Initial Venous Thromboembolism Event Research Articles

Venous thromboembolism and mortality in a multiethnic population: a report from the Birmingham Black Country VTE registry (BBC-VTE Investigators)

Abstract Background Most epidemiological studies into venous thromboembolism (VTE) are based on the white Caucasian population and unrepresentative of VTE outcomes in non-white ethnicities. Purpose Our VTE registry aims to get an insight into the outcomes of VTE patients as applicable to a developed world population with a multi-ethnic background. This will guide clinicians to make appropriate decisions with regards to management and prognosis. Methods The Birmingham Black Country VTE Registry (BBC-VTE) is a multi-ethnic cohort of patients in the West Midlands region of the United Kingdom, who suffered a first episode of VTE. In this study we compared baseline characteristics, treatment patterns and outcomes, and secondly, compared these among the different ethnic groups in this region. Results Between the years 2012–2014 there was a total of 1615 patients (mean age 65.5; 53.1% female) admitted with a first episode of VTE of whom, 134 (8.3%) were Asian, 92 (5.7%) Black, and 1213 (75.1%) White. Asian patients were younger (mean age 54, SD 19.3) vs Black patients (59, SD 19.7) and White patients (68, SD 17.4); and were less often female (50.7% vs. 55.4% and 53.8%) for Black and White patients respectively. The initial VTE event was a DVT in 680 (42.1%) and a PE±DVT in 935 patients (57.9%). Below-knee and above-knee DVT occurred in 95 (5.9%) and 585 (36.2%) patients respectively. Recurrent DVT occurred in 3.2% of those with an initial below-knee DVT and 12.5% of those with an initial above-knee DVT. Recurrent PE was also more common in those with an initial above knee DVT (4.8%) compared to those with below-knee DVT (3.2%). After the initial VTE event, 1269 (78.6%) were started on long-term anticoagulation for the prevention of recurrent VTE. Of those, 65.1% stayed on anticoagulation for up to 6 months after the initial VTE event, and 34.9% continued for longer than 6 months, including those on lifelong anticoagulation. Bleeding and major bleeding occurred in 6.8% and 2.5% respectively in those on anticoagulation for 6 or less months, vs. 10.4% and 3.5% in those anticoagulated for longer than 6 months. The most common site of bleeding was gastrointestinal in 42.3% of all bleeds and this site was also responsible for 54.3% of major bleeds. From evaluating the odds ratio for VTE mortality (see Fig. 1), ethnicity did not have a significant impact. Older age; the presence of diabetes mellitus; history of malignancy; as well as admission laboratory results for C-reactive protein and neutrophil count were all significantly associated with higher odds of mortality in this patient cohort. Conclusion BBC-VTE is a contemporary multi-ethnic cohort of patients providing insights into the risk factors among multi-ethnic patients that have developed VTE. Ethnicity did not emerge as an independent risk for VTE mortality. Funding Acknowledgement Type of funding sources: None.

Incidence and Risk Factors of Pulmonary Hypertension After Venous Thromboembolism: An Analysis of a Large Health Care Database.

Background Pulmonary hypertension (PH) is a devastating potential complication of pulmonary embolism, a manifestation of venous thromboembolism (VTE). The incidence of and risk factors for PH in those with prior VTE are poorly characterized. Methods and Results International Classification of Diseases (ICD) codes from inpatient and outpatient medical claims from MarketScan administrative databases for years 2011 to 2018 were used to identify cases of VTE, comorbidities before the VTE event, and PH occurring subsequent to the VTE event. Cumulative incidence and hazard ratios (HR), and their 95% CI, were calculated. The 170021 VTE cases included in the analysis were on average (±SD) 57.5±15.8years old and 50.5% were female. A total of 5943 PH cases accrued over an average follow-up of 1.94years. Two years after incident VTE, the cumulative incidence (95% CI) of PH was 3.5% (3.4%-3.7%) overall. It was higher among older individuals, among women (3.9% [3.8%-4.1%]) than men (3.2% [3.0%-3.3%]), and among patients presenting with pulmonary embolism (6.2% [6.0%-6.5%]) than those presenting with deep vein thrombosis only (1.1% [1.0%-1.2%]). Adjusting for age and sex, risk of PH was higher among patients with VTE with underlying comorbidities. Using the Charlson comorbidity index, there was a dose-response relationship, whereby greater scores were associated with increased PH risk (score ≥5 versus 0: HR, (2.50 [2.30-2.71])). When evaluating individual comorbidities, the strongest associations were observed with concomitant heart failure (HR, 2.17 [2.04-2.31]), chronic pulmonary disease (2.01 [1.90-2.14]), and alcohol abuse (1.66 [1.29-2.13]). Conclusions In this large, real-world population of insured people with VTE, 3.5% developed PH in the 2years following their initial VTE event. Risk was higher among women, with increasing age, and in those with additional comorbidities at the time of the VTE event. These data provide insights into the burden of PH and risk factors for PH among patients with VTE.

