Publications by authors named "Frederikus A Klok"

207 Publications

Therapeutic anticoagulation for splanchnic vein thrombosis in acute pancreatitis: A systematic review and meta-analysis.

Pancreatology 2021 Dec 22. Epub 2021 Dec 22.

Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Objectives: The optimal management of patients with acute pancreatitis (AP) and splanchnic vein thrombosis (SVT) remains unknown. This systematic review and meta-analysis aimed to see if therapeutic anticoagulation (AC) improves outcomes in patients with AP and SVT.

Methods: A systematic review was performed according to PRISMA guidelines. Main outcomes were recanalization, recurrent venous thromboembolism, development of varices, collaterals or cavernoma, haemorrhage and mortality. Meta-analysis were performed with the Mantel-Haenszel random effect models.

Results: Seven retrospective cohort studies (3495 patients) were included. SVT occurred in 233 (7%) patients and involved most frequently the splenic vein (44%). Therapeutic AC was administered to 109 (47%) patients, most frequently to those with triple vessel thrombosis (72%) and least to those with isolated splenic vein (22%) or superior mesenteric vein thrombosis (0%). Most studies administered (low molecular weight) heparin followed by warfarin (duration ranged between 1.5 and 12 months). This meta-analysis showed an absolute risk difference of 9% (95% confidence interval [CI] = -11-28%) for recanalization, -3% (95% CI = -19-12%) for the development of varices, collaterals or cavernoma, 3% (95% CI = -6-12%) for haemorrhage and 2% (95% CI = -8-12%) for mortality.

Conclusions: Based on the currently available data, it remains unclear if therapeutic anticoagulation provides benefit to acute pancreatitis patients with splanchnic vein thrombosis. These results are based on low quality data underlining the need for further higher quality studies.
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http://dx.doi.org/10.1016/j.pan.2021.12.008DOI Listing
December 2021

Association between myocardial fibrosis, as assessed with cardiac magnetic resonance T1 mapping, and persistent dyspnea after pulmonary embolism.

Int J Cardiol Heart Vasc 2022 Feb 28;38:100935. Epub 2021 Dec 28.

Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.

Background: Persistent dyspnea is a common symptom after pulmonary embolism (PE). However, the pathophysiology of persistent dyspnea is not fully clarified. This study aimed to explore possible associations between diffuse myocardial fibrosis, as assessed by cardiac magnetic resonance (CMR) T1 mapping, and persistent dyspnea in patients with a history of PE.

Methods: CMR with T1 mapping and extracellular volume fraction (ECV) calculations were performed after PE in 51 patients with persistent dyspnea and in 50 non-dyspneic patients. Patients with known pulmonary disease, heart disease and CTEPH were excluded.

Results: Native T1 was higher in the interventricular septum in dyspneic patients compared to non-dyspneic patients; difference 13 ms (95% CI: 2-23 ms). ECV was also significantly higher in patients with dyspnea; difference 0.9 percent points (95% CI: 0.04-1.8 pp). There was no difference in native T1 or ECV in the left ventricular lateral wall. Native T1 in the interventricular septum had an adjusted Odds Ratio of 1.18 per 10 ms increase (95% CI: 0.99-1.42) in predicting dyspnea, and an adjusted Odds Ratio of 1.47 per 10 ms increase (95% CI: 1.10-1.96) in predicting Incremental Shuttle Walk Test (ISWT) score < 1020 m.

Conclusion: Septal native T1 and ECV values were higher in patients with dyspnea after PE compared with those who were fully recovered suggesting a possible pathological role of myocardial fibrosis in the development of dyspnea after PE. Further studies are needed to validate our findings and to explore their pathophysiological role and clinical significance.
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http://dx.doi.org/10.1016/j.ijcha.2021.100935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717259PMC
February 2022

Safety and Efficiency of Diagnostic Strategies for Ruling Out Pulmonary Embolism in Clinically Relevant Patient Subgroups : A Systematic Review and Individual-Patient Data Meta-analysis.

Ann Intern Med 2021 Dec 14. Epub 2021 Dec 14.

Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands (M.A.M.S., M.V.H., F.A.K.).

Background: How diagnostic strategies for suspected pulmonary embolism (PE) perform in relevant patient subgroups defined by sex, age, cancer, and previous venous thromboembolism (VTE) is unknown.

Purpose: To evaluate the safety and efficiency of the Wells and revised Geneva scores combined with fixed and adapted D-dimer thresholds, as well as the YEARS algorithm, for ruling out acute PE in these subgroups.

Data Sources: MEDLINE from 1 January 1995 until 1 January 2021.

Study Selection: 16 studies assessing at least 1 diagnostic strategy.

Data Extraction: Individual-patient data from 20 553 patients.

Data Synthesis: Safety was defined as the diagnostic failure rate (the predicted 3-month VTE incidence after exclusion of PE without imaging at baseline). Efficiency was defined as the proportion of individuals classified by the strategy as "PE considered excluded" without imaging tests. Across all strategies, efficiency was highest in patients younger than 40 years (47% to 68%) and lowest in patients aged 80 years or older (6.0% to 23%) or patients with cancer (9.6% to 26%). However, efficiency improved considerably in these subgroups when pretest probability-dependent D-dimer thresholds were applied. Predicted failure rates were highest for strategies with adapted D-dimer thresholds, with failure rates varying between 2% and 4% in the predefined patient subgroups.

