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Comparison of the clinical history of symptomatic isolated distal deep‐vein thrombosis vs. proximal deep vein thrombosis in 11 086 patients

2009; Elsevier BV; Volume: 7; Issue: 12 Linguagem: Inglês

10.1111/j.1538-7836.2009.03629.x

1538-7933

J.‐P. Galanaud, Sara Quenet, Karine Rivron-Guillot, I. Quéré, Juan Francisco Sánchez Muñoz-Torrero, Carles Tolosa, Manuel Monréal,

Central Venous Catheters and Hemodialysis

Background: The clinical significance of symptomatic isolated distal deep vein thrombosis (DVT) is uncertain. Consequently, this leads to important disparities in its management. Objective: To examine the clinical history of isolated distal DVT and to compare it with that of proximal DVT. Methods: Using data from the international, prospective, RIETE registry on patients with confirmed symptomatic venous thromboembolism (VTE), we compared the risk factors and 3-month outcome in patients with isolated distal DVT vs. proximal DVT. Results: Eleven thousand and eighty-six patients with symptomatic DVT, but without pulmonary embolism, were included between 2001 and 2008; 1921 (17.3%) exhibited isolated distal DVT. Anticoagulant treatment was received by 89.1% (1680/1885) of isolated distal DVT and 91.8% (7911/8613) of proximal DVT patients for the entire follow-up period. Isolated distal DVTs were more associated with transient risk factors (i.e. recent travel, hospitalization, recent surgery), whereas proximal DVTs were more associated with chronic states (i.e. ≥75 years or with active cancer). At 3 months, major bleeding rate was lower in patients with isolated distal DVT (1.0% vs. 2.2%, P < 0.01), whereas VTE recurrence rate was equivalent (2.0% vs. 2.7%, P = 0.07). The mortality rate was lower in patients with isolated distal DVT (2.7% vs. 7.5%; P < 0.001); this was mainly due to a lower rate of non-VTE-related deaths (2.2% vs. 6.3%; P < 0.001). Active cancer was the main predictive factor of death in patients with isolated distal DVT. Conclusions: Proximal and isolated distal DVT patients differ in terms of risk factors and clinical outcomes, suggesting different populations. In the short term, the life expectancy of patients with isolated distal DVT depended chiefly on their cancer status. Distal or calf deep vein thrombosis (DVT) in the infra-popliteal veins of the lower limbs is a comparatively frequent event [1-3]. DVTs such as this are reputed to be less severe than proximal DVT because they are less prone to embolizing into the pulmonary circulation [4, 5]. However, in practise, their clinical significance is uncertain, as reflected by the disparities between countries in their management (i.e. diagnosis and treatment) [3, 6-9]. Furthermore, as distal DVTs below the calf trifurcation have been excluded from clinical trials for new anticoagulant drugs, no data on their clinical outcome is likely to be available in the future [10, 11]. Several facts may explain the uncertainty about the clinical significance of distal DVT. First, only one clinical trial has demonstrated any superiority of full therapeutic doses of anticoagulants over placebo in the treatment of distal DVT [12]. Furthermore, the conclusions of this trial are currently under question, as the number of patients included (51) was low and the procedures used to diagnose DVT recurrence (clinical examination and isotopic tests) were unreliable [3, 8]. Second, only a few distal DVTs have been included in epidemiological studies on venous thromboembolism (VTE) [13, 14]. Finally, the type of distal DVT (i.e. symptomatic or non-symptomatic, and associated with or without symptomatic pulmonary embolism (PE) at presentation) has not explicitly been taken into account in most studies [1, 13, 15]. Thus, no large epidemiological study to date has focused on symptomatic distal DVT without PE or symptomatic isolated distal DVT. Yet, symptomatic isolated distal DVTs are in reality the only distal DVT for which the optimal management is still debated, as suggested by the low grade of recommendation (2B) from the last international guidelines, which recommend treatment of unprovoked isolated distal DVT during the first 3 months as unprovoked proximal DVT [16]. Conversely, it is a relatively well-established practise not to test for asymptomatic isolated distal DVT and to treat distal DVT associated with PE as one would treat isolated PE [16]. Therefore, data on the clinical history of symptomatic isolated distal DVT are necessary as a first step towards determining the most appropriate mode of care. To this end, we analyzed data from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry, focusing on patients with symptomatic isolated distal and proximal DVT [17, 18]. Each DVT was managed according to each physician’s usual clinical practise. After comparing the risk factors and the 3-month outcomes of isolated distal vs. proximal DVT, we studied prognostic factors for death in patients with isolated DVT so as to stratify isolated distal DVT severity. The RIETE registry was initiated in March 2001, and is an ongoing, international, multicentre, prospective cohort of consecutive patients presenting with confirmed symptomatic VTE (DVT and/or PE) [17, 18]. Consecutive patients with acute symptomatic VTE (DVT and/or PE) confirmed by objective tests (contrast venography or ultrasonography for