Prevention Of Recurrent Venous Thromboembolism Research Articles

Clinical Efficacy and Safety of Novel Anticoagulants for the Management of Venous Thromboembolism in Patients with Cancer: A Systematic Review and Meta-Analysis.

Cancer patients face a four- to sevenfold higher risk of venous thromboembolism (VTE) than the general population. Novel oral anticoagulants (NOACs) provide convenient alternatives to traditional therapies. We performed a systematic literature search across PubMed, Embase, and the Cochrane Library, targeting studies that examined the use of NOACs in cancer-associated VTE. The search included randomized controlled trials (RCTs). Selected studies compared NOACs with low-molecular-weight heparin (LMWH) or vitamin K antagonists (VKA) in cancer patients diagnosed with VTE. A meta-analysis using a random-effects model was applied to estimate pooled effect sizes for outcomes. In this meta-analysis, we included 12 RCTs. Results showed NOACs were more effective than LMWH in preventing VTE recurrence (RR 0.66, 95% CI 0.52-0.83, p = 0.0004). Compared with VKAs, NOACs showed no significant difference (RR 0.63, 95% CI 0.34-1.15, p = 0.13). However, this finding is limited by the small patient sample. Major bleeding outcomes were similar between NOACs and LMWH/VKAs (RR 1.24, 95% CI 0.85-1.80, p = 0.28; RR 0.77, 95% CI 0.39-1.53, p = 0.46, respectively). Meta-regression analysis indicated a statistically significant positive correlation between mortality and major bleeding events when comparing NOACs with LMWH (p = 0.049). There was no significant difference in all-cause mortality between patients treated with NOACs and those treated with LMWH (RR 1.04, 95% CI 0.92-1.18, p = 0.54) or VKAs (RR 0.94, 95% CI 0.72-1.23, p = 0.65). Meta-analysis shows NOACs, especially factor Xa inhibitors, reduce VTE recurrence in cancer patients more effectively than LMWH. Comparison between NOACs and VKAs is inconclusive due to limited patient data. Further research is needed to assess NOACs' efficacy and safety against VKAs.

Non-Vitamin K Antagonist Oral Anticoagulants versus Low Molecular Weight Heparin for Cancer-Related Venous Thromboembolic Events: Individual Patient Data Meta-Analysis.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in cancer patients. Low molecular weight heparin (LMWH) has been the standard of care but new guidelines have approved the use of non-vitamin K antagonist oral anticoagulants (NOAC). By conducting an individual patient data (IPD) meta-analysis of randomised controlled trials (RCTs) comparing the outcomes of NOAC versus LMWH in cancer patients, we aim to determine an ideal strategy for the prophylaxis of VTE and prevention of VTE recurrence. Three databases were searched from inception until 19 October 2022. IPD was reconstructed from Kaplan-Meier curves. Shared frailty, stratified Cox and Royston-Parmar models were fit to compare the outcomes of venous thromboembolism recurrence and major bleeding. For studies without Kaplan-Meier curves, aggregate data meta-analysis was conducted using random-effects models. Eleven RCTs involving 4844 patients were included. Aggregate data meta-analysis showed that administering NOACs led to a significantly lower risk of recurrent VTE (RR = 0.65; 95%CI: 0.50-0.84) and deep vein thrombosis (DVT) (RR = 0.60; 95%CI: 0.40-0.90). In the IPD meta-analysis, NOAC when compared with LMWH has an HR of 0.65 (95%CI: 0.49-0.86) for VTE recurrence. Stratified Cox and Royston-Parmar models demonstrated similar results. In reducing risks of recurrent VTE and DVT among cancer patients, NOACs are superior to LMWHs without increased major bleeding.

Oral direct thrombin inhibitors or oral factor Xa inhibitors versus conventional anticoagulants for the treatment of deep vein thrombosis.

Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately one in 1000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of direct oral anticoagulants (DOACs) have been developed: oral direct thrombin inhibitors (DTIs) and oral factor Xa inhibitors, which have characteristics that may be favourable compared to conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or dose adjustment and few known drug interactions. DOACs are now commonly being used for treating DVT: recent guidelines recommended DOACs over conventional anticoagulants for both DVT and PE treatment. This Cochrane Review was first published in 2015. It was the first systematic review to measure the effectiveness and safety of these drugs in the treatment of DVT. This is an update of the 2015 review. OBJECTIVES: To assess the effectiveness and safety of oral DTIs and oral factor Xa inhibitors versus conventional anticoagulants for the long-term treatment of DVT. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.govtrials registers to 1 March 2022. We included randomised controlled trials (RCTs) in which people with a DVT, confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor compared with conventional anticoagulation or compared with each other for the treatment of DVT. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were recurrent venous thromboembolism (VTE), recurrent DVT and PE. Secondary outcomes included all-cause mortality, major bleeding, post-thrombotic syndrome (PTS) and quality of life (QoL). We used GRADE to assess the certainty of evidence for each outcome. We identified 10 new studies with 2950 participants for this update. In total, we included 21 RCTs involving 30,895 participants. Three studies investigated oral DTIs (two dabigatran and one ximelagatran), 17 investigated oral factor Xa inhibitors (eight rivaroxaban, five apixaban and four edoxaban) and one three-arm trial investigated both a DTI (dabigatran) and factor Xa inhibitor (rivaroxaban). Overall, the studies were of good methodological quality. Meta-analysis comparing DTIs to conventional anticoagulation showed no clear difference in the rate of recurrent VTE (odds ratio (OR) 1.17, 95% confidence interval (CI) 0.83 to 1.65; 3 studies, 5994 participants; moderate-certainty evidence), recurrent DVT (OR 1.11, 95% CI 0.74 to 1.66; 3 studies, 5994 participants; moderate-certainty evidence), fatal PE (OR 1.32, 95% CI 0.29 to 6.02; 3 studies, 5994 participants; moderate-certainty evidence), non-fatal PE (OR 1.29, 95% CI 0.64 to 2.59; 3 studies, 5994 participants; moderate-certainty evidence) or all-cause mortality (OR 0.66, 95% CI 0.41 to 1.08; 1 study, 2489 participants; moderate-certainty evidence). DTIs reduced the rate of major bleeding (OR 0.58, 95% CI 0.38 to 0.89; 3 studies, 5994 participants; high-certainty evidence). For oral factor Xa inhibitors compared with conventional anticoagulation, meta-analysis demonstrated no clear difference in recurrent VTE (OR 0.85, 95% CI 0.71 to 1.01; 13 studies, 17,505 participants; moderate-certainty evidence), recurrent DVT (OR 0.70, 95% CI 0.49 to 1.01; 9 studies, 16,439 participants; moderate-certainty evidence), fatal PE (OR 1.18, 95% CI 0.69 to 2.02; 6 studies, 15,082 participants; moderate-certainty evidence), non-fatal PE (OR 0.93, 95% CI 0.68 to 1.27; 7 studies, 15,166 participants; moderate-certainty evidence) or all-cause mortality (OR 0.87, 95% CI 0.67 to 1.14; 9 studies, 10,770 participants; moderate-certainty evidence). Meta-analysis showed a reduced rate of major bleeding with oral factor Xa inhibitors compared with conventional anticoagulation (OR 0.63, 95% CI 0.45 to 0.89; 17 studies, 18,066 participants; high-certainty evidence). AUTHORS' CONCLUSIONS: The current review suggests that DOACs may be superior to conventional therapy in terms of safety (major bleeding), and are probably equivalent in terms of efficacy. There is probably little or no difference between DOACs and conventional anticoagulation in the prevention of recurrent VTE, recurrent DVT, pulmonary embolism and all-cause mortality. DOACs reduced the rate of major bleeding compared to conventional anticoagulation. The certainty of evidence was moderate or high.

Achieving Therapeutic Anti-Xa Levels Using Rivaroxaban for Venous Thromboembolism in a Morbidly Obese Patient with a BMI >70

