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Use of Statins and the Subsequent Development of Deep Vein Thrombosis
Joel G. Ray, MD, FRCPC, MSc;
Muhamad Mamdani, PharmD, MA, MPH;
Ross T. Tsuyuki, PharmD, MSc, FCSHP;
David R. Anderson, MD, FRCPC;
Erik L. Yeo, MD, FRCPC;
Andreas Laupacis, MD, FRCPC, MSc
Arch Intern Med. 2001;161:1405-1410.
ABSTRACT
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Background Some of the benefit of statins for the prevention of cardiovascular
disease may be due to their antithrombotic properties. Little is known about
the effect of these drugs on the development of deep vein thrombosis.
Materials and Methods We conducted a retrospective cohort study over an 8-year period by linking
Ontario provincial health care administrative databases covering more than
1.4 million Ontario residents aged 65 years or older. We excluded those with
a documented history of atherosclerosis, venous thromboembolism, or cancer
within 36 months prior to study enrollment, as well as those prescribed warfarin
sodium within 12 months before enrollment. In the primary cohort, we evaluated
the subsequent risk of deep vein thrombosis (DVT) among men and women prescribed
thyroid replacement therapy, nonstatin lipid-lowering agents, or statins.
A second cohort of women only was evaluated in a similar fashion, but estrogen
use was added as a third comparison drug group.
Results There were 125 862 men and women in the primary cohort. After adjusting
for age; sex; prior hospitalization; newly diagnosed cancer; or prescribed
aspirin, warfarin, or estrogen, statin users (n = 77 993) had an associated
decreased risk of DVT relative to those prescribed thyroid replacement therapy
(n = 35 978) (adjusted hazard ratio [HR], 0.78; 95% confidence interval
[CI], 0.69-0.87). Compared with thyroid replacement therapy, users of nonstatin
lipid-lowering agents (n = 11 891) did not seem to be at lower risk for
deep vein thrombosis (HR, 0.97; 95% CI, 0.79-1.18). In the secondary cohort
of 89 508 women, after adjusting for age, prior hospitalization, newly
diagnosed cancer, or prescribed aspirin or warfarin, estrogen users (n = 29 165)
had an associated increased risk for DVT compared with those receiving thyroid
replacement therapy (n = 22 118) (HR, 1.16; 95% CI, 1.01-1.33), while
statin users had an associated decreased risk (HR, 0.68; 95% CI, 0.59-0.79).
Nonstatin lipid-lowering agents (n = 5155) were not associated with a reduced
risk of DVT compared with thyroid replacement therapy (HR, 0.84; 95% CI, 0.63-1.12).
Conclusion Among selected individuals aged 65 years or older, statins were associated
with a 22% relative risk reduction in the risk of DVT. A randomized clinical
trial is needed to evaluate the efficacy of statins for the primary and secondary
prevention of DVT.
INTRODUCTION
RANDOMIZED clinical trials have conclusively demonstrated that 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors (statins) are efficacious in the secondary
prevention of cardiovascular disease among individuals with both normal and
elevated lipid levels.1-4
In addition to their effect on lipid levels, these drugs seem to have antithrombotic
properties.5 In a retrospective, subgroup analysis
by the Heart Estrogen Replacement Study (HERS)6
investigators, statin use was associated with a 50% risk reduction of venous
thromboembolism (VTE). However, because statin use was one of many VTE risk
factors studied and because its protective effect was not explored a priori,
only limited conclusions can be drawn from these findings. Therefore, we further
investigated whether statin use was associated with a reduction in the risk
for deep vein thrombosis (DVT) in a large cohort of men and women.
