CORRESPONDENCE
(compared with plasma) have long
been known, and seem likely to result
from excess P-selectin liberated from
platelets activated, or even exhausted,
by the process of coagulation and clot
formation. Kirk and colleagues,5 with a
different ELISA kit to that of Malik
and colleagues, report a mean soluble
P-selectin in citrated plasma from 20
healthy normal people of 140 ng/mL,
but they also found mean
concentrations in serum of 616 ng/mL.
With the same ELISA kit as Malik and
colleagues, we generally detect a
concentration of around 40–50 ng/mL,
which is notably lower than the
concentrations they report whose cut-
off point for the lowest tertile was
95 mg/mL. Thus measurement of
serum soluble P-selectin may not
necessarily be a true reflection of
physiological levels.
An alternative reason for the failure
of Malik and colleagues to report that
increased soluble P-selectin predicts
outcome may be their analysis of its
predictive value for primary events.
Our work related to the predictive
value in patients with vascular disease.
Patients relatively free of disease might
have lower concentrations of soluble
P-selectin than patients with existing
atherosclerosis, but also the behaviour
of the platelets themselves in these two
populations may be quite different.
However, we find it most likely that
measurement of P-selectin in serum is
the major reason for their failure to find
a meaningful predictive value.
Whilst we agree broadly that
measurement of soluble adhesion
molecules may have little extra to offer
in the de novo prediction of
atherosclerosis, we submit that they
may have a role in dissecting the route
of the disease process and its
progression once fully established.
*Andrew D Blann, Gregory Y H Lip
Haemostasis Thrombosis and Vascular Biology
Unit, University Department of Medicine, City
Hospital, Birmingham B18 7QH, UK
(e-mail: a.blann@bham.ac.uk)
1 Malik I, Danesh J, Whincup P, et al. Soluble
adhesion molecules and prediction of
coronary heart disease: a prospective study
and meta-analysis. Lancet 2001; 358:
971–75.
2 Blann AD, Faragher EB, McCollum CN.
Increased soluble P-selectin in ischaemic
heart disease: a new marker for the
progression of atherosclerosis. Blood Coag
Fibrinolys 1997; 8: 383–90.
3 Blann AD, Lip GYH. Hypothesis: is soluble
P-selectin a new marker of platelet
activation? Atherosclerosis 1997; 128: 135–38.
4 Jilma B, Eichler HG, Vondrovec B, et al.
Effects of desmopressin on circulating
P-selectin. Br J Haematol 1996; 93: 432–36.
5 Kirk G, McLaren M, Belch JJF. Soluble
P-selectin assay: importance of correct
anticoagulant choice. Platelets 1997; 8:
159–62.
526
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Sir—We agree that Iqbal Malik and
colleagues results1 are an important
contribution towards a better
understanding of the role of circulating
adhesion molecules in the prediction of
coronary heart disease, but their
conclusions should be viewed with
caution and re-examined in the context
of the similar study done by
Blankenberg and colleagues.2
Malik and colleagues studied men
whose baseline assessment was done in
1978–80. At that time, the prevalence
of traditional risk factors for coronary
heart disease was high. The prevalence
of current smokers was around 45%,
the average cholesterol concentration
around 6·4 mmol/L and blood pressure
around 150/84 mm Hg. With such high
levels of risk factors, their results show
no additive predictive value of any of
the adhesion molecules to the risk of
coronary heart disease (even in those
without pre-existing disease).
However, other data on risk-factor
prevalence in English men suggest
much lower levels of these risk factors.
The 1996 Health Survey for England3
reports 26% of current smokers,
average total cholesterol of
5·8 mmol/L4 and blood pressure of
142/81 mm Hg.5 It is, therefore,
possible that the relative predictive
value attributable to the different
adhesion molecules may be greater in
the presence of lower levels of
traditional risk factors, thus limiting the
generalisability of Malik and
colleagues’ findings to population
groups with different levels of
competing risk of disease.
This explanation may be plausible
for the contrasting results between
Malik and colleagues’ and Blankenberg
and colleagues’ studies. Although
Blankenberg and colleagues endpoint is
cardiovascular death (rather than
coronary heart disease), the
population’s risk has since been
assessed in 1996–2000. The risk-factor
profile showed a 22% prevalence of
current smokers and average
cholesterol of 5·2 mmol/L. Despite a
shorter average period of follow-up
compared with Malik’s study,
sVCAM-1 concentrations were strong
predictors of cardiovascular events.
Extrapolations of Malik’s findings for
women, different ethnic groups,
populations with different risk factor
profiles, and to the potential effect on
different vascular endpoints is presently
difficult.
We believe that interest in the role
that adhesion molecules may have in
atherosclerosis should not diminish,
and that the current data should not be
generalised to all population groups.
We should have a moratorium on the
THE LANCET • Vol 359 • February 9, 2002 • www.thelancet.com
predictive role of adhesion molecules
in vascular disease until more
contemporary and generalisable
evidence is available.
*Francesco P Cappuccio, Michelle A Miller
Department of General Practice and Primary
Care, St George’s Hospital Medical School,
London SW17 ORE, UK
1 Malik I, Danesh J, Whincup P, et al. Soluble
adhesion molecules and prediction of
coronary heart disease: a prospective study
and meta-analysis. Lancet 2001; 358:
971–75.
2 Blankenberg S, Rupprecht HJ, Bickel C,
et al. Circulating cell adhesion molecules
and death in patients with coronary
artery disease. Circulation 2001; 104:
1336–42.
3 Primatesta P, Falaschetti E, Gupta S,
Marmot MG, Poulter NR. Association
between smoking and blood pressure:
evidence from the Health Survey for
England. Hypertension 2001; 37: 187–93.
4 Primatesta P, Poulter NR. Lipid
concentrations and the use of lipid lowering
drugs: evidence from a national cross
sectional survey. BMJ 2000; 321: 1322–25.
5 Primatesta P, Bost L, Poulter NR. Blood
pressure levels and hypertension status
among ethnic groups in England.
J Hum Hypertens 2000; 14: 143–48.
Authors’ reply
Sir—Our report involved more incident
cases of coronary heart disease (CHD)
and more long-term follow-up than any
previous prospective study, and we
showed that none of these factors was
strongly predictive of CHD risk after
allowances were made for baseline
concentrations of several standard
vascular risk factors.
This result was reinforced by meta-
analysis of previously published
prospective studies, which, when taken
together with our study, involved up to
about 1400 incident CHD cases for
each adhesion molecule. Blankenberg
and colleagues’ prospective study of
soluble E-selectin, ICAM-1, and
VCAM-1 in a cohort of individuals
with evidence of existing CHD
involved 88 deaths from cardiovascular
causes and 65 non-fatal myocardial
infarctions. However, that study has no
material impact on our numerical
findings or our conclusions because it
adds only about 10% of relevant data
to the previous totals.
We prespecified that the primary
statistical comparison was to be
between patients in the top and bottom
thirds of baseline values among
controls so that numerical results from
this study could be directly compared
with those reported in previous meta-
analyses of other inflammatory factors
(such as plasma concentrations of
C-reactive protein, fibrinogen, and
albumin) which also made comparisons
based on thirds.1,2 Odds ratios for CHD