Predicting the risk of recurrent venous thromboembolism (VTE)

J Thromb Thrombolysis (2015) 39:353 366 DOI 10.1007/s19-015-1188-4 Predicting the risk of recurrent venous thromboembolism (VTE) Michael B. Streiff Published online: 27 February 2015 Ó Springer Science+Business Media New York 2015 Abstract To optimize patient outcomes with anticoagulation for venous thromboembolism (VTE), it is essential to assess patients for their recurrence risk. In this article, I will review the impact of clinical and laboratory risk factors for recurrent VTE. The presence or absence of VTE risk factors at the time of the index thrombotic event provides important information regarding recurrence risk. Patients with potent situational risk factors for thrombosis (e.g., surgery) are at low risk for recurrence while patients suffering unprovoked events are at high risk for recurrence. The presence of non-surgical clinical risk factors place patients at intermediate recurrence risk. Other clinical risk factors of variable recurrence potential include age, sex, cancer, pregnancy/puerperium, hormonal therapy and obesity. Laboratory risk factors for recurrence include thrombophilia, D dimer and other global coagulation assays as well as residual venous obstruction. Several multivariate VTE risk assessment models have been developed that combine clinical and laboratory risk factors of recurrence. If validated, these risk scores may allow for personalized anticoagulation therapy tailored to patients individual recurrence risk. Keywords Venous thromboembolism Recurrence Risk factors D dimer Risk assessment models M. B. Streiff (&) Division of Hematology, Department of Medicine and Pathology, Johns Hopkins Medical Institutions, 1830 E. Monument Street, Suite 7300, Baltimore, MD 21205, USA e-mail: mstreif@jhmi.edu Introduction To optimize outcomes, it is essential to customize the duration of therapy based upon the patient s individual risk for recurrent VTE and bleeding during anticoagulation. In this paper, I will review clinical and laboratory characteristics as well as prediction models that have been used to estimate recurrence risk and discuss my current approach to VTE recurrence risk assessment when caring for a patient with a first episode of VTE. Situational prothrombotic triggers and VTE recurrence risk The most straight forward approach to estimating recurrence risk is to identify the presence or absence of situational prothrombotic triggers present at the time of a patient s thrombotic event. This approach to recurrence estimation is based upon observational studies such as Trevor Baglin s landmark 2003 Lancet publication. He and his colleagues prospectively followed a cohort of 570 consecutive patients with a first episode of symptomatic VTE. Patients with malignancy and antiphospholipid syndrome (APS) were excluded. The median age of the cohort was 67 years (range 19 100 years) and 251 (44 %) participants were men. After 2 years of follow up, none of the 86 patients who suffered VTE in association with a recent surgery (VTE within in 6 weeks of surgery) had developed recurrent VTE. In contrast, 32 of 196 patients (19.4 %, 95 % confidence interval (CI) 13 26 %) with unprovoked VTE and 21 of 279 patients (8.8 %, 95 % CI 5.1 12.5 %) with non-surgical risk factors suffered recurrent VTE. Patients with surgically-provoked VTE were at lower risk for recurrence while patients with unprovoked VTE were at

354 M. B. Streiff 2.2-fold higher risk of recurrence than patients with nonsurgically provoked events [1]. The findings of the Baglin et al. study have been corroborated by several other studies [2 4]. Iorio and coworkers conducted a systematic review of 15 prospective cohort studies and randomized controlled trials of patients with a first symptomatic VTE. The risk of recurrence for patients with a surgical risk factor following completion of anticoagulation was 0.7 % per patient year while the risk of recurrence for patients with a non-surgical risk factor was 4.2 % per patient year. Among patients with unprovoked VTE the risk of recurrence was 7.4 % per patient year [5]. These studies establish the importance of considering situational pro-thrombotic triggers when estimating the risk of recurrence. Patients with a surgical trigger are at sufficiently low risk of recurrent VTE that the bleeding risks of extended duration anticoagulation are not warranted by the risk of recurrence in the absence of anticoagulation. In contrast, the risk of recurrence associated with persistent non-surgical triggers and unprovoked VTE is sufficiently great that consideration of longer duration therapy is appropriate. However, even among patients with unprovoked VTE, a substantial proportion of patients do not suffer recurrent VTE even after years of follow up. Paolo Prandoni and colleagues followed 1626 consecutive patients for up to 10 years after a first episode of VTE. The adjusted hazard of recurrent VTE was 2.3 (95 % CI 1.82 2.90) in patients with unprovoked VTE. However, at 10 years of follow up after discontinuation of AC only 52.6 % of patients had suffered recurrent VTE [2]. Therefore, clearly all patients with unprovoked VTE do not benefit from indefinite AC and further risk stratification is required to target therapy to the patients most likely to benefit. Thrombophilia Thrombophilia has long been considered a risk factor for initial VTE. However, the influence of thrombophilia on the risk of recurrent VTE is less. In a systematic review of the literature, Segal et al. noted that factor V Leiden (FVL) heterozygosity is associated with a modest risk of recurrence (OR 1.56; 95 % CI 1.14 2.12) whereas FVL homozygosity results in more substantial risk (OR 2.65; 95 % CI 1.2 6.0). Patients with prothrombin gene mutation (PGM) heterozygosity had a lower recurrence risk (OR 1.45, 95 % CI 0.96 2.2) and insufficient data existed to assess the impact of PGM homozygosity [6]. In a retrospective family cohort study of patients with known thrombophilic defects, family members with antithrombin (AT), protein C (PC) and protein S (PS) deficiency experienced a cumulative recurrence rate of 19 % at 2 years, 40 % at 5 years and 55 % at 10 years after discontinuation of anticoagulation for an annual incidence of recurrence of 6.23 % (95 % CI 4.31 8.7). There was no difference in recurrence rates