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-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism.

BACKGROUND: Pulmonary embolism is one of the leading causes of maternal death in the Western world. Because of the low specificity and sensitivity of the d-dimer test, all pregnant women with suspected pulmonary embolism undergo computed tomographic (CT) pulmonary angiography or ventilation-perfusion scanning, both of which involve radiation exposure to the mother and fetus. Whether a pregnancy-adapted algorithm could be used to safely avoid diagnostic imaging in pregnant women with suspected pulmonary embolism is unknown. METHODS: In a prospective study involving pregnant women with suspected pulmonary embolism, we assessed three criteria from the YEARS algorithm (clinical signs of deep-vein thrombosis, hemoptysis, and pulmonary embolism as the most likely diagnosis) and measured the d-dimer level. Pulmonary embolism was ruled out if none of the three criteria were met and the d-dimer level was less than 1000 ng per milliliter or if one or more of the three criteria were met and the d-dimer level was less than 500 ng per milliliter. Adaptation of the YEARS algorithm for pregnant women involved compression ultrasonography for women with symptoms of deep-vein thrombosis; if the results were positive (i.e., a clot was present), CT pulmonary angiography was not performed. All patients in whom pulmonary embolism had not been ruled out underwent CT pulmonary angiography. The primary outcome was the incidence of venous thromboembolism at 3 months. The secondary outcome was the proportion of patients in whom CT pulmonary angiography was not indicated to safely rule out pulmonary embolism. RESULTS: A total of 510 women were screened, of whom 12 (2.4%) were excluded. Pulmonary embolism was diagnosed in 20 patients (4.0%) at baseline. During follow-up, popliteal deep-vein thrombosis was diagnosed in 1 patient (0.21%; 95% confidence interval [CI], 0.04 to 1.2); no patient had pulmonary embolism. CT pulmonary angiography was not indicated, and thus was avoided, in 195 patients (39%; 95% CI, 35 to 44). The efficiency of the algorithm was highest during the first trimester of pregnancy and lowest during the third trimester; CT pulmonary angiography was avoided in 65% of patients who began the study in the first trimester and in 32% who began the study in the third trimester. CONCLUSIONS: Pulmonary embolism was safely ruled out by the pregnancy-adapted YEARS diagnostic algorithm across all trimesters of pregnancy. CT pulmonary angiography was avoided in 32 to 65% of patients. (Funded by Leiden University Medical Center and 17 other participating hospitals; Artemis Netherlands Trial Register number, NL5726.).

Magnetic resonance imaging for diagnosis of recurrent ipsilateral deep vein thrombosis.

The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) is challenging, because persistent intravascular abnormalities after previous DVT often hinder a diagnosis by compression ultrasonography. Magnetic resonance direct thrombus imaging (MRDTI), a technique without intravenous contrast and with a 10-minute acquisition time, has been shown to accurately distinguish acute recurrent DVT from chronic thrombotic remains. We have evaluated the safety of MRDTI as the sole test for excluding recurrent ipsilateral DVT. The Theia Study was a prospective, international, multicenter, diagnostic management study involving patients with clinically suspected acute recurrent ipsilateral DVT. Treatment of the patients was managed according to the result of the MRDTI, performed within 24 hours of study inclusion. The primary outcome was the 3-month incidence of venous thromboembolism (VTE) after a MRDTI negative for DVT. The secondary outcome was the interobserver agreement on the MRDTI readings. An independent committee adjudicated all end points. Three hundred five patients were included. The baseline prevalence of recurrent DVT was 38%; superficial thrombophlebitis was diagnosed in 4.6%. The primary outcome occurred in 2 of 119 (1.7%; 95% confidence interval [CI], 0.20-5.9) patients with MRDTI negative for DVT and thrombophlebitis, who were not treated with any anticoagulant during follow-up; neither of these recurrences was fatal. The incidence of recurrent VTE in all patients with MRDTI negative for DVT was 1.1% (95% CI, 0.13%-3.8%). The agreement between initial local and post hoc central reading of the MRDTI images was excellent (κ statistic, 0.91). The incidence of VTE recurrence after negative MRDTI was low, and MRDTI proved to be a feasible and reproducible diagnostic test. This trial was registered at www.clinicaltrials.gov as #NCT02262052.

