Risk Of Recurrent Venous Thromboembolism Research Articles

The association between steroid use and recurrent venous thromboembolism: from the COMMAND VTE Registry-2

Abstract Background It is well known that use of oral steroids is a risk factor for development of venous thromboembolism (VTE). However, the impact of use of oral steroids on VTE recurrence has not been fully evaluated in the era of direct oral anticoagulants (DOAC), which has been a clinically relevant issue in the decision-making of anticoagulation strategies for patients who need oral steroids after VTE diagnosis. Purpose We aimed to investigate long-term clinical outcomes in VTE patients treated with oral steroids after VTE diagnosis in the DOAC era. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. The current study population were divided into 2 groups according to the use of oral steroids after VTE diagnosis; the steroid group and the non-steroid group. We compared clinical characteristics, management strategies, and outcomes including recurrent VTE, major bleeding and all-cause death, between the 2 groups. Results Patients with steroids and those without accounted for 693 (13%) and 4,504 (87%), respectively. Patients with steroids more often had chronic kidney disease (29% vs. 18%, P<0.001), autoimmune disease (50% vs. 5.4%, P<0.001), thrombocytopenia (7.7% vs 4.9%, P=0.002), and anemia (64.4% vs 54.1%, P<0.001), whereas there was no significant difference in the mean age (68.5 vs. 67.6 years old, P=0.16), the prevalence of women (62% vs 58%, P=0.06), active cancer (30% vs. 29%, P=0.42), and history of VTE (8.4% vs 6.8%, P=0.12) between the 2 groups. The cumulative 5-year incidence of discontinuation of anticoagulation therapy were not significantly different between the 2 groups (61.5% vs. 58.5%, log-rank P=0.16). The cumulative 5-year incidences of recurrent VTE nor major bleeding were not significantly different between the 2 groups (10.4% vs. 9.4%, log-rank P=0.55; 16.9% vs. 13.3%, log-rank P=0.16, respectively). Even after adjusting confounders, the risks of recurrent VTE nor major bleeding were not significantly different (adjusted hazard ratio = 0.97, 95% confidence interval = 0.65-1.45, P = 0.89; adjusted hazard ratio = 1.12, 95% confidence interval = 0.84-1.50, P = 0.44). The cumulative 5-year incidences of all-cause death was significantly different between the 2 groups (44.2% vs. 30.2%, log-rank P<0.001). Even after adjusting confounders, the risk of all-cause death remained significantly different (adjusted hazard ratio = 1.82, 95% confidence interval = 1.56-2.12, P<0.001). Conclusions Use of oral steroids after VTE diagnosis was not significantly associated with an increased risk of VTE recurrence in the DOAC Era, which might suggest that there could be no major concerns on an increased risk of recurrent VTE with oral steroids after VTE diagnosis under appropriate anticoagulation therapy.

A novel dynamic risk score to predict venous thromboembolism (VTE) recurrences after 3 months of anticoagulation in patients with incident VTE and without active cancer

Abstract Background Predicting the risk of recurrent venous thromboembolism (rVTE) during and following anticoagulation is complex. Current models lack the ability to adapt to changing patient conditions over time and fail to account for the direct impact of anticoagulation in real-world clinical settings. Purpose To develop a dynamic risk prediction model for rVTE to help clinicians decide on the duration of anticoagulant therapy in conjunction with a model for bleeding (also submitted to the conference). Methods UK Clinical Practice Research Datalink data (2001-2020) was used to generate a retrospective cohort with first VTE who had received 3 months of anticoagulation. Patient episodes of rVTE were evaluated. Covariates were collected at baseline and subsequently as time-varying data to capture changes post-VTE. Hazards with 95% confidence intervals (CI) were estimated and covariates included in a Fine & Gray model used as predictors of rVTE. An additive (logarithmic) scoring scheme was developed from subdistribution hazard ratios, discrimination (expressed by the C-statistic) estimated from 10-fold cross-validation. Results 51,465 patients with a first VTE were included; 4041 rVTE were identified in 200,698 person-years of observation. Incidence rates for rVTE were 2.01 per 100 person-years. Nineteen independent predictors of rVTE (recorded before or after the VTE diagnosis) were included in the model, 13 associated with increased risk and 6 with decreased risk, Table 1. Patients recognised as lower-risk, medium and higher-risk (10.5%, 37% and 52.5% of the population, respectively, at 90 days after first VTE, assuming no anticoagulation treatment) had an annualised rVTE incidence rate of 2.20, 3.84, and 7.44 per 100 person-years. The C-statistic for rVTE was 0.65 (95%CI, 0.64-0.66). The points scored can be added or subtracted to predict risk (Table 2). Conclusions Our dynamic risk score effectively identifies patients at risk of rVTE three months post their initial VTE diagnosis. It allows for continuous monitoring of risk, and modelling of treatment impact, providing clinicians with a pragmatic tool to help determine treatment duration, and adapt their strategies in response to evolving patient conditions.Table 1:Predictors for VTE recurrenceTable 2:VTE recurrence risk score

