Publications by authors named "Saskia Middeldorp"

258 Publications

Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

JAMA 2022 04;327(13):1247-1259

University of Pittsburgh, Pittsburgh, Pennsylvania.

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain.

Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19.

Design, Setting, And Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021).

Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis.

Main Outcomes And Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions.

Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm).

Conclusions And Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days.

Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.
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http://dx.doi.org/10.1001/jama.2022.2910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8941448PMC
April 2022

Effect of polypharmacy on bleeding with rivaroxaban versus vitamin K antagonist for treatment of venous thromboembolism.

J Thromb Haemost 2022 Mar 7. Epub 2022 Mar 7.

Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: Polypharmacy, including use of inhibitors of CYP3A4 and P-glycoprotein (P-gp), is common in patients with venous thromboembolism (VTE) and is associated with increased bleeding.

Methods: In 8246 patients included in the EINSTEIN-VTE studies for acute VTE, we evaluated the effect of polypharmacy on bleeding and on the relative differences between rivaroxaban and enoxaparin/vitamin K antagonist (VKA). We assessed the incidence of clinically relevant bleeding (major and clinically relevant nonmajor bleeding) by number of comedications (none, 1-3, ≥4) at baseline, and by use of CYP3A4 and/or P-gp inhibitors. Interaction between rivaroxaban versus enoxaparin/VKA and comedication was assessed by Cox regression analysis with p estimates.

Results: With increasing number of comedications, the incidence of clinically relevant bleeding rose from 5.7% to 13.3% in rivaroxaban recipients and from 9.1% to 11.1% in enoxaparin/VKA recipients. Whereas rivaroxaban was associated with a reduced bleeding risk compared with enoxaparin/VKA in patients without comedication (hazard ratio [HR] 0.6, 95% confidence interval [CI] 0.4-0.9), the risk was similar in patients with ≥4 comedications (HR 1.2, 95% CI 0.97-1.5, p .002). Use of CYP3A4 and/or P-gp inhibitors was associated with a doubled bleeding risk compared with no use, without a difference between rivaroxaban and enoxaparin/VKA.

Conclusion: We conclude that fixed-dose rivaroxaban as compared with enoxaparin followed by dose-adjusted VKA is not associated with an increased bleeding risk in patients with VTE administered polypharmacy in general and CYP3A4 and/or P-gp inhibitors specifically. This implies that the observed increased bleeding risks with polypharmacy and use of CYP3A4 and/or P-gp inhibitors are likely explained by comorbidities and frailty, and not by pharmacokinetic interactions.
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http://dx.doi.org/10.1111/jth.15692DOI Listing
March 2022

Women's representation in venous thromboembolism randomized trials and registries: The illustrative example of direct oral anticoagulants for acute treatment.

Contemp Clin Trials 2022 04 21;115:106714. Epub 2022 Feb 21.

Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Thrombosis Research Group, Brigham and Women's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.cct.2022.106714DOI Listing
April 2022

Thrombophilia, Thrombosis and Thromboprophylaxis in Pregnancy: For What and in Whom?

Hamostaseologie 2022 Feb 23;42(1):54-64. Epub 2022 Feb 23.

Division of Hematology, Department of Medicine I, University Hospital "Carl Gustav Carus" Dresden, Dresden, Germany.

Compared with nonpregnant women, pregnancy carries a four- to fivefold higher risk of venous thromboembolism (VTE). Despite increasing use of heparin prophylaxis in identified high-risk patients, pulmonary embolism still is the leading cause of maternal mortality in the western world. However, evidence on optimal use of thromboprophylaxis is scarce. Thrombophilia, the hereditary or acquired tendency to develop VTE, is also thought to be associated with complications in pregnancy, such as recurrent miscarriage and preeclampsia. In this review, the current evidence on optimal thromboprophylaxis in pregnancy is discussed, focusing primarily on VTE prevention strategies but also discussing the potential to prevent recurrent pregnancy complications with heparin in pregnant women with thrombophilia.
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http://dx.doi.org/10.1055/a-1717-7663DOI Listing
February 2022

Risk of recurrence in women with venous thromboembolism related to estrogen-containing contraceptives: Systematic review and meta-analysis.

J Thromb Haemost 2022 May 13;20(5):1158-1165. Epub 2022 Feb 13.

Department of Internal Medicine &, Radboud Institute of Health Sciences (RIHS), Radboud University Medical Centre, Nijmegen, The Netherlands.

Background: The risk of recurrence after a venous thromboembolism (VTE) related to estrogen-containing contraceptives is a key driver to guide anticoagulant treatment decisions.

Objective: To estimate the incidence rate of recurrent VTE after discontinuation of anticoagulant treatment in women with a first episode of VTE related to estrogen-containing contraceptives.

Methods: Embase, MEDLINE, and the CENTRAL were searched from 1 January 2008 to 27 May 2021 for prospective and retrospective studies reporting on recurrence after a first VTE related to estrogen-containing contraceptives. Risk of bias was assessed using QUIPS tool. Recurrence rates per 100 patient-years were pooled using Knapp-Hartung random-effects meta-analysis. Incidence rates were reported separately based on study follow-up duration (≤1 year, 1-5 years, and >5 years) and for several subgroups.

Results: A total of 4,120 studies were identified, of which 14 were included. The pooled recurrence rate was 1.57 (95%-CI: 1.10-2.23; I  = 82%) per 100 patient-years. Recurrence rates per 100 patient-years were 2.73 (95%-CI: 0.00-3643; I  = 80%) for studies with ≤1 year follow-up, 1.35 (95%-CI: 0.68-2.68; I  = 44%) for studies with 1-5 years follow-up, and 1.42 (95%-CI: 0.84-2.42; I  = 78%) for studies with >5 years follow-up.

Conclusion: Among women with VTE associated with estrogen-containing contraceptives, the risk of recurrence after stopping anticoagulation is low, which favors short-term anticoagulation. Large prospective studies on VTE recurrence rates and risk factors after stopping short-term anticoagulants are needed.
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http://dx.doi.org/10.1111/jth.15661DOI Listing
May 2022

Differences in thrombin and plasmin generation potential between East African and Western European adults: The role of genetic and non-genetic factors.

J Thromb Haemost 2022 May 10;20(5):1089-1105. Epub 2022 Feb 10.

Department of Internal Medicine, Radboudumc Center for Infectious Diseases, Radboud Institute of Health Science (RIHS), Radboud university medical center, Nijmegen, the Netherlands.

Background: Geographic variability in coagulation across populations and their determinants are poorly understood.

Objective: To compare thrombin (TG) and plasmin (PG) generation parameters between healthy Tanzanian and Dutch individuals, and to study associations with inflammation and different genetic, host and environmental factors.

Methods: TG and PG parameters were measured in 313 Tanzanians of African descent living in Tanzania and 392 Dutch of European descent living in the Netherlands and related to results of a dietary questionnaire, circulating inflammatory markers, genotyping, and plasma metabolomics.

Results: Tanzanians exhibited an enhanced TG and PG capacity, compared to Dutch participants. A higher proportion of Tanzanians had a TG value in the upper quartile with a PG value in the lower/middle quartile, suggesting a relative pro-coagulant state. Tanzanians also displayed an increased normalized thrombomodulin sensitivity ratio, suggesting reduced sensitivity to protein C. In Tanzanians, PG parameters (lag time and TTP) were associated with seasonality and food-derived plasma metabolites. The Tanzanians had higher concentrations of pro-inflammatory cytokines, which correlated strongly with TG and PG parameters. There was limited overlap in genetic variation associated with TG and PG parameters between the two cohorts. Pathway analysis of genetic variants in the Tanzanian cohort revealed multiple immune pathways that were enriched with TG and PG traits, confirming the importance of co-regulation between coagulation and inflammation.

