Recurrent Venous Thromboembolism Events Research Articles

JS5-3 Current status and core measures of cancer-associated thromboembolism

Thromboembolism is life-threating condition which is reported to be the second-leading cause of death in cancer patients after cancer itself. Cancer-associated thromboembolism (CAT) is classified as arterial thromboembolism and venous thromboembolism (VTE), but multiple pathologies are considered depending on the onset mechanism. A recent nationwide prospective cohort study revealed that the prevalence of VTE among treatment naïve Japanese cancer patients was 5.9% overall, and that VTE prevalence appeared to increase as the cancer stage increased, reaching a level of 11.2% at stage IV. Moreover, as cancer patients in Japan progressively age, comorbid VTE is expected to increase in prevalence in the next decade. CA-VTE is not rare at all. Although anticoagulant treatment is the recommended standard of care for acute CA-VTE, this treatment is complicated by both a high risk of recurrent VTE and bleeding events. Direct oral anticoagulants (DOACs) are recommended as new standard care for CA-VTE. The most updated meta-analysis demonstrated that the incidence of VTE recurrence was significantly lower with DOACs compared with low molecular weight heparin (LMWH), and that the risk of major bleeding was non-significantly higher with DOACs compared with LMWH. Unfortunately, no formal bleeding assessment scores are currently available to predict the risk of bleeding in cancer patients receiving DOACs. Clinicians should use them with caution, especially when patients have a high risk of bleeding such as luminal gastrointestinal cancers with an intact primary. In addition, recent trials showed that thromboprophylaxis with DOACs in ambulatory cancer patients at intermediate or high risk of VTE (Khorana score ≥2) was effective and safe. Taken together, DOACs will be more common all over the world. It should be noted that Japanese patients were rarely included in the pivotal international phase III trials mentioned above. Further complementary Japanese studies are warranted.

Long-Term Rivaroxaban for the Treatment of Acute Venous Thromboembolism in Patients with Active Cancer in a Prospective Multicenter Trial: KVTE13-01

BackgroundCancer patients with venous thromboembolism (VTE) are at a substantial risk of recurrent VTE despite anticoagulation therapy. Limited data is available regarding the effectiveness and safety of rivaroxaban in patients with active cancer and associated VTE.MethodsThis prospective, multicenter, open-label study enrolled patients with active cancer and newly diagnosed, objectively confirmed, lower-extremity deep vein thrombosis (DVT), pulmonary embolism (PE) or both between November 2013 and June 2016. Active cancer was defined as a histologically confirmed maligancy, which was diagnosed or treated within the previous 6 months, or as a recurrent/metastatic cancer. Patients received rivaroxaban 15mg twice daily for the first 3 weeks, followed by 20mg once daily for 6 months. The primary objective of this study was to assess the symptomatic, recurrent VTE events following rivaroxaban treatment. The secondary objectives included any recurrent VTE events, bleeding complications (major or non-major clinically relevant [NMCR] bleeding events), and overall mortality. Blinded central adjudication was performed for all recurrent VTEs, bleeding events, and deaths. The recurrent VTE and bleeding events were calculated using a cumulative incidence method that incorporated death from any cause as competing risk. The study was registered at www.clinicaltrials.gov as #NCT01989845.Results127 patients were screened from 9 centers in Korea. Of these, 3 patients were not enrolled because they did not meet the eligibility criteria. Thus, 124 patients were enrolled. Mean age was 67 years (range, 28-85) and 55 (44%) were female. 27 patients (22%) had baseline ECOG performance status of 2. The most common primary tumor sites were lung (N=30, 24%), colorectum (N=24, 19%), pancreaticobiliary tract (N=16, 13%), stomach (N=16, 13%); 14 patients (11%) had hematologic malignancies. 93 patients (75%) had metastatic disease and 110 (89%) were under cancer treatments (chemotherapy and/or radiation). The qualifying thrombotic event was PE ± lower-extremity DVT in 102 patients (82%) and presented as symptomatic in 78 patients (63%).During the 6-month study period, 7 patients (fatal PE, 4; non-fatal PE, 3) experienced symptomatic recurrent VTE (cumulative rate, 5.9%, Figure 1). There were 2 patients with incidental recurrent PE. Thus, cumulative rate of any recurrent VTE was 7.6%. Major bleeding events occurred in 6 patients (cumulative rate, 5.3%; Figure 2) and NMCR bleeding events in 11 (cumulative rate, 10.2%). 28 patients died during the study period (cumulative rate, 24.0%; Figure 3).ConclusionRivaroxaban appears to be an effective and safe treatment in patients with cancer-associated VTE. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Children with CVC-VTE: A Very High Risk Group for Recurrent Thrombosis