The initial high-dose versus maintenance-dose anticoagulation therapy with direct oral anticoagulants for cancer-associated venous thromboembolism: from the COMMAND VTE Registry-2

Abstract Background/Introduction Initial high-dose anticoagulation therapy with rivaroxaban and apixaban has been a standard treatment for venous thromboembolism (VTE), although there could be concerns of an increased risk of bleeding events especially among high bleeding-risk patients including those with active cancer. Purpose The present study aimed to evaluate the clinical outcome of initial high-dose anticoagulation therapy comparing to maintenance-dose anticoagulation therapy in patients with cancer-associated VTE using propensity score-matching analysis. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. Among 1507 patients with cancer-associated VTE, we evaluated 180-day clinical outcomes before discontinuation of anticoagulation therapy using a 1:1 propensity score-matching model with 21 risk-adjusting variables Results After the propensity score-matching, we enrolled 324 patients with initial high-dose anticoagulation therapy and 324 patients with initial maintenance dose anticoagulation therapy. Of patients with initial high-dose anticoagulation therapy, rivaroxaban and apixaban were administered in 198 and 126 patients, respectively. Of those with initial maintenance-dose anticoagulation therapy, rivaroxaban, apixaban, and edoxaban were administered in 34, 46 and 244 patients, respectively. The median durations of initial high-dose anticoagulation therapy were 18 [IQR: 15-21] days for rivaroxaban and 7 [IQR: 7-7] days for apixaban. In the current study population, the mean age was 67±12 years, 346 were women, and the mean body weight was 58±12 kg. There was no significant difference in the distribution of gastrointestinal cancer such as stomach and colorectal cancer between the 2 groups (4.6% vs. 4.9%, P=1.0, 8.3% vs. 11.4%, P=0.22). The cumulative 180-day incidence of discontinuation of anticoagulation was not significantly different between the 2 groups (27.8% vs. 30.5%, P=0.50). There were no significant differences in the cumulative 180-day incidences of recurrent VTE (3.1% vs. 1.0%, P=0.08), nor major bleeding (8.1% vs. 7.0%, P=0.66), nor all-cause death (25.1% vs. 21.6%, P=0.33) between the 2 groups. There were also no significant differences in the cumulative 180-day incidences of all clinically relevant bleeding (14.9% vs. 13.3%, P=0.72), gastrointestinal bleeding (8.4% vs. 5.4%, P=0.15), nor major gastrointestinal bleeding (5.4% vs. 2.7%, P=0.10). Conclusions There was no signal of an increased risk of recurrent VTE in the initial maintenance-dose anticoagulation therapy. Considering a numerically slightly higher incidence of gastrointestinal bleeding in the initial high-dose anticoagulation therapy for cancer-associated VTE, the initial maintenance-dose anticoagulation therapy could be a potential treatment option for selected patients including patients at a high risk of gastrointestinal bleeding.Study flow chartResults

Clinical features, outcomes, and anticoagulant strategies in lung cancer-associated isolated distal deep vein thrombosis

