Dose-related Effect of Statins in Venous Thrombosis Risk Reduction

CLINICAL RESEARCH STUDY

Dose-related Effect of Statins in Venous Thrombosis Risk
Reduction
Danai Khemasuwan, MD,a Young Kwang Chae, MD, MPH, MBA,a Shikha Gupta, MD,a Alejandra Carpio, MD,a
Jeong Hyun Yun, MD, MPH,a Stefan Neagu, MD,a Anabella B. Lucca, MD,a Matias E. Valsecchi, MD, MSc,b
Jorge I. Mora, MDc
a
Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pa; bDepartment of Medical Oncology, Thomas Jefferson
University Hospital, Philadelphia, Pa; cDivision of Pulmonary and Critical Care Medicine, Albert Einstein Medical Center,
Philadelphia, Pa.

ABSTRACT

BACKGROUND: Atherosclerosis and venous thromboembolism share similar pathophysiology based on
common inflammatory mediators. The dose-related effect of statin therapy in venous thromboembolism
remains controversial. This study investigated whether the use of antiplatelet therapy and statins decrease
the occurrence of venous thromboembolism in patients with atherosclerosis.
METHODS: We conducted a retrospective cohort study reviewing 1795 consecutive patients with athero-
sclerosis admitted to a teaching hospital between 2005 and 2010. Patients who had been treated with
anticoagulation therapy were excluded. Patients who either used statins for 2 months or never used them
were allocated to the nonuser group.
RESULTS: The final analysis included 1100 patients. The overall incidence of venous thromboembolism
was 9.7%. Among statin users, 6.3% (54/861) developed venous thromboembolism, compared with 22.2%
(53/239) in the nonuser group (hazard ratio [HR] 0.24; P .001). After controlling for confounding factors,
statin use was still associated with a lower risk of developing venous thromboembolism (HR 0.29;
P .001). High-dose statin use (average 50.9 mg/day) (HR 0.25; P .001) lowered the risk of venous
thromboembolism compared with standard-dose statins (average 22.2 mg/day) (HR 0.38; P .001). Dual
antiplatelet therapy with aspirin and clopidogrel decreased occurrence of venous thromboembolism (HR
0.19; P .001). Interestingly, combined statins and antiplatelet therapy further reduced the occurrence of
venous thromboembolism (HR 0.16; P .001).
CONCLUSIONS: The use of statins and antiplatelet therapy is associated with a significant reduction in the
occurrence of venous thromboembolism with a dose-related response of statins.
Published by Elsevier Inc. • The American Journal of Medicine (2011) 124, 852-859

KEYWORDS: Antiplatelet therapy; Atherosclerosis; Deep vein thrombosis; Pulmonary embolism; Statins; Venous
thromboembolism

The pathophysiology of venous thromboembolism was gen- port a new perspective on a possible common mechanism
erally considered to be different from that of thrombotic between venous thromboembolism and atherosclerotic dis-
atherosclerosis. However, there is growing evidence to sup- ease.1 The inflammatory cells present in the atherosclerotic
plaques release cytokines such as interleukin-6 (IL-6), IL-8,
and tumor necrosis factor alpha,2,3 which are essentially the
Funding: None.
Conflict of Interest: None of the authors has any conflict of interest to
same inflammatory mediators that were found to be elevated
disclose. in patients with venous thrombosis.4,5 A large population-
Authorship: All authors meet criteria for authorship including access based cohort also was supportive of the aforementioned
to the data, and all authors had a role in writing the manuscript. hypothesis. This study assessed the risk of hospitalization
Requests for reprints should be addressed to Danai Khemasuwan, MD,
Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA
due to myocardial infarction and stroke after the diagnosis
19141. of venous thromboembolism. It showed convincing evi-
E-mail address: danai_md@hotmail.com dence that patients with diagnosis of deep venous thrombo-

0002-9343/$ -see front matter Published by Elsevier Inc.
doi:10.1016/j.amjmed.2011.04.019

