Dose-related Effect of Statins in Venous Thrombosis Risk Reduction

1,060 views

Published on

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

Published in: Health & Medicine, Technology
  • Be the first to comment

  • Be the first to like this

Dose-related Effect of Statins in Venous Thrombosis Risk Reduction

  1. 1. CLINICAL RESEARCH STUDYDose-related Effect of Statins in Venous Thrombosis RiskReductionDanai Khemasuwan, MD,a Young Kwang Chae, MD, MPH, MBA,a Shikha Gupta, MD,a Alejandra Carpio, MD,aJeong Hyun Yun, MD, MPH,a Stefan Neagu, MD,a Anabella B. Lucca, MD,a Matias E. Valsecchi, MD, MSc,bJorge I. Mora, MDca Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pa; bDepartment of Medical Oncology, Thomas JeffersonUniversity 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 thromboembolismThe pathophysiology of venous thromboembolism was gen- port a new perspective on a possible common mechanismerally 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 elevateddisclose. 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 aforementionedto 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 diagnosis19141. 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
  2. 2. Khemasuwan et al Statins for Venous Thrombosis Risk Reduction 853sis and pulmonary embolism had a significantly increased 2 months were relegated to the nonuser group. All patientsrisk 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 firstof 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 theafter diagnosis.7 Additionally, a study focused on the occurrencerecent meta-analysis evaluating of venous thromboemblism,the prevalence of major cardiovas- which consisted of deep vein CLINICAL SIGNIFICANCEcular 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 ultrasoundlevel 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 wasthromboembolism revealed that used to diagnose deep venous pared with non-statin users.these were significantly increased thrombosis of femoral and poplitealin 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 probabilitylipoprotein (HDL) were associ- nous thromboembolism compared with on ventilation-perfusion scan wasated with a reduced risk of recur- standard-dose statins. used to diagnose pulmonaryrent 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- Procedureand lipid-lowering therapy (such currence of venous thromboembolism. All the data were collected from anas statins) in venous thromboem- electronic medical record system.bolism prevention. Demographic data, the presence of Based on the currently avail- risk factors for atherosclerosis andable data, we hypothesize that statins and antiplatelet ther- venous thromboembolism were collected, including historyapy may have a role for venous thromboembolism preven- of hypertension, diabetes mellitus, obesity (body mass indextion 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 ofassociation between the use of statins or antiplatelet therapy statins including dosage and duration, use of aspirin, andand 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 valuesMATERIALS 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 dosepatients with established diagnosis of atherosclerosis, in- classification of statins was based on the potency of eachcluding 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 ofmade 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 imagingscans. Myocardial infarction was determined by clinical astatin. On the other hand, high-dose usage of statins waspresentation of angina pectoris with either elevation of tro- defined as daily statin use 10 mg of rosuvastatin, and 40ponin 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 Analysis2010 were eligible for the study. The duration of statin use This study was a retrospective, cohort study designed toand 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 therosuvastatin, lovastatin, pravastatin, and fluvastatin. Statin primary cohort, adjustments were made for age and sex. Thedosage was calculated as an average dose per day over the comparative risk for venous thromboembolism betweenobservation 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
  3. 3. 854 The American Journal of Medicine, Vol 124, No 9, September 2011analysis of variance for continuous variables or the chi- P-Value .009squared test for categorical data. All the P values were .99 .49 .34 .23 .66 .22 .44 .02 .77 .16 .06 .68 .162-sided with a level of .05 for statistical significance. Theunivariate 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 1100were assessed. Multivariate Cox regression was used to Total 67.3control 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 88teraction analysis by using Wald test and likelihood ratio 67.7test. 