IntroductionThe clinical presentation, outcomes, and anticoagulation strategies in patients with lung cancer-associated isolated distal deep vein thrombosis (LC-iDDVT) are not well-defined. Materials and methodsThe study included 593 patients with LC-iDDVT and 260 patients with lung cancer-associated proximal DVT (LC-Proximal DVT). LC-iDDVT was further classified into axial venous thrombosis (AVT; 112 patients) and muscular venous thrombosis (MVT; 481 patients). Cox proportional risk regression models with Fine-Gray tests and competing risk models were employed to evaluate short-term (90-day) and long-term (1-year) outcomes (hazard ratio [HR]; 95 % confidence interval [CI]). ResultsAt the 90-day follow-up, patients with MVT had lower adjusted risks of pulmonary embolism (PE; HR = 0.20 [0.07–0.55], p = 0.002) and venous thromboembolism (VTE) recurrence (HR = 0.54 [0.34–0.88], p = 0.013) than those with LC-Proximal DVT. Similar results were observed at the 1-year follow-up. However, adjusted risks for PE (HR = 0.74 [0.29–1.92], p = 0.540; HR = 0.87 [0.42–1.78], p = 0.700) and VTE recurrence (HR = 0.96 (0.54–1.71), p = 0.890; HR = 0.99 [0.63–1.56], p = 0.970) at 90-day and 1-year were not significantly different between patients with AVT and those with LC-Proximal DVT. Among patients with LC-iDDVT, those receiving anticoagulation had reduced risks of VTE recurrence (HR = 0.57 [0.35–0.95], p = 0.030) and DVT deterioration (HR = 0.28 [0.13–0.60], p = 0.001) compared to those without anticoagulation. Moreover, AVT patients on >3 months of anticoagulation had a lower VTE recurrence risk (HR = 0.23 [0.03–0.92], p = 0.038) than those on ≤3 months of anticoagulation. ConclusionIn the context of lung cancer, patients with AVT may have a higher tendency for recurrent thrombosis compared to those with MVT, especially if anticoagulation is refused or given briefly.

Impact of Residual Vein Venous Thrombosis in Consecutive Patients with Cancer-Associated Thrombosis Treated with Tinzaparin—A Cohort Study

Background: The role of residual venous thrombosis (RVT) as a risk factor for recurrent venous thromboembolism (VTE) in patients with cancer-associated thrombosis (CAT) remains controversial. Methods: We conducted a cohort study on consecutive patients with CAT treated with tinzaparin recruited between 2007 and 2022. Primary outcome: RVT. Secondary outcomes: identification of variables associated with RVT and the role of RVT in VTE recurrences or clinically relevant bleeding (CRB). Results: Among 511 patients with CAT (age 64.1 years ± 13.4 years; 53.5% males) followed for 17.6 months (p25–75: 7.9–34), 35.8% (n = 183) presented RVT (at 6 months, 55.5%). Variables identified as being associated with RVT were ECOG performance status > 1, metastasis, and cancer location. Within 5 years, there were 57 CRB (11.2%; 95% CI: 8.6–14.2) and 67 VTE recurrences (13.1%, 95%CI: 10.3–16.4). Competing risk analysis identified that RVT at 6 months was associated with VTE recurrence within 5 years (sub-hazard ratio: 2.1; 95% CI: 1.2–3.7; p = 0.006), but not with CRB. Multivariate analysis confirmed that RVT at 6 months (HR: 2.1; 95% CI: 1.2–3.7) and metastases (HR: 1.7; 95% CI: 1.1–2.9) were associated with VTE recurrence within 5 years. Conclusions: RVT is high in patients with CAT. The presence of RVT at 6 months was associated with an increased risk of recurrent VTE over 5 years.

Risk of Recurrent Venous Thromboembolism in Patients with Cancer: An Individual Patient Data Meta-analysis and Development of a Prediction Model.

About 7% of patients with cancer-associated venous thromboembolism (CAT) develop a recurrence during anticoagulant treatment. Identification of high-risk patients may help guide treatment decisions. To identify clinical predictors and develop a prediction model for on-treatment recurrent CAT. For this individual patient data meta-analysis, we used data from four randomized controlled trials evaluating low-molecular-weight heparin or direct oral anticoagulants (DOACs) for CAT (Hokusai VTE Cancer, SELECT-D, CLOT, and CATCH). The primary outcome was adjudicated on-treatment recurrent CAT during a 6-month follow-up. A clinical prediction model was developed using multivariable logistic regression analysis with backward selection. This model was validated using internal-external cross-validation. Performance was assessed by the c-statistic and a calibration plot. After excluding patients using vitamin K antagonists, the combined dataset comprised 2,245 patients with cancer and acute CAT who were treated with edoxaban (23%), rivaroxaban (9%), dalteparin (47%), or tinzaparin (20%). Recurrent on-treatment CAT during the 6-month follow-up occurred in 150 (6.7%) patients. Predictors included in the final model were age (restricted cubic spline), breast cancer (odds ratio [OR]: 0.42; 95% confidence interval [CI]: 0.20-0.87), metastatic disease (OR: 1.44; 95% CI: 1.01-2.05), treatment with DOAC (OR: 0.66; 95% CI: 0.44-0.98), and deep vein thrombosis only as an index event (OR: 1.72; 95% CI: 1.31-2.27). The c-statistic of the model was 0.63 (95% CI: 0.54-0.72) after internal-external cross-validation. Calibration varied across studies. The prediction model for recurrent CAT included five clinical predictors and has only modest discrimination. Prediction of recurrent CAT at the initiation of anticoagulation remains challenging.