for patients with provoked or unprovoked events. In contrast, the cumulative recurrence rate among patients with FVL, PGMor elevated factor VIII levels was 7 % at 2 years, 11 % at 5 years and 25 % at 10 years after discontinuation of anticoagulation for an annual incidence of recurrent VTE of 2.25 % (95 % CI 1.52 3.21). Interestingly, no difference in recurrence rates was noted for patients with idiopathic or provoked events. Patients with elevated factor IX, factor XI and hyperhomocysteinemia were not at increased risk for initial or recurrent VTE [7]. The data from this large family cohort study indicate that the risk of recurrent VTE varies with different thrombophilic states. Patients with potent thrombophilic defects (AT, PC, and PS deficiency) were at an increased risk of recurrent VTE. In contrast, moderate thrombophilic defects (FVL or PGM heterozygosity or elevated FVIII levels) and mild thrombophilic defects (factor IX, XI and hyperhomocysteinemia) were not at substantially increased risk for recurrent VTE. It is important to recognize the limitations of these data. By their nature, family studies may not necessarily be generalizable to all patients with a given thrombophilic defect as the individual genetic background influences the phenotypic expression of these mutations. Therefore, it is conceivable that the families examined in this study may have other unknown genetic characteristics that influenced their risk of recurrence compared to patients in the general population. It is likely that the variable penetrance of genetic thrombophilic states reflects the combined impact of multiple procoagulant and anticoagulant factors that influence the hemostatic balance of an individual. The impact of thrombophilia on outcome has also been examined in prospective observational studies and randomized controlled trials of anticoagulation. Baglin et al. tested patients for FVL, PGM, AT, PC and PS after discontinuation of anticoagulation. The presence of FVL (HR 1.35, 95 % CI 0.65 2.80; p = 0.417), PGM (HR 1.74 [95 % CI 0.54 5.62]; p = 0.3508) or any form of heritable thrombophilia did not increase the risk of recurrent VTE (HR 1.50, 95 % CI 0.82 2.77; p = 0.187) (Table 1) [1]. In the MEGA study, Christiansen et al. included 474 consecutive patients with a first objective episode of DVT at least 3 months after discontinuation of anticoagulation. Testing for FVL, PGM, AT, PC, PS, factor VIII, IX, XI, fibrinogen and homocysteine was performed a median of 19 months after the thrombotic event. Two hundred fiftynine patients (55 %) had idiopathic DVT (absence of pregnancy/puerperium, oral contraceptive use within 30 days or surgery, trauma, immobilization or plaster cast within 3 months). Patients older than 70 years or with

Risk of recurrent VTE 355 Table 1 The impact of thrombophilia on the risk of recurrent VTE Study Patients Duration of follow up (months) Thrombophilia Number of affected patients/total patients (%; 95 % CI) Recurrent VTE (hazard ratio [95 % CI]) Baglin et al. [1] 570 first VTE 24 FVL 77/487 (16 %; 12.6 19.1) F2 20/476 (4 %; 2.6 6.4) AT 8/485 (2 %;0.7 3.2) PC 5/431 (1 %; 0.4 2.7) PS 27/428 (6 %; 4.2 9.1) Christiansen et al. [4] 474 first DVT 87 FVL 92/474 (19 %) F2 29/474 (6 %) AT, PC, PS deficiency 25/474 (5 %) F8 110/474 (23 %) F9 86/474 (18 %) F11 92/474 (19 %) Fib 87/474 (18 %) HC 83/474 (18 %) Prandoni et al. [2] 1626 first VTE 50 FVL 111/953 (11.6 %) F2 45/953 (4.7 %) AT 7/953 (0.7 %) PC 16/953 (1.7 %) PS 14/953 (1.5 %) LA 23/953 (2.4 %) Santamaria et al. [8] 267 first proximal DVT 47 FVL 15 (7.7 %) F2 14 (7.2 %) AT 3 (1.5 %) PC 2 (1.0 %) PS 2 (1.0 %) APS 4 (2.1 %) HC 7 (3.6 %) Ribierio et al. [9] 378 first VTE 43 FVL 37 (10 %) F2 20 (6 %) F8 47 (14 %) HC 13 (4 %) ABO Non-O 190 (73 %) 15 % versus 10 % (HR 1.50 [0.82 2.77]) 28 versus 22 per 1000 pt.-years. (HR 1.4 [0.9 2.2]) HR 2.02 (1.52 2.69) HR 1.78 (1.002 3.14) IRR 1.6 (0.5 5.5) FVL factor V Leiden, F2 factor 2 gene mutation, AT antithrombin deficiency, PC protein C deficiency, Protein S protein S deficiency, F8 elevated factor VIII activity, F9 elevated factor IX antigen, F11 elevated factor XI antigen, Fib elevated fibrinogen, LA lupus anticoagulant, APS antiphospholipid syndrome, HC hyperhomocysteinemia malignancies were excluded. During 7.3 years of follow up, 90 patients had a recurrent thrombotic event (overall incidence 25.9 per 1000 patient-years or 2.6 % per year). The cumulative incidence after 5 years was 12.4 %. No increase in recurrence risk was noted in the 319 patients who had at least 1 prothrombotic abnormality compared to those who had none (HR 1.4; 95 % CI 0.9 2.2). Patients with more than one prothrombotic abnormality were at modestly increased risk of recurrence. (HR 1.6; 95 % CI 1.0 2.7) No increased risk was seen for patients with FVL, PGM, elevated factor VIII, IX or XI or hyperhomocysteinemia. A trend toward increased risk was seen for the 25 patients with AT, PC or PS deficiency (HR 1.8; 95 % CI 0.9 3.7). Patients with fibrinogen exceeding 410 mg/dl were at increased risk for recurrent VTE (HR 1.7; 95 % CI 1.1 2.8) (Table 1) [4]. Santa Maria et al. evaluated the risk of recurrence associated with thrombophilia in 195 participants of the Warfarin Optimal Duration Italian Trial (WODIT) prospective randomized controlled trial of 3 versus 12 months of anticoagulation for a first episode of idiopathic proximal DVT. Patients with known malignancies, thrombophilia, and temporary risk factors for VTE including recent trauma, prolonged immobilization, surgery, pregnancy, delivery, puerperium, use of oral contraceptives or hormone replacement therapy were excluded. Patients