The Prognostic Value of Syncope on Mortality in Patients With Pulmonary Embolism: A Systematic Review and Meta-analysis.

STUDY OBJECTIVE: Syncope is a presenting symptom in 10% to 20% of patients with pulmonary embolism. We perform a meta-analysis to clarify the prognostic value of syncope on short-term mortality in pulmonary embolism patients and its association with hemodynamic instability. METHODS: PubMed, EMBASE, and the Cochrane Library were searched up until January 7, 2020. Studies reporting inhospital or 30-day mortality of adults with pulmonary embolism with and without syncope were included. Quality of included studies was evaluated with the Quality in Prognosis Studies tool. Meta-analysis was conducted to derive pooled odds ratios (ORs) and risk differences for the relation of syncope with mortality and hemodynamic instability. To study the influence of hemodynamic instability on the association between syncope and mortality, meta-regression was performed. RESULTS: Search and selection resulted in 26 studies, of which 20 were pooled, involving 9,419 of 335,120 patients (3%) with syncope. Syncope was associated with higher mortality (OR 1.82; 95% confidence interval [CI] 1.14 to 2.90; I2 88%; risk difference 4% [95% CI 1% to 8%]) and higher prevalence of hemodynamic instability (OR 4.36; 95% CI 2.27 to 8.37; I2 93%; risk difference 12% [95% CI 7% to 18%]). OR for mortality in patients with pulmonary embolism with syncope versus without it was higher in the presence of a larger difference in hemodynamic instability between groups (coefficient 0.05; 95% CI 0.01 to 0.09). CONCLUSION: The association between syncope and short-term mortality in patients with pulmonary embolism is explained by a difference in hemodynamic instability. This emphasizes the importance of risk stratification by hemodynamic status in pulmonary embolism patients with and without syncope.

Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study.

BACKGROUND: Validated diagnostic algorithms in patients with suspected pulmonary embolism are often not used correctly or only benefit subgroups of patients, leading to overuse of computed tomography pulmonary angiography (CTPA). The YEARS clinical decision rule that incorporates differential D-dimer cutoff values at presentation, has been developed to be fast, to be compatible with clinical practice, and to reduce the number of CTPA investigations in all age groups. We aimed to prospectively evaluate this novel and simplified diagnostic algorithm for suspected acute pulmonary embolism. METHODS: We did a prospective, multicentre, cohort study in 12 hospitals in the Netherlands, including consecutive patients with suspected pulmonary embolism between Oct 5, 2013, to July 9, 2015. Patients were managed by simultaneous assessment of the YEARS clinical decision rule, consisting of three items (clinical signs of deep vein thrombosis, haemoptysis, and whether pulmonary embolism is the most likely diagnosis), and D-dimer concentrations. In patients without YEARS items and D-dimer less than 1000 ng/mL, or in patients with one or more YEARS items and D-dimer less than 500 ng/mL, pulmonary embolism was considered excluded. All other patients had CTPA. The primary outcome was the number of independently adjudicated events of venous thromboembolism during 3 months of follow-up after pulmonary embolism was excluded, and the secondary outcome was the number of required CTPA compared with the Wells' diagnostic algorithm. For the primary outcome regarding the safety of the diagnostic strategy, we used a per-protocol approach. For the secondary outcome regarding the efficiency of the diagnostic strategy, we used an intention-to-diagnose approach. This trial is registered with the Netherlands Trial Registry, number NTR4193. FINDINGS: 3616 consecutive patients with clinically suspected pulmonary embolism were screened, of whom 151 (4%) were excluded. The remaining 3465 patients were assessed of whom 456 (13%) were diagnosed with pulmonary embolism at baseline. Of the 2946 patients (85%) in whom pulmonary embolism was ruled out at baseline and remained untreated, 18 patients were diagnosed with symptomatic venous thromboembolism during 3-month follow-up (0·61%, 95% CI 0·36-0·96) of whom six had fatal pulmonary embolism (0·20%, 0·07-0·44). CTPA was not indicated in 1651 (48%) patients with the YEARS algorithm compared with 1174 (34%) patients, if Wells' rule and fixed D-dimer threshold of less than 500 ng/mL would have been applied, a difference of 14% (95% CI 12-16). INTERPRETATION: In our study pulmonary embolism was safely excluded by the YEARS diagnostic algorithm in patients with suspected pulmonary embolism. The main advantage of the YEARS algorithm in our patients is the absolute 14% decrease of CTPA examinations in all ages and across several relevant subgroups. FUNDING: This study was supported by unrestricted grants from the participating hospitals.

