Surrogate markers, atherosclerosis and cardiovascular disease prevention

Surrogate markers, atherosclerosis and cardiovasculardisease prevention

Biochemical and physiological markers of endothelial

function has also been investigated but these are too

novel or too labile to have yet become established.

Most studies use radiological surrogates including

carotid intima-media thickness (cIMT), quantitative

coronary angiography (QCA), intravascular ultra-

sound (IVUS) and most recently coronary artery cal-

cium (CAC) scores to asses the progression of

disease. There was confidence in both cIMT and

QCA until recently but the results of the Ezetimibe

aNd simvastatin in Hypercholesterolemia enhANCEs

atherosclerosis regression (ENHANCE) study have

raised a furore about the relevance of cIMT (2). The

paucity of change on QCA is difficult to reconcile

with the large clinical effects of lipid-lowering thera-

pies. CAC is useful for screening but does not seem

to respond to therapeutic interventions. IVUS studies

offer the potential to follow intramural atherosclero-

sis but are only slowly becoming established and lack

confirmation in prospective end-point studies.

This article reviews the field of surrogate markers

of atherosclerosis illustrating the complexity of their

interpretation and why clinical end-point trials are

still essential to characterise the effects of new inter-

ventions.

Cardiovascular risk factors

A number of markers are used in the field of ath-

erosclerosis (Table 1). Many form part of the stan-

dard series of trials that are performed during

licensing (e.g. cardiovascular risk markers), some

are commonly measured as investi-

gator-initiated studies (e.g. endo-

thelial function) while others are

used as the basis of formal phase

IV trials of efficacy prior to the

outcomes of hard cardiovascular

end-point studies becoming avail-

able. The oldest and best estab-

lished are cardiovascular risk

factors – lipid fractions [total, low-

density lipoprotein (LDL) or high-

density lipoprotein cholesterol

(HDL-C)], glucose and blood pres-

sure. It is generally assumed that

moving these in the right direction

will confer benefits. However, this

is not always the case – d-thyrox-

ine and oestrogens both improved lipid profiles

but neither showed cardiovascular benefits in the

Coronary Drug Project in 1970–1975 (3). Thyroid

analogues then disappeared but have recently reap-

peared as compounds in development (4). Yet, the

fad for oestrogens continued as part of hormone

replacement therapy and it took the negative

results of the QCA study [Estrogen and Reduction

of Atherosclerosis (5)] and the first of a series of

negative end-point trials – Heart Estrogen-progestin

Replacement Study (6) to discredit their routine

use. Thus, using changes in risk factors as surro-

gate markers for atherosclerosis may not predict

clinical benefits for novel therapies.

Endothelial function

Other markers of early atherosclerosis such as

endothelial function (e.g. flow-mediated dilatation)

are related to cardiovascular risk (7) and are often

measured in clinical studies yet are considered too

labile and short term and thus have not been

accepted as true surrogates for atherosclerosis.

Long-term studies of the predictive ability of endo-

thelial function are underway (8). This also applies

to potential biochemical markers of atherosclerosis

although some risk factors ⁄ markers such inflamma-

tory markers [e.g. C-reactive protein (CRP)] are

sometimes suggested as surrogates (9). Newer

markers such as asymmetric dimethylarginine

although correlated with endothelial dysfunction

remain to be validated in large-scale prospective

Should lipids, endothelial function and arterial imaging be

used to assess whether drugs for cardiovascular disease

work or are endpoint studies needed? The histopathology

of atherosclerosis is distinctive but it is difficult using cur-

rent techniques to identify the presence of atherosclerosis

even though it occurs in adolescence ⁄ early adulthood (1).

Many approaches have been used to try to assess the bene-

fits of interventions without recourse to costly end-point

trials. Cardiovascular risk factors are well-established sur-

rogates and have proved useful for drug screening and

early licensing studies. However, lipid changes did not pre-

dict the lack of effects of oestrogens or thyroxine on car-

diovascular events.

doi: 10.1111/j.1742-1241.2008.01794.x

PERSPECT IVE

ª 2008 The AuthorJournal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, July 2008, 62, 7, 981–987 981

Using changes

in risk factors

as surrogate

markers for

atherosclerosis

may not pre-

dict clinical

benefits for

novel

therapies

studies in patients without cardiovascular disease or

its equivalents and to show consistent changes par-

alleling outcomes (10).