356 M. B. Streiff were screened for thrombophilia at the investigators discretion after the withdrawal of anticoagulation. The overall recurrence rate after 47 months of follow up was 6.2 % per patient year. Twenty of 57 patients (35.1 %) with thrombophilia and 29 of 138 patients (21 %) without thrombophilia suffered recurrent VTE for a hazard ratio of 1.78 (95 % CI 1.0 3.14). Interestingly, the difference in recurrent VTE among patients with thrombophilia was seen solely in patients who received only 3 months of anticoagulation (HR = 3.21, 95 % CI 1.349 7.616, p = 0.008). There was no difference in recurrence in patients treated for 12 months (HR = 1.09, 95 % CI 0.478 2.483, p = 0.840). The difference in recurrence among patients with thrombophilia was due to an increased risk of recurrence among patients with acquired thrombophilia (i.e., antiphospholipid antibodies) (HR = 3.31, 95 % CI 1.579 6.920, p = 0.002) (Table 1) [8]. Prandoni et al. followed 1626 patients with a first episode of proximal DVT and/or PE for a maximum of 10 years (median 50 months). Patients were excluded if they had active cancer, an indication for long term anticoagulation or could not follow up or had a life expectancy of 6 months or less. Patients were classified as having secondary VTE if they were pregnant, had given birth within the previous 3 months, or took estrogens; if they had had a recent (less than 3 months) leg trauma, fracture, or surgical intervention; or if they had been bedridden for more than 1 week because of a chronic medical illness. All other patients were regarded as having an unprovoked episode of VTE. Thrombophilia testing (AT, PC or PS, FVL, PGM and lupus-like anticoagulants) was performed prior to initiation of anticoagulation or after its discontinuation at the direction of the participating clinicians. Three hundred and seventy-three patients (22.9 %) suffered recurrent VTE. The cumulative incidence was 11.0 % (95 % CI 9.5 12.5) after 1 year, 19.6 % (17.5 21.7) after 3 years, 29.1 % (26.3 31.9) after 5 years, and 39.9 % (35.4 44.4) after 10 years. The risk of recurrent VTE was twofold higher among patients with thrombophilia (HR 2.02 [95 % CI 1.52 2.69]). Among patients with unprovoked VTE, thrombophilia was associated with an increased risk of recurrence (adjusted HR 1.91; 95 % CI 1.35 2.69). Six of 13 patients (46.2 %; 95 % CI 19.2 74.9) with multiple abnormalities suffered recurrent VTE as compared with 71 of 216 patients (32.9 %; 95 % CI 26.6 39.1) with single abnormalities (Table 1) [2]. These data indicate that thrombophilia is associated with an increased risk of recurrence. In contrast to Christiansen et al. and Baglin et al., Prandoni and colleagues performed testing for lupus inhibitors which may have contributed to the positive association of thrombophilia testing and recurrent VTE. Limitations of Prandoni et al. s analysis include the fact that thrombophilia testing was only performed in 59 % of patients at the discretion of investigators, testing was not centralized and it was performed in retrospect in some patients. Ribiero and coworkers performed a prospective cohort study of 378 consecutive patients referred for a first episode of VTE to a single tertiary care hospital between April 2000 and July 2011. Two hundred ninety-one patients (78 %) were women and 253 (67 %) had a provoked event. The median age was 36 years. The median follow up was 43 months. Recurrent VTE occurred in 35 patients (9 %) for an incidence of 22 per 1000 patient-years. Patients with any thrombophilia were not at increased risk for recurrent VTE (incidence rate ratio 1.6; 95 % CI 0.5 5.5). This result remained unchanged among patients with unprovoked (IRR 4.4; 0.6 33.3) and provoked VTE (IRR 0.7; 0.1 3.2) (Table 1) [9]. Limitations of this study include its small sample size, single tertiary care center study setting and a limited thrombophilia testing menu. Nevertheless the results of this study are consistent with previous studies that thrombophilia testing has a limited impact on the risk of recurrent VTE. This conclusion is also supported by several prospective cohort studies conducted to derive clinical prediction rules for recurrent VTE in patients with unprovoked VTE. Rodger et al. did not identify FVL, the PGMor homocysteine levels C15 lmol/las risk factors for recurrent VTE. In univariate analysis, antiphospholipid antibodies were associated with an increased risk of recurrence in men (relative risk (RR) 1.85; 95 % CI 1.14 2.99) but not women (RR 0.59; 0.28 1.23). Conversely, factor VIII C 2.0 units/ml was associated with an increased risk in women (RR 2.67; 95 % CI 1.33 5.37) while a factor VIII C 1.55 units/ml was not associated with increased risk in men (RR 1.56; 95 % CI 0.97 2.51) [10]. In their prospective cohort study of patients with a first unprovoked VTE, Eichinger et al. found that FVL was associated with a modest hazard ratio of 1.68 (95 % CI 1.00 2.71) while PGM was not associated with increased risk (HR 1.0; 95 % CI 0.38 2.19) [11]. Similarly using a pooled database of 2554 patients with first unprovoked VTE, Tosetto et al. noted no increase in the presence of thrombophilia among patients who did and did not suffer recurrent VTE during a median follow up of 22.4 months (23.4 vs. 20.9 %, p = 0.396) [12]. In conclusion, the collective weight of the available evidence does not support the use of inherited thrombophilia testing to determine the risk of recurrent VTE in individual patients APS has been identified as an important acquired thrombophilic state. The diagnosis of APS requires the presence of both clinical and laboratory features. Clinical manifestations of APS included 3 or more first trimester miscarriages, one or more fetal death in utero or objectively confirmed venous or arterial thrombotic events. Laboratory criteria include repeatedly positive (separated

Risk of recurrent VTE 357 by at least 12 weeks) lupus inhibitor testing or positive tests for cardiolipin or beta 2 glycoprotein 1 antibodies [13]. Schulman and coworkers demonstrated that the risk of recurrent VTE was twofold greater in patients with elevated titers of cardiolipin antibodies during four years of follow up (29 vs. 14 %, p = 0.00130) [14]. In a study of patients with a first episode of unprovoked VTE, Kearon and colleagues found the risk of recurrent VTE was almost fourfold higher among patients with antiphospholipid antibodies (RR 3.94; 95 % CI 1.83 8.48) [15]. Although APS has been considered a strong risk factor for recurrent VTE and an indication for indefinite anticoagulation, the evidence basis for this conclusion is limited. In a systematic review of APS and the risk of recurrent VTE, Garcia et al. found that the quality of evidence is low [16]. Only 8 studies have been published on this topic, 6 randomized trials and 2 cohort studies. APS testing differed considerably between the studies as some studies only tested patients once, some did not specify the criteria for a positive test, the criteria for a positive test varied as did