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Keywords:

  • anticoagulation;
  • atherosclerosis;
  • risk factors;
  • thrombophilia;
  • venous thromboembolism

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of conflict of interest
  9. References

Summary. Background: Recently, we reported an association between asymptomatic carotid atherosclerosis and venous thromboembolism (VTE) of unknown origin. We hypothesized that patients with VTE of unknown origin would be at a higher risk of developing symptomatic atherosclerosis than patients with VTE induced by known risk factors. Methods: To examine this hypothesis, we studied 1919 consecutive patients followed prospectively after their first VTE episode. The primary outcome was non-fatal and fatal symptomatic atherosclerotic disease in patients with VTE of unknown origin as compared to those with secondary VTE. An independent committee assessed all study outcomes, and adjusted hazard ratios (HR) were calculated using the Cox's proportional hazards model. Results: After a median follow-up of 48 and 51 months, respectively, at least one symptomatic atherosclerotic complication was detected in 160 of the 1063 patients (15.1%) with VTE of unknown origin, and in 73 of the 856 (8.5%) with secondary VTE. After adjusting for age and other risk factors of atherosclerosis, the HR for symptomatic atherosclerotic complications in patients with VTE of unknown origin compared to those with secondary VTE was 1.6 (95% confidence intervals; CI: 1.2–2.0). When the analysis was restricted to patients without previous symptomatic atherosclerosis, the HR became 1.7 (95% CI: 1.1–2.4). Conclusions: Patients with VTE of unknown origin have a 60% higher risk of developing symptomatic atherosclerotic disease than do patients with secondary venous thrombosis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of conflict of interest
  9. References

We recently described an unexpected association between asymptomatic atherosclerosis of the carotid arteries and deep vein thrombosis (DVT) of unknown origin [1]. The association held after controlling for possible confounding effects of risk factors for atherosclerosis.

In order to provide further elements in favor of this association, as well as to assess its clinical relevance, we examined a large group of consecutive patients who had been followed prospectively after an initial episode of DVT or pulmonary embolism (PE). We hypothesized that patients with venous thromboembolism (VTE) of unknown origin would be at a higher risk of developing symptomatic atherosclerotic events than patients with VTE induced by known risk factors.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of conflict of interest
  9. References

Consecutive patients admitted to each of three participating centers (Department of Medical and Surgical Sciences and Department of Cardiothoracic and Vascular Sciences in Padua, and Department of Internal Medicine, Angiology Unit in Reggio Emilia, Italy) between May 1991 and April 2003 with acute symptomatic DVT or PE were potentially eligible for the study. Diagnostic criteria for DVT were a non-compressible proximal vein on ultrasonography or an intraluminal filling defect on venography. Diagnostic criteria for PE were an intraluminal filling defect on spiral computed tomography (CT) or pulmonary angiography, a high-probability ventilation-perfusion lung scan, or a non-diagnostic lung scan with documentation of DVT either by compression ultrasonography or by venography. All patients were hospitalized and treated with intravenous adjusted-dose unfractionated heparin or fixed dose low molecular weight heparin. For those patients with severe PE, this treatment was preceded by thrombolytic drugs or, rarely, thromboembolectomy. All patients started oral anticoagulants within the week following the thromboembolic event, and continued taking them for 3–6 months. The decision to prolong anticoagulant treatment beyond these periods was made on an individual basis, depending on perceived risk of recurrent VTE.

Patients with the following conditions were ineligible for the study: a history of symptomatic VTE, active cancer, atrial fibrillation, valvular heart disease, or congestive heart failure. Patients also were excluded if they had mechanical or biological prosthetic heart valves, were unavailable for follow-up, had a life-expectancy of < 3 months, or declined to participate. The study was conducted in accord with the ethical principles of the Declaration of Helsinki, and the protocol was approved by the Institutional Review Board in each of the three participating centers.