Predictors of recurrent venous thromboembolism and major bleeding in patients with cancer: A secondary analysis of the CANVAS trial

IntroductionPatients with cancer have an increased risk of developing venous thromboembolism (VTE) but also have an increased risk of both recurrent VTE and bleeding with anticoagulation compared to anticoagulated patients without cancer. CANVAS, a randomized pragmatic effectiveness trial, compared the direct oral anticoagulants a class to low molecular weight heparin for treatment of a new VTE in patients with cancer. The aim of this prespecified secondary analysis of the CANVAS trial is to identify predictors of both recurrent VTE and major bleeding in patients with cancer and new VTE. MethodsData from the 671 participants in the analysis population were used to identify predictors of recurrent VTE and bleeding during the 6-month treatment period. Significant predictors identified in the univariable models were carried forward in the multivariable models to identify independent predictors of both risks. ResultsIndependent predictors of recurrent VTE include ECOG performance status ≥2 (HR, 3.19 [95 % CI, 1.45–7.02]; P < .005), presence of metastatic disease (HR, 2.57 [95 % CI, 1.14–5.80]; P = .023), treatment with bevacizumab (HR, 2.50 [95 % CI, 1.04–5.99]; P = .041), and deep vein thrombosis without pulmonary embolus as index VTE (HR, 1.86 [95 % CI, 1.04–3.33]; P = .037). Independent predictors of major bleeding include serum albumin <3.5 g/dL (HR 1.97 [95 % CI, 1.02–3.79]; P = .044) and metastatic disease (HR 2.80 [95 % CI, 1.08–7.22]; P = .034). ConclusionFindings from this pre-specified analysis of the CANVAS trial identified risk factors for recurrent VTE and major bleeding in a population of participants with cancer and new VTE that reflect current oncology clinical practice. Results can be used to identify at risk patients in practice and inform new risk prediction models to improve the care of these patients.

Secondary prophylaxis of venous thromboembolism (VTE) with low dose apixaban or rivaroxaban in major-thrombophilia carriers.

Direct oral anticoagulants (DOACs) are widely used for treatment and secondary prophylaxis of venous thromboembolism (VTE) and represent the gold standard for VTE secondary prophylaxis, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit widespread DOACs usage there are few literature data regarding their efficacy and safety in major thrombophilia carriers and almost no data is available for low intensity apixaban and rivaroxaban as secondary VTE prophylaxis in such patients. The aim of our study is to evaluate and confront the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis, in major thrombophilia carriers vs patients at high risk of VTE recurrence for other reasons. We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5mg BID or rivaroxaban 10mg daily and that were screened for thrombophilia. The examined patients were 339. Baseline characteristics such as sex, age, obesity rate, smoking, number of previous VTEs and comorbidities (such as cardiovascular diseases, diabetes, mild CKD) were equally distributed in either group. The median low-dose DOACs administration time was 19.20months (IQR 12.17-35.67). During low-dose DOACs treatment, 13 (3.8%) VTE recurrences were observed; 14 bleeding events were registered (4,1%), with no major bleeding (MB), 6 clinically relevant non major bleeding (CRNMB) (1.8%) and 8 minor bleeding (2.3%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between major thrombophilia carriers and non-major thrombophilia carriers. In multivariate analysis increased risk of VTE recurrence was found for patients with cardiovascular comorbidities (HR 4.00 - p = 0.034) and for patients with more than one previous VTE episode (HR 5.14-p = 0.034). Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis for carriers of major thrombophilia with no increase in VTE recurrence and/or bleeding risk.

Venous thromboembolism secondary prophylaxis in elderly people (over 75-year-old) with low-dose direct oral anticoagulants: single-center Italian experience

Nowadays, direct oral anticoagulants (DOACs) represent the gold standard for venous thromboembolism (VTE) treatment and VTE secondary prophylaxis; nevertheless, the percentage of elderly patients in major trials and literature data about DOACs usage for VTE secondary prophylaxis in the elderly are scant. Our retrospective study tried to evaluate low-dose DOACs efficacy and safety for elderly VTE secondary prophylaxis in a real-life setting. A cohort of 73 patients (≥ 75 years) considered at high risk of VTE recurrence was treated with apixaban 2.5 mg twice daily (b.i.d.) or rivaroxaban 10 mg daily as VTE secondary prophylaxis. The median low-dose DOACs administration time was 18.40 months. Three (4.1%) VTE recurrence events were observed, with four bleeding events registered (5.5%), including one major bleeding (MB) (1.4%) and two clinically relevant non major bleeding (CRNMB) (2.7%). Our data suggest that low-dose DOACs may be effective and well tolerated for secondary VTE prophylaxis in elderly patients at high risk of VTE recurrence.

