Recurrence risk of idiopathic venous thromboembolism

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Franco-Moreno, C.L. de Ancos-Aracil, M.J. García-Navarro" "autores" => array:3 [ 0 => array:4 [ "nombre" => "A.I." "apellidos" => "Franco-Moreno" "email" => array:1 [ 0 => "aifranco@torrejonsalud.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "C.L." "apellidos" => "de Ancos-Aracil" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "M.J." "apellidos" => "García-Navarro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Medicina Interna, Hospital Universitario de Torrejón, Torrejón de Ardoz, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Medicina Interna, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Riesgo de recurrencia en el tromboembolismo venoso idiopático" ] ] "textoCompleto" => "BackgroundPatients who have experienced a first episode of venous thromboembolism disease (VTE), in any of its 2 variants (deep vein thrombosis [DVT] and pulmonary embolism [PE]), have a greater risk of presenting a new thromboembolic episode after discontinuing the anticoagulation therapy. In a systematic review,<a class="elsevierStyleCrossRef" href="#bib0280">1</a> the recurrence rate was 10% annually and 30% at 5 years. The risk is also increases among those patients with permanent risk factors compared to those with temporary risk factors or in cases of idiopathic VTE.<a class="elsevierStyleCrossRefs" href="#bib0285">2–4</a> After approximately 3 months of anticoagulant therapy, patients with unprovoked VTE should be assessed for the need to extend the therapy to prevent the recurrence of new thromboembolic episodes. Moreover, the decision to extend the anticoagulation therapy depends not only on the risk of recurrence but also on the hemorrhagic risk. The mortality due to thrombotic recurrence and hemorrhage in the acute phase is similar. However, mortality due to VTE decreases in the long term, while mortality caused by hemorrhage persists and can be much higher than that resulting from a thrombotic recurrence.<a class="elsevierStyleCrossRef" href="#bib0300">5</a> Consequently, the recently published guidelines from the American College of Chest Physicians recommend that patients with pulmonary embolism and/or idiopathic proximal DVT should undergo long-term anticoagulant treatment if the risk of hemorrhage is low or moderate. The guidelines suggest a duration of only 3 months for those patients with a high risk of hemorrhage.<a class="elsevierStyleCrossRef" href="#bib0305">6</a> The ability to correctly determine the risk of recurrence after withdrawing anticoagulation therapy in idiopathic VTE is therefore essential for deciding on the optimal duration for anticoagulation therapy.Strategies for identifying patients with a high risk of recurrence in idiopathic venous thromboembolismA number of clinical variables, such as the male sex,<a class="elsevierStyleCrossRefs" href="#bib0310">7–10</a> when combined with laboratory data, such as dimer-d,<a class="elsevierStyleCrossRefs" href="#bib0330">11,12</a> can help identify a subgroup with greater risk of recurrence. In contrast, the persistence of residual DVT does not appear to be associated, unequivocally at least, with a greater risk of recurrence.<a class="elsevierStyleCrossRefs" href="#bib0340">13,14</a> The presence of congenital thrombophilia (antithrombin, protein C [PC] and protein S [PS] deficiency; activated protein C resistance; prothrombin gene mutation G20210A [PGM]; dysfibrinogenemia; increased coagulation factors VIII, IX and XI; presence of antiphospholipid antibodies [lupus anticoagulant, anticardiolipin and anti-ß2-glycoprotein]) have also shown a significant association with the risk of VTE recurrence, except for combined defects or very high-risk defects (antithrombin, PC and PS deficiency or antiphospholipid syndrome).<a class="elsevierStyleCrossRefs" href="#bib0350">15–18</a> A number of studies are currently underway to identify new predictors of recurrence risk, which could contribute to selecting those patients who require extended anticoagulant treatment. For example, the thrombotic disease workgroup of the Spanish Society of Thrombosis and Hemostasis is conducting a sequential, retrospective prospective study that, through the use of expression arrays, seeks new genetic markers predictive of recurrence.<a class="elsevierStyleCrossRef" href="#bib0370">19</a>At this time, the duration of anticoagulation therapy is based on the presence of a number of risk factors and the use of scales that predict thrombotic recurrence, and these are reviewed below.Risk factorsClinical risk markersMen are at greater risk of recurrence, although the mechanism responsible is not known. Kyrle et al.<a class="elsevierStyleCrossRef" href="#bib0375">20</a> analyzed the incidence rate of recurrent VTE in a cohort of patients who had experienced a first episode of idiopathic venous thromboembolism, followed-up prospectively for 36 months after discontinuing the anticoagulation therapy. The recurrence rate was 3.6-fold higher in men than in women (relative risk [RR] 3.6%; 95% confidence interval [95% CI] 2.3–5.5). This difference remained significant after adjusting for age and the presence of thrombophilia. Subsequent studies have confirmed this datum.<a class="elsevierStyleCrossRefs" href="#bib0310">7,8,21,22</a> In the recurrence prediction models developed by Eichinger et al.<a class="elsevierStyleCrossRef" href="#bib0380">21</a> and Tosetto et al.,<a class="elsevierStyleCrossRef" href="#bib0385">22</a> the male sex was independently associated with relapses. Two recent meta-analyses<a class="elsevierStyleCrossRefs" href="#bib0310">7,8</a> have confirmed the greater risk in men of undergoing VTE relapses after discontinuing the anticoagulation therapy. In the first meta-analysis, which included 15 studies and a total of 5416 patients with a first episode of idiopathic venous thromboembolism, the risk was 1.4-fold greater among the men (RR, 1.4%; 95% CI 1.17–1.68).<a class="elsevierStyleCrossRef" href="#bib0310">7</a> In the second, which included 7 studies and 2554 patients with unprovoked VTE, the increased risk of recurrence in the male sex was double (RR, 2.2%; 95% CI 1.7–2.8).<a class="elsevierStyleCrossRef" href="#bib0315">8</a>Excess weight and obesity also increased the risk of VTE recurrence.<a class="elsevierStyleCrossRefs" href="#bib0390">23,24</a> An Austrian study on 1107 patients with idiopathic VTE, who were monitored for a mean of 46 months after discontinuing anticoagulation, found that the recurrence rate increased from 9.3% (95% CI 6–12.7) to 16.7% (95% CI 11–22.3) and 17.5% (95% CI 13–22), for body mass indices (BMI) ≤25kg/m2, between 25 and 30kg/m2 and ≥30kg/m2, respectively.<a class="elsevierStyleCrossRef" href="#bib0400">25</a> In this study, the RR for patients with obesity was 1.6 (95% CI 1.1–2.4) and reached statistical significance. Several studies have demonstrated an independent association between obesity and the recurrence risk of thromboembolism.<a class="elsevierStyleCrossRefs" href="#bib0405">26,27</a> In the study by Olié et al.,<a class="elsevierStyleCrossRef" href="#bib0405">26</a> which analyzed a prospective cohort of patients with idiopathic VTE, the multiple regression analysis showed a 2.8-fold greater risk among women with a BMI≥30kg/m2 than the patient group with normal weight (RR, 2.8%; 95% CI 1.3–6).The initial presentation of VTE, either PE or DVT, does not appear to be clearly associated with the recurrence risk. Eichinger et al.<a class="elsevierStyleCrossRef" href="#bib0380">21</a> observed twice the risk among patients who debuted with PE compared with those who started with DVT. Other studies, such as the one by Prandoni et al.<a class="elsevierStyleCrossRef" href="#bib0290">3</a> observed an increase in recurrence risk among patients with DVT compared with those with PE (RR 1.5%; 95% CI 1–2.2). A meta-analysis that included 7 studies and 2925 patients found a similar recurrence rate, regardless of whether the initial presentation was PE or DVT.<a class="elsevierStyleCrossRef" href="#bib0415">28</a> However, among the patients whose index episode was a PE, the probability of recurrence as PE, compared with DVT, was 3–4-fold greater.<a class="elsevierStyleCrossRefs" href="#bib0420">29,30</a> Consequently, extended anticoagulation could be more appropriate for selected patients with a limited cardiopulmonary reserve who began with PD because a second episode would imply greater severity. A distal location for a DVT is associated with a lower recurrence rate than proximal DVT or PE.<a class="elsevierStyleCrossRef" href="#bib0415">28</a>The presence of residual DVT as a predictor of recurrence is a controversial subject. The DACUS study<a class="elsevierStyleCrossRef" href="#bib0430">31</a> investigated the significance of residual DVT after completing 3 months of anticoagulation therapy in patients with proximal DVT. One hundred-eighty patients presented residual DVT (detected by venous Doppler echocardiography), 88 of whom had had their anticoagulant therapy extended for 9 more months, while the remaining 92 had had their therapy discontinued. Seventy-eight patients presented no residual DVT. In the group with residual DVT, recurrence occurred in 23.3% of the cases. Of these, 27.3% occurred in the patient group that stopped the anticoagulation, and 19.3% occurred in those patients whose anticoagulant therapy was extended (RR, 1.58; 95% CI 0.85–2.93; p=.145). The recurrence in the group without residual DVT was 1.3%. The RR among the patients with and without residual DVT was 24.9 (95% CI 3.4–183.6; p=.002). The extension of the DACUS study<a class="elsevierStyleCrossRef" href="#bib0435">32</a> also showed an increased recurrence risk in patients with residual DVT. In this study, 136 patients without residual DVT completed 3 months of anticoagulation, while for the 273 patients who had residual DVT, the treatment was extended by 21 months. After a mean follow-up of 2 years, the group without residual DVT had a recurrence rate of 1.4% compared with the 10.4% from the group with residual DVT, despite the longer treatment duration (RR, 7.4; 95% CI 4.9–9.9; p=.0026). Prandoni et al., in the AESOPUS study,<a class="elsevierStyleCrossRef" href="#bib0440">33</a> observed a lower recurrence rate in patients with residual DVT treated for 21 months compared with those treated for only 9 months (RR, 0.62; 95% CI 0.39–0.97). In contrast to the previous studies, the REVERSE study<a class="elsevierStyleCrossRef" href="#bib0445">34</a> found no difference in recurrence among the patients with or without residual DVT. A meta-analyses of 14 studies that included 3203 patients with residual DVT (with a mean follow-up of 1–3 years after discontinuing the anticoagulation) found an increased recurrence risk only in patients with DVT in the proximal territory, which, however, did not achieve statistical significance.