Venous thromboembolism and atherosclerosis: common denominators or different diseases?

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1 Journal of Thrombosis and Haemostasis, 4: COMMENTARY Venous thromboembolism and atherosclerosis: common denominators or different diseases? G. AGNELLI and C. BECATTINI Division of Internal and Cardiovascular Medicine & Stroke Unit, Department of Internal Medicine, University of Perugia, Perugia, Italy To cite this article: Agnelli G, Becattini C. Venous thromboembolism and atherosclerosis: common denominators or different diseases? J Thromb Haemost 2006; 4: See also Prandoni P, Ghirarduzzi A, Prins MH, Pengo V, Davidson BL, Sørensen H, Pesavento R, Iotti M, Casiglia E, Iliceto S, Pagnan A, Lensing AWA. Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis. This issue, pp ; Eliasson Å, Bergqvist D, Björck M, Acosta S, Sternby NH, Ögren M. Incidence and risk of venous thromboembolism in patients with verified arterial thrombosis: a population study based on consecutive autopsies. This issue, pp ; van der Hagen PB, Folsom AR, Jenny NS, Heckbert SR, O Meara ES, Reich LM, Rosendaal FR, Cushman M. Subclinical atherosclerosis and the risk of future venous thrombosis in the Cardiovascular Health Study. This issue, pp ; Reich LM, Folsom AR, Key NS, Boland LL, Heckbert SR, Rosamond WD, Cushman M. Prospective study of subclinical atherosclerosis as a risk factor for venous thromboembolism. This issue, pp ; Ageno W, Prandoni P, Romualdi E, Ghirarduzzi A, Dentali F, Pesavento R, Crowther M and Venco A. The metabolic syndrome and the risk of venous thrombosis: a case control study. This issue, pp ; Young L, Ockelford P, Milne D, Rolfe-Vyson V, McKelvie S, Harper P. Post-treatment residual thrombus increases the risk of recurrent deep vein thrombosis and mortality. This issue, pp ; Squizzato A, Romualdi E, Ageno W. Why should statins prevent venous thromboembolism? A systematic literature search and a call for action. This issue, pp ; Lijfering WM, ten Kate MK, Sprenger HG, van der Meer J. Absolute risk of venous and arterial thrombosis in HIV-infected patients and effects of combination antiretroviral therapy. This issue, pp Thromboembolic arterial diseases (acute myocardial infarction; AMI, atherothrombotic stroke and peripheral artery disease; PAD) and venous thromboembolism (VTE) (deep venous thrombosis; DVT, and pulmonary embolism; PE) are generally considered as separate entities. Arterial thrombi are mainly composed of platelets (white clots) while venous thrombi are mainly composed of red blood cells and fibrin (red clots) [1]. The different role played by platelets and fibrin in arterial and venous thrombosis contributes to the concept of these diseases as distinct entities. The different role of antiplatelet and anticoagulant agents in the prevention and treatment of venous and arterial thromboembolism is often emphasized to reinforce the paradigm of this clear-cut distinction. This issue of the Journal publishes six papers on the correlation between atherosclerosis and VTE [2 7], re-opening the case for a potential link between venous and arterial thrombosis. This Commentary is intended to review the available evidence on this correlation, to draw attention to the consistencies and inconsistencies between these new findings and Correspondence: Giancarlo Agnelli, Sezione di Medicina Interna e Cardiovascolare & Stroke Unit, Dipartimento di Medicina Interna, Università di Perugia, Ospedale S. Maria della Misericordia, Via Gerardo Dottori 1, Perugia, Italy. Tel.: (or 6424); fax: ; agnellig@unipg.it previous observations, and to discuss the potential implications of the vision of the two diseases as less distant than previously believed. Risk factors for atherosclerosis and VTE The sharing of common risk factors would certainly reinforce the link between atherosclerosis and VTE and could lead to the view that arterial and venous thrombosis are different presentations of the same disease. In 855 men, all aged 50 or over, two well-established risk factors for arterial thrombosis, as waist circumference (odds ratio; OR 3.92; 95% confidence interval; CI , if >100 cm,) and smoking (OR 2.82; 95% CI , if 15 cigarettes per day) were found to be associated with VTE [8]. In a similar study in women, aged years, multivariate analysis showed that obesity, cigarette smoking, and hypertension were independent predictors of PE [9]. More recently, lower levels of high density lipoprotein cholesterol and higher levels of low density lipoprotein (LDL) cholesterol were found in 49 men younger than 55 years with VTE with respect to matched controls [10]. These results were only partially confirmed in the 8-year follow-up of subjects without previous VTE [11]. The incidence of VTE in the overall cohort was 1.45 per 1000 person-years. A higher incidence of VTE was associated with diabetes (OR 1.7; 95% CI ) and obesity (OR 2.27; 95% CI ), although not with hypertension, hyperlipidemia, or cigarette smoking. In a further study of 603 patients with VTE, high levels of

