Risk Of Recurrent VTE Research Articles

Cancer-Associated Deep Vein Thrombosis: The Role of Residual Vein Thrombosis for Assessing the Duration of Low Molecular Weight Heparin (the EXTENDED Cancer-DACUS)

▪Introduction. The optimal duration of Low Molecular Weight Heparin (LMWH) after cancer associated deep vein thrombosis (DVT) is unknown; current guidelines suggest to prolong anticoagulation until cancer is active. We have recently demonstrated, in a randomized trial, that detection of Residual Vein Thrombosis (RVT) after 6 months of LMWH identify patients who require or not extension of therapy with anticoagulants (JCO in press). Now we present data of a prospective study evaluating a RVT-based management of patients with cancer-associated DVT, in whom LMWH has been extended up to 2 years in patients considered at high-risk for recurrent DVT because of persistence of RVT.Material and Methods. Patients were included at the time of a first diagnosis of cancer-associated DVT of the lower limbs. All received LMWH at therapeutic dosage for the first month (approximately 100 UI anti-FXa b.i.d.) then reduced at 75% for the following months. After 6 months of heparin, the presence of RVT was detected: those without RVT (no-RVT group) suspended treatment, while those with RVT (RVT group) continued LMWH for up to 2 years. Recurrent thrombosis and/or bleeding events were recorded during treatment and one year after LMWH withdrawal. Baseline differences between groups were assessed by the chi-square test (Yates’ correction) for categorical variables and ANOVA test or Kruskal-Wallis test for parametric and nonparametric analyses. Relative risks (RRs) and 95% confidence intervals (CIs) were evaluated.Results. Between January 2009 and April 2011, 211 cancer patients were enrolled; RVT was detected in 129 patients (61.1%). Recurrent VTE occurred in 19 (14.7%); 4 episodes (3.1%) occurred while on heparin. Among patients without RVT (82), 3 (3.6%) developed recurrent VTE (after LMWH therapy). Adjusted HR for RVT vs no-RVT group was 5.8 (95% CI, 1.9 to 19.2; p 0.0003). Three major bleeding events occurred in RVT group and one in no-RVT group (during LMWH administration). The HR for major bleeding (RVT vs no-RVT group) was 2.58 (95% CI, 0.66 to 12.43;p 0.103). Overall, 44 patients (20.8%) died during follow-up as a result of cancer progression.Conclusions. These results indicate that in patients without RVT, a short period of treatment with a LMWH is sufficient; in those with persistent RVT, treatment extended to 2 years substantially reduces, but does not eliminate, the risk of recurrent thrombosis. However, when still on LMWH, the risk for recurrent VTE is low. DisclosuresNo relevant conflicts of interest to declare.

Tinzaparin and VKA use in patients with cancer associated venous thromboembolism: A retrospective cohort study

IntroductionAfter 6months, little is known about the optimal anticoagulant strategy for an acute episode of VTE in cancer patients. Aims, objectives and methodsThe objective was to determine the risk of recurrent VTE and anticoagulant-related bleeding at 6months of follow-up and after 6months, in cancer patients who received tinzaparin during at least 3months for an acute episode of VTE. We conducted a multicenter retrospective cohort study from January 2004 to March 2011. ResultsTwo hundred fifty patients were included. Stopping anticoagulation before 6months in patients considered at low risk by physicians (i.e.; patients who had prior cancer surgery) and for another reason than bleeding or death was the only factor associated with a significant increased risk of recurrent VTE (OR 7.2 95%CI, 2.0-25.7; p=0.002). The type of anticoagulation did not influence the risk of recurrent VTE. We found a trend towards an increased risk of recurrent VTE when anticoagulation was stopped because of major bleeding while on anticoagulant therapy and patients with metastatic cancer (OR 2.3, 95%CI, 0.9-5.4; p=0.07; and OR 1.8 95%CI, 1.0-3.3; p=0.07; respectively). No factors were found to increase the risk of major bleeding at 6months and after. The overall mortality was 42.8%. ConclusionsThe risk of recurrent VTE was mainly related to early discontinuation of anticoagulation in patients considered at low risk of recurrence (after surgery). When the anticoagulation was stopped before the sixth month, the risk was eight fold higher. After 6month, the risks of recurrent VTE, major bleeding and death were similar in patients with either VKA or tinzaparin when patients were treated according to the guidelines.