Radiological markers

Carotid intima-media thickness andquantitative coronary angiographyThe limitations of biochemical markers have

prompted the use of other surrogates based on imag-

ing atherosclerosis. The oldest and best established

are cIMT (11) and QCA to measure mean lumen

diameter (MLD) (12). The first measures non-focal

plaque related intimal hyperplasia and the second the

degree of luminal obstruction. However, despite a

multiplicity of studies there is no standardised proto-

col for measurement of cIMT. This bedevils its inter-

pretation (13). Given its vascular location cIMT is

highly driven by age and blood pressure and to a les-

ser extent by hyperlipidaemia, smoking and hyper-

glycaemia (14,15). Its relationship with changes in

lipids is complex (Figure 1) (16,17). In contrast

QCA–MLD follows coronary artery disease as mea-

sured by stenosis and thus indirectly the incidence of

angina which was included in the original cardiovas-

cular outcomes measured in epidemiological studies

such as the Framingham study. Yet, although MLD

is useful it was difficult to reconcile the minimal

changes in MLD with the large changes in cardiovas-

cular end-points seen in the lipid-lowering trials

especially in such analyses as the Pravastatin Athero-

sclerosis Intervention Program (18,19).

Direct arterial imaging: intra- or extravascularThe paucity of intra-luminal changes has led to the

development of methods to image mural as opposed

to luminal atherosclerosis as atheroma lesions ini-

tially grow externally before intruding on the lumen

(20). Both nuclear magnetic resonance (NMR) and

ultrasound methods have been developed for this

purpose with limits of resolution meaning that NMR

is currently applied to large carotid or femoral pla-

ques while IVUS is used for coronary arteries. How-

ever, the size of the catheter-transducer required

means that IVUS studies are only performed in ves-

sels with < 50% stenosis. In contrast QCA studies

use all artery segments and occlusions. Although

studies have shown correlations of baseline carotid

IMT with QCA and IVUS (21) and between QCA

and IVUS (r = 0.55–0.65) (22), only recently with

the results of the QCA substudy of the ‘A Study To

Evaluate the effect of Rosuvastatin On Intravascular

ultrasound-Derived coronary atheroma burden’ trial

has it been possible to validate changes with time

using the same drug (rosuvastatin) in the same popu-

lation with both methods (23). The results are reas-

suring in that the changes are consistent and in line

with previous studies. The press release announcing

the early cessation of the ‘Justification for the Use of

statins in primary Prevention: an Intervention

Trial Evaluating Rosuvastatin’ study of 20 mg rosu-

vastatin in 15,000 primary prevention patients with

elevated CRP (24) is also reassuring in this regard

that the results are internally consistent with this

drug (25).

Yet, not all is quite straightforward. Torcetrapib

showed little effect on cIMT in the Rating Athero-

sclerotic Disease change by Imaging With A New

Cholesterol Ester Transfer Protein (CETP) Inhibitor

trial (26) or IVUS in the Investigation of Lipid Level

management of atherosclerosis by CETP Inhibition

and HDL Elevation study (27) and caused excess

events in the Investigation of Lipid Level Manage-

ment to Understand its Impact in Atherosclerotic

Events trial (28). However, both cIMT and IVUS

studies could be consistent with hypothesised

changes in some models (17), but not others (27)

and it is only the end-points which are definitively

worse. Similar inter-modality discrepancies may exist

with other drugs. Pioglitazone, compared with glim-

Table 1 The characteristics and utility of surrogate markers of atherosclerosis

Marker

Correlation

with baseline

atheroma load

Correlation with change

in atheroma burden

Stability and

reproducibility

Discrepant results

in outcome studies

Total ⁄ LDL-cholesterol Yes Progression and regression Good Oestrogen, thyroxine

Endothelial function Yes Progression and regression

(small studies)

Labile and variable Unknown

Asymmetric dimethylarginine Yes Progression Good; good Unknown

Carotid intima-media thickness Yes Progression and regression Good; variable Ezetimibe

Quantitative coronary angiography Yes Progression and regression Good; reasonable None

Coronary intravascular ultrasound Yes Progression and regression Good; good Pioglitazone (possible)

Coronary calcium score Yes Progression Good; good Atorvastatin

Common sense

needs to pre-

vail: ezetimibe

remains a sec-

ond-line ther-

apy for those

unable to

attain targets

on statin

therapy

982 Perspective

ª 2008 The AuthorJournal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, July 2008, 62, 7, 981–987

epiride, improved cIMT in Carotid intima-media

tHICkness in Atherosclerosis usinG piOglitazone trial

(29) and also reduced coronary atheroma in IVUS

far more than predicted based on lipid changes in

the Pioglitazone Effect on Regression of Intravascular

Sonographic Coronary Obstruction Prospective Eval-

uation study (30) (Figure 2) yet its effects on cardio-

vascular events are borderline. The PROspective

pioglitAzone Clinical Trial In macroVascular Events

trial showed a 10% non-significant benefit on its pri-

mary end-point of total cardiovascular events and

procedures (usually a secondary end-point) yet a

modest 16% benefit on its secondary end-point of

cardiovascular events (usually a primary outcome)