suspected DVT; pulmonary angiography, lung scintigraphy or helical computed tomography scan for suspected PE) are eligible for inclusion in the registry. There are only two exclusion criteria: a likely follow-up of <3 months (except for those where there is a likely life expectancy of < 3 months, which is then not an exclusion criteria) and participation in a therapeutic clinical trial. Patients are managed according to the clinical practise of each physician of each participating hospital centre. For this study, only patients with symptomatic DVT of the lower limbs and without symptomatic PE at presentation were studied. After hospital discharge, all patients are followed-up for at least 3 months. The 3-month follow-up was validated after a medical visit or, in case of death, after a phone call to the general practitioner or the family. Any sign or symptom that is suggestive of either recurrent DVT or PE, or any bleeding complications is noted. Each episode of clinically suspected recurrent DVT or PE is documented by repeated compression ultrasonography, venography, lung scan, helical computed tomography scan, or pulmonary angiography. All patients are recruited after having given their oral consent to participation in the registry, according to the requirements of the ethics committee of each hospital. The attending physicians ensure that eligible patients are consecutively enrolled. Data are recorded on a computer-based case report form at each participating hospital. These reports are then submitted through a secure website to a centralized coordinating centre responsible for all data management. Patient identities remain confidential, each patient being identified solely by a unique number assigned by the study coordinating centre. The quality of data collection is regularly monitored and documented electronically. Any inconsistency or error is resolved by the local coordinators. Data quality is also monitored by members of the contract research organizations involved, who compare the data in medical records with those transferred online, during periodic visits to participating hospitals. Finally, a full data audit is performed periodically. For this study, the following parameters were analyzed: demographic data; clinical status, including any coexisting or underlying conditions; clinical characteristics of VTE; risk factors for VTE; and anticoagulant treatment and clinical outcomes during the first 3 months of follow-up. Transient risk factors of VTE analyzed were bed confinement (total bed rest with bathroom privileges for more than 4 days in the 2 months period before VTE diagnosis), recent surgery (any surgical intervention in the past 2 months), pregnancy and post partum within the last 2 months, travel (travel lasting more than 6 h in the previous 3 weeks), and estrogen intake within the last 2 months. Chronic risk factors of VTE analyzed were personal history of VTE, known thrombophilia at diagnosis, active cancer (newly diagnosed cancer or cancer receiving antineoplastic treatment of any type or cancer in palliative care), leg varicosities, and obesity (body mass index ≥ 30 kg m−2). Clinical outcomes were recurrent VTE, bleeding and death. Fatal PE, in the absence of autopsy, was defined as death within 48 h of PE diagnosis in the absence of any alternative cause of mortality. Bleeding complications were classified as ‘major’ if they were overt and required a transfusion of two units of blood or more, or were retroperitoneal, spinal or intracranial, or were fatal. Fatal bleeding was defined as any death occurring shortly after a major bleeding episode. Any other clinically relevant bleeding event was considered ‘minor’. Analyses were performed on all patients for whom data were available. Qualitative data were reported as numbers and percentages. Quantitative data were reported as median values with first quartile (Q1) and third quartile (Q3). A logistic regression model was used to examine the individual relationship between each variable and the relative risk of isolated distal vs. proximal DVT. We also examined the individual relationship between each demographic and clinical variable at baseline and the relative risk of death at 3 months in patients with isolated distal DVT. Any variable achieving a P value of less than 0.15 on univariate analysis was included in a multivariate logistic regression. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated. P values were considered statistically significant at a level of 0.05 or less. The cumulative rates of VTE recurrence, major bleeding and death were estimated using the Kaplan–Meier method. Data were processed and analyzed using SAS-Windows™ software (version 9.13; SAS Institute, Inc., Cary, NC, USA). As of February 2008, 21 411 consecutive patients with acute VTE were included in the RIETE study. A total of 11 086 (51.8%) patients exhibited symptomatic DVT of the lower limbs without symptomatic PE, and 9279 (43.3%) patients had symptomatic PE (with or without DVT). The median (Q1–Q3) age of patients with symptomatic DVT of the lower limbs without PE was 70 (55–78) years. A third of the patients were in-patients. Active cancer was reported in 20.5% of patients (Table 1). Among those patients with DVT, but without symptomatic PE, 1921 (17.3%) had isolated distal DVT and 9165 (82.7%) proximal DVT (Table 1). Among the various clinical