Background: Anticoagulation (AC) is the cornerstone of treatment for venous thromboembolism (VTE). Direct oral anticoagulants (DOACs) have become the standard of care during the acute and extended phases of therapy for VTE, mostly due to their ease of use, efficacy, and safety profiles. There is a 9.2% prevalence of severe obesity (BMI>40) in Americans as of 2017-2020 with a 6.2-fold increased risk of VTE in obese individuals. The 2021 International Society on Thrombosis and Haemostasis (ISTH) guidelines recommend using standard dosages of DOACs in patients with a BMI >40 kg/m2 or weight >120 kg. Despite these recommendations, their use in severely obese individuals at extremes of weight like our patient with a BMI > 70 kg/m2 remains uncertain. Case Presentation Herein, we present a 38-year-old morbidly obese female with no significant past medical history who presented with an acute worsening of dyspnea on exertion saturating 60% on room air. The diagnosis of intermediate-high risk pulmonary embolism (PE) was made based on computed tomographic angiography (CTA) with right ventricular strain and elevated cardiac biomarkers. A concomitant proximal DVT from the left common femoral to the distal peroneal vein was also noted. The patient's weight was 243kg with a calculated BMI of 72.3 kg/m2. After the patient had received parenteral anticoagulation with heparin for 4 days, it was decided to switch to Rivaroxaban 15mg BID for 21 days followed by 20 mg daily. With a history of irregular menses, the patient developed heavy menstrual bleeding (HMB) following the initiation of rivaroxaban. Her hemoglobin remained stable with no blood transfusion requirements. However, this led to the decision to switch to rivaroxaban 20 mg PO daily earlier than planned due to a lack of improvement in menstrual bleeding which was considered to be clinically relevant non-major bleeding (CRNMB). Despite this switch, there was no effect on efficacy and the patient did not develop any signs or symptoms of VTE recurrence during her prolonged hospital stay with a significant improvement in her oxygenation levels and VTE symptomatology. In our patient, we demonstrated the use of rivaroxaban in a morbidly obese individual with a BMI>70 by achieving therapeutic anti-Xa levels. Figure 1 shows the therapeutic peak and trough anti-Xa levels throughout the patient's hospitalization. The highest Anti Xa level of 314 mcg/mL was reported on day 19 correlating with the patient's menorrhagia, which self-limited with the transition from rivaroxaban 15 mg twice daily to 20 mg daily. Discussion: Two pivotal clinical trials, the EINSTEIN-DVT/PE trials, where 14% of patients in both arms weighed >100 kg, showed that patients on rivaroxaban (15 mg BID for 3 weeks, followed by 20 mg once daily) vs those on enoxaparin followed by a vitamin K antagonist, had no significant difference in recurrence rates of VTE and bleeding rates [Moore KT, et Al. Influences of Obesity, Am J Med 2017]. A recent post-hoc analysis of the EINSTEIN DVT/PE trials also portrayed no correlation between weight/BMI and risk of recurrent VTE or bleeding in those who received rivaroxaban. Our case illustrates the attainment of therapeutic anti-Xa levels with no recurrent VTE in our morbidly obese patient. Despite her heavy menstrual bleeding, the bleeding was controlled once the switch to rivaroxaban 20mg daily was completed. Another study in which its heaviest participant at 172 kg, showed compelling evidence that morbid obesity has minimal influence on the safety and efficacy of rivaroxaban [Speed V, et al. Fixed dose rivaroxaban. JTH 2020]. This remains true for our patient at 243 kg. Conclusion: Our case demonstrates that standard doses of rivaroxaban for the treatment of DVT/PE in individuals with morbid obesity with BMI>70 kg/m2 can be effective, and safer for the initial phase of treatment for VTE and in prevention of VTE recurrence. It also portrays that increased dosages attempting to account for high bodyweight/fat can potentially result in major bleeding events. Despite the 2021 ISTH guidelines, further prospective studies and randomized controlled trials are warranted, to assess the safety and efficacy of DOACs in VTE, particularly in such challenging clinical scenarios like morbid obesity. Alongside clinical assessment, additional studies will be essential to evaluate the need for universal and external validation of anti-Xa levels in patients taking DOACs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Direct Oral Anticoagulants for the Prevention and Acute Treatment of Cancer-Associated Thrombosis.

Cancer is a major risk factor for venous thromboembolism (VTE), and cancer-associated thrombosis (CAT) constitutes approximately 15–25% of all VTE cases. For decades, the standard treatment for CAT used to be daily subcutaneous low molecular weight heparin (LMWH). Data on the safety and efficacy of the direct oral anticoagulants (DOACs) in this population emerged only in recent years and specific DOACs were included into recent guidelines recommendations. In this narrative review of the literature, we reported the results of the phase III randomized controlled trials that evaluated the DOACs for the prevention and the acute treatment of CAT. For the acute phase treatment, the anti-Xa inhibitors (apixaban, edoxaban, rivaroxaban) showed better efficacy than LMWH in preventing VTE recurrence; however, rivaroxaban and edoxaban were also associated with an increased risk of bleeding events. For primary prevention of CAT in ambulatory cancer patients starting chemotherapy, apixaban and rivaroxaban showed better efficacy than placebo but a trend towards higher bleeding rates. Recent guidelines suggest the DOACs for the treatment of CAT in selected cancer patients (eg, low bleeding risk, no luminal gastrointestinal or genitourinary malignancies, no interfering medications). The DOACs are also suggested for primary thromboprophylaxis in selected ambulatory cancer patients at high risk of VTE (eg, Khorana score ≥2 prior to starting new chemotherapy, low bleeding risk, no interfering medications).

The Safety of Direct Oral Anticoagulants Versus Warfarin Among Older Individuals With Acute Venous Thromboembolism and CKD: A Population-Based Cohort Study

Individuals with chronic kidney disease (CKD) have an increased risk of bleeding and thrombosis.1 Although landmark trials of patients with acute venous thromboembolism (VTE) have demonstrated that direct oral anticoagulants (DOACs) are noninferior to vitamin K antagonists with regard to preventing VTE recurrence and the risk of bleeding events, these trials enrolled relatively few patients with CKD.2 Therefore, less information exists on the potential safety concerns associated with VTE treatment strategies in this population.

Effectiveness and Safety of Extended Oral Anticoagulant Therapy in Patients with Venous Thromboembolism: A Retrospective Cohort Study.