Patients were classified as having secondary VTE if they were pregnant, had given birth within the previous 3 months, had been immobilized because of chronic medical illness for more than 1 week, took estrogens, or had had a leg trauma, fracture, or surgical intervention within the past 3 months. All other patients were classified as having VTE of unknown origin. Carriers of thrombophilia were classified as having VTE of unknown origin or secondary VTE on the basis of their clinical presentation.

All consenting patients were evaluated for the presence of risk factors for atherosclerosis. Based on clinical history, clinical examination, or laboratory tests, data on the following variables were recorded on a standard form:

  • 1
    previous symptomatic atherosclerosis (defined as a history of ischemic stroke, transient ischemic attack, acute myocardial infarction [MI], angina, or intermittent claudication);
  • 2
    smoking status (with smoking defined as habitual daily use of 10 or more cigarettes with interruptions of < 1 month);
  • 3
    hypertension (defined by a systolic blood pressure of more than 140 mmHg or a diastolic blood pressure of more than 90 mmHg, or both, on at least two occasions, or by the use of hypotensive drugs);
  • 4
    obesity (defined by a body mass index [kg m2] of more than 30);
  • 5
    diabetes mellitus (defined by a plasma glucose level of at least 126 mg dL−1 [7.0 mmol L−1] after an overnight fast on at least two occasions or a level of at least 200 mg dL−1 [11.1 mmol L−1] 2 h after the administration of 75 g of oral glucose and at least once between 0 and 2 h, or by the use of anti-diabetic drugs);
  • 6
    hyperlipidemia (defined by a fasting venous cholesterol level exceeding 220 mg dL−1 [5.7 mmol L−1], a low density lipoprotein cholesterol level of at least 140 mg dL−1 [2.8 mmol L−1], or both on at least two occasions, or by the use of lipid-lowering drugs).

Follow-up and outcome assessment

Patients were prospectively followed up at least every 6 months during the first 2 years post-VTE episode and then yearly for up to 10 years. Whenever patients could not attend the scheduled follow-up visits, they were either interviewed by phone or visited at home. Date and cause of death were documented for patients who died during the follow-up period. An autopsy was sought whenever PE, stroke or MI could not be excluded. In those patients who died unexpectedly and in whom an autopsy could not be performed, the cause of death was attributed to PE whenever suspected by an independent physician, while all other patients were labeled as dying of sudden death. An independent expert committee totally blinded to type of venous thrombosis (of unknown origin or secondary to identifiable risk factors) assessed all study outcomes as retrieved from hospital charts or survey of attending physicians.

The primary outcome was non-fatal or fatal symptomatic cardiovascular disease, defined as ischemic stroke, ST-elevation or non-ST-elevation acute coronary syndrome, peripheral arterial disease, sudden unexplained death, or fatal heart failure from coronary artery disease and/or systemic hypertension. Ischemic stroke in turn was defined as a focal neurological deficit of sudden onset with a matching lesion observed by CT or magnetic resonance imaging. In the absence of these tests, a diagnosis of ischemic stroke was given only if symptoms consistent with such an event had lasted more than 24 h. ST-elevation or non-ST-elevation acute coronary syndrome was documented if symptoms met World Health Organization criteria and were associated with abnormal levels of cardiac enzymes and/or diagnostic electrocardiographic criteria. Peripheral arterial disease was diagnosed in the presence of an acute abdominal aneurysm, intestinal ischemia, or infarction or intermittent claudication [defined as pain, ache, cramp, numbness, or a sense of fatigue in the muscles during exercise (maximal walking distance 500 m) and relieved by rest]. This diagnosis required confirmation by objective assessment (color-Doppler test, contrast magnetic resonance, arteriography of the lower limbs, or ankle-brachial index < 0.9 on two occasions). Sudden unexplained death was defined as occurring unexpectedly, instantaneously, or within 1 h of symptom onset. Fatal heart failure was defined as a death resulting from acute or chronic heart failure in individuals with coronary artery disease and/or systemic hypertension associated with symptomatic or asymptomatic manifestations of atherosclerosis, after excluding other causes of heart failure (PE, chronic thromboembolic pulmonary hypertension, infectious diseases, infectious endocarditis, acute or chronic pericarditis, severe anemia, thyrotoxicosis, arrhythmias, rheumatic and other forms of myocarditis, valvulopathies, congenital heart diseases, pregnancy or puerperium, nutritional defects, drug or alcohol abuse, chemotherapy, or systemic hypertension of renal or endocrinological origin).