2 VTE and atherosclerosis 1887 lipoprotein (a), a marker of atherosclerosis, were an independent risk factor for idiopathic VTE (OR 2.1, 95% CI ) [12]. Lupus anticoagulant, antiphospholipid antibodies and increased levels of serum homocysteine have been reported to be associated with both arterial and venous thrombosis. Taken together these data indicate that some risk factors for arterial thrombosis, such as obesity and probably diabetes, may also have a role in VTE, while uncertainty remains for other risk factors such as smoking, hypertension and hyperlipidemia (Table 1). Whether these findings should change the common view that arterial and venous thrombosis are separate entities is unclear. Metabolic syndrome and VTE In this issue of the Journal,Agenoet al. [2] report the results of a case control study on the prevalence of the metabolic syndrome in patients with VTE and controls. The metabolic syndrome, a cluster of risk factors related to atherosclerosis, is defined by central obesity associated with at least two other risk factors among hypertriglyceridemia, low LDL cholesterol, high blood pressure and elevated fasting glucose. Ageno et al. [2] showed a higher prevalence of the metabolic syndrome in patients with idiopathic VTE in comparison with patients with VTE associated with temporary risk factors and with patients without VTE. The observation in this case control study of the association between the metabolic syndrome and VTE is certainly original and of potential interest, but should be confirmed in prospective cohort studies. Consecutive patients with the metabolic syndrome should be followed up for an adequate period of time in order to evaluate the incidence of VTE. Identification of an adequate control population appears critical to properly define the risk for VTE attributable to the metabolic syndrome. Risk of VTE in patients with arterial thrombosis In 136 patients with symptomatic PAD, screening with ultrasonography showed a DVT in 27 patients compared with two in 40 controls (P ¼ 0.03) [13]. All DVT were asymptomatic. Logistic regression revealed reduced ankle-brachial index as an independent predictor of VTE. In this issue of the Journal, Eliasson et al. [3] report the prevalence and risk of VTE in patients with verified arterial thrombosis by analyzing the results of autopsies performed in a single center. Overall, acute arterial thrombosis was found to be the cause of death in 3064 subjects. An increased prevalence of VTE was found in patients who died for acute arterial thrombosis (adjusted OR 1.3; 95% CI ). The excess in risk for VTE was mainly accounted for by acute cervico-cranial, visceral, ileo-femoral, and aortic thrombosis, but not by coronary artery thrombosis (OR 0.7; 95% CI ). The incidence of death due to PE was similar in patients with and without arterial thrombosis. The reduced risk for VTE in patients with acute coronary disease could be due to the aggressive antithrombotic treatment (usually including heparin) used in this clinical setting. The high risk for VTE observed in patients with cervico-cranial thrombosis is conceivably related to the immobilization and to the reduced use of antithrombotic agents due to the fear of bleeding complications. This study does not provide data regarding the timing of occurrence of VTE and its nature as idiopathic or associated with temporary risk factors. Table 1 Current evidence for an association between venous and arterial thrombosis Ref. Study design Study population Patient number Major findings Goldhaber et al. [9] Prospective cohort Women aged Hypertension, obesity and smoking RF for PE Hansson et al. [8] Prospective cohort Men aged Waist circumference and smoking RF for VTE Tsai et al. [11] Prospective cohort Adults > Obesity and diabetes RF for VTE Marcucci et al. [12] Case control Adults with VTE Healthy controls 603 vs. 430 Lp (a) is an independent predictor of VTE Deguchi et al. [10] Case control Males <55 with VT Age-matched controls 49 vs. 49 LDL and HDL cholesterol RF for VT Hong et al. [15] Case control Patients with idiopathic VTE and age- and gender-matched controls without VTE Prandoni et al. [14] Case control Patients with idiopathic VTE Patients with secondary VTE Age- and gender-matched controls Libertiny and Hands [13] Case control Patients with symptomatic PAD Controls without PAD Becattini et al. [16] Follow-up Patients with first idiopathic PE Patients with first secondary PE 89 vs. 89 Coronary artery calcium, diabetes and hypertension associated with VTE 153 vs. 146 vs. 150 Carotid atherosclerosis associated with idiopathic DVT 136 vs. 40 PAD and decreasing ABI associated with VT 209 vs. 151 AMI, stroke and sudden unexplained death associated with idiopathic PE Schulman et al. [17] Follow-up Patients with DVT 897 Death due to AMI and stroke more common following DVT ABI, ankle-brachial index; AMI, acute myocardial infarction; DVT, deep venous thrombosis; HDL, high density lipoprotein; LDL, low density lipoprotein; PAD, peripheral artery disease; PE, pulmonary embolism; RF, risk factor; VT, venous thrombosis; VTE, venous thromboembolism.