(31). In contrast the results of the VeIn-Coronary

aTherOsclerosis and Rosiglitazone after bypass sur-

gerY study with rosiglitazone in patients with diabe-

tes and coronary artery bypass vein grafts (32)

showed a non-significant reduction in IVUS ather-

oma volume which again exceeded expectations

based on lipid changes (+8% HDL-C) with a reduc-

tion in progression from 2.8% to 0.9 % at 1 year

(p = 0.22) and vastly exceeds those seen in 2-year

trials in native coronary arteries (Figure 2). Given

the controversy about the cardiovascular effects and

potential excess cardiovascular events associated with

rosiglitazone as opposed to pioglitazone (33), this

finding again suggests that IVUS may not be an ideal

surrogate marker. Only the final results of the

RECORD study (34) will determine whether cardio-

vascular outcomes are worse with rosiglitazone than

pioglitazone. Similarly, the results of the STrategy to

Reduce Atherosclerosis Development InvolVing

Administration of Rimonabant – the Intravascular

Ultrasound Study with rimonabant although non-

significant in terms of atheroma volume reduction

(35) are in line with changes in lipid fractions (Fig-

ure 2). The Comprehensive Rimonabant Evaluation

Study of Cardiovascular ENDpoints and Outcomes

cardiovascular outcomes trial due in 2012 will be

required to define the effects of rimonabant on hard

cardiovascular end-points (36).

Coronary artery calciumYet not all radiological surrogates have been

accepted. Although CAC scores are often used in the

diagnosis of established disease and risk stratification

(37) it has shown variable results when used as a

surrogate marker of atherosclerosis. CAC is a marker

of senescent plaques which are calcified but seem to

be able to mobilise calcium is response to external

stimuli. CAC scores predict risk of events over and

above the Framingham risk equation in the St Fran-

cis Heart Study (37) and also increase with time in

patients with type 2 diabetes in the PREDICT study

(38) with the changes dependent on age and glyca-

emia. However, results with intervention known to

reduce cardiovascular events are disappointing. Ator-

vastatin 80 mg in the Beyond Endorsed Lipid Lower-

ing with EBCT Study induced no regression of CAC

ENHANCE

ASAP

LIPID

ARBITER-2

RADIANCE-1 METEOR

CLAS

MARS

REGRESS

KAPS ACAPS

BCAPS PLAC-2 FAST

CAIUS

R 2 = 0.1164

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0 10 20 30 40 50 60 70 80Change in HDL-C & LDL-C (%)

Fra

ctio

nal

ch

ang

e in

car

oti

d IM

T

Figure 1 Changes in fractional common carotid intima-media thickness compared with relative concentrations of high-

density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Updated after Wierzbicki (17)

Perspective 983


(39). Thus, this marker seems to correlate with base-

line atheroma but not to be easily reversible.

Surrogate markers and ezetimibe

So what does this say about cIMT and ENHANCE?

First, this is the first major trial with carotid IMT

not to show the suggested benefits even in the com-

mon carotid segment that consistently shows the

greatest changes (40,41). The effects of ezetimibe on

both lipids and CRP were as expected yet no differ-

ence in cIMT was seen (2). The final LDL-cholesterol

(C) achieved in ENHANCE of 3.8 mmol ⁄ l was not

close to that likely required to stop progression of

atheroma based on IVUS studies – 2 mmol ⁄ l (Fig-

ure 3). No previous LDL-C-lowering therapy has

shown this lack of response in a cIMT study. Yet the

results are consistent with cIMT trends (Figure 1);

the trial was mostly performed in patients likely to

have been aggressively treated for at least 5 years;

some had been recruited to a discontinued previous

trial of a acyl-cholesterol acyl transferase inhibitor

(pactimibe); ezetimibe was added to high dose

underlying statin therapy so requiring it to deliver a

–1

–0.5

0

0.5

1

1.5

2

2.5

1.5 1.75 2 2.25 2.5 2.75 3

Final LDL-C (mmol/l)

Ch

ang

e in

ath

ero

ma

volu

me

(%)

Figure 3 Prediction of final low-density lipoprotein cholesterol (LDL-C) to be achieved to stop progression of

atherosclerosis as based on intravascular ultrasound (IVUS) studies. Modified after a series of studies by Nissen

CAMELOT

REVERSAL-A, ILLUSTRATE

STRADIVARIUS Px

STRADIVARIUS

ACTIVATE

PERISCOPE

A-plus

PERISCOPE Px

REVERSAL-P

ASTEROID

ILLUSTRATE-Px

A-plus Px

R 2 = 0.2405

–0.5

0

0.5

1

1.5

2

–20 0 20 40 60 80 100 120

Change in LDL-C & HDL-C (%)

Ch

ang

e in

ath

ero

ma

volu

me

(%)

Figure 2 Changes in atheroma volume on intravascular ultrasound with a variety of cardiovascular drugs compared with

relative concentrations of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).