Limitations: Between-study differences in scoring predictor items and D-dimer assays, as well as the presence of differential verification bias, in particular for classifying fatal events and subsegmental PE cases, all of which may have led to an overestimation of the predicted failure rates of adapted D-dimer thresholds.

Conclusion: Overall, all strategies showed acceptable safety, with pretest probability-dependent D-dimer thresholds having not only the highest efficiency but also the highest predicted failure rate. From an efficiency perspective, this individual-patient data meta-analysis supports application of adapted D-dimer thresholds.

Primary Funding Source: Dutch Research Council. (PROSPERO: CRD42018089366).
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http://dx.doi.org/10.7326/M21-2625DOI Listing
December 2021

Optimal follow-up after acute pulmonary embolism: a position paper of the European Society of Cardiology Working Group on Pulmonary Circulation and Right Ventricular Function, in collaboration with the European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology, endorsed by the European Respiratory Society.

Eur Heart J 2021 Dec 7. Epub 2021 Dec 7.

Dept. of Internal Medicine and Cardiology Medical University of Warsaw, Lindley St 4, Warsaw 00-005, Poland.

This position paper provides a comprehensive guide for optimal follow-up of patients with acute pulmonary embolism (PE), covering multiple relevant aspects of patient counselling. It serves as a practical guide to treating patients with acute PE complementary to the formal 2019 European Society of Cardiology guidelines developed with the European Respiratory Society. We propose a holistic approach considering the whole spectrum of serious adverse events that patients with acute PE may encounter on the short and long run. We underline the relevance of assessment of modifiable risk factors for bleeding, of acquired thrombophilia and limited cancer screening (unprovoked PE) as well as a dedicated surveillance for the potential development of chronic thromboembolic pulmonary hypertension as part of routine practice; routine testing for genetic thrombophilia should be avoided. We advocate the use of outcome measures for functional outcome and quality of life to quantify the impact of the PE diagnosis and identify patients with the post-PE syndrome early. Counselling patients on maintaining a healthy lifestyle mitigates the risk of the post-PE syndrome and improves cardiovascular prognosis. Therefore, we consider it important to discuss when and how to resume sporting activities soon after diagnosing PE. Additional patient-relevant topics that require Focused counselling are travel and birth control.
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http://dx.doi.org/10.1093/eurheartj/ehab816DOI Listing
December 2021

Splanchnic vein thrombosis-related mortality in the Veneto region (Italy), 2008-2019: Retrospective analysis of epidemiological data.

Thromb Res 2022 Jan 22;209:41-46. Epub 2021 Nov 22.

Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; Department of Angiology, University Hospital Zurich, Zurich, Switzerland. Electronic address:

Background: Splanchnic vein thrombosis (SVT) is an uncommon manifestation of venous thromboembolism. Epidemiological data on SVT-related mortality rate is not available to date.

Methods: We investigated time trends in SVT-related mortality rate, 2008-2019, in Veneto, an Italian high-income region of approximatively 5,000,000 inhabitants. SVT-related deaths were identified by the following ICD-10 codes: I81 (portal vein thrombosis), K75.1 (phlebitis of portal vein), K76.3 (liver infarction), K76.5 (hepatic veno-occlusive disease) or I82.0 (Budd-Chiari syndrome).

Results: During the study period, a total of 557,932 deaths were recorded. SVT was reported in 823 cases; 776 (94%) consisted of portal vein thrombosis. The age-standardized SVT-related mortality rate varied from 1.47 (year 2008) to 1.52 (year 2019) per 100,000 person-years. An increase in the cause-specific annual mortality rate was observed in women (0.56 in 2008 to 1.04 per 100,000 person-years in 2019; average annual percent change +5.7%, 95%CI +3.1; +8.3%). In men, the cause-specific mortality rate moved from 2.53 in 2008 to 2.03 per 100,000 person-years in 2019 (average annual percent change -1.2%, 95%CI -4.0; +1.6%). After conditioning for age and sex, the odds of having a concomitant liver disease were higher for SVT-related deaths (OR 31.6; 95%CI 17.1-37.0) compared with non-SVT-related deaths. This also applies to gastrointestinal cancers (OR 1.28; 95%CI 1.07-1.55), although to a lesser extent.

Conclusions: We report first epidemiological estimates of SVT-related mortality in a Western country. These values will serve as a reference to weight novel potential factors associated with SVT-related death and interpret them from an epidemiological perspective.
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http://dx.doi.org/10.1016/j.thromres.2021.11.005DOI Listing
January 2022

Prediction of chronic thromboembolic pulmonary hypertension with standardised evaluation of initial computed tomography pulmonary angiography performed for suspected acute pulmonary embolism.

Eur Radiol 2021 Dec 2. Epub 2021 Dec 2.

Department of Thrombosis and Hemostasis, Leiden University Medical Center, LUMC, (C7Q-14), Albinusdreef 2, Postbus 9600, 2300 RC, Leiden, The Netherlands.

Objectives: Closer reading of computed tomography pulmonary angiography (CTPA) scans of patients presenting with acute pulmonary embolism (PE) may identify those at high risk of developing chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to validate the predictive value of six radiological predictors that were previously proposed.

Methods: Three hundred forty-one patients with acute PE were prospectively followed for development of CTEPH in six European hospitals. Index CTPAs were analysed post hoc by expert chest radiologists blinded to the final diagnosis. The accuracy of the predictors using a predefined threshold for 'high risk' (≥ 3 predictors) and the expert overall judgment on the presence of CTEPH were assessed.