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 503RESULTS 69.1 OnlyOver the study period, 1795 consecutive patients with thediagnosis of cardiovascular diseases were identified. Amongthis 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 Onlytherapy (oral warfarin or therapeutic dosage of intravenous n 66 66.67heparin) 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 Therapyanticoagulation therapy after the diagnosis of cardiovasculardiseases, 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 Therapysulted 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-ValueThe overall incidence of venous thromboembolism was .062 .003 .003 .35 .05 .01 .03 .09 .39 .51 .28 .299.7% (n 107); 78.3% (n 861) were using statins during .7 .5the 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 1100use is listed in Table 2. Univariate analysis demonstratedthat having a history of diabetes, hypertension, cancer, cur- Total 67.3rent 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 239cancer, immobilization, hormonal use, and obesity statisti- Nonusercally increased the risk of developing venous thromboem- 69.1bolism (HR 2.37, 95% CI, 1.2-4.71; HR 2.0, 95% CI, high-density lipoprotein; LDL1.35-2.98; HR 3.25, 95% CI, 1.03-10.25; HR 1.54, 95% CI, Standard-dose1.05-2.29, 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 327oping venous thromboembolism (HR 0.24, 95% CI, 0.17- 67.90.36; 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 StatinsThe average duration of the follow-up period in the statin body mass index; HDL 66.1 Useruser group was 13.4 months (range 2-56 months). Amongstatins users, a majority of patients (62.1%) were takinghigh dosages of statins ( 10 mg of rosuvastatin, and 40 Race, African Americanmg of lovastatin, simvastatin, or atorvastatin). An average HDL( 40 M/ 50 F) Obesity (BMI 30) Metastatic cancerdose of statins in this group was 50.9 mg/day. On the other Immobilization Hormonal usehand, 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 Cancersimvastatin, or atorvastatin, and 10 mg of rosuvastatin).An average dose of statins in this group was 22.2 mg/day.
  4. 4. Khemasuwan et al Statins for Venous Thrombosis Risk Reduction 855 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 Analysisoccurrence of venous thromboembolism compared with A multivariate Cox regression analysis adjusting for knownstandard-dose statins use (Figure 2). risk factors for venous thromboembolism, including those factors that were statistically significant in the univariateAntiplatelet Therapy regression analysis and have been shown to be related to anThe 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 thromboembolismshowing 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 toFactors HR 95% CI P-Value a reduction in the occurrence of venous thromboembolismDiabetes 1.00 0.68–1.46 .99Hypertension 2.92 0.92–9.22 .07Smoking 0.72 0.47–1.10 .13Cancer 1.41 0.88–2.26 .15Metastatic cancer 2.37 1.20–4.71 .013Immobilization 2.00 1.35–2.98 .001Hormonal use 3.25 1.03–10.25 .04Obesity (BMI 30) 1.54 1.05–2.29 .03Hyper TG 0.7 0.42–1.76 .18High LDL 1.32 0.91–1.93 .15Low HDL 1.05 0.7–1.57 .23Statins 0.24 0.17–0.36 .001 Regular dose 0.31 0.20–0.49 .001 High dose 0.16 0.09–0.27 .001Antiplatelet 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.
  5. 5. 856 The American Journal of Medicine, Vol 124, No 9, September 2011 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 Antiplatelet95% CI, 0.11-0.82 with clopidogrel use only; and HR 0.19, Therapy95% CI, 0.1-0.34 with dual antiplatelet therapy) (Table 4).Multivariate logistic regression, when performed, showed In addition to isolated protective effect against venoussimilar results with the multivariate Cox regression. When thromboembolism of statins and antiplatelet therapy, ourcontrolled for the same multiple risk factors, statin use and study also showed a possible additive effect of combinedantiplatelet agent use were associated with reduced risk of statin and antiplatelet therapy. The Kaplan-Meier analysisvenous thromboembolism (statins: odds ratio [OR] 0.30, revealed that combined statin and antiplatelet therapy wasP .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 astatin use (high dose: OR 0.21, P .001; standard dose: OR multivariate Cox regression model, combined statin use and0.42, P .001) (data not shown). antiplatelet therapy reduced the occurrence of venous Figure 3 Kaplan-Meier plot showing the occurrence of venous thromboembo- lism compared between nonantiplatelet use, single antiplatelet therapy, and dual antiplatelet therapy.