Recommendations from the EGAPP Working Group: Routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members

Summary of RecommendationsThe Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found adequate evidence to recommend against routine testing for Factor V Leiden (FVL) and/or prothrombin 20210G>A (PT) in the following circumstances: (1) adults with idiopathic venous thromboembolism (VTE). In such cases, longer term secondary prophylaxis to avoid recurrence offers similar benefits to patients with and without one or more of these mutations. (2) Asymptomatic adult family members of patients with VTE and an FVL or PT mutation, for the purpose of considering primary prophylactic anticoagulation. Potential benefits are unlikely to exceed potential harms. The overall certainty of these findings was deemed “moderate.” The evidence was insufficient to determine whether FVL/PT testing might have clinical utility in some circumstances, such as for identifying FVL homozygosity among asymptomatic family members of adults with idiopathic VTE or counseling patients about the risks and benefits of antithrombotic therapy. Based on the available evidence, the certainty of net health benefit was deemed “low.” The recommendations do not extend to patients with other risk factors for thrombosis, such as contraceptive use, as the evidence review that serves as the basis for the recommendations focused primarily on idiopathic VTE. RationaleIn developing these recommendations the EGAPP Working Group considered evidence in the following three areas. Analytic ValidityThere is adequate evidence that testing accurately and reliably detects the R506Q (FVL) and 20210G>A (PT) variants in the Factor V and PT genes, respectively (a more complete definition of analytic validity, clinical validity, and clinical utility is contained under the “Clinical Considerations” section). Clinical ValidityThe presence of a heterozygous FVL variant seems to be a weak risk factor for recurrence of VTE (odds ratio [OR]: 1.56). Rare homozygous FVL mutations present somewhat greater risks of VTE recurrence (OR: 2.65). The evidence for this increased risk is convincing, but the magnitude of excess risk is not as great as previously thought. The evidence is insufficient to draw conclusions about excess VTE recurrence risk resulting from compound heterozygosity (FVL and PT), but it is likely to be at least as high as with FVL alone. The OR for compound heterozygosity is 6.69. The evidence is insufficient to draw conclusions about VTE recurrence risks associated with PT mutations alone. For family members of index VTE cases, there is convincing evidence that both heterozygosity and homozygosity for FVL are associated with higher risks for VTE occurrence (ORs 3.49 and 17.84, respectively) than for family members without FVL variants. Clinical UtilityThere is convincing evidence that longer term secondary prophylaxis after an initial idiopathic VTE event yields comparable benefits to those with and without a FVL or PT mutation. For asymptomatic family members of index cases, no prophylaxis trials have been reported. Hence, there is no direct evidence of particular benefit to family members. Potential net harm is possible if primary prophylaxis is administered to asymptomatic family members with one or more mutations, because the absolute risk of an initial VTE event is low, and the risk of anticoagulant-induced hemorrhage is relatively high.

LTP VTE–Long-Term Prevention of Venous ThromboEmbolism: Epidemiology and treatment patterns from a community-based study in western of France

Current guidelines recommend extended anticoagulation in patients with unprovoked venous thromboembolism (VTE). However, a precise description of these patients from the “real-world” is lacking. The EPI-GETBO study is a prospective epidemiologic study of VTE in the geographically well-defined Brest district area. All cases of symptomatic VTE between March 2013 and February 2015 were recorded, adjudicated, and included in the study. During the study period, 555 patients with unprovoked symptomatic VTE were included in EPI-GETBO. Patients’ median age was 72.0 years (IQR 57.0;83.0), 45.2% were male, 64.7% had a pulmonary embolism (PE) associated or not with a deep vein thrombosis (DVT) and 29.2% had a previous history of VTE. 5.6% of the patients had atrial fibrillation at the time of VTE diagnosis, 5.9% had a history of coronary artery disease, and 17.3% received antiplatelet medications. A total of 283 (51.0%) patients discontinued anticoagulation during the observation period. In these patients, the median duration of treatment was 183 days (range 0 to 853 days). Patients with PE associated or not with DVT were treated for a longer time than patients with isolated DVT ( P = 0.01). A total of 40 recurrences (14.1%) were observed during follow-up (up to 2 years after initial VTE event) after anticoagulation discontinuation. Based on indirect standardization, we expect an annual 50,054 cases of unprovoked VTE in France, including 32,346 PEs. The 14,1% recurrence rate of VTE after anticoagulation discontinuation confirms the need for extended duration of treatment in this patient population. Attention should be made for the significant number of patients with concomitant arterial disease who may need aspirin if low-dose DOAC is chosen for extended therapy or who may not be eligible for a low-dose DOAC in case of presence of atrial fibrillation.

Incidence of major adverse cardiovascular events among patients with provoked and unprovoked venous thromboembolism: Findings from the Registro Informatizado de Enfermedad Tromboembólica Registry

ObjectiveOverlap exists between the risk factors for coronary artery disease and venous thromboembolism (VTE). However, a paucity of data is available on the incidence of major acute cardiovascular events (MACE) and major adverse limb events (MALE) among patients presenting with VTE. Moreover, it is unknown whether the rate of cardiovascular outcomes differs among patients with unprovoked vs provoked VTE. MethodsWe analyzed the data from 2009 to 2017 in the Registro Informatizado de Enfermedad Tromboembólica registry, an ongoing, multicenter, international registry of consecutive patients with a diagnosis of objectively confirmed VTE. The query was restricted it to patients with data entry for the arterial outcomes. The baseline prevalence of coronary artery disease risk factors was compared between patients with provoked (ie, immobility, cancer, surgery, travel >6 hours, hormonal causes) and unprovoked VTE. After the initial VTE event, we followed up patients for the composite primary outcome of incident MACE (ie, stroke, myocardial infarction, unstable angina) and/or MALE (ie, major limb events). We used the χ2 test for baseline associations and a Cox proportional hazard for multivariate analysis. We used IBM SPSS, version 24 (IBM Corp, Armonk, NY) for statistical analysis. A P value of <.05 was considered statistically significant. ResultsWe analyzed the data from 41,259 patients with VTE, of whom 22,633 (55.6%) had experienced a provoked VTE. During follow-up, the patients with provoked VTE were more likely to develop MACE or MALE than were patients with unprovoked VTE (hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.1-1.5). The association of arterial events with recent immobility (HR, 1.4; 95% CI, 1.5-12.1) and cancer (HR, 1.7; 95% CI, 1.4-1.9) was strong. After adjusting for multiple conventional cardiovascular risk factors, provoked VTE, compared with unprovoked VTE, was significantly associated with an increased hazard for MACE (HR, 1.4; 95% CI, 1.1-1.7). Cancer remained a significant adjusted predictor for both MACE (HR, 1.7; 95% CI, 1.4-2.1) and MALE (HR, 2.1; 95% CI 1.01-4.6) in those with provoked VTE. ConclusionsAmong patients with VTE, provoked cases, specifically those with cancer-associated VTE, have an increased risk of major arterial events.