Statistical analysis

The clinical baseline characteristics of patients with VTE of unknown origin and patients with secondary VTE were compared using the Kruskal–Wallis test for continuous variables and the chi-squared test for dichotomous variables. Kaplan–Meier survival estimates were computed for the cumulative incidence of symptomatic atherosclerosis among patients with VTE of unknown origin and those with secondary VTE. Patients who, during follow-up, developed atrial fibrillation, valvulopathies, rheumatic myocarditis or other forms of myocarditis that could potentially account for the development of ischemic stroke or systemic embolism were censored at the time these conditions were detected. As a measure of relative risk we computed hazard ratios (HR) and their 95% confidence intervals (CI) using Cox's proportional hazards regression analysis. Initially, a crude relative risk was calculated for VTE of unknown origin vs. secondary VTE. Then a multivariate Cox model was constructed, accounting for age and other known risk factors for atherosclerosis (sex, previous symptomatic atherosclerosis, smoking status, hyperlipidemia, hypertension, obesity, and diabetes). All calculations were performed using SAS software, version 6.10 (SAS Institute, Inc, Cary, NC, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of conflict of interest
  9. References

We identified 3338 consecutive patients with confirmed symptomatic DVT, PE, or both conditions. Of these, 1469 were excluded for the following reasons: active cancer (n = 545), a history of previous symptomatic VTE (n = 409), atrial fibrillation (n = 101), valvular heart disease (n = 33), cardiomyopathies or congestive heart failure (n = 70), a life-expectancy of < 3 months (n = 101), and inaccessibility for follow-up (n = 170). Forty additional patients declined to participate. In total, 1919 patients took part in the study.

Based on clinical presentation, 1063 patients had VTE of unknown origin and 856 had secondary VTE. Table 1 provides demographic and other characteristics of study subjects, including presence of risk factors for atherosclerosis. They were all of Caucasian race. Median follow-up time for patients with VTE of unknown origin or secondary VTE was 48 and 51 months, respectively, and maximum follow-up time was 10 years. Seventy-eight patients with VTE of unknown origin were lost to follow-up, as were 63 patients with secondary VTE.

Table 1.   Characteristics of the study population
 Unprovoked thrombosis (n = 1063)Secondary thrombosis (n = 856)
  1. Number in parentheses indicate percentages, unless otherwise indicated.

  2. DVT, deep vein thrombosis; LMWH, low molecular weight heparin; OAT, oral anticoagulation therapy; PE, pulmonary embolism; VTE, venous thromboembolism.

Age, years (±SD)65.5 ± 15.359.6 ± 18.9
 Male sex, n (%)541 (50.9)322 (37.6)
Risk factors for atherosclerosis
 Previous atherosclerosis, n (%)163 (15.3)93 (10.9)
 Smoker, n (%)374 (35.2)290 (33.9)
 Hypertension, n (%)374 (35.2)251 (29.3)
 Hyperlipidemia, n (%)190 (17.9)132 (15.4)
 Obesity, n (%)139 (13.1)110 (12.9)
 Diabetes, n (%)89 (8.4)71 (8.3)
Risk factors for venous thrombosis
 Recent trauma, n (%) 300 (35.0)
 Recent surgery, n (%) 282 (32.9)
 Medical diseases, n (%) 113 (13.2)
 Hormonal treatment, n (%) 108 (12.6)
 Pregnancy, n (%) 29 (3.4)
 Collagenopathies, n (%) 18 (2.1)
 Puerperium, n (%) 6 (0.7)
 Thrombophilia, n (% of screened)239/606 (39.4)146/472 (30.9)
Type of VTE
 DVT alone, n (%)694 (65.3)560 (65.4)
 DVT with PE, n (%)204 (19.2)152 (17.8)
 PE alone, n (%)165 (15.5)144 (16.8)
Initial treatment
 Unfractionated heparin, n (%)672 (63.2)557 (65.1)
 LMWH, n (%)339 (31.9)267 (31.2)
 Other, n (%)47 (4.4)32 (3.7)
Follow-up, months
 Duration of OAT (months median, IQ-range)6 (6–12)6 (3–6)
 Duration (months; median, IQ-range)48 (27–72)51 (32–76)