Efficacy and Safety of Anticoagulant Therapy for the Treatment of Acute Cancer-Associated Thrombosis: A Systematic Review and Meta-Analysis

BackgroundCurrent clinical practice guidelines all recommend the use of therapeutic doses of low molecular weight heparins (LMWH) for the initial and long-term treatment of cancer-related thrombosis. The use of vitamin-K antagonists (VKA) is acceptable if LMWH is not available. Direct oral anticoagulants (DOACs) have been shown to be comparable to conventional therapy for the acute treatment of VTE but their efficacy and safety in cancer patients remains uncertain. MethodsA systematic literature search strategy was conducted using MEDLINE, EMBASE, and the EBM reviews. Randomized controlled trials (RCTs) reporting rates of recurrent VTE and major bleeding in cancer patients were included. Relative risks (RR) (95% confidence intervals (CI)) for these outcomes were generated. ResultsA total of 9 RCTs (2310 patients) were included in our analysis. In comparison to VKA, LMWH showed a significant reduction in recurrent VTE events (RR: 0.52; 95% CI: 0.36 to 0.74) whereas DOACs did not (RR: 0.66; 95% CI: 0.39 to 1.11). LMWH was associated with a non significant increase in the risk of major bleeding (RR: 1.06; 95% CI: 0.5 to 2.23) whereas DOACs showed a non significant reduction (RR: 0.78; 95% CI: 0.42 to 1.44). Annualized risks of recurrent VTE and major bleeding among patients randomized to VKA were higher in the LMWH studies as compared to the studies assessing DOACs suggesting that a higher risk cancer population were enrolled in the LMWH studies. ConclusionsLMWH should be used for the treatment of acute cancer-associated thrombosis. The use DOACs cannot be supported until trials comparing them to LMWH are conducted.

Risk factors for recurrent venous thromboembolism in young and middle-aged women

It is a matter of debate whether women with an episode of VTE associated with estrogen have a lower risk of recurrence than women with an unprovoked VTE. To identify risk factors for recurrent VTE in women and to assess the risk of recurrent VTE associated with combined oral contraceptives (CHC) or menopausal hormone treatment (HT), compared to surgery-related and unprovoked VTE. A cohort of 974 women aged 18-64 years with a first episode of VTE were followed-up for a median time of 5.2 years. All women were previously included as cases in the Swedish nation-wide case-control study "Thrombo Embolism Hormone Study" (TEHS). Hazard ratios for recurrence were calculated using univariable and multivariable Cox proportional hazards model. A total of 102 patients (10%) suffered from recurrent VTE. The annual rate of recurrence was 1.0% in patients with surgery/cast, 2.0% in patients with CHC/HT and 3.2% in patients with unprovoked first VTE. Adjusted hazards ratio (HRa) for recurrence was 0.35 (95% CI 0.20-0.61) in women with VT provoked by surgery/cast while women with estrogen-associated VTE had a HRa of 0.70 (95% CI 0.43-1.20) compared to women with unprovoked VTE. Women 18-64 years are at low risk of recurrent VTE. Women with hormone associated VTE had a lower risk of recurrence than women with unprovoked VTE, but not as low as surgery/cast provoked VTE.

Changes Of Coagulation Activation Parameters After Discontinuation Of VTE Treatment With Vitamin-K Antagonists, Apixaban, Rivaroxaban Or Dabigatran and Impact On Clinical Outcome After 12 Months

BackgroundAt the end of VTE treatment, increasing D-Dimer levels after discontinuation of Vitamin-K antagonists (VKA) have been shown to indicate coagulation activation and increased risk of VTE recurrence. However, it is unknown if changes of coagulation activation parameters will be similar after discontinuation of direct oral anticoagulants (DOAC) such as apixaban, rivaroxaban and dabigatran. Furthermore, the clinical impact of these changes is still unclear. ObjectivesTo quantify changes of coagulation activation parameters at the end of VTE treatment with VKA or DOAC and to evaluate their positive predictive value for VTE recurrence at 12 months. Patients and MethodsBlood samples for coagulation tests were collected from consenting patients with proximal VTE who discontinued anticoagulation treatment at the end of apixaban, dabigatran or rivaroxaban phase-III VTE treatment trials. Furthermore, similar samples were obtained from VKA patients at the end of treatment.From all patients, samples for D-dimer (DD), prothrombin fragments (F1+2) and thrombin-antithrombin complexes (TAT) measurements were collected at the end of treatment and 4 weeks later. Samples were analysed by blinded lab personnel and statistically evaluated for differences between VKA and DOAC regarding changes between both samples as well as absolute values at 4 weeks. Finally, all patients underwent 12 months follow-up by phone calls to establish rates of recurrent VTE or death from any cause. ResultsBlood samples were obtained from patients discontinuing apixaban (A; n=37), dabigatran (D; n=17), rivaroxaban (R; n=9) and VKA (n=184), respectively.Absolute values and relative changes of DD, F1+2 and TAT at baseline and 4 weeks were not significantly different between VKA or the DOAC cohorts. Irrespective of the anticoagulant treatment, DD and F1+2 but not TAT demonstrated a significant increase between baseline and week 4 (figure 1). [Display omitted] At 12 months, 18 patients (7.3%) had recurrent VTE and 2 patients (0.8%) were dead. Regarding clinical outcomes at 12 months, the negative predictive values (NPV) of DD, F1+2 and TAT were highest for patients after VKA treatment (at least 0.93) and systematically lower for DOAC patients (ranging between 0.86 and 0.91).In contrast, positive predictive values (PPV) of DD, F1+2 and TAT were systematically higher in DOAC patients (0.19 to 0.43) compared to VKA patients (0.03-0.16) with highest values for TAT-complexes > 200% baseline (PPV VKA 0.14; PPV DOAC 0.43), which was also seen in logistic regression analysis with a significant risk increase for VTE/death (Odds ratio for TAT > 200% baseline 5.0; p=0.006). None of the other parameters showed a correlation to the risk of recurrent VTE or death. ConclusionChanges of DD, F1+2 and TAT values post treatment are not different between patients discontinuing VTE treatment with VKA, apixaban, dabigatran or rivaroxaban. NPV of DD, F1+2 and TAT for recurrent VTE/death are higher in VKA than DOAC patients, while PPV are higher in DOAC patients.At 4 weeks, a TAT increase over 200% of baseline value was found to be associated with a 5-fold increase of recurrent VTE or death with a PPV of 0.14 for VKA patients and of 0.43 for DOAC patients. Disclosures:Werth:Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Research Funding, Speakers Bureau; Boehringer Ingelheim: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.