PARTICIPANTS, MATERIALS, AND METHODS
STUDY POPULATION
We conducted a retrospective cohort study by linking Ontario provincial
health care administrative databases covering more than 1.4 million senior
residents of Ontario over an 8-year period. All persons aged 65 years or older
and enrolled with the Ontario Health Insurance Plan for the province of Ontario
were considered eligible. The Ontario Health Insurance Plan covers all medical
care and prescription drug costs for every Ontario senior citizen. For the
primary cohort of men and women, the following mutually exclusive drug groups
were studied: (1) statins, the exposure of interest; (2) thyroid replacement
hormones, the referent control group, selected because of their lack of known
association with VTE; and (3) nonstatin lipid-lowering agents (ie, fibrates,
niacin, or bile acid sequestrants), a biological comparison group.
We also studied a second cohort of women only, derived from the same
Ontario population as the primary cohort, but included estrogen users as a
third, positive comparison drug group.6 This
secondary cohort of women was added to test our study design, in that we expected
there to be a positive association between estrogen use and DVT.6
Because the primary cohort consisted of both men and women, and since men
are not prescribed estrogens, an estrogen drug comparison group would have
been impossible. Finally, since estrogen use in the secondary cohort had to
be "mutually exclusive" (ie, no concomitant use of statins, thyroid replacement
hormones, or nonstatin lipid-lowering agents), secondary cohort participants
may have differed slightly from women in the primary cohort.
We studied all individuals who met the following inclusion criteria:
(1) had a prescription filled for a study drug between January 1, 1994, and
January 31, 1999; (2) had not filled a prescription for another study drug
within 365 days of the current study drug (ie. mutually exclusive drug groups);
and (3) had filled at least 2 prescriptions for the current study drug within
180 days of its initiation. Excluded were all individuals who (1) had a history
of angina, myocardial infarction, coronary revascularization, stroke, carotid
endarterectomy, peripheral vascular disease, or peripheral artery revascularization
within 36 months prior to study enrollment; (2) had a diagnosis of cancer
within 36 months prior to study enrollment; (3) had a diagnosis of DVT or
pulmonary embolism within 36 months prior to study enrollment; or (4) had
been prescribed warfarin sodium within 12 months prior to study enrollment.
Those who were newly prescribed warfarin or diagnosed with cancer after study
enrollment remained in the cohort, but the presence of either factor was adjusted
for, as outlined below.
The primary outcome of the study was the development of DVT during the
follow-up period, after initiation of a statin or control agent. The period
of observation was January 1, 1994, to March 31, 1999, but databases were
used from January 1, 1991, to March 31, 1999, to account for the presence
of antecedent inclusion and exclusion criteria. Individuals who began receiving
one of the study drugs were followed up over time to assess the outcome of
interest. Participants were censored (ie, determined not to have had a DVT
event up to that point) if they temporarily or permanently discontinued taking
the study medication. This was defined as having greater than 180 days between
subsequent prescriptions, died during the study period, or having reached
the end of follow-up to March 31, 1999. An individual was also censored if
he or she was prescribed a drug from another study drug group (ie, contamination
effect). At least 2 consecutive study drug prescriptions were required to
select individuals who were more likely to continue receiving their medications.
It has been demonstrated that 60% of patients discontinue their lipid-lowering
medications over a 12-month period, most within 3 months of starting treatment.7-8 Individuals older than 65 years are
more likely to continue receiving their medications,7
including statins,8 further increasing the
likelihood that our defined sample would continue receiving their prescribed
agent throughout the period of analysis.
The Ontario Drug Benefits database was used to identify the medications
each elderly participant was prescribed during the observation period. This
database is maintained by the Ontario Ministry of Health, Ottawa, and includes
encrypted patient identifiers, prescription dates, and drug information for
all residents of Ontario 65 years or older. Participants who received medications
from any of the study drug groups during the year prior to cohort enrollment
were excluded, allowing only new users of the medications to be included.