Symptomatic atherosclerotic complications

At least one symptomatic atherosclerotic complication was detected in 160 of the 1063 patients (15.1%) with VTE of unknown origin, and in 73 of the 856 patients (8.5%) with secondary VTE. Types of atherosclerotic complications associated with VTE of unknown origin and with secondary VTE are presented in Table 2, separately for men and women and for patients younger and older than 50 years. The 10-year cumulative incidence of symptomatic atherosclerotic complications was 25.4% (95% CI: 21.6–31.2) in patients with VTE of unknown origin, and 12.9% (95% CI: 9.5–16.3) in patients with secondary VTE (Fig. 1).

Table 2.   Type of atherosclerotic complication among patients with thrombosis of unknown origin and patients with secondary thrombosis (adjusted to age and sex)
 Unprovoked thrombosis (n = 1063)Secondary thrombosis (n = 856)
  1. Numbers in parentheses indicate percentages, unless otherwise indicated.

  2. CI, confidence interval.

Non-fatal events
Acute coronary syndrome (n = 42)
 Men ≤50 years3/107 (2.8)0/97 (0.0)
 Men >50 years16/434 (3.7)8/225 (3.5)
 Women ≤50 years0/69 (0.0)1/172 (0.6)
 Women >50 years6/453 (1.3)8/362 (2.2)
 Overall25/1063 (2.3; 95% CI, 1.5–3.4)17/856 (2.0; 95% CI, 1.2–3.2)
Ischemic stroke (n = 59)
 Men ≤50 years1/107 (0.9)0/97 (0.0)
 Men >50 years17/434 (3.9)10/225 (4.4)
 Women ≤50 years1/69 (1.4)2/172 (1.2)
 Women >50 years19/453 (4.2)9/362 (2.5)
 Overall38/1063 (3.6; 95% CI, 2.5–4.9)21/856 (2.4; 95% CI, 1.5–3.7)
Peripheral artery disease (n = 22)
 Men ≤50 years1/107 (0.9)0/97 (0.0)
 Men >50 years11/434 (2.5)3/225 (1.3)
 Women ≤50 years1/69 (1.4)0/172 (0.0)
 Women >50 years4/453 (0.9)2/362 (0.5)
 Overall17/1063 (1.6; 95% CI, 0.9–2.5)5/856 (0.6; 95% CI, 0.2–1.4)
Fatal events
Myocardial infarction (n = 17)
 Men ≤50 years1/107 (0.9)0/97 (0.0)
 Men >50 years6/434 (1.4)3/225 (1.3)
 Women ≤50 years1/69 (1.4)0/172 (0.0)
 Women >50 years4/453 (0.9)2/362 (0.5)
 Overall12/1063 (1.1; 95% CI, 0.6–2.0)5/856 (0.6; 95% CI, 0.2–1.4)
Ischemic stroke (n = 19)
 Men ≤50 years0/107 (0.0)0/97 (0.0)
 Men >50 years6/434 (1.4)3/225 (1.3)
 Women ≤50 years0/69 (0.0)0/172 (0.0)
 Women >50 years7/453 (1.5)3/362 (0.8)
 Overall13/1063 (1.2; 95% CI, 0.6–2.1)6/856 (0.7; 95% CI, 0.3–1.5)
Peripheral artery disease (n = 5)
 Men ≤50 years0/107 (0.0)0/97 (0.0)
 Men >50 years2/434 (0.5)1/225 (0.4)
 Women ≤50 years0/69 (0.0)0/172 (0.0)
 Women >50 years2/453 (0.4)0/362 (0.0)
 Overall4/1063 (0.4; 95% CI, 0.1–0.9)1/856 (0.1; 95% CI, 0.0–0.6)
Heart failure from coronary artery disease and/or systemic hypertension (n = 27)
 Men ≤50 years1/107 (0.9)0/97 (0.0)
 Men >50 years5/434 (1.1)1/225 (0.4)
 Women ≤50 years0/69 (0.0)0/172 (0.0)
 Women >50 years11/453 (2.4)9/362 (2.5)
 Overall17/1063 (1.6; 95% CI, 0.9–2.5)10/856 (1.2; 95% CI, 0.6–2.1)
Sudden death (n = 42)
 Men ≤50 years0/107 (0.0)0/97 (0.0)
 Men >50 years22/434 (5.1)1/225 (0.4)
 Women ≤50 years0/69 (0.0)0/172 (0.0)
 Women >50 years12/453 (2.6)7/362 (1.9)
 Overall34/1063 (3.2; 95% CI, 2.2–4.4)8/856 (0.9; 95% CI, 0.4–1.8)
image