Background: Venous thromboembolism (VTE) is the second most common contributor to harm in hospitalized pediatric patients.The presence of a central venous catheter (CVC) remains the most potent risk factor for the development of VTE in children. Children with chronic illnesses often require multiple CVCs throughout their lifetime. There is limited evidence regarding either risk factors for recurrent VTE with subsequent CVC placement or efficacy of secondary prophylaxis. Methods: We performed a single center retrospective cohort study and included subjects from 0-18 years of age with an initial CVC-associated VTE (CVC-VTE) that occurred between 1-1-2003 to 12-31-2013. Subject data was collected from the initial CVC-VTE event until either the end of the study period (9-30-2014) or a recurrent VTE event. Data collection included demographics, CVC details (total number of CVCs placed during the study period, line type, and duration), underlying medical conditions (acute and chronic), thrombophilia, and anticoagulation regimens. During the study period, our clinical practice included secondary VTE prophylaxis with enoxaparin for subsequent CVCs as long as a contraindication to anticoagulation did not exist. The enoxaparin dosing for prophylaxis dosing varied throughout the study period. The association between CVC-VTE recurrence and VTE risk factors for the first subsequent CVC was assessed using logistic regression. A forward stepwise selection approach was used for model building. Variables with a p-value Results: During the study period, 432 subjects had an initial CVC-associated VTE with a mean follow-up time of 27.3 ± 29.6 months. 222 (51.4%) had 1 or more additional CVCs placed with a mean of 1.8 ± 1.3 CVC per subject (Figure 1). For the entire cohort, 111/432 (25.7%) had a recurrent CVC-VTE. Limiting the analysis to the first additional CVC placement, 76/222 (34%) patients had a recurrent CVC-VTE. 67/222 (30%) of patients did not receive secondary prophylaxis. Demographics and distribution of VTE risk factors are listed in Table 1. On univariate analyses, congenital heart disease (OR 8.22; 95% CI 1.74, 38.8) and TPN dependence (OR 5.28; 95%CI 1.12, 25) were associated with an increased risk for VTE recurrence with the first additional CVC placement (Table 2). On multivariable analysis, none of the VTE risk factors remained statistically significant (Table 2). Conclusions: Over half (222/432) of all children with CVC-VTE in our study required a subsequent CVC. In those who had a subsequent CVC, 50% (111/222) experienced a recurrent CVC-VTE. This is an extremely high risk of thrombosis in a heterogeneous group of children with chronic medical conditions. On multivariable analysis we were unable to identify additional risk factors for VTE recurrence. While the use of secondary prophylaxis either prophylactic (0.76, 95%CI 0.31-1.88) or full dose (0.58, 95%CI 0.28-1.2) had associated odds ratios consistent with a decrease in VTE recurrence, they did not meet statistical significance. A history of a prior CVC-VTE is likely the strongest risk factor for recurrent CVC-VTE. This very high risk group (patients with prior CVC-VTE who require a subsequent CVC) is an ideal population to target in future interventional studies. Download : Download high-res image (132KB) Download : Download full-size image Disclosures Raffini: Green Cross Inc: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; Genetech: Consultancy.

Direct Oral Anticoagulants Compared With Dalteparin for Treatment of Cancer-Associated Thrombosis: A Living, Interactive Systematic Review and Network Meta-analysis

ObjectiveTo maintain living, interactive evidence (LIvE) on the benefits and harms of different treatment options in adults with cancer-associated thrombosis (CAT). MethodsWe have used a novel LIvE synthesis framework to maintain this living, interactive systematic review since September 19, 2018. Randomized controlled trials evaluating the efficacy and safety of direct oral anticoagulants (DOACs) compared with low-molecular-weight heparin for CAT are included in this analysis. Details of LIvE synthesis framework are available at the website https://cat.network-meta-analysis.com. ResultsThe results are constantly updated as new information becomes available (https://cat.network-meta-analysis.com/CAT.html). The living, interactive systematic review currently includes 4 randomized controlled trials (N=2894). Direct comparisons show that DOACs significantly decrease recurrent venous thromboembolism (VTE) events compared with dalteparin (odds ratio [OR], 0.59; 95% CI, 0.41 to 0.86; I2, 25%) without significantly increasing major bleeding (OR, 1.34; 95% CI, 0.83 to 2.18; I2, 28%). Mixed treatment comparisons show that apixaban (OR, 0.41; 95% credible interval [CrI], 0.16 to 0.95) and rivaroxaban (OR, 0.58; 95% CrI, 0.37 to 0.90) significantly decrease VTE recurrent events compared with dalteparin. Edoxaban significantly increases major bleeding compared with dalteparin (OR, 1.73; 95% CrI, 1.04 to 3.16), and rivaroxaban significantly increases clinically relevant nonmajor bleeding compared with dalteparin and other DOACs. There are no significant differences between DOACs in terms of VTE recurrences and major bleeding. ConclusionDOACs should be considered a standard of care for the treatment of CAT except in patients with a high risk of bleeding. Current evidence favors the use of apixaban for the treatment of CAT among other DOACs. RegistrationOpen Science Framework (https://osf.io/dth86).

