Episode Of Unprovoked Venous Thromboembolism Research Articles

Clinical outcomes after discontinuing anticoagulant therapy in patients with first unprovoked venous thromboembolism

BackgroundThe duration of anticoagulation for a first episode of unprovoked venous thromboembolism (VTE) should balance the likelihood of VTE recurrence against the risk of major bleeding. ObjectivesAnalyze rates and case-fatality rates (CFRs) of recurrent VTE and major bleeding after discontinuing anticoagulation in patients with a first unprovoked VTE after at least 3 months of anticoagulation. MethodsWe compared the rates and CFRs in patients of the Registro Informatizado Enfermedad Trombo Embólica (RIETE) and Contemporary management and outcomes in patients with venous thromboembolism registries. We used logistic regression models to identify predictors for recurrent pulmonary embolism (PE) and major bleeding. ResultsOf 8261 patients with unprovoked VTE in RIETE registry, 4012 (48.6%) had isolated deep vein thrombosis (DVT) and 4250 had PE. Follow-up (median, 318 days) showed 543 recurrent DVTs, 540 recurrent PEs, 71 major bleeding episodes, and 447 deaths. The Contemporary management and outcomes in patients with venous thromboembolism registry yielded similar results. Corresponding CFRs of recurrent DVT, PE, and major bleeding were 0.4%, 4.6%, and 24%, respectively. On multivariable analyses, initial PE presentation (hazard ratio [HR], 3.03; 95% CI, 2.49-3.69), dementia (HR, 1.47; 95% CI, 1.01-2.13), and anemia (HR, 0.72; 95% CI, 0.57-0.91) predicted recurrent PE, whereas older age (HR, 2.11; 95% CI, 1.15-3.87), inflammatory bowel disease (HR, 4.39; 95% CI, 1.00-19.3), and anemia (HR, 2.24; 95% CI, 1.35-3.73) predicted major bleeding. Prognostic scores were formulated, with C statistics of 0.63 for recurrent PE and 0.69 for major bleeding. ConclusionRecurrent DVT and PE were frequent but had low CFRs (0.4% and 4.6%, respectively) after discontinuing anticoagulation. On the contrary, major bleeding was rare but had high CFR (24%). A few clinical factors may predict these outcomes.

Identification of outcomes in clinical studies of interventions for venous thromboembolism in non‐pregnant adults

Identification of outcomes in clinical studies of interventions for venous thromboembolism in non‐pregnant adults

Extended anticoagulation for venous thromboembolism: A survey of the American Venous Forum and the European Venous Forum

ObjectiveExtended anticoagulation therapy should always be considered after standard treatment of an unprovoked episode of venous thromboembolism (VTE). It can also be considered for selected patients with provoked VTE. However, the evidence-based protocols suggested by some clinical guidelines and risk assessment tools to guide this practice are limited and ambiguous. The goal of the present survey research was to analyze current practices in applying extended anticoagulation therapy for patients with VTE among members of the American Venous Forum (AVF) and European Venous Forum (EVF). MethodsAn online survey was created by the AVF Research Committee. The survey consisted of 16 questions to identify the country of practice, specialty, experience of the participating physicians, and their clinical practice patterns in applying extended anticoagulation therapy for VTE patients. The survey was distributed via e-mail to the members of the AVF and EVF. ResultsA total of 144 practitioners, 48 AVF members (33%) and 96 EVF members (66%), participated in the survey. Most of the respondents identified themselves as vascular specialists with primary certification in vascular surgery (70%), vascular medicine or angiology (9%), and venous disease or phlebology (3%). Of the 144 respondents, 72% believed that the risk of VTE recurrence will generally overweigh the risk of bleeding for patients with unprovoked VTE. Extended anticoagulation therapy might be used by 97% of providers. Different patterns in real world clinical practice were identified. More than one half of the practitioners estimated the VTE recurrence and bleeding risk subjectively. The antithrombotic drugs most commonly used for secondary prophylaxis were rivaroxaban, apixaban, warfarin, dabigatran, and aspirin, in decreasing order of frequency. Among the reasons selected for not regularly considering extended anticoagulation therapy were the lack of specific clinical practice guidelines (24%), lack of reported evidence (9%), and absence of valid VTE and/or bleeding risk prediction calculators (8%). Twelve participants (8%) stated that extended anticoagulation therapy would not be beneficial for most patients with VTE. Ten participants (7%) indicated that prescribing extended anticoagulation therapy was outside the scope of their specialty. ConclusionsDifferent practice patterns exist regarding extending anticoagulation therapy beyond the standard treatment for patients with VTE. Major gaps in knowledge remain a serious challenge at least partially explaining the inaccuracy and inconsistency in long-term VTE management. Appropriately designed studies are needed to evaluate risk stratification tools when contemporary best medical therapy is used, accurately predict VTE recurrence and its long-term outcomes, and tailor safe and effective secondary prophylaxis.

Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE.

Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE.

Novel biomarkers to detect occult cancer in patients with unprovoked venous thromboembolism: Rationale and design of the PLATO-VTE study

Occult cancer is detected in about 5% of patients with unprovoked venous thromboembolism (VTE) in the 12 months following VTE diagnosis. Current guidance suggests conducting a ‘limited’ cancer screening in these patients, consisting of medical history taking, physical examination, routine blood tests, chest X-ray, and age- and gender-specific testing, over full-body imaging. However, almost half of underlying cancers remain undetected with this approach. Blood-based liquid biopsies may provide an attractive addition or alternative to current cancer screening strategies, with a potentially higher detection rate while avoiding radiation or invasive testing.The PLATO-VTE study is an ongoing, investigator-initiated, multinational, prospective, observational cohort study comparing the sensitivity of novel biomarkers for detecting cancer with that of limited cancer screening in the setting of unprovoked VTE. Patients older than 40 years with a first episode of unprovoked VTE are eligible, while those with major and minor transient provoking risk factors for VTE are excluded. Patients undergo standard-of-care ‘limited’ cancer screening and are followed for 12 months for the occurrence of cancer. A blood sample for biomarker analysis is drawn within 10 days; a second sample is taken at 3 months to assess test result consistency over time. Three biomarkers are assessed: platelet mRNA, circulating tumor DNA, and plasma proteomics analysis. The sensitivity and predictive value of the biomarkers at baseline will be compared with those of limited screening.The results from the PLATO-VTE study may lead to reconsider current approaches for cancer screening in patients with unprovoked VTE.

Does age-adjusted D-Dimer have a role in assessment of VTE recurrence rates?

It is known that D-dimer levels increase with age and several studies have evaluated the use of an age-adjusted (AA) cut-off in the initial assessment of suspected venous thromboembolism (VTE). We performed a retrospective study to assess the effect that using an AA D-dimer in the DASH score would have on the recommended duration of anticoagulant treatment for patients following a first unprovoked episode of VTE and then compared this with the advice that has been given to patients using a fixed cut-off D-dimer in the DASH score. Data were collected for the period from April 2014 to October 2017. For each patient, the DASH score by a single cut-off D-dimer value (500ng/mL) as well as an AA D-dimer cut-off value (D-dimer cut-off value equal to age in years×10) was calculated for patients over 50years. The Vienna prediction model was employed alongside this to compare the VTE recurrence risk using a well-established method. A total of 204 patients were eligible for analysis, 145 of whom were over the age of 50years. In 24 of these patients, the use of the AA D-dimer made a significant impact on the predicted risk of recurrence using the DASH score and would have likely changed the recommendation to offer long-term anticoagulation. As an age-adjusted D-dimer cut-off has been assessed in the diagnostic setting, it would be logical and appropriate to also consider this philosophy in the prediction of the risk of recurrence of VTE following a first unprovoked event.

Does cell-free DNA promote coagulation and inhibit fibrinolysis in patients with unprovoked venous thromboembolism?

