Publications by authors named "Walter Ageno"

481 Publications

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

Thromb Res 2021 Nov 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
November 2021

Study of immune-mediated mechanisms in patients tested positive for SARS-CoV-2: phenotypic and functional analysis of monocytes, NK and T cells in the blood of subjects affected by COVID 19.

JMIR Res Protoc 2021 Jul 26. Epub 2021 Jul 26.

General Emergency and Transplant Surgery Department, University of Insubria, V. Guicciardini, 9, Varese, IT.

Background: The novel coronavirus has a high mortality rate (over 1% for patients older than 50). This could be only partially ascribed to other comorbidities. Possible explanation could be something which assures the ability to prompt response to SARS-CoV-2 in younger people independently from the novelty of the virus itself. Something stimulated the immune system and it scattered immunity against more antigens. The only external stimulation, which healthy people receive, is vaccination (i.e. diphtheria, tetanus, and pertussis (DTP) vaccine). One hypothesis is that vaccination develops the specific immunity but generates a sprouting immunity against antigens in transit. The underlying immunological phenomena are "bystander effect" and "trained immunity". The developed immunity gives protection for years until the natural fade out. After the fifth decade a viral infection will find immune system almost incompetent and the novel coronavirus bursts into the body, developing an ARDS.

Objective: The first study's aim is to demonstrate that blood monocytes and NK cells show an overpowering hyperactivity, while CD4+ and CD8+ T cells experience an impediment to their defensive functions, in patients with severe infection to SARS-CoV-2. The secondary objectives are to correlate clinical data and vaccination history with laboratory immune pattern, to identify protective factors. Subsequently, we were also interested in characterizing the phenotype and state of degree of activation within peripheral blood mononuclear cells (PBMC), of monocytes, NK cells, CD4+ and CD8+ T cells in healthy subjects vaccinated with Pfizer.

Methods: Data will be collected using 3 approaches: An experimental analysis to study the innate immune response and to identify the genetic profiles; An epidemiological analysis to identify the patients' vaccination history; A clinical analysis to detect the immunological profile.

Results: The protocol was approved by the Ethics Committee on 16 April 2020 and the study started on 27 April 2020. As of February 2021 enrollment was completed. Immunological analysis is going on and we expect to complete this analysis by December 2021.

Conclusions: We suppose to recognize different populations of patients, each one with a specific immunological pattern in terms of cytokines, soluble factors serum level and immune cells activity. Anamnestic data such as preceding vaccinations and comorbidities, biochemical data findings as lymphocyte immunophenotyping and pre-existing persistent cytomegalovirus infection allow depicting the risk profile of severe COVID-19. The proof of a role of these immunological phenomena on the development of COVID-19 are bases for implementation of therapeutic immunomodulatory treatments.

Clinicaltrial: The protocol is available on the ClinicalTrials.gov website, its identifier is NCT04375176 (https://clinicaltrials.gov/ct2/show/NCT04375176?term=NCT04375176&draw=2&rank=1).

International Registered Report: DERR1-10.2196/29892.
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http://dx.doi.org/10.2196/29892DOI Listing
July 2021

Anticoagulant treatment for Upper Extremity Deep Vein thrombosis: a systematic review and meta-analysis.

J Thromb Haemost 2021 Nov 30. Epub 2021 Nov 30.

Department of Medicine, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore School of Medicine, Rome, Italy.

Background: Data on anticoagulant treatment for upper extremity deep vein thrombosis (UEDVT) are largely derived from studies on usual site venous thromboembolism (VTE).

Objectives: The objective of this meta-analysis was to evaluate the efficacy and safety of anticoagulant therapy for UEDVT.

Patients/methods: A systematic search of MEDLINE and EMBASE was conducted for studies including patients with UEDVT. Primary outcomes were recurrent VTE and major bleeding. Secondary outcomes included clinically-relevant non-major bleeding and all-cause mortality. Summary estimates with 95% confidence intervals (CIs) were calculated by random-effect meta-analysis.

