Risk Of Recurrent Venous Thromboembolism Research Articles

Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism

Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown. To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age. Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021. Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism. The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve). Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively). Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk. ClinicalTrials.gov Identifier: NCT00687882.

Association between obstructive sleep apnea and venous thromboembolism recurrence: results from a French cohort

BackgroundGrowing evidence suggests the relationship between obstructive sleep apnea (OSA) and venous thromboembolism (VTE). Few studies focused on VTE recurrence risk associated with OSA after anticoagulation cessation.MethodsIn a prospective cohort study, patients with documented VTE, were followed for an indefinite length of time and VTE recurrence were documented and adjudicated. The primary outcome was recurrent VTE after anticoagulation discontinuation. Secondary outcomes included all-cause mortality and the clinical presentation of VTE. Univariable and multivariable analyses were performed to identify risk factors for recurrence and mortality.ResultsAmong the 2109 patients with documented VTE included, 74 patients had moderate to severe OSA diagnosis confirmed by home sleep test or polysomnography. During a median follow-up of 4.8 (interquartile range 2.5–8.0) years recurrent VTE occurred in 252 patients (9 with OSA and 243 without OSA). The recurrence risk in the univariable and multivariable analysis was not increased in patients with OSA, regardless of the time of diagnosis (before or after index VTE or pooled). VTE phenotype was significantly more often PE with or without associated deep vein thrombosis in the first event and recurrence for OSA patients compared to non-OSA patients. The risk of death was not increased in the OSA population compared to non-OSA patients in multivariable analysis.ConclusionsIn patients with OSA and VTE, the risk of all-cause mortality and VTE recurrence after anticoagulation discontinuation was not increased compared to non-OSA patients.

Statins for venous event reduction in patients with venous thromboembolism: A multicenter randomized controlled pilot trial assessing feasibility

BackgroundStatins may reduce the risk for recurrent venous thromboembolism (VTE); however, no randomized trials have explored this hypothesis. We performed a pilot randomized trial to determine feasibility of recruitment for a larger trial of secondary VTE prevention with rosuvastatin. MethodsPatients with a newly diagnosed symptomatic proximal deep vein thrombosis and/or pulmonary embolism, receiving standard anticoagulation, were randomly allocated to adjuvant rosuvastatin 20 mg once daily for 180 days or no rosuvastatin for 6 months. ResultsBetween November 2016 and December 2019, 3391 patients were assessed for eligibility in six centers. Of these patients, 1347 (39.7%) were eligible and approached for participation in the trial and 312 (23.1%) were randomized. The mean rate of randomization was 8.2 ± 4.3 patients per month. During follow‐up, five recurrent VTE events were observed, three (1.9%) in the rosuvastatin group (two pulmonary embolism, one deep vein thrombosis), and two (1.3%) in the control group (two pulmonary embolism; P = 0.68). One major arterial event occurred in the rosuvastatin arm and none in the control arm (0.6% vs. 0%, P = 0.50). ConclusionThis pilot trial supports the feasibility of a larger scale randomized controlled trial to determine the efficacy of adjuvant rosuvastatin for the secondary prevention of VTE.

Effectiveness and safety of direct oral anticoagulants with antiplatelet agents in patients with venous thromboembolism: A multi‐database cohort study

BackgroundPatients with venous thromboembolism (VTE) often have comorbidities that require use of antiplatelets. However, evidence on the effects of concomitant use of direct oral anticoagulants (DOACs) and antiplatelets in this high‐risk population is scarce. Our international, multi‐database cohort study assessed the real‐world effectiveness and safety of concomitant use of DOACs and antiplatelets among patients with VTE. MethodsWe assembled two population‐based cohorts using administrative health care databases from Québec and Germany. We included patients with incident VTE who initiated treatment with a DOAC or a vitamin K antagonist (VKA), while being exposed to antiplatelets (acetylsalicylic acid, clopidogrel, ticagrelor, prasugrel, dipyridamole). The study period spanned from 2012 to 2016 (Québec) or 2019 (Germany). Concomitant use of DOACs and antiplatelets was compared with concomitant use of VKAs and antiplatelets, using inverse probability of treatment weighting to balance exposure groups. Cox proportional hazards models estimated site‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) of major bleeding, all‐cause mortality (primary outcomes), and recurrent VTE (secondary outcome). Site‐specific estimates were meta‐analyzed using random‐effects models. ResultsOverall, 4971 patients with VTE initiated concomitant use of a DOAC (n = 2289) or a VKA (n = 2682) and antiplatelets. Compared with concomitant use of VKAs and antiplatelets, concomitant use of DOACs and antiplatelets was associated with similar risks of major bleeding (HR, 0.81; 95% CI, 0.46‐1.45), all‐cause mortality (HR, 1.25; 95% CI, 0.87‐1.79), and recurrent VTE (HR, 0.96; 95% CI, 0.40‐2.27). ConclusionsAmong patients with VTE using antiplatelets, there were no major differences in effectiveness and safety between DOACs and VKAs.