Conclusions: Tanzanians have an enhanced TG and PG potential compared to Dutch individuals, which may relate to differences in inflammation, genetics and diet. These observations highlight the importance of better understanding of the geographic variability in coagulation across populations.
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http://dx.doi.org/10.1111/jth.15657DOI Listing
May 2022

Andexanet Alfa for Specific Anticoagulation Reversal in Patients with Acute Bleeding during Treatment with Edoxaban.

Thromb Haemost 2022 Jan 7. Epub 2022 Jan 7.

Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.

Background:  Andexanet alfa (andexanet) is approved for specific anticoagulation reversal in patients with life-threatening or uncontrolled bleeding during treatment with rivaroxaban or apixaban. There is limited experience with andexanet in patients with acute bleeding on edoxaban.

Methods:  Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a bolus and 2-hour follow-on infusion of andexanet. The co-primary efficacy outcomes were change in antifactor Xa activity and the percentage of patients achieving excellent or good hemostasis, 12 hours after andexanet treatment. Efficacy was analyzed in patients with confirmed major bleeding and baseline antifactor Xa activity ≥40 ng/mL. Safety was analyzed in all patients.

Results:  Thirty-six patients (mean age: 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 patients (80.6%). In the efficacy population ( = 28), median antifactor Xa activity decreased from 121.1 (interquartile range [IQR]: 70.3-202.4) ng/mL at baseline to 24.0 (IQR: 77.7-83.7) ng/mL at the end of andexanet bolus (median decrease: 68.9%, 95% confidence interval [CI]: 56.1-77.7%). Excellent or good hemostasis at 12 hours was achieved in 78.6% (95% CI: 59.0-91.7%) of patients. Within 30 days, four patients (11.1%) experienced a thrombotic event and four others (11.1%) died.

Conclusion:  In patients with acute major bleeding on edoxaban, andexanet significantly decreased antifactor Xa activity. Hemostatic efficacy was similar to that observed in patients with bleeding on rivaroxaban or apixaban. Thrombotic events occurred at a rate expected in such patients.
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http://dx.doi.org/10.1055/s-0041-1740180DOI Listing
January 2022

Randomized trials of therapeutic heparin for COVID-19: A meta-analysis.

Res Pract Thromb Haemost 2021 Dec 17;5(8):e12638. Epub 2021 Dec 17.

Department of Medicine Institute of Health Policy, Management and Evaluation Applied Health Research Centre St. Michael's Hospital Li Ka Shing Knowledge Institute University of Toronto Toronto ON Canada.

Background: Pulmonary endothelial injury and microcirculatory thromboses likely contribute to hypoxemic respiratory failure, the most common cause of death, in patients with COVID-19. Randomized controlled trials (RCTs) suggest differences in the effect of therapeutic heparin between moderately and severely ill patients with COVID-19. We did a systematic review and meta-analysis of RCTs to determine the effects of therapeutic heparin in hospitalized patients with COVID-19.

Methods: We searched PubMed, Embase, Web of Science, medRxiv, and medical conference proceedings for RCTs comparing therapeutic heparin with usual care, excluding trials that used oral anticoagulation or intermediate doses of heparin in the experimental arm. Mantel-Haenszel fixed-effect meta-analysis was used to combine odds ratios (ORs).

Results And Conclusions: There were 3 RCTs that compared therapeutic heparin to lower doses of heparin in 2854 moderately ill ward patients, and 3 RCTs in 1191 severely ill patients receiving critical care. In moderately ill patients, there was a nonsignificant reduction in all-cause death (OR, 0.76; 95% CI, 0.57-1.02), but significant reductions in the composite of death or invasive mechanical ventilation (OR, 0.77; 95% CI, 0.60 0.98), and death or any thrombotic event (OR, 0.58; 95% CI, 0.45-0.77). Organ support-free days alive (OR, 1.29; 95% CI, 1.07-1.57) were significantly increased with therapeutic heparin. There was a nonsignificant increase in major bleeding. In severely ill patients, there was no evidence for benefit of therapeutic heparin, with significant treatment-by-subgroup interactions with illness severity for all-cause death (= .034). In conclusion, therapeutic heparin is beneficial in moderately ill patients but not in severely ill patients hospitalized with COVID-19.
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http://dx.doi.org/10.1002/rth2.12638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8681879PMC
December 2021

ChAdOx1 vaccination, blood coagulation, and inflammation: No effect on coagulation but increased interleukin-6.

Res Pract Thromb Haemost 2021 Dec 7;5(8):e12630. Epub 2021 Dec 7.

Department of Surgery Radboud Institute of Health Sciences (RIHS) Radboud University Medical Center Nijmegen The Netherlands.

Background: Vaccination is the leading approach in combatting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. ChAdOx1 nCoV-19 vaccination (ChAdOx1) has been linked to a higher frequency of rare thrombosis and thromboembolism. This study aimed to explore markers related to the blood coagulation system activation and inflammation, before and after ChAdOx1 vaccination.

Patients And Methods: An observational cohort study including 40 health care workers. Whole blood samples were collected before, and either 1 or 2 days after vaccination. Activated coagulation factors in complex with their natural inhibitors were determined by custom ELISAs, including thrombin:antithrombin (T:AT), kallikrein:C1-esterase-inhibitor (PKa:C1Inh), factor(F)IXa:AT, FXa:AT, FXIaAT, FXIa:alpha-1-antitrypsin (α1AT), FXIa:C1inh, and FVIIa:AT. Plasma concentrations of interleukin (IL)-6 and IL-18 were quantified via ELISA. Analyses were performed using Wilcoxon signed-rank test.

Results: Levels of FVIIa:AT decreased with a median (IQR) of 707 (549-1028) pg/ml versus 598 (471-996) pg/ml,  = 0.01; and levels of IL-6 increased, 4.0 (1.9-6.8) pg/ml versus 6.9 (3.6-12.2) pg/ml,  = 0.02, after vaccination. No changes were observed in T:AT, PKa:C1Inh, FIXa:AT, FXa:AT, FXIaAT, FXIa:α1AT, FXIa:C1inh, and IL-18.

Conclusion: ChAdOx1 leads to an inflammatory response with increased levels of IL-6. We did not observe activation of the blood coagulation system 1-2 days following vaccination.
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http://dx.doi.org/10.1002/rth2.12630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8652129PMC
December 2021

Age-Stratified Risk of Cerebral Venous Sinus Thrombosis After SARS-CoV-2 Vaccination.

Neurology 2022 02 17;98(7):e759-e768. Epub 2021 Dec 17.

From the Departments of Neurology (K.K., A.v.d.M., M.S.v.K., J.M.C.) and Vascular Medicine (M.M.L.), Amsterdam University Medical Centers, University of Amsterdam, the Netherlands; Departments of Neurology (M.R.H., M.A.) and Hematology (J.A.K.H.), Inselspital, Bern University Hospital, University of Bern; Department of Neurology (K.J., E.L., T.T.), Sahlgrenska University Hospital; Department of Clinical Neuroscience (K.J., E.L., T.T.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Neurology (J.P.), Helsinki University Hospital and University of Helsinki, Finland; Department of Internal Medicine (S.M.) and Radboud Institute of Health Sciences (S.M.), Radboud University Medical Center, Nijmegen, the Netherlands; National Institute for Health Research University College London Hospitals Biomedical Research Centre (M.M.L.), UK; University of Lille (C.C.), Inserm, CHU Lille, U1172-Lille Neuroscience and Cognition, France; Department of Clinical Epidemiology and Biostatistics (A.H.Z.), Amsterdam University Medical Centers, University of Amsterdam, the Netherlands; and Department of Neurosciences and Mental Health (J.M.F., D.A.d.S.), Neurology Service, Hospital de Santa Maria/Centro Hospitalar Universitário Lisboa Norte (CHULN), University of Lisbon, Portugal.