Figure 1.  Cumulative incidence of symptomatic atherosclerotic complications in patients with venous thromboembolism (VTE) of unknown origin or secondary VTE.

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In the crude analyses, patients with VTE of unknown origin were more likely to have symptomatic atherosclerotic complications than those with secondary VTE (HR, 1.9; 95% CI: 1.4–2.5). In multivariate analyses, after adjusting for age and other risk factors for atherosclerosis the HR for symptomatic atherosclerotic complications in patients with VTE of unknown origin compared to those with secondary VTE became 1.6 (95% CI: 1.2–2.0). The contribution of known risk factors for atherosclerosis was generally in the expected direction, and reached statistical significance for age, male gender, and presence of previous atherosclerosis (Table 3). In analyses restricted to patients without previous symptomatic atherosclerosis, the adjusted HR was 1.7 (95% CI: 1.1–2.4).

Table 3.   Contribution of known risk factors for atherosclerosis to outcome in the multivariate analysis
Risk factorRelative risk95% CI
Age (per 10-year increment)1.91.7–2.2
Previous atherosclerosis2.51.9–3.4
Male gender1.41.1–1.9
Smoking1.10.8–1.5
Hypertension1.31.0–1.7
Hyperlipidemia1.20.8–1.6
Obesity1.20.8–1.8
Diabetes0.90.5–1.3

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of conflict of interest
  9. References

This long-term follow-up study showed that patients with VTE of unknown origin have a higher risk of subsequent symptomatic atherosclerosis than patients whose VTE episode is triggered by known risk factors. Notably, all types of atherosclerotic complications (i.e. ischemic stroke, coronary artery disease, peripheral artery disease, sudden death, and death from heart failure) occurred more frequently in patients with VTE of unknown origin than in those with secondary VTE.

Our findings are consistent with those from other recent studies. Becattini et al. prospectively followed 360 patients after an initial PE episode, and found a significantly higher incidence of both fatal and non-fatal cardiovascular events among patients with an embolism of unknown origin compared to those with a secondary embolism [2]. In a retrospective case–control study, Hong et al. found a significantly higher incidence of coronary artery calcium, as shown by pulmonary CT, in patients with idiopathic VTE than in age- and sex-matched control individuals without thrombosis [3]. In a large breast cancer prevention trial, Decensi et al. found a higher risk of tamoxifen-related VTE complications in women with than in women without conventional risk factors of atherosclerosis [4]. Taken together with the results from our recent case–control study showing an increased incidence of asymptomatic carotid plaques in patients with DVT of unknown origin as compared to patients with secondary DVT and matched control subjects without thrombosis [1], our findings challenge the common view that venous and arterial disorders are separate entities, suggesting instead that an association between atherosclerosis and venous thrombosis does indeed exist.