Clinical Outcomes of Cancer-Associated Thrombosis Beyond 6 Months of Anticoagulation

Introduction Randomized trials of venous thromboembolism (VTE) treatment in cancer have primarily focused on the initial 6-month period and the risk/benefit of additional anticoagulant therapy beyond this time point has not been fully evaluated. Current guidelines recommend continuing full dose anticoagulation after 6 months in patients who have ongoing active cancer and/or those undergoing anti-neoplastic treatment. This recommendation, however, is based on little evidence. Here, we describe clinical outcomes of patients who have completed at least 6 months of anticoagulation. Our aim was to compare VTE recurrence, bleeding rate, and overall survival in patients who continued vs. discontinued anticoagulation after the initial 6-month treatment period. Methods We evaluated a prospective cohort of patients referred to the Cleveland Clinic cancer-associated thrombosis clinic from 8/2014-12/2018. We evaluated clinical characteristics, VTE recurrence, bleeding (major or clinically relevant non-major bleeding (CRNMB) as defined by ISTH criteria), and overall survival in patients who continued vs. discontinued anticoagulation after 6 months. Low-risk for recurrent VTE was defined as not having active cancer and not receiving systemic therapy. Statistical methods included t-tests, chi-squared tests, Cox model, and log rank test where appropriate. Multivariable analysis was performed to analyze outcomes of interest. Results The study population was comprised 284 (73.2%) patients who were followed 6 months after the initial VTE event. Of these, 93 (32.7%) did not continue anticoagulation beyond 6 months, and 191 (67.3%) continued anticoagulation treatment (table 1). Anticoagulation was discontinued for the following reasons: low risk (n=33, 35.5%), bleeding (n=12, 12.9%), clinical decision (n=4, 4.3%) and other including financial reasons (n=43, 46.2%; table 2). In patients who continued anticoagulation, 86/191 (45%) had stage IV disease and the most frequent cancers were hematologic malignancies (58/191, 30.4%) and gastrointestinal cancers (37/191, 19.4%). Low molecular weight heparin was the most commonly prescribed anticoagulant (110/191; 57.6%) followed by direct oral anticoagulants (68/191, 35.6%). There was no difference in the rate of recurrent VTE in patients who remained on treatment beyond six months (23/191; 12%) vs. those who stopped treatment at six months (11/93; 11.8%; p= 0.81; figure 1). In patients who continued anticoagulation 6-12 months after the initial treatment period, 13/191 (6.8%) had a bleeding event (major bleeding n=4, CRNMB n=9). There was 1 major bleed and no CRNMB in the group that stopped anticoagulation. After multivariable analysis, recurrent VTE was associated with worse overall survival [hazard ratio (HR) 1.88; 95% Confidence Interval (CI) 1.06-3.35, p=0.03]. Discussion This prospective analysis found no difference in the rate of recurrent VTE and more bleeding in patients who continued anticoagulation, although recurrent VTE rates were high in both cohorts. Furthermore, a recurrent VTE event was associated with worse overall survival. Emerging data with DOACs may alter recurrence rates and the ability to continue treatment beyond 6 months. Although limited by a small study population, this study adds to available data regarding outcomes beyond six months of treatment. Future studies should focus on exploring the outcomes of extending anticoagulation and better identifying patients at risk for recurrent VTE. Disclosures McCrae: Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Khorana:Janssen: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy.

Decreased Bleeding Incidence with Direct Oral Anticoagulants Compared to Vitamin K Antagonist and Low-Molecular-Weight Heparin in Patients with Sickle Cell Disease and Venous Thromboembolism

Background: Venous thromboembolism (VTE) is a recognized complication of sickle cell disease (SCD), yet the optimal pharmacologic anticoagulant is unknown. Methods: A retrospective single-institution cohort study of patients with SCD complicated by first VTE from January 2009 through July 2017 was performed using ICD 9/10 codes. Data collected included the anticoagulant used, VTE recurrence, and incidence of bleeding. Results: 109 patients with VTE were identified. SCD genotypes included HbSS in 92 (84%), HbSC in 13 (12%), and HbS-β⁺ thalassemia in 4 (4%). After the initial VTE event, 32 patients received a vitamin K antagonist (VKA), 34 for low-molecular-weight heparin (LMWH), and 43 for direct oral anticoagulants (DOACs). 16 patients (15%) experienced a clinically significant bleeding event, including 9 on VKA, 5 on LMWH, and 2 on DOACs. At a median follow-up of 11.8 (range, 3.4–60) months, 33 patients had a recurrent VTE, including 10 on VKA, 10 on LMWH, and 13 on DOACs (p = 0.833). Bleeding incidence was least with the DOACs, which were associated with fewer bleeding events (OR 0.22), and greatest with VKA (OR 1.55) (p < 0.05). Conclusion: There was no difference between VTE recurrence and choice of anticoagulation in SCD patients with VTE. Bleeding events were lower for DOACs compared to VKA or LMWH.