Updated after Wierzbicki (17)

984 Perspective


significant extra incremental benefit; and the under-

lying cIMT was low (0.76 mm) in comparison with

that seen in ASAPS (1.1 mm) (42) done 4 years pre-

viously or in non-familial hypercholesterolaemia

patients prequalifying for the ‘low-risk’ group

recruited to the Measuring Effects on intima media

Thickness: an Evaluation of Rosuvastatin study

(> 1.2 mm) (43). The most significant confounder is

likely to be the effect of pretreatment with statins as

this will induce plaque stabilisation (and delipida-

tion) converting cIMT in this trial to an analogue of

CAC and thus reflecting previous not current dis-

ease.

Implications of the ENHANCE study

The simplicity of the ‘two sources’ message, the tol-

erability of ezetimibe, the statin-sparing regimen

popular in the USA (44) and heavy sales pressure

have led to an inevitable backlash when overly high

expectations were disappointed. Yet are the alterna-

tives better? High-dose statins cause more side effects

but are effective and evidence based (45). Current

formulations of niacin have only moderate tolerabil-

ity and the evidence for its efficacy comes from

QCA–MLD [HDL Atherosclerosis Treatment Study

(46); Familial Atherosclerosis Treatment Study

(FATS) (47)] and cIMT studies [ARterial Biology for

the Investigation of the Treatment Effects of Reduc-

ing cholesterol (48)]. End-point trials with niacin

added to statin without [Atherothrombosis Interven-

tion in Metabolic syndrome with low HDL-C ⁄ high

triglyceride and Impact on Global Health outcomes

(49)] and with prostaglandin D2-rtype 1 receptor

inhibitors (laropiprant) (Heart Protection Study-2

Treatment of HDL to Reduce the Incidence of Vas-

cular Events) are underway but are not because of

report until 2011–2012. Cholestyramine–statin com-

bination therapy has small-scale evidence again in

QCA–MLD studies and was added to niacin in FATS

(47). This combination has some outcome data from

the small combination therapy subgroups from the

few patients given prespecified secondary treatment

in the Cholesterol And Recurrent Events (50), Lipid

Intervention with Pravastatin in Ischaemic Disease

(51) and Air Force Texas Coronary Atheroma Pre-

vention (52) studies. There is no evidence for

fibrate–statin combinations apart from post hoc anal-

ysed statin drop-in data from the Fenofibrate Inter-

vention in Endpoint Lowering in Diabetes (53)

where no benefit was seen but it has to be noted that

the lipid changes were atypical of combination ther-

apy (54). The Action to Control Cardiovascular Risk

in Diabetes study of fenofibrate or placebo added to

baseline simvastatin in 6000 patients with type 2 dia-

betes will report in 2012, and at least with the recent

demise of the hypoglycaemic therapy co-randomisa-

tion, may be adequately powered.

Implementing evidence fromsurrogate end-point studies

The evidence base suggests maximising statin therapy

before adding additional drugs – a practice that was

not followed in the USA as opposed to Europe or

Canada (44). Only outcome trials will confirm the

utility of ezetimibe but as is common these days tri-

als are having to be enlarged (IMProved Reduction

of Outcomes: Vytorin Efficacy International Trial)

(55), lengthened [simvastatin 20 mg vs. 80 mg in the

Study of the Effectiveness of Additional Reduction in

Cholesterol and Homocysteine (SEARCH)] (56)

and ⁄ or end-points widened (SEARCH) to deliver

results given lower event rates. Ezetimibe remains a

second-line therapy for those unable to attain targets

on statin therapy (57,58) but likely no worse than

any other alternative given the necessary balance of

tolerability as opposed to presumed efficacy of other

drugs. Thus common sense needs to prevail. There is

no need to throw the bathroom suite out with the

baby or to pay excess regard to the ex-cathedra

encyclicals of the cardinals of cardiovascular disease.

Only end-point trials will determine whether ezetim-

ibe has a useful role to play in the treatment of ath-

erosclerosis.

Disclosures

Dr Wierzbicki has received grant support, lecture

honoraria and travel grants from Abbott, Fournier-

Solvay, GlaxoSmithKline, Merck kGA, Merck-Sharp

& Dohme, Pfizer, sanofi-aventis and Takeda pharma-

ceuticals. Dr Wierzbicki was a member of the tech-

nology appraisal committee for ezetimibe at the

National Institute of Health and Clinical Excellence.

A. S. WierzbickiDepartment of Chemical Pathology,

St. Thomas’ Hospital,London, UK

Email: [email protected]

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Surrogate markers, atherosclerosis and cardiovascular disease prevention