the type of antibodies investigated and the setting of laboratory testing (on vs. off anticoagulation, interval between thrombotic event and testing). The relative risk of recurrent VTE in APS patients was 1.41 (95 % CI 0.99 2.36). The unadjusted risk ratio for cardiolipin antibody positivity was 1.53 (95 % CI 0.76 3.11) and the risk ratio for lupus inhibitor positivity was 2.83 (95 % CI 0.83 9.64) [16]. These data underscore the need for larger higher-quality studies. Until these data are available, I believe that it is safer to consider patients with rigorously defined APS as being at high risk for recurrent VTE and to strongly consider long term anticoagulation in these patients. Gender In 2004 Kyrle et al. published a prospective cohort study of 826 patients followed for an average of 36 months after a first episode of spontaneous VTE that demonstrated that men were 3.6-fold more likely to develop recurrent VTE than women (20 vs. 6 %; RR 3.6 [95 % CI 2.3 5.5]) [17]. This risk remained unchanged after adjustment for age, the presence of FVL, the PGM and elevated levels of factor VIII or IX [17]. Subsequently, several other studies confirmed this observation [18, 19]. A study level metanalysis of 15 studies including 5416 patients conducted by McRae and colleagues found a relative risk of recurrent VTE of 1.6 (95 % CI 1.2 2) for men compared to women [20]. The relative risk for recurrence in men was lower in randomized trials (RR 1.3; 95 % CI 1.0 1.8) than in observational studies (2.1; 95 % CI 1.5 2.9). The increased recurrence risk among men remained after excluding studies that enrolled patients with hormonal risk factors (RR 1.4; 95 % CI 1.17 1.68). Likewise, the strength of this association was not influenced by the exclusion of patients with distal DVT [20]. Douketis et al. found similar results in a more recent patient-level metanalysis of 2554 patients followed for 27 months [21]. Among patients with unprovoked VTE, men were twofold more likely to suffer recurrent VTE than women (HR 2.2; 95 % CI 1.7 2.8). After exclusion of women with hormone-associated VTE, men remained more likely than women to suffer recurrent VTE (HR 1.8; 95 % CI 1.4 2.5). In contrast, there was no difference in recurrence risk between men and women after a first episode of provoked VTE (HR 1.2; 95 % CI 0.6 2.4). In women with hormone associated VTE in the absence of other risk factors, the risk of recurrence was less than in women with unprovoked VTE with no previous hormone use (HR 0.5; 95 % CI 0.3 0.8) [21]. A recent analysis of the MEGA population-based case control study found that when reproductive and hormonal risk factors for VTE are taken into account men have a 2.1- fold higher risk of first VTE compared to women (95 % CI 1.9 2.4) [22]. Therefore, men are at twofold greater risk of both initial and recurrent VTE. The reason for this increased risk remains unknown. These data suggest that gender is an important variable to consider when assessing the risk of recurrent VTE. Hormonal therapy and recurrent VTE Hormonal contraceptives and hormone replacement therapy increase the risk of VTE to a varying degree depending upon the dose of estrogen, the type of progestin in combined estrogen/progestin tablets and the route of administration [23]. In women who suffer a first episode of VTE associated with hormonal therapy, the recurrence rate varies depending upon whether hormonal therapy is discontinued. In the MEGA study, Christiansen et al. noted that the recurrence rate among women who discontinued hormonal therapy after a hormone-associated VTE was lower than among women who used hormonal therapy during follow up (9.7 per 1000 patient-years [95 % CI 4.3 21.5] vs. 27.3 per 1000 patient-years [95 % CI 14.7 50.7]). The rate was even higher if one focused only on the time period of hormone administration (55.3 per 1000 pt.-years (95 % CI 29.8 102.9). They did not note a difference in recurrence rates between women with or without hormonal therapy exposure prior to their initial VTE (9.7 per 1000 patient-years [4.3 21.5] vs. 16.2 per 1000 patient-years (8.7 30.2)) [4]. In the PREVENT study of low-dose warfarin therapy (INR 1.5 2.0 vs. placebo), the 3 year probability of recurrent VTE was 15.0 % (95 % CI 6.3 23.8) among the

358 M. B. Streiff 109 women with VTE unassociated with hormonal therapy compared to 5.0 % (95 % CI 1.1 8.9) among the 129 women with hormone-related thrombosis. Women with hormone-related thrombosis were at a 46 % lower recurrence risk (HR 0.54; 95 % CI 0.19 1.54) [24]. In their patient level metanalysis, Douketis et al. also found that women with hormone-associated VTE had a 50 % lower risk of recurrence than women without hormone-associated VTE (HR 0.5; 95 % CI 0.3 0.8). When the type of hormonal therapy was specified, women with oral contraceptive-associated VTE had a lower risk of recurrence than non-hormone users (HR 0.39, 95 % CI 0.16 0.91). The risk of recurrence among users of hormone replacement therapy was slightly less although not significant (HR 0.76, 95 % CI 0.39 1.49) [21]. Use of hormones at the time of the index VTE was also associated with a significant reduction in recurrence in the DASH cohort [12]. If hormonal therapy is medically necessary, anticoagulation should be continued as this has been shown to be effective in preventing recurrent VTE in patients on hormonal therapy [25]. Pregnancy-associated VTE Pregnancy is associated with a 4- to 5-fold increased risk of VTE. The risk of VTE is highest in the early postpartum period but the risk remains elevated up to 6 12 weeks post-partum [26, 27]. In the absence of thromboprophylaxis, women with a previous history of pregnancy-associated VTE have a 2 10 % chance of suffering a recurrent event during pregnancy (OR 24.8; 95 % CI 17.1 36.0) [28 30]. In an administrative database analysis, White and colleagues noted that the risk of recurrent VTE was lower among women with pregnancyassociated VTE than women with unprovoked VTE (5.8 vs. 10.4 %, HR 0.6; [95 % CI 0.4 0.9] p = 0.02). However, 12 of 34 subsequent VTE among women with pregnancy-associated VTE (35 %) occurred during a subsequent pregnancy compared with 29 of 331 events among women with unprovoked VTE (8.7 %) (p \ 0.001). Overall, the incidence of recurrent VTE during subsequent pregnancies was higher in patients with