Khemasuwan et al Statins for Venous Thrombosis Risk Reduction 853

sis and pulmonary embolism had a significantly increased 2 months were relegated to the nonuser group. All patients
risk of subsequent cardiovascular events during a follow-up included in the analysis had a minimum of 2 hospital visits.
period of up to 20 years.6 Conversely, patients with history Patients who were taking oral anticoagulation on the first
of myocardial infarction or stroke had significantly in- admission or who started them after the diagnosis of car-
creased risk for venous thromboembolism within 3 months diovascular disease, were excluded. The outcome of the
after diagnosis.7 Additionally, a study focused on the occurrence
recent meta-analysis evaluating of venous thromboemblism,
the prevalence of major cardiovas- which consisted of deep vein
CLINICAL SIGNIFICANCE
cular risk factors such as meta- thrombosis or pulmonary embo-
bolic syndrome and high serum ● The use of statins reduced the risk of lism, or both. Doppler ultrasound
level of low-density lipoprotein subsequent venous thrombosis with a with the criterion of venous com-
(LDL) in patients with venous hazard ratio of 0.24 (P .001) com- pressibility with transducer was
thromboembolism revealed that used to diagnose deep venous
pared with non-statin users.
these were significantly increased thrombosis of femoral and popliteal
in patients with venous thrombo- ● Statins may have an antithrombotic ef- veins. Computed pulmonary an-
embolism.8-10 On the contrary, fect in a dose-related manner. High- giography with the presence of pul-
high serum levels of high-density dose statin use lowered the risk of ve- monary emboli or high probability
lipoprotein (HDL) were associ- nous thromboembolism compared with on ventilation-perfusion scan was
ated with a reduced risk of recur- standard-dose statins. used to diagnose pulmonary
rent venous thromboembolism.11 embolism.
These associations may suggest a ● The combination of statins and anti-
clinical implication of antiplatelet platelet therapy further reduced the oc- Procedure
and lipid-lowering therapy (such currence of venous thromboembolism. All the data were collected from an
as statins) in venous thromboem- electronic medical record system.
bolism prevention. Demographic data, the presence of
Based on the currently avail- risk factors for atherosclerosis and
able data, we hypothesize that statins and antiplatelet ther- venous thromboembolism were collected, including history
apy may have a role for venous thromboembolism preven- of hypertension, diabetes mellitus, obesity (body mass index
tion in patients at high risk for atherosclerotic disease. 30), smoking, cancer, metastatic cancer, immobilization,
Therefore, we conducted this study in order to explore the use of estrogen hormone therapy or its derivatives, use of
association between the use of statins or antiplatelet therapy statins including dosage and duration, use of aspirin, and
and the occurrence of venous thromboembolism among use of clopidogrel. Patients with diagnosis of either a pul-
patients with history of atherosclerosis. monary embolism or a deep vein thrombosis were allocated
in the venous thromboembolism group. Laboratory values
MATERIALS AND METHODS that were recorded included serum LDL level, serum HDL
level, and serum triglyceride.
Patients and Data Collection
Statin dosage was collected from the medical reconcili-
This is a retrospective cohort study that was focused on
ation form upon each admission for each patient. The dose
patients with established diagnosis of atherosclerosis, in-
classification of statins was based on the potency of each
cluding ischemic stroke and myocardial infarction. The di-
statin on the standard conversion chart.12 As a result, stan-
agnosis of transient ischemic attack or ischemic stroke was
dard-dose usage of statins was defined as daily statin use of
made by a history of sudden-onset, focal or global neuro-
80 mg of fluvastatin or pravastatin, and 40 mg of lova-
logical deficits, which were confirmed when possible by
statin, simvastatin, or atorvastatin, and 10 mg of rosuv-
computed tomography or magnetic resonance imaging
scans. Myocardial infarction was determined by clinical astatin. On the other hand, high-dose usage of statins was
presentation of angina pectoris with either elevation of tro- defined as daily statin use 10 mg of rosuvastatin, and 40
ponin I or electrocardiogram changes. All the patients with mg of lovastatin, simvastatin, or atorvastatin.
diagnosis of cardiovascular diseases admitted at Albert Ein-
stein Medical Center between November 2005 and January Statistical Analysis
2010 were eligible for the study. The duration of statin use This study was a retrospective, cohort study designed to
and antiplatelet therapy, including aspirin and clopidogrel, determine occurrence of venous thromboembolism in pa-
was recorded. Statin use included: atorvastatin, simvastatin, tients with atherosclerotic disease. For the analysis of the
rosuvastatin, lovastatin, pravastatin, and fluvastatin. Statin primary cohort, adjustments were made for age and sex. The
dosage was calculated as an average dose per day over the comparative risk for venous thromboembolism between
observation period. The cardiovascular risk factors and pos- each group was expressed as the adjusted hazard ratio (HR)
sible risk factors for venous thromboembolism were re- along with its 95% confidence interval (CI). Baseline char-
corded. Patients who never used statins or had used them for acteristics were compared within each group using either an