Predicting the risk of recurrent venous thromboembolism

SummaryVenous thromboembolism (VTE) is a disease, which often recurs. The recurrence risk is highest in patients with unprovoked proximal deep-vein thrombosis (VT) or pulmonary embolism. Men have a higher risk than women. The risk is low in patients with VTE related to a temporary risk factor such as surgery or estrogen use. Other risk factors include overweight, post-thrombotic syndrome, history of VTE, residual VT or a vena cava filter.Both factor V Leiden and the prothrombin mutation confer a negligible increase in recurrence risk. High clotting factor levels, deficiency of a natural coagulation inhibitor, or hyperhomocysteinaemia are also associated with an increased risk. Reasons why routine laboratory thrombophilia screening however is no longer warranted are addressed in this article. Prediction rules combining clinical characteristics and coagulation assays have recently been developed. One such model, the Vienna Prediction Model, allows predicting recurrent VTE on the basis of VTE location, sex and D-dimer. This article describes strategies to distinguish between patients with high risk of recurrent VTE from those with a lower risk, who might not benefit from long-term antithrombotic therapy.

The occurrence of venous thromboembolism in cancer patients following major surgery

BackgroundVenous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is common in cancer patients and surgery is an important risk factor. ObjectiveTo describe the occurrence of VTE in cancer patients following major surgery and to determine the risk of VTE recurrence. MethodsUsing the administrative health claims (RAMQ) and hospital discharge (MED-ECHO) databases of the province of Québec, Canada, we constructed a cohort of all individuals with incident VTE between January 1, 1994 and December 31, 2004 diagnosed with cancer and who had major surgery in the 91days prior to the VTE. The timing of VTE after surgery was determined. Recurrent VTE was defined as re-hospitalization with a principal discharge diagnosis of VTE. ResultsOur cohort consisted of 2706 cancer patients with VTE following major surgery. The mean age was 65.9years (Standard Deviation 12.6) and 54% were female. The median duration of surgical hospitalization was 18days (range 1-735days). The median time to VTE following surgery was 15days (range 1-659days), and 34% of VTE events were diagnosed after hospital discharge. The 1-year cumulative rate of recurrence was 6.7% (95% CI 5.7, 7.9) and the 5-year cumulative rate was 12.6% (95% CI 10.7, 14.7). Increasing comorbidity (adjusted hazard ratio (HR) 2.49, 95% CI 1.58-3.95) and VTE diagnosed after hospital discharge (adjusted HR 1.48, 95% CI 1.09-2.01) were associated with recurrence. ConclusionsA significant proportion of VTE episodes among surgical patients with cancer are diagnosed after discharge from hospital. This suggests that surgical patients with cancer are at risk for VTE beyond the immediate postoperative period.

Incidental Versus Symptomatic Pulmonary Embolism in Cancer Patients: A Multivariate Analysis of Recurrent VTE and Mortality.