D-dimer - uloga u hemostaznom sistemu i primena u specifičnim kliničkim stanjima

D-dimer is a soluble fibrin degradation product, which is formed by the breakdown of cross-linked fibrin monomers, previously created under thrombin activity, formed as a result of hemostatic activation. The degradation of cross-linked fibrin occurs as part of the activation of the fibrinolysis system, whose task is to remove the created coagulum and ensure the patency of the blood vessel. This process takes place under the influence of the most important fibrinolytic enzyme, plasmin. D-dimer can, therefore be considered a biomarker of coagulation activation and fibrinolysis, and is routinely used to rule out venous thromboembolism (VTE). D-dimer is increasingly used to assess the risk of VTE recurrence and to help define the optimal duration of anticoagulant therapy in the treatment of patients with VTE, to diagnose disseminated intravascular coagulation (DIC), to screen medical patients at increased risk of VTE. In particular, the use of D-dimer, which is sometimes unjustifiably high, should be emphasized, as part of the monitoring and treatment of patients with COVID-19 infection. This review article aims to: (1) define the origin and role of D-dimer in the hemostatic system, (2) the method of performing the analysis, the selection of adequate tests and interpretation in accordance with the consideration of possible preanalytical variables that affect the measurement of D-dimer; (3) consideration of its application in specific clinical settings or diseases.

Effectiveness and Safety of Apixaban versus Warfarin in Venous Thromboembolism Patients with Chronic Kidney Disease.

There has been limited evidence reported about the outcomes of oral anticoagulants among patients with venous thromboembolism (VTE) and chronic kidney disease (CKD), especially those with stage V/end-stage renal disease (ESRD). This retrospective cohort analysis of five U.S. claims databases evaluated the risk of recurrent VTE, major bleeding (MB), and clinically relevant nonmajor bleeding (CRNMB) for apixaban versus warfarin among VTE patients diagnosed with CKD, including ESRD. Inverse probability treatment weighting (IPTW) was used to balance patient characteristics between treatment cohorts. Hazard ratios (HRs) were calculated for recurrent VTE, MB, and CRNMB among patients with CKD who experienced an index VTE. An interaction analysis was conducted to evaluate treatment effects across different stages of CKD. A total of 29,790 VTE patients with CKD were selected for analyses, of whom 10,669 (35.8%) initiated apixaban and 19,121 (64.2%) initiated warfarin. Among IPTW-balanced patient cohorts, the apixaban group had significantly lower risk of recurrent VTE (HR: 0.78; 95% confidence interval [CI]: 0.66–0.92), MB (HR: 0.76; 95% CI: 0.65–0.88), and CRNMB (HR: 0.86; 95% CI: 0.80–0.93) than the warfarin group. When stratified by CKD stage (stage I/II: 8.2%; stage III: 49.4%; stage IV: 12.8%; stage V/ESRD: 12.0%; stage unspecified: 17.6%), no significant interaction was observed for effects of apixaban versus warfarin on recurrent VTE or MB. In summary, apixaban was associated with a significantly lower risk of recurrent VTE and MB than warfarin among VTE patients with CKD. CKD stages did not have significant impact on treatment effects for recurrent VTE and MB.

Do Patients with a Family or Personal History of Venous Thromboembolism have an Increased Risk of Recurrence?

A family (FH) and personal history (PH) of venous thromboembolism (VTE) are commonly evaluated risk factors for recurrence. We examined the association between FH/PH of VTE and the risk of recurrence and whether a stronger history status (i.e., both FH/PH vs. no FH/PH) carries an increased recurrence risk. We prospectively followed 813 patients aged ≥ 65 years with acute VTE from 9 Swiss hospitals. We classified patients into four groups: no FH/PH, FH only, PH only, and both FH/PH. The primary outcome was recurrent VTE during the full observation period. We examined the association between FH/PH status and the time to VTE recurrence using competing risk regression, adjusting for confounders and periods of anticoagulation. Of 813 patients with VTE, 59% had no FH/PH, 11% a FH only, 24% a PH only, and 7% had both a FH and PH of VTE. Overall, 105 patients had recurrent VTE during the full observation period. After adjustment, patients with a FH only (subhazard ratio [SHR] 0.8, 95% confidence interval [CI] 0.4-1.7), PH only (SHR 1.5, 95% CI 0.9-2.5), and both FH/PH (SHR 1.4, 95% CI 0.6-3.1) did not have an increased risk of recurrent VTE compared with those without FH/PH. When we considered the period after the completion of initial anticoagulation only, the results were similar. Our findings indicate that in patients with acute VTE, a FH and/or PH of VTE does not convey an increased risk of recurrent VTE. In particular, we did not find a "dose-effect" relationship between FH/PH status and VTE recurrence.

Multi-center retrospective study evaluating the efficacy and safety of apixaban versus warfarin for treatment of venous thromboembolism in patients with severe obesity.