<a class="elsevierStyleCrossRef" href="#bib0340">13</a> The recent meta-analysis by Donnadini et al.<a class="elsevierStyleCrossRef" href="#bib0450">35</a> included 10 studies with a prospective, observational cohort design, with a total of 2527 patients with idiopathic DVT followed-up for a mean of 23.3 months. Among the 1380 patients with residual DVT, the DVT reoccurred in 399 patients (15.8%), and the RR compared with the patients without residual DVT was 1.32% (95% CI 1.06–1.65; p=.01). The recurrence risk was greater among the patients in whom the residual DVT was detected in the first 3 months after the DVT diagnosis (RR, 2.17%; 95% CI 1.11–4.25; p=.087).Laboratory testsThe patients with persistently high d-dimer concentrations during the anticoagulant therapy had a greater risk of recurrence. In the PROLONG trial,<a class="elsevierStyleCrossRef" href="#bib0455">36</a>d-dimer was measured one month after discontinuing the anticoagulant therapy in 608 patients with DVT or idiopathic PE. The results of the d-dimer test were positive for 223 patients (36.7%). After a follow-up of 1.4 years, the number of recurrences was significantly higher among the patients with high d-dimer levels who discontinued the anticoagulant therapy than among those with high d-dimer levels who restarted the anticoagulation (15% vs. 2.9%; RR, 4.26; 95% CI 1.23–14.6; p=.02) or who had normal d-dimer levels (15% vs. 6.2%; RR, 2.27; 95% CI 1.15–4.46; p=.02). In another study of 610 patients with a first episode of idiopathic VTE, d-dimer levels were measured 3 weeks after discontinuing the anticoagulant therapy.<a class="elsevierStyleCrossRef" href="#bib0460">37</a> The cumulative probability of recurrence after 2 years of follow-up was 3.7% (95% CI 0.9–6.5) in the patients with d-dimer levels <250ng/mL compared with 11.5% (95% CI 8–15) in those with d-dimer levels >250ng/mL (p=.001). Lastly, the largest published meta-analysis, which analyzed 7 studies that included 1888 patients, found that the recurrence rate after discontinuing anticoagulant therapy was 8.9% (95% CI 5.8–11.9) for the patients with a positive d-dimer result, compared with 3.5% (95% CI 2.7–4.3) for those who had negative results (p=.002).<a class="elsevierStyleCrossRef" href="#bib0465">38</a> The d-dimer measurement was performed between 3 weeks and 2 months after discontinuing the treatment and employed high-sensitivity techniques with different cutoff points for a positive value (>500mg/L and >250mg/L). The d-dimer measurement should be performed after a washout period of 3–4 weeks after completing the anticoagulant therapy to ensure that the therapy does not affect the d-dimer results.<a class="elsevierStyleCrossRef" href="#bib0335">12</a>Congenital and acquired thrombophilia increases the risk of a first thrombotic event, but it is unclear whether it is associated or increases the recurrence risk.<a class="elsevierStyleCrossRef" href="#bib0420">29</a> The studies by Tosetto et al.<a class="elsevierStyleCrossRef" href="#bib0385">22</a> and Rodger et al.<a class="elsevierStyleCrossRef" href="#bib0410">27</a> showed that the presence of factor V Leiden (FVL) or of PGM was not associated with an increased recurrence risk of VTE. In the Eichinger et al. model,<a class="elsevierStyleCrossRef" href="#bib0380">21</a> only FVL was associated with a slight increase in risk (RR, 1.68; 95% CI 1–2.71; p=.106). The Segal et al. series<a class="elsevierStyleCrossRef" href="#bib0470">39</a> found a weak association between heterozygosity for FVL and the recurrence of thrombosis (RR, 1.56; 95% CI 1.14–2.12; p=.005), which increased among the homozygotes (RR, 2.65; 95% CI 1.2–6; p=.08). In the above study, PGM was not associated with an increased recurrence risk. The antiphospholipid syndrome has been equated to acquired thrombophilia, which predisposes to relapses.<a class="elsevierStyleCrossRefs" href="#bib0475">40,41</a> Schulman et al. showed that patients with high anticardiolipin antibodies titers have twice the risk of VTE.<a class="elsevierStyleCrossRef" href="#bib0475">40</a> Other studies of patients with idiopathic VTE have also shown that the recurrence risk increased up to 4-fold among patients with positive antiphospholipid antibodies (RR, 3.94; 95% CI 1.83–8.48; p=.03).<a class="elsevierStyleCrossRef" href="#bib0485">42</a> A series of 2479 patients with a first episode of VTE and CP, SP or antithrombin deficiency observed recurrence rates of 6% at 1 year, 19% at 2 years, 40% at 5 years and 55% at 10 years after discontinuing the anticoagulation therapy (RR at 1 year for CP deficiency, 1.52; 95% CI 1.06–2.11; p=.001; for SP deficiency, 1.90; 95% CI 1.32–2.64; p=.001; and for antithrombin deficiency, 1.77; 95% CI 1.14–2.60; p=.001).<a class="elsevierStyleCrossRef" href="#bib0355">16</a> There were no differences between the patients with a first idiopathic episode or a provoked event. A number of studies have stated that hyperhomocysteinemia could be associated with an increased risk of VTE,<a class="elsevierStyleCrossRefs" href="#bib0490">43,44</a> although others have suggested that this is an epiphenomenon.<a class="elsevierStyleCrossRefs" href="#bib0500">45,46</a> We found only one study that analyzed the prognostic relationship between homocysteine concentrations and the recurrence risk in idiopathic VTE.<a class="elsevierStyleCrossRef" href="#bib0510">47</a> This was a multicenter study that included 264 patients and monitored the homocysteine concentrations after anticoagulant therapy suppression. Concentrations that exceeded the 95th percentile of the control group were considered high. After 24 months of follow-up, the number of recurrences was significantly greater in the patient group with hyperhomocysteinemia (18.2% vs. 8.1%), with a cumulative probability of recurrence of 19.2% (RR, 2.7; 95% CI 1.3–5.8; p=.009). An increase in factor VIII activity above 150% was considered an independent marker of thrombotic risk. The study by Legnani et al.<a class="elsevierStyleCrossRef" href="#bib0515">48</a> is the only one to date that has evaluated the impact of factor VIII activity on VTE recurrence. Those patients with an activity greater than the 90th percentile showed an increased recurrence risk 5-fold greater than that of the control group (RR, 5.43%; 95% CI 1.76–16.8; p=.0097). The relationship between thrombophilia and VTE recurrence was evaluated in the MEGA study,<a class="elsevierStyleCrossRef" href="#bib0520">49</a> which consecutively included 474 patients with a first episode of unprovoked VTE. After discontinuing the anticoagulation therapy, laboratory tests for thrombophilia were performed using the measurement of FVL, PGM, and the concentrations and activity of CP and SP, antithrombin, factors VIII-IX-XI, fibrinogen and homocysteine. During a mean follow-up of 7.3 years, 90 patients experienced recurrences. The factors associated with the recurrences were CP, SP or antithrombin deficiency (RR, 1.8; 95% CI 0.9–3.7) and the combined defects (RR, 1.6%; 95% CI 1.0–2.7). Nevertheless, most experts do not recommend the routine thrombophilia studies.<a class="elsevierStyleCrossRefs" href="#bib0350">15,50–52</a> Hypercoagulability screening might be justified for young patients with a personal or family history of thrombosis, for thrombosis of unusual location or when associated with pregnancy and for women with unexplained pregnancy complications.<a class="elsevierStyleCrossRef" href="#bib0540">53</a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows a summary of the main risk factors for recurrence in unprovoked VTE.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Predictive modelsSeveral authors have tried to define models to assess the risk of unprovoked VTE recurrence after discontinuing anticoagulation therapy. However, external validation is needed to understand their actual usefulness in clinical practice. These models include the following scales: MEN continue and HER DOO2 (Gender, Hyperpigmentation, Edema, Redness, d-dimer, Obesity, Older age),<a class="elsevierStyleCrossRef" href="#bib0410">27</a> Vienna<a class="elsevierStyleCrossRef" href="#bib0380">21</a> and DASH (d-dimer, Age, Sex, Hormonal therapy).<a class="elsevierStyleCrossRef" href="#bib0385">22</a>The Canadian model MEN continue and HER DOO2 was developed based on data from the REVERSE study performed at the University of Ottawa.<a class="elsevierStyleCrossRef" href="#bib0410">27</a> The study included 646 patients with a first episode of idiopathic VTE treated with anticoagulants for a minimum period of 5–7 months and a mean follow-up of 18 months. Up to 69 predictors of potential recurrence were analyzed. d-dimer and thrombophilia tests were performed during the anticoagulation therapy. Ninety-one (15.16%) relapses occurred in the 600 patients who completed the follow-up. The variables associated with a greater risk of recurrence were an age of 65 years or older, a high d-dimer level (≥250μg/L), clinical signs of post-thrombotic syndrome and obesity (BMI≥30kg/m2). According to this scale (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>), indefinite anticoagulation should be considered for men with 1 or more risk factors and for women with 2 or more risk factors, because its annual recurrence risk would be 9.9% (95% CI 8.3–11.8; p<.05) and 8.3% (95% CI 5.7–11.3; p<.05) for men and women, respectively. For men with no risk factors and women with one or no risk factors, discontinuing the anticoagulation therapy after a period of 3–6 months could be considered, because the annual recurrence risk was 1.3% (95% CI 0.5–2.8). Nevertheless, this scale is being validated in the REVERSE II study, whose results have yet to be published.