parameters identified to be potential risk factors for either isolated distal DVT or proximal DVT on univariate analyses, the multivariate analysis confirmed that recent travel, hospitalization, recent surgery and the presence of leg varicosities independently increased the risk of isolated distal DVT (P < 0.01) (Table 1). In contrast, the risk of proximal DVT was significantly increased in pregnant or postpartum women, in elderly patients (≥75 years), and in patients with active cancer, recent major bleeding or a personal history of VTE (P < 0.01). Of patients with isolated distal DVT, 89.1% (n = 1680/1885) were treated with anticoagulant therapy (low molecular weight or unfractionated heparins, fondaparinux, vitamin K antagonists) during the entire follow-up, and 0.7% (n = 14/1921) was treated with a vena cava filter (Table 2). At 3 months, the overall rates of VTE recurrence, major bleeding and death were 2.6% (n = 287), 2.0% (n = 218) and 6.7% (n = 741), respectively (Table 3). The cumulative rates of major bleeding, recurrent VTE and death were significantly lower (plog rank ≤ 0.05) in patients who initially exhibited isolated distal DVT than in those who initially presented with proximal DVT (Fig. 1). Kaplan–Meier analysis of time to venous thromboembolism recurrence (A), major bleeding (B) and death (C) according to the type of index deep vein thrombosis (isolated distal vs. proximal deep vein thrombosis). Of the patients with isolated distal DVT, 2.9% (2/70) were left untreated or were treated for < 10 days. Of the isolated distal DVT patients that were treated for more than 10 days, 1.9% (36/1851) exhibited a recurrence of VTE (P = 0.59). On univariate analysis, active cancer, age ≥ 75 years, in-patient status, bed confinement, recent surgery, recent major bleeding and obesity were found to potentially either increase or decrease the risk of death at 3 months (Table S1). The multivariate analysis confirmed that three parameters independently increased the risk of death: active cancer (OR=16.5 (95% CI: 8.8–31.0); P < 0.001), age ≥ 5 years (OR= 3.8 (95% CI: 2.1–6.9); P = 0.001) and confinement to bed (OR=2.3 (95% CI: 1.2–4.4); P = 0.01). The RIETE registry provided us with a large prospective series of consecutive patients with symptomatic VTE. The vast majority of these patients were treated with anticoagulant drugs during the entire follow-up period. Using these patients, our data demonstrated substantial differences in clinical status and early outcomes between patients with isolated distal DVT and those with proximal DVT. Among patients with different types of DVT (asymptomatic DVT, symptomatic DVT with and without PE), we showed that isolated distal DVT and proximal DVT do not share the same risk factors profile. Isolated distal DVT was more associated with transient risk factors, whereas proximal DVT was more associated with chronic risk factors [1, 13, 15, 19]. This finding suggests that there are differences between the proximal and distal DVT populations. The 3-month adverse clinical outcome results provide information on distal DVT response to treatment, and in turn suggest possible lines of management. First, the significant lower mortality rate amongst patients with isolated distal DVT only serves to illustrate their better clinical status. This was reflected by the difference in terms of mortality mainly being due to non-VTE related deaths (2.2% vs. 6.3%; P < 0.001). Cancer appears to be a key element in the vital prognosis of patients with isolated distal DVT, as those patients with cancer (main independent predictive factor of death among this population in RIETE) exhibited a 3-month mortality rate that was even higher than the global mortality rate of those patients with proximal DVT, but without cancer (12.9% vs. 7.5%, respectively, P = 0.001). In the study by Bernardi et al., the estimation of the spontaneous rate of proximal extension of isolated distal DVT was as high as 21.5% (14/65). This could be linked to the profile of the population studied, which had a particularly high incidence of cancer: 29% (607/2098) [9, 20]. Similarly, Macdonald et al. [14] provided evidence that cancer was the only predictive factor of spontaneous proximal extension of muscular distal DVT. We were unable to confirm these latter findings, as our study was not appropriate to identify factors predictive of VTE recurrence due to the large majority of isolated distal DVT patients receiving anticoagulant treatment during the whole follow-up. Thus, cancer is the main predictive factor of death and probably also of proximal extension of isolated distal DVT. This would seem to be the main element of stratification of isolated distal DVT clinical prognosis. Whether cancer status should influence distal DVT management (detection and treatment) remains to be determined. The 3-month DVT recurrence rates for those patients receiving anticoagulant treatment were similar in both isolated distal DVT and in proximal DVT patients (2.0% vs. 2.7%, P = 0.07). Our inability to find a statistically significant difference between these patients despite their different profiles of risk factors may be the consequence of: (i) almost all DVT patients being treated with anticoagulant therapies, notably proximal DVT, protecting them from a greater likelihood of recurrence, and isolated distal DVT patients being slightly but