AbstractAbstract 2257Venous thromboembolism (VTE) is a major cause of morbidity and mortality in cancer. In the context of frequent high-resolution imaging, pulmonary emboli (PE) are frequently identified incidental to other indications for imaging. Several key questions need answers. In cancer, are incidentally identified and symptomatic PEs of comparable clinical importance regarding risk of recurrent VTE and death? Can we identify a subgroup of patients with incidentally identified PEs for whom the risk of recurrent VTE is sufficiently low that long-term anticoagulation may not be necessary? Several recent studies suggest that incidental PE may result in comparable rates of recurrent VTE and death as symptomatic PE. However, those studies did not control for cancer type and anatomic distribution of the initial PE. We now report a comprehensive data set on PE in cancer, derived from MSKCC. All PE in a 2-year period (2008–9) were reviewed, with 2-year follow-up. We evaluated the cases for all cause mortality with time, as well as all recurrent VTE.There were 755 initial symptomatic PE with 122 recurrent VTE events and 574 initial incidental PEs with 124 recurrent VTE. 43.2% of all PEs were identified incidentally. The percent of total PEs that were identified incidentally varied markedly with different cancer types, pancreas (70.7%), colorectal (61.4%), hematologic (33.3%), gastro-esophageal (37.7%), lung (32.8%), breast (15.1%), gynecological (30.0%), brain (5.0%). Brain tumor patients less frequently undergo comprehensive body imaging for cancer staging, and therefore, asymptomatic PEs may be less likely identified incidentally. Because of the well-recognized differences in rates of recurrent VTE and mortality in different cancer types, differences in the percent of incidental PEs supports the necessity of considering cancer type in outcome analysis.The overall hazard ratios of death and recurrent VTE were highest in the first month after the initial PE, gradually declining with time. The cumulative rates of all cause mortality was higher for symptomatic PE in the initial 2 months, but equalized by 12 months. (All cause mortality, symptomatic PE: 1 month: 15%, 2 month: 24%, 6 month: 40%, 12 month: 53%. Incidental PE: 1 month: 6%, 2 month: 12%, 6 month: 30%, 12 month: 47%). Cumulative rates of recurrent VTE were similar in both cohorts. (Symptomatic PE: 3 month: 11.0%, 6 month: 13.6%, 12 month: 16.0%. Incidental PE: 3 month: 11.7%, 6 month: 17.1%, 12 month: 21.4%). For most major cancer types, early (1-month) mortality and 12-month recurrent VTE rates were similar regardless of the incidental versus symptomatic nature of the initial PE. However, for colorectal cancer, the 1-month mortality for symptomatic PE was 14.3% (8 of 56), but only 3.4% (3 of 89) for incidental PE, and the 12-month recurrent VTE rate was 17.9% for symptomatic PE and 5.6% for incidental PE.The anatomic location of the initial PE also evaluated. Segmental arteries were the most common initial location of symptomatic (45%) and incidental (47%) PE. Importantly, after an initial incidental PE, the risk of recurrent VTE was consistent, regardless of the initial anatomic location. For each category; main plus saddle, lobar, segmental, and subsegmental, the recurrent VTE rates were between 20 – 25%. The fact that a cancer patient exhibits a PE predicts recurrent VTE, with less relevance to the anatomic location of the initial event. Conclusions:In our institution, 43.2% of PEs in cancer patients were identified incidentally, by imaging studies performed for cancer staging, or evaluation of complaints not typically associated with PE. All cause mortality was twice as high in the first two months after a symptomatic PE as an incidental PE, but by the third month, the monthly rates became equivalent. The hazard ratio of recurrent VTE was similar between the symptomatic PE and incidental PE cohorts, including subgroups. A possible exception is in colorectal cancer, in which the 1- month mortality and 12-month recurrent VTE rates were higher for symptomatic PE. However, due to the retrospective nature of this study, and the multiple parameters considered, that observation needs confirmation. As even “small” subsegmental PEs are associated with recurrent VTE rates comparable to large proximal PEs, our data do not suggest that there are any subgroups for which anticoagulation is not justified. Disclosures:No relevant conflicts of interest to declare.

Benefit of Extended Maintenance Therapy for Venous Thromboembolism with Dabigatran Etexilate Is Maintained Over 1 Year of Post-Treatment Follow-up

AbstractAbstract 21 Background:The RE-SONATE trial compared 6 months of dabigatran etexilate (DE) 150 mg twice daily to placebo in patients at equipoise for needing additional oral anticoagulation following 6–18 months of anticoagulant therapy with a vitamin K antagonist. DE provided a 92% relative risk reduction for recurrent symptomatic VTE compared with placebo and a low risk of major bleeding. We present here the results of an extended observational follow-up period of 12 months following completion of study treatment, which was conducted to determine whether there was an increase in VTE recurrence following discontinuation of study treatment. Methods:RE-SONATE is an international, randomized, double-blind, event-driven, superiority study for efficacy. Patients were ≥ 18 years of age with creatinine clearance ≥ 30 mL/min. The primary efficacy endpoint (assessed by an independent adjudication committee blinded to treatment allocation) was symptomatic recurrent VTE (including symptomatic deep vein thrombosis, non-fatal and fatal pulmonary embolism) and unexplained death. The primary safety endpoint was major bleeding. Events were counted within the intended treatment period plus 3 days. A protocol amendment extended the post-treatment follow-up period from 1 month to 12 months. The extended follow-up population, used for the analysis of efficacy for patients who continued into this period, was a subset of the full analysis set, including patients who signed the consent form for the relevant protocol amendment. Results:In the initial double-blind treatment period of up to 6 months from randomization, recurrent symptomatic VTE or unexplained death occurred in 3 (0.4%) of 681 patients treated with DE and 37 (5.6%) of 662 patients treated with placebo (hazard ratio [HR] 0.08; 95% CI 0.02, 0.25%; P < 0.0001). Two patients had major bleeds (0.39%) on treatment with DE versus none in the placebo group. No unexplained deaths occurred in the DE group compared with one in the placebo group (Schulman et al. J Thromb Haem 2011 Supp 2 11–10626).In the extended follow-up analysis of 1323 patients, the cumulative incidences of recurrent symptomatic VTE and unexplained death at intermediate time points during the uncontrolled, post-treatment follow-up were (Table 1): at 40 days, 2.0% in the former DE group versus 5.7% in the former placebo group (p=0.0005); and at 6 months, 6.0% versus 10.2% (p=0.0060), respectively. These represent absolute risk differences of 3.7% and 4.3% after 40 days and 6 months of uncontrolled follow-up, respectively. At 1 year of follow-up (540 days after randomization), these events occurred in 7.8% in the former DE group compared with 11.6% in the former placebo group (p=0.0261), for a risk difference of 3.8% (95% CI 0.5%, 7.1%). Conclusions:The reduced risk of recurrent VTE associated with extending treatment with DE during the double-blind treatment period is preserved during 1 year of follow-up after discontinuation of study drug. However, the high rate of recurrent VTE, even in the former DE treatment group (7–8%), suggests that a longer duration of anticoagulant therapy may be warranted.Table 1Rates and risk differences for symptomatic recurrent VTE and unexplained death at different durations of follow-up after the double-blind treatment periodDEPlacebo40 daysPatients with events/total, n/n (%)13/614 (2.0)37/566 (5.7)Absolute risk difference, % (95% CI)3.7 (1.6, 5.8)Superiority P-value0.00056 monthsPatients with events/total, n/n (%)37/557 (6.0)63/502 (10.2)Absolute risk difference, % (95% CI)4.3 (1.2, 7.3)Superiority P-value0.006012 monthsPatients with events/total, n/n (%)47/378 (7.8)70/355 (11.6)Absolute risk difference, % (95% CI)3.8 (0.5, 7.1)Superiority P-value0.0261 Disclosures:Off Label Use: Dabigatran etexilate is an oral thrombin inhibitor under investigation for anticoagulant prophylaxis or treatment in venous and arterial thrombomebolism. Baanstra:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.