Results: CTEPH was confirmed in nine patients (2.6%) during 2-year follow-up. Any sign of chronic thrombi was already present in 74/341 patients (22%) on the index CTPA, which was associated with CTEPH (OR 7.8, 95%CI 1.9-32); 37 patients (11%) had ≥ 3 of 6 radiological predictors, of whom 4 (11%) were diagnosed with CTEPH (sensitivity 44%, 95%CI 14-79; specificity 90%, 95%CI 86-93). Expert judgment raised suspicion of CTEPH in 27 patients, which was confirmed in 8 (30%; sensitivity 89%, 95%CI 52-100; specificity 94%, 95%CI 91-97).

Conclusions: The presence of ≥ 3 of 6 predefined radiological predictors was highly specific for a future CTEPH diagnosis, comparable to overall expert judgment, while the latter was associated with higher sensitivity. Dedicated CTPA reading for signs of CTEPH may therefore help in early detection of CTEPH after PE, although in our cohort this strategy would not have detected all cases.

Key Points: • Three expert chest radiologists re-assessed CTPA scans performed at the moment of acute pulmonary embolism diagnosis and observed a high prevalence of chronic thrombi and signs of pulmonary hypertension. • On these index scans, the presence of ≥ 3 of 6 predefined radiological predictors was highly specific for a future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), comparable to overall expert judgment. • Dedicated CTPA reading for signs of CTEPH may help in early detection of CTEPH after acute pulmonary embolism.
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http://dx.doi.org/10.1007/s00330-021-08364-0DOI Listing
December 2021

A model for estimating the health economic impact of earlier diagnosis of chronic thromboembolic pulmonary hypertension.

ERJ Open Res 2021 Jul 6;7(3). Epub 2021 Sep 6.

Dept of Medicine - Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.

Background: Diagnostic delay of chronic thromboembolic pulmonary hypertension (CTEPH) exceeds 1 year, contributing to higher mortality. Health economic consequences of late CTEPH diagnosis are unknown. We aimed to develop a model for quantifying the impact of diagnosing CTEPH earlier on survival, quality-adjusted life-years (QALYs) and healthcare costs.

Material And Methods: A Markov model was developed to estimate lifelong outcomes, depending on the degree of delay. Data on survival and quality of life were obtained from published literature. Hospital costs were assessed from patient records (n=498) at the Amsterdam UMC - VUmc, which is a Dutch CTEPH referral center. Medication costs were based on a mix of standard medication regimens.

Results: For 63-year-old CTEPH patients with a 14-month diagnostic delay of CTEPH (median age and delay of patients in the European CTEPH Registry), lifelong healthcare costs were estimated at EUR 117 100 for a mix of treatment options. In a hypothetical scenario of maximal reduction of current delay, improved survival was estimated at a gain of 3.01 life-years and 2.04 QALYs. The associated cost increase was EUR 44 654, of which 87% was due to prolonged medication use. This accounts for an incremental cost-utility ratio of EUR 21 900/QALY.

Conclusion: Our constructed model based on the Dutch healthcare setting demonstrates a substantial health gain when CTEPH is diagnosed earlier. According to Dutch health economic standards, additional costs remain below the deemed acceptable limit of EUR 50 000/QALY for the particular disease burden. This model can be used for evaluating cost-effectiveness of diagnostic strategies aimed at reducing the diagnostic delay.
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http://dx.doi.org/10.1183/23120541.00719-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8628742PMC
July 2021

Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation : A Multicenter Prospective Cohort Study.

Ann Intern Med 2021 Nov 23. Epub 2021 Nov 23.

Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (A.P., P.P., P.W., M.C.).

Background: The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown.

Objective: To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation.

Design: Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818).

Setting: Eighteen sites between February 2011 and February 2021.

Patients: Patients with isolated subsegmental pulmonary embolism.

Intervention: At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy.

Measurements: The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period.

Results: Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism.

Limitation: The study was restricted to patients with low-risk subsegmental pulmonary embolism.

Conclusion: Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism.

Primary Funding Source: Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.
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http://dx.doi.org/10.7326/M21-2981DOI Listing
November 2021

Vaccine-induced immune thrombotic thrombocytopenia.

Lancet Haematol 2022 Jan 11;9(1):e73-e80. Epub 2021 Nov 11.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK; Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK.

In response to the COVID-19 pandemic, vaccines for SARS-CoV-2 were developed, tested, and introduced at a remarkable speed. Although the vaccine introduction had a major impact on the evolution of COVID-19, some potential rare side-effects of the vaccines were observed. Within a short period, three scientific groups from Norway, Germany, and the UK reported cerebral venous sinus thrombosis with thrombocytopenia and anti-platelet factor 4 (anti-PF4) antibodies in individuals following AstraZeneca-Oxford vaccination and named this new syndrome vaccine-induced immune thrombotic thrombocytopenia (VITT). This syndrome was subsequently reported in individuals who received Johnson & Johnson vaccination. In this Viewpoint, we discuss the epidemiology, pathophysiology, and optimal diagnostic and therapeutic management of VITT. Presentation of an individual with possible VITT should raise prompt testing for anti-PF4 antibodies and initiation of treatment targeting autoimmune processes with intravenous immunoglobulin and prothrombotic processes with non-heparin anticoagulation.
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http://dx.doi.org/10.1016/S2352-3026(21)00306-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585488PMC
January 2022

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on post-discharge thromboprophylaxis.

Blood Adv 2021 Nov 2. Epub 2021 Nov 2.