Background And Objectives: Cerebral venous sinus thrombosis (CVST) as a part of the thrombosis and thrombocytopenia syndrome is a rare adverse drug reaction of severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) vaccination. Estimated background rate of CVST with thrombocytopenia is 0.1 per million per month. We assessed the age-stratified risk of CVST with and without thrombocytopenia after SARS-CoV-2 vaccination.

Methods: We estimated the absolute risk of CVST with and without thrombocytopenia within 28 days of a first dose of 4 SARS-CoV-2 vaccinations using data from the European Medicines Agency's EudraVigilance database (until June 13, 2021). As a denominator, we used data on vaccine delivery from 31 European countries. For 22.8 million adults from 25 countries, we estimated the absolute risk of CVST after the first dose of ChAdOx1 nCov-19 per age category.

Results: The absolute risk of CVST within 28 days of first-dose vaccination was 7.5 (95% confidence interval [CI] 6.9-8.3), 0.7 (95% CI 0.2-2.4), 0.6 (95% CI 0.5-0.7), and 0.6 (95% CI 0.3-1.1) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2, and mRNA-1273, respectively. The absolute risk of CVST with thrombocytopenia within 28 days of first dose vaccination was 4.4 (95% CI 3.9-4.9), 0.7 (95% CI 0.2-2.4), 0.0 (95% CI 0.0-0.1), and 0.0 (95% CI 0.0-0.2) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2, and mRNA-1273, respectively. In recipients of ChAdOx1 nCov-19, the absolute risk of CVST, both with and without thrombocytopenia, was the highest in the 18- to 24-year-old group (7.3 per million, 95% CI 2.8-18.8 and 3.7 per million, 95% CI 1.0-13.3, respectively). The risk of CVST with thrombocytopenia in ChAdOx1 nCov-19 recipients was the lowest in the age group ≥70 years (0.2, 95% CI 0.0-1.3). Age <60 years compared to ≥60 years was a predictor for CVST with thrombocytopenia (incidence rate ratio 5.79, 95% CI 2.98-11.24, < 0.001).

Discussion: The risk of CVST with thrombocytopenia within 28 days of first-dose vaccination with ChAdOx1 nCov-19 was higher in younger age groups. The risk of CVST with thrombocytopenia was slightly increased in patients receiving Ad26.COV2.S compared with the estimated background risk. The risk of CVST with thrombocytopenia was not increased in recipients of SARS-CoV-2 mRNA vaccines.
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http://dx.doi.org/10.1212/WNL.0000000000013148DOI Listing
February 2022

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 2022 Apr 2;32(4):2178-2187. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921171PMC
April 2022

Antithrombotic therapy for live birth in women with recurrent pregnancy loss: do not confound available high-level evidence.

Hum Reprod 2021 12;37(1):190-191

Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1093/humrep/deab247DOI Listing
December 2021

Growth differentiation factor-15 for prediction of bleeding in cancer patients.

J Thromb Haemost 2022 01 2;20(1):138-144. Epub 2021 Nov 2.

Department of Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, ON, Canada.

Background: Growth differentiation factor-15 (GDF-15) is a strong predictor for bleeding in patients with atrial fibrillation, but there are no data on cardiovascular outcomes for this biomarker in cancer patients. Bleeding risk assessment is important in cancer patients when considering primary thromboprophylaxis because it is associated with an increased bleeding risk.

Objectives: To evaluate GDF-15 as predictor for bleeding events in cancer patients previously enrolled in the AVERT trial.

Patients/methods: In this trial, 574 participants were randomized to prophylactic apixaban or placebo and followed for 180 days for venous thromboembolism, major bleeding, clinically relevant nonmajor bleeding, and any bleeding. Plasma concentrations of GDF-15 were measured centrally with the Elecsys GDF-15 commercial assay kit (Roche Diagnostics GmbH).

Results: In apixaban recipients, the area under the receiver operator characteristic curve of GDF-15 for major bleeding was 0.73 (95% confidence interval [CI], 0.44-1.00). Compared with the lowest GDF-15 tertile (<1470 ng/L), major bleeding risk was significantly higher in the highest tertile (≥2607 ng/L; hazard ratio [HR] 3.19; 95% CI, 2.41-4.22), also when adjusting for sex, age, antiplatelet use, and gastrointestinal cancer (adjusted HR 2.80; 95% CI, 1.91-4.11). GDF-15 was also significantly associated with clinically relevant nonmajor bleeding (adjusted HR 1.67; 95% CI, 1.08-2.58) and any bleeding (adjusted HR 2.12; 95% CI, 1.38-3.25).

Conclusions: Although hypothesis generating, this is the first study to show that GDF-15 predicts bleeding in cancer patients receiving thromboprophylaxis.
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http://dx.doi.org/10.1111/jth.15559DOI Listing
January 2022

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.

BMJ 2021 10 14;375:n2400. Epub 2021 Oct 14.

St Michael's Hospital, University of Toronto, Toronto, ON, Canada.

Objective: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards.

Design: Randomised controlled, adaptive, open label clinical trial.

Setting: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US.

Participants: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237).

Interventions: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death.

Main Outcome Measures: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated.

Results: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69).

Conclusions: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial.

Trial Registration: ClinicalTrials.gov NCT04362085.
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http://dx.doi.org/10.1136/bmj.n2400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515466PMC
October 2021

Hematoma Expansion and Clinical Outcomes in Patients With Factor-Xa Inhibitor-Related Atraumatic Intracerebral Hemorrhage Treated Within the ANNEXA-4 Trial Versus Real-World Usual Care.

Stroke 2022 02 14;53(2):532-543. Epub 2021 Oct 14.

Department of Neurology, University Hospital Erlangen, Germany (H.B.H., S.T.G., J.B.K., S.S.).

Background And Purpose: It is unestablished whether andexanet alfa, compared with guideline-based usual care including prothrombin complex concentrates, is associated with reduced hematoma expansion (HE) and mortality in patients with factor-Xa inhibitor-related intracerebral hemorrhage (ICH). We compared the occurrence of HE and clinical outcomes in patients treated either with andexanet alfa or with usual care during the acute phase of factor-Xa inhibitor-related ICH.

Methods: Data were extracted from the multicenter, prospective, single-arm ANNEXA-4 trial (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) and a multicenter observational cohort study, RETRACE-II (German-Wide Multicenter Analysis of Oral Anticoagulant-Associated Intracerebral Hemorrhage - Part Two). HE was based on computed tomography scans performed within 36 hours from baseline imaging. Inverse probability of treatment weighting was performed to adjust for baseline comorbidities and ICH severity. Patients presenting with atraumatic ICH while receiving apixaban or rivaroxaban within 18 hours of admission were included. Patients with secondary ICH or not fulfilling the inclusion criteria for the ANNEXA-4 trial were excluded. We compared ANNEXA-4 patients, who received andexanet alfa for hemostatic treatment, with RETRACE-II patients who were treated with usual care, primarily administration of prothrombin complex concentrates. Primary outcome was rate of HE defined as relative increase of ≥35%. Secondary outcomes comprised mean absolute change in hematoma volume, as well as in-hospital mortality and functional outcome.

Results: Overall, 182 patients with factor-Xa inhibitor-related ICH (85 receiving andexanet alfa versus 97 receiving usual care) were selected for analysis. There were no relevant differences regarding demographic or clinical characteristics between both groups. HE occurred in 11 of 80 (14%) andexanet alfa patients compared with 21 of 67 (36%) usual care patients (adjusted relative risk, 0.40 [95% CI, 0.20-0.78]; =0.005), with a reduction in mean overall hematoma volume change of 7 mL. There were no statistically significant differences among in-hospital mortality or functional outcomes. Sensitivity analysis including only usual care patients receiving prothrombin complex concentrates demonstrated consistent results.

