Recurrent venous thromboembolism and bleeding with extended anticoagulation: the VTE-PREDICT risk score

Aims Deciding to stop or continue anticoagulation for venous thromboembolism (VTE) after initial treatment is challenging, as individual risks of recurrence and bleeding are heterogeneous. The present study aimed to develop and externally validate models for predicting 5-year risks of recurrence and bleeding in patients with VTE without cancer who completed at least 3 months of initial treatment, which can be used to estimate individual absolute benefits and harms of extended anticoagulation. Methods and results Competing risk-adjusted models were derived to predict recurrent VTE and clinically relevant bleeding (non-major and major) using 14 readily available patient characteristics. The models were derived from combined individual patient data from the Bleeding Risk Study, Hokusai-VTE, PREFER-VTE, RE-MEDY, and RE-SONATE (n = 15,141, 220 recurrences, 189 bleeding events). External validity was assessed in the Danish VTE cohort, EINSTEIN-CHOICE, GARFIELD-VTE, MEGA, and Tromsø studies (n = 59 257, 2283 recurrences, 3335 bleeding events). Absolute treatment effects were estimated by combining the models with hazard ratios from trials and meta-analyses. External validation in different settings showed agreement between predicted and observed risks up to 5 years, with C-statistics ranging from 0.48–0.71 (recurrence) and 0.61–0.68 (bleeding). In the Danish VTE cohort, 5-year risks ranged from 4% to 19% for recurrent VTE and 1% –19% for bleeding. Conclusion The VTE-PREDICT risk score can be applied to estimate the effect of extended anticoagulant treatment for individual patients with VTE and to support shared decision-making

Pregnancy and venous thromboembolism

Pregnancy and the postpartum period are associated with an increased risk of venous thromboembolism (VTE), which complicates 1 to 2 of 1,000 pregnancies and represents a leading cause of mortality during pregnancy in developed countries. Strong evidence for the management of pregnancy-related VTE is missing, mostly because pregnant women have been excluded from all major trials investigating different diagnostic tools and treatment regimens. Nevertheless, proper evaluation of the involved risk factors is mandatory to reduce the incidence of pregnancy-related VTE and improve outcomes. Low-molecular-weight heparins are considered as a first-line option in the management of pregnancy-related VTE. With regard to future research, there is a need for methodologically strong studies in pregnant women, especially with respect to risk stratification, optimal heparin doses, usefulness of anti-FXa levels and their correlation with clinical outcomes, and correct management of anticoagulation during deliver

Short-term versus extended anticoagulant treatment for unprovoked venous thromboembolism : A survey on guideline adherence and physicians' considerations

Background: In patients with unprovoked venous thromboembolism (VTE), anticoagulant treatment duration should be decided by weighing bleeding risk versus risk of recurrent VTE, considering patient's preference. Because both risks differ between individuals, this recommendation presumably leads to wide variation in clinical management. Objectives: To identify physician's considerations when deciding between short-term and extended anticoagulation and to assess how current guidelines are put to practice. Materials and methods: An online, 33-item survey was developed, containing questions on clinical management, considerations regarding treatment duration, risk scores, information tools and shared decision-making. It was distributed to internists, pulmonologists and residents treating patients with VTE in the Netherlands. Results: 69 internists and 73 pulmonologists including 24 residents participated in the survey. Extended treatment was preferred by 73% (104/142) of participants. Most important reasons for extended treatment were, in descending order: patient's preference, active malignancy, low estimated bleeding risk, history of VTE and hemodynamic instability during previous VTE. Most important reasons for short-term treatment were frequent falls, history of major bleeding, previous bleeding during anticoagulation, patient's preference and thrombocytopenia. Although existing risk scores are infrequently used, physicians express their need for scores combining risks of recurrence and bleeding to aid individualized decision-making. Conclusion: Our results confirm a wide variety of considerations regarding treatment duration in patients with unprovoked VTE. Although most participants followed guidelines' recommendations to prescribe indefinite treatment in absence of contraindications, rationale is not always supported by evidence. A clinical decision tool to estimate and weigh risks of recurrence and bleeding is warranted