Outcomes in children with provoked venous thrombosis and antiphospholipid antibodies: findings from the Kids-DOTT trial

AbstractFew studies have prospectively evaluated the incidence and outcomes in children with provoked venous thromboembolism (VTE) and transient or persistent antiphospholipid antibodies (aPLs). We compared outcomes of patients aged <21 years with a first-episode acute provoked VTE and positive aPL at diagnosis, enrolled in the Multicenter Evaluation of the Duration of Therapy for Thrombosis in Children trial. aPLs were tested at enrollment and, when positive, repeated at 6 weeks after VTE diagnosis. Subsequent testing was performed at the discretion of the treating hematologist. Of 524 patients, 116 (22%) had positive aPLs at enrollment. At follow-up, 70 (60%) had transient (n = 66) or low-titer aPLs (n = 4), 11 (10%) had persistent aPLs meeting the criteria for antiphospholipid antibody syndrome (APS), and 35 (30%) had no repeat testing. Patients with APS were older (15.8 vs 9.9 years; P = .014) and had a statistically significant higher risk of symptomatic recurrent VTE (18% vs 1%; odds ratio [OR], 12.2; 95% confidence interval [CI], 1.4-108; P = .025) and a statistically nonsignificant but clinically meaningful difference in the risk of anticoagulant-related clinically relevant bleeding (9% vs 0%; OR, 20.1; 95% CI, 0.7-558; P = .077) compared with those in the transient or low-titer aPL group. In conclusion, aPLs are common in young patients with acute provoked VTE and are mostly transitory and clinically insignificant. Patients with APS and provoked VTE appear to have an increased risk of recurrent VTE compared with patients with transitory or low-titer aPLs. Future collaborative studies should investigate the optimal VTE management for children with provoked VTE who meet the criteria for APS. The trial was registered at www.ClinicalTrials.gov as #NCT00687882.

Women-specific aspects of venous thromboembolism

Women have a higher lifetime risk of venous thromboembolism (VTE) than men. Hormone-associated risk factors such as pregnancy, contraception and hormone replacement therapy contribute significantly to this. Contraception with combined hormonal contraception increases the risk of VTE in young women, with the extent of the increase in risk being determined by the level of the estrogen dose and the progestin component. After hormone associated VTE, temporary anticoagulation is sufficient in many cases, provided there are no additional persistent risk factors. Affected women should be informed that the risk of VTE recurrence is increased in a subsequent pregnancy and usually requires VTE prophylaxis with low molecular weight heparin during pregnancy. If the suspicion of recurrent VTE arises during pregnancy, diagnostics must be carried out promptly so that deep vein thrombosis and/or pulmonary embolism can be reliably confirmed or ruled out.

Impact of the VTE-PREDICT calculator on clinicians’ decision making in fictional patients with venous thromboembolism: a randomized controlled trial

BackgroundAfter 3 months of anticoagulation for venous thromboembolism (VTE), the decision needs to be made whether to stop anticoagulation or extend treatment indefinitely. The VTE-PREDICT calculator can be used to estimate individual risks of VTE recurrence and bleeding to guide this decision. ObjectivesTo evaluate the impact of predicted individual risks of recurrence and bleeding on clinicians’ decisions on anticoagulation duration and to assess usefulness of the VTE-PREDICT calculator. MethodsA randomized controlled trial and within-subject study was conducted among clinicians treating VTE patients. The clinicians were asked to complete an online survey containing 6 fictional case vignettes. Group A proposed anticoagulant duration for each case without additional information first and subsequently after seeing calculator-predicted risks (within-subject analysis). Group B was directly provided with calculator risks and proposed treatment duration for each case vignette (for comparison with group A results in a randomized controlled trial analysis). Then, group B received questions on usefulness and credibility of the calculator. ResultsForty-five clinicians were assigned to group A and 48 to B. Overall, group A did not propose different anticoagulation durations than group B. However, individual clinicians in group A changed proposed duration in 35% of the cases after seeing the calculator risks. The calculator was considered useful and credible by most clinicians. ConclusionOverall, use of the VTE-PREDICT calculator did not affect proposed anticoagulation duration. However, individual clinicians frequently changed their proposed duration after using the calculator, especially for patients with high bleeding risk.