3 1888 G. Agnelli and C. Becattini VTE and atherosclerosis It was actually the study by Prandoni et al. on the association between DVT and asymptomatic carotid atherosclerosis, as assessed by ultrasound examination, that re-opened the case of the potential link between arterial and venous thrombosis [14]. In this cross-sectional case control study, a higher prevalence of asymptomatic carotid atherosclerosis was found in patients with idiopathic VTE compared to patients with VTE associated with temporary risk factors (OR 2.3; 95% CI ) or healthy controls. The association held after controlling for possible confounders, including age. A higher prevalence of coronary artery calcium was found in 89 patients with confirmed venous thrombosis (51.7%) than in 89 age- and gender-matched controls (28.1%) (OR 4.3; 95% CI ) [9]. Coronary artery calcium was significantly associated with VTE with an odds ratio of 4.3 (95% CI ) in a multivariable model. In this study, diabetes and hypertension were also significantly associated with VTE. This issue of the Journal, contains two studies [5,6] reporting on the prevalence of sub-clinical atherosclerosis in patients with VTE. Subclinical atherosclerosis was identified by assessing the presence of carotid plaques and the carotid intima media thickness or by measuring the ankle-brachial index. In the first of the two studies, by Reich et al. [5], subjects included in the Atherosclerosis Risk in Communities (ARIC) study, aged years, underwent carotid ultrasonography to assess the intima media thickness and the presence of atherosclerotic plaques. After a follow-up of more than 10 years, individuals in the third quartile of baseline intima-media thickness had a 64% higher crude risk of VTE. However, no evidence of consistent association between intima media thickness and VTE was found across quartiles. Furthermore, the association disappeared after adjusting for demographic features (age, gender, etc.) and risk factors for arterial thrombosis (body mass index, diabetes, etc). At multivariate analysis the occurrence of cardiovascular and cerebrovascular events was associated with VTE (hazard ratio ¼ 2.6; 95% CI ). No association was found between the presence of carotid plaques and the occurrence of VTE. In the second study, van der Hagen et al. [6] report on 4108 subjects included in the Cardiovascular Health Study and follow-up for about 11 years. No relationship was found between carotid atherosclerosis (plaques and intima media thickness) or ankle-brachial index and VTE. The results did not change when only idiopathic episodes of VTE were considered. Unexpectedly, some forms of subclinical atherosclerosis, such as carotid plaques, were associated with a lower risk of VTE. The results of these two recent studies [5,6] do not confirm the results previously reported by Prandoni et al. [14]. This inconsistency may appear difficult to explain. However, differences in the study design (case control study vs. prospective investigations), measurement in the study end-points (documented objective diagnosis of VTE vs. medical records), and features of the control population (in-hospital vs. population-based controls) may explain the differences in the results. The observation made in the Cardiovascular Health Study on the inverse relationship between carotid plaques and VTE is difficult to interpret but deserves attention. In general, further observations are required before ruling in or ruling out the association between carotid atherosclerosis and VTE. Incidence of arterial events after VTE The incidence of arterial thromboembolic events after VTE was assessed for the first time in a long-term prospective study on the long-term follow-up in 360 patients with a first episode of PE [16]. In this study, Becattini et al. showed a higher incidence of arterial events in patients affected by idiopathic (or unprovoked) PE than in patients with PE associated with temporary risk factors (RR 7.2; 95% CI ). After adjusting for age, the idiopathic nature of the index PE was confirmed to be an independent risk factor for arterial cardiovascular events at the long-term follow-up. These results were somewhat confirmed by the recently published extended 10-year follow-up of the DURAC study in patients with VTE [17]. In this study, the mortality associated with AMI and stroke in patients with previous VTE was higher than expected in the general population (standardized incident ratio 1.28; 95% CI ). The extended DURAC study does not provide data on the relative incidence of arterial events in patients with idiopathic VTE or VTE associated with temporary risk factors. In this issue of the Journal, Prandoni et al. [7] report the results of a prospective follow-up study in 1919 consecutive patients with a first episode of VTE. Patients were followed up for the incidence of symptomatic arterial disease, such as ischemic stroke, ST-elevation or non-st-elevation acute coronary syndromes, PAD, sudden unexplained death, or fatal heart failure from coronary artery disease and/or systemic hypertension. After a median follow-up of about 4 years, at least one arterial event occurred in 15.1% of patients with idiopathic VTE when compared with 8.5% in patients with secondary venous VTE. The difference related to the nature of the venous events was confirmed after adjusting for age and other risk factors of atherosclerosis (HR 1.6; 95% CI ) and when considering only patients without previous symptomatic atherosclerosis (HR 1.7; 95% CI ). Taken together, these three studies indicate, with a remarkable consistency, that patients with VTE have an increased risk of experiencing an arterial thromboembolic event in their longterm follow-up. This seems to be particularly the case for patients with idiopathic or unprovoked VTE. Interestingly, the increased risk of arterial thromboembolic events was consistent over the three studies, despite the differences in reporting the rates of events and to measure the events. Indeed, rate of events were reported as cumulative incidence by Prandoni et al.; percentage per patient/year by Becattini et al.; absolute incidence and standardized incidence ratio by Schulman et al. Similarly, event measurement was made through national death registries or through codes of standardized nomenclature of diseases as reported by the attending physicians.