American University of Beirut, Lebanon.

Background: COVID-19 related acute illness is associated with an increased risk of venous thromboembolism (VTE).

Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19 who do not have confirmed or suspected VTE.

Methods: ASH formed a multidisciplinary guideline panel, including three patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including performing systematic evidence reviews (up to March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment.

Results: The panel agreed on one additional recommendation. The panel issued a conditional recommendation against the use of outpatient anticoagulant prophylaxis in patients with COVID-19 being discharged from the hospital who do not have suspected or confirmed VTE or another indication for anticoagulation.

Conclusions: This recommendation was based on very low certainty in the evidence, underscoring the need for high-quality, randomized controlled trials assessing the role of post-discharge thromboprophylaxis. Other key research priorities include better evidence on assessing risk of thrombosis and bleeding outcomes in patients with COVID-19 after hospital discharge.
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http://dx.doi.org/10.1182/bloodadvances.2021005945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566097PMC
November 2021

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

Thromb Haemost 2021 Sep 20. Epub 2021 Sep 20.

Department of Acute Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1055/s-0041-1735251DOI Listing
September 2021

Ruling out Pulmonary Embolism in Patients with (Suspected) COVID-19-A Prospective Cohort Study.

TH Open 2021 Jul 15;5(3):e387-e399. Epub 2021 Sep 15.

Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, South-Holland, The Netherlands.

 Diagnostic strategies for suspected pulmonary embolism (PE) have not been prospectively evaluated in COVID-19 patients.  Prospective, multicenter, outcome study in 707 patients with both (suspected) COVID-19 and suspected PE in 14 hospitals. Patients on chronic anticoagulant therapy were excluded. Informed consent was obtained by opt-out approach. Patients were managed by validated diagnostic strategies for suspected PE. We evaluated the safety (3-month failure rate) and efficiency (number of computed tomography pulmonary angiographies [CTPAs] avoided) of the applied strategies.  Overall PE prevalence was 28%. YEARS was applied in 36%, Wells rule in 4.2%, and "CTPA only" in 52%; 7.4% was not tested because of hemodynamic or respiratory instability. Within YEARS, PE was considered excluded without CTPA in 29%, of which one patient developed nonfatal PE during follow-up (failure rate 1.4%, 95% CI 0.04-7.8). One-hundred seventeen patients (46%) managed according to YEARS had a negative CTPA, of whom 10 were diagnosed with nonfatal venous thromboembolism (VTE) during follow-up (failure rate 8.8%, 95% CI 4.3-16). In patients managed by CTPA only, 66% had an initial negative CTPA, of whom eight patients were diagnosed with a nonfatal VTE during follow-up (failure rate 3.6%, 95% CI 1.6-7.0).  Our results underline the applicability of YEARS in (suspected) COVID-19 patients with suspected PE. CTPA could be avoided in 29% of patients managed by YEARS, with a low failure rate. The failure rate after a negative CTPA, used as a sole test or within YEARS, was non-negligible and reflects the high thrombotic risk in these patients, warranting ongoing vigilance.
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http://dx.doi.org/10.1055/s-0041-1735155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443402PMC
July 2021

Extended Anticoagulant Treatment with Full- or Reduced-Dose Apixaban in Patients with Cancer-Associated Venous Thromboembolism: Rationale and Design of the API-CAT Study.

Thromb Haemost 2021 Sep 17. Epub 2021 Sep 17.

INNOVTE-FCRIN, Saint-Etienne, France.

Cancer-associated thrombosis (CT) is associated with a high risk of recurrent venous thromboembolic (VTE) events that require extended anticoagulation in patients with active cancer, putting them at risk of bleeding. The aim of the API-CAT study (NCT03692065) is to assess whether a reduced-dose regimen of apixaban (2.5 mg twice daily [bid]) is noninferior to a full-dose regimen of apixaban (5 mg bid) for the prevention of recurrent VTE in patients with active cancer who have completed ≥6 months of anticoagulant therapy for a documented index event of proximal deep-vein thrombosis and/or pulmonary embolism. API-CAT is an international, randomized, parallel-group, double-blind, noninferiority trial with blinded adjudication of outcome events. Consecutive patients are randomized to receive apixaban 2.5 or 5 mg bid for 12 months. The primary efficacy outcome is a composite of recurrent symptomatic or incidental VTE during the treatment period. The principal safety endpoint is clinically relevant bleeding, defined as a composite of major bleeding or nonmajor clinically relevant bleeding. Assuming a 12-month incidence of the primary outcome of 4% with apixaban and an upper limit of the two-sided 95% confidence interval of the hazard ratio <2.0, 1,722 patients will be randomized, assuming an up to 10% loss in total patient-years (β = 80%; α one-sided = 0.025). This trial has the potential to demonstrate that a regimen of extended treatment for patients with CT beyond an initial 6 months, with a reduced apixaban dose, has an acceptable risk of recurrent VTE recurrence and decreases the risk of bleeding.
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http://dx.doi.org/10.1055/a-1647-9896DOI Listing
September 2021

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: May 2021 update on the use of intermediate-intensity anticoagulation in critically ill patients.

Blood Adv 2021 10;5(20):3951-3959

Michael G. DeGroote Cochrane Canada, McGRADE Centre, Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

Background: COVID-19-related critical illness is associated with an increased risk of venous thromboembolism (VTE).

Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19-related critical illness who do not have confirmed or suspected VTE.