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Eichinger et al.<a class="elsevierStyleCrossRef" href="#bib0380">21</a> developed a nomogram to predict the recurrence risk in patients with a first episode of idiopathic VTE, based on the results of a prospective cohort study of 929 patients with a first episode of unprovoked VTE, followed-up for 43.3 months after discontinuing the anticoagulation therapy. There was VTE recurrence in 176 patients (18.9%), most cases of which were idiopathic (90.90%). The clinical and laboratory variables analyzed were age, sex, location of the thrombosis, BMI, thrombin generation test, thrombophilia tests (FVL and PGM) and d-dimer concentration 3 weeks after completing the anticoagulant therapy. The variables associated with a greater recurrence risk were the male sex (RR, 1.90; 95% CI 1.31–2.75; p=.001), the presence of proximal DVT vs. distal DVT (RR, 2.08; 95% CI 1.16–3.74; p=.01), PE vs. distal DVT (RR, 2.60; 95% CI 1.49–4.53; p=.001) and a high d-dimer concentration (RR, 1.27; 95% CI 1.08–1.51; p=.005). A nomogram was developed with these variables, which, using a scale, estimated the cumulative probability of recurrence in an individual patient (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). This scale has been tested in an independent population.<a class="elsevierStyleCrossRef" href="#bib0545">54</a> In its prospective validation, the model discriminated well the recurrence risk in the study population except among the elderly patients.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>The DASH scale also assessed the recurrence risk of unprovoked VTE.<a class="elsevierStyleCrossRef" href="#bib0385">22</a> The model included 2554 patients from 7 meta-analyses but excluded 727 of these patients diagnosed with nonidiopathic VTE and 9 others who had no d-dimer reading 3–5 weeks after discontinuing the anticoagulant therapy. This left a total of 1818 patients with idiopathic VTE treated for at least 3 months with anticoagulation and followed-up for an average of 22.4 months. There were recurrences in 13.14% of the patients. The following variables were analyzed: age, sex, BMI, use of hormonal contraceptives or hormone therapy replacement (in women), the presence of thrombophilia, a high d-dimer concentration after discontinuing the anticoagulation and the duration of the anticoagulant therapy (which lasted a mean of 6.7 months in the 2 groups; in those who relapsed and those who did not). The multivariate analysis showed that the main predictors of recurrence were an age younger than 50 years, the male sex and a high d-dimer level. In women, the presence of VTE associated with hormone replacement therapy or hormonal contraceptives was considered a protective factor (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). The authors concluded that a DASH score ≤1, which in the study represented a low annual recurrence risk (3.1%, 95% CI 2.3–3.9; p=.0001), could justify discontinuing the anticoagulation therapy after 3 to 6 months. In contrast, maintaining the anticoagulation for a longer period should be considered for DASH scores ≥2 (RR, 9.3%; 95% CI 8.1–10.8; p=.0001). Nevertheless, this scale has yet to be validated.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Of the 3 models (MEN continue and HER DOO2, Vienna and DASH), the design of DASH<a class="elsevierStyleCrossRef" href="#bib0385">22</a> stands apart. It included more patients and was developed based on a meta-analysis. Given that the study was retrospective, as indicated by the authors, there could have been biases inherent in this type of design. In addition, the study included women undergoing hormonal treatment. According to the guidelines of the American College of Chest Physicians, estrogen hormone therapy is a risk factor associated with VTE (RR, 2.96), which would be incompatible with a diagnosis of idiopathic VTE.<a class="elsevierStyleCrossRef" href="#bib0550">55</a> For these reasons, the usefulness of the DASH model for assessing thrombosis recurrence in patients with idiopathic VTE is questionable. The MEN continue and HER DOO2<a class="elsevierStyleCrossRef" href="#bib0410">27</a> and the Vienna<a class="elsevierStyleCrossRef" href="#bib0380">21</a> predictive models, in contrast, were developed with cohorts of patients with exclusively idiopathic VTE. From the comparative analysis of the 2 models, we can deduce that the Vienna model,<a class="elsevierStyleCrossRef" href="#bib0380">21</a> which was developed with more patients and had a longer follow-up period, presents the best profile for applicability to clinical practice because it contains fewer predictive variables, and the variables are not subjective. Nevertheless, the Vienna model has the disadvantage that d-dimer was treated as a continuous variable after its measurement using the ELISA technique (Asserachrom d-dimer, Boehringer Mannheim, Germany). The model is therefore not applicable to cases in which d-dimer is determined by different methods (quantitative, semiquantitative or qualitative latex).ConclusionsVTE is associated with significant long-term morbidity, such as recurrent VTE, for example.<a class="elsevierStyleCrossRef" href="#bib0290">3</a> Anticoagulant therapy reduces this risk significantly but does so at the expense of increasing the risk of hemorrhage.<a class="elsevierStyleCrossRef" href="#bib0300">5</a> Between 30% and 50% of VTE cases are idiopathic and have a greater recurrence risk.<a class="elsevierStyleCrossRefs" href="#bib0280">1,3,4</a> Therefore, the clinical guidelines of the American College of Chest Physicians<a class="elsevierStyleCrossRef" href="#bib0305">6</a> suggest that patients with proximal DVT or idiopathic PE should undergo anticoagulant therapy for prolonged periods, provided the risk of hemorrhage is low or moderate, limiting the anticoagulant therapy to 3 months if the risk of hemorrhage is high.<a class="elsevierStyleCrossRef" href="#bib0305">6</a> Nevertheless, the presence or absence of risk factors for recurrence and a number of the models described help further individualize this generic recommendation. A number of risk markers such as the male sex, the presence of high-risk thrombophilia and a high d-dimer level should be considered when planning the duration of anticoagulant therapy. The Vienna model<a class="elsevierStyleCrossRef" href="#bib0380">21</a> could also be employed to assess the need for extending the anticoagulation in secondary prevention. Lastly, the patient's preferences should also be taken into account when deciding on the duration of the anticoagulant therapy.<a class="elsevierStyleCrossRef" href="#bib0305">6</a>Conflict of interestsThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres763843" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec765214" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres763842" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec765215" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Strategies for identifying patients with a high risk of recurrence in idiopathic venous thromboembolism" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0015" "titulo" => "Risk factors" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical risk markers" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Laboratory tests" ] ] ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Predictive models" ] ] ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interests" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec765214" "palabras" => array:4 [ 0 => "Venous thromboembolism disease" 1 => "Recurrence" 2 => "Risk factor" 3 => "Clinical prediction" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec765215" "palabras" => array:4 [ 0 => "Enfermedad tromboembólica venosa" 1 => "Recurrencia" 2 => "Factor de riesgo" 3 => "Predicción clínica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "For patients with idiopathic venous thromboembolism (unprovoked), the risk of recurrence is high. Secondary prophylaxis with anticoagulant therapy reduces the thrombotic risk but at the expense of an increased risk of hemorrhage. A number of factors, such as the male sex and an increase in dimer-d concentrations after completing the anticoagulation therapy, are associated with an increased risk of recurrence. Other factors such as residual venous thrombosis have a more controversial and sometimes contradictory relationship. A number of models have been proposed for predicting thrombotic recurrence risk after anticoagulation therapy in unprovoked venous thromboembolism. However, these models need external validation to determine their current usefulness in clinical practice. In this article, we analyze the risk factors for thrombotic recurrence and the existing prediction models." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "En pacientes con enfermedad tromboembólica venosa idiopática (no provocada) el riesgo de recurrencia es elevado. La profilaxis secundaria con terapia anticoagulante reduce el riesgo trombótico, pero a expensas de un incremento del riesgo de hemorragias. Algunos factores, como el sexo masculino o una elevación de la concentración de dímero-D tras finalizar la anticoagulación, se asocian a un mayor riesgo de recidiva; otros, como la trombosis venosa residual, tienen una relación más controvertida, incluso contradictoria. Se han propuesto algunos modelos de predicción del riesgo de recurrencia trombótica tras la anticoagulación en la enfermedad tromboembólica venosa (ETEV) no provocado, pero necesitan una validación externa para conocer su utilidad real en la práctica clínica. En este artículo se analizan los factores de riesgo de recidiva trombótica y los modelos de predicción existentes." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Franco-Moreno AI, de Ancos-Aracil CL, García-Navarro MJ. Riesgo de recurrencia en el tromboembolismo venoso idiopático. Rev Clin Esp. 2016;216:488–494." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factor \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male sex \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Obesity (body mass index >30kg/m2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">History of idiopathic venous thromboembolism disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Residual deep vein thrombosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Positive d-dimer during anticoagulation and after withdrawing the anticoagulant treatment<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Thrombophilia<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1261814.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Based on the cutoffs for the various quantitative and qualitative techniques for measuring it (agglutination in latex, plate enzyme immunoanalysis, agglutination from whole blood)." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "C protein deficiency, S protein deficiency or antithrombin deficiency, presence of antiphospholipid antibodies or combined defects." ] ] ] "descripcion" => array:1 [ "en" => "Risk factors for recurrence in unprovoked venous thromboembolism disease.<a class="elsevierStyleCrossRefs" href="#bib0310">7–12,16,23,24,31,32,40–42</a>" ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factor \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Score \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hyperpigmentation of the legs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Edema in the legs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Flushing in the legs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">d-dimer ≥250μg/L<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Body mass index ≥30kg/m2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age ≥65 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1261817.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "d-Dimer measured during anticoagulation." ] ] ] "descripcion" => array:1 [ "en" => "MEN continue and HER DOO2 model (gender, HER, d-dimer, obesity, older age).<a class="elsevierStyleCrossRef" href="#bib0410">27</a>" ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "DVT, deep vein thrombosis." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factor \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male sex>female \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Presentation of thrombosis: pulmonary embolism>proximal DVT>distal DVT distal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">d-dimer<a class="elsevierStyleCrossRef" href="#tblfn0020">a</a>: greater concentration=greater risk \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1261815.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "a" "nota" => "d-Dimer measured 3 weeks after discontinuing the anticoagulation. Considered positive with a value≥100μg/L determined using ELISA technique (Asserachrom d-dimer, Boehringer Mannheim, Germany). Vienna prediction model online calculator version 2.0 [consulted 27 Nov 2012]. Available at: <a class="elsevierStyleInterRef" id="intr0005" href="http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/">http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/</a>." ] ] ] "descripcion" => array:1 [ "en" => "Vienna prediction model.<a class="elsevierStyleCrossRef" href="#bib0380">21</a>" ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factor \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Score \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">High d-dimer<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age<50 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Venous thromboembolism disease associated with hormone therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−2 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1261816.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "a" "nota" => "d-Dimer measured 3–5 weeks after discontinuing the anticoagulation. 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Recurrence risk of idiopathic venous thromboembolism

Riesgo de recurrencia en el tromboembolismo venoso idiopático

A.I. Franco-Morenoa,

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aifranco@torrejonsalud.com

Corresponding author.

, C.L. de Ancos-Aracilb, M.J. García-Navarroa

a Medicina Interna, Hospital Universitario de Torrejón, Torrejón de Ardoz, Madrid, Spain

b Medicina Interna, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain

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    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Riesgo de recurrencia en el tromboembolismo venoso idiop&#225;tico"
      ]
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Patients who have experienced a first episode of venous thromboembolism disease &#40;VTE&#41;&#44; in any of its 2 variants &#40;deep vein thrombosis &#91;DVT&#93; and pulmonary embolism &#91;PE&#93;&#41;&#44; have a greater risk of presenting a new thromboembolic episode after discontinuing the anticoagulation therapy&#46; In a systematic review&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">1</span></a> the recurrence rate was 10&#37; annually and 30&#37; at 5 years&#46; The risk is also increases among those patients with permanent risk factors compared to those with temporary risk factors or in cases of idiopathic VTE&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">2&#8211;4</span></a> After approximately 3 months of anticoagulant therapy&#44; patients with unprovoked VTE should be assessed for the need to extend the therapy to prevent the recurrence of new thromboembolic episodes&#46; Moreover&#44; the decision to extend the anticoagulation therapy depends not only on the risk of recurrence but also on the hemorrhagic risk&#46; The mortality due to thrombotic recurrence and hemorrhage in the acute phase is similar&#46; However&#44; mortality due to VTE decreases in the long term&#44; while mortality caused by hemorrhage persists and can be much higher than that resulting from a thrombotic recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">5</span></a> Consequently&#44; the recently published guidelines from the American College of Chest Physicians recommend that patients with pulmonary embolism and&#47;or idiopathic proximal DVT should undergo long-term anticoagulant treatment if the risk of hemorrhage is low or moderate&#46; The guidelines suggest a duration of only 3 months for those patients with a high risk of hemorrhage&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">6</span></a> The ability to correctly determine the risk of recurrence after withdrawing anticoagulation therapy in idiopathic VTE is therefore essential for deciding on the optimal duration for anticoagulation therapy&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Strategies for identifying patients with a high risk of recurrence in idiopathic venous thromboembolism</span><p id="par0010" class="elsevierStylePara elsevierViewall">A number of clinical variables&#44; such as the male sex&#44;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">7&#8211;10</span></a> when combined with laboratory data&#44; such as dimer-<span class="elsevierStyleSmallCaps">d</span>&#44;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">11&#44;12</span></a> can help identify a subgroup with greater risk of recurrence&#46; In contrast&#44; the persistence of residual DVT does not appear to be associated&#44; unequivocally at least&#44; with a greater risk of recurrence&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">13&#44;14</span></a> The presence of congenital thrombophilia &#40;antithrombin&#44; protein C &#91;PC&#93; and protein S &#91;PS&#93; deficiency&#59; activated protein C resistance&#59; prothrombin gene mutation G20210A &#91;PGM&#93;&#59; dysfibrinogenemia&#59; increased coagulation factors VIII&#44; IX and XI&#59; presence of antiphospholipid antibodies &#91;lupus anticoagulant&#44; anticardiolipin and anti-&#223;2-glycoprotein&#93;&#41; have also shown a significant association with the risk of VTE recurrence&#44; except for combined defects or very high-risk defects &#40;antithrombin&#44; PC and PS deficiency or antiphospholipid syndrome&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">15&#8211;18</span></a> A number of studies are currently underway to identify new predictors of recurrence risk&#44; which could contribute to selecting those patients who require extended anticoagulant treatment&#46; For example&#44; the thrombotic disease workgroup of the Spanish Society of Thrombosis and Hemostasis is conducting a sequential&#44; retrospective prospective study that&#44; through the use of expression arrays&#44; seeks new genetic markers predictive of recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">19</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">At this time&#44; the duration of anticoagulation therapy is based on the presence of a number of risk factors and the use of scales that predict thrombotic recurrence&#44; and these are reviewed below&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Risk factors</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical risk markers</span><p id="par0020" class="elsevierStylePara elsevierViewall">Men are at greater risk of recurrence&#44; although the mechanism responsible is not known&#46; Kyrle et al&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">20</span></a> analyzed the incidence rate of recurrent VTE in a cohort of patients who had experienced a first episode of idiopathic venous thromboembolism&#44; followed-up prospectively for 36 months after discontinuing the anticoagulation therapy&#46; The recurrence rate was 3&#46;6-fold higher in men than