Limited real-world evidence exists for effectiveness and safety of extended oral anticoagulation beyond 6months of initial treatment in prevention of recurrent venous thromboembolism (VTE) and adverse major bleeding events among patients with VTE. Using MarketScan Commercial and Medicare Supplemental databases (2013-2019), we conducted a retrospective cohort study to compare the risk of recurrent VTE and major bleeding events during extended treatment among patients with VTE who completed the 6-month initial treatment and received extended oral anticoagulant treatment with apixaban, warfarin, or no extended treatment. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards modeling with inverse probability treatment weighting. We identified 14,818 patients with extended treatment of apixaban (n=4,338), warfarin (n=5,298), or no extended treatment (n=5,182). Compared with no extended treatment, apixaban use was associated with decreased risk of recurrent VTE (HR: 0.10, 95% CI: 0.04-0.26) without increased risk of major bleeding events (HR: 1.06, 95% CI: 0.52-2.17); warfarin use was associated with decreased risk of recurrent VTE (HR: 0.23, 95% CI: 0.12-0.44) but with increased risk of major bleeding events (HR: 2.64, 95% CI: 1.51-4.59). Compared with warfarin, apixaban use was associated with decreased risk of major bleeding events (HR: 0.42, 95% CI: 0.22-0.80) but no difference in risk of recurrent VTE (HR: 0.46, 95% CI: 0.15-1.36). In a real-world clinical setting, extended anticoagulation with apixaban or warfarin was associated with decreased risk of recurrent VTE compared with no extended treatment, and apixaban had a better safety profile with fewer major bleeding events compared with warfarin among commercially insured patients with VTE.

Role of anticoagulants in therapy and prevention of recurrent venous thromboembolism in patients with cancer: a meta-analysis of randomized trials with apixaban

Background Venous thromboembolic complications (VTEC) are a major non-oncological cause of death of patients with malignant neoplasm (MNP). This determines the high significance of antithrombotic therapy for the treatment and secondary prevention of VTEC in this population. During recent years, low-molecular weight heparins (LMWH) have been a "gold standard" for the treatment of cancer-associated venous thrombosis (CAVT). In the recent decade, direct oral anticoagulants (DOACs) have become extensively used for the treatment and prevention of VTEC relapse in non-oncological patients and also for primary prevention of VTEC following orthopedic surgery. Taking into account the oral route of administration, the predictable and convenient pharmacokinetic profile, and the absence of need for coagulation monitoring, it seems possible to use DOACs for the treatment and secondary prevention of VTEС in oncological patients. A meta-analysis of 4 randomized clinical trials (RCTs) showed a higher efficacy of DOACs compared to LMWHs, however, with a greater risk of bleedings in CAVT. In two of four studies using apixaban (more than 40% of weight in meta-analysis), no increase in bleedings was noted.Aim The aim of this study was to perform a systematic search for comparative clinical studies with apixaban and to perform a meta-analysis to answer the question on clinical efficacy and safety of apixaban in the treatment and secondary prevention of recurrent VTEC in patients with CAVT.Material and methods The systematic search was performed in three reference databases, Medline (PubMed), Cochrane Library (CENTRAL), and eLibrary. The search was aimed at publications containing results of RCTs using apixaban for the treatment and prevention of VTEC in patients with MNP. A totality of 678 titles was found; 15 articles were selected for detailed studying, and 4 RCTs were included into the final analysis. The meta-analysis was performed according to the criteria of PRISMA guidelines. Relative risk (RR) was used as a measure of the effect. The meta-analysis was performed by the Mantel-Haenszel method using the R software. Statistical heterogeneity was evaluated with the Cochran criterion (I2); heterogeneity was considered significant at I2 ≥50 %, which was a reason for performing a random-effects meta-analysis. For this meta-analysis, the primary outcome measure was new VTECs (symptomatic or detected proximal deep vein thrombosis and/or symptomatic, detected or fatal pulmonary thromboembolism plus symptomatic upper extremity thromboses, celiac veinous thromboses, and cerebral veinous thromboses if they were included into the efficacy endpoint of the primary studies). The primary safety measure was major bleeding according to ISTH criteria. Other variables included major and clinically significant minor bleedings as well as overall death rate.Results During the systematic search, 4 RCTs were selected. The meta-analysis of the treatment and secondary prevention of VTEC in patients with MNP showed that apixaban was more effective than the active control (88% of LMWHs) in prevention of VTEC relapse. The RR was 0.59; 95 % confidence interval (CI): 0.40-0.86 in the absence of statistically significant differences from the control in the risk of major bleedings (statistically non-significant decrease by 21%), the sum of major and clinically significant minor bleedings, and overall death rate.Conclusion According to the results of the meta-analysis, the DOAC apixaban may be a drug of choice for the treatment and prevention of VTEC relapse in patients with MNO.

Non-vitamin K antagonist oral anticoagulants in venous thromboembolism patients: a meta-analysis of real-world studies