Direct oral anticoagulants are the standard of care for venous thromboembolism (VTE) treatment. These agents are recommended regardless of patient weight and body mass index (BMI). However, there remains limited evidence supporting the use of apixaban in patients with severe obesity with a BMI ≥40kg/m2 or weight ≥120kg. The purpose of this study was to evaluate the efficacy and safety of apixaban for VTE in patients with a BMI ≥40kg/m2 or weight ≥120kg. This multi-center, retrospective study compared the use of apixaban versus warfarin in patients with severe obesity for the treatment of VTE between January 1, 2012, and December 31, 2019. Patients were identified by diagnosis codes for acute VTE and a weight ≥120kg or BMI ≥40kg/m2 . The primary efficacy outcome was time to recurrence of VTE within 12months, and the primary safety outcome was time to major bleeding within 12months. Secondary outcomes included incidence of recurrent VTE, major bleeding, clinically relevant non-major bleeding (CRNMB), all-cause mortality, number of total hospital encounters, and switch in anticoagulant. A total of 1099 patients were included in the study. Of these, 314 patients received apixaban and 785 received warfarin. The mean weight and BMI were 137kg and 46kg/m2 , respectively. Time to recurrent VTE was significantly longer in those treated with apixaban compared to warfarin (p=0.018). After controlling for confounding factors, apixaban use was associated with a reduced risk of recurrent VTE compared to warfarin (hazard ratio [HR]=0.54, 95% confidence interval [CI]: 0.29-0.97, p=0.04). There were no significant differences in major bleeding, CRNMB, or all-cause mortality between groups. In patients with a BMI ≥40kg/m2 or weight ≥120kg, apixaban appears to be effective and safe for the treatment of VTE.

Treatment Algorithm in Cancer-Associated Thrombosis: Updated Canadian Expert Consensus.

Patients with cancer-associated thrombosis (CAT) are at high risk of recurrent venous thromboembolism (VTE) and major bleeding complications. Risks vary significantly between individuals based on cancer status, treatment, and other characteristics. To facilitate the evidence-based management of anticoagulant therapy in this patient population, a committee of 11 Canadian clinical experts updated a consensus-based algorithm for the acute and extended treatment of symptomatic and incidental CAT that was developed in 2018. Following a systematic review of the literature, updates to the algorithm were discussed during an online teleconference, and the algorithm was subsequently refined based on feedback from committee members. Clinicians using this treatment algorithm should consider bleeding risk, type of cancer, and drug–drug interactions, as well as patient and clinician preferences, in tailoring anticoagulation for patients with CAT. Anticoagulant therapy should be adapted as the patient’s cancer status and management change over time.

Adherence to rivaroxaban for the treatment of venous thromboembolism–Results from the FIRST registry

BackgroundMedication nonadherence can result in poor clinical outcomes and significant costs to health care providers. When treating venous thromboembolism (VTE), subtherapeutic anticoagulation may contribute to complications such as recurrent VTE or postthrombotic syndrome. ObjectivesTo describe the extent, reasons for, and predictors of nonadherence to rivaroxaban for the treatment of VTE in clinical practice in the United Kingdom reported by participants of the FIRST registry. Patients/MethodsThe FIRST registry was an observational, multicenter registry reporting on the use of rivaroxaban in routine clinical practice. FIRST registry participants completed an adherence screening questionnaire during their treatment and follow‐up. ResultsIn total, 1028 participants completed 1660 questionnaires over 2 years. One hundred thirteen of 1028 (11%) reported nonadherence at 28 days (interquartile range, 21‐45). Reasons given for nonadherence at 1 month were forgetfulness (8.6% vs 74.7%; P < .001), carelessness (2.7% vs 27.3%; P < .001) or a change in routine (7.4% vs 25.5%; P < .001) reported by adherent and nonadherent participants, respectively. Older age (10‐year increments) was the strongest predictor of good adherence (adjusted odds ratio, 1.21; 95% confidence interval, 1.06‐1.39; 1 = adherent). ConclusionsOverall adherence to rivaroxaban was high, and most nonadherence was unintentional. Identification of those at risk of nonadherence may reduce the risk of VTE recurrence and long‐term complications.

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.

Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation : A Multicenter Prospective Cohort Study.

The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown. To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation. Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818). Eighteen sites between February 2011 and February 2021. Patients with isolated subsegmental pulmonary embolism. At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy. The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period. Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism. The study was restricted to patients with low-risk subsegmental pulmonary embolism. Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism. Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.

The utility of hereditary thrombophilia testing among patients with unprovoked venous thromboembolism.

Hereditary-thrombophilia (HT) testing is often sent during the evaluation of patients with unprovoked venous thromboembolism (VTE). This remains a frequent practice even though the results of such testing are often of unclear practical significance. We conducted a multicenter retrospective study to assess whether HT is associated with risk of recurrent VTE among patients who discontinue anticoagulation (AC) following an unprovoked VTE. A total of 528 adult patients were included, 28% of whom (N=110) tested positive for HT. Median follow-up was 55months (IQR 40-66months) following AC discontinuation. One hundred and twenty-four patients (23%) had a recurrent VTE during follow-up, including 29/110 with HT (26%) and 95/418 without HT (23%). Risk of recurrent VTE over time was similar between the two groups (logrank P=.47). The HR for recurrence among patients with HT was 1.17 (95% CI 0.76 to 1.81). On multivariable analysis, HT was not associated with recurrence of VTE (HR with HT=1.07 (95% CI 0.69-1.65), P=.74). The only factor significantly associated with risk of VTE recurrence on multivariable analysis was presence of PE (as opposed to DVT alone) (HR=1.54, 95% CI 1.02-2.30, P=.035). The presence of HT was not associated with risk of recurrent VTE in this cohort of patients. These findings underscore the questionable clinical utility of routine thrombophilia testing among patient with unprovoked VTE and suggest that such testing should not be routinely pursued.