Imaging for the exclusion of pulmonary embolism in pregnancy.

BACKGROUND: 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. OBJECTIVES: 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. SEARCH METHODS: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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%). AUTHORS' CONCLUSIONS: 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 studies.

Balancing risks of recurrent venous thromboembolism and bleeding with extended anticoagulation: a decision analysis.

Background: A decision to stop or continue anticoagulation after 3 months of anticoagulation for venous thromboembolism (VTE) should be made by weighing individual risks of recurrence and bleeding. Objectives: To determine the optimal ratio of recurrence risk reduction to increase the risk of bleeding in terms of maximizing quality-adjusted life years (QALYs) gained. Methods: Using a microsimulation model, outcomes within 5 years were simulated after assigning extended treatment if absolute recurrence risk reduction outweighed absolute increase in clinically relevant bleeding risk (International Society on Thrombosis and Haemostasis definition), weighted by a certain ratio. Data were simulated based on the Bleeding Risk Study, a prospective cohort including patients after ≥3 months of anticoagulation for unprovoked VTE or provoked VTE with history of VTE. The VTE-PREDICT risk score was used to estimate 5-year risks of recurrent VTE and clinically relevant bleeding. Results: Among 10,000 individuals (mean age, 60.2 years, 36% female), the ratio of 0.90 (95% CI, 0.51-3.40; ie, bleeding is considered 0.90 the severity of recurrent VTE), with 99% of patients assigned extended anticoagulation, was considered optimal and resulted in 93 (95% CI, -23 to 203) additional QALYs compared with the least favorable ratio (5.10, 0% extended anticoagulation). At the optimal ratio, treatment based on VTE-PREDICT yielded 44 (95% CI, -69 to 157) additional QALYs versus standard of care. Conclusion: With the current evidence, the optimal ratio between relevant bleeding risk and absolute recurrence risk reduction remains uncertain. Our results confirm that clinical equipoise exists regarding the decision to stop or continue anticoagulation after initial VTE treatment, emphasizing the importance of shared decision-making.

Predictors of bleeding complications during catHeter-dirEcted thrombolysis for peripheral arterial occlusions (POCHET).

INTRODUCTION: The risk of major bleeding complications in catheter directed thrombolysis (CDT) for acute limb ischemia (ALI) remains high, with reported major bleeding complication rates in up to 1 in every 10 treated patients. Fibrinogen was the only predictive marker used for bleeding complications in CDT, despite the lack of high quality evidence to support this. Therefore, recent international guidelines recommend against the use of fibrinogen during CDT. However, no alternative biomarkers exist to effectively predict CDT-related bleeding complications. The aim of the POCHET biobank is to prospectively assess the rate and etiology of bleeding complications during CDT and to provide a biobank of blood samples to investigate potential novel biomarkers to predict bleeding complications during CDT. METHODS: The POCHET biobank is a multicentre prospective biobank. After informed consent, all consecutive patients with lower extremity ALI eligible for CDT are included. All patients are treated according to a predefined standard operating procedure which is aligned in all participating centres. Baseline and follow-up data are collected. Prior to CDT and subsequently every six hours, venous blood samples are obtained and stored in the biobank for future analyses. The primary outcome is the occurrence of non-access related major bleeding complications, which is assessed by an independent adjudication committee. Secondary outcomes are non-major bleeding complications and other CDT related complications. Proposed biomarkers to be investigated include fibrinogen, to end the debate on its usefulness, anti-plasmin and D-Dimer. DISCUSSION AND CONCLUSION: The POCHET biobank provides contemporary data and outcomes of patients during CDT for ALI, coupled with their blood samples taken prior and during CDT. Thereby, the POCHET biobank is a real world monitor on biomarkers during CDT, supporting a broad spectrum of future research for the identification of patients at high risk for bleeding complications during CDT and to identify new biomarkers to enhance safety in CDT treatment.