The importance of clinical probability assessment in interpreting a normal d-dimer in patients with suspected pulmonary embolism

BACKGROUND: The d-dimer test is widely applied in the diagnostic workup of patients with suspected pulmonary embolism (PE). The objective of this study was to investigate how often the d-dimer test fails when clinical probability is not taken into account. METHODS: We used data collected in 1,722 consecutive patients with clinically suspected PE to analyze the 3-month venous thromboembolism (VTE) rate in all patients with a normal d-dimer concentration and separately for patients who have a normal d-dimer concentration with an unlikely or likely clinical probability for PE, as assessed by the Wells clinical decision rule. RESULTS: The 3-month VTE rate in all patients with a normal d-dimer concentration (n = 563) was 2.3% (95% confidence interval [CI], 1.4 to 3.9%). In the patients with an unlikely probability of PE (n = 477), VTE was confirmed in 1.1% of the patients with a normal d-dimer concentration (95% CI, 0.4 to 2.4%). In those patients with a likely clinical probability of PE (n = 86), VTE was confirmed in 9.3% of the patients with a normal d-dimer concentration (95% CI, 4.8 to 17.3%). The difference in VTE incidence between patients with unlikely and likely clinical probabilities of PE was significant (p < 0.001). CONCLUSIONS: Our findings indicate that it is of utmost importance to first examine the patient and assess the clinical probability, after which the d-dimer concentration can be taken into account, in order to prevent physicians from being influenced by a normal d-dimer test result when they evaluate the clinical probability of PE. Patients with a likely clinical probability should undergo further testing, regardless of the d-dimer test outcom

Prediction models for recurrence and bleeding in patients with venous thromboembolism: A systematic review and critical appraisal

Introduction: Prediction models for recurrence and bleeding are infrequently used when deciding on anticoagulant treatment duration after venous thromboembolism (VTE) due to concerns about performance and validity. Our aim was to critically appraise these models by systematically summarizing data from derivation and validation studies. Materials and methods: MEDLINE and CENTRAL were searched until November 15th, 2019. Studies on prediction models for recurrence or bleeding after at least 3 months of anticoagulation in adult patients with VTE were included. The PROBAST, ROBINS-I and RoB2 tools were used to assess risk of bias and applicability. Results: Selection yielded 18 studies evaluating 8 models for recurrence (7 on development; 9 on validation; 1 update). Generally, models for recurrent VTE appeared to perform poorly to moderately in external validation studies (C-statistics 0.39–0.66, one 0.83). However, impact studies show that HERDOO2 and Vienna prediction model may identify patients with unprovoked VTE at low recurrence risk. Sixteen studies evaluating 14 models for anticoagulation-related bleeding were identified (7 on development; 9 on validation). Although some models seemed promising in development studies, their predictive performance was poor to moderate in external validation (C-statistics 0.52–0.71). All but 3 studies were considered at high risk of bias, mainly due to limitations in the statistical analysis. Conclusions: Prognostic models for recurrence and anticoagulation-related bleeding risk often have important methodological limitations and insufficient predictive accuracy. These findings do not support their use in clinical practice to weigh risks of recurrence and bleeding when deciding on continuing anticoagulation after initial treatment of VTE

