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Pravastatin and cognitive function in the elderly. Results of the PROSPER study
Trompet, S.; van Vliet, P.; de Craen, A.J.; Jolles, J.; Buckley, B.M.; Gronenschild, E.H.;
Murphy, M.B.; Ford, I.; Macfarlane, P.W.; Sattar, N.; Packard, C.J.; Stott, D.J.; Shepherd,
J.; Bollen, E.L.; Blauw, G.J.; Jukema, J.W.; Westendorp, R.G.
published in
Journal of Neurology
2009
DOI (link to publisher)
10.1007/s00415-009-5271-7
document version
Publisher's PDF, also known as Version of record
Link to publication in VU Research Portal
citation for published version (APA)
Trompet, S., van Vliet, P., de Craen, A. J., Jolles, J., Buckley, B. M., Gronenschild, E. H., Murphy, M. B., Ford, I.,
Macfarlane, P. W., Sattar, N., Packard, C. J., Stott, D. J., Shepherd, J., Bollen, E. L., Blauw, G. J., Jukema, J.
W., & Westendorp, R. G. (2009). Pravastatin and cognitive function in the elderly. Results of the PROSPER
study. Journal of Neurology, 257(1), 85-90. https://doi.org/10.1007/s00415-009-5271-7
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ORIGINAL COMMUNICATION
Pravastatin and cognitive function in the elderly.
Results of the PROSPER study
Stella Trompet Æ Peter van Vliet Æ Anton J. M. de Craen Æ Jelle Jolles Æ Brendan M. Buckley Æ
Michael B. Murphy Æ Ian Ford Æ Peter W. Macfarlane Æ Naveed Sattar Æ Chris J. Packard Æ
David J. Stott Æ Jim Shepherd Æ Eduard L. E. M. Bollen Æ Gerard J. Blauw Æ J. Wouter Jukema Æ
Rudi G. J. Westendorp
Received: 25 June 2009 / Revised: 13 July 2009 / Accepted: 21 July 2009 / Published online: 4 August 2009
Ó Springer-Verlag 2009
Abstract Observational studies have given conflicting
results about the effect of statins in preventing dementia
and cognitive decline. Moreover, observational studies are
subject to prescription bias, making it hard to draw definite
conclusions from them. Randomized controlled trials are
therefore the preferred study design to investigate the
association between statins and cognition. Here we present
detailed cognitive outcomes from the randomized placebo-
controlled PROspective Study of Pravastatin in the Elderly
at Risk (PROSPER). Cognitive function was assessed
repeatedly in all 5,804 PROSPER participants at six
different time points during the study using four neuro-
psychological performance tests. After a mean follow-up
period of 42 months, no difference in cognitive decline at
any of the cognitive domains was found in subjects treated
with pravastatin compared to placebo (all p [ 0.05).
Pravastatin treatment in old age did not affect cognitive
decline during a 3 year follow-up period. Employing statin
therapy in the elderly in an attempt to prevent cognitive
decline therefore seems to be futile.
Keywords Statins Clinical trial Cognition
Elderly
S. Trompet (&) P. van Vliet A. J. M. de Craen
G. J. Blauw R. G. J. Westendorp
Department of Gerontology and Geriatrics, C-2-R,
Leiden University Medical Center,
PO Box 9600, 2300 RC Leiden, The Netherlands
e-mail: s.trompet@lumc.nl
S. Trompet J. W. Jukema
Department of Cardiology, Leiden University Medical Centre,
Leiden, The Netherlands
J. Jolles
Department of Special Education,
Faculty of Psychology and Education,
VU University Amsterdam, Amsterdam,
The Netherlands
B. M. Buckley M. B. Murphy
Department of Pharmacology and Therapeutics,
Cork University Hospital, Cork, Ireland
I. Ford
Robertson Centre for Biostatistics, University of Glasgow,
Glasgow, Scotland
P. W. Macfarlane
Division of Cardiovascular and Medical Sciences,
University of Glasgow, Glasgow, Scotland
N. Sattar
BHF Glasgow Cardiovascular Research Centre,
Faculty of Medicine, University of Glasgow,
Glasgow, Scotland
C. J. Packard J. Shepherd
Department of Vascular Biochemistry, University of Glasgow,
Glasgow, Scotland
D. J. Stott
Department of Geriatric Medicine, University of Glasgow,
Glasgow, Scotland
E. L. E. M. Bollen
Department of Neurology, Leiden University Medical Centre,
Leiden, The Netherlands
J. W. Jukema
Durrer Center for Cardiogenetic Research,
Interuniversity Cardiology Institute, Amsterdam,
The Netherlands
R. G. J. Westendorp
Netherlands Consortium for Healthy Ageing, Leiden,
The Netherlands
123
J Neurol (2010) 257:85–90
DOI 10.1007/s00415-009-5271-7
Introduction
Lowering cholesterol levels to preserve cognitive function
has received much attention with the increasing emphasis
on vascular disease as a risk factor of dementia and cog-
nitive impairment [1, 16]. Observational studies have
shown that high cholesterol levels in middle age are a risk
factor for cognitive impairment later in life [17]. Besides
increasing the risk of cardiovascular disease with sub-
sequent increased risks of cognitive decline, high choles-
terol levels might also directly influence the risk of
cognitive decline. High total serum cholesterol levels have
been shown to associate with lower cerebral spinal fluid
levels of b-amyloid and larger amounts of b-amyloid
deposition in brain autopsy studies [9, 10].