Outpatient management of cancer-associated pulmonary embolism: A post-hoc analysis from the HOME-PE trial.

INTRODUCTION: Cancer-related pulmonary embolism (PE) is associated with poor prognosis. Some decision rules identifying patients eligible for home treatment categorize cancer patients at high risk of complications, precluding home treatment. We sought to assess the effectiveness and the safety of outpatient management of patients with low-risk cancer-associated PE. METHODS: In the HOME-PE trial, hemodynamically stable patients with symptomatic PE were randomized to either triaging with Hestia criteria or sPESI score. We analyzed 3 groups of low-risk PE patients: 47 with active cancer treated at home (group 1), 691 without active cancer treated at home (group 2), and 33 with active cancer as the only sPESI criterion qualifying them for hospitalization (group 3). The main outcome was the composite of recurrent venous thromboembolism, major bleeding, and all-cause death within 30 days after randomization. RESULTS: Patients treated at home had composite outcome rates of 4.3 % (2/47) for those with cancer vs. 1.0 % (7/691) for those without (odds ratio (OR) 4.98, 95%CI 1.15-21.49). Patients with cancer had rates of complications of 4.3 % when treated at home vs. 3.0 % (1/33) when hospitalized (OR 1.19, 95%CI 0.15-9.47). In multivariable analysis, active cancer was associated with an increased risk of complications for patients treated at home (OR 7.95; 95%CI 1.48-42.82). For patients with active cancer, home treatment was not associated with the primary outcome (OR 1.19, 95%CI 0.15-9.74). CONCLUSIONS: Among patients treated at home, active cancer was a risk factor for complications, but among patients with active cancer, home treatment was not associated with adverse outcomes.

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 delivery.

The upper extremity postthrombotic syndrome score: an international Delphi consensus study to determine the score's functional disability component.

Background: In upper extremity thrombosis research, the occurrence of upper extremity postthrombotic syndrome (UE-PTS) is commonly used as the main outcome parameter. However, there is currently no reporting standard or a validated method to assess UE-PTS presence and severity. In a recent Delphi study, consensus was reached on a preliminary UE-PTS score, combining 5 symptoms, 3 signs, and the inclusion of a functional disability score. However, no consensus was reached on which functional disability score to be included. Objectives: The aim of the current Delphi consensus study was to determine the specific type of functional disability score to finalize UE-PTS score. Methods: This Delphi project was designed as a three-round study using open text questions, statements with 7-point Likert scales, and multiple-choice questions. The CREDES recommendations for Delphi studies were applied. In this context, a systematic review was conducted before the start of the Delphi rounds to identify the available functional disability scores as available in the literature and present these to the expert panel. Results: Thirty-five of 47 initially invited international experts from multiple disciplines completed all the Delphi rounds. In the second round, consensus was reached on the incorporation of the quick disabilities of the arm, shoulder, and hand (QuickDASH) in the UE-PTS score, rendering the third round obsolete. Conclusion: Consensus was reached that the QuickDASH should be incorporated in the UE-PTS score. The UE-PTS score will need to be validated in a large cohort of patients with upper extremity thrombosis before it can be used in clinical practice and future research.