in women &#40;relative risk &#91;RR&#93; 3&#46;6&#37;&#59; 95&#37; confidence interval &#91;95&#37; CI&#93; 2&#46;3&#8211;5&#46;5&#41;&#46; This difference remained significant after adjusting for age and the presence of thrombophilia&#46; Subsequent studies have confirmed this datum&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">7&#44;8&#44;21&#44;22</span></a> In the recurrence prediction models developed by Eichinger et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">21</span></a> and Tosetto et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">22</span></a> the male sex was independently associated with relapses&#46; Two recent meta-analyses<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">7&#44;8</span></a> have confirmed the greater risk in men of undergoing VTE relapses after discontinuing the anticoagulation therapy&#46; In the first meta-analysis&#44; which included 15 studies and a total of 5416 patients with a first episode of idiopathic venous thromboembolism&#44; the risk was 1&#46;4-fold greater among the men &#40;RR&#44; 1&#46;4&#37;&#59; 95&#37; CI 1&#46;17&#8211;1&#46;68&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">7</span></a> In the second&#44; which included 7 studies and 2554 patients with unprovoked VTE&#44; the increased risk of recurrence in the male sex was double &#40;RR&#44; 2&#46;2&#37;&#59; 95&#37; CI 1&#46;7&#8211;2&#46;8&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Excess weight and obesity also increased the risk of VTE recurrence&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">23&#44;24</span></a> An Austrian study on 1107 patients with idiopathic VTE&#44; who were monitored for a mean of 46 months after discontinuing anticoagulation&#44; found that the recurrence rate increased from 9&#46;3&#37; &#40;95&#37; CI 6&#8211;12&#46;7&#41; to 16&#46;7&#37; &#40;95&#37; CI 11&#8211;22&#46;3&#41; and 17&#46;5&#37; &#40;95&#37; CI 13&#8211;22&#41;&#44; for body mass indices &#40;BMI&#41; &#8804;25<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#44; between 25 and 30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> and &#8805;30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">25</span></a> In this study&#44; the RR for patients with obesity was 1&#46;6 &#40;95&#37; CI 1&#46;1&#8211;2&#46;4&#41; and reached statistical significance&#46; Several studies have demonstrated an independent association between obesity and the recurrence risk of thromboembolism&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">26&#44;27</span></a> In the study by Oli&#233; et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">26</span></a> which analyzed a prospective cohort of patients with idiopathic VTE&#44; the multiple regression analysis showed a 2&#46;8-fold greater risk among women with a BMI<span class="elsevierStyleHsp" style=""></span>&#8805;30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> than the patient group with normal weight &#40;RR&#44; 2&#46;8&#37;&#59; 95&#37; CI 1&#46;3&#8211;6&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The initial presentation of VTE&#44; either PE or DVT&#44; does not appear to be clearly associated with the recurrence risk&#46; Eichinger et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">21</span></a> observed twice the risk among patients who debuted with PE compared with those who started with DVT&#46; Other studies&#44; such as the one by Prandoni et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">3</span></a> observed an increase in recurrence risk among patients with DVT compared with those with PE &#40;RR 1&#46;5&#37;&#59; 95&#37; CI 1&#8211;2&#46;2&#41;&#46; A meta-analysis that included 7 studies and 2925 patients found a similar recurrence rate&#44; regardless of whether the initial presentation was PE or DVT&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">28</span></a> However&#44; among the patients whose index episode was a PE&#44; the probability of recurrence as PE&#44; compared with DVT&#44; was 3&#8211;4-fold greater&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">29&#44;30</span></a> Consequently&#44; extended anticoagulation could be more appropriate for selected patients with a limited cardiopulmonary reserve who began with PD because a second episode would imply greater severity&#46; A distal location for a DVT is associated with a lower recurrence rate than proximal DVT or PE&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">28</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The presence of residual DVT as a predictor of recurrence is a controversial subject&#46; The DACUS study<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">31</span></a> investigated the significance of residual DVT after completing 3 months of anticoagulation therapy in patients with proximal DVT&#46; One hundred-eighty patients presented residual DVT &#40;detected by venous Doppler echocardiography&#41;&#44; 88 of whom had had their anticoagulant therapy extended for 9 more months&#44; while the remaining 92 had had their therapy discontinued&#46; Seventy-eight patients presented no residual DVT&#46; In the group with residual DVT&#44; recurrence occurred in 23&#46;3&#37; of the cases&#46; Of these&#44; 27&#46;3&#37; occurred in the patient group that stopped the anticoagulation&#44; and 19&#46;3&#37; occurred in those patients whose anticoagulant therapy was extended &#40;RR&#44; 1&#46;58&#59; 95&#37; CI 0&#46;85&#8211;2&#46;93&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;145&#41;&#46; The recurrence in the group without residual DVT was 1&#46;3&#37;&#46; The RR among the patients with and without residual DVT was 24&#46;9 &#40;95&#37; CI 3&#46;4&#8211;183&#46;6&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;002&#41;&#46; The extension of the DACUS study<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">32</span></a> also showed an increased recurrence risk in patients with residual DVT&#46; In this study&#44; 136 patients without residual DVT completed 3 months of anticoagulation&#44; while for the 273 patients who had residual DVT&#44; the treatment was extended by 21 months&#46; After a mean follow-up of 2 years&#44; the group without residual DVT had a recurrence rate of 1&#46;4&#37; compared with the 10&#46;4&#37; from the group with residual DVT&#44; despite the longer treatment duration &#40;RR&#44; 7&#46;4&#59; 95&#37; CI 4&#46;9&#8211;9&#46;9&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0026&#41;&#46; Prandoni et al&#46;&#44; in the AESOPUS study&#44;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">33</span></a> observed a lower recurrence rate in patients with residual DVT treated for 21 months compared with those treated for only 9 months &#40;RR&#44; 0&#46;62&#59; 95&#37; CI 0&#46;39&#8211;0&#46;97&#41;&#46; In contrast to the previous studies&#44; the REVERSE study<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">34</span></a> found no difference in recurrence among the patients with or without residual DVT&#46; A meta-analyses of 14 studies that included 3203 patients with residual DVT &#40;with a mean follow-up of 1&#8211;3 years after discontinuing the anticoagulation&#41; found an increased recurrence risk only in patients with DVT in the proximal territory&#44; which&#44; however&#44; did not achieve statistical significance&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">13</span></a> The recent meta-analysis by Donnadini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">35</span></a> included 10 studies with a prospective&#44; observational cohort design&#44; with a total of 2527 patients with idiopathic DVT followed-up for a mean of 23&#46;3 months&#46; Among the 1380 patients with residual DVT&#44; the DVT reoccurred in 399 patients &#40;15&#46;8&#37;&#41;&#44; and the RR compared with the patients without residual DVT was 1&#46;32&#37; &#40;95&#37; CI 1&#46;06&#8211;1&#46;65&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;01&#41;&#46; The recurrence risk was greater among the patients in whom the residual DVT was detected in the first 3 months after the DVT diagnosis &#40;RR&#44; 2&#46;17&#37;&#59; 95&#37; CI 1&#46;11&#8211;4&#46;25&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;087&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Laboratory tests</span><p id="par0040" class="elsevierStylePara elsevierViewall">The patients with persistently high <span class="elsevierStyleSmallCaps">d</span>-dimer concentrations during the anticoagulant therapy had a greater risk of recurrence&#46; In the PROLONG trial&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">36</span></a><span class="elsevierStyleSmallCaps">d</span>-dimer was measured one month after discontinuing the anticoagulant therapy in 608 patients with DVT or idiopathic PE&#46; The results of the <span class="elsevierStyleSmallCaps">d</span>-dimer test were positive for 223 patients &#40;36&#46;7&#37;&#41;&#46; After a follow-up of 1&#46;4 years&#44; the number of recurrences was significantly higher among the patients with high <span class="elsevierStyleSmallCaps">d</span>-dimer levels who discontinued the anticoagulant therapy than among those with high <span class="elsevierStyleSmallCaps">d</span>-dimer levels who restarted the anticoagulation &#40;15&#37; vs&#46; 2&#46;9&#37;&#59; RR&#44; 4&#46;26&#59; 95&#37; CI 1&#46;23&#8211;14&#46;6&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#41; or who had normal <span class="elsevierStyleSmallCaps">d</span>-dimer levels &#40;15&#37; vs&#46; 6&#46;2&#37;&#59; RR&#44; 2&#46;27&#59; 95&#37; CI 1&#46;15&#8211;4&#46;46&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#41;&#46; In another study of 610 patients with a first episode of idiopathic VTE&#44; <span class="elsevierStyleSmallCaps">d</span>-dimer levels were measured 3 weeks after discontinuing the anticoagulant therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">37</span></a> The cumulative probability of recurrence after 2 years of follow-up was 3&#46;7&#37; &#40;95&#37; CI 0&#46;9&#8211;6&#46;5&#41; in the patients