Use of Direct Oral Anticoagulants in Patients with Sickle Cell Disease and Venous Thromboembolism Is Associated with a Significant Decrease in Incidence of Bleeding Compared to Vitamin K Antagonists and Low-Molecular-Weight Heparins

Background: Venous thromboembolism (VTE) is a recognized complication of sickle cell disease (SCD). Several studies confirm that SCD itself is an independent risk factor for development of VTE. However, the optimal pharmacologic anticoagulant remains unknown.Methods: This retrospective single-institution cohort study was exempt by the Institutional Review Board. Data were collected via review of electronic medical records including ambulatory, emergency department, general floor, and intensive care unit encounters. Patients with SCD were identified spanning 1/2009-7/2017 using ICD 9/10 codes. Inclusion criteria were age ≥18 years at time of VTE diagnosis, imaging confirming VTE, and documented compliance based on INR values and/or provider/pharmacy documentation. VTE diagnosis included deep vein thrombosis (DVT) at any location and pulmonary embolism based on documented imaging and ICD 9/10 codes. Anticoagulants included direct oral anticoagulants (DOACs), vitamin K antagonists (VKA), and low-molecular-weight heparin (LMWH). The DOACs used in this study were rivaroxaban, apixaban and dabigatran. Exclusion criteria were known active malignancy, confirmed hypercoagulable risk factors beyond SCD, atrial fibrillation and/or history of major bleeding prior to anticoagulation. Due to low event rates, a log likelihood ratio test of independence was calculated for associations between drug type and two endpoints: bleeding rate and rate of VTE recurrence. Rate of VTE recurrence was defined as a newly diagnosed VTE within 6 months of initiation of anticoagulation. Bleeding rate was defined using International Society on Thrombosis and Hemostasis criteria: bleeding event into a critical site and/or a ≥2 point decrease in baseline hemoglobin.Results: A total of 109 patients with SCD met inclusion criteria. 66 patients (60%) were female. SCD genotypes represented included HbSS in 91 patients (83%), HbSC in 12 (11%) and HbS β+ thalassemia in 4 (4%). There were no patients with HbS-β0 thalassemia. VTEs consisted of 69 DVTs and 43 pulmonary emboli. 31 out of 109 VTEs were provoked, including 30 catheter-related incidents. After initial VTE event, 32 patients received a VKA, 34 received LMWH, and 43 received a DOAC. Within the class of DOACs, 31 patients received rivaroxaban, 5 received apixaban, and 7 received dabigatran.Sixteen of 109 patients (15%) experienced a clinically significant bleeding event, including 8 on VKA, 6 on LMWH, and 2 on a DOAC. Bleeding incidence was least with the DOAC class [0.22 CI (0.04-0.84) p < 0.05], greatest with warfarin [1.55 CI (0.57-4.33) p < 0.05] and slightly less with LMWH [0.64 CI (0.23-1.73) p < 0.05]. There was a significant decrease in incidence of bleeding events in patients receiving a DOAC for anticoagulation, compared to a VKA or LMWH (p = 0.033).At a median follow-up of 11.8 months (range, 3.4 - 60 months), 33 patients had a recurrent VTE, including 10 on VKA, 10 on LMWH and 13 taking a DOAC (p = 0.833). An association between VTE and SCD genotype could not be identified due to small numbers of patients with non-HbSS genotypes.Conclusion: In patients with SCD and VTE, there was a significant decrease in incidence of bleeding events in patients receiving a DOAC for anticoagulation, compared to a VKA or LMWH (p = 0.033). There was no difference between VTE recurrence rate and choice of initial anticoagulation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Recurrence risk of venous thromboembolism and hormone use in women from England: a cohort study using clinical practice research datalink.

It is vital to identify people with low recurrence risk of venous thromboembolism (VTE) so as to protect them from dangers of prolonged anticoagulation therapy. Among women who develop VTE following hormone use, the evidence as to whether their risk of recurrence is low if they cease this therapy is conflicting. We investigated whether women whose initial VTE event was hormone-related have a lower risk of VTE recurrence than women whose initial event had no obvious cause (unprovoked). A cohort study utilising the Clinical Practice Research Datalink linked to Hospital Episode Statistics data from England was conducted. We selected 4170 women aged between 15 and 64years who were diagnosed with a first VTE event between 1997 and 2011. Cox regression models were used to obtain hazard ratios (HR). Hormone users had 29% lower recurrence risk than non-users (adjusted HR=0·71; 95% confidence interval 0·58-0·88), a relationship which existed both in women aged 15-44years (predominantly oral contraceptive users) and those aged 45-64years (predominantly hormone replacement therapy users). In conclusion, having a hormone-associated VTE is associated with a lower recurrence risk than one that is unprovoked after discontinuation of the hormone-containing preparation. Prolonged anticoagulation may therefore be unjustified in such women.

Limited evidence on persistence with anticoagulants, and its effect on the risk of recurrence of venous thromboembolism: a systematic review of observational studies.