Thoracic outlet syndrome (TROTS) registry: A study protocol for the primary upper extremity deep venous thrombosis section.

INTRODUCTION: There is a lack of comprehensive and uniform data on primary upper extremity deep venous thrombosis (pUEDVT). pUEDVT includes venous thoracic outlet syndrome related upper extremity deep venous thrombosis (UEDVT) and idiopathic UEDVT. Research on these conditions has been hampered by their rarity, lack of uniform diagnostic criteria, and heterogeneity in therapeutic strategies. To improve current research data collection using input of all various pUEDVT treating medical specialists, we initiated the ThoRacic OuTlet Syndrome (TROTS) registry. The aim of the TROTS registry is to a) collect extensive data on all pUEDVT patients through a predefined protocol, b) give insight in the long term outcome using patient reported outcome measures, c) create guidance in the diagnostic and clinical management of these conditions, and thereby d) help provide content for future research. METHODS AND ANALYSIS: The TROTS registry was designed as an international prospective longitudinal observational registry for data collection on pUEDVT patients. All pUEDVT patients, regardless of treatment received, can be included in the registry after informed consent is obtained. All relevant data regarding the initial presentation, diagnostics, treatment, and follow-up will be collected prospectively in an electronic case report form. In addition, a survey containing general questions, a Health-related Quality of Life questionnaire (EQ-5D-5L), and Functional Disability questionnaire (Quick-DASH) will be sent periodically (at the time of inclusion, one and two years after inclusion, and every five years after inclusion) to the participant. The registry protocol was approved by the Medical Ethical Review Board and registered in the Netherlands Trial Register under Trial-ID NL9680. The data generated by the registry will be used for future research on pUEDVT and published in peer reviewed journals. CONCLUSION: TROTS registry data will be used to further establish the optimal management of pUEDVT and lay the foundation for future research and guidelines.

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.

Noninvasive diagnostic work-up for suspected acute pulmonary embolism during pregnancy: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Few studies evaluated the performance of noninvasive diagnostic strategies for suspected acute pulmonary embolism (PE) in pregnant women. OBJECTIVES: The aim of this study was to establish the safety and efficiency of the Wells rule with fixed and adapted D-dimer threshold, and the YEARS algorithm, combined with compression ultrasonography (CUS), in pregnant women with suspected PE in an individual patient data meta-analysis. METHODS: We performed a systematic review to identify prospective diagnostic management studies in pregnant women with suspected PE. Primary outcomes were safety, defined as the failure rate, ie, the 3-month venous thromboembolism (VTE) incidence after excluding PE without chest imaging, and efficiency, defined as the proportion of patients in whom chest imaging could be avoided. RESULTS: We identified 2 relevant studies, of which individual patient-level data were analyzed in a fixed-effect meta-analysis, totaling 893 pregnant women. The Wells rule with fixed and adapted D-dimer threshold as well as the YEARS algorithm could safely rule out acute PE (failure rate, 0·37%-1·4%), but efficiency improved considerably when applying pretest probability-adapted D-dimer thresholds. The efficiency of bilateral CUS was limited (2·3% overall; number needed to test 43), especially in patients without symptoms of deep-vein thrombosis (efficiency 0·79%; number needed to test 127). CONCLUSION: This study supports the latest guideline recommendations (European Society of Cardiology 2019) to apply pretest probability assessment and D-dimer tests to rule out PE in pregnant women. From an efficiency perspective, the use of a strategy with pretest probability-adapted D-dimer threshold is preferred. The yield of CUS was very limited in patients without concomitant symptoms of deep-vein thrombosis.

Cost-Effectiveness of Performing Reference Ultrasonography in Patients with Deep Vein Thrombosis.