There is little missing information in the Ontario databases (<1%), while
there is a high degree of coding accuracy.9
Hospitalizations, identified using the Canadian Institute for Health Information
Discharge Abstract Database, were used to characterize subsequent events and
comorbid illnesses. The discharge abstracts contain the unique health care
number, age, and sex of the participant, date of admission, and up to 16 diagnoses,
as coded by the International Classification of Diseases,
Ninth Revision (ICD-9). The Ontario Health Insurance Plan database,
which contains records of all outpatient visits by Ontario residents, including
a service date and diagnosis field, was used to capture outpatient diagnoses
of VTE. Participant age and sex were retrieved from the Registered Persons
Database. This database contains demographic information and health care numbers
for all individuals eligible for the Ontario Health Insurance Plan. All data
at Institute for Clinical Evaluative Sciences are maintained in an anonymous
fashion to ensure confidentiality.
STATISTICAL ANALYSIS
Time-to-event analyses were conducted using the Cox proportional hazards
regression model. For the analysis of the primary cohort, adjustments were
made for age, sex, hospitalization within 1 year prior to study enrollment,10 newly diagnosed cancer,11
or concurrent prescription of aspirin,12 warfarin,13-14 or estrogen6
during the observation period. For the analysis of the secondary cohort of
women, since conjugated estrogen was added as a third comparison agent, no
adjustment was made for its use. All participants were identified as being
exposed to a potential confounder if the confounding event occurred at any
time between 100 days prior to study enrollment and the end of follow-up.
The comparative risk for DVT between drug classes was expressed as the adjusted
hazard ratio (HR) along with its 95% confidence interval (CI).
Baseline characteristics between men and women were compared within
each drug group using either an analysis of variance for continuous variables
or the  2 test for categorical data. All P values were 2-sided and a statistical significance level of .05 was
set a priori. All statistical analyses were performed using SAS for UNIX,
Version 6.12 (SAS Institute, Cary, NC).
RESULTS
PRIMARY COHORT OF MEN AND WOMEN
There were 125 862 adults in the primary cohort, for a total of
190 601 person-years of drug use (Table 1). The mean age of all participants was 72.9 years. The average
duration of observation varied from 1.1 years for nonstatin lipid-lowering
agents to 1.4 years for both statins and thyroid replacement therapy. Within
each drug class, men were more likely to be hospitalized or diagnosed as having
cancer during the period of observation (P<.001),
and had a higher rate of both concurrent aspirin and warfarin use compared
with women (P<.001) (Table 1).
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Table 1. Characteristics of the Primary Cohort and the Risk for Deep
Vein Thrombosis (DVT) According to Drug Class
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During the period of observation, statin users experienced a lower rate
of DVT (7.4 per 1000 person-years) than those prescribed thyroid replacement
therapy (10.9 per 1000 person-years) (HR, 0.78; 95% CI, 0.69-0.87) (Table 1 and Figure 1). No significant difference was observed between those
prescribed nonstatin lipid-lowering agents vs thyroid replacement drugs (HR,
0.97; 95% CI, 0.79-1.18).
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Rate of deep vein thrombosis (DVT) among men and women according
to agent.
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Women experienced a higher rate of DVT than men in the thyroid replacement
group (12.0 per 1000 person-years vs 7.8 per 1000 person-years), nonstatin
lipid-lowering group (10.1 per 1000 person-years vs 8.4 per 1000 person-years),
and statin group (8.1 per 1000 person-years vs 6.7 per 1000 person-years)
(Table 1). Furthermore, statins
were associated with a lower risk of DVT to a greater extent among women (HR,
0.72; 95% CI, 0.63-0.82) than men (HR, 0.97; 95% CI, 0.78-1.22).
SECONDARY COHORT OF WOMEN ONLY
There were 89 508 women included in the secondary cohort, for a
total of 124 568 person-years of drug use (Table 2). Their overall mean age was 73.5 years. The rate of concurrent
aspirin use was highest among those prescribed statins (35.6%) and lowest
in the estrogen replacement therapy group (18.9%), while warfarin use was
highest among those prescribed thyroid replacement therapy (8.3%) and lowest
among estrogen recipients (3.9%).