PurposeThe risk of venous thromboembolism (VTE) recurrence is high following an initial VTE event, and it persists over time. This recurrence risk decreases rapidly after starting with anticoagulation treatment and reduces by ~80%–90% with prolonged anticoagulation. Nonpersistence with anticoagulants could lead to increased risk of VTE recurrence. This systematic review aimed to estimate persistence at 3, 6, and 12 months with anticoagulants in patients with VTE, and to evaluate the risk of VTE recurrence in nonpersistent patients.MethodsPubMed and Embase® were searched up to May 3, 2014 and the search results updated to May 31, 2015. Studies involving patients with VTE aged ≥18 years, treatment with anticoagulants intended for at least 3 months or more, and reporting data for persistence were included. Proportions were transformed using Freeman–Tukey double arcsine transformation and pooled using the DerSimonian–Laird random-effects approach.ResultsIn total, 12 observational studies (7/12 conference abstracts) were included in the review. All 12 studies either reported or provided data for persistence. The total number of patients meta-analyzed to estimate persistence at 3, 6, and 12 months was 71,969 patients, 58,940 patients, and 68,235 patients, respectively. The estimated persistence for 3, 6, and 12 months of therapy was 83% (95% confidence interval [CI], 78–87; I2=99.3%), 62% (95% CI, 58–66; I2=98.1%), and 31% (95% CI, 22–40; I2=99.8%), respectively. Only two studies reported the risk of VTE recurrence based on nonpersistence – one at 3 months and the other at 12 months.ConclusionLimited evidence showed that persistence was suboptimal with an estimated 17% patients being nonpersistent with anticoagulants in the crucial first 3 months. Persistence declined over 6 and 12 months. Observational data on persistence with anticoagulation treatment, especially direct oral anticoagulants, in patients with VTE and its effect on risk of VTE recurrence were scarce and further research is required.

Extended Anticoagulant and Aspirin Treatment for the Secondary Prevention of Thromboembolic Disease: A Systematic Review and Meta-Analysis.

BackgroundPatients who have had an unprovoked deep venous thrombosis (DVT) or pulmonary embolus (PE) are at a high risk for recurrent venous thromboembolism (VTE). Extended “life-long” anticoagulation has been recommended in these patients. However, the risk benefit ratio of this approach is controversial and the role of the direct oral anticoagulants (DOACs) and aspirin is unclear. Furthermore, in some patients with a “weak provoking factor” there is clinical equipoise regarding continuation or cessation of anticoagulant therapy after treatment of the acute VTE event.ObjectiveA systematic review and meta-analysis to determine the risks (major bleeding) and benefits (recurrent VTE and mortality) of extended anticoagulation with vitamin k antagonists (VKA), DOACs and aspirin in patients with an unprovoked VTE and in those patients with clinical equipoise regarding continuation or cessation of anticoagulant therapy. In addition, we sought to determine the risk of recurrent VTE events once extended anti-thrombotic therapy was discontinued.Data SourcesMEDLINE, Cochrane Register of Controlled Trials, citation review of relevant primary and review articles.Study SelectionRandomized placebo-controlled trials (RCTs) that compared the risk of recurrent VTE in patients with an unprovoked DVT or PE who had been treated for at least 3 months with a VKA or a DOAC and were then randomized to receive an oral anti-thrombotic agent or placebo for at least 6 additional months. We included studies that included patients in whom clinical equipoise existed regarding the continuation or cessation of anticoagulant therapy.Data ExtractionIndependent extraction of articles by both authors using predefined data fields, including study quality indicators. Data were abstracted on study size, study setting, initial event (DVT or PE), percentage of patients where the initial VTE event was unprovoked, the number of recurrent VTE events, major bleeds and mortality during the period of extended anticoagulation in the active treatment and placebo arms. In addition, we recorded the event rate once extended treatment was stopped. Meta-analytic techniques were used to summarize the data. Studies were grouped according to the type of anti-thrombotic agent.Data SynthesisSeven studies which enrolled 6778 patients met our inclusion criteria; two studies evaluated the extended use of Coumadin, three studies evaluated a DOAC and two studies evaluated the use of aspirin. The duration of followup varied from 6 to 37 months. In the Coumadin and aspirin studies 100% of the randomized patients had an unprovoked VTE, while in the DOAC studies between 73.5% and 93.2% of the VTE events were unprovoked. In the control group recurrent VTE occurred in 9.7% of patients compared to 2.8% in the active treatment group (OR 0.21; 95% CI 0.11–0.42, p<0.0001). VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with VKA and DOACs being significantly more effective than aspirin. Major bleeding events occurred in 12 patients in the control group (0.4%) and 25 of 3815 (0.6%) patients in the active treatment group (OR 1.64; 95% CI 0.69–3.90, NS). There were 39 (1.3%) deaths in control patients and 33 (0.9%) deaths in the anti-thrombotic group during the treatment period (OR 0.73; 95% CI 0.40–1.33, NS). Patients whose initial VTE event was a PE were more likely to have a recurrent PE than a DVT. The annualized event rate after discontinuation of extended antithrombotic therapy was 4.4% in the control group and 6.5% in the active treatment arm.ConclusionsVKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with DOACs and VKA being more effective than aspirin. The decision regarding life-long anticoagulation following an unprovoked DVT or PE should depend on the patients’ risk for recurrent PE as well as the patients’ values and preferences.

Incremental Health Care Burden of Bleeding Among Patients with Venous Thromboembolism in the United States.