Methods: ASH formed a multidisciplinary guideline panel that included 3 patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process by performing systematic evidence reviews (up to 5 March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update on guidelines published in February 2021.

Results: The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation in favor of prophylactic-intensity over intermediate-intensity anticoagulation in patients with COVID-19-related critical illness who do not have confirmed or suspected VTE.

Conclusions: This recommendation was based on low certainty in the evidence, which underscores the need for additional high-quality, randomized, controlled trials comparing different intensities of anticoagulation in critically ill patients. Other key research priorities include better evidence regarding predictors of thrombosis and bleeding risk in critically ill patients with COVID-19 and the impact of nonanticoagulant therapies (eg, antiviral agents, corticosteroids) on thrombotic risk.
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http://dx.doi.org/10.1182/bloodadvances.2021005493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416320PMC
October 2021

Chronic thromboembolic pulmonary hypertension anno 2021.

Curr Opin Cardiol 2021 11;36(6):711-719

Department of Medicine - Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.

Purpose Of Review: In the past decades, the diagnostic and therapeutic management of chronic thromboembolic pulmonary hypertension (CTEPH) has been revolutionized.

Recent Findings: Advances in epidemiological knowledge and follow-up studies of pulmonary embolism patients have provided more insight in the incidence and prevalence. Improved diagnostic imaging techniques allow accurate assessment of the location and extend of the thromboembolic burden in the pulmonary artery tree, which is important for the determination of the optimal treatment strategy. Next to the pulmonary endarterectomy, the newly introduced technique percutaneous pulmonary balloon angioplasty and/or P(A)H-targeted medical therapy has been shown to be beneficial in selected patients with CTEPH and might also be of importance in patients with chronic thromboembolic pulmonary vascular disease.

Summary: In this era of a comprehensive approach to CTEPH with different treatment modalities, a multidisciplinary approach guides management decisions leading to optimal treatment and follow-up of patients with CTEPH.
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http://dx.doi.org/10.1097/HCO.0000000000000907DOI Listing
November 2021

Evaluation and management of patients with chronic thromboembolic pulmonary hypertension - consensus statement from the ISHLT.

J Heart Lung Transplant 2021 11 3;40(11):1301-1326. Epub 2021 Aug 3.

Pulmonary Hypertension and CTEPH Research Program, Temple Heart and Vascular Institute, Temple University, Lewis Katz School of Medicine, Philadelphia, Pennsylvania.

ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence.
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http://dx.doi.org/10.1016/j.healun.2021.07.020DOI Listing
November 2021

Efficacy and safety of a 12-week outpatient pulmonary rehabilitation program in Post-PE Syndrome.

Thromb Res 2021 Oct 17;206:66-75. Epub 2021 Aug 17.

Department of Medicine - Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background: The Post-Pulmonary Embolism Syndrome (PPES) comprises heterogeneous entities, including chronic thromboembolic disease with/without pulmonary hypertension (CTEPH/CTEPD), and deconditioning.

Objectives: To assess underlying physiological determinants of PPES, and efficacy and safety of rehabilitation training in these patients.

Methods: 56 consecutive PE patients with persistent dyspnea and/or functional limitations despite ≥3 months of anticoagulation underwent standardized diagnostic work-up including exercise testing as part of routine practice. All diagnostic (imaging and cardiopulmonary function) tests were interpreted by a core group of experienced clinicians. A subgroup of patients without CTEPH or other treatable conditions was referred for a 12-week personalized rehabilitation program, studying changes in physical condition and patient-reported outcome measures.

Results: Persistent vascular occlusions were observed in 21/56 patients (38%) and CTEPH was confirmed in ten (18%). Regarding those without CTEPH, impaired cardiopulmonary responses were evident in 18/39 patients with available CPET data (46%), unrelated to chronic thrombi. Rehabilitation was completed by 27 patients after excluding 29 (patients with CTEPH or treatable comorbidities, refusal, ineligibility, or training elsewhere). Training intensity, PE-specific quality of life (PEmb-QoL) and fatigue (CIS) improved with a median difference of 20 W (p = 0.001), 3.9 points (p < 0.001) and 16 points (p = 0.003), respectively. Functional status (Post-VTE Functional Status Scale) improved ≥1 grade in 18 (67%) patients, and declined in one (3.7%).

Conclusions: Our findings suggest that abnormal cardiopulmonary responses to exercise are common in patients with PPES and are not limited to those with chronic thrombi. Offering pulmonary rehabilitation to patients not treated otherwise seems safe and promising.
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http://dx.doi.org/10.1016/j.thromres.2021.08.012DOI Listing
October 2021

Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial.

Lancet Haematol 2021 Sep 4;8(9):e627-e636. Epub 2021 Aug 4.

Internal and Subintensive Medicine Department, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.

Background: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe.

Methods: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555).

Findings: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran.

Interpretation: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation.

Funding: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim.
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http://dx.doi.org/10.1016/S2352-3026(21)00203-9DOI Listing
September 2021

Triaging acute pulmonary embolism for home treatment by Hestia or simplified PESI criteria: the HOME-PE randomized trial.

Eur Heart J 2021 08;42(33):3146-3157

F-CRIN, INNOVTE, Saint-Etienne, France.

Aims: The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment.