Numerous observational studies have investigated the
possible beneficial effect of statins in preventing dementia
and cognitive decline. Cross-sectional and case-control
studies have generally indicated a beneficial effect of
statins on cognitive outcomes [5, 12, 18], while observa-
tional studies with long follow-up periods have failed to
confirm these results [17, 19]. This discrepancy might be
explained by prescription bias, in that subjects who are
cognitively impaired are less likely to have been prescribed
a statin. Therefore, randomized controlled trials are the
necessary instrument to investigate the effect of statins on
cognitive function.
Until now only two large scale randomized controlled
trials have examined the influence of statins on cognitive
function. The Heart Protection Study showed that use of
simvastatin did not decrease the risk of developing
dementia [2]. However, cognitive function was not an
initially specified endpoint and was only assessed once at
the end of the study by a telephone questionnaire. In
contrast, the PROspective Study of Pravastatin in the
Elderly at Risk (PROSPER) [14]isasyettheonlyran-
domized controlled trial that has been set up to test
whether use of pravastatin preserved cognitive function,
and therefore involved repeated assessment of various
cognitive domains both at baseline and during follow-up
as one of the major prespecified outcomes. In order to
help clarify the ongoing debate on the effects of statins on
cognition, we present here these observations in full
detail, which strongly extends our earlier preliminary
conclusions presented in the main PROSPER manuscript
[14].
Methods
A detailed description of the study has been published
elsewhere [14, 15]. A short summary is provided here.
Participants
PROSPER was a prospective multicentre randomized pla-
cebo-controlled trial to assess whether treatment with
pravastatin diminishes the risk of major vascular events in
elderly people. Between December 1997 and May 1999,
we screened and enrolled subjects in Scotland (Glasgow),
Ireland (Cork), and the Netherlands (Leiden). Men and
women aged 70–82 years were recruited if they had pre-
existing vascular disease or increased risk of such disease
because of smoking, hypertension, or diabetes. A total
number of 5,804 subjects were randomly assigned to
pravastatin or placebo.
Cognitive function assessment
The Mini-Mental State Examination (MMSE) was used to
measure global cognitive function. Participants with poor
cognitive function (MMSE \24) were not eligible to par-
ticipate. Four neuropsychological performance tests were
used to measure various cognitive domains. Executive
functioning was assessed with the Stroop-Colour-Word-
test for attention and the Letter-Digit Coding Test (LDT)
for processing speed. The outcome parameter for the
Stroop test was the total number of seconds required to
complete the third Stroop card containing 40 items. The
outcome variable for the LDT was the total number of
correct entries completed in 60 s. Memory was assessed
with the 15-Picture Learning test (PLT) which measures
immediate and delayed recall. The main outcome variable
for immediate recall was the accumulated number of pic-
tures recalled over the three learning trials and for delayed
recall the number of pictures recalled after 20 min. The
reliability and sensitivity of these tests in an elderly pop-
ulation have been assessed and presented elsewhere [7].