Conclusions: As compared with usual care, andexanet alfa was associated with a lower rate of HE in atraumatic factor-Xa inhibitor-related ICH, however, without translating into significantly improved clinical outcomes. A comparative trial is needed to confirm the benefit on limiting HE and to explore clinical outcomes across patient subgroups and by time to treatment. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT02329327 and NCT03093233.
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http://dx.doi.org/10.1161/STROKEAHA.121.034572DOI Listing
February 2022

Characteristics and Outcomes of Patients With Cerebral Venous Sinus Thrombosis in SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia.

JAMA Neurol 2021 11;78(11):1314-1323

Department of Neurology, Saudi German Hospital, Jeddah, Saudi Arabia.

Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson).

Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS.

Design, Setting, And Participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination.

Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria.

Main Outcomes And Measures: Clinical characteristics and mortality rate.

Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later.

Conclusions And Relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.
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http://dx.doi.org/10.1001/jamaneurol.2021.3619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479648PMC
November 2021

ACTION-1: study protocol for a randomised controlled trial on ACT-guided heparinization during open abdominal aortic aneurysm repair.

Trials 2021 Sep 19;22(1):639. Epub 2021 Sep 19.

Department of Vascular Surgery, Dijklander ziekenhuis, Maelsonstraat 3, 1624, NP, Hoorn, The Netherlands.

Background: Heparin is used worldwide for 70 years during all non-cardiac arterial procedures (NCAP) to reduce thrombo-embolic complications (TEC). But heparin also increases blood loss causing possible harm for the patient. Heparin has an unpredictable effect in the individual patient. The activated clotting time (ACT) can measure the effect of heparin. Currently, this ACT is not measured during NCAP as the standard of care, contrary to during cardiac interventions, open and endovascular. A RCT will evaluate if ACT-guided heparinization results in less TEC than the current standard: a single bolus of 5000 IU of heparin and no measurements at all. A goal ACT of 200-220 s should be reached during ACT-guided heparinization and this should decrease (mortality caused by) TEC, while not increasing major bleeding complications. This RCT will be executed during open abdominal aortic aneurysm (AAA) surgery, as this is a standardized procedure throughout Europe.

Methods: Seven hundred fifty patients, who will undergo open AAA repair of an aneurysm originating below the superior mesenteric artery, will be randomised in 2 treatment arms: 5000 IU of heparin and no ACT measurements and no additional doses of heparin, or a protocol of 100 IU/kg bolus of heparin and ACT measurements after 5 min, and then every 30 min. The goal ACT is 200-220 s. If the ACT after 5 min is < 180 s, 60 IU/kg will be administered; if the ACT is between 180 and 200 s, 30 IU/kg. If the ACT is > 220 s, no extra heparin is given, and the ACT is measured after 30 min and then the same protocol is applied. The expected incidence for the combined endpoint of TEC and mortality is 19% for the 5000 IU group and 11% for the ACT-guided group.

Discussion: The ACTION-1 trial is an international RCT during open AAA surgery, designed to show superiority of ACT-guided heparinization compared to the current standard of a single bolus of 5000 IU of heparin. A significant reduction in TEC and mortality, without more major bleeding complications, must be proven with a relevant economic benefit. TRIAL REGISTRATION {2A}: NTR NL8421 ClinicalTrials.gov NCT04061798 . Registered on 20 August 2019 EudraCT 2018-003393-27 TRIAL REGISTRATION: DATA SET {2B}: Data category Information Primary registry and trial identifying number ClinicalTrials.gov : NCT04061798 Date of registration in primary registry 20-08-2019 Secondary identifying numbers NTR: NL8421 EudraCT: 2018-003393-27 Source(s) of monetary or material support ZonMw: The Netherlands Organisation for Health Research and Development Dijklander Ziekenhuis Amsterdam UMC Primary sponsor Dijklander Ziekenhuis Secondary sponsor(s) N/A Contact for public queries A.M. Wiersema, MD, PhD [email protected] 0031-229 208 206 Contact for scientific queries A.M. Wiersema, MD, PhD [email protected] 0031-229 208 206 Public title ACT Guided Heparinization During Open Abdominal Aortic Aneurysm Repair (ACTION-1) Scientific title ACTION-1: ACT Guided Heparinization During Open Abdominal Aortic Aneurysm Repair, a Randomised Trial Countries of recruitment The Netherlands. Soon the recruitment will start in Germany Health condition(s) or problem(s) studied Abdominal aortic aneurysm, arterial disease, surgery Intervention(s) ACT-guided heparinization 5000 IU of heparin Key inclusion and exclusion criteria Ages eligible for the study: ≥18 years Sexes eligible for the study: both Accepts healthy volunteers: no Inclusion criteria: Study type Interventional Allocation: randomized Intervention model: parallel assignment Masking: single blind (patient) Primary purpose: treatment Phase IV Date of first enrolment March 2020 Target sample size 750 Recruitment status Recruiting Primary outcome(s) The primary efficacy endpoint is 30-day mortality and in-hospital mortality during the same admission. The primary safety endpoint is the incidence of bleeding complications according to E-CABG classification, grade 1 and higher. Key secondary outcomes Serious complications as depicted in the Suggested Standards for Reports on Aneurysmal disease: all complications requiring re-operation, longer hospital stay, all complications.
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http://dx.doi.org/10.1186/s13063-021-05552-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449992PMC
September 2021

Use of novel antithrombotic agents for COVID-19: Systematic summary of ongoing randomized controlled trials.

J Thromb Haemost 2021 12 30;19(12):3080-3089. Epub 2021 Sep 30.

Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Coronavirus disease 2019 (COVID-19) is associated with macro- and micro-thromboses, which are triggered by endothelial cell activation, coagulopathy, and uncontrolled inflammatory response. Conventional antithrombotic agents are under assessment in dozens of randomized controlled trials (RCTs) in patients with COVID-19, with preliminary results not demonstrating benefit in several studies.

Objectives: Given the possibility that more novel agents with antithrombotic effects may have a potential utility for management of patients with COVID-19, we assessed ongoing RCTs including these agents with their potential mechanism of action in this population.

Methods: We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to identify RCTs of novel antithrombotic agents in patients with COVID-19.

Results: Based on a systematic literature search, 27 RCTs with 10 novel antithrombotic agents (including nafamostat, dociparstat, rNAPc2, and defibrotide) were identified. The results from these trials have not been disseminated yet. The studied drugs in the ongoing or completed RCTs include agents affecting the coagulation cascade, drugs affecting endothelial activation, and mixed acting agents. Their postulated antithrombotic mechanisms of action and their potential impact on patient management are summarized.

Conclusion: Some novel antithrombotic agents have pleiotropic anti-inflammatory and antiviral effects, which may help reduce the viral load or fibrosis, and improve oxygenation. Results from ongoing RCTs will elucidate their actual role in the management of patients with COVID-19.
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http://dx.doi.org/10.1111/jth.15533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646701PMC
December 2021

Declining mortality of cerebral venous sinus thrombosis with thrombocytopenia after SARS-CoV-2 vaccination.

Eur J Neurol 2022 01 1;29(1):339-344. Epub 2021 Oct 1.

Department of Neurology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background And Purpose: High mortality rates have been reported in patients with cerebral venous sinus thrombosis (CVST) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) after vaccination with adenoviral vector SARS-CoV-2 vaccines. The aim of this study was to evaluate whether the mortality of patients with CVST-VITT has decreased over time.

Methods: The EudraVigilance database of the European Medicines Agency was used to identify cases of CVST with concomitant thrombocytopenia occurring within 28 days of SARS-CoV-2 vaccination. Vaccines were grouped based on vaccine type (adenoviral or mRNA). Cases with CVST onset until 28 March were compared to cases after 28 March 2021, which was the day when the first scientific paper on VITT was published.