Imaging for the exclusion of pulmonary embolism in pregnancy

Pulmonary embolism is a leading cause of pregnancy-related death. An accurate diagnosis in pregnant patients is crucial to prevent untreated pulmonary embolism as well as unnecessary anticoagulant treatment and future preventive measures. Applied imaging techniques might perform differently in these younger patients with less comorbidity and altered physiology, who largely have been excluded from diagnostic studies. To determine the diagnostic accuracy of computed tomography pulmonary angiography (CTPA), lung scintigraphy and magnetic resonance angiography (MRA) for the diagnosis of pulmonary embolism during pregnancy. We searched MEDLINE and Embase until July 2015. We used included studies as seeds in citations searches and in 'find similar' functions and searched reference lists. We approached experts in the field to help us identify non-indexed studies. We included consecutive series of pregnant patients suspected of pulmonary embolism who had undergone one of the index tests (computed tomography (CT) pulmonary angiography, lung scintigraphy or MRA) and clinical follow-up or pulmonary angiography as a reference test. Two review authors performed data extraction and quality assessment. We contacted investigators of potentially eligible studies to obtain missing information. In the primary analysis, we regarded inconclusive index test results as a negative reference test, and treatment for pulmonary embolism after an inconclusive index test as a positive reference test. We included 11 studies (four CTPA, five lung scintigraphy, two both) with a total of 695 CTPA and 665 lung scintigraphy results. Lung scintigraphy was applied by different techniques. No MRA studies matched our inclusion criteria.Overall, risk of bias and concerns regarding applicability were high in all studies as judged in light of the review research question, as was heterogeneity in study methods. We did not undertake meta-analysis. All studies used clinical follow-up as a reference standard, none in a manner that enabled reliable identification of false positives. Sensitivity and negative predictive value were therefore the only valid test accuracy measures.The median negative predictive value for CTPA was 100% (range 96% to 100%). Median sensitivity was 83% (range 0% to 100%).The median negative predictive value for lung scintigraphy was 100% (range 99% to 100%). Median sensitivity was 100% (range 0% to 100%).The median frequency of inconclusive results was 5.9% (range 0.9% to 36%) for CTPA and 4.0% (range 0% to 23%) for lung scintigraphy. The overall median prevalence of pulmonary embolism was 3.3% (range 0.0% to 8.7%). Both CTPA and lung scintigraphy seem appropriate for exclusion of pulmonary embolism during pregnancy. However, the quality of the evidence mandates cautious adoption of this conclusion. Important limitations included poor reference standards, necessary assumptions in the analysis regarding inconclusive test results and the inherent inability of included studies to identify false positives. It is unclear which test has the highest accuracy. There is a need for direct comparisons between diagnostic methods, including MR, in prospective randomized diagnostic studie

Simplification of the revised Geneva score for assessing clinical probability of pulmonary embolism

BACKGROUND: The revised Geneva score is a fully standardized clinical decision rule (CDR) in the diagnostic workup of patients with suspected pulmonary embolism (PE). The variables of the decision rule have different weights, which could lead to miscalculations in an acute setting. We have validated a simplified version of the revised Geneva score. METHODS: Data from 1049 patients from 2 large prospective diagnostic trials that included patients with suspected PE were used and combined to validate the simplified revised Geneva score. We constructed the simplified CDR by attributing 1 point to each item of the original CDR and compared the diagnostic accuracy of the 2 versions by a receiver operating characteristic curve analysis. We also assessed the clinical utility of the simplified CDR by evaluating the safety of ruling out PE on the basis of the combination of either a low-intermediate clinical probability (using a 3-level scheme) or a "PE unlikely" assessment (using a dichotomized rule) with a normal result on a highly sensitive D-dimer test. RESULTS: The complete study population had an overall prevalence of venous thromboembolism of 23%. The diagnostic accuracy between the 2 CDRs did not differ (area under the curve for the revised Geneva score was 0.75 [95% confidence interval, 0.71-0.78] vs 0.74 [0.70-0.77] for the simplified revised Geneva score). During 3 months of follow-up, no patient with a combination of either a low (0%; 95% confidence interval, 0.0%-1.7%) or intermediate (0%; 0.0%-2.8%) clinical probability, or a "PE unlikely" assessment (0%; 0.0%-1.2%) with the simplified score and a normal result of a D-dimer test was diagnosed as having venous thromboembolism. CONCLUSION: This study suggests that simplification of the revised Geneva score does not lead to a decrease in diagnostic accuracy and clinical utility, which should be confirmed in a prospective study