with <span class="elsevierStyleSmallCaps">d</span>-dimer levels &#60;250<span class="elsevierStyleHsp" style=""></span>ng&#47;mL compared with 11&#46;5&#37; &#40;95&#37; CI 8&#8211;15&#41; in those with <span class="elsevierStyleSmallCaps">d</span>-dimer levels &#62;250<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; Lastly&#44; the largest published meta-analysis&#44; which analyzed 7 studies that included 1888 patients&#44; found that the recurrence rate after discontinuing anticoagulant therapy was 8&#46;9&#37; &#40;95&#37; CI 5&#46;8&#8211;11&#46;9&#41; for the patients with a positive <span class="elsevierStyleSmallCaps">d</span>-dimer result&#44; compared with 3&#46;5&#37; &#40;95&#37; CI 2&#46;7&#8211;4&#46;3&#41; for those who had negative results &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;002&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">38</span></a> The <span class="elsevierStyleSmallCaps">d</span>-dimer measurement was performed between 3 weeks and 2 months after discontinuing the treatment and employed high-sensitivity techniques with different cutoff points for a positive value &#40;&#62;500<span class="elsevierStyleHsp" style=""></span>mg&#47;L and &#62;250<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#41;&#46; The <span class="elsevierStyleSmallCaps">d</span>-dimer measurement should be performed after a washout period of 3&#8211;4 weeks after completing the anticoagulant therapy to ensure that the therapy does not affect the <span class="elsevierStyleSmallCaps">d</span>-dimer results&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">12</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Congenital and acquired thrombophilia increases the risk of a first thrombotic event&#44; but it is unclear whether it is associated or increases the recurrence risk&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">29</span></a> The studies by Tosetto et al&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">22</span></a> and Rodger et al&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">27</span></a> showed that the presence of factor V Leiden &#40;FVL&#41; or of PGM was not associated with an increased recurrence risk of VTE&#46; In the Eichinger et al&#46; model&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">21</span></a> only FVL was associated with a slight increase in risk &#40;RR&#44; 1&#46;68&#59; 95&#37; CI 1&#8211;2&#46;71&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;106&#41;&#46; The Segal et al&#46; series<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">39</span></a> found a weak association between heterozygosity for FVL and the recurrence of thrombosis &#40;RR&#44; 1&#46;56&#59; 95&#37; CI 1&#46;14&#8211;2&#46;12&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&#41;&#44; which increased among the homozygotes &#40;RR&#44; 2&#46;65&#59; 95&#37; CI 1&#46;2&#8211;6&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;08&#41;&#46; In the above study&#44; PGM was not associated with an increased recurrence risk&#46; The antiphospholipid syndrome has been equated to acquired thrombophilia&#44; which predisposes to relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">40&#44;41</span></a> Schulman et al&#46; showed that patients with high anticardiolipin antibodies titers have twice the risk of VTE&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">40</span></a> Other studies of patients with idiopathic VTE have also shown that the recurrence risk increased up to 4-fold among patients with positive antiphospholipid antibodies &#40;RR&#44; 3&#46;94&#59; 95&#37; CI 1&#46;83&#8211;8&#46;48&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;03&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">42</span></a> A series of 2479 patients with a first episode of VTE and CP&#44; SP or antithrombin deficiency observed recurrence rates of 6&#37; at 1 year&#44; 19&#37; at 2 years&#44; 40&#37; at 5 years and 55&#37; at 10 years after discontinuing the anticoagulation therapy &#40;RR at 1 year for CP deficiency&#44; 1&#46;52&#59; 95&#37; CI 1&#46;06&#8211;2&#46;11&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#59; for SP deficiency&#44; 1&#46;90&#59; 95&#37; CI 1&#46;32&#8211;2&#46;64&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#59; and for antithrombin deficiency&#44; 1&#46;77&#59; 95&#37; CI 1&#46;14&#8211;2&#46;60&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">16</span></a> There were no differences between the patients with a first idiopathic episode or a provoked event&#46; A number of studies have stated that hyperhomocysteinemia could be associated with an increased risk of VTE&#44;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">43&#44;44</span></a> although others have suggested that this is an epiphenomenon&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">45&#44;46</span></a> We found only one study that analyzed the prognostic relationship between homocysteine concentrations and the recurrence risk in idiopathic VTE&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">47</span></a> This was a multicenter study that included 264 patients and monitored the homocysteine concentrations after anticoagulant therapy suppression&#46; Concentrations that exceeded the 95th percentile of the control group were considered high&#46; After 24 months of follow-up&#44; the number of recurrences was significantly greater in the patient group with hyperhomocysteinemia &#40;18&#46;2&#37; vs&#46; 8&#46;1&#37;&#41;&#44; with a cumulative probability of recurrence of 19&#46;2&#37; &#40;RR&#44; 2&#46;7&#59; 95&#37; CI 1&#46;3&#8211;5&#46;8&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;009&#41;&#46; An increase in factor VIII activity above 150&#37; was considered an independent marker of thrombotic risk&#46; The study by Legnani et al&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a> is the only one to date that has evaluated the impact of factor VIII activity on VTE recurrence&#46; Those patients with an activity greater than the 90th percentile showed an increased recurrence risk 5-fold greater than that of the control group &#40;RR&#44; 5&#46;43&#37;&#59; 95&#37; CI 1&#46;76&#8211;16&#46;8&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0097&#41;&#46; The relationship between thrombophilia and VTE recurrence was evaluated in the MEGA study&#44;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">49</span></a> which consecutively included 474 patients with a first episode of unprovoked VTE&#46; After discontinuing the anticoagulation therapy&#44; laboratory tests for thrombophilia were performed using the measurement of FVL&#44; PGM&#44; and the concentrations and activity of CP and SP&#44; antithrombin&#44; factors VIII-IX-XI&#44; fibrinogen and homocysteine&#46; During a mean follow-up of 7&#46;3 years&#44; 90 patients experienced recurrences&#46; The factors associated with the recurrences were CP&#44; SP or antithrombin deficiency &#40;RR&#44; 1&#46;8&#59; 95&#37; CI 0&#46;9&#8211;3&#46;7&#41; and the combined defects &#40;RR&#44; 1&#46;6&#37;&#59; 95&#37; CI 1&#46;0&#8211;2&#46;7&#41;&#46; Nevertheless&#44; most experts do not recommend the routine thrombophilia studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">15&#44;50&#8211;52</span></a> Hypercoagulability screening might be justified for young patients with a personal or family history of thrombosis&#44; for thrombosis of unusual location or when associated with pregnancy and for women with unexplained pregnancy complications&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">53</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows a summary of the main risk factors for recurrence in unprovoked VTE&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Predictive models</span><p id="par0055" class="elsevierStylePara elsevierViewall">Several authors have tried to define models to assess the risk of unprovoked VTE recurrence after discontinuing anticoagulation therapy&#46; However&#44; external validation is needed to understand their actual usefulness in clinical practice&#46; These models include the following scales&#58; MEN <span class="elsevierStyleItalic">continue</span> and HER DOO2 &#40;Gender&#44; Hyperpigmentation&#44; Edema&#44; Redness&#44; <span class="elsevierStyleSmallCaps">d</span>-dimer&#44; Obesity&#44; Older age&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">27</span></a> Vienna<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">21</span></a> and DASH &#40;<span class="elsevierStyleSmallCaps">d</span>-dimer&#44; Age&#44; Sex&#44; Hormonal therapy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">22</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The Canadian model MEN <span class="elsevierStyleItalic">continue</span> and HER DOO2 was developed based on data from the REVERSE study performed at the University of Ottawa&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">27</span></a> The study included 646 patients with a first episode of idiopathic VTE treated with anticoagulants for a minimum period of 5&#8211;7 months and a mean follow-up of 18 months&#46; Up to 69 predictors of potential recurrence were analyzed&#46; <span class="elsevierStyleSmallCaps">d</span>-dimer and thrombophilia tests were performed during the anticoagulation therapy&#46; Ninety-one &#40;15&#46;16&#37;&#41; relapses occurred in the 600 patients who completed the follow-up&#46; The variables associated with a greater risk of recurrence were an age of 65 years or older&#44; a high <span class="elsevierStyleSmallCaps">d</span>-dimer level &#40;&#8805;250<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L&#41;&#44; clinical signs of post-thrombotic syndrome and obesity &#40;BMI<span class="elsevierStyleHsp" style=""></span>&#8805;30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46; According to this scale &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; indefinite anticoagulation should be considered for men with 1 or more risk factors and for women with 2 or more risk factors&#44; because its annual