Safety and Effectiveness of Direct Oral Anticoagulants Versus Warfarin in Patients with Venous Thromboembolism using Real-World Data: A Systematic Review and Meta-Analysis.

Direct oral anticoagulants (DOACs) have shown comparable efficacy and a superior safety profile in clinical trials for patients with venous thromboembolism (VTE). However, further study is needed to assess DOACs' effectiveness and safety compared to warfarin in a real-world context. Thus, this meta-analysis compares the effectiveness and safety of warfarin and DOACs in patients with VTE. A systematic review of the literature using PubMed and EMBASE was conducted from inception until June 2024. We examined observational studies that compared safety and effectiveness between DOACs and warfarin when used in treating VTE and reported adjusted hazard ratios (HRs) and/or odds ratios (ORs) for recurrent VTE, major bleeding, clinically relevant non-major bleeding, gastrointestinal bleeding, intracranial hemorrhage, and death from any cause. We then estimated the pooled effect using the random-effects model for meta-analysis. A total of 25 studies were included in the current meta-analysis. DOAC therapy was associated with significantly lower risks of recurrent VTE (HR 0.76, 95% confidence interval [CI] 0.69-0.85), major bleeding (HR 0.77, 95% CI 0.72-0.83), clinically relevant non-major bleeding (HR 0.82, 95% CI 0.77-0.88), and gastrointestinal bleeding (HR 0.75, 95% CI 0.68-0.83) compared to warfarin. However, no statistically significant difference was observed in all-cause mortality between the two groups (HR 0.96, 95% CI 0.83-1.10). This meta-analysis found that DOACs are associated with a significant reduction in VTE recurrence in addition to the known favorable safety profile when compared to warfarin.

Baseline platelet count and long-term clinical outcomes in patients with acute venous thromboembolism: a prospective cohort study.

An abnormal platelet count (PC) is common in acute venous thromboembolism (VTE) but its relationship with clinical outcomes remains ill-defined. We aimed to explore the association between baseline PC and the long-term risk of clinically relevant outcomes in a prospective cohort of 991 patients with acute VTE. We classified patients into four PC groups: very low (< 100 G/l), low (≥ 100 to < 150 G/l), normal (≥ 150 G/l to ≤ 450 G/l), and high (> 450 G/l). The primary outcome was major bleeding (MB), secondary outcomes were recurrent VTE and overall mortality. We examined the association between PC and clinical outcomes, adjusting for confounders, competing risk for mortality, and periods of anticoagulation. After a median follow-up of 30 months, 132 (13%) of patients experienced MB, 122 (12%) had recurrent VTE, and 206 (21%) died. Compared to patients with a normal PC, patients with a very low PC had a sub-distribution hazard ratio (SHR) for MB of 1.23 (95% confidence interval [CI] 0.52-2.91) and those with a high PC a SHR of 1.87 (95%CI 0.82-4.29). Patients with a low PC had a twofold increased VTE recurrence risk (SHR 2.05, 95%CI 1.28-3.28). Patients with low and very low PC had a hazard ratio for mortality of 1.43 (95%CI 0.99-2.08) and of 1.55 (95%CI 0.80-2.99), respectively. Our findings do not suggest a consistent relationship between baseline PC and long-term clinical outcomes in patients with VTE.

Recurrent venous thromboembolism and vaginal estradiol in women with prior venous thromboembolism: A nested case-control study.

Whether vaginal estradiol use is associated with an increased risk of recurrent venous thromboembolism (VTE) in women with prior VTE is unknown. We sought to evaluate the association between vaginal estradiol use and recurrent VTE in women with prior VTE. We performed a nationwide nested case-control study among 44 024 women aged ≥45 years who developed a first VTE without a history of vaginal estrogen use prior to VTE diagnosis. Cases with recurrent VTE were matched 1:2 on birth year with controls using incidence density sampling. Exposure to vaginal estradiol tablets was categorized into current use (0-2 months before index), prior use (2-24 months before index) and past use (more than 24 months prior to index). We identified 5066 cases and 10 127 age-matched controls. In fully adjusted analysis vaginal estrogen was not associated with recurrent VTE with a hazard ratio of 0.75, p = .07 for current use, 0.83, p = .13 for prior use, and 1.24, p = .06 for past use. Use of vaginal estradiol tablets in women with prior VTE was not associated with an increased rate of recurrent VTE. Our study indicates that vaginal estradiol therapy is unlikely to increase risk of recurrent VTE in women with prior VTE.