854 The American Journal of Medicine, Vol 124, No 9, September 2011

analysis of variance for continuous variables or the chi-

P-Value

.009
squared test for categorical data. All the P values were

.99
.49
.34
.23
.66

.22
.44
.02
.77
.16
.06
.68
.16
2-sided with a level of .05 for statistical significance. The
univariate relationship between use of statins or antiplatelet

578 (49.8%)
838 (76.3%)

1,015 (92.3%)
350 (31.8%)
183 (16.6%)

249 (22.6%)

266 (24.2%)
238 (21.6%)
496 (45.1%)
728 (66.2%)
572 (52%)

45 (4%)

10 (1%)
therapy and the occurrence of venous thromboembolism

n 1100
were assessed. Multivariate Cox regression was used to

Total

67.3
control for all other potential confounding variables, includ-
ing diabetes mellitus, obesity (body mass index 30),
smoking, cancer, metastatic cancer, immobilization, and use

48 (53.3%)
68 (75.6%)
42 (46.7%)

23 (25.6%)
19 (21.1%)
15 (16.6%)
23 (25.5%)

14 (15.6%)
40 (44.4%)
81 (90%)

18 (20%)

54 (60%)
of estrogen hormone or its derivatives. We performed in-

Nonuser

0 (0%)
n 88
teraction analysis by using Wald test and likelihood ratio

67.7
test. For all statistical analyses, we used STATA, version 9
(StataCorp LP, College Station, Tex).

258 (51.3%)
393 (78.1%)
262 (52.1%)
463 (92.1%)
140 (27.8%)
87 (17.3%)

120 (23.8%)
97 (19.3%)
236 (46.9%)
323 (64.2%)
Aspirin Use

24 (4.7%)

5(1.9%)
131 (26%)
n 503
RESULTS

69.1
Only
Over the study period, 1795 consecutive patients with the
diagnosis of cardiovascular diseases were identified. Among
this group, patients who had been treated with anticoagulation

Clopidogrel

40 (61.5%)
44 (67.8%)
41 (63.1%)
62 (95.4%)
22 (33.8%)
14 (21.5%)

16 (24.6%)

10 (15.4%)

30 (46.2%)
42 (64.6%)
1 (1.5%)

1(1.5%)

15 (23%)
Use Only
therapy (oral warfarin or therapeutic dosage of intravenous

n 66

66.67
heparin) before their first admission or who had received

Demographic Data and Factors Related to VTE with the Use of Statins and the Use of Antiplatelet Therapy
anticoagulation therapy after the diagnosis of cardiovascular
diseases, were excluded (n 208). Also, patients who had

230 (52.5%)
333 (75.3%)
227 (51.4%)
409 (92.5%)
165 (37.3%)
63 (14.3%)

79 (17.9%)

118 (26.7%)
112 (25.3%)

309 (69.9%)
Antiplatelet

15 (3.4%)
a single hospital visit were excluded (n 487). This re-

190 (43%)
4 (9%)
n 443
Therapy
sulted in a total of 1100 patients in the final analysis.