BackgroundThe real-world studies on recurrent venous thromboembolism (VTE) and bleeding events of non-vitamin K antagonist oral anticoagulants (NOACs) in VTE patients have reported conflicting findings. Our study aimed to provide the direct comparison evidence of different NOACs for VTE patients in clinical practice settings.MethodsSearch of the medical literature was conducted using PubMed, Web of Science, EMBASE, Clinical Trials.gov, and the Cochrane Library from inception to March 22, 2021. Among the 19,996 citations retrieved, a total of 63,144 patients from 6 studies were analyzed. Clinical outcomes included recurrent VTE, death, and different bleeding events.ResultsAdjusted hazard ratio (HR) analysis suggested that apixaban had significant lower bleeding riskthan rivaroxaban (major, minor and any bleeding: HR = 0.61, 0.56, 0.70; p = 0.008, < 0.0001, 0.006, respectively), but no statistics difference found in recurrent VTE events (HR = 1.02, 95% confidence interval (CI) 0.71–1.47, p = 0.93). There was no significant difference of major bleeding between dabigatran and rivaroxaban (odds ratios (OR) = 0.41, 95% CI 0.09–1.90, p = 0.25), apixaban and dabigatran (OR 0.64, 95% CI 0.15–2.72, p = 0.83). No significant difference was found in the comparison of edoxaban and other NOACs in VTE recurrence, major bleeding and composite outcome.ConclusionsIn the prevention of bleeding events, apixaban was associated with a lower risk than rivaroxaban, but equivalent efficacy for different NOACs in prevention of recurrent VTE. Evidence generated from the meta-analysis based on real-world data can help to guide selection between apixaban and rivaroxaban in routine clinical practice.Trial registration: This systematic review and meta-analysis were conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis and Meta-analysis of Observational Studies in Epidemiology statements and was registered with PROSPERO (CRD42019140553).

Incidence of venous thromboembolism in advanced lung cancer and efficacy and safety of direct oral anticoagulants: a multicenter, prospective, observational study (Rising-VTE/NEJ037 study).

Background:Venous thromboembolism (VTE) is a well-known type of cancer-associated thrombosis and a common complication of malignancy. However, the incidence of VTE associated with lung cancer and the effectiveness of direct oral anticoagulants remain unclear. This study aimed to identify the incidence of VTE associated with lung cancer at the time of diagnosis or during treatment, the efficacy and safety of edoxaban, and associated risk factors.Methods:The Rising-VTE/NEJ037 study was a multicenter prospective observational study. Altogether, 1021 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Patients with VTE at the time of lung cancer diagnosis started treatment with edoxaban. The primary endpoint of this trial was the rate of newly diagnosed VTE after enrollment or recurrence rate 6 months after treatment initiation.Results:Data were available for 1008 patients. The median age was 70 years (range: 30–94 years), and 70.8% were men. Sixty-two patients had VTE at the time of lung cancer diagnosis, and 38 (9.9%) developed VTE at follow-up. No cases of VTE recurrence were recorded 6 months after treatment initiation with edoxaban. Major and clinically relevant non-major bleeding events occurred in 4.9% of patients and increased to 22.7% in the edoxaban treatment group.Conclusions:VTE occurrence should be monitored during lung cancer treatment. Although treatment with edoxaban was highly effective in preventing VTE recurrence, its administration should be cautiously considered because of the high bleeding rate.Trial registration:jRCTs061180025.

Factor Xa inhibitor for venous thromboembolism management in patient with cancer: a systematic review and meta-analysis.

Background: An earlier systematic review reported no differences in the incidence of recurrent venous thromboembolism and major bleeding between factor Xa inhibitors and standard anticoagulation. The present meta-analysis aimed to assess the effectiveness of factor Xa inhibitors for the management of venous thromboembolism (VTE), specifically in patients with cancer, as there were more randomized clinical trials (RCTs) available. Methods: The PubMed and Cochrane Library databases were systematically screened for all RCTs assessing factor Xa inhibitor efficacy for VTE management in cancer patients. Using RevMan 5.3, we performed a Mantel-Haenszel fixed-effects meta-analysis of the following outcomes: recurrent VTE, VTE events, and major bleeding rates. Results: We identified 11 studies involving 7,965 patients. Factor Xa inhibitors were superior in preventing VTE recurrence, compared to low-molecular-weight heparin (LMWH) (OR 0.60; 95% CI 0.45-0.80; P < 0.01) and vitamin K antagonists (VKA) (OR 0.51; 95% CI 0.33-0.78; P < 0.01). As prophylaxis, factor Xa inhibitors had a similar rate of VTE compared to VKAs (OR 1.08 [95% CI 0.31-3.77]; P = 0.90) and a lower rate compared to placebo (OR 0.54 [95% CI 0.35-0.81]; P < 0.01). Major bleeding rates were higher with factor Xa inhibitors than with LMWHs (OR 1.34 [95% CI 0.83-2.18]; P = 0.23), but significantly lower than VKAs (OR 0.71 [95% CI 0.55-0.92]; P < 0.01). Conclusions: Factor Xa inhibitors are effective for VTE management in patients with cancer; however, they are also associated with an increased bleeding risk compared to LMWH, but decreased when compared to VKA.