recurrence risk would be 9&#46;9&#37; &#40;95&#37; CI 8&#46;3&#8211;11&#46;8&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; and 8&#46;3&#37; &#40;95&#37; CI 5&#46;7&#8211;11&#46;3&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; for men and women&#44; respectively&#46; For men with no risk factors and women with one or no risk factors&#44; discontinuing the anticoagulation therapy after a period of 3&#8211;6 months could be considered&#44; because the annual recurrence risk was 1&#46;3&#37; &#40;95&#37; CI 0&#46;5&#8211;2&#46;8&#41;&#46; Nevertheless&#44; this scale is being validated in the REVERSE II study&#44; whose results have yet to be published&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Eichinger et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">21</span></a> developed a nomogram to predict the recurrence risk in patients with a first episode of idiopathic VTE&#44; based on the results of a prospective cohort study of 929 patients with a first episode of unprovoked VTE&#44; followed-up for 43&#46;3 months after discontinuing the anticoagulation therapy&#46; There was VTE recurrence in 176 patients &#40;18&#46;9&#37;&#41;&#44; most cases of which were idiopathic &#40;90&#46;90&#37;&#41;&#46; The clinical and laboratory variables analyzed were age&#44; sex&#44; location of the thrombosis&#44; BMI&#44; thrombin generation test&#44; thrombophilia tests &#40;FVL and PGM&#41; and <span class="elsevierStyleSmallCaps">d</span>-dimer concentration 3 weeks after completing the anticoagulant therapy&#46; The variables associated with a greater recurrence risk were the male sex &#40;RR&#44; 1&#46;90&#59; 95&#37; CI 1&#46;31&#8211;2&#46;75&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; the presence of proximal DVT vs&#46; distal DVT &#40;RR&#44; 2&#46;08&#59; 95&#37; CI 1&#46;16&#8211;3&#46;74&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;01&#41;&#44; PE vs&#46; distal DVT &#40;RR&#44; 2&#46;60&#59; 95&#37; CI 1&#46;49&#8211;4&#46;53&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; and a high <span class="elsevierStyleSmallCaps">d</span>-dimer concentration &#40;RR&#44; 1&#46;27&#59; 95&#37; CI 1&#46;08&#8211;1&#46;51&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&#41;&#46; A nomogram was developed with these variables&#44; which&#44; using a scale&#44; estimated the cumulative probability of recurrence in an individual patient &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; This scale has been tested in an independent population&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">54</span></a> In its prospective validation&#44; the model discriminated well the recurrence risk in the study population except among the elderly patients&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The DASH scale also assessed the recurrence risk of unprovoked VTE&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">22</span></a> The model included 2554 patients from 7 meta-analyses but excluded 727 of these patients diagnosed with nonidiopathic VTE and 9 others who had no <span class="elsevierStyleSmallCaps">d</span>-dimer reading 3&#8211;5 weeks after discontinuing the anticoagulant therapy&#46; This left a total of 1818 patients with idiopathic VTE treated for at least 3 months with anticoagulation and followed-up for an average of 22&#46;4 months&#46; There were recurrences in 13&#46;14&#37; of the patients&#46; The following variables were analyzed&#58; age&#44; sex&#44; BMI&#44; use of hormonal contraceptives or hormone therapy replacement &#40;in women&#41;&#44; the presence of thrombophilia&#44; a high <span class="elsevierStyleSmallCaps">d</span>-dimer concentration after discontinuing the anticoagulation and the duration of the anticoagulant therapy &#40;which lasted a mean of 6&#46;7 months in the 2 groups&#59; in those who relapsed and those who did not&#41;&#46; The multivariate analysis showed that the main predictors of recurrence were an age younger than 50 years&#44; the male sex and a high <span class="elsevierStyleSmallCaps">d</span>-dimer level&#46; In women&#44; the presence of VTE associated with hormone replacement therapy or hormonal contraceptives was considered a protective factor &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; The authors concluded that a DASH score &#8804;1&#44; which in the study represented a low annual recurrence risk &#40;3&#46;1&#37;&#44; 95&#37; CI 2&#46;3&#8211;3&#46;9&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41;&#44; could justify discontinuing the anticoagulation therapy after 3 to 6 months&#46; In contrast&#44; maintaining the anticoagulation for a longer period should be considered for DASH scores &#8805;2 &#40;RR&#44; 9&#46;3&#37;&#59; 95&#37; CI 8&#46;1&#8211;10&#46;8&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41;&#46; Nevertheless&#44; this scale has yet to be validated&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Of the 3 models &#40;MEN <span class="elsevierStyleItalic">continue</span> and HER DOO2&#44; Vienna and DASH&#41;&#44; the design of DASH<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">22</span></a> stands apart&#46; It included more patients and was developed based on a meta-analysis&#46; Given that the study was retrospective&#44; as indicated by the authors&#44; there could have been biases inherent in this type of design&#46; In addition&#44; the study included women undergoing hormonal treatment&#46; According to the guidelines of the American College of Chest Physicians&#44; estrogen hormone therapy is a risk factor associated with VTE &#40;RR&#44; 2&#46;96&#41;&#44; which would be incompatible with a diagnosis of idiopathic VTE&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">55</span></a> For these reasons&#44; the usefulness of the DASH model for assessing thrombosis recurrence in patients with idiopathic VTE is questionable&#46; The MEN <span class="elsevierStyleItalic">continue</span> and HER DOO2<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">27</span></a> and the Vienna<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">21</span></a> predictive models&#44; in contrast&#44; were developed with cohorts of patients with exclusively idiopathic VTE&#46; From the comparative analysis of the 2 models&#44; we can deduce that the Vienna model&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">21</span></a> which was developed with more patients and had a longer follow-up period&#44; presents the best profile for applicability to clinical practice because it contains fewer predictive variables&#44; and the variables are not subjective&#46; Nevertheless&#44; the Vienna model has the disadvantage that <span class="elsevierStyleSmallCaps">d</span>-dimer was treated as a continuous variable after its measurement using the ELISA technique &#40;Asserachrom <span class="elsevierStyleSmallCaps">d</span>-dimer&#44; Boehringer Mannheim&#44; Germany&#41;&#46; The model is therefore not applicable to cases in which <span class="elsevierStyleSmallCaps">d</span>-dimer is determined by different methods &#40;quantitative&#44; semiquantitative or qualitative latex&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0080" class="elsevierStylePara elsevierViewall">VTE is associated with significant long-term morbidity&#44; such as recurrent VTE&#44; for example&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">3</span></a> Anticoagulant therapy reduces this risk significantly but does so at the expense of increasing the risk of hemorrhage&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">5</span></a> Between 30&#37; and 50&#37; of VTE cases are idiopathic and have a greater recurrence risk&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">1&#44;3&#44;4</span></a> Therefore&#44; the clinical guidelines of the American College of Chest Physicians<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">6</span></a> suggest that patients with proximal DVT or idiopathic PE should undergo anticoagulant therapy for prolonged periods&#44; provided the risk of hemorrhage is low or moderate&#44; limiting the anticoagulant therapy to 3 months if the risk of hemorrhage is high&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">6</span></a> Nevertheless&#44; the presence or absence of risk factors for recurrence and a number of the models described help further individualize this generic recommendation&#46; A number of risk markers such as the male sex&#44; the presence of high-risk thrombophilia and a high <span class="elsevierStyleSmallCaps">d</span>-dimer level should be considered when planning the duration of anticoagulant therapy&#46; The Vienna model<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">21</span></a> could also be employed to assess the need for extending the anticoagulation in secondary prevention&#46; Lastly&#44; the patient&#39;s preferences should also be taken into account when deciding on the duration of the anticoagulant therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interests</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Strategies for identifying patients with a high risk of recurrence in idiopathic venous thromboembolism"
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            0 => "Venous thromboembolism disease"