Increased ADAMTS13 activity in patients with venous thromboembolism

Increased levels of inflammatory markers and clotting factors have been related to the pathogenesis and prognosis of venous thromboembolism. In particular, the imbalance between VWF and ADAMTS13 has been described in patients with arterial thrombosis. In this study, 77 patients with previous VTE and 77 matched controls were selected for the evaluation of the inflammatory markers, FVW, ADAMTS 13 and D-dimer. The presences of post-thrombotic syndrome and residual vein obstruction were also assessed in patients. Serum levels of TNF-α and IL-6 were significantly increased in patients compared to controls (median=2.25 vs 1.59pg/mL, P≤0.001; 1.16 vs 0.98pg/ml, P=0.013, respectively). Plasma levels and activity of VWF (median=150.25 vs 95.39U/dL, P≤0.001; 145.26% vs 92.39%, P≤0.001) and ADAMTS 13 (median=1088.84 vs 950.80ng/mL, P≤0.001; 96.03 vs 83.64%, P≤0.001) were also higher in patients. We further analysed the subgroups of patients with higher risk for VTE recurrence or VTE sequelae, defined as the presence of high D-dimer levels, RVO or PTS. All inflammatory markers were significantly higher in patients with increased D-dimer. The presence of PTS or RVO was not associated with higher inflammatory or coagulation parameters. The increased levels of inflammatory markers and VWF may suggest that there is a persistence of inflammatory activity in patients even at long periods after the VTE episode. In this context, it may be postulated that increased levels of ADAMTS13 could represent a compensatory mechanism against persistently increased levels of VWF. Moreover, increased inflammatory activity was associated with increased D-dimer levels, thus it is possible that this inflammatory activity may also be related to the risk of VTE recurrence.

Validation of the Caprini risk assessment model in Chinese hospitalized patients with venous thromboembolism

IntroductionVenous thromboembolism (VTE) occurs frequently in at-risk hospitalized patients, and prophylaxis of VTE is significantly underused. We sought to preliminarily assess the validity of Caprini risk assessment model, a famous individual VTE risk assessment model, in Chinese hospitalized patients with VTE. Materials and MethodsWe undertook a retrospective study combined with a follow-up study among 347 confirmed VTE patients from a Chinese hospital. ResultsCompared with the other two risk assessment models (RAMs), Caprini model can classify much more VTE patients into high or highest risk level and the differences were statistically significant (Caprini model vs Kucher model, p<0.0001; Caprini model vs the Padua Prediction Score, p<0.0001). Caprini model exhibited much more effect at assessing patient's VTE risk among surgical patients than nonsurgical patients(average risk score, 5.71±2.54 vs 4.36±2.51, p<0.0001; by Wilcoxon rank sum test, p=0.001 in favor of the prediction effect of the RAM in surgical patients). Kaplan-Meier analysis showed that patients classified into low and highest risk level by Caprini model had increased hazard for VTE recurrence when compared with patients classified into moderate and high risk level, but the result was not statistically significant (p=0.222). ConclusionsOur study preliminarily suggests that the Caprini risk assessment model is a practical and effective tool to assess the risk of VTE among unselected Chinese inpatients and may also be useful in predicting the risk of VTE recurrence. However, future studies with control group and prospective validation of the model in Chinese inpatients are needed.