Direct Oral Anticoagulants in Sickle Cell Disease, Where We Stand and Where We Are Heading: A Systematic Review

Introduction:Sickle Cell Disease (SCD) is a hemolytic disorder with an increased risk of venous thromboembolism (VTE). By the age of 40 years around 11-12% of sickle cell disease patients will have at least one episode of VTE. VTE among patients with SCD is associated with a two to four times increase in mortality compared to SCD patients without VTE. Nevertheless, the evidence guiding VTE management in SCD, specifically in terms of anticoagulant choice, is scarce. Therefore, we conducted a systematic review that evaluates the effectiveness and safety of direct oral anticoagulants (DOACs) in SCD with VTE.Methods:We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the English literature (PubMed, SCOPUS, and Google Scholar) for randomized controlled trials, observational studies, reviews, case series, and case reports for patients with SCD treated with DOAC for thromboembolic disease. We used the terms in combination: “Sickle cell disease” or “Sickle cell anemia”, and “DOAC”, “rivaroxaban”, “apixaban”, “dabigatran” “edoxaban”. The search included all articles published up to 20th April 2021. Quality and risk of bias assessment were done by two independent authors for each included study.Results:A total of 7 articles were included; four observational studies, and three case series addressing this matter. Patel A et al. found that the use of DOACs, including rivaroxaban, dabigatran, and apixaban in comparison to vitamin K antagonists (VKAs) and low molecular weight heparin (LMWH) for the treatment of VTE in SCD among adults was associated with similar VTE recurrence rate and a better safety profile in terms of a significant reduction in major bleeding events. Similarly, Roberts MZ et al. reported that the use of DOACs for VTE treatment in SCD compared to VKAs resulted in similar effectiveness in terms of VTE recurrence, but the use of DOACs was associated with a similar safety in comparison to VKAs in contrary to the results reported by Patel A et al. in their retrospective study. With regards to the risk of major hemorrhagic events associated with the use of non-VKAs, Gupta VK et al. showed that among 55 patients with SCD treated with VKAs, DOACs, or injectable anticoagulants, only patients treated with VKAs had major bleeding events.Discussion:The current data demonstrated that the use of DOACs for VTE in SCD has similar effectiveness in the prevention of VTE recurrence in comparison to other anticoagulants, including VKAs and injectable anticoagulants with a better safety profile. However, given the absence of clinical practice guidelines for the treatment of VTE among patients with SCD, the clinical practice guidelines recommendations for VTE treatment can be applied to patients with SCD. According to the latest CHEST guidelines (2016) for the treatment of VTE, the use of DOACs is recommended in patients with VTE over VKAs. Similarly, the latest American Society of Hematology (2020) guidelines for VTE suggest the use of DOACs over VKAs, except among patients with renal insufficiency (creatinine clearance less than 30 mL/min), moderate to severe liver disease, or those with antiphospholipid syndrome.Conclusion:In view of the current evidence and based on the results observed; using DOACs was associated with lesser bleeding incidence and fewer complications comparing to VKAs. We think it is rational to use DOACs for VTE treatment among patients with SCD rather than use VKAs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effectiveness and safety of DOACs for the prevention of recurrent VTE: a prospective cohort study

Abstract Background In the direct oral anticoagulants (DOACs) era, extended anticoagulation after 6–12 months of treatment is an attractive strategy in patients with venous thromboembolism (VTE). Real-life data on the clinical benefit of DOAC over time is lacking. Purpose The aim of this study is to assess the effectiveness and safety of DOACs in patients with acute VTE treated for variable periods. Methods Data on patients with an objective diagnosis of acute VTE treated with DOACs were included in prospective cohort study. Study outcomes were recurrent VTE and major bleeding (ISTH definition). Results Overall, 934 patients were included (mean age 67.0±16.0, male gender 51.4%). Three-hundred and forty-six patients had a deep vein thrombosis (37.0%), 98 (10.5%) had isolated pulmonary embolism and 490 (52.5%) had both. One-hundred and sixty-nine patients (18.1%) had an active cancer, 59 (6.3%) a history of cancer and 365 patients (39.1%) an unprovoked VTE. During DOAC treatment (mean 21.6 months), 7 recurrent VTEs and 25 major bleedings occurred. In 546 and in 98 patients, DOAC was continued with full and reduced doses, respectively. In 290 patients (43.8% unprovoked, 13.8% active cancer, 42.4% associated with non-cancer risk factor), anticoagulants were withdrawn (average treatment duration 8.8 months) and 22 recurrent VTEs occurred over a follow-up off-treatment period of 31.9 months. In these patients, 2 episodes of major bleeding were observed. Overall, 201 patients died; fatal PE occurred in 4 and fatal bleeding in 1 patient. Time course for recurrent VTE according to 2019 ESC risk for recurrence is reported in the Figure. Conclusions In this cohort study, DOACs showed a good risk to benefit profile in the extended phase after an acute VTE event. Funding Acknowledgement Type of funding sources: None. Figure 1. Cumulative incidence of recurrent VTE

Direct Oral Anticoagulants for the Prevention of Recurrent Venous Thromboembolism: A Systematic Review & Network Meta-Analysis