Effects of statins in primary and secondary prevention for venous thromboembolism events: A meta analysis

ObjectiveThe associations between statins use and incidence or recurrence of venous thromboembolism (VTE) are controversial. We aimed to conduct a meta-analysis to reconcile the conflicting results. MethodsWe searched PubMed, Embase and Cochrane Library for studies published from database inception until May 31, 2021. Cohort studies and Randomized Controlled Trials that reported incidence or recurrence of VTE using statins compared with placebo or non-statins were included for meta-analysis. ResultsA total of 43 studies comprising over 8.6 million participants were included for analysis. The median follow-up duration was 38.1 months. Compared with no statins treatment, statins appeared to have a protective effect in primary prevention of VTE (RR 0.78, 95% CI 0.72–0.85), but significant heterogeneity was found among included studies (I2 = 81%). Statins was also associated with a 26% reduced risk of recurrent VTE (RR 0.74, 95% CI 0.70–0.78), even in patients receiving anticoagulant therapy (RR 0.77, 95% CI 0.65–0.92). In patients with a history of VTE, statins was associated with a reduced risk of bleeding and all cause mortality. The NNT of statins to prevent one case of VTE in the cancer population, and one case of recurrent VTE in patients with a history of VTE was 103.1 and 90.7 person-years respectively. ConclusionIn high-risk patients, statins treatment may reduce the incidence of VTE. Statins can also reduce the risk of recurrent VTE and all-cause mortality in patients with a history of VTE.

Comparative Effectiveness and Safety of Extended Anticoagulant Therapy Among Medicare Beneficiaries with Venous Thromboembolism

▪Introduction: Approximately 30% of patients with venous thromboembolism (VTE) experience a recurrence within 10 years of the initial event with their recurrence risk peaking during the first 6-12 months. Two large randomized clinical trials AMPLIFY-EXT and PADIS-PE reported that extended treatment with apixaban and warfarin beyond 6 months of initial treatment reduced recurrent VTE without increasing the rate of major bleeding compared to placebo, respectively. Little is known about real-world effectiveness and safety of extended oral anticoagulation beyond 6 months of initial treatment for Medicare beneficiaries with VTE, despite the fact that VTE disproportionately affects the elderly. We assessed the effectiveness and safety of extended use of apixaban and warfarin beyond 6 months of initial treatment for prevention of recurrent VTE and adverse major bleeding events among Medicare beneficiaries with newly diagnosed VTE.Methods: A retrospective cohort study using 2014-2018 Medicare data (5% samples in 2014-2016 and 15% samples of Medicare beneficiaries in 2017-2018) was conducted for patients aged ≥18 years with a diagnosis of deep vein thrombosis or pulmonary embolism ascertained from inpatient claims. Patients were included if they initiated anticoagulants within 30 days of their first VTE diagnosis, completed 6 months of therapy defined as ≥83% proportion days covered with oral anticoagulants during the initial 6-month period, and received extended treatment with either apixaban or warfarin or no extended therapy. We compared the risks of recurrent VTE and major bleeding between apixaban, warfarin, and no treatment groups. To adjust for differences in baseline characteristics and clinical factors (e.g., HAS-BLED score, active cancer, and provoked VTE) between groups, we used the stabilized inverse probability treatment weighting (IPTW) method. Follow-up continued until the occurrence of the first event, switch to the comparator, disenrollment, death, or end of the study period. Multivariable Cox proportional hazards modeling with IPTW was used to obtain adjusted hazard ratios (aHR) and 95% confidence intervals (95%CI).Results: The study cohort (mean age=74 ±12 years, 40% male, 76% White) consisted of 2,315 users of extended apixaban treatment (83% with 5 mg twice a day and 17% with 2.5 mg twice a day; mean duration=6.2 months), 2,757 users of extended warfarin treatment (mean duration=8.2 months), and 2,328 patients with no extended treatment following completion of an initial 6 months of anticoagulant treatment. The incidence rates of recurrent VTE were 0.42, 1.73, and 1.72 per 100 person-years, and those of major bleeding were 2.28, 3.62, and 1.43 per 100 person-years in the apixaban, warfarin, and no treatment groups, respectively (Table 1). Compared to no extended treatment, the use of apixaban was associated with an 80% decreased risk of recurrent VTE (aHR=0.19, 95%CI=0.06-0.55) without increasing the risk of major bleeding (aHR=1.19, 95%CI=0.65-2.19); the use of warfarin did not lower the risk of recurrent VTE (aHR=0.75, 95%CI=0.42-1.37) but increased the risk of major bleeding (aHR=1.92, 95%CI=1.13-3.25). Compared to the use of warfarin, the use of apixaban was associated with a decreased risk of recurrent VTE (aHR=0.26, 95% CI=0.09-0.76) and no difference in major bleeding risk (aHR=0.61, 95%CI=0.36-1.06). These findings remained consistent in subgroup (e.g., patients with provoked vs. unprovoked VTE, patients with active cancer vs. those without, and patients with chronic kidney diseases vs. those without) and sensitivity analyses (e.g., ≥92% proportion days covered with oral anticoagulants during the initial 6-month period).Conclusions: Compared to no extended therapy, extended anticoagulation with apixaban was associated with a reduced risk of recurrent VTE without increasing the risk of major bleeding, whereas warfarin did not lower risk of recurrent VTE but increased the risk of major bleeding among Medicare beneficiaries with VTE. In the head-to-head comparison, the use of apixaban was more effective than warfarin in preventing recurrent VTE, without increasing the risk of major bleeding events. Our findings suggest that apixaban is an effective and safer option for extended treatment of VTE when compared to warfarin or no treatment among Medicare beneficiaries with VTE. [Display omitted] DisclosuresPark: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Kang: BMS/Pfizer Alliance American Thrombosis InvestigatorInitiated Research Program: Research Funding. Huang: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Lo-Ciganic: MERCK: Research Funding; BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Dietrich: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Murphy: North American Thrombosis Foundation: Honoraria. DeRemer: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding; Portola Pharmaceuticals: Current equity holder in publicly-traded company; BMS advisory board attendee: Honoraria.