Effectiveness and Safety of Extended Treatment Apixaban Versus Low-Molecular-Weight Heparin in Cancer-Associated Venous Thromboembolism.

Limited real-world evidence is available comparing the safety and effectiveness of apixaban and low-molecular-weight heparins (LMWHs) for preventing recurrent venous thromboembolism (VTE) in patients with active cancer receiving anticoagulation in an extended treatment setting. This study evaluated the risk of bleeding and recurrent VTE in patients with cancer-associated VTE who were prescribed apixaban or LMWH for ≥3 months. A US commercial claims database was used to identify adult patients with VTE and active cancer who initiated apixaban or LMWH 30 days following the first VTE diagnosis and had ≥3 months of continuous enrollment and 3 months of primary anticoagulation treatment. Patients were followed from the day after the end of primary anticoagulation treatment until the earliest of: date of disenrollment, discontinuation of index anticoagulant, switch to another anticoagulant, or end of the study period. Inverse-probability treatment weighting (IPTW) was used to balance treatment cohorts. Incidence rates (IRs) for the outcomes were calculated per 100 person-years (PY). Cox proportional hazard models were used to evaluate the adjusted risk of recurrent VTE, major bleeding (MB), and clinically relevant nonmajor bleeding (CRNMB). A total of 13,564 apixaban- and 2,808 LMWH-treated patients were analyzed. Post-IPTW, the treatment cohorts were balanced. Patients receiving apixaban had lower adjusted IRs for recurrent VTE (4.1 vs 9.6 per 100 PY), MB (6.3 vs 12.6), and CRNMB (26.1 vs 36.0) versus LMWH (P<.0001 for all comparisons) during the follow-up period. Patients on apixaban had a lower adjusted risk of recurrent VTE (hazard ratio [HR], 0.42; 95% CI, 0.34-0.53), MB (HR, 0.50; 95% CI, 0.41-0.61), and CRNMB (HR, 0.76; 95% CI, 0.68-0.85) versus LMWH. Extended anticoagulation treatment of ≥3 months with apixaban was associated with lower rates of recurrent VTE, MB, and CRNMB compared with LMWH in adults with cancer-associated VTE.

Temporal Changes in Long-Term Outcomes of Venous Thromboembolism From the Warfarin Era to the Direct Oral Anticoagulant Era.

There have been limited data on the changes in clinical outcomes after the introduction of direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) in real clinical practice. We evaluated the changes in management strategies and long-term outcomes from the warfarin era to the DOAC era. We compared the 2 series of multicenter COMMAND VTE (Contemporary Management and Outcomes in Patients With Venous Thromboembolism) registries in Japan enrolling consecutive patients with acute symptomatic VTE: Registry 1: 3027 patients in the warfarin era (2010-2014) and Registry 2: 5197 patients in the DOAC era (2015-2020). The prevalence of DOAC use increased more in Registry 2 than in the Registry 1 (Registry 1: 2.6% versus Registry 2: 79%, P<0.001). The cumulative 5-year incidence of recurrent VTE was significantly lower in Registry 2 than in Registry 1 (10.5% versus 9.5%, P=0.02), and the risk reduction of recurrent VTE in Registry 2 remained significant even after adjusting the confounders (hazard ratio [HR], 0.78 [95% CI, 0.65-0.93]; P=0.005). The cumulative 5-year incidence of major bleeding was not significantly different between the 2 registries (12.1% versus 13.7%, P=0.26), and the risk of major bleeding between the 2 registries was not significantly different even after adjusting the confounders (HR, 1.04 [95% CI, 0.89-1.21]; P=0.63). Along with the shift from warfarin to DOACs, there was a lower risk of recurrent VTE in the DOAC era than in the warfarin era, whereas there was no apparent change in the risk of major bleeding, which might still be an unmet need even in the DOAC era.

Statins during Anticoagulation for Emergency Life-Threatening Venous Thromboembolism: A Review.

Venous thromboembolism (VTE) is the leading cause of morbidity and death worldwide, after cancer and cardiovascular diseases. VTE is defined to include pulmonary embolism (PE) and/or deep vein thrombosis (DVT). Approximately 25% of PE patients experience sudden death as an initial symptom of VTE, and between 10% and 30% of patients die within the first month after diagnosis. Currently, the only drugs approved for the treatment of both acute and chronic VTE are vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). However, their effectiveness is limited due to their associated risk of bleeding. Ideally, therapy should be able to treat VTE and limit the risk of VTE recurrence without increasing the risk of bleeding. Several studies have shown that the use of statins during anticoagulation for VTE reduces the risk of death and VTE recurrence. However, to date, there are conflicting data on the impact of statins during anticoagulation for VTE. A biological protective function of statins during anticoagulation has also been reported. Statins affect D-dimer levels; tissue factor (TF) gene expression; and VIII, VII, and Von Willebrand clotting factors-the major clotting factors they are able to affect. However, the usefulness of statins for the treatment and prevention of VTE is currently under debate, and they should not be substituted for guideline-recommended VTE prophylaxis or anticoagulation treatment. In this review of the literature, we illustrate the advances on this topic, including data on the role of statins in primary VTE prevention and secondary VTE prevention, related biological mechanisms, the risk of bleeding during their use, and their ability to reduce the risk of death.

Venous thromboembolism in women with hormone-dependent breast cancer. To continue or discontinue hormonal treatment? Insights from the RIETE registry

IntroductionHormone therapy (HT) for breast cancer is associated with an increased risk of venous thromboembolism (VTE). This study examines the effects of continuing versus discontinuing HT on VTE recurrence, major bleeding, and mortality, after an acute VTE event. MethodsUsing data in the RIETE-registry from March 2001 through September 2021, we calculated incidence rates and rate-ratios (RR) for VTE events in patients on- and off HT. Cox regression models assessed the impact of HT continuation. ResultsAmong 479 women with breast cancer on HT who developed VTE (pulmonary embolism 279, isolated deep vein thrombosis 200), 350 (73 %) continued HT. These women were slightly older (70 ± 13 vs. 67 ± 16 years) than those discontinuing HT, with no significant differences in other baseline characteristics. Over a median follow-up of 294 days, 25 (5.2 %) developed VTE recurrences, 18 (3.7 %) had major bleeding, and 73 (15.2 %) died. Rates of VTE recurrence did not differ significantly between groups (RR: 1.28, 95 % CI 0.44–3.75), except in the first three months post-VTE, where a higher rate was observed in those continuing HT (6.02/100 patients-year vs. no events). On multivariable analysis, HT continuation showed no association with VTE recurrences after adjusting for other thromboembolic risk factors (adjusted hazard ratio [aHR] 1.49, 95 % CI 0.5–4.45). ConclusionContinuing HT after a VTE event in women with breast cancer does not generally affect the long-term risk of VTE recurrences but is associated with a higher risk in the first three months. These findings highlight the need for careful monitoring during this period.

Exploratory rivaroxaban trial for isolated calf deep vein thrombosis with a risk factor of thrombosis extension: an open-label, multicenter, randomized controlled trial

BackgroundLimited evidence exists regarding the incidence of recurrent venous thromboembolism (VTE) in patients diagnosed with isolated distal deep vein thrombosis (DVT) who are at risk of thrombosis extension whether they receive anticoagulation therapy or not. ObjectivesThe study aimed to investigate the incidence of recurrent VTE and the impact of rivaroxaban in this patient population. MethodsThis open-label, exploratory, and randomized controlled trial was conducted at 7 centers in Japan between April 2019 and April 2022. Adult patients with isolated distal DVT at risk of thrombosis extension received either rivaroxaban combined with physical therapy or physical therapy alone for 90 days. Whole-leg ultrasound was performed at 14 and 90 days. We assessed a composite outcome of symptomatic or asymptomatic proximal DVT or symptomatic pulmonary embolism as the primary outcome until the end of the treatment period using an intention-to-treat analysis. Major bleeding was evaluated as a key secondary outcome. ResultsOut of 90 enrolled patients, 3 were excluded due to withdrawal of consent; therefore, we analyzed 87 participants. The rivaroxaban group (n = 42) reported no primary outcomes (0%; 95% CI, 0.0%-8.4%), whereas the physical therapy group (n = 45) had 2 cases of symptomatic proximal DVT (4.4%; 95% CI, 0.5%-15.1%). Major bleeding events occurred in 4 patients in the rivaroxaban group (9.5%; 95% CI, 2.7%-22.6%), whereas no events occurred in the physical therapy group (0%; 95% CI, 0%-7.9%). ConclusionPreliminary data suggest that rivaroxaban may reduce the risk of VTE recurrence among this patient subset, albeit with an increased incidence of bleeding events.