The incidence of risk factors for atherosclerosis and of previous symptomatic atherosclerosis was higher in patients with VTE of unknown origin compared to those with secondary VTE. These findings accord with those in another recent report [5]; in their case–control study, Ageno et al. observed a significantly higher incidence of metabolic syndrome among patients with DVT of unknown origin than among those with secondary VTE and among matched controls. In our own study, even after adjusting for age and other risk factors for atherosclerosis patients with VTE of unknown origin still had a statistically significant 60% higher risk of developing subsequent symptomatic atherosclerosis than patients with secondary VTE; this risk did not change when patients with previous atherosclerosis were removed from the analysis.

Our results appear robust for several reasons. First, the occurrence of atherosclerotic complications was recorded prospectively, although our hypothesis was generated after patients with VTE began to be included in this long-term follow-up study. Second, consecutive patients were enrolled in the study, and all had an objectively confirmed diagnosis of DVT or PE. Finally, the assessment of atherosclerotic complications was done by an independent committee, which applied uniform and stringent criteria.

We cannot exclude that PE accounted for a proportion of patients who died suddenly. For the purpose of the current study, we labeled as dying of sudden death, potentially induced by an underlying coronary or cerebral vascular disease of atherosclerotic origin, only those patients in whom an autopsy could not be performed and in whom PE was excluded as cause of death by an independent physician, and consistently applied this criterion in both study groups. It should be noted that sudden death constituted less than 20% of all study outcomes. In contrast, documented fatal or non-fatal acute coronary syndromes, stroke, peripheral arterial disease, and congestive heart failure constituted more than 80% of outcomes, with each condition consistently occurring more frequently in patients with VTE of unknown origin than in those with secondary VTE.

Although our data suggest the existence of an association between atherosclerosis and VTE, they do not clarify the nature of this association. On one hand, atherosclerosis has the potential to promote the development of thrombotic disorders in the venous system. Atherosclerotic disease is indeed associated with a detectable activation of both platelets and blood coagulation, as well as with increased fibrin turnover [6–12]. The role of this prothrombotic state in favoring venous thrombotic events is plausible given the assumption that activated platelets and coagulation factors appear in the slow-flowing venous system. On the other hand, the two clinical conditions may share common risk factors. Of interest, several recent data suggest that a few risk factors of atherosclerosis may also account for an increased risk of VTE [13–18], although a few investigations failed to show an association of arterial disease risk factors with venous thrombosis risk [19–21].

In conclusion, patients with VTE of unknown origin have a 60% higher risk of developing symptomatic atherosclerotic disease than do patients with secondary venous thrombosis. These findings suggest an association between atherosclerosis and venous thrombosis. Future studies are needed to clarify the nature of this association, to assess its extent by comparing the rate of atherosclerotic complications in patients with venous thrombosis with that occurring in control individuals from the general population, and to evaluate its implications for clinical practice.

Addendum

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of conflict of interest
  9. References

Conception and design: P. Prandoni, A.W.A. Lensing, B.L. Davidson, H. Sorensen; provision of study material or patients: P. Prandoni, R. Pesavento, A. Ghirarduzzi, V. Pengo, M. Iotti; analysis and interpretation of the data: M.H. Prins, E. Casiglia; drafting of the article: P. Prandoni, A.W.A. Lensing, M.H. Prins, B.L. Davidson, H. Sorensen; critical revision of the article for important intellectual content: S. Iliceto, A. Pagnan.

Disclosure of conflict of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of conflict of interest
  9. References

A. Lensing is an employee of Bayer Healthcare, Medical Division (Wuppertal, Germany). The other authors declare that they have no conflicts of interest to disclose regarding this study.

References

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of conflict of interest
  9. References
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