Cognitive function was tested before randomisation, at
baseline, after 9, 18, and 30 months, and at the end of the
study. The time point of this last measurement was dif-
ferent for the participants (at 36–48 months) therefore we
performed the analyses with their individually varying
time-point but report the results for the mean of these time
points (at 42 months). The pre-randomized measurement
was discarded in all analyses to preclude possible learning
effects. Since the MMSE is not suitable for longitudinal
research in this age group because of learning and ceiling
effects, sequential MMSE scores are not reported here.
Statistical analyses
The effect of statin use on cognitive function during fol-
low-up was assessed using linear mixed models for repe-
ated measurements which included interim measures taken
86 J Neurol (2010) 257:85–90
123
between the baseline and the final assessment [6]. The
model incorporated time, statin treatment, and the inter-
action term of time with statin treatment. The main variable
of interest in the model was the estimate for the interaction
between time and statin treatment. A significant difference
in this term would indicate that cognitive decline over
42 months differed between the statin and placebo treated
groups. All analyses were adjusted for sex, age, educational
status, country, and version of test where appropriate.
Subjects were defined as the random factor; all other
variables were fixed within the model. Furthermore we
analysed the association between pravastatin treatment and
cognitive function in males or females, in subjects with or
without a history of vascular disease or diabetes, with or
without APOE e4 carriership, and with low or high HDL or
total cholesterol levels at baseline. SPSS software (version
14.0, SPSS Inc, Chicago, Ill) was used for all statistical
analyses. p values lower than 0.05 were considered statis-
tically significant.
Results
Table 1 shows the baseline characteristics of the 5,804
participants in PROSPER. A total of 2,913 subjects were
randomized to placebo and 2,891 to pravastatin treatment.
The mean age of all subjects at study entry was 75.3 years
and approximately 50% of the participants were female.
The mean follow-up period of this trial was 42 months
(range 36–48 months). The two treatment groups were well
balanced with respect to all relevant baseline characteris-
tics except for the Stroop-Colour-Word test which, at
baseline, was significantly different between the groups
(Table 1). This we presume was due to the play of chance.
Figure 1 represents graphically the effect of pravastatin
on various domains of cognitive function over time. The
mean cognition scores at baseline, different from those
given in Table 1, are adjusted for sex, age, educational
status, country and version of test where appropriate. All
cognitive tests showed a significant decline over time,
confirming their adequate sensitivity to pick up deteriora-
tion of cognitive function in old age. Users of pravastatin
did not show any difference in the change in any of the
cognitive tests compared to placebo users during follow-up
(all p [ 0.3).
Table 2 shows the association between pravastatin
treatment and cognitive decline in pre-specified subgroups.
There was no pravastatin versus placebo difference in
cognitive decline in males or females, subjects with or
without a history of vascular disease or history of diabetes,
with or without APOE e4 carriership, with low or high
HDL and total cholesterol levels (all p [ 0.05). Although
the effect of pravastatin on processing speed within the
APOE e2 carriers and within the low cholesterol group was
significant (p = 0.01), this finding lost statistical signifi-
cance after correction for multiple testing, and there was no
consistent parallel change in the other cognitive perfor-
mance tests.
Discussion
In this large scale randomized controlled trial in an elderly
population at risk of cognitive decline we found no effect
(beneficial or detrimental) of pravastatin on cognitive
function. This association was assessed with a sensitive,
well-validated cognitive test battery, using repeated mea-
surements in a large homogenous group of elderly people.