IntroductionCell-free DNA (CFDNA) is the major structural component of neutrophil extracellular traps (NETs). CFDNA contributes to the prothrombotic potential of NETs by promoting thrombin generation and inhibiting fibrinolysis. Patients with venous thromboembolism (VTE) have elevated circulating nucleosomes (i.e. DNA-histone complexes). In this study, we investigated if CFDNA contributes to a procoagulant and an antifibrinolytic state in patients with unprovoked VTE. Materials and methodsPlasma samples from patients with a first episode of unprovoked VTE were obtained from the D-Dimer Optimal Duration Study (DODS). We measured CFDNA plasma levels in 263 patients while on warfarin and 1-month after stopping. Thrombin generation assays and clot lysis assays were measured in patients after stopping warfarin. Comparisons were made with healthy controls. ResultsCFDNA levels in VTE patients who stopped warfarin (5.53 μg/mL; 95%CI: 5.34–5.72) were higher than during warfarin therapy (3.11 μg/mL; 95%CI: 2.98–3.25; p < .001), and higher than in healthy controls (2.77 μg/mL; 95%CI: 2.42–3.11; p < .001). VTE patients had a procoagulant state as evidenced by a shorter lag time (30.8 min; 95%CI: 29.2–32.4) compared to controls (48.2 min; 95%CI :41.0–55.5; p < .001) and a greater endogenous thrombin potential (2656 nM∗min; 95%CI: 2479–2836) compared to healthy controls (1198 nM ∗ min; 95%CI: 793–1603). There was a higher proportion of clots generated from patient plasma that were resistant to lysis (43.7%) compared to healthy controls (46.3%; p < .05). CFDNA levels were not associated with enhanced thrombin generation or impaired fibrinolysis in VTE patients. ConclusionCFDNA levels are elevated in patients with unprovoked VTE but do not correlate with the procoagulant or anti-fibrinolytic properties of patient plasma. This study suggests that additional factors in addition to CFDNA may contribute to the pathogenesis of VTE.

Extending anticoagulation treatment for unprovoked venous thromboembolism

Two recent systematic reviews have addressed uncertainties about extending anticoagulation beyond the usually recommended periods in patients with unprovoked venous thromboembolism. The appropriate duration of anticoagulation after a first episode...

A randomised controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism (VTE) and post-thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (the ExACT study).

Venous thromboembolism (VTE) is prevalent and impactful, with a risk of death, morbidity and recurrence. Post-thrombotic syndrome (PTS) is a common consequence and associated with impaired quality of life (QoL). The ExACT study was a non-blinded, prospective, multicentred randomised controlled trial comparing extended versus limited duration anticoagulation following a first unprovoked VTE (proximal deep vein thrombosis or pulmonary embolism). Adults were eligible if they had completed ≥3months anticoagulation (remaining anticoagulated). The primary outcome was time to first recurrent VTE from randomisation. The secondary outcomes included PTS severity, bleeding, QoL and D-dimers. Two-hundred and eighty-one patients were recruited, randomised and followed up for 24months (mean age 63, male:female 2:1). There was a significant reduction in recurrent VTE for patients receiving extended anticoagulation [2·75 vs. 13·54 events/100 patient years, adjusted hazard ratio (aHR) 0·20 (95% confidence interval (CI): 0·09 to 0·46, P<0·001)] with a non-significant increase in major bleeding [3·54 vs. 1·18 events/100 patient years, aHR 2·99 (95% CI: 0·81-11·05, P=0·10)]. Outcomes of PTS and QoL were no different between groups. D-dimer results (on anticoagulation) did not predict VTE recurrence. In conclusion, extended anticoagulation reduced VTE recurrence but did not reduce PTS or improve QoL and was associated with a non-significant increase in bleeding. Results also suggest very limited clinical utility of D-dimer testing on anticoagulated patients.

Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis

ObjectivesTo determine the rate of a first recurrent venous thromboembolism (VTE) event after discontinuation of anticoagulant treatment in patients with a first episode of unprovoked VTE, and the cumulative incidence...