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            0 => "Enfermedad tromboemb&#243;lica venosa"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">For patients with idiopathic venous thromboembolism &#40;unprovoked&#41;&#44; the risk of recurrence is high&#46; Secondary prophylaxis with anticoagulant therapy reduces the thrombotic risk but at the expense of an increased risk of hemorrhage&#46; A number of factors&#44; such as the male sex and an increase in dimer-<span class="elsevierStyleSmallCaps">d</span> concentrations after completing the anticoagulation therapy&#44; are associated with an increased risk of recurrence&#46; Other factors such as residual venous thrombosis have a more controversial and sometimes contradictory relationship&#46; A number of models have been proposed for predicting thrombotic recurrence risk after anticoagulation therapy in unprovoked venous thromboembolism&#46; However&#44; these models need external validation to determine their current usefulness in clinical practice&#46; In this article&#44; we analyze the risk factors for thrombotic recurrence and the existing prediction models&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">En pacientes con enfermedad tromboemb&#243;lica venosa idiop&#225;tica &#40;no provocada&#41; el riesgo de recurrencia es elevado&#46; La profilaxis secundaria con terapia anticoagulante reduce el riesgo tromb&#243;tico&#44; pero a expensas de un incremento del riesgo de hemorragias&#46; Algunos factores&#44; como el sexo masculino o una elevaci&#243;n de la concentraci&#243;n de d&#237;mero-D tras finalizar la anticoagulaci&#243;n&#44; se asocian a un mayor riesgo de recidiva&#59; otros&#44; como la trombosis venosa residual&#44; tienen una relaci&#243;n m&#225;s controvertida&#44; incluso contradictoria&#46; Se han propuesto algunos modelos de predicci&#243;n del riesgo de recurrencia tromb&#243;tica tras la anticoagulaci&#243;n en la enfermedad tromboemb&#243;lica venosa &#40;ETEV&#41; no provocado&#44; pero necesitan una validaci&#243;n externa para conocer su utilidad real en la pr&#225;ctica cl&#237;nica&#46; En este art&#237;culo se analizan los factores de riesgo de recidiva tromb&#243;tica y los modelos de predicci&#243;n existentes&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Please cite this article as&#58; Franco-Moreno AI&#44; de Ancos-Aracil CL&#44; Garc&#237;a-Navarro MJ&#46; Riesgo de recurrencia en el tromboembolismo venoso idiop&#225;tico&#46; Rev Clin Esp&#46; 2016&#59;216&#58;488&#8211;494&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Obesity &#40;body mass index &#62;30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">History of idiopathic venous thromboembolism disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Residual deep vein thrombosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Positive <span class="elsevierStyleSmallCaps">d</span>-dimer during anticoagulation and after withdrawing the anticoagulant treatment<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Thrombophilia<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Risk factors for recurrence in unprovoked venous thromboembolism disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">7&#8211;12&#44;16&#44;23&#44;24&#44;31&#44;32&#44;40&#8211;42</span></a></p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk factor&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Presentation of thrombosis&#58; pulmonary embolism<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>proximal DVT<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>distal DVT distal&nbsp;\t\t\t\t\t\t\n
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">DASH score &#40;<span class="elsevierStyleSmallCaps">d</span>-dimer&#44; age&#44; sex&#44; hormonal therapy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">22</span></a></p>"
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        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:55 [
            0 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Risk of recurrent venous thromboembolism after stopping treatment in cohort studies&#58; recommendation for acceptable rates and standardized reporting"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46; Kearon"
                            1 => "A&#46; Iorio"
                            2 => "G&#46; Palareti"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1538-7836.2010.03991.x"
                      "Revista" => array:6 [
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                        "volumen" => "8"
                        "paginaInicial" => "2313"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20738761"
                            "web" => "Medline"
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                        ]
                      ]
                    ]
                  ]
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              ]
            ]
            1 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Optimal duration of anticoagulation in patients with venous thromboembolism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "P&#46; Prandoni"
                            1 => "C&#46; Piovella"
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                            3 => "F&#46; dalla Valle"
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                        ]
                      ]
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                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
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            ]
            2 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism&#46; A prospective cohort study in 1&#44;626 patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Prandoni"
                            1 => "F&#46; Noventa"
                            2 => "A&#46; Ghirarduzzi"
                            3 => "V&#46; Pengo"
                            4 => "E&#46; Bernardi"
                            5 => "R&#46; Pesavento"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Haematologica"
                        "fecha" => "2007"
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            3 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism&#46; Duration of Anticoagulation Trial Study Group"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Schulman"
                            1 => "A&#46;S&#46; Rhedin"
                            2 => "P&#46; Lindmarker"
                            3 => "A&#46; Carlsson"
                            4 => "G&#46; L&#228;rfars"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM199506223322501"
                      "Revista" => array:6 [
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                        ]
                      ]
                    ]
                  ]
                ]
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            ]
            4 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Systematic review&#58; case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46; Carrier"
                            1 => "G&#46; Le Gal"
                            2 => "P&#46;S&#46; Wells"
                            3 => "M&#46;A&#46; Rodger"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.7326/0003-4819-152-9-201005040-00008"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Intern Med"
                        "fecha" => "2010"
                        "volumen" => "152"
                        "paginaInicial" => "578"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20439576"
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                        ]
                      ]
                    ]
                  ]
                ]
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            ]
            5 => array:3 [
              "identificador" => "bib0305"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antithrombotic therapy for VTE disease&#58; CHEST guideline and expert panel report"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Kearon"
                            1 => "E&#46;A&#46; Akl"
                            2 => "J&#46; Ornelas"
                            3 => "A&#46; Blaivas"
                            4 => "D&#46; Jimenez"
                            5 => "H&#46; Bounameaux"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.chest.2015.11.026"
                      "Revista" => array:6 [
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                        "fecha" => "2016"
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                        "paginaInicial" => "315"
                        "paginaFinal" => "352"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26867832"
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                        ]
                      ]
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              ]
            ]
            6 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of patient&#39;s sex on risk of recurrent venous thromboembolism&#58; a meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46; McRae"
                            1 => "H&#46; Tran"
                            2 => "S&#46; Schulman"
                            3 => "J&#46; Ginsberg"
                            4 => "C&#46; Kearon"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(06)69110-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2006"
                        "volumen" => "368"
                        "paginaInicial" => "371"
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                            "web" => "Medline"
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                        ]
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                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Risk of recurrence after venous thromboembolism in men and women&#58; patient level meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Douketis"
                            1 => "A&#46; Tosetto"
                            2 => "M&#46; Marcucci"
                            3 => "T&#46; Baglin"
                            4 => "B&#46; Cosmi"
                            5 => "M&#46; Cushman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "BMJ"
                        "fecha" => "2011"
                        "volumen" => "342"
                        "paginaInicial" => "d813"
                        "link" => array:1 [
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                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High risk of recurrent venous thromboembolism in men"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "T&#46; Baglin"
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2016.06.002

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