Table 1 Baseline characteristics of the participants in the PROSPER
study
Placebo
(n = 2,913)
Pravastatin
(n = 2,891)
Continuous variables (mean, SD)
Age (years) 75.3 (3.4) 75.4 (3.3)
Education (years) 15.1 (2.0) 15.2 (2.1)
Systolic blood pressure (mmHg) 154.6 (21.8) 154.7 (21.9)
Diastolic blood pressure (mmHg) 83.9 (11.7) 83.6 (11.2)
Height (m) 1.7 (0.1) 1.7 (0.1)
Weight (kg) 73.4 (13.5) 73.4 (13.3)
Body mass index (kg/m
2
) 26.8 (4.3) 26.8 (4.1)
Alcohol (units per week) 5.1 (8.9) 5.3 (9.7)
Total cholesterol (mmol/L) 5.7 (0.9) 5.7 (0.9)
LDL cholesterol (mmol/L) 3.8 (0.8) 3.8 (0.8)
HDL cholesterol (mmol/L) 1.3 (0.3) 1.3 (0.4)
Triglycerides (mmol/L) 1.5 (0.7) 1.5 (0.7)
Mini mental state examination score 28.0 (1.6) 28.0 (1.5)
Stroop-Colour-Word test 67.5 (28.3) 65.5 (25.5)
Letter-Digit Coding Test 22.9 (7.8) 23.2 (7.9)
Picture Learning test immediate 9.3 (1.8) 9.3 (1.9)
Picture Learning test delayed 10.2 (2.6) 10.1 (2.6)
Categorical variates (n,%)
Males 1,408 (48.3) 1,396 (48.3)
Current smoker 805 (27.6) 753 (26.0)
History of diabetes 320 (11.0) 303 (10.5)
History of hypertension 1,793 (61.6) 1,799 (62.2)
History of angina 753 (25.8) 806 (27.9)
History of claudication 192 (6.6) 198 (6.8)
History of myocardial infarction 399 (13.7) 377 (13.0)
History of stroke or TIA 321 (11.0) 328 (11.3)
History of vascular disease
a
1,259 (43.2) 1,306 (45.2)
a
Any of stable angina, intermittent claudication, stroke, transient
ischemic attack, myocardial infarction, peripheral artery disease sur-
gery, or amputation for vascular disease more than 6 months before
study entry
J Neurol (2010) 257:85–90 87
123
Fig. 1 Effect of pravastatin on
cognitive function over time.
p values represent the statistical
significance of the difference in
test score changes over time
between statin users and non-
users. Means were assessed
using linear mixed models
adjusted for sex, age,
educational status, country, and
version of test where
appropriate
Table 2 Difference in cognitive decline between subjects treated with pravastatin and placebo in various subgroups
Stroop-Colour-Word test Letter-Digit Coding test Picture Learning test immediate Picture Learning test delayed
Est 95% CI Est 95% CI Est 95% CI Est 95% CI
Sex
Females 0.25 -0.10; 0.61 -0.01 -0.09; 0.07 -0.01 -0.04; 0.02 -0.02 -0.07; 0.03
Males 0.004 -0.39; 0.40 0.01 -0.07; 0.09 -0.01 -0.04; 0.02 0.02 -0.02; 0.07
History of vascular disease
No -0.05 -0.41; 0.32 0.002 -0.08; 0.08 -0.02 -0.05; 0.01 -0.03 -0.07; 0.02
Yes 0.36 -0.02; 0.74 -0.02 -0.08; 0.09 0.002 -0.03; 0.04 0.04 -0.01; 0.09
History of diabetes
No 0.22 -0.06; 0.49 0.01 -0.05; 0.07 -0.01 -0.03; 0.01 0.01 -0.03; 0.04
Yes -0.56 -1.52; 0.40 -0.11 -0.29; 0.07 -0.02 -0.09; 0.05 -0.04 -0.14; 0.06
APOE genotype
e2 Carriers -0.27 -1.09; 0.56 0.15 -0.02; 0.32 -0.09 -0.17;
-0.04** -0.01 -0.11; 0.08
e3/e3 0.30 -0.03; 0.63 -0.03 -0.10; 0.04 -0.01 -0.03; 0.02 0.00 -0.04; 0.05
e4 Carriers* -0.16 -0.70; 0.37 -0.003 -0.11; 0.12 0.02 -0.03; 0.07 0.02 -0.06; 0.09
Plasma total cholesterol
Low 0.21 -0.17; 0.59 0.02 -0.06; 0.10 -0.04 -0.08; -0.01** -0.03 -0.08; 0.02
High 0.05 -0.32; 0.41 -0.02 -0.10; 0.06 0.02 -0.01; 0.06 0.03 -0.02; 0.08
Plasma HDL cholesterol
Low 0.25 -0.13 (0.62) -0.002 -0.08; 0.08 -0.01 -0.04; 0.02 0.01 -0.04; 0.05
High -0.01 -0.36; 0.38 0.003 -0.08; 0.08 -0.01 -0.04; 0.02 -0.004 -0.05; 0.04
Estimates (Est) and 95% confidence intervals (95% CI) were assessed with linear mixed models adjusted for age, educational status, country and,
where appropriate, for sex and version of test. Estimates represent the additional annual change of the pravastatin treatment group compared to
placebo treatment. * e2/e4 carriers (n = 119) were included in the
e4 carriers subgroup. ** p value = 0.01
88 J Neurol (2010) 257:85–90
123