Methods And Results: Normotensive patients with PE of 26 hospitals from France, Belgium, the Netherlands, and Switzerland were randomized to either triaging with Hestia or sPESI. They were designated for home treatment if the triaging tool was negative and if the physician-in-charge, taking into account the patient's opinion, did not consider that hospitalization was required. The main outcomes were the 30-day composite of recurrent venous thrombo-embolism, major bleeding or all-cause death (non-inferiority analysis with 2.5% absolute risk difference as margin), and the rate of patients discharged home within 24 h after randomization (NCT02811237). From January 2017 through July 2019, 1975 patients were included. In the per-protocol population, the primary outcome occurred in 3.82% (34/891) in the Hestia arm and 3.57% (32/896) in the sPESI arm (P = 0.004 for non-inferiority). In the intention-to-treat population, 38.4% of the Hestia patients (378/984) were treated at home vs. 36.6% (361/986) of the sPESI patients (P = 0.41 for superiority), with a 30-day composite outcome rate of 1.33% (5/375) and 1.11% (4/359), respectively. No recurrent or fatal PE occurred in either home treatment arm.

Conclusions: For triaging PE patients, the strategy based on the Hestia rule and the strategy based on sPESI had similar safety and effectiveness. With either tool complemented by the overruling of the physician-in-charge, more than a third of patients were treated at home with a low incidence of complications.
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http://dx.doi.org/10.1093/eurheartj/ehab373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408662PMC
August 2021

Identification of chronic thromboembolic pulmonary hypertension on CTPAs performed for diagnosing acute pulmonary embolism depending on level of expertise.

Eur J Intern Med 2021 11 20;93:64-70. Epub 2021 Jul 20.

Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.

Background: Expert reading often reveals radiological signs of chronic thromboembolic pulmonary hypertension (CTEPH) or chronic PE on computed tomography pulmonary angiography (CTPA) performed at the time of acute pulmonary embolism (PE) presentation preceding CTEPH. Little is known about the accuracy and reproducibility of CTPA reading by radiologists in training in this setting.

Objectives: To evaluate 1) whether signs of CTEPH or chronic PE are routinely reported on CTPA for suspected PE; and 2) whether CTEPH-non-expert readers achieve comparable predictive accuracy to CTEPH-expert radiologists after dedicated instruction.

Methods: Original reports of CTPAs demonstrating acute PE in 50 patients whom ultimately developed CTEPH, and those of 50 PE who did not, were screened for documented signs of CTEPH. All scans were re-assessed by three CTEPH-expert readers and two CTEPH-non-expert readers (blinded and independently) for predefined signs and overall presence of CTEPH.

Results: Signs of chronic PE were mentioned in the original reports of 14/50 cases (28%), while CTEPH-expert radiologists had recognized 44/50 (88%). Using a standardized definition (≥3 predefined radiological signs), moderate-to-good agreement was reached between CTEPH-non-expert readers and the experts' consensus (k-statistics 0.46; 0.61) at slightly lower sensitivities. The CTEPH-non-expert readers had moderate agreement on the presence of CTEPH (κ-statistic 0.38), but both correctly identified most cases (80% and 88%, respectively).

Conclusions: Concomitant signs of CTEPH were poorly documented in daily practice, while most CTEPH patients were identified by CTEPH-non-expert readers after dedicated instruction. These findings underline the feasibility of achieving earlier CTEPH diagnosis by assessing CTPAs more attentively.
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http://dx.doi.org/10.1016/j.ejim.2021.07.001DOI Listing
November 2021

Global reporting of pulmonary embolism-related deaths in the World Health Organization mortality database: Vital registration data from 123 countries.

Res Pract Thromb Haemost 2021 Jul 15;5(5):e12520. Epub 2021 Jun 15.

Center for Thrombosis and Hemostasis University Medical Center Mainz Mainz Germany.

Introduction: Pulmonary embolism (PE) has not been accounted for as a cause of death contributing to cause-specific mortality in global reports.

Methods: We analyzed global PE-related mortality by focusing on the latest year available for each member state in the World Health Organization (WHO) mortality database, which provides age-sex-specific aggregated mortality data transmitted by national authorities for each underlying cause of death. PE-related deaths were defined by International Classification of Diseases, Tenth Revision codes for acute PE or nonfatal manifestations of venous thromboembolism (VTE). The 2001 WHO standard population served for standardization.

Results: We obtained data from 123 countries covering a total population of 2 602 561 422. Overall, 50 (40.6%) were European, 39 (31.7%) American, 13 (10.6%) Eastern Mediterranean, 13 (10.6%) Western Pacific, 3 (2.4%) Southeast Asian, and 2 (1.6%) African. Of 116 countries classifiable according to population income, 57 (49.1%) were high income, 42 (36.2%) upper-middle income, 14 (12.1%) lower-middle income, and 3 (2.6%) low income. A total of 18 726 382 deaths were recorded, of which 86 930 (0.46%) were attributed to PE. PE-related mortality rate increased with age in most countries. The reporting of PE-related deaths was heterogeneous, with an age-standardized mortality rate ranging from 0 to 24 deaths per 100 000 population-years. Income status only partially explained this heterogeneity.

Conclusions: Reporting of PE-related mortality in official national vital registration was characterized by extreme heterogeneity across countries. These findings mandate enhanced efforts toward systematic and uniform coverage of PE-related mortality and provides a case for full recognition of PE and VTE as a primary cause of death.
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http://dx.doi.org/10.1002/rth2.12520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268665PMC
July 2021

Toward a tailored diagnostic standard for future diagnostic studies in pulmonary embolism: Communication from the SSC of the ISTH.

J Thromb Haemost 2021 07;19(7):1834-1835

Department of Medicine - Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.