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Table 2. Characteristics of the Secondary Cohort of Women and the Risk
for Deep Vein Thrombosis (DVT) According to Drug Class
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Women prescribed estrogen replacement therapy were at increased risk
for DVT compared with those receiving thyroid replacement therapy (HR, 1.16;
95% CI, 1.01-1.33). Relative to thyroid replacement therapy, statins were
associated with a statistically significant reduced risk for DVT (HR, 0.68;
95% CI, 0.59-0.79), while nonstatin lipid-lowering agents were not (HR, 0.84;
95% CI 0.63-1.12).
COMMENT
In a large retrospective cohort of individuals aged 65 years or older,
prescribed statins were associated with a 22% relative reduction in the risk
for DVT compared with control. This benefit seemed to be only significant
in women. Prescription of nonstatin lipid-lowering agents was not associated
with a decrease in DVT.
We excluded all individuals with a history of a malignant neoplasm within
36 months prior to study enrollment and further adjusted for prior hospital
admission or a concurrent diagnosis of cancer during the observation period.6, 10 Although controlling for such VTE
risk factors may have produced less biased estimates, we acknowledge the potential
for misclassification of either DVT or confounding disease event by depending
on physician diagnostic billing codes, which may be unreliable for some hospital
diagnoses.15 Such misclassification, if nondifferential,
may have lead to an underestimation of the association between either statin
or estrogen use and the risk of DVT. Furthermore, we did not account or control
for the possibility that some individuals may have been taking over-the-counter
aspirin preparations, which could potentially lower their risk for DVT and
affect our results.12
This study was composed of a large sample of men and women derived from
a population of senior citizens whose health care and medications were covered
by the Ontario Health Insurance Plan. By omitting individuals with a previous
diagnosis of cardiovascular disease, we hoped to reduce the likelihood of
confounding by indication,16 because statin
use could merely reflect the presence of atherosclerosis and, accordingly,
the use of antithrombotic drugs and lifestyle changes that might reduce an
individual's risk of VTE. We also applied strict criteria to define drug use,
in that individuals could not receive a drug belonging to another group, and
had at least 2 prescriptions filled within 180 days of initiation of study
enrollment.8 Finally, these data were based
on more than 110 000 person-years of statin use, thus providing reasonable
precision for our estimates.
The incidence of DVT in our secondary cohort of women prescribed estrogens
was higher than in other studies.6, 10, 17
In the HERS trial, during 10 985 person-years of follow-up, the rate
of combined DVT and pulmonary embolism (PE) in the hormone-treated group was
6.2 per 1000 person-years,6 half that observed
in the current study (12.6 per 1000 person-years). Such differences may be
explained by the fact that participants in randomized clinical trials tend
to be healthier than the general population, and that women in the HERS trial
were younger (mean age, 67 years), had established coronary heart disease,
and were more likely to receive aspirin (79%) or a lipid-lowering drug (45%)
therapy.6 Nevertheless, our observation that
estrogens increase the risk for DVT is consistent with that of other studies,6, 18 further increasing the likelihood
that our data were valid.
It is puzzling that we observed a protective effect from statins in
the subgroup of women but not men, since these drugs seemed to be equally
effective in both sexes for the treatment of established coronary artery disease.1, 3-4 Exploring differences
between sexes was not a primary research question, and the detected variance
may have been due to chance. Furthermore, the higher rate of aspirin and warfarin
use among the men in our study (Table 1) may have resulted in a diminution of any potential protective
effect from statins. Our overall findings are supported by those of the HERS
investigators, who observed an even greater reduction in DVT or PE with statin
use (adjusted HR, 0.5; 95% CI, 0.2-0.9).6 We
chose to not evaluate the effect of statins on the risk for PE since testing
strategies for PE are often less accurate than for DVT.19-20
Thus, even though they are part of the same spectrum of disease, it remains
to be established whether these drugs appear protective against PE.