significantly less treated with anticoagulant drugs; (ii) our follow-up being too short to evidence a possible difference; and (iii) a possible lack of statistical power of our study. Although no conclusion can be drawn from this registry about the natural history of isolated distal DVT, our results nevertheless provide insight into VTE potential. Our study cannot answer the still contentious key question of whether or not isolated distal DVT should be treated with anticoagulant drugs [6-8]. However, it does indicate that proximal and isolated distal DVT populations are likely to differ from each other. They also probably differ in their ability to tolerate anticoagulant treatment, as illustrated by the lower rate of major bleeding among patients with isolated distal DVT (1.0% vs. 2.0%, P < 0.002). This lower rate of bleeding among distal DVT patients is multifactorial. This is probably a result of their better clinical status, but also because they have been slightly but significantly less treated with anticoagulant drugs and possibly with a lower intensity treatment. It is therefore inappropriate to extrapolate data from therapeutic trials on proximal DVT for the management of isolated distal DVT. New specific therapeutic studies focusing on isolated distal DVT are now necessary to address this issue. Our study presents a number of strengths and limitations. It clearly focused on a well-defined group of patients (i.e. patients with symptomatic isolated distal DVT or proximal DVT without symptomatic PE). The results were obtained from the largest prospective and adequately validated registry of patients with objectively confirmed VTE [21]. The type and quality of diagnostic procedures were not controlled, but the proportions of patients with isolated distal (17.3%) vs. proximal DVT (82.7%) were comparable with those reported in the majority of studies in this setting, indicating that distal DVT was likely to be appropriately diagnosed 7, 9, 22. The 6.7% death rate is in the upper range of the rates reported in recent clinical trials, but unlike these studies, the RIETE registry imposes no disease-related exclusion criteria for the recruitment of patients with DVT 10, 11, 22. The registry indeed reflects the ‘real world’ of patients with symptomatic VTE, managed according to the current practises prevalent in the participating countries (France, Israel, Italy and Spain). A longer follow-up would be necessary to study long-term complications after discontinuation of anticoagulant treatments. The intensity of the anticoagulant treatment was not taken into account, but the analysis of such data when no therapeutic protocol is imposed is a complex issue. In conclusion, our study provides evidence that the characteristics of the patients and the 3-month clinical outcomes for those patients receiving anticoagulant treatment for proximal and isolated distal DVT are different. This suggests that specific therapeutic studies on isolated distal DVT are now required to determine an optimal and consensual treatment. Furthermore, the isolated distal DVT patient population was found to be heterogeneous, its prognosis being mainly driven by cancer status at inclusion. Whether or not isolated distal DVT management (detection and/or treatment) should be stratified according to cancer status requires further studies. We express our gratitude to Sanofi-Aventis Spain for supporting this Registry with an unrestricted educational grant. We also express our gratitude to Bayer Schering Pharma for supporting this Registry. Bayer Schering Pharma’s support was limited to the international part of RIETE (excluding patients from Spain), which accounts for 9.8% of the total patients included in the RIETE Registry. We also thank the Registry Coordinating Center, S & H Medical Science Service, for their quality control, and logistic and administrative support. The authors state that they have no conflict of interest. This study was supported by grants from Sanofi-Aventis and Bayer Schering Pharma. The funding source was not involved in the design of the study, the collection, analysis or interpretation of the data, the writing of the report, or the decision to submit this paper for publication. The corresponding author, Jean-Philippe Galanaud, had full access to all the data in the study and had final responsibility for the decision to submit this article for publication. Spain: Alcalde M, Arcelus JI, Barba R, Blanco A, Barrón M, Casado I, Cañas I, Cisneros E, Conget F, Fernández-Capitán C, Gabriel F, Gallego P, García-Bragado F, Grau E, Guil M, Gutiérrez J, Hermosa MJ, Hernández L, Herrera S, León JM, Lobo JL, López L, Lorenzo A, Luque JM, Madridano O, Maestre A, Marchena PJ, Martín-Villasclaras JJ, Monreal M, Montes J, Muñóz FJ, Naufall MD, Nieto JA, Oribe M, Portillo J, Riera A, Ruiz-Gamietea A, Ruiz-Giménez N, Sahuquillo JC, Samperiz AL, Sánchez Muñoz-Torrero JF, Sánchez R, Sandoval R, Soler S, Tiberio G, Tirado R, Todolí JA, Tolosa C, Trujillo J, Uresandi F, Valdés V, Valle R, Vasco B, Vela J.. France: Rivron-Guillot K, Boccalon H, Falvo N, Quere I, Szwebel TA. Israel: Brenner B. Italy: Di Micco P, Duce R, Poggio R, Prandoni P, Schenone A, Tiraferri E, Visonà A. Table S1. Prognostic factors for death at three months after an initial distal deep vein thrombosis (univariate analysis). Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.