Long-term death and recurrence in patients with acute venous thromboembolism: The MASTER registry

BackgroundThe long-term clinical outcome of VTE has been essentially assessed in cohorts of selected patients. The aim of this multicenter registry was to prospectively assess the long-term clinical outcome in a cohort of unselected patients with objectively confirmed acute VTE. Materials and MethodsDeath and VTE recurrence at 24months were the main study outcomes. Univariate and multivariate survival analyses were performed according to the Kaplan-Meyer and Cox proportional hazard model, respectively. Results2119 patients with acute VTE were included in the registry: 1541 (72.7%) with deep vein thrombosis, 206 (9.7%) with pulmonary embolism and 372 (17.6%) with both. Information about death was available in 2021 patients (95.4%) and about recurrence in 1988 patients (93.8%). 167 patients (4.55% patient-year) died during follow-up. After adjusting for age, cancer (Hazard ratio [HR]: 7.2; 95%CI 4.8-10.8), long-term heparin treatment (HR: 2.5; 95%CI 1.8-3.5), in-hospital management of VTE (HR: 2.0; 95%CI 1.3-3.0), and ileo-caval thrombosis (HR: 1.7; 95%CI 1.2-2.4) were found to be independent predictors of death. 124 (3.63% patient-year) patients had a VTE recurrence during follow-up. In-hospital management of VTE (HR: 1.8; 95%CI 1.2-2.9), male gender (HR: 1.7; 95%CI 1.2-2.4) were independent risk factors for recurrent VTE. Cancer (HR: 1.6; 95%CI 1.0-2.8) showed a trend for increased risk of VTE recurrence (p=0.056). The reported rate of major bleeding was 2.5%. ConclusionsIn a large cohort of unselected VTE patients, cancer, ileo-caval thrombosis, long-term heparin treatment and in-hospital management were associated with increased mortality during long-term follow-up. In-hospital management, male gender were associated with an increased risk of VTE recurrence.

Is the Pooled Analysis of the North Central Cancer Treatment Group Phase III Trials N9741 and N9841 Biased?

(VTE) may be associated with a poor outcome. 2 VTE is a major public health issue and one of the most important causes of morbidity and mortality in patients with cancer, with a negative impact on their quality of life. It has been estimated that VTE is the second leading cause of death in hospitalized and ambulatory patients with cancer. While receiving chemotherapy, patients with cancer have a seven-fold risk of developing VTE as compared with other patients without cancer. 3 In the N9741 and N9841 trials, Franko et al 1 did not report this type of toxicity. There are several reasons for the underreporting of VTE events. First, in its initial version, the National Cancer Institute Criteria for Common Toxicity did not include VTE. This observation is particularly pertinent for the study published by Franko et al because the authors used version 2 of the Common Toxicity Criteria. Second, the current toxicity definitions with respect to VTE are poor and need clarification. No differences are highlighted between proximal and distal venous thrombosis, although patients with deep vein thrombosis (DVT) of the calf have approximately half the risk of recurrent VTE as those who have had a proximal DVT. Furthermore, the risk of developing pulmonary embolism is increased for patients with proximal DVT as compared to those with distal DVT. In addition, grade 2 and grade 3 are strictly related to the need of a therapeutic approach, whereas clinical situations where oncologist cannot give an active treatment because of thrombocytopenia or other transient medical conditions are not uncommon.

Clinical scores to predict recurrence risk of venous thromboembolism

Venous thromboembolism (VTE) is a common and chronic disease with a considerable risk of recurrence. Patients with unprovoked (in the absence of a transient risk factor) VTE have a recurrence risk as high as 30% within five years after cessation of anticoagulation. Depending on patient selection the case-fatality rate of recurrence ranges between 3.6%-10%. Thus, indefinite anticoagulation treatment should be considered in these patients. However, anticoagulation confers a considerable risk of bleeding (fatal bleedings 0.1%-0.5%/year). It is therefore of utmost clinical importance to identify those patients, who will not benefit from indefinite anticoagulation, i.e. patients, in whom the bleeding risk during anticoagulant treatment is higher than the risk of recurrence. Several attempts to discriminate patients with a high from those with a low risk of recurrence including screening for acquired and inherited thrombotic risk factors or measurement of coagulation activation markers have either failed (thrombophilia screening) or were of moderate success (stratification according to D-dimer only). A novel approach for assessing risk of recurrent VTE consists of linking clinical patient characteristics with laboratory testing. Several such scoring models which can be used to assess the risk of recurrent VTE have been developed and await prospective validation before they can be applied in daily routine care. The aim of this report is to describe currently available scoring systems in more detail.