65.2
Dual

Characteristics of the 1100 patients are shown in Table 1.
The mean age of the study sample was 67.3 years; 49.8% of

triglyceride.
the patients were female; and 76% were African American.
P-Value

The overall incidence of venous thromboembolism was
.062

.003
.003
.35

.05
.01
.03
.09

.39
.51
.28
.29
9.7% (n 107); 78.3% (n 861) were using statins during
.7

.5
the follow-up period. The P-value in Table 1 was derived

low-density lipoprotein; TG
578 (49.8%)
838 (76.3%)

1,015 (92.3%)
350 (31.8%)
183 (16.6%)

249 (22.6%)

266 (24.2%)
238 (21.6%)
496 (45.1%)
728 (66.2%)
from analysis of variance test. The distribution of the statins
572 (52%)

45 (4%)

10 (1%)
n 1100

use is listed in Table 2. Univariate analysis demonstrated
that having a history of diabetes, hypertension, cancer, cur-
Total

67.3

rent smoking, high-serum triglyceride, high-serum LDL,
and low HDL did not affect the occurrence of venous
121 (50.7%)
176 (73.6%)
104 (43.5%)

68 (28.5%)
49 (20.5%)

66 (27.6%)

52 (21.8%)
45 (18.8%)
107 (44.7%)
152 (63.6%)
thromboembolism during the follow-up period. Metastatic
16 (6.7%)

3 (1.3%)
208 (87%)
n 239

cancer, immobilization, hormonal use, and obesity statisti-
Nonuser

cally increased the risk of developing venous thromboem-
69.1

bolism (HR 2.37, 95% CI, 1.2-4.71; HR 2.0, 95% CI, high-density lipoprotein; LDL
1.35-2.98; HR 3.25, 95% CI, 1.03-10.25; HR 1.54, 95% CI,
Standard-dose

1.05-2.29, respectively). Use of statins and use of antiplate-
256 (78.3%)
190 (58.1%)
308 (94.2%)
93 (28.4%)
63 (19.3%)

74 (22.6%)

87 (26.6%)
67 (21.4%)
130 (41.5%)
Statins User

16 (4.9%)

4 (1.2%)
170 (52%)

219 (70%)

let therapy were related to a reduced occurrence of devel-
n 327

oping venous thromboembolism (HR 0.24, 95% CI, 0.17-
67.9

0.36; HR 0.32, 95% CI, 0.19-0.52, respectively) (Table 3).
406 (76.03%)
287 (53.7%)

278 (52.1%)
499 (93.5%)
189 (35.4%)
71 (13.3%)

109 (20.4%)

127 (23.8%)
126 (22.9%)
259 (47.3%)
357 (65.1%)
13 (2.4%)

3 (0.5%)

Statins
High-dose

n 534
Statins

The average duration of the follow-up period in the statin
body mass index; HDL
66.1
User

user group was 13.4 months (range 2-56 months). Among
statins users, a majority of patients (62.1%) were taking
high dosages of statins ( 10 mg of rosuvastatin, and 40
Race, African American

mg of lovastatin, simvastatin, or atorvastatin). An average
HDL( 40 M/ 50 F)
Obesity (BMI 30)
Metastatic cancer

dose of statins in this group was 50.9 mg/day. On the other
Immobilization
Hormonal use

hand, 327 patients (37.9%) took standard dosages of statins
Hypertension

LDL ( 100)
Sex, female

TG ( 150)
Age, years
Table 1

( 80 mg of fluvastatin, pravastatin, 40 mg of lovastatin,
BMI
Diabetes

Smoking
Cancer

simvastatin, or atorvastatin, and 10 mg of rosuvastatin).
An average dose of statins in this group was 22.2 mg/day.


Table 2 Summary of Different Types of Statin Therapy and the Risk of Venous
Thromboembolism
Standard Dose High Dose Total Number Number of VTE
n 327 n 534 of Patients Occurrence
Type of Statins Used (37.9%) (62.1%) n 861 n 54
Atorvastatin 191 368 559 29
Simvastatin 101 138 239 20
Lovastatin 11 20 31 3
Rosuvastatin 0 8 8 0
Pravastatin 18 0 18 2
Fluvastatin 6 0 6 0
VTE venous thromboembolism.