The health care and economic burden of venous thromboembolism (VTE) has been evaluated in regard to acute VTE, VTE recurrence, and some VTE complications, such as postthrombotic syndrome, but the cost burden attributed to bleedings is not well understood. To evaluate health care resource utilization and costs associated with major bleeding (MB) and clinically relevant nonmajor bleeding (CRNMB) among a large U.S. commercially and Medicare-insured population with VTE. Patients (≥ 18 years of age, continuously insured) with a diagnosis of VTE between January 1, 2008, and December 31, 2011, were identified from the Truven Health Analytics Commercial and Medicare MarketScan databases. Patients who did not have any bleedings during the study period were grouped into a no-bleedings cohort and a random date after VTE diagnosis was selected as the index date. VTE patients who experienced MB within 1 year of the initial VTE diagnosis were grouped into a MB cohort, and patients without MB but with CRNMB were grouped into a CRNMB cohort. Baseline patient demographics and clinical characteristics were determined for study cohorts. All-cause and bleeding-related health care resource utilization and costs (inflation adjusted to 2013 level) during a 12-month follow-up period after the index date of the initial bleeding event were measured and compared. Descriptive statistics were used to evaluate differences in demographics, clinical characteristics, and unadjusted health care resource utilization and costs of patient cohorts. Multivariable generalized linear models were used to evaluate incremental health care costs of bleedings after adjusting for key patient characteristics. Among the 112,885 patients identified with a VTE diagnosis, 14% (n = 15,897) had MB and 14% (n = 15,842) had CRNMB; 72% (n = 81,146) had neither of these events occur during the study period. The mean ages of the MB and CRNMB cohorts were both 63.6 years, while the mean age of the no-bleedings cohort was significantly lower at 59.6 years (P less than 0.001). Mean Charlson Comorbidity Index scores were highest for the MB cohort (3.2), followed by those of the CRNMB cohort (2.5) and the no-bleedings cohort (1.6). The MB cohort had the greatest proportion of patients with an initial VTE event of pulmonary embolism only (23.5%), followed by that of the CRNMB cohort (20.2%), and the no-bleedings cohort (16.7%). For MB and CRNMB cohorts, the total mean bleeding-related inpatient and outpatient costs during the follow-up period were $49,779 (SE = $820) and $2,187 ($89), respectively. After adjustment for key patient characteristics, the estimated mean differences in total bleeding-related medical costs were $45,367 ($1,853) for patients with MB and $2,140 ($88) for patients with CRNMB versus patients with no bleedings. Among patients with VTE diagnosis in the United States, approximately 28% have a bleeding event within 1 year of VTE diagnosis, and about half of these patients experience MB. Patients with MB have greatly elevated health care costs.

Red cell distribution width is associated with incident venous thromboembolism (VTE) and case-fatality after VTE in a general population

Recent studies suggest an association between red cell distribution width (RDW) and incident venous thromboembolism (VTE). We aimed to investigate the impact of RDW on risk of incident and recurrent VTE, and case-fatality, in a general population. RDW was measured in 26,223 participants enrolled in the Tromsø Study in 1994-1995. Incident and recurrent VTE events and deaths during follow-up were registered until January 1, 2012. Multivariate Cox proportional hazards regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI). There were 647 incident VTE events during a median of 16.8 years of follow-up. Individuals with RDW in the highest quartile (RDW≥13.3%) had 50% higher risk of an incident VTE than those in the lowest quartile (RDW≤12.3%). The association was strongest for unprovoked deep-vein thrombosis (HR highest vs lowest quartile of RDW: 1.8, 95% CI 1.1-3.1). VTE patients with baseline RDW≥13.3% had 30% higher risk of all-cause mortality after the initial VTE event than VTE patients with RDW<13.3%. There were no association between RDW and risk of recurrent VTE. Our findings suggest that high RDW is a risk factor of incident VTE, and that RDW is a predictor of all-cause mortality in VTE patients.

Abstract 11972: Venous Thromboembolism Recurrence Rate and Risk Factors in a European Population

Introduction: This study estimated venous thromboembolism (VTE) recurrence and risk factors in a European population, given limited data in this region. Methods: This retrospective cohort study included data collected from physicians recruited from an online panel in France, Spain, Italy, and Germany. Physicians completed case report forms for the next 3-4 patients seen in consultation for any reason who had an initial VTE event in the prior 3 to 24 months (i.e., patients who survived 90 days since their initial VTE). Included were 376 general practitioners and 307 specialists, providing 2,184 patient records and information on patient demographics, comorbidities, and VTE recurrence. Kaplan-Meier estimation provided cumulative incidence survival functions accounting for censored data (patient records varied from 3-24 months post-initial VTE). Risk factors for VTE were assessed. Results: Patients’ mean age was 61.3 years (SD=14.3) and 47.4% were female. Of 2,184 patients, 379 developed recurrent VTE over 1,298 person-years of follow-up. The table shows cumulative incidence of VTE in the overall population and by risk categories. The 6-month cumulative incidence of VTE recurrence was 11.7%; the 12-month cumulative incidence was 27.6%. VTE cumulative incidence did not differ by age, gender or initial VTE type. However, it was higher in patients with moderate-to-strong vs. weak Anderson &amp; Spencer summary risk scores (p=.001); e.g., 12-month rates of 33.8%, vs. 20.9%, respectively. Conclusions: VTE recurrence is high in this European population and increases with time since initial VTE event, suggesting the need for targeted anticoagulant treatment following an initial VTE event and longer term prevention of VTE recurrence. Among risk factors investigated, Anderson &amp; Spencer scores help differentiate patients more likely to experience recurrence within 12 months of initial VTE.

Incremental health care resource utilization and economic burden of venous thromboembolism recurrence from a U.S. payer perspective.