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http://dx.doi.org/10.1111/jth.15357DOI Listing
July 2021

Evolution of CT findings after anticoagulant treatment for acute pulmonary embolism in patients with and without an ultimate diagnosis of chronic thromboembolic pulmonary hypertension.

Eur Respir J 2021 12 23;58(6). Epub 2021 Dec 23.

Dept of Radiology and Nuclear Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Introduction: The pulmonary arterial morphology of patients with pulmonary embolism (PE) is diverse and it is unclear how the different vascular lesions evolve after initiation of anticoagulant treatment. A better understanding of the evolution of computed tomography pulmonary angiography (CTPA) findings after the start of anticoagulant treatment may help to better identify those PE patients prone to develop chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess the evolution of various thromboembolic lesions on CTPA over time after the initiation of adequate anticoagulant treatment in individual acute PE patients with and without an ultimate diagnosis of CTEPH.

Methods: We analysed CTPA at diagnosis of acute PE (baseline) and at follow-up in 41 patients with CTEPH and 124 patients without an ultimate diagnosis of CTEPH, all receiving anticoagulant treatment. Central and segmental pulmonary arteries were scored by expert chest radiologists as normal or affected. Lesions were further subclassified as 1) central thrombus, 2) total thrombotic occlusion, 3) mural thrombus, 4) web or 5) tapered pulmonary artery.

Results: Central thrombi resolved after anticoagulant treatment, while mural thrombi and total thrombotic occlusions either resolved or evolved into webs or tapered pulmonary arteries. Only patients with an ultimate diagnosis of CTEPH exhibited webs and tapered pulmonary arteries on the baseline scan. Moreover, such lesions always persisted after follow-up.

Conclusions: Webs and tapered pulmonary arteries at the time of PE diagnosis strongly indicate a state of chronic PE and should raise awareness for possible CTEPH, particularly in patients with persistent dyspnoea after anticoagulant treatment for acute PE.
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http://dx.doi.org/10.1183/13993003.00699-2021DOI Listing
December 2021

D-dimer testing after anticoagulant discontinuation to predict recurrent venous thromboembolism.

Eur J Intern Med 2021 07 26;89:25-26. Epub 2021 May 26.

Center for Thrombosis and Hemostasis, Johannes Gutenberg University, Mainz, Germany; Department of Medicine - Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.

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http://dx.doi.org/10.1016/j.ejim.2021.05.008DOI Listing
July 2021

Prevalence of pulmonary embolism in 127 945 autopsies performed in cancer patients in the United States between 2003 and 2019.

J Thromb Haemost 2021 06;19(6):1591-1593

Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

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http://dx.doi.org/10.1111/jth.15321DOI Listing
June 2021

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

Thromb Haemost 2021 May 26. Epub 2021 May 26.

Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.

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 ( = 181) and 4.3 days for those initially treated in hospital ( = 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.
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http://dx.doi.org/10.1055/a-1518-1847DOI Listing
May 2021

Recovery from COVID-19: a sprint or marathon? 6-month follow-up data from online long COVID-19 support group members.

ERJ Open Res 2021 Apr 24;7(2). Epub 2021 May 24.

Dept of Research and Development, Ciro, Horn, The Netherlands.

Background: It remains unknown whether and to what extent members of online "long COVID" peer support groups remain symptomatic and limited over time. Therefore, we aimed to evaluate symptoms in members of online long COVID peer support groups up to 6 months after the onset of coronavirus disease 2019 (COVID-19)-related symptoms.

Methods: Demographics, symptoms, health status, work productivity, functional status and health-related quality of life were assessed about 3 and 6 months after the onset of COVID-19-related symptoms in members of online long COVID peer support groups.

Results: Data from 239 patients with a confirmed COVID-19 diagnosis (83% women; median (interquartile range) age 50 (39-56) years) were analysed. During the infection, a median (interquartile range) of 15 (11-18) symptoms was reported, which was significantly lower 3 and 6 months later: 6 (4-9) and 6 (3-8), respectively (p<0.05). From 3 to 6 months follow-up, the proportion of patients without symptoms increased from 1.3% to only 5.4% (p<0.001). Patients also reported a significantly improved work productivity (work absenteeism and presenteeism: 73% 52% and 66% 60%, respectively), self-reported good health (9.2% 16.7%), functional status (mean±sd Post-COVID-19 Functional Status scale: 2.4±0.9 2.2±1.0) and health-related quality of life (all p<0.05).

Conclusion: Although patients with confirmed COVID-19, who were all members of online long COVID peer support groups, reported significant improvements in work productivity, functional status and quality of life between 3 and 6 months follow-up, these data clearly highlight the long-term impact of COVID-19, as approximately 6 months after the onset of COVID-19-related symptoms a large proportion still experienced persistent symptoms, a moderate-to-poor health, moderate-to-severe functional limitations, considerable loss in work productivity, and/or an impaired quality of life. Action is needed to improve the management and healthcare of these patients.
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http://dx.doi.org/10.1183/23120541.00141-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012818PMC
April 2021

Detection of upper extremity deep vein thrombosis by magnetic resonance non-contrast thrombus imaging.

J Thromb Haemost 2021 08 16;19(8):1973-1980. Epub 2021 Jun 16.

Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.

Background: Compression ultrasonography (CUS) is the first-line imaging test for diagnosing upper extremity deep vein thrombosis (UEDVT), but often yields inconclusive test results. Contrast venography is still considered the diagnostic standard but is an invasive technique.

