Atherosclerosis and Its Impact on the Outcomes of Patients with Deep Venous Thrombosis

Karsten Keller, Jürgen H Prochaska, Meike Coldewey, Sebastian Göbel, Volker H Schmitt, Omar Hahad, Alexander Ullmann, Markus Nagler, Heidrun Lamparter, Christine Espinola-Klein, Thomas Münzel, Philipp S Wild, Karsten Keller, Jürgen H Prochaska, Meike Coldewey, Sebastian Göbel, Volker H Schmitt, Omar Hahad, Alexander Ullmann, Markus Nagler, Heidrun Lamparter, Christine Espinola-Klein, Thomas Münzel, Philipp S Wild

Abstract

Introduction: Atherosclerosis and pulmonary embolism (PE) affect cardiovascular mortality substantially. We aimed to investigate the impact of atherosclerosis on the outcomes of patients with deep venous thrombosis (DVT) and to identify the differences in DVT patients with and without PE. Methods: Patients with DVT with and without symptomatic atherosclerosis (defined as coronary artery disease, myocardial infarction and/or peripheral artery disease) as well as with and without PE under oral anticoagulation were enrolled during January 2011−April 2013 and compared. The impact of symptomatic atherosclerosis on several outcomes was analyzed. Results: Overall, 509 DVT patients (70.0 [56.0−77.0] years, 51.9% females) were included in this study. Among them, 179 (36.3%) had symptomatic atherosclerosis and 204 (40.1%) a concomitant PE. DVT patients with symptomatic atherosclerosis were older (74.0 [IQR 65.0−80.0] vs. 63.0 [48.0−75.0] years, p < 0.0001), more often male (56.4% vs. 43.9%, p = 0.0087) and had a higher prevalence of classical CVRF and a higher Charlson comorbidity index (7.00 [5.00−8.00] vs. 4.00 [2.00−6.00], p < 0.001). Symptomatic atherosclerosis was associated with increased mortality (HR 1.98 [95%CI 1.12−3.49], p = 0.018) and hospitalizations (HR 1.64 [95%CI 1.21−2.21], p = 0.0012) and primary long-term outcome (HR 1.99 [95%CI 1.31−3.04], p = 0.0013) during the 2 years follow-up-period in DVT patients. DVT patients without PE had diabetes mellitus (28.2% vs. 16.3%, p < 0.01) and symptomatic atherosclerosis (42.9% vs. 26.4%, p < 0.001) more often compared to DVT patients with PE, and symptomatic atherosclerosis was associated with isolated DVT (without PE) (OR 2.01 [95%CI 1.28−3.16], p < 0.01). Conclusions: Atherosclerosis was associated with isolated DVT (without PE) and increased mortality in DVT patients under oral anticoagulation. The profile of CVRF and comorbidities differed between DVT patients with and without a concomitant PE. In the case of DVT or PE, patients should be screened for concomitant atherosclerotic disease. Clinical Trial Registration: at clinicaltrials with Unique identifier NCT01809015.

Keywords: age; atherosclerosis; deep vein thrombosis; diabetes; peripheral artery disease; pulmonary embolism.

Conflict of interest statement

No support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work. P.S.W. and T.M. are PIs of the German Center for Cardiovascular Research (DZHK). The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Associations of classical cardiovascular risk factors and comorbidities with DVT with or without PE. (A) Cardiovascular risk factors as independent predictors for a history of PE in multivariable logistic regression models in patients with DVT: the model contained the following variables: sex, age, diabetes, obesity, hypertension, dyslipidemia, family history of myocardial infarction or stroke and smoking. (B) Multivariable logistic regression models were used to evaluate the association with concomitant history of PE (i.e., the dependent variable; reference: no history of PE). In model 1, each concomitant disease was adjusted for cardiovascular risk factors (i.e., the independent variables) in a separate model, and in model 2, all concomitant diseases (MI was not taken for adjustment due to the co-linearity with CAD and PAD; CAD and MI were not taken for adjustment due to the co-linearity with symptomatic atherosclerosis) and CVRF were included in one model. Symptomatic atherosclerosis was defined as the presence of CAD, MI and/or PAD. (C) Multivariable logistic regression models were used to evaluate the association between DVT with concomitant PE (i.e., the dependent variable; reference: no history of PE) and the escalation of anti-diabetic treatment under adjustment for cardiovascular risk factors (i.e., the independent variables). (D) Multivariable logistic regression models were used to evaluate the association between a DVT with PE (i.e., the dependent variable; reference: no history of PE) and the sub-classes of obesity while adjusting for cardiovascular risk factors (i.e., the independent variables) in DVT patients. The obesity sub-classes were defined according to the World health Organization (WHO, 2008), which defined obesity class I as BMI a between 30.0 and 34.9 kg/m2, class II as a BMI between 35.0–39.9 kg/m2 and class III as a BMI ≥ 40.0 kg/m2. Abbreviations: BMI = body mass index; DVT = deep venous thrombosis; PE = pulmonary embolism; NIDDM = non-insulin-dependent diabetes mellitus; IDDM = insulin-dependent diabetes mellitus. p-values < 0.05 were considered as significant associations.
Figure 2
Figure 2
Comparison of DVT patients with and without additional symptomatic atherosclerosis regardless of the presence of additional PE during a 2-year follow-up period under VKA treatment. (A) Kaplan–Meier-curve for mortality of DVT patients with and without symptomatic atherosclerosis. (B) Kaplan–Meier-curve for primary long-term outcome of DVT patients with and without symptomatic atherosclerosis. (C) Kaplan–Meier-curve for hospitalizations of DVT patients with and without symptomatic atherosclerosis. (D) Kaplan–Meier-curve for major or clinically relevant bleeding of DVT patients with and without symptomatic atherosclerosis. (E) Kaplan–Meier-curve for thromboembolic arterial and venous events of DVT patients with and without symptomatic atherosclerosis. (F) Kaplan–Meier-curve for recurrent VTE of DVT patients with and without symptomatic atherosclerosis. Abbreviations: DVT = deep venous thrombosis; PE = pulmonary embolism. Differences in Kaplan–Meier curves were tested with the log-rank test. p-values < 0.05 were considered as significant associations.

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