Incidence of Cancer after a Second Unprovoked Venous Thromboembolic Event.

Patients with two unprovoked venous thromboembolism (VTE) events could be at high risk for cancer diagnosis and may therefore benefit from extended cancer screening strategies. However, accurate data on the incidence of cancer in this population is lacking. In a prospective cohort study, we followed-up with all patients who experienced two unprovoked symptomatic VTE events that occurred in less than 2 years apart. We estimated the 1-year incidence rate of cancer following the second unprovoked VTE event using the Kaplan-Meier method. Potential predictors for cancer diagnosis were assessed using a Cox proportional hazard regression model. Between May 2000 and December 2013, we included 197 patients with two episodes of symptomatic unprovoked VTE that occurred in less than 2 years apart. Their mean age was 66.2 ± 16.3 years, and 122 (51.8%) were male. Seventeen patients were diagnosed with cancer during the year following the second episode of unprovoked VTE, corresponding to a cumulative incidence rate of 9.19% (95% confidence interval [CI]: 5.81-14.37). The 1-year cumulative incidence rate of cancer was 35.88% (95% CI: 19.75-59.25) in patients with VTE recurrence on anticoagulation, 5.51% (95% CI: 2.9-10.32) among patients with a second episode of unprovoked VTE occurring after stopping anticoagulation and 1.15% (95% CI: 0.16-7.88) when time elapsed between the first and recurrent VTE was > 1 year. Our study suggests that the incidence of cancer in patients with a second episode of unprovoked VTE that occurs off anticoagulation, or > 1 year after the first event, is similar to that of patients with a first unprovoked VTE event.

Outcomes beyond the Third Month of Anticoagulation in Patients Aged &gt;75 Years with a First Episode of Unprovoked Venous Thromboembolism

Background The ideal duration of anticoagulant therapy in elderly patients with unprovoked venous thromboembolism (VTE) has not been consistently evaluated. Methods We used the RIETE ( R egistro I nformatizado E nfermedad T rombo E mbólica) registry to compare the rate and severity of pulmonary embolism (PE) recurrences versus major bleeding beyond the third month of anticoagulation in patients >75 years with a first episode of unprovoked VTE. Results As of September 2017, 7,830 patients were recruited: 5,058 (65%) presented with PE and 2,772 with proximal deep vein thrombosis (DVT). During anticoagulant therapy beyond the third month (median, 113 days), 44 patients developed PE recurrences, 36 developed DVT recurrences, 101 had major bleeding, and 241 died (3 died of recurrent PE and 19 of bleeding). The rate of major bleeding was twofold higher than the rate of PE recurrences (2.05 [95% confidence interval, CI: 1.68–2.48] vs. 0.90 [95% CI: 0.66–1.19] events per 100 patient-years) and the rate of fatal bleeding exceeded the rate of fatal PE events (0.38 [95% CI: 0.24–0.58] vs. 0.06 [95% CI: 0.02–0.16] deaths per 100 patient-years). On multivariable analysis, patients who had bled during the first 3 months (hazard ratio [HR]: 4.32; 95% CI: 1.58–11.8) or with anemia at baseline (HR: 1.87; 95% CI: 1.24–2.81) were at increased risk for bleeding beyond the third month. Patients initially presenting with PE were at increased risk for PE recurrences (HR: 3.60; 95% CI: 1.28–10.1). Conclusion Prolonging anticoagulation beyond the third month was associated with more bleeds than PE recurrences. Prior bleeding, anemia, and initial VTE presentation may help decide when to stop therapy.