Single center experience of inferior vena cava filter retrieval in trauma patients: contrast-enhanced CT-based retrieval within hospital stay

PurposeTo assess the safety and retrieval rate of a predischarge inferior vena cava (IVC) filter retrieval strategy based on contrast computed tomography (CT). MethodsIVC filter insertion for trauma patients from 2010 to 2018 were reviewed. An active filter retrieval strategy was established in March 2017. The strategy sought early evaluation of venous thromboembolism (VTE) status and filter retrieval before a patient's discharge. The possibility of early IVC filter retrieval was evaluated by a multidisciplinary team based on pre-filter retrieval VTE-CT findings. Overall VTE-CT findings, retrieval rate, indwelling time, and recurrence of venous thromboembolic events were compared before and after the filter retrieval strategy setup. Results177 IVC filters were inserted in trauma patients. All patients underwent pre-filter retrieval VTE-CT. VTE-CT findings were as follows: completely resolved VTE, n = 108 (61%); partially improved, n = 58 (33%); no change, n = 8 (5%); aggravated, n = 3 (2%). The overall retrieval rate was 84% with a mean indwelling time of 32 days. In subgroup analyses, 95 (53%) had filter retrieval with the before strategy (BS) setup and 82 (47%) with the after strategy (AS) setup. The retrieval rate was significantly higher in the AS group [81/82 (99%) vs. 68/95 (72%), (p < 0.001)]. No patients had recurrent VTE during the follow-up period. ConclusionsThe active strategy of VTE-CT-based filter retrieval during the hospital stay markedly improved the filter retrieval rate from 72% to 99% without evidence of recurrence of VTE. Hazards of low retrieval rate versus CT-related radiation exposure should be studied in the future.

Treatment of catheter-related thrombosis in patients with hematologic malignancies: A Venous thromboEmbolism Network U.S. retrospective cohort study

IntroductionOptimal treatment of catheter-related thrombosis (CRT) is uncertain in patients with hematologic malignancy. We aimed to evaluate the treatment strategies, outcomes, and predictors of recurrent venous thromboembolism (VTE) associated with catheter-related thrombosis (CRT) in patients with hematologic malignancy. MethodsWe performed a multicenter retrospective cohort study of eight institutions through the Venous thromboEmbolism Network US. Patients with hematologic malignancies with documented CRT were identified using ICD-9 and ICD-10 diagnostic codes. Semi-competing risks proportional hazard regression models were created. Results and conclusionsOf the 663 patients in the cohort, 124 (19%) were treated with anticoagulation alone, 388 (58%) were treated with anticoagulation and catheter removal, 119 (18%) treated with catheter removal only, and 32 (5%) had neither catheter removal nor anticoagulation. 100 (15%) patients experienced a recurrent VTE event. In the 579 patients who had catheter removal, the most common reason for catheter removal was the CRT [392 (68%)]. For subjects who received any anticoagulation (n = 512), total anticoagulation duration was not associated with VTE recurrence [1.000 (0.999–1.002)]. After adjustment patients treated with catheter removal only had an increased risk of VTE recurrence [2.50 (1.24–5.07)] and death [4.96 (2.47–9.97)]. Patients with no treatment had increased risk of death [16.81 (6.22–45.38)] and death after VTE recurrence [27.29 (3.13–238.13)].In this large, multicenter retrospective cohort, we found significant variability in the treatment of CRT in patients with hematologic malignancy. Treatment without anticoagulation was associated with recurrent VTE.

Retrieval of Bard Simon Nitinol inferior vena cava filters: Approaches, technical successes, complications, and clinical outcomes.

The Simon Nitinol filter is a bi-level filtration device designed for permanent implantation that is no longer commercially available, but may result in similar complications to current commercially available long term indwelling temporary or permanent filters. Complications related to indwelling inferior vena cava filters include inferior vena cava thrombosis, inferior vena cava penetration, filter migration, and filter fracture. There is a paucity of reports describing the technical aspects related to retrieval of Simon Nitinol filters. This study consisted of five patients with Simon Nitinol filters and describes the indication for retrieval, the retrieval techniques used to remove the filters, technical success, complications, and clinical course. The indications for retrieval included: abdominal pain (n = 2; 40%), iliocaval thrombosis (n = 1; 20%), identification of an intracardiac filter fragment (n = 1; 20%), and recurrent venous thromboembolic events (n = 1; 20%). Retrieval techniques included: biopsy forceps (n = 3; 60%), excimer laser extraction sheaths (n = 3; 60%), hangman modified loop snares (n = 3; 60%), rigid endobronchial forceps (n = 2; 40%), and balloon deflection (n = 2; 40%). All filters were successfully retrieved. One patient developed a post-procedural intramuscular hematoma near the site of right internal jugular sheath placement. Simon Nitinol filters may be retrieved safely and effectively using advanced inferior vena cava filter retrieval techniques.

The Impact of Pulmonary Vascular Obstruction on the Risk of Recurrence of Pulmonary Embolism: A French Prospective Cohort.