Results: In total, 270 cases of CVST with thrombocytopenia were identified, of which 266 (99%) occurred after adenoviral vector SARS-CoV-2 vaccination (ChAdOx1 nCoV-19, n = 243; Ad26.COV2.S, n = 23). The reported mortality amongst adenoviral cases with onset up to 28 March 2021 was 47/99 (47%, 95% confidence interval 37%-58%) compared to 36/167 (22%, 95% confidence interval 16%-29%) in cases with onset after 28 March (p < 0.001). None of the four cases of CVST with thrombocytopenia occurring after mRNA vaccination died.

Conclusion: The reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector-based SARS-CoV-2 vaccines has significantly decreased over time, which may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after VITT.
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http://dx.doi.org/10.1111/ene.15113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8652752PMC
January 2022

How to write a guideline: a proposal for a manuscript template that supports the creation of trustworthy guidelines.

Blood Adv 2021 11;5(22):4721-4726

Michael G. DeGroote Cochrane Canada and McMaster GRADE Centres and.

Trustworthy health guidelines should provide recommendations, document the development process, and highlight implementation information. Our objective was to develop a guideline manuscript template to help authors write a complete and useful report. The McMaster Grading of Recommendations Assessment, Development and Evaluation Centre collaborated with the American Society of Hematology (ASH) to develop guidelines for the management of venous thromboembolism. A template for reporting the guidelines was developed based on prior approaches and refined using input from other key stakeholders. The proposed guideline manuscript template includes: (1) title for guideline identification, (2) abstract, including a summary of key recommendations, (3) overview of all recommendations (executive summary), and (4) the main text, providing sufficient detail about the entire process, including objectives, background, and methodological decisions from panel selection and conflict-of-interest management to criteria for updating, as well as supporting information, such as links to online (interactive) tables. The template further allows for tailoring to the specific topic, using examples. Initial experience with the ASH guideline manuscript template was positive, and challenges included drafting descriptions of recommendations involving multiple management pathways, tailoring the template for a specific guideline, and choosing key recommendations to highlight. Feedback from a larger group of guideline authors and users will be needed to evaluate its usefulness and refine. The proposed guideline manuscript template is the first detailed template for transparent and complete reporting of guidelines. Consistent application of the template may simplify the preparation of an evidence-based guideline manuscript and facilitate its use.
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http://dx.doi.org/10.1182/bloodadvances.2020003577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759117PMC
November 2021

Risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer using edoxaban.

J Thromb Haemost 2021 12 12;19(12):3008-3017. Epub 2021 Sep 12.

Department of Vascular Medicine, Amsterdam Cardiovascular Science, Medical Centers, Amsterdam University, University of Amsterdam, Amsterdam, The Netherlands.

Background: In the Hokusai VTE Cancer study, the risk of major bleeding was 2.9% higher in the edoxaban group compared with the dalteparin group, mainly due to more gastrointestinal bleedings in patients with gastrointestinal cancer. The identification of risk factors for gastrointestinal bleeding may help to guide the use of DOACs in these patients.

Objectives: To evaluate risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban.

Patients/methods: In this nested case-control study in patients with gastrointestinal cancer randomized to edoxaban in the Hokusai VTE Cancer study, cases (patients with clinically relevant gastrointestinal bleeding during treatment) were randomly matched to three controls (patients who had no gastrointestinal bleeding). Data for the 4-week period prior to bleeding were retrospectively collected. Odds ratios (ORs) were calculated in a crude conditional logistic regression model and a multivariable model adjusted for age, sex, and cancer type.

Results: Twenty-four cases and 64 matched controls were included. In the multivariable analysis, advanced cancer, defined as regionally advanced or metastatic cancer (OR 3.6, 95% CI 1.01-12.6) and low hemoglobin levels (OR 4.8, 95% CI 1.5-16.0) were significantly associated with bleeding. There was no significant difference in patients with resected tumors (OR 0.4, 95% CI 0.1-1.4), or in patients on chemotherapy (OR 1.3, 95% CI 0.5-3.5).

Conclusion: Advanced cancer and low hemoglobin levels were associated with an increased risk of gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. We were unable to identify other risk factors, mainly due to limited statistical power.
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http://dx.doi.org/10.1111/jth.15516DOI Listing
December 2021

Pregnancy in women with an inferior vena cava filter: a tertiary center experience and overview of the literature.

Blood Adv 2021 10;5(20):4044-4053

Department of Vascular Medicine.

Patients with an inferior vena cava (IVC) filter that remains in situ encounter a lifelong increased risk of deep vein thrombosis and IVC filter complications including fracture, perforation, and IVC filter thrombotic occlusion. Data on the safety of becoming pregnant with an in situ IVC filter are scarce. The objective was to evaluate the risk of complications of in situ IVC filters during pregnancy. We performed a retrospective cohort study of pregnant patients with an in situ IVC filter from a tertiary center between 2000 and 2020. We collected data on complications of IVC filters and pregnancy outcomes. Additionally, we performed a systematic literature search in MEDLINE, Embase, and gray literature. We identified 7 pregnancies in 4 patients with in situ IVC filters with a mean time since IVC filter insertion of 3 years (range, 1-8). No complications of IVC filter occurred during pregnancy. Review of literature yielded five studies including 13 pregnancies in 9 patients. In 1 pregnancy a pre-existent, until then asymptomatic, chronic perforation of the vena cava wall by the IVC filter caused major bleeding and uterine trauma with fetal loss. Overall, the complication rate was 5%. It seems safe to become pregnant with an indwelling IVC filter that is intact and does not show signs of perforation, but because of the low number of cases, no firm conclusions about safety of in situ IVC filters during pregnancy can be drawn. We suggest imaging before pregnancy to reveal asymptomatic IVC filter complications.
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http://dx.doi.org/10.1182/bloodadvances.2020003930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945633PMC
October 2021

Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19.

N Engl J Med 2021 Aug 4;385(9):777-789. Epub 2021 Aug 4.