  6. 6. Khemasuwan et al Statins for Venous Thrombosis Risk Reduction 857Table 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 periodThromboembolism compared with placebo.13 Statins also can exhibit anti- thrombotic properties and alter coagulation cascadesFactors HR 95% CI P-Value through various mechanisms, which are not associated withMetastatic cancer 2.24 0.93–5.44 .07 changes in cholesterol profiles.14-16Immobilization 1.83 1.22–2.76 .004 The evidence of use of antiplatelet therapy in venousHormonal 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 withStatins 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 .001Antiplatelet 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, thethromboembolism (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 increasedoccurrence of venous thromboembolism, which revealed no occurrence of venous thromboembolism. These risk factorsstatistically significant interaction between the statin use are well-studied risk factors for venous thromboembolismand 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 byStatins are currently considered the most effective choles- several retrospective and prospective studies.22-26 A recentterol-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 thating serum inflammatory markers and enhancing vascular the use of statins was associated with a reduction in theendothelial function. Simvastatin showed a direct anti-in- occurrence of venous thromboembolism.27 Figure 4 Kaplan-Meier plot showing the occurrence of venous thromboembo- lism compared between combined statin and antiplatelet therapy, either use of statin and antiplatelet therapy, and nonuser.
  7. 7. 858 The American Journal of Medicine, Vol 124, No 9, September 2011 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 wasprotein 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 plateletthromboembolism prevention among patients with athero- thromboxane A-2 in platelet aggregation process.37 Thissclerotic 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 thetomatic venous thromboembolism compared with pla- effect of statins and antiplatelet combination therapy incebo.29 A recent meta-analysis concluded that statins may patients at high risk of venous thromboembolism.lower the risk of venous thromboembolism.30 However, therandomized controlled trials in this meta-analysis had ve- Strengths and Limitationsnous thromboembolism as a secondary outcome. Based on Several points should be included in consideration of thethis 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 incardiovascular 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 includedvascular outcomes demonstrated that the use of high-dose in the analysis. Moreover, our data do not include otherstatins 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 protectiveknowledge, 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 thating 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. Thesefindings are consistent with other prospective studies of risk CONCLUSIONSfactors for venous thromboembolism, which have shown no Our study suggests a possible protective effect of statinsassociation between lipid profile and subsequent venous therapy used as a single agent with a possible dose-relatedthromboembolism.32-34 It is reasonable to postulate that the response, or in combination with antiplatelet therapy. Thisprotective 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 ofpic 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 arevenous thromboembolism. Interestingly, dual antiplatelet warranted.therapy exerts a better outcome on subsequent venousthromboembolism compared with single antiplatelet therapyin this study population. Szczeklik et al35 suggested thataspirin impaired thrombin formation in both in vitro and exvivo models by acetylating prothrombin or macromolecules ACKNOWLEDGMENTof platelet membrane. Our finding contradicts a randomized This study was approved by Institutional Review Boardtrial of healthy women that showed no clear benefit of (IRB) at Albert Einstein Medical Center, Philadelphia, PAaspirin 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-ies addressing the potential benefit of this drug on the Referencesoccurrence of venous thromboembolism. The possible im- 1. Piazza G, Goldhaber SZ. Venous thromboembolism and atherothrom- bosis: an integrated approach. Circulation. 2010;121:2146-2150.plication of dual antiplatelet therapy on the occurrence of 2. Rus HG, Vlaicu R, Niculescu F. Interleukin-6 and interleukin-8 pro-venous thromboembolism warrants further prospective tein and gene expression in human arterial atherosclerotic wall. Ath-studies. erosclerosis. 1996;127:263-271.
  8. 8. Khemasuwan et al Statins for Venous Thrombosis Risk Reduction 859 3. Rus HG, Niculescu F, Vlaicu R. Tumor necrosis factor-alpha in human 20. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel and long-term arterial wall with atherosclerosis. Atherosclerosis. 1991;89:247-254. outcomes after drug-elution stent implantation. JAMA. 2007;297:159- 4. van Aken BE, Reitsma PH, Rosendaal FR. Interleukin 8 and venous 168. thrombosis: evidence for a role of inflammation in thrombosis. Br J 21. Anderson FA Jr, Spencer FA. Risk factors for venous thromboembo- Haematol. 2002;116:173-177. lism. Circulation. 2003;107(23 Suppl 1):I9-I16. 5. van Aken BE, den Heijer M, Bos GM, et al. Recurrent venous throm- 22. Lacut K, Oger E, Le Gal G, et al. Statins but not fibrates are associated bosis and markers of inflammation. Thromb Haemost. 2000;83:536- with a reduced risk of venous thromboembolism: a hospital-based 539. case-control study. Fundam Clin Pharmacol. 