4 VTE and atherosclerosis 1889 As a warning to excessive enthusiasm, it should be considered that all the three studies have some not negligible limitations. First, none of these follow-up studies included a healthy control group but instead used patients with VTE associated with temporary risk factors as comparison for patients with idiopathic VTE. Secondly, national death registries or codes of standardized nomenclature of diseases may be inappropriate when looking for cardiovascular events. Thirdly, AMI may often be the final cause of death in patients severely compromised for different diseases. Potential implications of the increased risk for arterial events in patients with idiopathic VTE If confirmed, the increased risk of arterial thromboembolic events in patients with idiopathic VTE could have several implications. The pathophysiology of VTE, and in particular the role of platelets in this condition, should be probably reassessed. The long-term management studies of VTE should probably have more comprehensive composite outcomes. Arterial events such as stroke and MI should probably be part of the study outcome in association with recurrence of VTE. More importantly, should the distance between arterial and venous thrombosis be reduced by the recent evidence, then the role of agents currently used for prevention and treatment of arterial diseases, for example aspirin and statins, could be reconsidered or considered, respectively for the long-term management of VTE. Potential role of aspirin and statins in VTE The currently available evidence for a role of aspirin in VTE is quite limited. A systematic overview published by the Antiplatelet TrialistsÕ Collaboration, which included more than 8000 patients from randomized trials on antiplatelet therapy vs. control, suggests that antiplatelet therapy is effective for the prevention of VTE in high-risk patients [18]. Indeed, antiplatelet therapy was associated with a statistically significant relative risk reduction of 39% in the incidence of VTE in high-risk medical patients or in patients undergoing orthopedic or general surgery. A pre-specified secondary analysis in 6600 patients of the European Stroke Prevention Study 2 (ESPS 2) showed that aspirin was associated with a 30% reduction in the incidence of VTE [19]. The treatment of VTE requires effective anticoagulation, as initial heparin or low-molecular-weight heparin followed by vitamin K antagonists. However, the case is open for the optimal patient management after discontinuation of oral anticoagulants. Data on aspirin on the long-term treatment of VTE will be provided by two twin non-profit studies currently ongoing in Italy and Austria (Warfasa, agnellig@unipg.it) and in Australia and New Zealand (Aspire, aspire@ctc.usyd. edu.au). Both studies are aimed at assessing the clinical benefit of 100 mg of aspirin given after the completion of anticoagulant treatment (6 months or 1 year) after a first episode of idiopathic VTE. The Warfasa study includes stroke, MI and sudden unexplained death in the composite study end-point, while Aspire includes those events in the secondary end-point. The currently available evidence for a role of statins in venous diseases is even more limited than that of aspirin and it is nothing more than a working hypothesis [4]. In a retrospective analysis, a reduced incidence of VTE was observed in patients treated with statins [20]. The incidence of VTE was not reduced in patients treated with lipid-lowering agents other than statins. For this reason, the preventive effect of VTE may be attributed to statins as part of their pleiotropic effects. Conclusions Whether venous and arterial thromboembolism share common risk factors and whether this sharing is supportive of the common nature of the two diseases remains undefined. The new data on the association between VTE and the metabolic syndrome are interesting but require further prospective data. The post-mortem data on the association are of interest but do not provide information about the timing of the disease process. The discrepancies concerning the association between carotid atherosclerosis and VTE precludes any definitive conclusion about this issue. The findings about the high incidence of arterial events in patients with idiopathic VTE are consistent and have potential clinical implications. The role of antiplatelet therapy in the long-term management of VTE should be revisited and the potential role of statins should be explored. Disclosure of Conflict of Interests The authors state that they have no conflict of interest. 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