From the University of Toronto (E.C.G., P.R.L., L.C.G., M.E.F., V.D., R.A.F., J.P.G., M.H., A.S.S.), University Health Network (E.C.G., M.H.), Peter Munk Cardiac Centre at University Health Network (P.R.L., L.C.G., M.E.F., V.D.), Ozmosis Research (L.B., V.W.), Sunnybrook Health Sciences Centre (J.P.G.), Toronto, Ottawa Hospital Research Institute (M. Carrier, L.A.C., D.A.F., G.L.G., D.M.S.), Institut du Savoir Montfort (M. Carrier, G.L.G.), and the University of Ottawa (L.A.C., D.A.F., D.M.S.), Ottawa, the University of Manitoba (A. Kumar, B.L.H., R.Z., S.A.L., D.S., G.V.-G.) and CancerCare Manitoba (B.L.H., R.Z.), Winnipeg, Université Laval and Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Quebec, QC (A.F.T.), McGill University, Montreal (S.R.K., E.G.M.), St. Michael's Hospital Unity Health, Toronto (J.C.M., Z.B., M.S., A.S.S.), McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON (P.L.G.) Université de Sherbrooke, Sherbrooke, QC (F.L.), St. Boniface Hospital, Winnipeg, MB (N.M.), the University of British Columbia, Vancouver (S. Murthy), and the University of Alberta, Edmonton (S.D.) - all in Canada; University of Bristol and University Hospitals Bristol and Weston NHS Foundation Trust, Bristol (C.A.B.), the London School of Hygiene and Tropical Medicine (B.-A.K.), Imperial College London (A.C.G., F.A.-B., M.A.L.), Imperial College Healthcare NHS Trust, St. Mary's Hospital (A.C.G.), University College London Hospital (R.H.), Kings Healthcare Partners (B.J.H.), and Intensive Care National Audit and Research Centre (ICNARC) (P.R.M., K.R.), London, Queen's University Belfast and Royal Victoria Hospital, Belfast (D.F.M.), and Oxford University (A. Beane, L.J.E., S.J.S.) and NHS Blood and Transplant (L.J.E., S. Mavromichalis, S.J.S.), Oxford - all in the United Kingdom; the University of Pittsburgh (B.J.M., D.C.A., M.M.B., M.D.N., H.F.E., J.D.F., Z.F., D.T.H., A.J.K., C.M.L., K.L., M.M., S.K.M., C.W.S., Y.Z.), University of Pittsburgh Medical Center (B.J.M., D.C.A., M.D.N., K.L.), the Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, University of Pittsburgh (T.D.G.), and University of Pittsburgh Medical Center Children's Hospital of Pittsburgh (C.M. Horvat) - all in Pittsburgh; New York University (NYU) Grossman School of Medicine (J.S.B., H.R.R., J.S.H., T.C., A.C., N.M.K., S. Mavromichalis, S.P.), NYU Langone Health, NYU Langone Hospital (T.A., T.C., A.C., J.M.H., E.Y.), and Bellevue Hospital (N.M.K.), Icahn School of Medicine at Mount Sinai (R.S.R.), and Mount Sinai Heart (R.S.R.), New York, Montefiore Medical Center (M.N.G., H.H.B., S.C., J.-T.C., A.A. Hope, R.N.) and Albert Einstein College of Medicine (M.N.G., H.H.B., B.T.G., A.A. Hope), Bronx, and NYU Langone Long Island, Mineola (A.A. Hindenburg) - all in New York; Zuckerberg San Francisco General Hospital-University of California, San Francisco (L.Z.K., C.M. Hendrickson, M.M.K., A.E.K., B.N.-G., J.J.P.), Harbor-UCLA Medical Center, Torrance (R.J.L.), Global Coalition for Adaptive Research (M. Buxton) and the University of California, Los Angeles (G.L.), Los Angeles, the University of California San Diego School of Medicine, San Diego (T.W.C.), and Stanford University School of Medicine, Palo Alto (J.G.W.) - all in California; the University of Illinois (K.S.K., J.R.J., J.G.Q.), the University of Chicago (J.D.P.), and the Chartis Group (J.S.) - all in Chicago; University Medical Center Utrecht, Utrecht University (L.P.G.D., M. Bonten, R.E.G.S., W.B.-P.), and Utrecht University (R.E.G.S.), Utrecht, and Radboud University Medical Center, Nijmegen (S. Middeldorp, F.L.V.) - all in the Netherlands; Larner College of Medicine at the University of Vermont, Burlington (M. Cushman); Inselspital, Bern University Hospital, University of Bern, Bern (T.T.), and SOCAR Research, Nyon (B.-A.K., S. Brouwer) - both in Switzerland; Instituto do Coracao, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo (L.C.G., F.G.L., J.C.N.), Avanti Pesquisa Clínica (A.S.M.), and Hospital 9 de Julho (F.O.S.), Sao Paulo, Hospital do Coração de Mato Grosso do Sul (M.P.), the Federal University of Mato Grosso do Sul (M.P.), Hospital Universitário Maria Aparecida Pedrossia (D.G.S.), and Hospital Unimed Campo Grande (D.G.S.), Campo Grande, and Instituto Goiano de Oncologia e Hematologia, Clinical Research Center, Goiânia (M.O.S.) - all in Brazil; the Australian and New Zealand Intensive Care Research Centre, Monash University (Z.M., C.J.M., S.A.W., A. Buzgau, C.G., A.M.H., S.P.M., A.D.N., J.C.P.), Monash University (A.C.C.), and Alfred Health (A.C.C., A.D.N.), Melbourne, VIC, St. John of God Subiaco Hospital, Subiaco, WA (S.A.W., E. Litton), Flinders University, Bedford Park, SA (S. Bihari), and Fiona Stanley Hospital, Perth, WA (E. Litton) - all in Australia; Berry Consultants, Austin (R.J.L., L.R.B., E. Lorenzi, S.M.B., M.A.D., M.F., A.M., C.T.S.), and Baylor Scott and White Health, Temple (R.J.W.) - both in Texas; Auckland City Hospital (C.J.M., S.P.M., R.L.P.) and the University of Auckland (R.L.P.), Auckland, and the Medical Research Institute of New Zealand, Wellington (C.J.M., A.M.T.) - all in New Zealand; Fédération Hospitalo-Universitaire Saclay and Paris Seine Nord Endeavour to Personalize Interventions for Sepsis (FHU-SEPSIS), Raymond Poincaré Hospital, Université de Versailles Saint-Quentin-en-Yvelines, Garches (D. Annane), and Aix-Marseille University, Marseille (B.C.) - both in France; King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia (Y.M.A.); Nepal Mediciti Hospital, Lalitpur (D. Aryal), and the Nepal Intensive Care Research Foundation, Kathmandu (D. Aryal); Versiti Blood Research Institute, Milwaukee (L.B.K.); National Intensive Care Surveillance (NICS)-Mahidol Oxford Tropical Medicine Research Unit (MORU), Colombo, Sri Lanka (A. Beane); Jena University Hospital, Jena, Germany (F.B.); Cleveland Clinic, Cleveland (A.D.), and the University of Cincinnati, Cincinnati (K.H.) - both in Ohio; Ochsner Medical Center, University of Queensland-Ochsner Clinical School, New Orleans (M.B.E.); Instituto Mexicano del Seguro Social, Mexico City (J.E., E.M.G.); Brigham and Women's Hospital (B.M.E., Y.K., S.M.H.), Massachusetts General Hospital (N.S.R., A.B.S.), and Harvard Medical School (B.M.E., Y.K., N.S.R., A.B.S.) - all in Boston; University of Alabama, Birmingham (S.G.); TriStar Centennial Medical Center, Nashville (A.L.G.); University of Antwerp, Wilrijk, Belgium (H.G.); Rutgers New Jersey Medical School, Newark, New Jersey (Y.Y.G.); University of Oxford, Bangkok, Thailand (R.H.); the University of Michigan, Ann Arbor (R.C.H., P.K.P.), Beaumont Health, Royal Oak (G.B.N.), and Oakland University William Beaumont School of Medicine, Auburn Hills (G.B.N.) - all in Michigan; Apollo Speciality Hospital OMR, Chennai, India (D.J.); Oregon Health and Science University, Portland (A. Khan); National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A. Kindzelski, E.S.L.); University of Mississippi Medical Center, Jackson (M.E.K.); IdiPaz Research Institute, Universidad Autonoma, Madrid (J.L.-S.); University College Dublin, Dublin (A.D.N.); the University of Kansas School of Medicine, Kansas City (L.S.); and Duke University Hospital, Durham, North Carolina (L.W.).

Background: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.

Methods: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.

Results: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.

Conclusions: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).
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http://dx.doi.org/10.1056/NEJMoa2103417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362592PMC
August 2021

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.

N Engl J Med 2021 Aug 4;385(9):790-802. Epub 2021 Aug 4.