Adherence Trajectories of Extended Direct-Acting Oral Anticoagulants and Risk of Recurrent Venous Thromboembolism and Major Bleeding: A Retrospective Cohort Study

▪Introduction: The optimal duration of extended oral anticoagulant treatment for patients with venous thromboembolism (VTE) beyond the initial 3 to 6 months of the treatment remains undetermined. Group-based trajectory modeling (GBTM) is a data-driven method that can categorize patients with similar longitudinal adherence patterns over time into distinct subgroups. This study identified distinct patient subgroups with similar adherence trajectories of extended treatment of direct-acting oral anticoagulants (DOACs), and then examined the association between adherence trajectories and the risk of recurrent VTE and major bleeding among patients with VTE.Methods: We identified patients ≥18 years with a diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE) from inpatient claims using 2013-2019 Truven Commercial and Medicare Supplemental database. Patients were included if they initiated anticoagulants within 30 days of their first VTE diagnosis, completed 6 months of therapy-defined as ≥83% proportion days covered (PDC) with oral anticoagulants during the initial 6-month treatment period, and had extended treatment with any DOACs or no extended therapy. Based on the monthly PDC as the DOAC adherence measure, we used GBTM to identify DOAC adherence trajectories during 6 months of the extended treatment. The final trajectory model was chosen by assessing the Bayesian information criteria, Nagin's criteria, and having at least 10% of patients in each trajectory group for improving clinical utility. We compared recurrent VTE and major bleeding among adherence trajectory subgroups. Patients were followed up from the initiation of the extended treatment until the occurrence of the study outcomes, discontinuation of DOACs, switching to warfarin, end of study period, or end of enrollment, whichever occurred first. Cox proportional hazard modeling with inverse probability treatment weighting (IPTW) was used to obtain hazard ratios (HR) and 95% confidence intervals (95% CI).Results: The study cohort (mean age=58.7 years and 51.1% males) consisted of 10,960 patients with extended treatment of DOACs (4,294 apixaban, 6,409 rivaroxaban, 238 dabigatran, and 19 edoxaban users) with a mean treatment duration of 7.7 months and 5,133 patients with no extended treatment following completion of an initial 6 months of anticoagulant treatment. The final GBTM models identified four distinct adherence trajectories for extended therapy including (1) patients with consistent adherence (group 1, 40.7%), (2) patients with gradually declining adherence (group 2, 14.3%), (3) patients with rapidly declining adherence (group 3, 13.1%), and (4) patients with no extended treatment (reference group, 31.9%) (Figure 1). The incidence rates of recurrent VTE were 18.6, 46.9, 84.1, and 160.7 per 10,000 person-years, and those of major bleeding were 61.0, 125.1, 168.3, and 48.7 per 10,000 person-years in group 1, group 2, group 3, and the reference group, respectively. After IPTW, demographics and clinical characteristics (e.g., HAS-BLED bleeding risk score, provoked VTE) were comparable across the four trajectory groups with <0.1 of the standardized mean difference for each pairwise comparison. Compared to the reference group, group 1 (HR=0.09, 95% CI=0.05-0.17) and group 2 (HR=0.16, 95% CI=0.04-0.58) had decreased risk of recurrent VTE without increasing risk of major bleeding (HR=1.26, 95% CI=0.76-2.10 in group 1, HR=2.28, 95% CI=0.96-5.36 in group 2). There was no difference in the risk of recurrent VTE (HR=0.32, 95% CI=0.09-1.16) in group 3 but they had an increased risk of major bleeding (HR=2.69, 95% CI=1.00-7.23). The findings were consistent across different types of DOACs, suggesting a class effect of DOACs as extended therapy.Conclusions: We identified 4 distinct trajectories of DOAC adherence during the 6 months of extended therapy among patients who completed 6 months of initial treatment. Compared to no extended treatment, persistent use of DOACs during extended treatment was associated with a lower risk of recurrent VTE without increasing major bleeding risk, whereas a rapid decline in adherence was associated with an increased risk of major bleeding with no difference in the risk of recurrence. Our findings provide evidence on the benefits of continuing and being adherent to extended anticoagulant treatment in patients with VTE without increasing the risk of major bleeding. [Display omitted] DisclosuresKang: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Jones: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Lo-Ciganic: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding; MERCK: Research Funding. DeRemer: BMS advisory board attendee: Honoraria; Portola Pharmaceuticals: Current equity holder in publicly-traded company; BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Dietrich: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Huang: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Murphy: North American Thrombosis Foundation: Honoraria. Park: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding.