pregnancy-associated VTE (21 of 465, 4.5 %) than patients with previous unprovoked VTE (37 of 1353, 2.7 %, RR = 1.7, 95 % CI 1.0 2.8) [31]. These data indicate that women with pregnancy-associated VTE are at especially high risk for recurrence during subsequent pregnancies so thromboprophylaxis is essential. The appropriate dose of thromboprophylaxis (prophylactic, intermediate or therapeutic dose) remains to be determined although treatment failures have been noted in patients receiving prophylactic dose anticoagulation [32]. Obesity Obesity has been associated with an increased risk of initial and recurrent VTE [33 36]. In the Austrian Study of Recurrent Venous Thromboembolism, 1107 patients were followed prospectively for 46 months after completion of anticoagulation for a first episode of unprovoked VTE. Four years after discontinuation of anticoagulant therapy, the probability of recurrent VTE was 9.3 % (95 % CI 6.0 12.7 %) for patients with a BMI less than 25, 16.7 % (95 % CI 11.0 22.3 %) for patients with a BMI of 25 30 and 17.5 % (95 % CI 13.0 22.0 %) for patients with a BMI [ 30. Compared with their normal weight counterparts, the adjusted hazard ratio for recurrent VTE was 1.3 (95 % CI 0.9 1.9) (p = 0.20) among overweight patients and 1.6 (95 % CI 1.1 2.4) (p = 0.02) among obese individuals [36]. In a smaller prospective cohort study, Olie et al. found that obesity among women increased the risk of recurrent VTE by 2.8-fold (95 % CI 1.3 6.0) compared with normal weight subjects [37]. These studies identify obesity as an important modifiable risk factor for recurrent VTE. Cancer Cancer is associated with a 2- to 4-fold increased risk of recurrent VTE [38, 39]. In the Olmsted County cohort, Heit et al. noted that patients with malignant disease were at 2.2-fold higher risk of recurrence than patients without cancer. Cancer patients undergoing chemotherapy had a 4.2-fold greater risk of recurrence [38]. In a prospective cohort study of 842 patients, Prandoni and colleagues noted a recurrent thrombosis rate of 20.7 % (95 % CI 15.6 25.8 %) among patients with cancer versus 6.8 % (95 % CI 3.9 9.7 %) for patients without cancer (HR 3.2 [95 % CI 1.9 5.4]). The extent of cancer influenced recurrence risk. In patients with TNM stage IV, stage III, or stage I or II disease, the frequency of recurrent VTE per 100 patient-years was 54.1, 44.1, and 14.5, respectively. Compared to patients without cancer, these rates correspond to hazard ratios for recurrent VTE of 4.6 (95 % CI 2.3 9.0), 5.3 (95 % CI 2.5 10.9), and 1.9 (95 % CI 0.8 4.2) [39]. Major bleeding was also more common among cancer patients. Major bleeding occurred in 12.4 % (95 % CI 6.5 18.2 %) of cancer patients and 4.9 % (95 % CI 2.5 7.4 %) of patients without cancer (HR 2.2 [95 % CI 1.2 4.1]). Similar to recurrent VTE, major bleeding was associated with cancer disease burden. The frequency of major bleeding per 100 patient-years was 42.8, 19.1, and 3.4 in patients with TNM stage IV, stage III and stage I or II cancer. Compared to patients without cancer, the hazard

Risk of recurrent VTE 359 ratios for major bleeding was 4.8 (95 % CI 2.3 10.1), 2.5 (95 % CI 0.9 6.7), and 0.5 (95 % CI 0.1 2.1) in patients with TNM stage IV, stage III and stage I or II cancer, respectively. Episodes of major bleeding were not associated with excessive anticoagulation [39]. These data in conjunction with data from other studies of cancer patients with VTE support long-term anticoagulation in patients with cancer as long as their cancer is active or undergoing therapy. To develop a VTE risk assessment model, Louzada et al. performed a retrospective cohort study of cancer patients treated for VTE at the Thrombosis unit of the Ottawa Hospital [40]. In their 543 patient cohort, 200 (36.8 %) were treated with warfarin and 343 (63.2 %) were treated with LMWH. The mean age of participants was 63 years and 240 (44 %) were males. Four hundred eighty-five patients had solid tumors (89 %) and 58 (11 %) had hematologic malignancies. Distant metastases were present in 238 patients (44 %) at the time of VTE diagnosis and 306 patients (63 %) had adenocarcinomas. Fifty-five patients (10 %) developed recurrent VTE within the first 6 months of anticoagulation. There were 19 (9.5 %) recurrent events in patients taking VKA and 36 (10.5 %) in patients taking LMWH (relative risk, 1.13; 95 % CI 0.743 1.711; p = 0.565). Multivariate analysis identified 4 independent predictors of recurrent VTE; sex, primary tumor site, tumor stage, and prior history of VTE. Predictors associated with an increased risk of recurrence included female sex (1 point), lung cancer (1 point) and a history of previous VTE (1 point). Predictors associated with a lower risk of VTE included breast cancer (1 point) and localized disease (TNM stage I) (2 points). Patients with a score of 0 had a low risk for recurrent VTE (4.5 %) while patients with a score C1 point had a high risk for recurrence (19 %). The model was predictive of recurrence regardless of treatment (warfarin vs. LMWH). The authors validated their model using participants from the CLOT and CANTHANOX studies. Patients with a score less than 0 had a low risk of recurrence (5.1 %), patients with a score of zero had an intermediate risk (9.8 %), and patients with a score C1 had a high risk (15.8 %) (Table 2) [40]. Table 2 Ottawa prediction rule for recurrent VTE in cancer patients Risk factor Points Female sex?1 Lung cancer?1 Prior VTE?1 Breast cancer -1 Low stage (TNM stage I) -2 Low risk B 0 points, intermediate risk = 0 points, high risk = 1or more points The Ottawa Prediction rule has recently been validated in a separate patient cohort by den Exter et al. [41] They used data from a previously published, multicenter observational study of LMWH and vitamin K antagonists in the treatment of VTE in cancer patients. Similar to Louzada et al., original publication, den Exter and colleagues found that the Ottawa Prediction Rule identified patients in their cohort at low (2.4 %), intermediate (8.8 %) and high cumulative risk (15.9 %) of recurrent VTE over 6 months of follow up [41]. A limitation of both studies is the inclusion of patients who treated with vitamin K antagonists while current guidelines recommend LMWH for treatment of cancer-associated VTE. Nonetheless, these studies indicate that the Ottawa