Background:Several studies have reported the superiority of extended anticoagulation with rivaroxaban, apixaban, dabigatran and aspirin as superior to placebo for the prevention of recurrent venous thromboembolism (VTE). However, it is unknown if this is a class effect applicable to all direct oral anticoagulants (DOACs) or if one agent is superior. Network meta-analysis allows for indirect comparisons of agents or interventions that have not been formally evaluated in head-to-head trials while preserving randomization of the original trials.Methods:We performed a systematic review and network meta-analysis of randomized controlled trials that compared extended anticoagulation with DOACs to other oral agents (e.g., another DOAC, aspirin or placebo) for the prevention of recurrent VTE. We excluded data on extended treatment with vitamin K antagonists or low-molecular-weight-heparin. Data extraction and assessment of methodological quality with the GRADE approach was assessed by two independent reviewers and verified by the primary investigator. Effect size estimates were calculated and pooled using techniques of network meta-analysis. Effect size was expressed as hazard ratios and 95% confidence intervals.Results:Six randomized trials with a total of 9,610 participants were analyzed. All trials were of high methodological quality. Prior to randomization, all participants had completed an initial period of anticoagulation for an index VTE event; the majority were treated for 6 to 18 months for an unprovoked event prior to starting extended treatment for VTE prevention. Two trials compared low-dose aspirin (100 mg daily) to placebo (ASPIRE and WARFASA), one compared rivaroxaban 10 mg or 20 mg daily to low-dose aspirin (EINSTEIN CHOICE), and the others evaluated rivaroxaban 20 mg daily (EINSTEIN-EXT), apixaban 2.5 mg or 5 mg twice-daily (AMPLIFY-EXT) and dabigatran 150 mg twice-daily (RE-SONATE) versus placebo for the prevention of recurrent VTE. The results are summarized in Figure 1b. Compared to placebo, aspirin and all DOACs effectively reduced VTE recurrence. Apixaban, rivaroxaban, and dabigatran were superior to aspirin and demonstrated comparable efficacy in preventing VTE recurrence. There was no statistically significant difference in bleeding rates between any agents compared to placebo.Conclusion:Our results demonstrate that all DOACs can be used interchangeably for secondary prophylaxis of VTE, likely due to a drug class effect. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The comparative effectiveness of direct oral anti-coagulants and low molecular weight heparins for prevention of recurrent venous thromboembolism in cancer: The CANVAS pragmatic randomized trial.

12020 Background: Previous randomized trials in cancer patients suggest that DOACs are non-inferior to LMWH for preventing recurrent VTE but have higher risk of bleeding. However, the balance of benefits and burdens remains uncertain. Objective: The CANVAS pragmatic trial compared recurrent VTE, bleeding and death in cancer patients following an initial VTE treated with either DOAC or LMWH therapy. Methods: CANVAS was an unblinded hybrid comparative effectiveness non-inferiority trial, with randomized and preference cohorts. Between 12/16 and 4/20, 671 participants were randomized and followed for 6-months. Between 12/16 and 12/17, 140 participants declined randomization, chose their preferred anticoagulant and were followed for 6-months. The preference cohort was closed when predetermined stopping criteria were met. Final follow-up was 11/30/20. Randomized patients were assigned 1:1 to receive either a DOAC or a LMWH. If assigned to LMWH, transitions to warfarin were allowed. Physicians and patients could choose among any DOAC or LMWH. Doses were suggested based on FDA-approved labeling but not mandated. Patients from 67 practices in the US with any invasive solid tumor, lymphoma, multiple myeloma or CLL and a diagnosis of symptomatic or radiographically detected VTE within 30 days of enrollment were eligible. The 1° analysis was conducted in the randomized modified-into to treat popululation, (all subjects who received study drug). The 1° outcome was recurrent VTE. The aim was to establish noninferiority of anticoagulation with a DOAC as defined by the upper limit of the 2-sided 90% CI for the difference in the event rate at 6 months of &lt; 3%. Secondary outcomes included death and bleeding. Hypothesis testing included only the randomized cohort but propensity score adjusted results for the preference and combined cohorts are also shown. Results: The non-inferiority criteria for recurrent VTE was met. Conclusions: Among adult cancer patients with VTE, the use of a DOAC compared with a LMWH resulted in a noninferior risk of recurrent VTE with no differences in rates of bleeding or death in randomized patients. Clinical trial information: NCT02744092. [Table: see text]

ANTITHROMBOTIC EFFECTS OF SULODEXIDE: A REVIEW ARTICLE

Objectives: To review the current knowledge regarding the mechanisms of action and the clinical indications of Sulodexide, a glycosaminoglycan with established efcacy for the prevention of recurrent venous thromboembolism, with reduced bleeding risk. A critical review of the Methods: literature regarding Sulodexide in several data sources between 1975 and 2020. A total of 481 articles were found and analyzed but only 21 articles were considered for this review. Antithrombotic effects of Sulodexide include vas Results: cular endothelial protection, diminished platelet aggregation in response to several stimuli, inhibition of plasma coagulation factors Xa and thrombin, enhancement of brinolysis secondary to reducing PAI-1 and increasing of tPA, and decreased blood viscosity. Compared with other extended treatments, Sulodexide decreases mortality and bleeding episodes. Due to its broad range of pleiotropic effects and mainly a Conclusions: ntithrombotic, Sulodexide has emerged as a therapeutic option for the prevention of recurrent venous thromboembolism in subjects with high risk of bleeding, including elderly patients.