The Kaplan-Meier analysis revealed that statin use was apy, which is either aspirin or clopidogrel, and dual anti-
associated with a lower risk of developing venous throm- platelet therapy, is shown in Figure 3.
boembolism (log rank test P-value .001; Figure 1). Fur-
thermore, high-dose statin use appears to be related to lower Multivariate Cox Regression Analysis
occurrence of venous thromboembolism compared with A multivariate Cox regression analysis adjusting for known
standard-dose statins use (Figure 2). risk factors for venous thromboembolism, including those
factors that were statistically signiﬁcant in the univariate
Antiplatelet Therapy regression analysis and have been shown to be related to an
The average duration of the follow-up period of antiplatelet occurrence of venous thromboembolism (metastatic cancer,
therapy users was 13.48 months in the aspirin-user group immobilization, hormonal use, and obesity), as well as the
(range 2-78 months), and 13.53 months for the clopidogrel- use of statins and use of antiplatelet therapy, was performed.
user group (range 1-48 months). The Kaplan-Meier plots The increase in occurrence of venous thromboembolism
showing the occurrence of venous thromboembolism, com- persisted for immobilization and obesity (HR 1.83, 95% CI,
pared between nonantiplatelet user, single antiplatelet ther- 1.22-2.76 and HR 1.64, 95% CI, 1.09-2.45, respectively).
Interestingly, statin use continued to be related to a reduc-
tion in the occurrence of venous thromboembolism (HR
0.29, 95% CI, 0.19-0.44), possibly in a dose-related manner,
Table 3 Univariate Cox Regression Analysis of Factors
in standard-dose statin users (HR 0.38, 95% CI, 0.24-0.6)
Related to Venous Thromboembolism and Occurrence of Venous
and in high-dose statin users (HR 0.25, 95% CI, 0.15-0.4).
Thromboembolism
In addition to statins, antiplatelet therapy also was related to
Factors HR 95% CI P-Value a reduction in the occurrence of venous thromboembolism
Diabetes 1.00 0.68–1.46 .99
Hypertension 2.92 0.92–9.22 .07
Smoking 0.72 0.47–1.10 .13
Cancer 1.41 0.88–2.26 .15
Metastatic cancer 2.37 1.20–4.71 .013
Immobilization 2.00 1.35–2.98 .001
Hormonal use 3.25 1.03–10.25 .04
Obesity (BMI 30) 1.54 1.05–2.29 .03
Hyper TG 0.7 0.42–1.76 .18
High LDL 1.32 0.91–1.93 .15
Low HDL 1.05 0.7–1.57 .23
Statins 0.24 0.17–0.36 .001
Regular dose 0.31 0.20–0.49 .001
High dose 0.16 0.09–0.27 .001
Antiplatelet 0.32 0.19–0.52 .001
Aspirin only 0.47 0.28–0.79 .004
Clopidogrel only 0.30 0.11–0.82 .019
Dual antiplatelet 0.19 0.10–0.34 .001
BMI body mass index; CI conﬁdence interval; HDL high-
Figure 1 Kaplan-Meier plot showing the occurrence of ve-
density lipoprotein; HR hazard ratio; LDL low-density lipoprotein; nous thromboembolism compared between statin use and non-
TG triglyceride. statin use.


Figure 2 Kaplan-Meier plot showing the occurrence of venous thromboembo-
lism compared between nonstatin use, standard-dose statin use, and high-dose
statin use.

(HR 0.47, 95% CI, 0.28-0.79 with aspirin use only; HR 0.3, Additive Effect of Statins and Antiplatelet
95% CI, 0.11-0.82 with clopidogrel use only; and HR 0.19, Therapy
95% CI, 0.1-0.34 with dual antiplatelet therapy) (Table 4).
Multivariate logistic regression, when performed, showed In addition to isolated protective effect against venous
similar results with the multivariate Cox regression. When thromboembolism of statins and antiplatelet therapy, our
controlled for the same multiple risk factors, statin use and study also showed a possible additive effect of combined
antiplatelet agent use were associated with reduced risk of statin and antiplatelet therapy. The Kaplan-Meier analysis
venous thromboembolism (statins: odds ratio [OR] 0.30, revealed that combined statin and antiplatelet therapy was
P .001; antiplatelet agent: OR 0.44, P .007). High-dose associated with a lower risk of developing venous throm-
statin use showed lower risk compared with standard-dose boembolism (log rank test P-value .001; Figure 4). In a
statin use (high dose: OR 0.21, P .001; standard dose: OR multivariate Cox regression model, combined statin use and
0.42, P .001) (data not shown). antiplatelet therapy reduced the occurrence of venous

lism compared between nonantiplatelet use, single antiplatelet therapy, and dual
antiplatelet therapy.