Thrombin Generation to Predict the Risk of Venous Thromboembolism Recurrence, Major Bleeding and Death in the Elderly: A Prospective Multicenter Cohort Study

Introduction: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), constitutes a worldwide major health issue, and a leading cause of death. VTE incidence increases exponentially with age mainly due to the accumulation of risk factors and comorbidities predisposing to thrombosis. This leads to greater morbidity impact of VTE on elderly patients, who are also at higher risk of bleeding. Consequently, identification of older patients who might benefit from indefinite anticoagulation treatment is paramount. In order to facilitate the identification of these patients, the benefit/risk ratio should be carefully evaluated by considering clinical and laboratory information. Thrombin activity can be recorded by continuously measuring cleavage of a fluorescent substrate, resulting in a thrombin generation (TG) curve. Recent association studies show promising data of thrombin generation parameters predicting first VTE in elderly (Wang H et. al. RPTH 2021, 5:e12536). However, the predictive ability of thrombin generation for recurrent VTE, major bleeding and mortality in the elderly is unknown. The goal of this study was to prospectively investigate the performance of the TG assay one year after index VTE in predicting the risk of VTE, recurrence, major bleeding and mortality up to 2 years in elderly population.Methods: The study was conducted as part of the Swiss Cohort of Elderly Patients with VTE (SWITCO65+), a prospective multicenter cohort study to assess medical outcomes and quality of life in elderly patients with acute VTE in Switzerland. For the present study, the clinical outcomes were VTE recurrence, major bleeding and mortality, which were assessed parallel to clinical data of thrombosis and other general laboratory parameters including thrombophilia testing in over a 3-year period. Blood samples for assessment of TG parameters were drawn 12 month after the index VTE. Venous blood was drawn after minimal venostasis and processed by double centrifugation according to the recommendation of the subcommittee of the Scientific and Standardization Committee of ISTH. TG measurements were performed with the calibrated automated thrombogramm assay (Stago, Asnières-sur-Seine, France) in two experimental settings: 1pM tissue factor (TF) with/without thrombomodulin (TM) and 13.6 pM TF with/without activated protein C (APC). In addition, reference plasma (Cryocheck Reference Control Normal, PrecisionBiologic, Dartmouth, Canada) was tested in all experiments in order to correct day-to-day variations. Lag time, velocity index, time to peak, peak height, endogenous thrombin potential (ETP) were measured and peak and ETP ratio obtained in presence/absence of TM or APC were calculated. Results from the reference plasma were used to calculate the normalized ETP and peak ratio in 1 pM setting and peak ratio in 13.6 pM TF setting.Results: TG was assessed in 565 patients 12 months after the index VTE. At this time, 59% of patients were still anticoagulated. Eleven percent of them had cancer-related VTE, 20% provoked VTE and 68% unprovoked VTE. The prevalence of inherited risk factors for VTE was in line with previous reports on European patients with VTE.Patients still anticoagulated 12 months after the index VTE were less likely to develop recurrent VTE in the next 24 months than patients without anticoagulation. However, the incidence of major bleeding and mortality was comparable in anticoagulated and non-anticoagulated patients.TG was faster and lower in anticoagulated than in non-anticoagulated patients.Some thrombin generation parameters measured 12 months after the index VTE (Figure 1) were discriminatory for VTE recurrence, major bleeding and mortality (Table 1). In addition, several thrombin generation parameters measured in patients not under anticoagulation 12 months after the index VTE were associated with an increased risk of VTE recurrence, major bleeding and mortality up to 24 months. These associations remained after adjustment for potential confounding factors for the risk of VTE recurrence, major bleeding and mortality (Table 2).Conclusion: In elderly patients, several parameters of thrombin generation were associated with VTE recurrence, major bleeding and/or mortality. These findings may serve as the basis for validation in a prospective interventional outcome trial. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Role of Vitamin D Levels in Venous Thrombosis