Spontaneous hemothorax under rivaroxaban treatment

Rivaroxaban associated spontaneous hemothorax&#x0D; Rivaroxaban is a highly selective direct thrombin inhibitor indicated in stroke prevention, non-valvular atrial fibrilation, treatment of pulmonary embolism and deep vein thrombosis, prevention of recurrent venous thromboembolism and VTE after elective hip/knee replacement surgery and secondary prevention after acute coronary syndrome. Hemorrhage is the major concern of the drug use. Subdural hematoma, cerebral hemorrhage, GIS hemorrhage, and also intra-articular bleeding has been published in postmarketing reports. Here, we report a case of spontaneous hemothorax under rivaroxaban treatment.&#x0D; A 73-year-old of man was consulted due to acute dyspnea and palpitation. His x-ray pulmonary images and thorax computed tomography were compatible with hemothorax, consequently, we performed thoracentesis, and macroscopic appearance, cell count revealed hemothorax. There was no sign of any disease, such as low pleural fluid pH and glucose, leucocytic dominance, dysplastic cell, which would indicate an another cause of the bleeding. He was taking rivaroxaban (15 mg Daily) due to chronic atrial fibrillation. Hemorrhage was drained and the drug was cessated. Hemothorax did not relapse in the three month-follow-up periods.&#x0D; Rivaroxaban (Xarelto) is a member of new anticoagulant drug class and has become favorable in the patient carrying systemic embolism risk with nonvalvular atrial fibrillation. It has predictable pharmacokinetics features, fewer food interactions, bleeding risk, and contrast to warfarin it does not need frequent INR monitoring. Despite promising features, serious hemorrhagic complications have been reported and bleeding risk is still its major challenge in clinical use. Cases of subdural hematoma, cerebral hemorrhage, GIS hemorrhage, and also intra-articular bleeding has been published (1). Hemothorax was assumed as a rare complication until recently published case reports (2, 3). Here, we announce our case to keep in mind that rivaroxaban is a cause of spontaneous hemothorax, as not uncommonly

Individualised Risk Assessments for Recurrent Venous Thromboembolism: New Frontiers in the Era of Direct Oral Anticoagulants

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality and is associated with high recurrence rates. The introduction of direct oral anticoagulants (DOACs) in the 2010s has changed the landscape of VTE management. DOACs have become the preferred anticoagulant therapy for their ease of use, predictable pharmacokinetics, and improved safety profile. Increasingly, guidelines have recommended long term anticoagulation for some indications such as following first unprovoked major VTE, although an objective individualised risk assessment for VTE recurrence remains elusive. The balance of preventing VTE recurrence needs to be weighed against the not insignificant bleeding risk, which is cumulative with prolonged use. Hence, there is a need for an individualised, targeted approach for assessing the risk of VTE recurrence, especially in those patients in whom the balance between benefit and risk of long-term anticoagulation is not clear. Clinical factors alone do not provide the level of discrimination required on an individual level. Laboratory data from global coagulation assays and biomarkers may provide enhanced risk assessment ability and are an active area of research. A review of the prediction models and biomarkers for assessing VTE recurrence risk is provided, with an emphasis on contemporary developments in the era of DOACs and global coagulation assays.

Treatment Patterns and Clinical Outcomes in Korean Cancer Patients With Venous Thromboembolism: A Retrospective Cohort Study.

This study assessed epidemiologic data and clinical outcomes, including venous thromboembolism (VTE) recurrence and bleeding events, in patients with cancer-associated VTE, and assessed factors associated with clinical outcomes. Data were extracted from retrospective medical-chart review of adult patients diagnosed with cancer-associated deep vein thrombosis or pulmonary embolism who received anticoagulation treatment for ≥3 months. Patients were classified by: low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), and other anticoagulants. First VTE recurrence and bleeding events, and factors associated with their occurrence, were assessed during the initial 6 months of treatment. Overall, 623 patients (age: 63.7 ± 11.3 years, 49.3% male) were included (119, 132, and 372 patients in LMWH, DOACs and other anticoagulants groups, respectively). The cumulative 6-month incidence of VTE recurrence was 16.6% (total), 8.3% (LMWH), 16.7% (DOACs), and 20.7% (other); respective bleeding events were 22.5%, 11.0%, 12.3%, and 30.7%). VTE recurrence and bleeding rates differed only between LMWH and other anticoagulants (HR 2.4, 95% CI: 1.2-5.0 and 3.6, 1.9-6.8, respectively). These results highlight the importance of initial VTE treatment choice for preventing VTE recurrence and bleeding events. LMWH or DOACs for ≥3 months can be considered for effective VTE management in cancer patients.

PCV11 Comparative Efficacy and Safety of Sulodexide for Prevention of Recurrent Venous Thromboembolism: A Network Meta-Analysis

PCV11 Comparative Efficacy and Safety of Sulodexide for Prevention of Recurrent Venous Thromboembolism: A Network Meta-Analysis