META-ANALYSIS OF LONG-TERM RISK OF FATAL PULMONARY EMBOLISM AFTER DISCONTINUING ANTICOAGULANT THERAPY FOR FIRST UNPROVOKED VENOUS THROMBOEMBOLISM

Venous thromboembolism (VTE), manifesting itself as deep vein thrombosis and/or pulmonary embolism (PE) is a leading cause of cardiovascular death. The optimal duration of anticoagulant therapy in patients with a first unprovoked VTE is controversial, due to closely balanced risks of mortality from recurrent VTE if anticoagulation is discontinued, and mortality form major bleeding if anticoagulation is continued. As such, when deciding whether to discontinue anticoagulation after completing initial course of treatment, the subsequent risk of fatal PE is an important prognostic consideration. This risk however, is unclear, hindering decision making. We performed a systematic review and meta-analysis of randomized clinical trials and prospective observational studies to establish precise and reliable estimates of the absolute, long-term risk of fatal PE at standardized time intervals of 1, 2, 5, and 10 years after discontinuing anticoagulant therapy, as well the case-fatality rate of recurrent VTE in patients with a first episode of unprovoked VTE, who had completed at least three months of initial anticoagulation. Absolute rate of fatal PE was calculated for each study from the total number of fatal PE events and the corresponding patient-years of follow-up. Case-fatality rate was defined as the proportion of overall recurrent VTE events that were fatal. Study results were pooled using random-effects meta-analyses. Of 896 identified records, data was available and/or obtained from authors of 15 eligible studies involving 6,627 patients. The weighted, pooled absolute rate of fatal PE (per 100 patient-years) after stopping anticoagulation was 0.4 events (95% CI, 0.2-0.7) in the first year; 0.3 events (95% CI, 0.2-0.6) in the second year; and average 0.1 events/year (95% CI, 0.0-0.3) in the subsequent eight years off treatment (i.e. between year 2 and 10) [Table 1], resulting in a cumulative 10-year risk of 1.5% after discontinuing anticoagulant therapy. Based on a total of 1,035 recurrent VTE and 48 fatal PE events, the weighted, pooled case-fatality rate for recurrent VTE after stopping anticoagulation was 4.0% (95% CI, 2.1%-6.3%) [Figure 1]. Unselected patients with a first episode unprovoked VTE have a low long-term risk (<1% per year) of fatal PE after stopping anticoagulation. This information, together with the case-fatality rate of recurrent VTE helps inform patient prognosis, and may assist clinicians when considering the risks of mortality from recurrent VTE and major bleeding to decide whether to stop or continue anticoagulant therapy for unprovoked VTE.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

The Optimal Duration and Selection of Anti-coagulants after First Episode of Unprovoked Venous Thromboembolism

The Optimal Duration and Selection of Anti-coagulants after First Episode of Unprovoked Venous Thromboembolism

Effect of testing for cancer on cancer- and venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE.

Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). A proportion of patients with VTE have no underlying or immediately predisposing risk factors and the VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying malignancy. This has raised the question of whether patients with an unprovoked VTE should be investigated for an underlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis would ensure that patients received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore, an appropriate cancer diagnosis at an earlier, potentially curative stage could avoid the risk of cancer progression and thus lead to improvements in cancer-related mortality and morbidity.To determine whether testing for undiagnosed cancer in patients with a first episode of unprovoked VTE (DVT or PE) is effective in reducing cancer and VTE-related mortality and morbidity and to establish which tests for cancer are most useful.The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (CRS) (2014, Issue 12). Clinical trials databases were searched. The reference lists of relevant articles were also checked.Randomised and quasi-randomised trials in which patients with an unprovoked VTE were allocated to receive specific tests for cancer or clinically indicated tests only were eligible for inclusion in this review. Primary outcomes included all-cause mortality, cancer-related mortality and VTE-related mortality.Selection of the studies, quality assessment and data extraction were completed independently by two review authors. Any disagreements were resolved by discussion.Two studies with a combined total of 396 patients met the inclusion criteria for this review. Both studies assessed the effect of testing for cancer versus clinically indicated tests only in patients with an unprovoked VTE. The quality of the evidence was moderate because although the studies were judged to be at low or unclear risk of bias, there was concern that the studies were small as reflected in the wide confidence intervals (CIs). Pooled analysis showed that testing for cancer was consistent with either a benefit or no benefit on cancer-related mortality (odds ratio (OR) 0.49, 95% CI 0.15 to 1.67, P = 0.26). One study showed that, overall, malignancies were less advanced in patients belonging to the extensive screening group than in patients of the control group (64% versus 20%, P = 0.047) and that tested patients were diagnosed earlier than untested patients (mean 1 month versus 11.6 months to cancer diagnosis from the time of diagnosis of VTE). Standard deviations were not provided for time to diagnosis, so it was not possible to perform an independent statistical analysis on this association. Neither study measured all-cause mortality, VTE-related morbidity and mortality, side effects of anticoagulation, side effects of cancer tests or patient satisfaction.Testing for cancer in patients with idiopathic VTE leads to earlier diagnosis of cancer at an earlier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in patients with a first episode of unprovoked VTE (DVT or PE) in reducing cancer and VTE-related morbidity and mortality. The results are imprecise and could be consistent with either harm or benefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can be made.