Venous thromboembolism (VTE) is a complex condition that impacts over 900,000 people in theUnited States annually. It is estimated that about 100,000 people in the US die from deep veinthrombosis (DVT) or pulmonary embolism (PE) annually. Several biomarkers, includingVitamin D most recently, have been investigated and linked to the risk of developing VTE orrecurrent VTE. Vitamin D is known to control the expression of over 200 genes and it has shownto have anti-thrombotic effects through various mechanisms. There is emerging data regardingits role in the coagulation pathway, platelet activation, inflammatory pathways and endothelialactivation (1). There have been a few international studies linking Vitamin D deficiency toVTE(2). However; no such study has been replicated in the North American population where the prevalence of Vitamin D deficiency is 40%. The focus of this study will be to determine theprevalence of Vitamin D deficiency in patients with VTE. Based on the role of Vitamin D in thepathway for thrombogenesis and antithrombin effects, there is likely a correlation between VTEand Vitamin D levels.This is a retrospective chart review of all patients admitted to Franciscan Health- Olympia Fieldswith VTE between July 2018 and June2020. A total of 181 patients with VTE were reviewed.Data such as age, gender, race, D-dimer, and Vitamin D levels were collected. Vitamin D levels<30ng/mL was defined as deficient. In addition, further data collection, included provoked vsunprovoked VTE, presence of malignancy, and the severity of DVT and PE based on locationand extent of the VTE (severity was scored on a scale of 1-3 with 1 being mild and 3 as severe).A regression analysis was done to find a correlation between several variables and T-test wasused to determine P-value.Of the 181 patients, 110 had a vitamin D level documented at the time of their VTE and datawas specifically analyzed for this subgroup. There were 46 males and 64 females, 53.6%AA,7.3% Hispanic, 38.2% Caucasian, and 0.9% unknown. 25.5% had an unprovoked VTE eventand 74.5% had a provoked event. 39 patients had a known active malignancy and a likelycancer associated thrombosis. 85.7% of patients with unprovoked DVT had a low Vitamin Dlevel. In patients with cancer associated thrombosis there was no significant correlation withvitamin D levels. A strong correlation was noted between vitamin D levels and the severity of PE(p value=0.036).This retrospective chart review from a patient population at a community hospital indicates thatthere is some correlation between venous thromboembolism and Vitamin D levels. Specifically,it appears that patients with an unprovoked VTE have low Vitamin D levels suggesting thatvitamin D deficiency may be a risk factor for VTE development as indicated by previousinternational studies (2). In addition, it appears that there is an inverse relationship between theseverity of PE and vitamin D levels. Perhaps Vitamin D may be used as a biomarker for VTErisk assessment and management. Large scale studies are needed in the future to determinethe exact relationship between VTE and Vitamin D and further studies are needed to test therole of vitamin D supplementation and risk of recurrent VTE. DisclosuresNo relevant conflicts of interest to declare.

Direct Oral Anticoagulant Versus Low Molecular Weight Heparin for the Treatment of Cancer-Associated Thromboembolism: 2021 Updated Meta-Analysis of Randomized Controlled Trials

Introduction: International clinical practice guidelines (ITAC, ASCO, NCCN and ASH) have progressively endorsed direct factor Xa inhibitors (edoxaban, rivaroxaban and apixaban) as an alternative to monotherapy with low-molecular-weight heparin (LMWH) for the treatment of venous thromboembolism (VTE) in cancer patients. The results from new randomized controlled trials (RCT) which assessed the efficacy and the safety of direct oral anticoagulants (DOAC) compared to LMWH for the treatment of cancer-associated thrombosis (CAT) were released during the past months. We therefore performed an updated meta-analysis of all publicly available data from RCT comparing DOAC with LMWH for the treatment of CAT.Methods: Embase, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and conference proceedings from all languages were searched up to August 2, 2021. Search strategy, study selection, data extraction and statistical analysis were performed in accordance with the Preferred Reporting Items for Meta-Analyses (PRISMA) guidelines. The primary efficacy outcome was recurrent VTE, and the primary safety outcome was major bleeding. Secondary outcomes included clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. Risk of bias was assessed by using the Cochrane risk-of-bias tool in randomized controlled trials version 2.0. Pooled relative risk (RR) and 95% confidence intervals (CIs) were estimated using the Mantel-Haenszel method of Der Simonian and Laird within a random-effect model. Heterogeneity of effect size across studies was assessed using the I 2 statistic. Publication bias was assessed by visual inspection of funnel plots. All the statistical analyses were performed with the RevMan 5.3 software.Results: Six RCT comparing the efficacy and safety of DOAC versus LMWH, which enrolled a total of 3,690 cancer patients with acute VTE (1850 randomized to the DOAC arms and 1840 randomized to the LMWH arms), were included in the pooled analysis. Main study characteristics are summarized in Table 1. During a follow-up of 3 to 6 months under anticoagulant treatment, recurrent VTE occurred in 99 of 1,850 (5.3%) patients receiving DOACs versus 152 of 1,840 (8.3%) patients receiving LMWH. The risk of recurrent VTE was significantly lower with DOAC than with LMWH (RR 0.67, 95% CI 0.52-0.85, p = 0.001, I 2 = 0%, Figure 1A). Major bleeding occurred in 78 (4.2%) patients with CAT treated with DOAC versus 65 (3.5%) patients treated with LMWH. The risk of major bleeding was non significantly higher with DOAC (RR 1.20, 95% CI 0.85-1.70, p = 0.31, I 2= 7%, Figure 1B). CRNMB was more frequent in cancer patients receiving DOAC compared to those receiving LMWH (10.3% versus 6.3%, RR 1.63, 95% CI 1.25-2.11, p = 0.0003, I²= 6%, Figure 1C). The rates of all-cause mortality did not differ between the two groups (23.6% in the DOAC arms versus 23.3% in the LMWH arms, RR 1.02, 95% CI 0.89-1.16, p = 0.80, I² = 13%, Figure 1D).Conclusions: In this August 2021 meta-analysis of 3,690 patients treated for CAT, DOAC significantly reduced the risk of recurrent VTE compared with LMWH, without increasing the risk of major bleeding. However, as previously highlighted, the use of DOAC was associated with an increased risk of CRNMB. Our results provide additional evidence for the use of DOAC as a safe and effective first-line option for the treatment of CAT in patients who are not at high risk of bleeding. These findings may increase the level of certainty for the evidence used in the national or international clinical practice guidelines supporting the use of DOAC in cancer patients with CAT. [Display omitted] DisclosuresConnors: CSL Behring: Research Funding; Pfizer: Honoraria; Alnylam: Consultancy; takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Abbott: Consultancy.