Prediction Rule could facilitate the individualized anticoagulation for cancer patients. Prospective management studies testing this hypothesis are warranted. Chee et al. recently published a retrospective analysis of the Olmsted County cohort of cancer patients who had suffered VTE between 1966 and 2000 [42]. Of the 681 patients with incident VTE and active cancer, 204 (30 %) died on the day of diagnosis or were diagnosed with VTE on autopsy, leaving 477 patients for study. The median age of the cohort was 68.9 years and 46.3 % were women. Sixty-six percent had stage IV disease and 10.7 % had stage III disease. Incident thrombotic events included 280 DVT only (including 22 arm DVT, three mesenteric vein thrombosis, three IVC thrombosis, two ovarian vein thromboses and four renal vein thromboses) and 197 PE ± DVT. During 1533 person-years of follow up, 139 patients (29 %) developed recurrent VTE (64 PE ± DVT and 75 DVT alone) and 303 (89.6 %) of the 338 who did not recur died. Independent predictors of recurrent VTE from multivariate Cox proportional hazards analysis included stage IV pancreatic cancer (HR 6.38), brain cancer (HR 4.57), myeloproliferative or myelodysplastic disorder (HR 3.49), ovarian cancer (HR 3.22), stage IV cancer (non-pancreas) (HR 2.85), lung cancer (HR 2.73), neurologic disease with paresis (HR 2.38) and cancer stage progression (HR 2.14). Patients with one or more of these risk factors had a threefold (HR 3.02; 95 % CI 2.43 3.76; p \ 0.001) higher risk of recurrence than patients without any of these risk factors. Cancer patients without risk factors were at similar risk of recurrence as VTE patients without cancer (HR 1.4; 95 % CI 0.9 2.1; p = 0.16) [42]. Limitations of Chee et al. s analysis include that its cohort is more than 10 years old so the outcomes and treatments of the patients may differ substantially from contemporary patient cohorts. In addition, the population of Olmsted County is predominantly white and non-latino so the results may not be generalizable to other populations. Nevertheless the Olmsted and Ottawa studies provide valuable information on risk factors for recurrent VTE in cancer patients that warrant validation in prospective management studies.

360 M. B. Streiff Residual vein obstruction Residual venous obstruction (RVO) at the conclusion of therapy has also been identified as a predictor of recurrent VTE [43 46]. Conceptually, residual vein occlusion is a rational and potentially biologically relevant marker for future thrombotic potential for several reasons; (1) it is a rough measure of the original thrombus burden which may be a surrogate measure of an individual s procoagulant potential, (2) it may provide an estimation of an individual patient s fibrinolytic system which may be inversely proportional to their risk of recurrent thrombus formation, (3) it provides a direct measure of residual thrombus which by slowing local blood flow may increase the risk for recurrent ipsilateral DVT. However, the prognostic value of RVO is difficult to assess as different studies have used different criteria for RVO, assessed RVO at different time points during the course of therapy and studied patient populations with different risks for recurrent VTE. Donnadini et al. performed a patient-level metanalysis of 10 studies investigating the use of RVO to assess the risk of recurrent VTE in patients after a first episode of unprovoked VTE [47]. Their analysis included 2527 patients with a median age of 65 years. There were 1106 women (44 %). RVO was detected in 1380 patients (55.1 %) a median of 6 months after diagnosis. Recurrent VTE developed in 399 patients (15.8 %) during a median follow up of 23.3 months. RVO was modestly associated with recurrent VTE (HR 1.32; 95 % CI 1.06 1.65). RVO measured at 3 months was associated with a higher risk of recurrent VTE (HR 2.17; 95 % CI 1.11 4.25) while RVO detected beyond 6 months was not a significant predictor of recurrence risk (HR 1.19; 95 % CI 0.87 1.61) [47]. Therefore, the presence of RVO at the conclusion of a course of anticoagulation for unprovoked VTE is a modest predictor of recurrence risk. In my opinion, RVO is insufficiently predictive to be used alone in assessing patients risk for recurrent VTE. In combination with other risk factors, however, RVO may prove useful. Several ongoing studies are assessing the prognostic value of RVO when incorporated with other variables into a risk assessment model. Global measures of activated coagulation D dimer, a by-product of fibrinolysis of cross-linked fibrin clot has been used extensively to assess the recurrence risk of patients after a course of anticoagulation. The first major study to assess the utility of D dimer in this role was published by Palareti et al. in 2006 [48]. In the PROLONG study, Palareti and coworkers performed D dimer testing 1 month after discontinuation of anticoagulation in 608 patients who had completed at least 3 months of anticoagulation for a first episode of unprovoked VTE. D dimer was measured using the Clear view Simplify D dimer assay. 385 patients with normal D dimer levels were assigned to observation only. Two hundred twenty-three patients (36.7 %) with an abnormal D dimer were randomly assigned to anticoagulation (target INR 2 3) (N = 103) or observation (N = 120). During a mean follow up of 1.4 years, 18 of the 120 patients (15 %) with abnormal D dimer levels who stopped anticoagulation suffered recurrent VTE compared with 3 of 103 patients (2.9 %) with abnormal D dimer levels who resumed anticoagulation (HR 2.27; 95 % CI 1.15 4.46) (p = 0.02). Recurrent VTE occurred in 24 of 385 patients (6.2 %) who had normal D dimer levels and remained off anticoagulation. This landmark study established the strategy of employing D dimer in the risk stratification of patients with unprovoked VTE [48]. This result has been verified by a number of subsequent studies. A systematic review of seven studies of D dimer assays in 1888 patients with a first episode of unprovoked VTE found that the annual risk of recurrence was 8.9 % (95 % CI 5.8 11.9 %) in patients with an abnormal D dimer and 3.5 % (95 % CI 2.7 4.3 %) in patients with normal D dimers [49]. Several limitations of this analysis are that different D dimer assays were used for testing in the different papers, testing was performed at