Scoring Systems for Estimating the Risk of Recurrent Venous Thromboembolism.

The risk of recurrence after suspension of anticoagulant treatment in patients with a first episode of unprovoked venous thromboembolism (VTE) is highly variable from patient to patient. Not all patients are candidates for life-long anticoagulant therapy, essentially because there remain concerns for such an option regarding hemorrhagic complications and clinical monitoring. Thus, the "treat all" approach may be inadequate for some patients at low risk of relapse. Proper assessment of the recurrence risk may be helpful to decide the optimal therapeutic strategy in such patients. In recent years, attempts have been made to develop and validate clinical prediction rules to estimate the absolute risk of VTE recurrence in individual patients. This article highlights the advantages and disadvantages of such options, presenting three different prediction rules that have been published so far.

Long-term strategies in patients with unprovoked venous thromboembolism

SummaryOnce anticoagulation is stopped, the risk of recurrent venous thromboembolism (VTE) over years approaches 40 % of all patients with a first episode of VTE. The risk is twice as high in patients with unprovoked VTE than in those with minor (either transient or persistent) risk factors of thrombosis. Although the latest international guidelines suggest indefinite anticoagulation for most patients with a first episode of unprovoked VTE, strategies that incorporate the assessment of residual vein thrombosis and D-dimer have the potential to identify a substantial proportion of subjects in whom anticoagulation can be safely discontinued. For those patients in whom anticoagulation cannot be discontinued, new opportunities are offered by the availability of low-dose anti-Xa compounds, which have been found to possess an extremely favorable benefit/risk profile.

Optimal duration of anticoagulation in patients with unprovoked venous thromboembolism: the impact of novel anticoagulants.

Once anticoagulation is stopped, the risk of recurrent venous thromboembolism (VTE) over years approaches 50% of all patients with a first episode of unprovoked VTE. The persistence of residual vein thrombosis at ultrasound assessment has consistently been shown to increase the risk, as do persistently high values of D-dimer. Although the latest international guidelines suggest indefinite anticoagulation for most patients with the first episode of unprovoked VTE, strategies that incorporate the assessment of residual vein thrombosis and D-dimer have the potential to identify a substantial proportion of subjects in whom anticoagulation can be safely discontinued. For those patients in whom anticoagulation cannot be discontinued, new opportunities are offered by the availability of low-dose anti-Xa compounds, which have been found to possess an extremely favourable benefit/risk profile.

Real-Life Incidence of Cancer Following a First Unprovoked Venous Thrombosis: Results from the Epigetbo Study

▪Background: Venous thromboembolism (VTE) can be the first manifestation of cancer. Whether screening for an occult malignancy should be systematically performed in patients with unprovoked VTE is a daily challenge for clinicians. Recently, two randomized trials demonstrated that limited cancer screening in patients with a first unprovoked VTE could be the standard of care. However, the one-year incidence of occult malignancy found in these trials was unexpectedly low (4.5%) raising the hypothesis of an inclusion bias. We aimed at estimating the real-life one-year incidence of cancer following a first unprovoked VTE to inform physicians and policy makers in establishing recommendations for cancer screening in VTE patients.Methods: The EPIGETBO study is an epidemiologic study that aimed to measure the incidence of VTE in the Brest District, France1. All symptomatic VTE cases (deep vein thrombosis of the lower limb and pulmonary embolism) diagnosed between March 1st, 2013 and February 28th, 2014 among the 367,911 inhabitants of the district were recorded and validated by an adjudication committee. A systematic follow-up was planned in order to study patients’ outcome. Unprovoked VTE was defined as the absence of surgical procedure, pregnancy, delivery, immobilization, admission to hospital for an acute medical illness in the 3 months preceding VTE or known active cancer. The 1-year cumulative incidence of cancer was estimated using the Kaplan-Meier method. Then, the hazard for occult cancer diagnosis associated with age>60, male sex, and current smoking was assessed by Cox regression.Results: During the study period, 576 symptomatic validated VTE events were diagnosed in 562 inhabitants of the Brest District. Five patients did not undergo follow-up (4 refusals, 1 aged<18). The VTE event at study entry was unprovoked in 310 patients (55.6%) and this was a first unprovoked VTE event in 257. Patients’ mean age was 67.9 ± 2.2 years, 114 (44.3%) were men, 38 (14.8%) had a prior unprovoked VTE event. In the year following VTE, 9 of the 257 patients with a first unprovoked VTE event were diagnosed with cancer, corresponding to an overall 1-year cumulative incidence of occult cancer of 3.68% (95% CI 1.93-6.96). This incidence was 3.78% (95% CI 1.91-7.43) in the 219 patients with a first unprovoked VTE event and no prior history of provoked VTE (8 cancers). In non-smokers, the 1-year incidence rate of occult cancer was 0.81% (95% CI 0.11-5.59) as compared with 8.05% (95% CI 3.92-16.14) in smokers (p=0.004 by log-rank test). In multivariate analysis, age>60 and male sex were associated with a non significant increased risk for occult cancer diagnosis (HR 4.92; 95% CI 0.60-40.30 and 1.42; 95% CI 0.25-8.13 respectively). Conversely, current smoking was independently associated with a significant 11.8-fold increased risk for occult cancer diagnosis (HR 11.80; 95% CI 1.19-116.52). No cancer was diagnosed in patients aged≤50 years.Conclusion: In this comprehensive real-life epidemiological study, we confirmed that the one-year incidence of occult malignancy following a first episode of unprovoked VTE is low, especially in non-smokers. Current smoking was associated with a higher risk for occult cancer diagnosis; however, even in this patient subgroup, the absolute frequency was no higher than 8%.1 Thromb Haemost 2016; Epub ahead of print DOI: 10.1160/TH16-03-0205 DisclosuresNo relevant conflicts of interest to declare.

Risk Factors Predictive of Occult Cancer Detection in Patients with Unprovoked Venous Thromboembolism

▪Background: Venous thromboembolism (VTE) may be the earliest sign of cancer. Risk factors associated with the presence of an occult cancer in patients with a first acute unprovoked VTE are unknown. We sought to assess the risk factors predictive of occult cancer detection in patients with a first unprovoked symptomatic VTE.Methods:Post-hoc, pre-defined analyses of the multicenter open-label randomized controlled trial - Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial (Carrier M et al. N Engl J Med 2015). The trial compared comprehensive computed tomography (cCT) of the abdomen and pelvis in addition to limited occult-cancer screening (complete history and examination, basic laboratory testing, chest radiography, and breast, cervical and prostate cancer screening) with limited occult-cancer screening alone in patients with a first unprovoked episode of VTE. Cox proportional hazard models were used to analyze the effect of specific risk factors on the outcome of occult cancer within 12 months of a diagnosis of unprovoked VTE. Multivariable analysis was performed using Cox proportional hazard models that included all variables that achieved a p value of < 0.20 in univariate analyses.Results: A total of 854 patients were randomized to limited occult cancer screening only, or limited occult cancer screening in combination with a cCT. The mean age was 54 years and 67.4% were males. A total of 33 (3.9%; 95% C.I. 2.8-5.4) patients received a new diagnosis of cancer at 12 months follow-up. Age ≥ 60 years, compared to age < 60 years, was a predictor of cancer with a corresponding hazard ratio (HR) of 2.90 (95% C.I. 1.44-5.83, p=0.003). A previous provoked VTE in patients was also associated with a higher risk of developing cancer (HR=3.57, 95% C.I. 1.38-9.25, p=0.009). Patients with an unprovoked deep vein thrombosis (DVT), compared to either those with a pulmonary embolism (PE) only or both DVT and PE, seemed more likely to have a diagnosis of cancer. However, this trend was not statistically significant. (Table 1) These results were confirmed on multivariable analysis. Patients exhibiting one of these characteristics had a three-fold higher risk of occult cancer compared with patients without these characteristics. (Table 1)Conclusion: Age at unprovoked VTE diagnosis (≥ 60 years) and prior provoked VTE are predictors of occult cancer, and could potentially be used to identify a group of patients with unprovoked VTE at high risk of underlying cancer. Table 1Risk factors of occult malignancy among patients with a first unprovoked symptomatic VTE.Patients without cancer (%) (n = 821)Patients with cancer (%) (n = 33)Univariate analysis Hazard Ratio (95% C.I.)P valueMultivariable analysis Hazard Ratio (95% C.I.)P valueAge at diagnosis ≥ 60 years288 (35.1)20 (60.6)2.90 (1.44-5.83)0.0033.0 (1.47-5.99)0.002Male sex555 (67.6)21 (63.6)0.72 (0.35-1.46)0.358--Prior provoked VTE42 (5.1)5 (15.2)3.57 (1.38-9.25)0.0093.8 (1.46-10.03)0.006Type of current VTEDVT only444 (54.3)24 (72.7)1.91 (0.89-4.12)0.0972.1 (0.97-4.51)0.061PE only271 (33.1)7 (21.2)0.60 (0.26-1.38)0.229--DVT + PE103 (12.6)2 (6.1)0.54 (0.13-2.24)0.392--Baseline medicationsOral contraceptive pill48 (5.8)0 (0.0)----Exogenous estrogen18 (2.2)1 (3.0)1.51 (0.21-11.07)0.685--Antiplatelet agent39 (4.8)1 (3.0)0.62 (0.09-4.56)0.641--Oral anticoagulant688 (83.8)26 (78.8)0.66 (0.29-1.53)0.337--LMWH391 (47.7)15 (45.5)0.68 (0.34-1.36)0.275--VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; LMWH, low molecular weight heparin DisclosuresLazo-Langner:Pfizer: Honoraria, Other: Participated in studies funded by this organization, Speakers Bureau; LEO Pharma: Honoraria, Other: Participated in studies funded by this organization; Boehringer Ingelheim: Honoraria, Other: Participated in studies funded by this organization; Bayer: Honoraria, Other: Participated in studies funded by this organization; Daiichi-Sankyo: Other: Participated in studies funded by this organization; Novartis: Other: Participated in studies funded by this organization; Celgene: Other: Participated in studies funded by this organization; Alexion: Research Funding. Shivakumar:Bayer: Honoraria. Routhier:Sanofi-Aventis: Research Funding. Douketis:Janssen: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Honoraria; Sanofi-Aventis: Honoraria; Daiichi-Sankyo: Consultancy; Actelion: Consultancy; Biotie: Other: Advisory board; The Medicines Company: Other: Advisory board; Bayer: Consultancy; Boehringer Ingelheim: Consultancy, Honoraria. Carrier:LEO Pharma: Consultancy, Research Funding; BMS: Research Funding; Bayer: Consultancy; Pfizer: Consultancy.