ways that lead to tissue calcification. Calcific
aortic stenosis is not atherosclerosis. Although
there is overlap in clinical risk factors, in tissue
n engl j med 359;13  www.nejm.org  september 25, 2008
The New England Journal of Medicine
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Copyright © 2008 Massachusetts Medical Society. All rights reserved.
characteristics, and in the association between the
presence of calcific valve disease and atheroscle-
rotic clinical events, there also are major differ-
ences. In aortic valve stenosis, tissue calcification
is more severe; the mechanism of clinical events
is increased leaflet stiffness, not plaque rupture;
and the severity of coronary and valve disease in
an individual patient often is discordant.
Demonstrating clinical benefit of potential
therapies for calcific aortic stenosis will be chal-
lenging. The evaluation of clinical end points re-
quires a large study group, and enrollment in
prospective, randomized trials is slow, given the
relatively low prevalence of valve disease. Calcific
valve disease progresses slowly over decades,
whereas clinical trials usually follow patients for
only a few years. Clinical end points often are
difficult to assess because indications for valve
replacement remain somewhat subjective and be-
cause therapy may affect other cardiovascular
end points, which limits our understanding of the
mechanism of benefit. Doppler echocardiography
allows assessment of the effect of therapy on the
degree of stenosis, but it is not perfect, because
hemodynamic obstruction occurs only with a sub-
stantial amount of leaflet thickening. The ideal
end point for measuring the effect of therapy
would be direct evaluation of tissue changes in
the valve leaflets. Such analysis is possible in
experimental models but in humans is limited
to the examination of leaflets removed at the
time of valve surgery.9 Computed tomographic
imaging allows measurement of leaflet calcifica-
tion but not of other tissue components. In the
future, molecular imaging approaches may provide
sensitive measures of tissue changes sequential-
ly over time, allowing detection of significant
differences between small study groups.10
It is time to integrate and expand our under-
standing of the interactions between initiating
factors, genetic and clinical cofactors, and the
mechanisms of progression from an early in-
flammatory lesion to phenotypic transformation
of valve myofibroblasts and then to the end stage
of severe valve calcification. Discovery of an ef-
fective medical therapy for calcific aortic steno-
sis will require innovative approaches to disease
prevention and ingenuity in proving the mecha-
nism of benefit.
No potential conflict of interest relevant to this article was re-
ported.
1397
 The n e w e ng l a n d j o u r na l of m e dic i n e

From the Division of Cardiology, Department of Medicine, Uni-
versity of Washington, Seattle.
1. Roberts WC, Ko JM. Frequency by decades of unicuspid, bi-
cuspid, and tricuspid aortic valves in adults having isolated aor-
tic valve replacement for aortic stenosis, with or without associ-
ated aortic regurgitation. Circulation 2005;111:920-5.
2. Katz R, Wong ND, Kronmal R, et al. Features of the meta-
bolic syndrome and diabetes mellitus as predictors of aortic
valve calcification in the Multi-Ethnic Study of Atherosclerosis.
Circulation 2006;113:2113-9.
3. Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1
cause aortic valve disease. Nature 2005;437:270-4.
4. Helske S, Oksjoki R, Lindstedt KA, et al. Complement sys-
tem is activated in stenotic aortic valves. Atherosclerosis 2008;
196:190-200.
5. Akat K, Borggrefe M, Kaden JJ. Aortic valve calcification —
basic science to clinical practice. Heart 2008 July 16 (Epub ahead
of print).
6. Weiss RM, Ohashi M, Miller JD, Young SG, Heistad DD. Cal-
cific aortic valve stenosis in old hypercholesterolemic mice. Cir-
culation 2006;114:2065-9.
7. Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spels-
berg TC. Atorvastatin inhibits hypercholesterolemia-induced
calcification in the aortic valves via the Lrp5 receptor pathway.
Circulation 2005;112:Suppl:I229-I234.
8. Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid
lowering with simvastatin and ezetimibe in aortic stenosis.
N Engl J Med 2008;359:1343-56.
9. Anger T, Pohle FK, Kandler L, et al. VAP-1, Eotaxin3 and
MIG as potential atherosclerotic triggers of severe calcified and
stenotic human aortic valves: effects of statins. Exp Mol Pathol
2007;83:435-42.
10. Aikawa E, Nahrendorf M, Sosnovik D, et al. Multimodality
molecular imaging identifies proteolytic and osteogenic ac­
tivities in early aortic valve disease. Circulation 2007;115:377-
86.
Copyright © 2008 Massachusetts Medical Society.

Ezetimibe and Cancer — An Uncertain Association

Jeffrey M. Drazen, M.D., Ralph B. D’Agostino, Ph.D., James H. Ware, Ph.D.,
Stephen Morrissey, Ph.D., and Gregory D. Curfman, M.D.

The randomized clinical trial is considered to be
the most reliable tool to assess the efficacy and
safety of new drugs. At times, however, random-
ized trials detect adverse events that are unan-
ticipated and not easily explained on the basis of
current knowledge. An unexpected finding of this
kind may ultimately prove to be due to chance,
but follow-up studies sometimes confirm the ad-
verse drug effect. Particularly when an unexpected
finding raises a safety concern with regard to a
drug, physicians face uncertainty about how to
act on the information.
In this issue of the Journal, we publish the re-
sults of the Simvastatin and Ezetimibe in Aortic
Stenosis (SEAS) trial (ClinicalTrials.gov number,
NCT00092677),1 a clinical trial of lipid-lowering
therapy that, even before its publication, has gen-
erated considerable public attention. In the trial,
a combination of simvastatin and ezetimibe was
compared with placebo with respect to the inci-
dence of cardiovascular events in older people with
aortic-valve stenosis. The treatment had no impact
on the progression of aortic stenosis or on cardio-
vascular clinical events in general, with the ex-
ception of coronary-artery bypass surgery, which
was performed (usually at the time of aortic-valve
replacement) less frequently in the active-treat-
ment group than in the placebo group. There was
little uncertainty, however, that the primary end
point was null, since the hazard ratio for treat-
ment relative to placebo was 0.96, with a 95%
confidence interval (CI) of 0.83 to 1.12.
There was, however, an unexpected finding in
the trial. An excess of incident cancers was ob-
served in the simvastatin–ezetimibe group, with
105 in that group as compared with 70 in the
placebo group (P = 0.01). There was an increase
in the incidence of a variety of cancers, including
prostate, gastrointestinal, and skin cancers. Also,
deaths from cancer were more frequent in the
active-treatment group (39 deaths, vs. 23 in the
placebo group), although the difference achieved
only borderline statistical significance (P = 0.05).
The SEAS investigators suggested that the dif-
ference in incident cancers could have occurred
by chance but acknowledged that the unantici-
pated findings should be pursued through addi-
tional studies. Using existing data, the Clinical
Trial Service Unit and Epidemiological Studies Unit
at Oxford University were able to undertake such
a study. The researchers had access to interim
cancer data in two large ongoing clinical trials,
the Study of Heart and Renal Protection (SHARP)
(NCT00125593) and the Improved Reduction of

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