From the Peter Munk Cardiac Centre at University Health Network (P.R.L., M.E.F., V.D., J.P.G., L.C.G., G.H.), the University of Toronto (P.R.L., E.C.G., A.S.S., M.E.F., V.D., R.A.F., L.C.G., G.H., M.H.), University Health Network (E.C.G., M.H.), St. Michael's Hospital Unity Health (A.S.S., Z.B., J.C.M., M.S.), Ozmosis Research (L.B., L.P.G.D., V.W.), and Sunnybrook Health Sciences Centre (J.P.G.), Toronto, Ottawa Hospital Research Institute (M. Carrier, L.A.C., D.A.F., G.L.G., D.M.S.), Institut du Savoir Montfort (Marc Carrier, G.L.G.), and the University of Ottawa (L.A.C., D.A.F., D.M.S.), Ottawa, Université Laval (A.F.T.) and CHU de Québec-Université Laval Research Center (A.F.T.), Quebec, QC, the University of Manitoba (B.L.H., A. Kumar, R.Z., S.A.L., D.S., G.V.-G.), CancerCare Manitoba (B.L.H., R.Z.), and St. Boniface Hospital (N.M.), Winnipeg, MB, McGill University, Montreal (S.R.K., E.G.M.), McMaster University (P.L.G.) and the Thrombosis and Atherosclerosis Research Institute (P.L.G.), Hamilton, ON, Université de Sherbrooke, Sherbrooke, QC (F.L.), the University of British Columbia, Vancouver (S. Murthy, K.R.), and the University of Alberta, Edmonton (S.D.) - all in Canada; NYU Grossman School of Medicine (J.S.B., H.R.R., J.S.H., T.C., N.M.K., S.P.), the Icahn School of Medicine at Mount Sinai and Mount Sinai Heart (R.S.R.), NYU Langone Health, NYU Langone Hospital (T.C., J.M.H., E.Y.), and Bellevue Hospital (N.M.K.), New York, Montefiore Medical Center (M.N.G., H.H.B., S.C., J.T.C., R.N.) and Albert Einstein College of Medicine (M.N.G., H.H.B., B.T.G., A. Hope), Bronx, and NYU Langone Long Island, Mineola (R.D.H., A. Hindenburg) - all in New York; the University of Pittsburgh (M.D.N., B.J.M., D.T.H., M.M.B., D.C.A., A.J.K., C.M.L., K.L., S.K.M., C.W.S.), UPMC (M.D.N., B.J.M., D.C.A., K.L., S.K.M.), the Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, University of Pittsburgh (T.D.G.), and UPMC Children's Hospital of Pittsburgh (C. Horvat), Pittsburgh, and Emergency Medicine, Penn State Hershey Medical Center, Hershey (S.C.M.) - all in Pennsylvania; Instituto do Coracao, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo (J.C.N., L.C.G., F.G.L.), Avanti Pesquisa Clínica (A.S.M.), Hospital de Julho (F.O.S.), and Hospital do Coracao (F.G.Z.), Sao Paulo, Hospital do Coração de Mato Grosso do Sul and the Federal University of Mato Grosso do Sul (M.P.), Hospital Universitário Maria Aparecida Pedrossia (D.G.S.J.), and Hospital Unimed Campo Grande (D.G.S.J.), Campo Grande, and INGOH, Clinical Research Center, Goiânia (M.O.S.) - all in Brazil; Instituto Mexicano del Seguro Social, Mexico City (J.E., Y.S.P.G.); the University of Bristol and University Hospitals Bristol and Weston NHS Foundation Trust (C.A.B.), Bristol, Imperial College London (A.C.G., F.A.-B., M.A.L.), Imperial College Healthcare NHS Trust, St. Mary's Hospital (A.C.G.), the London School of Hygiene and Tropical Medicine (B.-A.K.), University College London Hospital (R.H.), Kings Healthcare Partners (B.J.H.), the Intensive Care National Audit and Research Centre (P.R.M.), Guy's and St. Thomas' NHS Foundation Trust (M.S.-H.), and King's College London (M.S.-H.), London, Oxford University (A. Beane, S.J.S.) and NHS Blood and Transplant (L.J.E., S.J.S.), Oxford, and Queen's University Belfast and Royal Victoria Hospital, Belfast (D.F.M.) - all in the United Kingdom; Zuckerberg San Francisco General Hospital, University of California, San Francisco (L.Z.K., C. Hendrickson, M.M.K., A.E.K., M.A.M., B.N.-G.), Harbor-UCLA Medical Center, Torrance (R.J.L., S. Brouwer), Global Coalition for Adaptive Research (M. Buxton) and the University of California Los Angeles (G.L.), Los Angeles, the University of California San Diego School of Medicine, San Diego (T.W.C.), and Stanford University School of Medicine, Palo Alto (J.G.W.) - all in California; Larner College of Medicine at the University of Vermont, Burlington (M. Cushman); Australian and New Zealand Intensive Care Research Centre, Monash University (Z.M., A.M.H., C.J.M., S.A.W., A. Buzgau, C.G., S.P.M., A.D.N., J.C.P., A.C.C.), and Alfred Health (A.C.C., A.D.N.), Melbourne, VIC, St. John of God Subiaco Hospital (S.A.W., E. Litton) and Fiona Stanley Hospital (E. Litton), Perth, WA, and Flinders University, Bedford Park, SA (S. Bihari) - all in Australia; the University of Illinois (K.S.K., J.R.J., J.G.Q.), Cook County Health and Rush Medical College (S. Malhotra), and the University of Chicago (J.D.P.) - all in Chicago; SOCAR Research SA, Nyon (B.-A.K.), and Inselspital, Bern University Hospital, University of Bern (T.T.), Bern - all in Switzerland; Berry Consultants, Austin (R.J.L., E. Lorenzi, S.M.B., L.R.B., M.A.D., M.F., A.M., C.T.S.), University of Texas Southwestern Medical Center, Dallas (A.P.), and Baylor Scott and White Health, Temple (R.J.W.) - all in Texas; Auckland City Hospital (C.J.M., S.P.M., R.L.P.) and the University of Auckland (R.L.P.), Auckland, and the Medical Research Institute of New Zealand, Wellington (C.J.M., A.M.T.) - all in New Zealand; Vanderbilt University Medical Center (A.W.A.) and TriStar Centennial Medical Center (A.L.G.) - both in Nashville; Fédération Hospitalo Universitaire, Raymond Poincaré Hospital, Université de Versailles Saint-Quentin-en-Yvelines, Garches (D. Annane), and Aix-Marseille University, Marseille (B.C.) - both in France; King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Y.M.A.); Nepal Mediciti Hospital, Lalitpur, and Nepal Intensive Care Research Foundation, Kathmandu (D. Aryal) - both in Nepal; Versiti Blood Research Institute, Milwaukee (L.B.K., L.J.E.), and the University of Wisconsin School of Medicine and Public Health, Madison (J.P.S.); National Intensive Care Surveillance-Mahidol Oxford Tropical Medicine Research Unit, Colombo, Sri Lanka (A. Beane); the University Medical Center Utrecht, Utrecht University, Utrecht (M. Bonten, R.E.G.S., W.B.-P.), and Radboud University Medical Center, Nijmegen (S. Middeldorp, F.L.V.) - both in the Netherlands; Jena University Hospital, Jena, Germany (F.B.); Cleveland Clinic (A.D.) and Case Western Reserve University, the Metro Health Medical Centre (V.K.) - both in Cleveland; Ochsner Medical Center, University of Queensland-Ochsner Clinical School, New Orleans (M.B.E.); Harvard Medical School (B.M.E., Y.K., N.S.R., A.B.S), Brigham and Women's Hospital (B.M.E., Y.K., S.M.H.), Boston University School of Medicine and Boston Medical Center (N.M.H.), and Massachusetts General Hospital (A.B.S., N.S.R.) - all in Boston; University of Alabama, Birmingham (S.G.); Hospital Ramón y Cajal (S.G.-M., J.L.L.-S.M., R.M.G.) and IdiPaz Research Institute, Universidad Autonoma (J.L.-S.), Madrid, and University Hospital of Salamanca-University of Salamanca-IBSAL, Salamanca (M.M.) - all in Spain; University of Antwerp, Wilrijk, Belgium (H.G.); Rutgers New Jersey Medical School, Newark (Y.Y.G.); University of Oxford, Bangkok, Thailand (R.H.); Ascension St. John Heart and Vascular Center, Tulsa (N.H.), and the University of Oklahoma College of Medicine, Oklahoma City (N.H.); the University of Cincinnati, Cincinnati (K.H.); University of Michigan, Ann Arbor (R.C.H., P.K.P.), Beaumont Health, Royal Oak, and the OUWB School of Medicine, Auburn Hills (G.B.N.) - all in Michigan; Mayo Clinic, Rochester (V.N.I.), and the Hennepin County Medical Center, Minneapolis (M.E.P.) - both in Minnesota; Apollo Speciality Hospital-OMR, Chennai, India (D.J.); Oregon Health and Science University, Portland (A. Khan, E.S.L.); the National Heart, Lung, and Blood Institute, Bethesda, MD (A.L.K.); University of Mississippi Medical Center, Jackson (M.E.K.); University College Dublin, Dublin (A.D.N.); University of Kansas School of Medicine, Kansas City (L.S.); Duke University Hospital, Durham, NC (L.W.); and Emory University, Atlanta (B.J.W.).