BACKGROUND: The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) with compression ultrasonography (CUS) may be hindered by residual intravascular obstruction after previous DVT. A reference CUS, an additional ultrasound performed at anticoagulant discontinuation, may improve the diagnostic work-up of suspected recurrent ipsilateral DVT by providing baseline images for future comparison. OBJECTIVES: To evaluate the cost-effectiveness of routinely performing reference CUS in DVT patients. METHODS: Patient-level data (n = 96) from a prospective management study (Theia study; NCT02262052) and claims data were used in a decision analytic model to compare 12 scenarios for diagnostic management of suspected recurrent ipsilateral DVT. Estimated health care costs and mortality due to misdiagnosis, recurrent venous thromboembolism, and bleeding during the first year of follow-up after presentation with suspected recurrence were compared. RESULTS: All six scenarios including reference CUS had higher estimated 1-year costs (€1,763-€1,913) than the six without reference CUS (€1,192-€1,474). Costs were higher because reference CUS results often remained unused, as 20% of patients (according to claims data) would return with suspected recurrent DVT. Estimated mortality was comparable in scenarios with (14.8-17.9 per 10,000 patients) and without reference CUS (14.0-18.5 per 10,000). None of the four potentially most desirable scenarios included reference CUS. CONCLUSION: One-year health care costs of diagnostic strategies for suspected recurrent ipsilateral DVT including reference CUS are higher compared to strategies without reference CUS, without mortality benefit. These results can inform policy-makers regarding use of health care resources during follow-up after DVT. From a cost-effectiveness perspective, the findings do not support the routine application of reference CUS.

Deciding on Treatment Duration for Unprovoked Venous Thromboembolism: What is Important to Patients?

BACKGROUND: After 3 months of anticoagulation for unprovoked venous thromboembolism (VTE), a decision must be made to stop or continue indefinitely by weighing risks of recurrence and bleeding through shared decision-making (SDM). Despite the importance of patient involvement, patients' perspectives on treatment duration are understudied. AIM: To describe the knowledge of VTE and anticoagulation, need for education, perception of risks and benefits of extended treatment, and factors influencing patient's preference to stop or continue treatment after unprovoked VTE. METHODS: Semistructured interviews were conducted between May 2019 and August 2020 with adults with unprovoked VTE in one university hospital and one general hospital. Interviews were audio-recorded and transcribed verbatim. Data were analyzed using conventional content analysis. RESULTS: Eighteen patients were interviewed (median age 64, range: 32-83 years). Three major themes were identified: diagnosis and initial treatment, SDM, and perception of treatment. Education, knowledge, coping, and attitude toward health care suffused major themes. The impact of VTE on daily life varied between individuals, as did the preferred extent of SDM. Overall, patients who felt involved and informed were more satisfied with received care, more aware of risks and benefits of treatment, and more likely to be treatment adherent. Generally, patients were more concerned with risk of recurrent VTE than with risk of bleeding during anticoagulation. We identified a multitude of aspects important to patients when deciding to stop or continue anticoagulation. CONCLUSION: Sufficient information and an individualized extent of SDM are of crucial importance for patients when deciding on treatment duration after unprovoked VTE.

Post-thrombotic syndrome after upper extremity deep vein thrombosis: An international Delphi consensus study.

OBJECTIVES: Primary deep vein thrombosis of the upper extremity (UEDVT) is a rare condition but up to 60% of patients may develop post-thrombotic syndrome in the upper extremity (UE-PTS) with significant morbidity and decreased quality of life. However, there is no universally accepted method to diagnose and classify UE-PTS, hampering scientific research on UEDVT treatment. Through this international Delphi consensus study we aimed to determine what a clinical score for diagnosing UE-PTS should entail. METHODS: An online focus group survey among 20 patients treated for UEDVT was performed to provide clinical parameters before the start of a four round electronic Delphi consensus study among 25 international experts. The CREDES recommendations on Conducting and Reporting Delphi Studies were applied. Open text questions, multiple selection questions, and 9-point Likert scales were used. Consensus was set at 70% agreement. RESULTS: After four rounds, agreement was reached on a composite score of five symptoms and three clinical signs, combined with a functional disability score. The signs and symptom will each be scored on a severity scale of 0-3 and the total score expressed as an ordinal variable; no/mild/moderate/or severe PTS. The functional disability portion measures the impact of the signs and symptoms on the functionality of the patient's arm. CONCLUSION: Consensus was reached on a composite score of signs and symptoms of UE-PTS combined with a functional disability score. Clinical validation of the UE-PTS score in a large patient cohort is mandatory to facilitate application in future research.