2004;18:477-482. 6. Sørensen HT, Horvath-Puho E, Pedersen L, et al. Venous thrombo- 23. Yang CC, Jick SS, Jick H. Statins and the risk of idiopathic venous embolism and subsequent hospitalization due to acute arterial cardio- thromboembolism. Br J Clin Pharmacol. 2002;53:101-105. vascular events: a 20-year cohort study. Lancet. 2007;370:1773-1779. 24. Ray JG, Mamdani M, Tsuyuki RT, Anderson DR, Yeo EL, Laupacis 7. Sorensen HT, Horvath-Puho E, Sogaard KK, et al. Arterial cardiovas- A. Use of statins and the subsequent development of deep vein throm- cular events, statins, low-dose aspirin and subsequent risk of venous bosis. Arch Intern Med. 2001;161:1405-1410. thromboembolism: a population-based case-control study. J Thromb 25. Ramcharan AS, Van Stralen KJ, Snoep JD, et al. HMG-CoA reductase Haemost. 2009;7:521-528. inhibitors, other lipid-lowering medication, antiplatelet therapy, and 8. Ageno W, Becattini C, Brighton T, et al. Cardiovascular risk factors the risk of venous thrombosis. J Thromb Haemost. 2009;7:514-520. and venous thromboembolism: a meta-analysis. Circulation. 2008; 26. Herrington DM, Vittinghoff E, Lin F, et al. Statin therapy, cardiovas- 117:93-102. cular events, and total mortality in the Heart and Estrogen/Progestin 9. Ageno W, Prandoni P, Romualdi E, et al. The metabolic syndrome and Replacement Study (HERS). Circulation. 2002;105:2962-2967. the risk of venous thrombosis: a case-control study. J Thromb Hae- 27. Khemasuwan D, Divietro ML, Tangdhanakanond K, et al. Statins decrease the occurrence of venous thromboembolism in patients with most. 2006;4:1914-1918. cancer. Am J Med. 2010;123:60-65.10. Sofi F, Marcucci R, Abbate R, et al. Lipoprotein (a) and venous 28. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent thromboembolism in adults: a meta-analysis. Am J Med. 2007;120: vascular events in men and women with elevated C-reactive protein. 728-733. N Engl J Med. 2008;359:2195-2207.11. Eichinger S, Pecheniuk NM, Hron G, et al. High-density lipoprotein 29. Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of and the risk of recurrent venous thromboembolism. Circulation. 2007; rosuvastatin in the prevention of venous thromboembolism. N Engl 115:1609-1614. J Med. 2009;360:1851-1861.12. Weng TC, Yang YH, Lin SJ, et al. A systematic review and meta- 30. Squizzato A, Galli M, Romualdi E, et al. Statins, fibrates, and venous analysis on the therapeutic equivalence of statins. J Clin Pharm Ther. thromboembolism: a meta-analysis. Eur Heart J. 2010;31:1248-1256. 2010;35:139-151. 31. Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis of car-13. Devaraj S, Chan E, Jialal I, et al. Direct demonstration of anti- diovascular outcomes trials comparing intensive versus moderate sta- inflammatory effect of simvastatin in subjects with the metabolic tin therapy. J Am Coll Cardiol. 2006;48:438-445. syndrome. J Clin Endocrinol Metab. 2006;91:4489-4496. 32. Holst AG, Jensen G, Prescott E. Risk factors for venous thromboem-14. Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagu- bolism: results from the Copenhagen City Heart Study. Circulation. lation. Arterioscler Thromb Vasc Biol. 2005;25:287-294. 2010;121:1896-1903.15. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglu- 33. Mahmoodi BK, Gansevoort RT, Veeger NJGM, et al; Prevention of taryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol. Renal and Vascular End-stage Disease (PREVEND) Study Group. 2001;21:1712-1719. Microalbuminuria and risk of venous thromboembolism. JAMA. 2009;16. Krysiak R, Okopien B, Herman ZS. Effects of HMG-CoA reductase ´ 301:1790-1797. inhibitors on coagulation and fibrinolysis processes. Drugs. 2003;63: 34. Chamberlain AM, Folsom AR, Heckbert SR, Rosamond WD, Cush- 1821-1854. man M. High-density lipoprotein cholesterol and venous thromboem-17. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis bolism in the Longitudinal Investigation of Thromboembolism Etiol- of randomized trials of antiplatelet therapy for prevention of death, ogy (LITE). Blood. 2008;112:2675-2680. myocardial infarction, and stroke in high-risk patients. BMJ. 2002; 35. Szczeklik A, Krzanowski M, Góra P, et al. Antiplatelet drugs and 324:71-86. generation of thrombin in clotting blood. Blood. 1992;80:2006-2011.18. Glynn RJ, Ridker PM, Goldhaber SZ, et al. Effect of low-dose aspirin 36. Glynn RJ, Ridker PM, Goldhaber SZ, et al. Effect of low-dose aspirin on the occurrence of venous thromboembolism: a randomized trial. on the occurrence of venous thromboembolism: a randomized trial. Ann Intern Med. 2007;147:525-533. Ann Intern Med. 2007;147:525-533.19. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to 37. Santos MT, Fuset MP, Ruano M, et al. Effect of Atorvastatin on aspirin in patients with acute coronary syndromes without ST-segment platelet thromboxane A(2) synthesis in aspirin-treated patients with elevation. N Engl J Med. 2001;345:494-502. acute myocardial infarction. Am J Cardiol. 2009;104:1618-1623.

×