different times after discontinuation of anticoagulation and the duration of anticoagulation prior to testing differed. A metanalysis performed by Bruinstroop et al. that focused solely on studies enrolling patients with a first idiopathic VTE who performed D dimer testing 1 month after discontinuation of anticoagulation noted similar results (recurrent VTE-elevated D dimer 16.6 % vs. normal D dimer 7.2 %; odds ratio 2.36 [95 % CI 1.65 3.36]) [50]. In a patient-level metanalysis of seven studies with 1818 patients with unprovoked VTE, Douketis et al. found that an abnormal D dimer was associated with a hazard ratio of 2.59 (95 % CI 1.90 3.52) for recurrent VTE. The risk of recurrent VTE was 3.7 per 100 patient years (95 % CI 3.2 4.3) in patients with negative D dimer assays and 8.8 per 100 patient years (95 % CI 6.2 11.3) in patients with abnormal D dimer results. Regardless of the timing of D dimer testing after discontinuation of anticoagulation (less than 3 weeks, 3 5 weeks, greater than 5 weeks), an abnormal D dimer was associated with an increased risk of recurrent VTE. Similarly, abnormal D dimer levels predicted a higher risk of recurrence regardless of age or cut point (500 vs. 250 lg/l) [51]. In the PROLONG2 study, Cosmi et al. examined the predictive values of serial D dimer tests on identification of patients at risk for recurrent VTE [52]. At the intended end of anticoagulation, patients underwent D dimer testing if

Risk of recurrent VTE 361 their INR was in the therapeutic range. Patients with normal D dimers discontinued anticoagulation while those with abnormal D dimers continued anticoagulation for an additional 6 months. In the group with normal D dimers at the conclusion of intended therapy, D dimer testing was repeated 30 days after discontinuation. Patients with abnormal D dimer results at this time point resumed AC while patients with normal D dimers remained off AC and underwent bimonthly D dimer testing for 1 year. The D dimer result was normal 1 month after discontinuation of anticoagulation in 243 of 355 patients (68 %). Among these 243 patients, 8 patients (3.3 %; 95 % CI 1 6 %) suffered a recurrent VTE prior to the next D dimer test on day 90. Among patients whose D dimer at day 90 was abnormal and remained persistently abnormal, the hazard ratio of recurrent VTE was ninefold higher than patients whose D dimer was normal at day 90 and remained normal thereafter (Recurrent VTE 27 per 100 patient years [95 % CI 12 48] vs. 2.9 per 100 patient years [95 % CI 1 7]; HR 9.38, p = 0.0004). Patients who developed an abnormal D dimer after day 90 and whose D dimer remained persistently abnormal thereafter were at almost fourfold greater risk of recurrent VTE than patients with persistently normal D dimers from day 90 forward (Recurrent VTE 11.1 per 100 patient years [95 % CI 4 24] vs. 2.9 per 100 patient years [95 % CI 1 6]; HR 3.78; p = 0.047) [52]. These results indicate that serial D dimer testing especially in the first 3 months after discontinuation of anticoagulation can identify a subgroup of patients with unprovoked VTE who are at low risk for recurrence. Limitations of this study included its open label design, the limited size of its subject population and the use of a qualitative D dimer test which may introduce a degree of subjectivity when assessing test results. The same research team has also investigated the utility of D dimer testing for assessment of recurrence risk in patients after a first episode of provoked VTE [53]. In 296 patients the authors performed a compression ultrasound on the day of discontinuation of anticoagulation. D dimer levels were measured on day 0 (day of anticoagulation discontinuation) and day 30 after discontinuation of anticoagulation using the VIDAS D-dimer ELISA (biomerieux, Lyon, France; cut-off 500 ng/ml). VTE were considered provoked if they were associated with surgery or trauma in the previous 3 months, prolonged immobilization or hospitalization (longer than 3 days) for an acute medical illness in the previous 3 months, current use of oral contraception or hormonal replacement therapy, ongoing pregnancy or puerperium, or prolonged travel ([4 h) in the previous 4 weeks. The median duration of anticoagulation was 5 months (range 3 37 months) for patients with DVT and 7 months (range 3 78 months) for PE. RVO was present in 44.8 % (132/294) of patients. RVO was not associated with an increased risk of recurrence (adjusted HR 1.1; 95 % CI 0.3 3.2). An abnormal D dimer at the time of discontinuation of anticoagulation (day 0) (11.1 VTE per 100 patient-years [95 % CI 4 24] vs. 2.2 VTE per 100 patient-years [95 % CI 1 4]; adjusted HR 4.2 [1.2 14.2]) and 30 days after discontinuation of anticoagulation (day 30) (6.7 VTE per 100 patient-years [95 % CI 3 12] vs. 1.5 VTE per 100 patient-years [95 % CI 0 3]; adjusted HR 3.8 [1.2 12.1]) were both associated with an increased risk of recurrence [53]. This study provides evidence that D dimer testing may be of utility in assessing recurrence risk in patients with provoked VTE. Palareti et al. conducted a prospective management study using D dimer testing to determine the duration of therapy in patients who had suffered a first episode of unprovoked or provoked VTE in association with weak risk factors (minor, arthroscopic or laparoscopic surgery, pregnancy, estrogen therapy, long haul travel ([6 h), minor trauma not requiring hospitalization or plaster cast, medical hospitalization or reduce mobility (but not immobility) [54]. All participants had at least 3 months of anticoagulation. A duplex ultrasound was done of the proximal leg veins at prior to discontinuation of anticoagulation. A quantitative D dimer was done at the time of anticoagulation discontinuation (Time 0, T0). Patients with abnormal D dimer assays were instructed to continue anticoagulation. Patients with normal D dimer studies on T0 discontinued anticoagulation and performed serial D dimer assays after 15 18 days (T15), 25 35 (T30), 55 65 (T60), and 85 95 (T90) days. Patients were recommended to resume anticoagulation at the first positive D-dimer result. Age- and sex-specific cutoffs were used for D dimer assays. Of 1010 patients, anticoagulation was stopped in 528 (52.3 %) with persistently negative D-dimer who subsequently experienced 25 recurrences (3.0 % per patientyear; 95 % CI 2.0 4.4 %). Of the remaining 482 patients, 373 resumed anticoagulation and 109 refused. Recurrent VTE developed in 15 patients (8.8 % per patient-year; 95 % CI 5.0 14.1) of the latter group and in 4 of the former patients (0.7 % per patient-year; 95 % CI 0.2 1.7; hazard ratio 2.92; 95 % CI 1.87 9.72; p = 0.0006). Major bleeding occurred in 14 patients (2.3 % per patient-year; 95 % CI 1.3 3.9) who resumed anticoagulation [54]. This study demonstrated that serial D dimer measurements can identify patients with unprovoked or minimally provoked VTE who are at low risk for recurrent VTE. Endogenous thrombin potential or thrombin generation Endogenous thrombin potential is another global measure of activated coagulation that has been investigated as a potential risk factor for recurrent VTE. Several different

