HMG CoA reductase inhibitors and the risk of venous
thrombosis among postmenopausal women
C. J. M. DOGGEN,*§ R. N. LEMAITRE,? N. L. SMITH,* S. R. HECKBERT,* and B. M. PSATY*??
Departments of *Epidemiology, ?Medicine and ?Health Services, Cardiovascular Health Research Unit, University of Washington, Seattle,
Washington, USA; §Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
To cite this article: Doggen CJM, Lemaitre RN, Smith NL, Heckbert SR, Psaty BM. HMG CoA reductase inhibitors and the risk of venous thrombosis
among postmenopausal women. J Thromb Haemost 2004; 2: 700–1.
See also Ray JG. Do we care if statins prevent venous thromboembolism? This issue, pp. 695–6.
In addition to lowering blood lipid levels, statins (HMG CoA
reductase inhibitors) inhibit platelet aggregation and maintain
a favorable balance between prothrombotic and fibrinolytic
mechanisms . Perhaps these effects may account for the
association of statins with a reduced risk of venous thrombosis
[2,3]. Because different statins have different properties , the
possibility that the risk of venous thrombosis varied by specific
statin was also investigated.
A population-based case–control study was conducted at
Group Health Cooperative (GHC), a large health mainten-
ance organization in western Washington state, USA. Cases
were all postmenopausal women aged 30–89 years who had
a first venous thrombosis between January 1, 1995 and
December 31, 2000. This particular case-control study is one
of several on-going case-control studies that share a single
control group, which presents a stratified random sample of
postmenopausal female Group Health members. For histor-
ical and sample-size reasons, the controls were frequency
matched on age, calender year of identification, and treated
hypertension status to distributions of myocardial infarction
cases . The index date for cases was the date of their first
venous thrombosis, while for controls it was a random date
during the calendar year in which they were selected to
participate. We used GHC computerized pharmacy records
to ascertain current use of lipid lowering medications at the
index date, and categorized women into non-users of lipid
lowering medications; statin users; and users of other
lipid lowering medications, including bile-acid sequestrants,
fibrates and niacins. Current use was defined as the receipt
of at least one lipid lowering prescription prior to the index
date with enough medications to last until the index date,
assuming 80% compliance. Duration of use was calculated
as the number of days that each prescription would last
assuming 80% compliance and by summing this for each
prescription since starting date. Simvastatin and pravastatin
were used by 97.8% of the current statin users. Three
women who used other statins (lovastatin or atorvastatin)
and 17 women with chronic liver disease were excluded from
the analysis. Women prescribed less than 40 mg of simvast-
atin were defined as low-dose users, and women prescribed
40 mg or more were defined as high-dose users.
Included in this study were 465 postmenopausal women
with a first venous thrombosis and 1962 controls. Venous
thrombosis was objectively verified with a venogram, Dop-
pler or Duplex study, a pulmonary angiography, lung scan
with a high probability, or a computer tomography scan in
93% of all cases. Of the remaining 32 women, 13 died before
any diagnostic test or treatment could be started and
19 women were treated with coumadin or had a vena cava
filter after the diagnosis of venous thrombosis was clinically
made. Deep vein thrombosis (DVT) in the leg occurred in
348 cases, a pulmonary embolism (PE) in 42, and 75 cases
were diagnosed with both DVT and PE.
At the index date, 4.5% of cases and 5.6% of controls were
current users of statins. The median duration of statin use
among cases was 435 (range 13–1751) days as compared to 354
(range 4–2505) days among control subjects. Among current
users, 76.2% of cases and 85.5% of controls used simvastatin.
Current statin users appeared to have a slightly lower risk of
venous thrombosis than non-users after adjustment for the
matching factors (OR 0.84; 95% CI 0.51–1.37) (Table 1).
Adjustment for current estrogen use did not alter any of the
odds ratios, in contrast to adjustment for vascular disease
which decreased the risk. Further adjustment for weight and
height or diabetes did not substantially effect the odds ratios.
The reduced risk of venous thrombosis seemed to be confined
to women using simvastatin as opposed to pravastatin and
was found among both low-dose and high-dose users of
simvastatin. Because of time trends in use direct comparison
Correspondence: C.J.M. Doggen, Department of Clinical Epidemiol-
ogy, Leiden University Medical Center C9-P, PO Box 9600, 2300 RC
Leiden, the Netherlands.
Tel.: +31 71 526 4037; fax: +31 71 526 6994; e-mail: C.J.M.Doggen@
Received 20 November 2003, accepted 15 January 2004
Journal of Thrombosis and Haemostasis, 2: 700–701
? 2004 International Society on Thrombosis and Haemostasis
between individual statin medications may not be reliable,
but the comparison suggested a decreased risk of venous
thrombosis for simvastatin compared to pravastatin users
(OR adjusted matched factors 0.14; 95% CI 0.02–0.88).
The study results suggest that statins may reduce the risk
of venous thrombosis, as has been found before [2,3].
However, there seems to be heterogeneity between the
individual statin medications, and in this study only
simvastatin was associated with a decreased risk. Several
mechanisms, other than chance, may explain this potential
heterogeneiety. First, in vitro, the lipophilic simvastatin
suppresses tissue factor activity and antigen and tissue factor
expression in macrophages, an effect not found with the
hydrophilic pravastatin . As tissue factor initiates blood
coagulation, it may act as a risk factor for venous
thrombosis. Secondly, simvastatin treatment impairs activa-
tion of prothrombin, factor (F) V and FXIII, and enhances
FVa inactivation by activated protein C , which may lead
to a reduced risk of venous thrombosis. To our knowledge,
the effect of pravastatin on these factors has not been
reported. Finally, the disparate findings for individual statin
medications may be due to differences in metabolism . One
limitation of this study is the low power. While there are
several plausible biologic explanations for the differences in
venous thrombosis risk found between individual statins,
these suggestive findings need to be replicated in other
The research reported in this article was supported in part
by the following grants: HL43201, HL40628, and HL60739
from the National Heart, Lung, and Blood Institute; AG09556
from the National Institute on Aging; 9970178N from the
Patient Care and Outcomes Research Program of the Ameri-
can Heart Association (AHA); 0270054N from the AHA
Pharmaceutical Roundtable Outcomes Research Program. Dr
C.J.M. Doggen was supported by the Netherlands Organiza-
tion for Scientific Research (NWO grant no. S94-191).
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Table 1 Association of drug therapy to lower cholesterol levels and the risk of venous thrombosis among postmenopausal women
Drug to lower cholesterol levelsCasesControlsOR (95% CI)*OR (95% CI)?
*Odds ratio adjusted for matching factors; ?odds ratio adjusted for matching factors and vascular disease (history of myocardial infarction, angina
pectoris, stroke, transient ischemic attack or claudication).
HMG CoA reductase inhibitors and venous thrombosis 701
? 2004 International Society on Thrombosis and Haemostasis