The third leading cause of cardiovascular-associated death, venous thromboembolism (VTE), represents a significant health care and economic burden. Although the burden of a one-time VTE event has been assessed, there are limited data regarding the burden of VTE recurrence. To assess the rate and predictors of VTE recurrence within 1 year in the United States and evaluate the incremental health care resource utilization and costs associated with such VTE recurrences. Patients (≥ 18 years) diagnosed with deep vein thrombosis and/or pulmonary embolism between January 1, 2008, and December 31, 2010, were identified from the Truven Health Analytics MarketScan Commercial and Medicare databases. The earliest VTE diagnosis was defined as the index VTE event. Patients were required to have 12 months of continuous insurance coverage before (baseline period) and after (follow-up period) the index event. Patients were further required to have initiated anticoagulant usage within 30 days of the index VTE event and have at least 30 days of treatment. The incidence of recurrent VTE, defined as a hospitalization or emergency room (ER) visit with a VTE diagnosis in the follow-up period, was determined for the commercially insured and Medicare populations separately. A proportional hazards model was used to assess the predictors of time to VTE recurrences. All cause and VTE-related health care resource utilization including hospitalizations, length of stay, outpatient medical service claims, and outpatient pharmacy claims were assessed along with the associated costs incurred during the 30-day and 12-month post-index event periods. Commercially insured and Medicare patients with and without recurrent VTE were evaluated and compared separately. Generalized linear models were used to further assess the incremental cost burden of recurrent VTE. Among the commercially insured population, 29,275 patients were diagnosed with VTE and received anticoagulant therapy. A recurrence of VTE associated with a hospitalization or ER visit occurred within 12 months of the index VTE in 15.4% of patients with a mean time to recurrence of 74.1 days. Among the Medicare insured population (n = 14,509), 11.4% of patients experienced another VTE with a mean time to recurrence of 115.6 days. A consistent predictor of VTE recurrence across both populations was greater comorbidity as indicated by Charlson Comorbidity Index scores. Among commercially insured VTE patients, total payments for health care resource utilization for all causes, including inpatient, outpatient medical services, and outpatient pharmacy use were higher for patients with a recurrent VTE relative to those without a recurrent VTE ($82,110 [$106,918] vs. $36,918 [$54,852], P less than 0.001). The primary driver for the higher health care payments was greater use of inpatient care. Total payments for VTE-related resource use was also greater for patients with a VTE recurrence ($38,591 [$51,479] vs. $15,123 [$22,186], P less than 0.001) with the majority (62.9%) attributed to care that took place within 30 days of the index VTE. After adjustment for key patient characteristics, VTE recurrence was associated with 2.2-fold and 3.0-fold higher post-index health care payments for all causes and for VTE-related claims, respectively. Similar results were observed for the Medicare population. VTE recurrence associated with a hospitalization or ER visit is associated with substantial health care resource utilization, which is primarily inpatient care undergone within the first 30 days following an initial VTE event. Thus, a sizeable portion of the economic burden of recurrent VTE is also incurred during this short period of time following an initial VTE event. Given that rates of VTE recurrence were high among patients identified as having received anticoagulant treatment, strategies to improve anticoagulation therapy among VTE patients in addition to other preventative measures are needed to lessen the health care and economic burdens of VTE.

Prevalence of thrombophilia according to age at the first manifestation of venous thromboembolism: results from the MAISTHRO registry

Thrombophilia is a well-established risk factor for a venous thromboembolic event (VTE), and it has been proposed that hereditary thrombophilia may substantially contribute to the development of VTE in young patients. We aimed to analyse the prevalence of thrombophilia with special regard to the age of VTE manifestation. The study cohort consisted of 1490 patients (58% females) with a median age 43years at the time of their first VTE. At least one thrombophilic disorder was identified in 50·1% of patients. The probability of detecting a hereditary thrombophilia declined significantly with advancing age (from 49·3% in patients aged 20years and younger to 21·9% in patients over the age of 70years; P<0·001). This may be primarily attributed to the decreasing frequencies of the F5 R506Q (factor V Leiden) mutation and deficiencies of protein C or protein S with older age at the time of the initial VTE event. Moreover, thrombophilia was more prevalent in unprovoked compared with risk-associated VTE (57·7% vs. 47·7%; P=0·001). The decline in the prevalence of hereditary thrombophilia with older ages supports the use of a selected thrombophilia screening strategy dependent on age and the presence or absence of additional VTE risk factors.

Taller women are at greater risk of recurrent venous thromboembolism: The Iowa Women's Health Study

Venous thromboembolism (VTE) recurs frequently. Greater height is associated with increased risk of incident VTE, but it is unclear whether height is related to risk of VTE recurrence. Recurrent VTE is associated with substantial morbidity and mortality, thus identifying individuals at greatest risk of experiencing a recurrent event, who may benefit from extended anticoagulant therapy, is vitally important. Using data from the Iowa Women,s Health Study, we explored whether greater height was associated with increased risk of VTE recurrence.Among 1,691 women who experienced an initial VTE event, 286(16.9%) experienced a recurrent event. Risk of recurrence was 76%(95% CI: 16% -186%) higher among women >66 inches [168 cm] tall relative to those ≤62 inches [158 cm] tall, after adjustment for age and waist circumference. Future research should evaluate whether body height improves clinical prediction of VTE recurrence risk.