362 M. B. Streiff assays have been used to measure thrombin generation including The Calibrated Automated Thrombogram Ò (Thrombinoscope BV, Maastricht, The Netherlands) and the Technothrombin Ò TGA (Technoclone, Vienna, Austria) which both use a fluorogenic substrate, and the Endogenous Thrombin Potential Assay Ò (Siemens Healthcare Diagnostic Inc., Deerfield, IL, USA) and the Pefakit Thrombin Dynamics Test Ò (Pentapharm, Basel, Switzerland) which employ a chromogenic substrate. In a prospective study of 914 patients with an unprovoked VTE who were followed for an average of 47 months, Hron et al. measured thrombin generation (TG) using the Technothrombin Ò TGAassay [55]. Blood for the assay was collected a median of 13 months (range 3 weeks to 94 months) after discontinuation of anticoagulation. VTE recurred in 100 patients. Recurrence was unprovoked in 90 patients and provoked by surgery or trauma in 10 patients. In a multivariate analysis, patients with a peak thrombin generation of less than 300 nm (nm) had a relative risk of recurrent VTE of 0.37 [95 % CI 0.20 0.67]) compared to patients with TG greater than 400 nm. Patients with TG between 300 and 400 nm were also significantly less like to suffer recurrent VTE (RR 0.45 [95 % CI 0.28 0.73]). After 4 years, the probability of recurrence was 6.5 % (95 % CI 4.0 8.9 %) among patients with thrombin generation less than 400 nm compared with 20.0 % (95 % CI 14.9 25.1 %) among patients with higher values (p = 0.001) [55]. Using the ThrombinoscopeTM Assay Ò (Thrombinoscope BV, Maastricht, The Netherlands) Besser et al. also noted that TG could be useful in risk stratification of patients for recurrent VTE [56]. In a prospective cohort of 188 patients with a first episode of unprovoked VTE or VTE provoked by a non-surgical trigger, the authors noted that patients with a high endogenous thrombin potential (ETP) (above the 50th percentile) had a significantly higher rate of unprovoked recurrence than those with a low ETP (below the 50th percentile) (HR 2.9, 95 % CI 1.3 6.6, cumulative recurrence at 4 years 27 vs. 11 %). A high ETP remained a significant predictor of recurrent VTE even after adjustment for D dimer level, presence of thrombophilia, sex and whether or not the first event was unprovoked (HR 2.6, 95 % CI 1.2 6.0) [56]. In a prospective study of 254 patients after a first episode of unprovoked VTE, Tripodi et al. found that patients with ETP of greater than 960 nm times minutes or peak TG greater than 193 nm measured in the presence of thrombomodulin had hazard ratios (HR) for recurrent VTE of 3.41 (95 % CI 1.34 8.68) and 4.57 (95 % CI 1.70 12.2), respectively as compared with those with an ETP less than 563 nm times minutes or peak TG of less than 115 nm [57]. Tests performed in the absence of thrombomodulin were less predictive of recurrence risk. These papers establish that various laboratory parameters associated with measurement of endogenous thrombin potential are associated with the risk of recurrent VTE. A limitation of all these studies is the technical nature of thrombin generation assays which at the present do not lend themselves to use in routine clinical laboratories. Several other global laboratory assays have been examined in risk stratification of patients for recurrent VTE. Patients with an aptt ratio C0.95 had a relative risk of recurrent VTE of 0.58 (95 % CI 0.39 0.87, p = 0.009) after adjustment for sex, age, FVL and PGM compared to patients with an APTT ratio \0.95 [58]. Among patients with P selectin levels above the 75 percentile for the population, the probability of recurrence after 4 years of follow up was 20.6 % (95 % CI 12.6 28.5) versus 10.8 % (95 % CI 7.2 14.3) among patients with lower values for an adjusted risk of recurrence of 1.7-fold (95 % CI 1.0 2.9, p = 0.045) [59]. Multivariable models for risk assessment of recurrent VTE The ideal approach to developing a risk assessment model for recurrent VTE would be based upon prospective observation of a large population of well characterized patients with VTE. Several risk assessment models have taken this approach. The first study to take this approach was that published by Marc Rodger and colleagues in 2009 in the Canadian Medical Association Journal [10]. In a multicenter prospective study, they enrolled 646 patients with a first episode of unprovoked symptomatic VTE. They defined unprovoked venous thromboembolism as one that occurred in the absence of a leg fracture or plaster cast, immobilization or surgery within 3 months and no history of cancer within 5 years. They collected demographic, clinical and laboratory data on 69 potential predictors of recurrent VTE during 5 7 months of anticoagulation. D dimer and select thrombophilia testing was performed during therapy. After completion of therapy, participants were seen every 6 months for a mean duration of 18 months (range 1 47). Six hundred of 665 participants completed follow up. Ninety-one objectively documented episodes of VTE occurred for a 9.3 % annual risk of recurrence (95 % CI 7.7 11.3 %). No fatal episodes of VTE occurred. The annual risk of recurrent VTE was higher among men (13.7 %; 95 % CI 10.8 17.0 %) than women (5.5 %; 95 % CI 3.7 7.8 %). Men with signs and symptoms of post-thrombotic syndrome had an especially high annual risk of recurrence (24 %). With the available data set of clinical and demographic variables, the authors were able to identify a subgroup of women with a low annual risk of recurrence (Table 3). This model identified 52.2 %