There is some biological basis to explain how statins may attenuate
the risk for VTE. Data from 2 case-control studies have demonstrated a strong
association between combined hypercholesterolemia and hypertriglyceridemia
and DVT in middle-aged adults (crude odds ratio, 5.1; 95% CI, 2.0-13.0),21 as well as elevated lipoprotein(a) levels and VTE
in children (adjusted odds ratio, 7.2; 95% CI, 3.7-14.5).22
Circulating lipids seem to have both prothrombotic and endothelial altering
properties.23 For example, ingestion of a fatty
meal seems to cause venous endothelial dysfunction, manifested by reduced
acetylcholine-mediated venodilatation in healthy adults.24
Thus, it is conceivable that specific circulating lipoproteins heighten the
risk for VTE, and that their suppression might be protective. However, because
we and the HERS investigators6 failed to observe
any beneficial effect against DVT with use of nonstatin lipid-lowering agents,
we speculate that statins may also possess other protective properties.
In the Post Coronary Artery Bypass Graft Trial,25
aggressive lipid-lowering with lovastatin effectively reduced both the rate
of progression of atherosclerosis in saphenous vein coronary artery bypass
grafts, as well as the need for coronary revascularization. Beyond their lipid-reducing
ability, statins also seem to alter elements within the vascular endothelium
and coagulation cascade, consistent with an antithrombotic effect. For example,
6 months of pravastatin treatment significantly lowered levels of prothrombin
fragment 1 + 2 in women,26 indicating reduced
thrombin generation, while simvastatin produced the same effect in men.27 Others hypothesize that these drugs may inhibit platelet-derived
protease-activated receptor 1 and tissue factor up-regulation that leads to
thrombin generation,28 in addition to reducing
the levels of both factor VIIc29 and soluble
thrombomodulin.30 Collaborative research among
those who study lipid-related disorders and arterial and venous thrombotic
disease could help to clarify whether it is their lipid-reducing or antithrombotic
properties, or both, that best explain the beneficial role of statins in the
treatment of atherosclerosis,5 and their potential
to do the same for VTE.
We believe that these preliminary data provide the rationale for a randomized
clinical trial of statins for the secondary prevention of recurrent VTE. Consenting
individuals who have completed 3 months of anticoagulant therapy following
a first idiopathic VTE event could be randomized to either continue warfarin
therapy for another 12 to 18 months,13-14
or to stop warfarin therapy and begin taking a statin drug for the same duration.
The major end point in this trial would be the development of recurrent VTE,
balanced against major bleeding. Current or future clinical trials designed
to examine the effect of statins on cardiovascular disease might consider
collecting secondary data on VTE events as well, which could be combined in
a systematic overview. Future observational studies may provide greater insight
as to which statins and what dose is there a maximal reduction in primary
or secondary VTE events, including PE.
AUTHOR INFORMATION
Accepted for publication March 3, 2001.
This investigation was supported in part by the Thrombosis Research
Fund, University Health Network, Toronto, Ontario, and the Institute for Health
Economics, Edmonton, Alberta.
This study is in memory of Christa Bos, MD, whose encouragement to pursue
new ideas was not forgotten.
Corresponding author: Joel G. Ray, MD, FRCPC (e-mail: rayjg{at}mcmaster.ca).
From the Department of Medicine (Drs Ray, Yeo, and Laupacis), Institute
for Clinical Evaluative Sciences (Drs Mamdani and Laupacis), and the Faculty
of Pharmacy (Dr Mamdani), University of Toronto, Toronto, Ontario; Department
of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton,
Ontario (Dr Ray); EPICORE Centre, Division of Cardiology, Department of Medicine,
University of Alberta, Edmonton, Alberta (Dr Tsuyuki); and the Department
of Medicine, Dalhousie University, Halifax, Nova Scotia (Dr Anderson).
Dr
Tsuyuki has conducted research on behalf of some statin pharmaceutical companies,
none of which were involved in the current study.
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NEJM 2003;348:1435-1441.
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JAMA 2003;289:1652-1658.
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ASH Education Book 2003;2003:520-539.
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