Influence of Preceding Length of Anticoagulant Treatment and Initial Presentation of Venous Thromboembolism on Risk of Recurrence After Stopping Treatment: Analysis of Individual Participants' Data From Seven Trials

Conclusion: Risk of recurrent venous thromboembolism (VTE) after 3 months of anticoagulation therapy is similar to longer courses of anticoagulation. A higher risk of recurrence is present when the initial VTE event is a proximal deep venous thrombosis (DVT) or pulmonary embolism (PE). Summary: Randomized data indicate that at least 3 months of anticoagulation is preferable to shorter periods to reduce recurrent VTE after an initial VTE episode. Studies evaluating the optimal length of vitamin K antagonist treatment after VTE have compared two lengths of treatment. When only two lengths of treatment are compared, it is not possible to tell if the superior length of treatment from one individual study is the overall optimal length of treatment. The authors pooled data from seven individual comparative trials using a spectrum of lengths of treatment for VTE. The primary goal was to identify the shortest treatment length that most reduces the risk of recurrent VTE after stopping treatment with vitamin a K antagonist. They also sought to determine the optimal length of anticoagulant treatment with respect to specific subgroups at time of presentation VTE (proximal or distal DVT or PE) and whether thrombus recurrence was influenced by a temporary risk factor or whether the VTE was unprovoked. The seven studies comprised 2925 men and women with a first-time VTE event who did not have cancer. The primary end point was the first recurrent venous VTE event after stopping anticoagulation during up to 24 months of follow-up. The pooled data indicated recurrence was lower after isolated distal DVT then after proximal DVT (HR, 0.49; 95% CI, 0.34-0.71). Recurrence was similar after PE and proximal DVT (HR, 1.19; 95% CI, 0.87-1.63). Recurrence was lower after a VTE event associated with a temporary risk factor than after an unprovoked VTE (HR, 0.55; 95% CI, 0.41-0.74). Recurrence was similar if treatment was stopped at 3 months compared with 6 months or later (HR 1.19; 95% CI, 0.86-1.65). Recurrence was higher if anticoagulation was stopped at 1 or 1.5 months compared with 3 months or later (HR, 1.52; 95% CI, 1.14-2.02). Overall, higher rates of recurrence were associated with shorter durations of anticoagulation and were confined to the first 6 months after stopping vitamin K antagonist therapy. Comment: The analysis indicates patients with a VTE event who do not have an obvious indication for indefinite anticoagulation can stop vitamin K antagonist treatment after 3 months. Among the limitations of this study were that D-dimer levels and vascular laboratory assessment of the status of the venous thrombus at the end of anticoagulation were not included as potential variables influencing duration of anticoagulation. Perhaps patients with unprovoked VTE will, in the future, be better stratified by additional variables to determine which patients will have a low risk of recurrence with only 3 months of treatment.

Venous thromboembolism (VTE) in patients with lung cancer (LC).

e19565 Background: VTE is a leading cause of death and morbidity in cancer patients. A better knowledge of the epidemiology and the behavior of VTE can contribute to a better prevention and optimal management. The aim of our study was to determine the clinical characteristics and outcome of cancer patients with VTE with regards tumor type. Methods: A prospective observational study of consecutive cancer patients newly diagnosed with VTE was performed between May 2006 and April 2009. VTE was treated in accordance with the 2004 American College of Chest Physicians Guidelines. Data analysis was performed in July 2009. Results: 339 cancer patients with VTE were included. LC was the most frequent tumor in our series 25.4% (66 male, 20 female; median age 62 ± 11 years). Histologies were: adenocarcinoma 40 (46%), squamous cell carcinoma 18 (21%), undifferentiated 15 (17%) and small-cell carcinoma 9 (10%). The proportion of patients treated with chemotherapy in both LC and other tumors (OT) was similar (70% vs. 62%, p = 0.19). In LC, pulmonary embolism was the most frequent VTE event (51% vs. 29%, p<0.0001) and it presented earlier than in OT (median time after first cancer diagnose of 4 vs. 7 months respectively, p<0.0001). Rethrombosis was frequent in tumors (17% LC and 13% OT, p = 0.362) with a higher actuarial probability of rethrombosis in the LC group (median time from the initial VTE event of 6 vs. 17 months, p<0.0001). Conclusions: VTE in patients with LC is a common adverse event that occurs soon after tumor diagnosis, with a higher incidence of pulmonary embolism and a worse outcome regarding venous rethrombosis than in patients with OT. No significant financial relationships to disclose.

PO-01 Venous thromboembolism in patients with lung cancer

Introduction: Venous thromboembolism (VTE) is a leading cause of death and morbidity in cancer patients. Improving knowledge about the epidemiology and behavior of VTE can contribute to its prevention and optimal management of this life-threatening complication. Aim: To describe clinical characteristics and outcome of cancer patients with VTE regarding if they whether had lung cancer (LC) or other cancers (OC). Patients and Methods: A prospective observational study of consecutive cancer patients and newly diagnosisof VTE was performed between May 2006 and April 2009. All patients were uniformly treated according to the 2004 American College of Chest Physicians guidelines and followed up. Data analysis was performed in July 2009. Results: A total of 339 patients were included. LC was the most frequent tumor in our series and occurred in 86 patients (25.4%) (66 males; median age 62±11 years). Histological subtypes of LC were: adenocarcinoma = 40 (46%), squamous cell carcinoma = 18 (21%), non-small cell carcinoma unspecified =15 (17%) and small-cell carcinoma = 9 (10%). Patients with LC had more frequently arterial hypertension (38% vs 25%, p = 0.01) and smoking habit (83% vs 41%, p < 0.0001) and presented more frequently with pulmonary embolism (51% vs 29%, p < 0.0001) than patients with OC. VTE was diagnosed earlier in patients with LC after the initial cancer diagnosis, with a median of 4 months (95% CI 2.79–5.2) compared to 7 months (95% CI 4.40–9.59) in patients with OC (p < 0.0001). The actual probability of rethrombosis was higher in LP, with a median of 6 months (95% CI 3.74–8.26) vs 17 months (95% CI 11.58–22.42) from the initial VTE event to venous rethrombosis (p < 0.0001) compared to patients with OC. Conclusions: VTE in patients with LC occurs earlier in the course of cancer and has a worse outcome regarding venous rethrombosis than observed in patients with OC.