Anatomical Distribution of First VTE Event and Risk of VTE Recurrence: Long Term Follow-up and Retrospective Analysis of 346 Patients. Experience From a Single Center

Abstract 1224▪▪This icon denotes a clinically relevant abstractVenous thromboembolism (VTE) is a chronic disease with recurrence risk that persists over the years. Predicting the chance of recurrence on an individual basis is of paramount importance for the appropriate tailoring of anticoagulant therapy. Recurrence risk is affected by thrombophilia and is lower in patients with provoked VTE than in patients with unprovoked thrombosis. Up to date there are no studies focused on the recurrence risk according to the anatomical distribution of the 1st VTE event.In order to evaluate the risk factors of VTE recurrence, after a review of relevant literature we set specific laboratory and clinical variables, which could be associated with VTE recurrence. Moreover, we evaluated retrospectively 346 patients of the Haemostasis Unit, who had already had an episode of VTE concerning the risk of VTE recurrence. Data statistical analysis was done with SPSS package 15.0. At first a monovariable statistical model was used with significance levels set at p= 0.05. For the multivariable statistical analysis model we used all variables with p< 0.1 from the previous model and those mentioned at recent medical literature as significantly related with VTE recurrence.The 346 patients enrolled had already suffered a first episode of VTE and are being followed up regarding VTE recurrence. The study population, 169 (48.7%) male and 178 (51.3%) female, had a mean age at first VTE of 41.54 years. The exclusion criteria of our study were: high risk patients for VTE recurrence who received indefinite anticoagulation (n=72), patients who have suffered VTE and had a follow up period after discontinuation of anticoagulation shorter than 2 years (n=73) and patients who were lost at follow up (n=15). Among 194 patients who were enrolled 108 (55.7%) were women and 86 (44.3%) men, with a mean age at 1st VTE of 40.10 years. 114 patients had only one VTE episode, 59 suffered two, 16 patients had tree episodes and 5 patients had >= 4 episodes.Based on previously published data we tried to define whether the following variables are high risk factors for VTE recurrence in our population: gender, age of diagnosis, thrombophilic factors (FVLeiden, FII, HCY, VIII, AT, PrC, PrS, PAI1, Lp(a), XII), the presence of unprovoked VTE episode and VTE location (DVT, PE, CNS Thrombosis). Male gender p=0,038, FVLeiden homozygous p=0.036, the presence of unprovoked VTE p=0.029, and VTE location p= 0.05 reached statistical significance on a monovariable analysis.Based on the previous analysis and on previously published data we applied gender, age at the time of diagnosis, presence of unprovoked VTE episode and VTE location on a multiple regression analysis in order to define independent risk factors concerning VTE recurrence (Table 1).Table 1Independent Risk factors concerning VTE recurrenceRisk FactorORCI 95%FVLeiden9.7931.07–89.62Unprovoked VTE9.7571.404–5.414Pulmonary embolism11.5321.419–93.746Deep Venus Thrombosis (DVT)17.7932.232–141.841Concerning VTE location, CNS thrombosis has the lowest risk for VTE recurrence and Pulmonary embolism and DVT are independent risk factors compared to the first one.Among VTE events CNS thrombosis and DVT/PE share similarities regarding the transient risk factors and the presence of predisposing thrombophilias. As far as the recurrence risk after a first VTE our study demonstrates ( in agreement with current literature) that CNS thrombosis carries recurrence risk statistically lesser than PE and the highest recurrence risk carry the patients after a first DVT event. Our study is the first observational study regarding recurrence risk after VTE coming from Greece. Disclosures:No relevant conflicts of interest to declare.

Guidelines on oral anticoagulation with warfarin – fourth edition

Guidelines on oral anticoagulation with warfarin – fourth edition

Low prevalence of JAK2 V617F mutation in patients with first unprovoked venous thromboembolism

Low prevalence of <i>JAK2</i> V617F mutation in patients with first unprovoked venous thromboembolism

Mortality and recurrence after treatment of VTE: Long term follow-up of patients with good life-expectancy

Introduction After completed anticoagulant treatment for acute VTE, both the subsequent mortality and risk of recurrent VTE are high, probably related to the frequent presence of serious disease in these patients. The aim of the study was to determine survival and recurrence in selected patients with good life-expectancy, and to evaluate risk factors. Methods The 323 patients were followed for median 7.4 years (range 4.1-11.9) after cessation of anticoagulation. Survival analysis and Cox-regression were used for univariate and multivariate analysis. Results The cumulative incidence of survival after 5 years was 93.4%. Standardised mortality ratio was 1.42 for men and 1.28 for women. Patients without a transient risk factor prior to the index VTE were associated with higher risk of mortality compared to risk of mortality in patients with a transient risk factor (hazard ratio (HR) 2.81; 95% CI 1.40-5.62). Recurrence of VTE after 5 years was 19.0%. A persistent risk factor or a spontaneous VTE was associated with higher risk of recurrence compared to a transient risk factor (HR 2.39; 95% CI 1.44-3.95). Elevated D-dimer levels increased the risk, and immobilisation prior to the index VTE reduced the risk of recurrence. Sex, age and thrombophilia were not independent risk factors for recurrence. Conclusions Despite a low mortality rate in this selected cohort, the recurrence rate and risk factors for recurrence were similar to findings reported in unselected populations. VTE unrelated to a transient risk factor was associated with increased mortality compared to mortality in patients with a transient risk factor.