Table 4 Multivariate Cox Regression Analysis of Factors
flammatory effect, with significant decrease in high sensi-
Related to Venous Thromboembolism and Occurrence of Venous tive C-reactive protein levels at 8 weeks of study period
Thromboembolism compared with placebo.13 Statins also can exhibit anti-
thrombotic properties and alter coagulation cascades
Factors HR 95% CI P-Value through various mechanisms, which are not associated with
Metastatic cancer 2.24 0.93–5.44 .07 changes in cholesterol profiles.14-16
Immobilization 1.83 1.22–2.76 .004 The evidence of use of antiplatelet therapy in venous
Hormonal use 2.35 0.68–8.11 .18 thromboembolism prevention is still controversial. A meta-
Obesity (BMI 30) 1.64 1.09–2.45 .02 analysis on short-term antiplatelet therapy in patients with
Statins 0.29 0.19–0.44 .001 cardiovascular risk factors showed a significant reduction in
Regular dose 0.38 0.24–0.6 .001
the risk of fatal or nonfatal pulmonary embolism with the
High dose 0.25 0.15–0.4 .001
Antiplatelet 0.43 0.25–0.72 .001 odds reduction of 25%.17 However, a randomized trial of
Aspirin only 0.47 0.28–0.79 .004 healthy women revealed no supporting evidence of aspirin
Clopidogrel only 0.30 0.11–0.82 .02 use in long-term prevention of venous thromboembolism.18
Dual antiplatelet 0.19 0.10–0.34 .001 Clinical trials have shown the benefit of clopidogrel in
BMI body mass index; CI confidence interval; HR hazard ratio. prevention of atherosclerosis, more specifically, in acute
coronary syndrome and post-drug-eluting stent placement in
myocardial infarction, being used either as combined mono-
therapy or in combination with aspirin.19,20 However, the
thromboembolism (HR 0.16; 95% CI, 0.09-0.31, P-value evidence on the clopidogrel use in venous thromboembo-
.001). lism prophylaxis is still inconclusive.
Interaction analysis was performed to identify the poten- In our study, history of metastatic cancer, immobiliza-
tial interaction between statin and antiplatelet therapy on the tion, hormonal use, and obesity were related to increased
occurrence of venous thromboembolism, which revealed no
occurrence of venous thromboembolism. These risk factors
statistically significant interaction between the statin use
are well-studied risk factors for venous thromboembolism
and the antiplatelet use (Wald test P .40).
in the general population.21 We found an association be-
tween statin use and decreased occurrence of venous throm-
DISCUSSION bosis in our study population, as previously supported by
Statins are currently considered the most effective choles- several retrospective and prospective studies.22-26 A recent
terol-lowering drugs available. In addition to lipid-lowering retrospective study of hospitalized cancer patients with in-
effects, statins also exert anti-inflammatory effects, reduc- herently high risk for venous thromboembolism showed that
ing serum inflammatory markers and enhancing vascular the use of statins was associated with a reduction in the
endothelial function. Simvastatin showed a direct anti-in- occurrence of venous thromboembolism.27

lism compared between combined statin and antiplatelet therapy, either use of
statin and antiplatelet therapy, and nonuser.