Background: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.

Methods: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.

Results: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.

Conclusions: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).
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http://dx.doi.org/10.1056/NEJMoa2105911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362594PMC
August 2021

Hyperemesis gravidarum and vitamin K deficiency: a systematic review.

Br J Nutr 2021 Jul 30:1-13. Epub 2021 Jul 30.

Amsterdam University Medical Centers, University of Amsterdam, Department of Obstetrics and Gynaecology, Amsterdam Reproduction & Development Research Institute, Meibergdreef 9, Amsterdam, The Netherlands.

Hyperemesis gravidarum (HG), severe nausea and vomiting in pregnancy, can lead to vitamin deficiencies. Little is known about HG-related vitamin K deficiency. We aimed to summarise available evidence on the occurrence of HG-related vitamin K deficiency and corresponding maternal and neonatal complications. A systematic review was conducted, searching Medline and EMBASE from inception to 12 November 2020. We identified 1564 articles, of which we included fifteen in this study: fourteen case reports (n 21 women) and one retrospective cohort study (n 109 women). Nine out of twenty-one women reported in case reports had a prolonged prothrombin time (PT). The cohort study measured PT in 39/109 women with HG, of whom 10/39 women (26 %) had prolonged PT. In total, 30-50 % women received vitamin K supplementation after vitamin K deficiency had been diagnosed. Four case reports (n 4 women) reported corresponding maternal complications, all consisting of coagulopathy-related haemorrhage. Nine case reports (n 16 neonates) reported corresponding neonatal complications including intracranial haemorrhage (n 2 neonates) and embryopathy (n 14 neonates), which consisted of Binder phenotype (n 14 neonates), chondrodysplasia punctata (n 9 neonates) and grey matter heterotopia (n 3 neonates). In conclusion, vitamin K deficiency and related complications occur among women with HG. In our systematic review, we were unable to assess the incidence rate.
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http://dx.doi.org/10.1017/S0007114521002865DOI Listing
July 2021

Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency.

Eur J Neurol 2021 11 4;28(11):3656-3662. Epub 2021 Aug 4.

Department of Neurosciences and Mental Health, Neurology Service, Hospital de Santa Maria/CHULN, University of Lisbon, Lisbon, Portugal.

Background And Purpose: Cerebral venous sinus thrombosis (CVST) has been described after vaccination against SARS-CoV-2. The clinical characteristics of 213 post-vaccination CVST cases notified to the European Medicines Agency are reported.

Methods: Data on adverse drug reactions after SARS-CoV-2 vaccination notified until 8 April 2021 under the Medical Dictionary for Regulatory Activities Term 'Central nervous system vascular disorders' were obtained from the EudraVigilance database. Post-vaccination CVST was compared with 100 European patients with CVST from before the COVID-19 pandemic derived from the International CVST Consortium.

Results: In all, 213 CVST cases were identified: 187 after AstraZeneca/Oxford (ChAdOx1 nCov-19) vaccination and 26 after a messenger RNA (mRNA) vaccination (25 with Pfizer/BioNTech, BNT162b2, and one with Moderna, mRNA-1273). Thrombocytopenia was reported in 107/187 CVST cases (57%, 95% confidence interval [CI] 50%-64%) in the ChAdOx1 nCov-19 group, in none in the mRNA vaccine group (0%, 95% CI 0%-13%) and in 7/100 (7%, 95% CI 3%-14%) in the pre-COVID-19 group. In the ChAdOx1 nCov-19 group, 39 (21%) reported COVID-19 polymerase chain reaction tests were performed within 30 days of CVST symptom onset, and all were negative. Of the 117 patients with a reported outcome in the ChAdOx1 nCov-19 group, 44 (38%, 95% CI 29%-47%) had died, compared to 2/10 (20%, 95% CI 6%-51%) in the mRNA vaccine group and 3/100 (3%, 95% CI 1%-8%) in the pre-COVID-19 group. Mortality amongst patients with thrombocytopenia in the ChAdOx1 nCov-19 group was 49% (95% CI 39%-60%).

Conclusions: Cerebral venous sinus thrombosis occurring after ChAdOx1 nCov-19 vaccination has a clinical profile distinct from CVST unrelated to vaccination. Only CVST after ChAdOx1 nCov-19 vaccination was associated with thrombocytopenia.
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http://dx.doi.org/10.1111/ene.15029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444640PMC
November 2021

Quality of life in patients with pulmonary embolism treated with edoxaban versus warfarin.

Res Pract Thromb Haemost 2021 Jul 14;5(5):e12566. Epub 2021 Jul 14.

Daiichi Sankyo Pharma Development Basking Ridge NJ USA.

Background: Long-term sequelae of acute pulmonary embolism (PE) include decreased quality of life (QoL). Evidence suggests that adequacy of initial anticoagulant treatment in the acute phase of venous thrombosis has a key impact on late postthrombotic complications. We hypothesize that patients with acute PE treated with edoxaban for acute PE experience have improved QoL compared to those treated with warfarin.

Methods: Patients with PE who participated in the Hokusai-VTE trial were contacted between June 2017 and September 2020 for a single long-term follow-up visit. Main outcomes were the generic and disease-specific QoL measured by the 36-Item Short Form Health Survey (SF-36) and Pulmonary Embolism Quality of Life questionnaire.

Results: We included 251 patients from 26 centers in eight countries, of which 129 (51%) had been assigned to edoxaban and 122 (49%) to warfarin. Patient- and thrombus-specific characteristics were similar in both groups. Mean time since randomization in the Hokusai-VTE trial was 7.0 years (standard deviation, 1.0). No relevant or statistical differences were observed in the QoL for patients treated with edoxaban compared to patients treated with warfarin. The mean difference between patients treated with edoxaban and patients with PE treated with warfarin was 0.8 (95% confidence interval [CI]. -1.6 to 3.2) for the SF-36 summary mental score and 1.6 (95% CI, -0.9 to 4.1) for summary physical score.

Conclusion: Our findings indicate that patients with an index PE treated with edoxaban or warfarin have a similar long-term QoL. Since our study was a follow-up study from a well-controlled clinical trial setting, future studies should be designed in a daily clinical practice setting. We suggest a longitudinal design for investigation of changes in QoL over time.
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http://dx.doi.org/10.1002/rth2.12566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279124PMC
July 2021

Heparin for Moderately Ill Patients with Covid-19.

medRxiv 2021 Jul 12. Epub 2021 Jul 12.

Background: Heparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death.

Methods: We randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat.

Results: At 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85).

Conclusions: In moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days. Trial registration numbers: NCT04362085 ; NCT04444700.
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http://dx.doi.org/10.1101/2021.07.08.21259351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282099PMC
July 2021
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