Redefining clinical venous thromboembolism phenotypes: a novel approach using latent class analysis

Background - Patients with venous thromboembolism (VTE) are commonly classified by the presence or absence of provoking factors at the time of VTE to guide treatment decisions. This approach may not capture the heterogeneity of the disease and its prognosis. Objectives - To evaluate clinically important novel phenotypic clusters among patients with VTE without cancer and to explore their association with anticoagulant treatment and clinical outcomes. Methods - Latent class analysis was performed with 18 baseline clinical variables in 3062 adult patients with VTE without active cancer participating in PREFER in VTE, a noninterventional disease registry. The derived latent classes were externally validated in a post hoc analysis of Hokusai-VTE (n = 6593), a randomized trial comparing edoxaban with warfarin. The associations between cluster membership and anticoagulant treatment, recurrent VTE, bleeding, and mortality after initial treatment were studied. Results - The following 5 clusters were identified: young men cluster (n = 1126, 37%), young women cluster (n = 215, 7%), older people cluster (n = 1106, 36%), comorbidity cluster (n = 447, 15%), and history of venous thromboembolism cluster (n = 168, 5%). Patient characteristics varied by age, sex, medical history, and treatment patterns. Consistent clusters were evident on external validation. In Cox proportional hazard models, recurrence risk was lower in the young women cluster (hazard ratio [HR], 0.27; 95% CI, 0.12-0.61) compared with the comorbidity cluster, after adjusting for extended anticoagulation. The risk of bleeding was lower in young men, young women, and older people clusters (HR, 0.50; 95% CI, 0.38-0.66; HR, 0.23; 95% CI, 0.11-0.46; and HR, 0.55; 95% CI 0.41-0.73, respectively). Conclusion - The heterogeneity of VTE cases extends beyond the distinction between provoked and unprovoked VTE

Determinants of the Quality of Warfarin Control after Venous Thromboembolism and Validation of the SAMe-TT2-R2 Score: An Analysis of Hokusai-VTE

BACKGROUND:  Time in therapeutic range (TTR) measures the quality of vitamin K antagonist (VKA) anticoagulation. In patients with atrial fibrillation, the dichotomized SAMe-TT2-R2 score (≥2 vs. < 2 points) can predict if adequate TTR is unlikely to be achieved. AIMS:  We validated the SAMe-TT2-R2 score in patients with venous thromboembolism (VTE) randomized to the warfarin arm of the Hokusai-VTE trial. PATIENTS AND METHODS:  A total of 3,874 patients were included in the primary analysis (day 31-180 from randomization). The efficacy and safety outcomes were symptomatic recurrent VTE and major or clinically relevant non-major bleeding. RESULTS:  The rates of recurrent VTE and bleeding events were higher in patients with a TTR below the median (< 66% vs. ≥66%) resulting in an absolute risk difference (ARD) of +0.5% (95% confidence interval: 0%, +1.1%) and +2.2% (0.9%, +3.5%), respectively. Patients with high SAMe-TT2-R2 score were 76% of total and had lower median TTR (64.7% vs. 70.7%). The SAMe-TT2-R2 score exhibited low negative (0.59) and positive (0.52) predictive value (TTR threshold 66%), and poor discrimination (c-statistic, 0.58). ARD between patients with high and low score was 0% (-0.6%, +0.7%) for recurrence and +1.3% (-0.1%, +2.7%) for bleeding. Results were confirmed in sensitivity analyses focusing on the whole study period (day 1-365). CONCLUSION:  In VTE patients, the SAMe-TT2-R2 score showed unsatisfactory discrimination and predictive value for individual TTR and did not correlate well with clinical outcomes. The choice of starting a patient on VKA cannot be based on this parameter and its routine use after VTE may not translate into clinical usefulness.status: publishe