Furthermore, a recent randomized control trial (the Focusing on the additive effect of statin use and anti-
JUPITER study) in healthy adults demonstrated the efficacy platelet therapy on subsequent venous thromboembolism,
of rosuvastatin in the reduction of high-sensitive C-reactive our study indicates that the highest protective effect was
protein levels by 37% after a median follow-up of 1.9 seen with combined statins use and antiplatelet therapy.
years.28 These anti-inflammatory and antithrombotic prop- There is a theoretically attractive possibility that the com-
erties of statins may have clinical implication in venous bination therapy of atrovastatin and aspirin reduced platelet
thromboembolism prevention among patients with athero- thromboxane A-2 in platelet aggregation process.37 This
sclerotic disease. A large randomized controlled trial in a mechanism may play an important role in arterial and ve-
healthy population demonstrated that rosuvastatin was sig- nous thrombosis. Therefore, this theory needs further inves-
nificantly associated with decreased occurrence of symp- tigation in a randomized controlled trial, evaluating the
tomatic venous thromboembolism compared with pla- effect of statins and antiplatelet combination therapy in
cebo.29 A recent meta-analysis concluded that statins may patients at high risk of venous thromboembolism.
lower the risk of venous thromboembolism.30 However, the
randomized controlled trials in this meta-analysis had ve- Strengths and Limitations
nous thromboembolism as a secondary outcome. Based on Several points should be included in consideration of the
this limitation, its results should be cautiously interpreted. interpretation of our study. Our study would be the first to
Our study results suggest that statin use in patients with exhibit the possible dose-related relationship of statins in
cardiovascular disease decreases the occurrence of venous the prevention of venous thromboembolism. An innate lim-
thromboembolism in this study population in a dose-related itation is that ours is a retrospective study. There are pos-
manner. A meta-analysis on the effect of statins on cardio- sible confounding factors that may not have been included
vascular outcomes demonstrated that the use of high-dose in the analysis. Moreover, our data do not include other
statins provides better outcomes over standard-dose therapy serum markers of inflammation besides high-sensitive C-re-
for preventing nonfatal cardiovascular events.31 To our active protein, which may be explained by the protective
knowledge, ours is the first study to exhibit the possible effect of statins against the occurrence of venous thrombo-
dose-related relationship in terms of prevention for venous embolism. Lastly, in our study, we used medical reconcili-
thromboembolism in a population with cardiovascular ation forms to assess medication adherence of the subjects.
disease. These forms were designed to record every subject’s med-
Our study also included the serum lipid profiles, includ- ication list from each hospital visit. Thus, we assumed that
ing serum triglyceride, serum HDL, and serum LDL in the the subjects complied with their medications in the fol-
initial univariate analysis. We did not find any relationship low-up period. These limitations should be taken into con-
between abnormalities of these lipid profiles and the subse- sideration and need to be addressed in future studies.
quent development of venous thromboembolism. These
findings are consistent with other prospective studies of risk
CONCLUSIONS
factors for venous thromboembolism, which have shown no
Our study suggests a possible protective effect of statins
association between lipid profile and subsequent venous
therapy used as a single agent with a possible dose-related
thromboembolism.32-34 It is reasonable to postulate that the
response, or in combination with antiplatelet therapy. This
protective effect of statins on venous thromboembolism is
protective effect seems to be independent of the other ve-
possibly through non-lipid-lowering properties or pleiotro-
nous thromboembolism risk factors, including history of
pic effects of statins. metastatic cancer, immobilization, hormonal use, and obe-
Regarding antiplatelet therapy, our study showed the sity. Prospective, randomized control trials cautiously in-
benefit of both aspirin and clopidogrel on the occurrence of vestigating the suggested pleiotropic effect of statins are
venous thromboembolism. Interestingly, dual antiplatelet warranted.
therapy exerts a better outcome on subsequent venous
thromboembolism compared with single antiplatelet therapy
in this study population. Szczeklik et al35 suggested that
aspirin impaired thrombin formation in both in vitro and ex
vivo models by acetylating prothrombin or macromolecules ACKNOWLEDGMENT
of platelet membrane. Our finding contradicts a randomized This study was approved by Institutional Review Board
trial of healthy women that showed no clear benefit of (IRB) at Albert Einstein Medical Center, Philadelphia, PA
aspirin in terms of long-term prevention of venous throm- (IRB number – EX-579, Albert Einstein Medical Center).
boembolism.36 As for clopidogrel, there are no recent stud-
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