Objectives: We aimed to determine the diagnostic accuracy of magnetic resonance noncontrast thrombus imaging (MR-NCTI) for the diagnosis of UEDVT.

Methods: In this international multicenter diagnostic study, we prospectively included patients with clinically suspected UEDVT who were managed according to a diagnostic algorithm that included a clinical decision rule (CDR), D-dimer test, and diagnostic imaging. UEDVT was confirmed by CUS or (computed tomography [CT]) venography. UEDVT was excluded by (1) an unlikely CDR and normal D-dimer, (2) a normal serial CUS or (3) a normal (CT) venography. Within 48 h after the final diagnosis was established, patients underwent MR-NCTI. MR-NCTI images were assessed post hoc by two independent radiologists unaware of the presence or absence of UEDVT. The sensitivity, specificity, and interobserver agreement of MR-NCTI for UEDVT were determined.

Results: Magnetic resonance noncontrast thrombus imaging demonstrated UEDVT in 28 of 30 patients with UEDVT and was normal in all 30 patients where UEDVT was ruled out, yielding a sensitivity of 93% (95% CI 78-99) and specificity of 100% (95% CI 88-100). The interobserver agreement of MR-NCTI had a kappa value of 0.83 (95% CI 0.69-0.97).

Conclusions: Magnetic resonance noncontrast thrombus imaging is an accurate and reproducible method for diagnosing UEDVT. Clinical outcome studies should determine whether MR-NCTI can replace venography as the second-line imaging test in case of inconclusive CUS.
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http://dx.doi.org/10.1111/jth.15394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361740PMC
August 2021

Adherence to direct oral anticoagulant treatment for atrial fibrillation in the Netherlands: A surveillance study.

Pharmacoepidemiol Drug Saf 2021 08 4;30(8):1027-1036. Epub 2021 May 4.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

Background: Adherence to direct oral anticoagulants (DOACs) in patients with atrial fibrillation in every day practice may be less than in clinical trials.

Aims: To assess adherence to DOACs in atrial fibrillation patients in every day practice and identify predictors for non-adherence.

Methods: Individual linked dispensing data of atrial fibrillation patients who used DOACs were obtained from the Foundation for Pharmaceutical Statistics covering the Netherlands between 2012 and 2016. One year adherence to DOAC was calculated for initial DOAC as proportion of days covered (PDC) ≥80% and the association between clinical variables and adherence was assessed using logistic regression. In addition, we measured non-persistence, that is, patients who completely stopped their initial DOAC within 1 year follow-up.

Results: A total of 4797 apixaban-, 20 454 rivaroxaban- and 18 477 dabigatran users were included. The mean age was 69 years (n = 43 910), which was similar for the DOAC types. The overall proportion of patients with PDC ≥80% was 76%, which was highest for apixaban- (87%), followed by dabigatran- (80%) and rivaroxaban (69%) users. Multivariable analyses revealed that age ≤60 years, no concomitant drug use were predictors for non-adherence. Of atrial fibrillation patients who continued treatment, 97% had a PDC ≥80%, compared with only 56% for those who discontinued their DOAC treatment within 1 year.

Conclusions: Non-adherence to DOACs was associated with age ≤60 years and no concomitant drugs use. Non-adherence was higher in patients who later discontinued DOAC treatment. Results of our study support research into interventions to improve adherence.
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http://dx.doi.org/10.1002/pds.5242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360064PMC
August 2021

Sex-specific differences in the presentation, clinical course, and quality of life of patients with acute venous thromboembolism according to baseline risk factors. Insights from the PREFER in VTE.

Eur J Intern Med 2021 06 31;88:43-51. Epub 2021 Mar 31.

Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Clinic of Angiology, University Hospital Zurich, Zurich, Switzerland.

Introduction: Sex and the presence of specific provoking risk factors, along with age, influence the presentation and prognosis of venous thromboembolism (VTE). We investigated the presentation, course and quality of life in women and men with acute VTE classified according to their VTE provoking factors.

Methods: PREFER in VTE is an international, non-interventional registry of patients with a first episode of acute symptomatic VTE. Baseline provoking factors were classified as follows: major transient, minor transient, active cancer, and none identifiable. The primary outcome was recurrent VTE. Quality of life and treatment satisfaction were secondary outcomes.

Results: Of 3,455 patients with acute VTE, 1,623 (47%) were women. The mean age at the time of VTE was 61 (SD 18) in women, 60 (SD 15) in men. The distribution of provoking risk factors was similar between sexes, despite a tendency for higher frequency of minor and major transient risk factors in women, and cancer or unprovoked VTE in men. At 12-month follow-up, VTE recurrence was reported in 74 (6.5%) women and 80 (6.4%) men (absolute risk difference -0.1%, 95% CI -1.9%; +2.1%). In patients with unprovoked VTE, the VTE recurrence rate was 38/612 (6.2%) in women and 53/798 (6.6%) in men (absolute risk difference -0.4, 95% CI -3.0; +2.1%). Multivariable Cox regressions confirmed the absence of sex differences. Quality of life and treatment satisfaction scores one year after VTE were lower in women than in men irrespective of the provoking risk factors (p<0.001 for both scores).

Conclusions: Despite differences in the provoking risk factors for VTE, women and men had a similar rate VTE recurrence at one year. After acute VTE, women had lower quality of life and treatment satisfaction scores.
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http://dx.doi.org/10.1016/j.ejim.2021.03.014DOI Listing
June 2021
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