We aimed to assess whether high pulmonary vascular obstruction index (PVOI) measured at the time of pulmonary embolism (PE) diagnosis is associated with an increased risk of recurrent venous thromboembolism (VTE). French prospective cohort of patients with a symptomatic episode of PE diagnosed with spiral computerized tomography pulmonary angiography (CTPA) or ventilation-perfusion (V/Q) lung scan and a follow-up of at least 6 months after anticoagulation discontinuation. PVOI was assessed based on the available diagnostic exam (V/Q lung scan or CTPA). All patients had standardized follow-up and independent clinicians adjudicated all deaths and recurrent VTE events. Main outcome was recurrent VTE after stopping anticoagulation. A total of 418 patients with PE were included. During a median follow-up period of 3.6 (1.2-6.0) years, 109 recurrences occurred. In multivariate analysis, PVOI ≥ 40% was an independent risk factor for recurrence (hazard ratio 1.77, 95% confidence interval 1.20-2.62, p < 0.01), whether PE was provoked by a major transient risk factor or not. A threshold at 41% was identified as the best value associated with the risk of recurrence 6 months after stopping anticoagulation (area under curve = 0.64). PVOI ≥ 40% at PE diagnosis was an independent risk factor for recurrence VTE. Further prospective validation studies are needed.

Direct oral anticoagulants (DOAC) for prevention of recurrent arterial or venous thromboembolic events (ATE/VTE) in myeloproliferative neoplasms

In patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial or venous thromboembolic events (ATE/VTE) are a major burden. In order to control these complications, vitamin K antagonists (VKA) are widely used. There is no robust evidence supporting the use of direct oral anticoagulants (DOAC) in MPN patients. We therefore compared the efficacy and safety of both anticoagulants in 71 cases from a cohort of 782 MPN patients. Seventy-one of 782 MPN patients (9.1%) had ATE/VTE with nine ATE (12.7%) and 62 VTE (87.3%). Forty-five of 71 ATE/VTE (63.4%) were treated with VKA and 26 (36.6%) with DOAC. The duration of anticoagulation therapy (p = 0.984), the number of patients receiving additional aspirin (p = 1.0), and the proportion of patients receiving cytoreductive therapy (p = 0.807) did not differ significantly between the VKA and DOAC groups. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1–20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. For all bleeding events (p = 0.516) or major bleeding (p = 1.0), no significant differences were observed between VKA and DOAC. In our experience, the use of DOAC was as effective and safe as VKA, possibly even potentially beneficial with a lower number of recurrences and no increased risk for bleedings. However, further and larger studies are required before DOAC can be routinely used in MPN patients.

Direct Oral Anticoagulants (DOACs) Vs. Low Molecular Weight Heparins (LMWH) for Venous Thromboembolism (VTE) in Patients with Primary Brain Tumors or Secondary Brain Metastases

Background: Management of venous thromboembolism (VTE) in patients with central nervous system (CNS) malignancies is challenging as there is an increased risk of recurrent VTE and intracranial hemorrhage (ICH). Low molecular weight heparins (LMWH) have historically been the standard of care for treatment of cancer-associated thrombosis (CAT). Current guidelines recommend direct oral anticoagulants (DOACs) for CAT treatment, but patients with CNS malignancies have limited representation in the supporting clinical trials. This multicenter, retrospective cohort study evaluated the safety and efficacy of DOACs compared to LMWH for CAT in patients with primary brain tumors or secondary brain metastases. Patients/Methods: In this multicenter, retrospective cohort study, adult patients with a diagnosis of primary brain tumor or secondary brain metastases who received either a DOAC or LMWH for CAT were evaluated. The primary outcome was the incidence of any bleeding event within a 6-month period following the initiation of anticoagulation. Secondary outcomes included incidence of recurrent VTE events, major bleeding, clinically relevant non-major bleeding (CRNMB), and minor bleeding, within a 6-month period following the initiation of anticoagulation. Patients were excluded if their indication for anticoagulation was stroke, non-cancer-associated VTE, or VTE prophylaxis, were on LMWH for one week or less while bridging to warfarin, or received a diagnosis of VTE at an outside hospital. All bleeding events were defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria. Primary and secondary outcomes were analyzed using Fisher's exact test for categorical variables and Wilcoxon rank-sum tests for non-parametric continuous variables. Results: Between January 1, 2012 to October 9, 2019, one-hundred eleven patients met inclusion criteria. Of the patients who met inclusion criteria, 26 (23.4%) patients had primary brain tumors and 85 (76.6%) patients had secondary brain metastases. Bleeding events occurred in 7 of 55 patients (12.7%) in the DOAC group compared to 13 of 56 (23.2%) patients in the LMWH group (RR 0.55, 95% CI 0.24-1.27). Recurrent VTE events occurred in 3 of 55 (5.5%) patients in the DOAC group compared to 3 of 56 (5.4%) patients in the LMWH group (RR 1.02, 95% CI 0.21-4.83). Major bleeding occurred in 3 of 55 (5.5%) patients in the DOAC group, compared to 4 of 56 (7.1%) patients in the LMWH group (RR 0.76, 95% CI 0.18-3.26). There were no differences in the rates of CRNMB and rates of minor bleeding between groups. Conclusion: In this multicenter retrospective cohort study, therapeutic anticoagulation with DOACs showed no significant difference in bleeding events or recurrent VTE events when compared to LMWH, in patients with primary brain tumors or secondary brain metastases. We conclude that DOACs may be potentially safe and efficacious for VTE treatment in patients with primary brain tumors or secondary brain metastases. As prescribing practices are expected to continue to shift towards DOACs, this study provides preliminary evidence of the safety of DOACs in this high-bleeding risk patient population. Disclosures No relevant conflicts of interest to declare.

Anticoagulant Usage Patterns for Acute Venous Thromboembolism in Patients with Advanced Liver Disease

Introduction: Management of acute venous thromboembolism (VTE) in patients with chronic liver diseases is challenging due to the risk of bleeding and thrombotic complications. No clinical trials have studied vitamin K antagonists (VKA) or low molecular weight heparins (LMWH) use in this population. Pivotal clinical trials evaluating direct oral anticoagulants (DOAC) such as apixaban, edoxaban, rivaroxaban, and dabigatran lead to the U.S. Food and Drug Administration approval for VTE treatment but these studies excluded patients with clinically significant liver disease. Methods: We conducted a single-center retrospective chart review of anticoagulant practice patterns in adult patients with cirrhosis (Child-Pugh Class A-C) diagnosed with acute VTE managed between January 1, 2010 through January 2, 2020. Acute VTE was defined as pulmonary embolism, deep vein thrombosis (DVT), and splanchnic vein thrombosis (SVT), which included portal vein thrombosis (PVT). Primary outcomes were recurrent VTE, bleeding events, and anticoagulant practice patterns and were calculated in the study population, as well as a subset excluding patients with only PVT. Cirrhosis, VTE, and bleeding diagnoses were based on ICD-9 and ICD-10 codes. Anticoagulant prescribing patterns were recorded in both the inpatient and outpatient setting, along with demographic, VTE risk factors, and key laboratory data. Baseline laboratory data were determined as the closest measured lab ≤180 days from the acute VTE diagnosis date. Child-Pugh score was calculated using the closest laboratory data and ICD-9 and ICD-10 codes ±180 days from the VTE diagnosis date. Anticoagulant usage was considered if ≥1 dose was administered. Statistical analysis was performed using SAS® version 9.4. Results: Baseline characteristics of the 1335 patients in the study are listed (Table 1-3). Median age was 65 years (range 19-98) with 845 male patients (63.3%). Following acute VTE, 467 patients (35.0%) received therapeutic anticoagulation, 114 patients (8.5%) received prophylactic anticoagulation, and 754 patients (56.5%) did not receive anticoagulation. Of patients that received therapeutic anticoagulation, 78 received apixaban, 1 received argatroban, 2 received bivalirudin, 7 received dabigatran, 1 received dalteparin, 0 received edoxaban, 180 received therapeutic enoxaparin, 19 received therapeutic fondaparinux, 231 received unfractionated heparin, 28 received rivaroxaban, and 159 received warfarin. Of patients that received prophylactic anticoagulation, 59 received enoxaparin, 10 received fondaparinux, and 246 received heparin. Of 599 patients with acute VTE without PVT only, 287 patients (47.9%) received therapeutic anticoagulation, 64 patients (10.7%) received only prophylactic anticoagulation, and 248 patients (41.4%) did not receive any anticoagulation. Many patients received more than one type of anticoagulant. Therapeutic anticoagulant usage patterns by year are depicted (Figure 1-2). Recurrent VTE occurred in 329 of all patients (24.6%). Recurrent VTE occurred in 196 of 467 patients (42.0%) on therapeutic anticoagulation, 33 of 114 patients (28.9%) on prophylactic anticoagulation, and 100 of 754 patients (13.3%) who did not receive any anticoagulation. Bleeding occurred in 721 of all patients (54.0%). Bleeding occurred in 288 of 467 patients (61.7%) on therapeutic anticoagulation, 67 of 114 patients (58.8%) on prophylactic anticoagulation, and 366 of 754 patients (48.5%) who did not receive any anticoagulation. Conclusion: Management of anticoagulant medications in patients with advanced liver disease has marked practice variation. Anticoagulant usage patterns changed over time with the approval of DOACs and increasing familiarity with these drugs. VKA and LMWH usage appeared to decrease over time as DOAC usage rose. Close to half of all patients did not receive any anticoagulation, even when excluding patients with only PVT from the population due to the common practice of monitoring PVT patients without anticoagulation. Further analysis of recurrent VTE and bleeding events based on individual anticoagulant medications and rationale for prescribed anticoagulant regimens is underway. We hope these findings will guide and encourage future studies evaluating safety and efficacy of anticoagulant medications in patients with advanced liver disease and VTE. Disclosures Kelkar: Acorn AI by Medidata, a Dassault Systemes Company: Current Employment. Rajasekhar:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma Plasma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxter: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Direct Oral Anticoagulant Use in Chronic Kidney Disease and Dialysis Patients With Venous Thromboembolism: A Systematic Review of Thrombosis and Bleeding Outcomes.

To evaluate how treatment with DOACs for VTE affects thrombosis and bleeding outcomes compared to warfarin in CKD and dialysis patients. A literature search was conducted for studies evaluating VTE and bleeding outcomes with DOAC use in CKD and dialysis patients. Searches conducted through EMBASE, MEDLINE/PubMed, Scopus, and Cochrane Central Register of Controlled Trials, from inception to September 22, 2020. Randomized controlled trials, cohort studies, and case series with ≥10 patients included. From 7286 studies, nine studies met inclusion criteria. There was no significant difference between DOACs (dabigatran, rivaroxaban, apixaban) and warfarin for reducing recurrent VTE and bleeding events in moderate CKD patients. The risk of overall major bleeding increased when the degree of kidney impairment increased. There was no significant difference between apixaban and warfarin for VTE outcomes in dialysis patients. There continues to be a controversial debate whether it may be more beneficial to use DOACs versus warfarin in CKD/dialysis patients with venous thromboembolism (VTE). The risk vs benefit of using DOACs in the CKD/ESKD population should continue to be evaluated for each individual patient. Apixaban may be used cautiously as an alternative in acute VTE treatment in severe CKD patients. Insufficient evidence is available to suggest the use of dabigatran and rivaroxaban in this patient population. The benefit of using DOACs in this population for VTE treatment should be weighed against the potential bleeding risk in patients with CKD.

Outcomes with enoxaparin dose reductions during thrombocytopenia in patients with hematopoietic stem cell transplantation (HSCT).

Appropriate dosing of therapeutic anticoagulation during periods of thrombocytopenia remains uncertain for patients undergoing hematopoietic stem cell transplants (HSCT). There is a paucity of literature on treatment outcomes for HSCT patients treated with non-prophylactic, but reduced doses of therapeutic anticoagulation during thrombocytopenia. The primary objective was to determine the incidence of major bleeding events during thrombocytopenia when reduced-dose enoxaparin was administered. This is a retrospective review of patients with a venous thromboembolic event (VTE) who underwent HSCT and received reduced-dose enoxaparin during thrombocytopenia at the Massachusetts General Hospital (MGH) from April 1, 2016 to August 31, 2018. Incidence of recurrent VTE and bleeding events for up to one month were investigated. Rates of recurrent VTE and enoxaparin dose adjustments (0.5 mg/kg twice daily vs 1 mg/kg daily) were also reviewed. Out of 172 patients reviewed, 27 patients met inclusion criteria. There were no recurrent VTEs within one month of initial enoxaparin dose reduction. There was one major bleeding episode that occurred while a patient was on full-dose enoxaparin; believed to be related to cyclophosphamide cardiopulmonary toxicity and resulted in death. There were six non-major bleeding episodes, only one of which was clinically significant and resulted in the discontinuation of enoxaparin. Our evaluation of therapeutic enoxaparin dose reductions for thrombocytopenia in the HSCT patient population found this practice to be effective in reducing the recurrence of VTE with no major bleeding adverse events. However, the rate of non-significant minor bleeds should be monitored while on reduced-dose enoxaparin.

Use of direct oral anticoagulants in cerebral venous thrombosis: a systematic review.

: We are here to review the efficacy and safety of direct oral anticoagulants (DOACs) in the treatment of Cerebral Venous Thrombosis (CVT). A search strategy was developed with a research librarian. All published articles including trials, studies, case series, and case reports were reviewed from NCBI/PubMed up to May 2019 by two independent reviewers. A total of 11 studies were identified, which included 70 patients with CVT on DOACs. After 6 months follow-up more than 86.7% of these patients had a good outcome on the Modified Rankin Scale (mRS) of 0--1 at 6 months and no recurrence of venous thromboembolic events (VTE) at 12 months. Recanalization rate at 6 months varied from 55 to 100%. Only two patients had a side effect of minor bleeding because of DOAC usage. Although the current American Heart Association/American Stroke Association and European Stroke Organization guidelines do not endorse the use of DOACs for treatment of CVT because of lack of evidence from large randomized clinical trials, Use of DOACs in CVT appears to be well tolerated and efficacious with favorable outcomes. Further evidence is needed to establish their use in CVT.

Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism

IntroductionThe direct oral anti-coagulants (DOAC) edoxaban and rivaroxaban are suggested treatment alternatives for cancer-associated venous thromboembolism (VTE) together with low molecular-weight heparins. New studies indicate that the DOAC apixaban also is an option for cancer-associated VTE. The current study assessed recurrent VTE, arterial thrombosis, bleedings and adverse events in a cohort of apixaban treated cancer patients with VTE. Materials and methodsSingle-arm, interventional study of apixaban as treatment of cancer-associated VTE. Inclusion criteria were cancer with objectively verified VTE. Patients received apixaban 10 mg bid for seven days, then 5 mg bid for six months. Primary efficacy and safety outcomes were recurrent VTE and bleeding respectively. This trial is registered with ClinicalTrials.gov identifier NCT02581176. ResultsWe recruited 298 cancer patients with VTE. During six months treatment, recurrent VTE or death related to VTE occurred in 12 patients (4.0%, 95% confidence interval (CI) 2.1–6.9%). Major bleeding occurred in 16 patients (5.4%, 95% CI 2.8–7.9), most frequently gastrointestinal bleeding. There were no overrepresentation of major bleedings among patients with gastrointestinal cancer (7/126, 5.5%, 95% CI 2.3–11%). Twenty-six patients experienced one or more clinically relevant non-major bleedings (8.9%, 95% CI 5.5–12%). Twelve patients had arterial thrombosis (4.0%, 95% CI 2.1–6.9%), of which the majority were strokes in patients with pancreatic cancer. Death occurred in 35 patients (12%, 95% CI 8.3–16%). ConclusionThe frequency of recurrent VTE and major bleedings are in line with other studies on apixaban in cancer-associated VTE. Arterial thrombosis was a frequent serious adverse event.

Comparative Effectiveness and Safety of Direct-acting Oral Anticoagulants and Warfarin in Patients with Venous Thromboembolism and Active Cancer: An Observational Analysis

PurposeThere is limited evidence to support the use of direct-acting oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and active cancer. This study aimed to assess the effectiveness of DOACs versus warfarin for the prevention of recurrent VTE and major bleeding events in patients with VTE and active cancer. MethodsWe identified patients with incident VTE and active cancer who newly initiated treatment with DOACs or warfarin from Truven Health MarketScan Commercial Claims and Medicare supplemental databases. Patients were followed up from treatment initiation (index date) until the occurrence of >7-day gap in treatment, the start of the study comparator, an outcome of interest (recurrent VTE or major bleeding), inpatient death, disenrollment, or end of the study period, whichever occurred first. We controlled for confounders via propensity score matching and estimated the hazard ratios (HRs) using Cox proportional hazards regression models. FindingsA total of 9952 patients were included in the matched cohort (4976 DOACs users and 4976 warfarin users). Patient characteristics were well balanced after matching. We observed a lower incidence of recurrent VTE (3 vs 5 per 100 person-years) and major bleeding events (2 vs 3 per 100 person-years) in the DOAC group compared to warfarin group, respectively. In Cox regression models, use of DOACs (vs warfarin) was associated with a lower risk of recurrent VTE (hazard ratio (HR), 0.59; 95% CI, 0.42–0.82) and major bleeding events (HR, 0.64; 95% CI, 0.44–0.94). ImplicationsOn the basis of our findings, among patients with VTE and active cancer, DOACs offer superior effectiveness with a lower risk of bleeding when compared with warfarin for the secondary prevention of VTE.

Adherence to and persistence with direct oral anticoagulant therapy among patients with new onset venous thromboembolism receiving extended anticoagulant therapy and followed by a centralized anticoagulation service

BackgroundExtended direct oral anticoagulant (DOAC) therapy may be required for patients with a venous thromboembolism (VTE); thus, DOAC adherence may impact the risk of recurrent VTE or bleeding. Materials and methodsThis was a retrospective cohort study. Adult patients with a VTE who were initiated on a DOAC between January 1, 2010 and December 31, 2017 for a cumulative >90 days of therapy were included. Adherence, measured with the proportion of days covered (PDC), was assessed during the six, 12, and 18 months after initiation. Patients were assigned to PDC ≥ 80% (adherent) or PDC < 80% (non-adherent) groups during the 1- to 6-month follow-up period. Rates of recurrent VTE and hemorrhagic events were compared between the groups. ResultsA total of 305 patients were included. The mean PDC were 96.0% (±8.0%), 94.7% (±8.2%), and 94.4% (±7.7%) during the 6-, 12-, and 18-month follow-ups, respectively, with 17 (5.6%) and 288 (94.4%) patients classified as non-adherent and adherent, respectively. Patients in the non-adherent group were more likely to have had a recurrent VTE during the 1- to 6-month (11.8% vs. 1.0%, p = 0.007) and 1- to 12-month follow-ups (16.6% vs. 3.6%, p = 0.030). There were no statistically significant differences between the groups in the rates of bleeding during any follow-up periods (all p > 0.05). ConclusionsIn patients who had >90 days of initial DOAC therapy, adherence to DOAC therapy was high throughout the 18-month follow-up while DOAC non-adherence (i.e., PDC < 80%) increased the risk of recurrent VTE.

Implementation of clinical decision support system for anticoagulant prescribing for patients with deep vein thrombosis

Background: Physicians adherence to recommendations for appropriate antithrombotic therapy of venous thromboembolism (VTE) can reduce the risk of recurrent VTE, pulmonary hypertension, bleeding and other adverse events. Clinical decision support systems (CDSS) are shown to increase physicians adherence to clinical guidelines.&#x0D; Aims: To assess effectivenes and safety of CDSS for anticoagulant prescribing for inhospital patients with VTE.&#x0D; Methods: A prospective cohort study was conducted in a Moscow general hospital from 06.30.2017 to 06.23.2018 to compare physicians compliance with clinical guidelines for DVT anticoagulant therapy, the rate of drug errors and direct costs of anticoagulant therapy before and after CDSS implementation (55 patients in control group and 49 in experimental group).&#x0D; Results: The rate of anticoagulant prescribing for patients with DVT did not alter significantly after CDSS implementation (96% compared with 91% before CDSS), but physicians compliance with recommendations on anticoagulant dosage increased from 32.7% to 73.5% (p = 0.0003) with corresponding decrease in the rate of anticoagulant prescribing errors from 1.35 to 0.65 per 1 patient (p = 0.0005). The length of stay and hemorrhagic complication rate did not differ between control and experimental groups. LMWH replacement with new oral anticoagulants has reduced the cost of anticoagulant therapy for 1 patient from 11.800 rubles (IQR = 7000) to 5.430 rubles (IQR = 5700) (p 0.005).&#x0D; Conclusions: СDSS can increase physicians adherence to recommended anticoagulant therapy for patients with DVT: to prevent unreasonable under-/overdosing or prolongation of anticoagulant therapy. CDSS for DVT drug therapy can be economically feasible.

Direct versus conventional anticoagulants for treatment of cancer associated thrombosis: a pooled and interaction analysis between observational studies and randomized clinical trials.

There are emerging observational studies (OSs) to assess real-world comparative effectiveness and safety of direct oral anticoagulants (DOACs) in cancer associated thrombosis (CAT). We conducted a pooled and interaction analysis to compare the treatment effect estimates of DOACs between OSs and randomized controlled trials (RCTs). We systematically searched PUBMED, EMBASE and Cochrane Library for OSs and RCTs that reported recurrent venous thromboembolism (VTE) and/or major bleeding events in CAT patients receiving DOACs and conventional anticoagulants [warfarin or low molecular-weight heparins (LMWHs)]. Relative risks (RRs) for OSs and RCTs were calculated using random-effects models separately, and interaction analyses were afterward applied to assess the comparability between OSs and RCTs. Baseline characteristic was comparable between identified 10 OSs (35,142 patients) and 8 RCTs (2,602 patients). Overall, no significant difference of treatment effect estimates between OSs and RCTs was detected (Pinteraction: 0.42 for recurrent VTE; Pinteraction: 0.38 for major bleeding). DOACs significantly decreased the risk of recurrent VTE compared with conventional anticoagulants in CAT patients (RR: 0.74, 95% CI: 0.63-0.86, I2: 0% for OSs; RR: 0.65, 95% CI: 0.49-0.86; I2: 0% for RCTs), without increasing major bleeding risk (RR: 0.90, 95% CI: 0.76-1.07, I2: 24.0% for OSs; RR: 1.17, 95% CI: 0.72-1.88, I2: 26.2% for RCTs). Whereas, increased risk of gastrointestinal bleeding (GIB) was found with DOACs versus conventional anticoagulants in CAT patients (RR: 2.77, 95% CI: 1.35-5.68, I2: 0% for RCTs). Analyses of subgroups, based on comparators and follow-up duration, did not significantly affect results. In this study, effectiveness and safety of DOACs versus conventional anticoagulants in CAT from OSs are in agreement with those from RCTs, confirming a low risk of recurrent VTE and similar risk of major bleeding in CAT patients receiving DOACs.

Comparative effectiveness and safety of apixaban versus warfarin in patients with venous thromboembolism

Compared with conventional therapy (enoxaparin followed by warfarin), the direct-acting oral anticoagulant apixaban is thought to offer similar protection against recurrent venous thromboembolism (VTE) with lower bleeding risk. However, evidence regarding the heterogeneity of treatment effect from real-world data is lacking. The study described here aimed to compare the effectiveness and safety of use of apixaban versus warfarin in patients with VTE. We conducted a retrospective cohort analysis of commercial and Medicare supplemental databases (data coverage period, 2014-2017) among patients with a diagnosis of VTE who were new users of apixaban or warfarin. We controlled for confounding using propensity score [PS] 1:4 matching. Cox proportional hazard models were used to obtain hazard ratios (HRs) and 95% confidence intervals (CIs). Heterogeneity of treatment effect was assessed among patients with provoked VTE versus unprovoked VTE. After PS matching, a total of 36,907 patients were included in the cohort (n = 8,094 apixaban users and n = 28,813 warfarin users). In Cox regression models, the use of apixaban versus warfarin was associated with lower risks of recurrent VTE (HR, 0.54; 95% CI, 0.45-0.65) and major bleeding events (HR, 0.67; 95% CI, 0.54-0.84); these results remained consistent in patients with provoked VTE and those with unprovoked VTE. This population-based analysis of patients with VTE extends results of randomized clinical trials indicating lower risks of development of recurrent VTE and major bleeding events with use of apixaban versus warfarin in real-world settings. The observed benefits of apixaban extended to selected subgroups of the VTE population, including patients with provoked VTE.