Estimating Bleeding Risk in Patients with Cancer-Associated Thrombosis: Evaluation of Existing Risk Scores and Development of a New Risk Score.

BACKGROUND: Bleeding risk is highly relevant for treatment decisions in cancer-associated thrombosis (CAT). Several risk scores exist, but have never been validated in patients with CAT and are not recommended for practice. OBJECTIVES: To compare methods of estimating clinically relevant (major and clinically relevant nonmajor) bleeding risk in patients with CAT: (1) existing risk scores for bleeding in venous thromboembolism, (2) pragmatic classification based on cancer type, and (3) new prediction model. METHODS: In a posthoc analysis of the Hokusai VTE Cancer study, a randomized trial comparing edoxaban with dalteparin for treatment of CAT, seven bleeding risk scores were externally validated (ACCP-VTE, HAS-BLED, Hokusai, Kuijer, Martinez, RIETE, and VTE-BLEED). The predictive performance of these scores was compared with a pragmatic classification based on cancer type (gastrointestinal; genitourinary; other) and a newly derived competing risk-adjusted prediction model based on clinical predictors for clinically relevant bleeding within 6 months after CAT diagnosis with nonbleeding-related mortality as the competing event ("CAT-BLEED"). RESULTS: Data of 1,046 patients (149 events) were analyzed. Predictive performance of existing risk scores was poor to moderate (C-statistics: 0.50-0.57; poor calibration). Internal validation of the pragmatic classification and "CAT-BLEED" showed moderate performance (respective C-statistics: 0.61; 95% confidence interval [CI]: 0.56-0.66, and 0.63; 95% CI 0.58-0.68; good calibration). CONCLUSION: Existing risk scores for bleeding perform poorly after CAT. Pragmatic classification based on cancer type provides marginally better estimates of clinically relevant bleeding risk. Further improvement may be achieved with "CAT-BLEED," but this requires external validation in practice-based settings and with other DOACs and its clinical usefulness is yet to be demonstrated.

Home Treatment Compared to Initial Hospitalization in Normotensive Patients with Acute Pulmonary Embolism in the Netherlands: A Cost Analysis.

BACKGROUND: Venous thromboembolism constitutes substantial health care costs amounting to approximately 60 million euros per year in the Netherlands. Compared with initial hospitalization, home treatment of pulmonary embolism (PE) is associated with a cost reduction. An accurate estimation of cost savings per patient treated at home is currently lacking. AIM: The aim of this study was to compare health care utilization and costs during the first 3 months after a PE diagnosis in patients who are treated at home versus those who are initially hospitalized. METHODS: Patient-level data of the YEARS cohort study, including 383 normotensive patients diagnosed with PE, were used to estimate the proportion of patients treated at home, mean hospitalization duration in those who were hospitalized, and rates of PE-related readmissions and complications. To correct for baseline differences within the two groups, regression analyses was performed. The primary outcome was the average total health care costs during a 3-month follow-up period for patients initially treated at home or in hospital. RESULTS: Mean hospitalization duration for the initial treatment was 0.69 days for those treated initially at home (n = 181) and 4.3 days for those initially treated in hospital (n = 202). Total average costs per hospitalized patient were €3,209 and €1,512 per patient treated at home. The adjusted mean difference was €1,483 (95% confidence interval: €1,181-1,784). CONCLUSION: Home treatment of hemodynamically stable patients with acute PE was associated with an estimated net cost reduction of €1,483 per patient. This difference underlines the advantage of triage-based home treatment of these patients.