A Large, Population Based Study of Sex Differences In the Risk of Recurrent Venous Thromboembolism

AbstractAbstract 4204 Background.Most reports of patient sex differences in the risk of recurrent VTE have been based on small or moderate sized cohorts of selected patients with VTE. Objectives.We used the administrative hospital discharge registry of Quebec, Canada to conduct a population-based retrospective cohort study to evaluate the effect of sex on rates of recurrent VTE. Methods.Using data from the province-wide hospital discharge database (Med-Echo) which systematically records information on all hospital admissions in the province of Quebec since 1967, we constructed a cohort of all individuals who had a first-time discharge diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE) between January 1, 1996 and December 31, 2004 and no prior discharge diagnosis for DVT or PE back to 1983. Subjects were followed from the time of diagnosis until first VTE recurrence, death, or end of study (December 31, 2005). DVT and PE were defined based on the International Classification of Diseases, 9th edition, Clinical Modification. Results.The cohort comprised 55,314 patients (43% men and 57% women) with incident VTE. Mean age was 61.9 years (60.4 years (men) vs. 63.1 years (women); p=0.0001), and 33,535 (61%) had DVT alone, 14,574 (26%) had PE alone and 7,205 (13%) had both DVT and PE. During a mean follow-up of 3.9 years, 5,243 (9.5%) of patients developed recurrent VTE, which corresponded to an incidence rate of 2.4 events per 100 patient-years (95% confidence interval (CI), 2.3–2.5 per 100 patient-years). In survival analysis, men had significantly higher rate of recurrence than women (age- and comorbidity-adjusted hazard ratio = 1.14; 95% CI, 1.08–1.21), and at 5 years, the cumulative risk of recurrent VTE was 8.3% among men vs. 7.3% among women (p=0.0001). Mean age at the time of VTE recurrence in men vs. women was 61.1 years and 64.4 years, respectively (p=0.0001). Conclusion.Our study of over 55,000 patients hospitalized with VTE is the largest to date to report an effect of patient sex on risk of VTE recurrence, with men having about a 15% higher risk of recurrence than women. This provides further evidence that the difference in risk of VTE recurrence between men and women is significant and if confirmed by ongoing prospective management studies, patient sex should be considered in determining duration of anticoagulation treatment in patients with VTE. Disclosures:Taglalakis:Pfizer: Research Funding; Sanofi Aventis: Honoraria. Kahn:Sigvaris: Research Funding; sanofi-aventis: Advisory Board, Research Funding; Boehringer Ingelheim:.

Patients with Cancer Who Develop a First Venous Thromboembolic Event After Surgery Are at High Risk of Venous Thromboembolism Recurrence During the Anticoagulation Period

AbstractAbstract 4202 Background:It is unknown whether patients with cancer who develop VTE after a surgical procedure have the same risk of recurrent VTE as clinical patients cancer-associated thrombosis. VTE recurrence risk in non-cancer patients with VTE after surgery is approximately 1% in the 3 months following completion of anticoagulation. It is unknown whether surgical patients with cancer follow the low risk of recurrence as other provoked VTEs or whether they have the high recurrence risk typical of cancer patients. Methods:We performed a post-hoc analysis of a single centre retrospective cohort study conducted at the Thrombosis Unit of the Ottawa Hospital. The charts of patients with cancer and VTE followed from 2002 to 2004 and from 2007 to 2008 were reviewed. We sought to compare the risk of recurrent VTE between patients with cancer who developed a first VTE after major surgery with all other patients with cancer-associated thrombosis. We included patients > or = 18 years of age with active malignancy and objectively diagnosed index VTE [pulmonary embolism (PE), proximal deep venous thrombosis (DVT) of the legs or arms, PE + DVT; unusual site thrombosis]. After the first VTE, all patients received a minimum of 6 months of anticoagulation. In the surgery group, index VTE was considered associated with the intervention if it occurred within the first 3 months after the procedure. Results:543 patients were included. 121 patients had VTE after surgery and 17 (13.1%) developed a recurrence during therapeutic anticoagulation. Of 422 clinical patients, 61 (14.7%) had a recurrent VTE (Table). The relative risk of recurrent VTE comparing patients who had and who did not have surgery was non-significant (RR= 0.97 (95%CI: 0.587 – 1.574; p= 1.000) suggesting that patients with cancer who undergo surgery have similar risk of developing a recurrent VTE during anticoagulation as patients with cancer-associated VTE who do not undergo surgery. VTE recurrence occurred predominantly within the first 6 months of anticoagulation [Surgery: 9 of 17 patients (52.9 %); no surgery: 45 of 61 (73.7%) patients (p=0.1377)] (Figure). There was no significant difference in VTE recurrence risk according to anticoagulant strategy, tumor site, histology, TNM stage, age or gender between surgery and no surgery groups. Conclusion:Patients with cancer who develop VTE after surgery have similar risk of developing a recurrent VTE during the anticoagulation period as clinical patients with cancer-associated VTE. [Display omitted] Disclosures:Rodger:Pfizer: Research Funding; Leo Pharma: Research Funding; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Institutes of Health Research: Research Funding; Heart and Stroke Foundation: Research Funding.