Risk of Recurrent Venous Thromboembolism and Hemorrhage Following Interruption of Anticoagulation at Delivery

Background: Current guidelines for regional anesthesia advise for the discontinuation of prophylactic and therapeutic low molecular weight heparin (LMWH) 12 hours and 24 hours, respectively prior to the use of neuraxial anesthesia (NA) for obstetric patients. Re initiating a prophylactic dose 12 hours following epidural catheter insertion/spinal anesthesia (SA) and at least 4 hours following epidural catheter removal is also recommended. There are limited data on the recurrent risk of venous thromboembolism (VTE) and bleeding using these standards. We conducted a retrospective single center study to assess the risk of VTE and/or bleeding in pregnant women using these criteria.Methods: Consecutive patients from 2013 to 2018 at Mount Sinai Hospital, a university affiliated tertiary care center in Toronto, Canada who were prescribed therapeutic or prophylactic LMWH antenatally and postpartum and who had NA were included. Hospital records were reviewed to determine the indication and dosage of LMWH, presence of thrombophilia, time of first LMWH injection postpartum, the mode of neuraxial anesthesia and delivery, the time of epidural catheter/spinal anesthesia, the time of epidural catheter removal, laboratory parameters and comorbid illnesses. Patients requiring therapeutic or prophylactic LMWH were assessed in the Hematology clinic and were advised to discontinue anticoagulation according to current recommendations. The primary outcomes were frequency of VTE, spinal hematoma and volume of postpartum blood loss. Statistical Analysis: Continuous variables were summarized as medians and interquartile ranges. Categorical variables were summarized as percentages. Characteristics associated with VTE and hemorrhage were analyzed using regression analysis.Results: Of 169 pregnancies, 158 fulfilled criteria, and 110 had complete data for the time of epidural catheter removal and initiation of LMWH. Median age was 34 (IQR 5) years and median weight 90 (IQR 70) kgs. Diagnoses included antiphospholipid syndrome, Budd Chiari, provoked and unprovoked VTE. Median platelet count at delivery was 185 (IQR 76) x 10(9)/L. Thirty-three percent were using concomitant ASA antenatally. Forty-four percent (n=48) had a vaginal delivery (VD). Sixty five (59%) had epidural anesthesia, 43 (39%) had SA and, two had combined spinal/epidural anesthesia. Median time to restarting LMWH was 7.8 (IQR 4.7) hours from epidural catheter removal/spinal insertion and 9 (IQR 3.9) hours from SA. There were no spinal hematomas. Median blood loss was 500 (IQR 400) ml. One patient, who received prophylactic dose LMWH antepartum, had a Caesarean delivery, spinal anesthesia and a prophylactic dose re-started 13.7 hours after SA, developed a delayed postpartum hemorrhage. One patient developed a VTE (1%). She developed a distal and superficial thrombus immediately after delivery. She was using antenatal prophylactic LMWH as she had an unprovoked VTE predating pregnancy, was heterozygous for the prothrombin gene mutation, had epidural anesthesia and VD. She received prophylactic LMWH three hours after catheter removal which was also 10 hours after catheter insertion.Limitations: Time of discontinuation of LMWH prior to induction could not be confirmed definitively as this was a retrospective review.Conclusion: Prospective studies are required to confirm these findings and to determine the safety of current recommendations of interrupting anticoagulation prior to regional anesthesia and delivery and to identify risk factors for hemorrhage and recurrent VTE to optimize anticoagulation regimens for these patients. DisclosuresMalinowski: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy.