Secondary Prevention Of Venous Thromboembolism Research Articles

Long-Term Efficacy and Safety of Direct Oral Anticoagulants at Reduced Doses in the Secondary Prevention of Venous Thromboembolism and Post-Thrombotic Syndrome.

Background: Anticoagulation for venous thromboembolism (VTE) is required for at least three to six months; however, it is advisable to extend the duration in certain cases, in which case a reduced dose of Direct Oral Anticoagulants (DOACs) may be an option. Our objective was to investigate the efficacy and safety of reduced-dose DOACs in extended anticoagulation treatment compared to full doses. Methods and Results: This retrospective single-centre study included 185 patients treated with DOACs for at least 6 months who were divided into two groups: (1) the Full Dose (FD) group (n = 113) and (2) the Reduced Dose (RD) group (n = 72), which included patients treated with Apixaban at 2.5 mg bis in die (BID) and Rivaroxaban at 10 mg once daily (OD). Post-thrombotic syndrome (PTS) and its progression were evaluated. During an overall follow-up of 48.32 ± 29.49 months, no VTE occurred, and no patients experienced major bleeding; clinically relevant non-major bleeding occurred in three patients in each group (2.7% vs. 4.2% in FD vs. RD, respectively, p = 0.57). From baseline to follow-up, the prevalence of PTS was not significantly decreased in either group (FD: 54.9% vs. 51.3%, p = 0.29; RD 51.4% vs. 44.4%, p = 0.12); conversely, the Villalta score values were significantly decreased at the last follow-up (FD: 5.51 ± 4.18 vs. 5.12 ± 4.36, p < 0.001; RD 5.49 ± 4.06 vs. 5.11 ± 3.73, p = 0.006). Conclusion: In this real-world retrospective registry, very long-term extended anticoagulant therapy with DOACs at full or reduced doses showed comparable efficacy, safety, and impact on PTS progression. Larger studies are needed.

Extending venous thromboembolism secondary prevention with apixaban in cancer patients. The EVE trial

BackgroundCancer-associated venous thromboembolism (VTE) management guideline recommendations include continued therapeutic anticoagulation while active cancer persists. The Federal Drug Administration label for apixaban for secondary VTE prevention includes a dose reduction to 2.5 mg twice daily after 6 months of treatment. ObjectivesThe study’s purpose was to determine whether this dose reduction is advisable for cancer-associated VTE. MethodsA randomized, double-blind trial compared apixaban 2.5 mg with 5 mg twice daily for 12 months among cancer patients with VTE who had completed 6 to 12 months of anticoagulation therapy. The primary outcome was combined major bleeding plus clinically relevant nonmajor bleeding. ResultsOf 370 patients recruited, 360 were included in the intention-to-treat analyses. Major plus clinically relevant nonmajor bleeding occurred in 16 of 179 patients (8.9%) in the apixaban 2.5 mg group compared with 22 of 181 patients (12.2%) in the 5 mg group (hazard ratio [HR], 0.72; 95% CI, 0.38-1.37; P = .39). Major bleeding occurred in 2.8% of the apixaban 2.5 mg group and in 2.2% of the 5 mg group (HR, 1.26; 95% CI, 0.34-4.66; P = .73). Recurrent VTE or arterial thrombosis occurred in 9 of 179 patients (5.0%) in the apixaban 2.5 mg group and 9 of 181 patients (5.0%) in the 5 mg group (HR, 1.0; 95% CI, 0.40-2.53; P = 1.00). All-cause mortality rates were similar between groups, 13% vs 12% (HR, 1.14; 95% CI, 0.63-2.04; P = .67). ConclusionFor secondary prevention of cancer-associated VTE, apixaban 2.5 mg compared with 5 mg twice daily did not lower combined bleeding events (EVE trial NCT03080883).

Safety profile of rivaroxaban in first-time users treated for venous thromboembolism in four European countries.

The European rivaroxaban post-authorization safety study evaluated bleeding risk among patients initiated on rivaroxaban or vitamin K antagonists for the treatment and secondary prevention of venous thromboembolism in routine clinical practice. Cohorts were created using electronic healthcare databases from the UK, the Netherlands, Germany and Sweden. Patients with a first prescription of rivaroxaban or vitamin K antagonist during the period from December 2011 (in the UK, January 2012) to December 2017 (in Germany, December 2016) for venous thromboembolism indication, with no record of atrial fibrillation or recent cancer history, were observed until the occurrence of each safety outcome (hospitalization for intracranial, gastrointestinal, urogenital or other bleeding), death or study end (December 2018; in Germany, December 2017). Crude incidence rates of each outcome per 100 person-years were computed. Overall, 44 737 rivaroxaban and 45 842 vitamin K antagonist patients were enrolled, mean age, 59.9-63.8 years. Incidence rates were similar between rivaroxaban and vitamin K antagonist users with some exceptions, including higher incidence rates for gastrointestinal bleeding in rivaroxaban users than in vitamin K antagonist users. Among rivaroxaban users, mortality and bleeding risk generally increased with age, renal impairment and diabetes. This study provides further data from routine clinical practice that broadly support safety profile of rivaroxaban for VTE indication and complement findings from previous randomized clinical trials.

Dabigatran for Treatment and Secondary Prevention of Venous Thromboembolism in Pediatric Congenital Heart Disease.

Congenital heart disease (CHD) is common in children and associated with greater risk of thrombotic complications. Management of these complications with standard-of-care treatment is suboptimal for these children. The effectiveness and safety of dabigatran were demonstrated in pivotal pediatric studies for the treatment of acute venous thromboembolism (VTE; NCT01895777) and secondary VTE prevention (NCT02197416). We report safety and efficacy outcomes from subgroup analyses of these studies for children with CHD (diagnosed according to local practice) and those without. In NCT01895777, 17/21 (81.0%) and 16/27 (59.3%) patients with CHD (including cyanotic) treated with dabigatran and standard of care, respectively, met the primary end point (complete thrombus resolution, freedom from recurrent VTE, and freedom from VTE-related death; odds ratio [OR], 0.34 [95% CI, 0.08-1.23]). In patients without CHD, 41.0% (n=64) versus 34.9% (n=22) achieved this end point with the respective treatments (OR, 0.77 [95% CI, 0.42-1.41]). Although numerical differences were observed, no heterogeneity in treatment effect of dabigatran on the composite primary end point was detected in patients with and without CHD (interaction P =0.2674). In NCT02197416, recurrent VTE at 12 months occurred in 0/17 patients with CHD versus 3/194 (1.5%) without. No patient with CHD experienced major or clinically relevant nonmajor bleeding events. Data on favorable anticoagulant alternatives for the unmet needs of children with CHD are emerging, and our exploratory results suggest that dabigatran could be an appropriate treatment choice, although challenging sample size limitations in pediatric studies require cautious interpretation of findings. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01895777, NCT02197416.

Qualitative experiences, values, and decisional needs of patients with unprovoked venous thromboembolism who suffer bleeding—“This pill will keep you alive tonight”

BackgroundContemporary guidelines recommend extended-duration anticoagulation among patients with a first unprovoked venous thromboembolism (VTE). Little is known about whether this recommendation aligns with patient values after a bleeding complication. ObjectivesTo explore the experiences, values, and decisional needs of patients with unprovoked VTE related to extended-duration treatment after an anticoagulant-associated bleed. MethodsIn this descriptive, qualitative study, face to face online semistructured interviews were conducted with patients with unprovoked VTE who had experienced bleeding and continued anticoagulant treatment in one academic hospital in Canada. Data were analyzed using directed content analysis to identify themes. Themes were mapped onto the Ottawa Decisional Support Framework to identify decisional needs. ResultsBetween September and December 2021, 14 patients were interviewed (age 41-69 years; 9 females). Many patients were not aware of the option to stop anticoagulation and had limited understanding of the decision about treatment duration. Despite the negative quality-of-life impact of clinically relevant bleeding during VTE treatment, the majority continued anticoagulation due to emotional trauma of VTE diagnosis, a perception that bleeding would be more manageable than VTE recurrence, a desire to maintain a connection to subspecialty care or non-VTE related benefits (eg, cancer diagnosis, protection from COVID-19). Patients’ decisional needs included lack of choice awareness, inadequate support for participation, lack of personalized risk stratification, and inadequate information on monitoring and managing heavy menstrual bleeding. ConclusionDespite the impact of anticoagulant-associated bleeding on quality of life, patients preferred continuing with anticoagulation for reasons extending beyond secondary VTE prevention. Effective decision-support interventions are needed to address unmet decisional needs.

Provoked vs minimally provoked vs unprovoked VTE: does it matter?

Venous thromboembolism (VTE) is a multifactorial disease, and its risk depends on exposure to risk factors and predisposing conditions. Based on their strength of association with a VTE episode, risk factors are classified as major or minor and determined using a temporal pattern to be transient or persistent. All patients with VTE should receive anticoagulant treatment for at least 3 months in the absence of an absolute contraindication. Beyond this period, selected patients may be candidates for an extended phase of anticoagulation aimed at secondary VTE prevention. The risk of recurrent VTE if anticoagulation is discontinued is probably the main driver of decision-making regarding extended treatment. The risk of recurrence after VTE associated with major risk factors is low if the risk factor is no longer present. In this case, treatment can be discontinued. If the major risk factor is persistent, anticoagulation should be continued. After VTE occurring in the absence of risk factors, anticoagulation should probably be continued indefinitely if the risk for bleeding is low and preferably with minimal effective doses of anticoagulants. VTE occurring after exposure to minor risk factors is probably the most challenging situation, especially if the clinical manifestation was acute pulmonary embolism. Understanding the actual role of minor risk factors in the occurrence of VTE helps in estimating the risk of recurrence and avoiding the dangers associated with unnecessary anticoagulation. The availability of safer strategies for anticoagulation could allow personalized strategies for secondary prevention of VTE.

Oral Anticoagulant Therapy in Patients with Philadelphia-Negative Myeloproliferative Neoplasms: A Real-Life Comparison between Vitamin K Antagonists and Direct Oral Anticoagulants

BACKGROUND Chronic myeloproliferative neoplasms (MPN) are characterized by an high risk of thrombosis and bleeding. Historically, vitamin K inhibitors (VKAs) have been the preferred oral anticoagulant therapy (OAT) for these patients (pts). However, nowadays, VKAs are being used less frequently, and direct oral anticoagulants (DOACs) are becoming more popular. Despite this trend, there is still limited evidence in the literature regarding the efficacy and safety of these drugs in the context of MPN. Specifically, there is a lack of data directly comparing VKAs and DOACs in a real-world clinical setting. AIMS The study aimed to conduct a real-world analysis comparing the efficacy and safety of DOACs and VKAs in patients with MPN. Both medications were prescribed for the treatment and secondary prevention of venous thromboembolism (VTE) or for the prevention of thrombosis in pts with atrial fibrillation (AF). The secondary endpoints were to assess the influence of common demographic, clinical, and hematological variables on the incidence of thrombotic events (TE) and bleeding events (BE) METHODS We conducted an observational retrospective monocentric study that enrolled all consecutive pts with MPN, followed at the MPN Clinic of the IRCCS Foundation S. Gerardo dei Tintori - Monza between 1993 and 2022, who received OAT with VKAs or DOACs for VTE or AF. For each pts, we collected demographic, clinical, biological, therapeutic, and hematological data. TE were categorized based on their type (arterial or venous) and location. BE were classified as minor, major, or clinically relevant non-major bleeding, according to the ISTH classification. Thrombosis-free survival (TFS) and bleeding-free survival (BFS) were assessed from the initiation of OAT until the occurrence of the first TE or BE, respectively, and estimated using Kaplan-Meier analysis. The other analyses were conducted using common statistical methods. Multivariable analyses included previously established risk factors for BE and TE. RESULTS A total of 156 pts were enrolled: 89 were women (57%). The median age was 69 years (range 25-92); 61 were affected by myelofibrosis, 35 by polycythemia vera, and 48 by essential thrombocythemia. 64 pts received OAT with VKAs (41%), and 92 with DOACs (59%). For 82 pts OAT was prescribed for AF (52.6%), and for 74 for VTE (47.4%). 17 pts treated with DOACs for VTE received a reduced-dose extended treatment (45.9%). The median exposure time to OAT was 5.8 years in the VKAs group (range 0.2-20 years) and 1.77 years in the DOACs group (range 0.2-10 years). After a median follow-up of 3,2 years, 14 TE were reported: 5 (35.7%) in the DOAC-treated group, of which 4 were arterial (80%), and 9 (64.3%) in the VKA-treated group (7 arterial - 77.8%). The incidence rate of TE was 2.11 thrombosis/pts/year in the VKAs group and 2.14 thrombosis/pts/year in the DOACs group. There were no significant differences in terms of TFS between the two groups, whether considering the entire population or analyzing the therapeutic indications separately (respectively p=0.72, p=0.53, p=0.55). Overall, there were 27 BE: 13 in the DOACs group (51.9%), 14 in the VKAs group (48.1%). Among these, we report 8 major BE, 4 in both groups. The incidence rate of BE was 5.6/pts/year in the DOACs group and 3.3/pts/year in the VKAs group. We did not observe significant differences in terms of BFS analyzing the whole population and the VTE group (respectively p=0.13 and p=0.75), while we found a trend for lower BFS in pts treated with DOACs for AF (p=0.08, Fig. 1). In a multivariate model, adjusted for time of exposition to OAT, age, gender and antiplatelet treatment, the risk of BE was associated solely with DOACs administration (hazard ratio 3.7, p=0.01) We found no significant differences in the risk of TE and BE when considering the various types of DOACs used. Moreover, 45 (28.8%) patients received concomitant antiplatelet therapy, and we found no significant differences in the risk of BE or TE compared to the other group (p=0.39 and p=0.41, respectively). CONCLUSIONS To our knowledge, this is the largest study investigating the safety and efficacy of DOACs compared to VKAs for the treatment and prevention of TE in pts with MPN and VTE or AF. Our findings suggest that DOACs are as effective as VKAs, but they appear to exhibit a trend towards a higher overall risk of BE, especially in the AF group. More data from prospective multicentric studies are necessary to validate our results.

A Survey of Clinician Perspectives on the Management of Catheter-Related Upper Extremity Deep Vein Thrombosis in Patients with Cancer

Background: Central venous catheters (CVCs) are commonly used in cancer patients to facilitate blood draws, administration of chemotherapy or other supportive care treatment. Catheter-related upper extremity deep vein thrombosis (DVT) is a major complication of CVCs, with studies reporting a rate of symptomatic venous thromboembolism (VTE) of 7% over 3 months in patients with active cancer and a new CVC. Despite the frequent occurrence, the optimal management in patients with cancer and catheter-related upper extremity DVT is unclear, given the lack of high-quality data. Objective: We conducted a survey aiming to characterize practice patterns and perceptions of clinicians who treat patients with cancer and catheter-related upper extremity DVT. Methods: An online survey was distributed to international clinicians who manage patients with cancer and catheter-related upper extremity DVT. The survey explored the type and duration of anticoagulation, focusing on the management after the initial 3 months of anticoagulation, as well as treatment strategies upon catheter removal and interests in future clinical studies. Descriptive statistics was used to summarize survey responses. Results: The survey was generated on LimeSurvey ® in English and publicized by Twitter ® and email communications via multiple international organizations of hematologists, oncologists, and/or thrombosis specialists, including the International Society on Thrombosis and Haemostasis (ISTH), Thrombosis Canada, the Canadian Venous Thromboembolism Research Network (CanVECTOR), and more. As of July 30, 2023, 115 clinicians from 26 countries had completed the survey. The majority of the respondents specialized in thrombosis (N=72, 62.6%) and/or hematology (N=60, 52.2%), followed by internal medicine (N=38, 33.0%) and oncology (N=14, 12.2%) (multiple selection was permitted for this question). For the initial management of a patient without unresected gastrointestinal (GI) or genitourinary (GU) cancer, thrombocytopenia, or relevant drug-drug interactions, 75% of clinicians would prescribe a direct oral anticoagulant (DOAC) and 25% would give low-molecular-weight heparin (LMWH). On the other hand, in patients with unresected GI/GU cancer, the majority (N=105, 91.3%) of respondents chose to initiate LMWH. After the initial 3 months of anticoagulation, if the CVC remains in place in a patient with active cancer, the majority (N=112/114, 98.2%) of clinicians would continue anticoagulation, but with variable doses (57% and 43% chose therapeutic and prophylactic dosing, respectively). If the CVC remains in place but the cancer is in remission, fewer (70%) respondents would continue anticoagulation, and more would continue prophylactic as compared to therapeutic dosing (73% vs. 27%) in this setting. Practice variation further increases upon catheter removal, especially in the presence of active cancer (Figures 1 and 2). The majority of respondents (N=111, 96.5%) agree that there is a need for prospective studies to evaluate the management of patients with cancer and catheter-related upper extremity DVT, and over 91% (N=105) would consider enrolling their patients in a study to evaluate prophylactic dosing of anticoagulation for secondary prevention of VTE in patients with cancer and catheter-related upper extremity DVT. To help plan such a study, we evaluated respondents' perception on the maximal “tolerable” recurrent VTE rate between 3 and 6 months (as the main interest is in the management strategy after the initial 3 months), and 2% and 3% were the most common responses (41.2% and 31.6% of the respondents, respectively). Conclusions: Our survey demonstrates that current practice in managing patients with cancer and catheter-related upper extremity DVT is heterogenous, especially after the initial 3 months of anticoagulation and upon catheter removal. Well-conducted prospective studies in this population are needed, which is supported by most clinicians.

Use and Outcomes of Secondary Anticoagulation in Patients &amp;lt;21 Years Old Following Completion of a Primary Course of Anticoagulation for Treatment of Acute Provoked VTE: Findings from the Multinational Kids-DOTT Trial

Background: Although the rate of venous thromboembolism (VTE) recurrence is low among pediatric patients with provoked VTE, children with a history of VTE who have persistent prothrombotic risk factors such as central venous catheters (CVCs), thrombophilia and cancer have been shown to have increased risk for recurrent VTE (e.g., Brandao et al., Lancet Hematology 2020). Prospective multicenter data on the use of secondary anticoagulation in patients with a first provoked VTE are limited. Objective: We sought to characterize the use and outcomes of secondary anticoagulation in patients &amp;lt;21 years old with provoked VTE, via the multinational Kids-DOTT trial. We hypothesized that older patient age is associated with use of secondary anticoagulation among patients with provoked VTE who have persistent prothrombotic risk factors following completion of a primary course of anticoagulation for treatment of acute provoked VTE, and that frequencies of clinically relevant bleeding and recurrent VTE are low in this setting. Methods: We conducted a secondary analysis of patients enrolled in the NIH-sponsored, multinational randomized controlled Kids-DOTT trial (NCT00687882; Goldenberg et al., JAMA 2022) who received secondary anticoagulation. We defined secondary anticoagulation as anticoagulant use beyond the initial treatment period of 6-12 weeks for the purpose of secondary VTE prevention, as captured in case report forms. “Chronic” secondary anticoagulation was defined as that which began within 2 weeks of the prescribed treatment course; otherwise, secondary anticoagulation was defined as “episodic”. The presence of new and/or recurrent prothrombotic risk factors was captured in association with each episode. Variables were summarized as counts and percentages for categorical variables and medians with interquartile ranges (IQR) for continuous variables. To compare groups that did versus did not receive secondary anticoagulation, Mann-Whitney U test was used for continuous variables and chi-square, or Fisher's exact test was used for categorical variables, with alpha &amp;lt;0.05 considered significant. All statistical analyses were performed using R version 4.1.2 (R Core Team, 2021). Results: Among 532 patients enrolled in the Kids-DOTT trial, 18 (3.4%) received secondary anticoagulation, all of whom had persistence or recurrence of prothrombotic risk factors (Table 1). The most frequent prothrombotic risk factors associated with use of secondary anticoagulation were a new or persistent central venous catheter (28%, N=5) and infection (17%, N=3). Despite having persistence or recurrence of prothrombotic risk factors, only 1 patient who received secondary anticoagulation developed recurrent VTE and 2 patients experienced clinically relevant bleeding during a median follow-up of 1.99 years [IQR 1.06-2.02], none of which was temporally related to secondary anticoagulation use. As shown in Table 2, patients who received secondary anticoagulation were older (median 12.9 years [IQR 7.6-15.5 years] vs. 8 years [1-15 years], P=0.05) and more likely to have upper extremity deep vein thrombosis (50% vs. 29%; P=0.003) when compared to those who did not receive secondary anticoagulation. Conclusion: These findings suggest that use of secondary anticoagulation is low among patients &amp;lt;21 years old with provoked VTE. However, among those who receive secondary anticoagulation for persistent or recurrent prothrombotic risk factors, the risks of recurrent VTE and clinically relevant bleeding may be low. Furthermore, focused study of use and outcomes of chronic and episodic secondary anticoagulation is warranted to inform future practice on secondary prevention in children, adolescents, and young adults with a history of provoked VTE.

Review of Topical Sodium Heparin 1000 IU/g Gel in Symptomatic Uncomplicated Superficial Thrombophlebitis.

Heparin, a mixture of sulfated polymorphic polysaccharides (glycosaminoglycan) chains of variable lengths and weights and a natural anticoagulant, is widely used in medical practice to prevent intravascular blood coagulation. Heparin has demonstrated antithrombotic and anti-inflammatory activity, and it is mostly administered systemically (intravenously or subcutaneously) for primary or secondary prevention of venous thromboembolism after surgical interventions, or immobilized patients, or on short-term antithrombotic therapy of patients with atrial fibrillation who must undergo treatment. However, since systemic administration of heparin could be, in certain cases, linked to an increased risk of bleeding, topical heparin is widely used for the prevention and treatment of local symptoms of peripheral vascular disorders, such as venous insufficiency, varicose veins, or superficial thrombophlebitis. This review summarizes the main safety and efficacy characteristics of the topical formulation of Heparin in Gel form (1000 International Units of Heparin/g Gel) currently in use, which has demonstrated an excellent efficacy and tolerability profile in reducing signs and symptoms of peripheral vascular disease, e.g., varicose syndromes and their complications, phlebothrombosis, thrombophlebitis, superficial periphlebitis, varicose ulcers, for post-operative varicophlebitis, sequelae of saphenectomy, for traumas and contusions, local edemas and infiltrates, subcutaneous hematoma and for traumatic affections of musculotendinous and capsuloligamentous apparatuses.

Low-Dose Rivaroxaban to Prevent Recurrences of Venous Thromboembolism in Cancer: A Real-Life Experience with a Focus on Female Patients.

The way in which to prevent recurrent venous thromboembolism (VTE) is an unmet clinical need in cancer patients. International guidelines only provide conditional recommendations and do not specify which anticoagulant and dose should be used. In the last 2 years, we have been using low-dose rivaroxaban to prevent VTE recurrences in cancer patients. The results of this real-life experience are presented in this study. All patients had cancer and had previously completed a cycle of at least six months of full-dose anticoagulation for the treatment of a VTE index event, before receiving a prescription of low-dose rivaroxaban (10 mg once daily) for secondary prevention of VTE. Effectiveness and safety of this therapeutic regimen were evaluated in terms of VTE recurrences, major bleedings (MB), and clinically relevant non-major bleedings (CRNMB). The analysis included 106 cancer patients. Their median age was 60 years (IQR 50-69). Metastatic cancer was present in 87 patients (82.1%). Six patients (5.7%) had brain metastases. Over a median follow-up time of 333 days (IQR 156-484), the incidence of VTE recurrences was 3.8% (95%CI 1.0-9.4), with a recurrence rate of 4.0 per 100 person-years (95%CI 1.1-10.2). We observed no MB (0.0%) and three CRNMB (2.8%) (95%CI 0.6-8.1). Low-dose rivaroxaban is potentially effective and safe in cancer patients that require prevention of recurrent VTE. Large-scale studies are needed to confirm these findings.

Direct oral anticoagulants in pediatric venous thromboembolism: Experience in specialized pediatric hemostasis centers in the United States

BackgroundBefore the official US Food and Drug Administration approval in 2021, pediatric hematologists across the United States have used direct oral anticoagulants (DOACs) “off-label” and based on extrapolation from labeling for adults with venous thromboembolism (VTE) and interim results of pediatric-specific DOAC clinical studies. ObjectivesThe American Thrombosis and Hemostasis Network 15 (ATHN 15) study aimed to characterize the use of DOACs from 2015 to 2021 at 15 specialized pediatric hemostasis centers in the United States, with emphasis on safety and effectiveness. MethodsEligible participants were those aged 0 to 21 years who had a DOAC included as part of their anticoagulation regimen for the treatment of acute VTE or secondary prevention of VTE. Data were collected for up to 6 months after initiation of the DOAC. ResultsA total of 233 participants were enrolled, with a mean age of 16.5 years. Rivaroxaban was the most commonly prescribed DOAC (59.1%) followed by apixaban (38.8%). Thirty-one (13.8%) participants reported bleeding complications while on a DOAC. Major or clinically relevant nonmajor bleeding events occurred in 1 (0.4%) and 5 (2.2%) participants, respectively. Worsening menstrual bleeding was reported in 35.7% of females aged >12 years and occurred more frequently in those using rivaroxaban (45.6%) compared with apixaban (18.9%). The recurrent thrombosis rate was 4%. ConclusionPediatric hematologists at specialized hemostasis centers in the United States have been using DOACs for the treatment and prevention of VTEs, primarily in adolescents and young adults. Reported DOAC use showed adequate safety and effectiveness rates.

Anticoagulation Use for Secondary Prophylaxis Against Recurrent Venous Thromboembolism in Hospitalized Children: A Report from the Children's Hospital-Acquired Thrombosis (CHAT) Consortium

Introduction: Most venous thromboembolism (VTE) in children are provoked and have an overall low risk for recurrence, especially if the original provoking factor is mitigated. Nonetheless, certain factors heighten VTE recurrence risk, including hospitalization. In fact, the rate of VTE in hospitalized children has increased more than 200% since 20011. This staggering discovery emphasizes the dire need for more effective tactics aimed at VTE prevention. Historically, pediatric providers have been hesitant to initiate pharmacologic (i.e. anticoagulant) measures in children for a number of reasons. In our recent survey of practice patterns of secondary prevention against recurrent VTE in pediatrics, we found low use (<25%) of pharmacologic prophylaxis in high-risk children2. Additionally, most respondents did not feel comfortable initiating secondary pharmacologic prophylaxis in younger children2. In the wake of the COVID-19 pandemic, numerous trials have been conducted to evaluate anticoagulation for VTE prevention in affected individuals. The recently published COVID-19 Anticoagulation in Children- Thromboprophylaxis trial showed safety of low-dose enoxaparin in children hospitalized with COVID-19 or multisystem inflammatory syndrome in children (MIS-C)3. Furthermore, trials of direct oral anticoagulants have also shown safety and efficacy in secondary VTE prevention in children4. Importantly, these studies have consistently demonstrated low rates of bleeding. Methods: The CHAT Registry is an IRB-approved registry that captures clinical data on hospital-acquired VTE in children <21 years of age and non-VTE controls. Subjects were enrolled from 2012-2021 across 8 participating pediatric hospitals. Using this REDCap database, we performed a retrospective study of enrolled subjects to explore trends for secondary anticoagulation prophylaxis use in hospitalized children. Subjects (cases and controls) were included if they had a history of VTE. Descriptive statistics were used to analyze demographics/characteristics and VTE prophylaxis measures. Results: Fifty-two subjects (%) out of 2219 total CHAT subjects (1273 cases, 946 controls) reviewed had a prior history of VTE. Characteristics of these subjects are presented in Table 1. The mean age was 9.6 years with a slight male predominance (54%). Regarding VTE prophylaxis (Figure 1), 18 (35%) received VTE prophylaxis (mechanical and/or pharmacologic) during hospitalization. Of these, 11 subjects (61%) were prescribed pharmacologic prophylaxis either alone (8) or in combination with mechanical prophylaxis (3). The remaining seven (39%) received only mechanical prophylaxis. Four subjects were already on anticoagulation at the time of admission. Forty-four (85%) subjects experienced a hospital-acquired VTE recurrence. Only 16 (36%) of these had received some method of VTE prophylaxis. Of those who did not receive pharmacologic prophylaxis, only 3 had a documented contraindication. The most commonly documented contraindications to pharmacologic prophylaxis pertained to risk of bleeding, and included uncorrected coagulopathy, ongoing/uncontrolled hemorrhage and thrombocytopenia. The median time between admission and VTE event was 9 days. Conclusion: There is a high rate of recurrent VTE in hospitalized children with a history of prior VTE. These results underscore the significance of implementing consistent pharmacologic prophylaxis in high-risk children where appropriate. As the landscape is actively changing in terms of available anticoagulant formulations available for children, providers may feel more confident in initiating secondary pharmacologic prophylaxis particularly as new data confirm the safety. Nevertheless, ongoing definitive studies are required to better understand which particular factors yield the highest rates of VTE and hence warrant pharmacologic prophylaxis above standard mechanical measures. We want to acknowledge the CHAT Consortium sites who contributed to the CHAT Registry. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of Recurrent Venous Thromboembolism in Selected Subgroups of Men: A Danish Nationwide Cohort Study.

Background Although men are considered at high risk for recurrent venous thromboembolism (VTE), sex-specific data on prognostic factors are lacking. We estimated the cumulative recurrence risks associated with clinical characteristics and comorbidities known or suspected to be associated with the development of VTE recurrence: major surgery, trauma, history of cancer, rheumatic disorder, ischemic heart disease, congestive heart failure, chronic obstructive pulmonary disease, diabetes, chronic renal disease, varicose veins, alcohol-related diseases, and arterial hypertension. Methods We linked nationwide Danish health registries to identify all incident VTE in- and outpatients in men from 2008 through 2018. Recurrent VTE risk 2 years after anticoagulant discontinuation was calculated using the Aalen-Johansen estimator, stratified by age above/below 50 years. Results The study included 13,932 men with VTE, of whom 21% ( n = 2,898) were aged <50 years. For men aged <50 years with at least one of the clinical characteristics, 2-year recurrence risk ranged from 6% (major surgery) to 16% (history of cancer). For men ≥50 years with at least one of the characteristics, recurrence risk ranged from 7% (major surgery) to 12% (ischemic heart disease, chronic obstructive pulmonary disease, and chronic renal disease). Men aged <50 and ≥50 years without the clinical characteristics all had a recurrence risk of 10%. Discussion We demonstrated a 2-year recurrence risk of at least 6%, regardless of age category and disease status, in this nationwide cohort of men with VTE. The recurrence risk must be balanced against bleeding risk. However, the high recurrence risk across all subgroups might ultimately lead to greater emphasis on male sex in future guidelines focusing on optimized secondary VTE prevention.

Dabigatran in the treatment and secondary prophylaxis of venous thromboembolism in children with thrombophilia

AbstractIn the phase 2b/3 DIVERSITY trial, 3 months treatment with dabigatran was noninferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm, phase 3, secondary VTE prevention study, up to 12 months dabigatran use was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in the DIVERSITY trial and safety in both studies. Thrombophilia types were similar between the DIVERSITY trial (total population) and secondary prevention studies: factor V Leiden, 42% vs 33%; prothrombin mutation (G20210A), 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; and antiphospholipid antibodies, 18% vs 20% of patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary end point (Mantel-Haenszel–weighted rate difference, −0.135; 95% confidence interval, −0.36 to 0.08; noninferiority P = .0014); comparable to the total DIVERSITY trial population (46% vs 42%) showing dabigatran noninferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia. These trials were registered at www.clinicaltrials.gov as #NCT01895777 and #NCT02197416.

Evolving Knowledge on Primary and Secondary Prevention of Venous Thromboembolism in Carriers of Hereditary Thrombophilia: A Narrative Review

The association between heritability of venous thromboembolism (VTE) and thrombophilia was first reported clinically in 1956, later followed by the first description of a congenital cause of hypercoagulability-antithrombin deficiency-in 1965. Since then, our knowledge of hereditary causes of hypercoagulability, which may predispose carriers to VTE has improved greatly. Novel genetic defects responsible for severe thrombophilia have been recently identified and we have learned that a wide range of interactions between thrombophilia and other genetic and acquired risk factors are important determinants of the overall individual risk of developing VTE. Furthermore, therapeutic strategies in thrombophilic patients have benefited significantly from the introduction of direct oral anticoagulants. The present review is an overview of the current knowledge on the mechanisms underlying inherited thrombophilia, with a particular focus on the latest achievements in anticoagulation protocols and prevention strategies for thrombosis in carriers of this prothrombotic condition.

Secondary prevention of venous thromboembolism: Predictors and outcomes of guideline adherence in a long-term prospective cohort study

BackgroundPrevention of recurrent venous thromboembolism (VTE) is considered a main goal of VTE management. However, the extent to which physicians adhere to the recommendations from evidence-based guidelines is unknown.AimFrom a large, prospective clinical cohort, we aimed to (1) quantify the adherence of treatment recommendations to evidence-based guidelines and establish its predictors, and (2) estimate its impact on clinical outcomes and costs in patients with VTE.MethodsWe included 6'243 consecutive patients with VTE treated at the university outpatient unit. Detailed clinical characteristics and treatment recommendations were recorded. Adherence of treatment recommendations to evidence-based guidelines at risk assessment was assessed in terms of duration of anticoagulant treatment. Data on death were obtained from the Swiss Central Compensation Office. Health care claims data recorded between 2014 and 2019 were retrieved from Helsana, one of the largest Swiss health insurance companies.ResultsThe adherence to evidence-based guidelines was 36.1%. Among patients with non-adherence, overtreatment was present in 70.1%. Significant patient-related predictors of guideline adherence were (a) age above 50 years, (b) male sex, (c) pulmonary embolism, (d) unprovoked VTE, (e) multiple VTE, (f) laboratory tests not ordered, and (g) various cardiovascular comorbidities. Non-adherence was not significantly associated with mortality, hospitalization, admission to nursing home, and costs.ConclusionsThe adherence to evidence-based guidelines was low, and several unrelated predictors appeared. Although these results need to be confirmed in other settings, they highlight the need for implementation of evidence-based guidelines in clinical practice.

Adverse Events of DOACs in Children.

Venous thromboembolism (VTE) has an increasing rate of significance in pediatric patients. The currently standardized anticoagulants (unfractionated heparin, low molecular weight heparin and vitamin K antagonists) and their dose regimens were not comprehensively trialed in pediatric patients. Recently, several direct oral anticoagulants (DOACs) have been studied in clinical trials in the pediatric population and further trials are ongoing. Dabigatran etexilate and rivaroxaban results show that these DOACs are safe and efficient in the treatment and secondary prevention of pediatric VTE. This review will focus on adverse events (AEs) between specific DOACs reported in the clinical trials in children and compare them to standard of care. This will assist clinicians in decision making of selecting the right anticoagulation for their pediatric patients.

Prevencia a liečba venózneho tromboembolizmu spojeného s malignitou - interdisciplinárny konsenzus

The increasing volume of the data and experience with direct oral anticoagulants (DOACS) in the primary and secondary prevention of venous thromboembolism in oncologic patients (CAVTE) has recently lead to changes in several international guidelines. We reflect these changes within the conditions in Slovak republic. In the primary prevention of CAVTE we recognise oncosurgical patients and nonsurgical patients: hospitalised and out patients. Low molecular weight heparins are still dominant in the primary prevention of CAVTE. Regarding the treatment and the secondary prevention of CAVTE, we recommend always to consider the possibility to use DOACs as they proved to be non inferior to LMWH. However, LMWH should be prefered over DOACs as well as over warfarin (VKA) in all patients who are in a clinically unstable condition with the high risk of bleeding and/or interaction with the systemic treatment. Primarily in the patients with intraluminal tumours of the upper part of the gastrointestinal tract and genitourinary tumours with the high risk of bleeding. As for the lack of data, LMWH are still preferd also in patients with primary tumours and metastatic disease of the central nervous system and in hemato oncology.

Dabigatran Etexilate: A Review in Pediatric Venous Thromboembolism

Although rare in children, venous thromboembolism (VTE) is markedly more likely in hospitalized patients, particularly with the use of central venous access devices. Dabigatran etexilate (Pradaxa®) is one of the first direct non-vitaminK antagonist oral anticoagulants (DOAC) approved for use in pediatric patients. It is approved in the EU and USA for the treatment of VTE in patients who have been treated with a parenteral anticoagulant for ≥ 5 days, and for the prevention of recurrent VTE. In an open-label, phase2b/3 clinical trial in pediatric patients with acute VTE treated for ≈ 3months, dabigatran etexilate was non-inferior to standard of care (SOC) treatment for the primary composite endpoint of complete thrombus resolution, freedom from recurrent VTE and VTE-related death. In a single-arm phase3 safety study, few patients experienced recurrent VTE with ≤ 12months of anticoagulation with dabigatran etexilate. Dabigatran etexilate was generally well tolerated in both studies; bleeding events were mostly minor and, in the phase 2b/3 study, occurred at a similar incidence to SOC. Although further data will be useful, dabigatran etexilate is a valuable and convenient treatment option in pediatric VTE.