Results: A total of 1473 patients from 11 prospective and 9 retrospective studies were included. Sixty percent of patients had an indwelling catheter and 56.1% had cancer. Anticoagulant treatment consisted of direct oral anticoagulants, low-molecular-weight heparin followed by vitamin K antagonists, and low-molecular-weight heparin alone in 45.1%, 35.0%, and 19.9% of patients, respectively. During a median follow-up of 13 months, recurrent VTE occurred in 3% of patients (95% CI, 2% to 4%; 21/1334 patients), major bleeding in 3% (95% CI, 2% to 5%; 29/1235 patients), clinically-relevant non-major bleeding in 4% (95% CI, 3% to 6%; 40/1075 patients), and all-cause mortality in 9% (95% CI, 5% to 15%; 108/1084 patients). Rates of these outcomes were not significantly different between patients with or without cancer, patients with or without an indwelling catheter, and among those receiving different anticoagulant treatments.

Conclusions: In patients with UEDVT, anticoagulant treatment is associated with a low risk of recurrent VTE and a non-negligible risk of major bleeding.
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http://dx.doi.org/10.1111/jth.15614DOI Listing
November 2021

Current practices of standardized risk assessment for venous thromboembolism: results from a global survey from the World Thrombosis Day steering committee.

J Thromb Haemost 2021 Nov 26. Epub 2021 Nov 26.

Thrombosis & Haemophilia Centre, Guys & St Thomas' NHS Foundation Trust, London, United Kingdom.

The global annual incidence of venous thromboembolism (VTE) is estimated to be 0.75-2.69 per 1,000 population (1). Up to 60% of VTE events occur during or within three months after hospital admission: these are known as hospital-associated VTE and account for an estimated 10 million cases of VTE globally (2). Without preventive measures being used, hospital-associated VTE is the leading preventable cause of hospital death (2). The age-standardized pulmonary embolism (PE)-related mortality rate is similar in magnitude to respiratory infections and obstructive pulmonary disease. Although the impact of PE-related deaths is relatively high among young women (3), its global awareness by the public is low (4).
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http://dx.doi.org/10.1111/jth.15608DOI Listing
November 2021

An update on the global use of risk assessment models and thromboprophylaxis in hospitalized patients with medical illnesses from the World Thrombosis Day steering committee: systematic review and meta-analysis.

J Thromb Haemost 2021 Nov 25. Epub 2021 Nov 25.

Department of Angiology, University Hospital Zurich, Zurich, Switzerland.

Introduction: Venous thromboembolism (VTE) is a leading cause of cardiovascular morbidity and mortality. The majority of VTE events are hospital-associated. In 2008, the ENDORSE multinational survey reported that only around 40% of medical patients at risk of VTE received adequate thromboprophylaxis.

Methods: In our systematic review and meta-analysis, we aimed at providing updated figures concerning the use of thromboprophylaxsis globally. We focused on: (i) the frequency of patients with an indication to thromboprophylaxis according with individual models; (ii) the use of adequate thromboprophylaxis; (iii) reported contraindications to thromboprophylaxis. Observational non-randomized studies or surveys focusing on medically ill patients were considered eligible.

Results: After screening, we included 27 studies from 20 countries for a total of 137,288 patients. Overall, 50.5% (95%CI: 41.9%-59.1%, I 99%) of patients had an indication to thromboprophylaxis: of these, 54.5% (95%CI: 46.2%-62.6%, I 99%) received adequate thromboprophylaxis. The use of adequate thromboprophylaxis was 66.8% in Europe (95%CI: 50.7% to 81.1%; I 98%), 44.9% in Africa (95%CI: 31.8% to 58.4% I 96%), 37.6% in Asia (95%CI: 25.7%-50.3%, I 97%), 58.3% in South America (95%CI 31.1%-83.1%, I 99%), and 68.6% in North America (95%CI 64.9%-72.6%, I 96%). No major differences in adequate thromboprophylaxis use were found across risk assessment models. Bleeding, thrombocytopenia, and renal/hepatic failure were the most frequently reported contraindications to thromboprophylaxis.

Conclusions: The use of anticoagulants for VTE prevention has been proven effective and safe, but thromboprophylaxis prescriptions are still unsatisfactory among hospitalized medically ill patients around the globe with marked geographical differences.
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http://dx.doi.org/10.1111/jth.15607DOI Listing
November 2021

Milvexian for the Prevention of Venous Thromboembolism.

N Engl J Med 2021 Nov 15. Epub 2021 Nov 15.

From the Thrombosis and Atherosclerosis Research Institute and McMaster University (J.I.W., R.R.) - both in Hamilton, ON, Canada; Janssen Research and Development, Raritan, NJ (J.S., R.S.N.); the University of Insubria, Varese, Italy (W.A.); Vanderbilt University Medical Center, Nashville (D.G.); Boston University School of Medicine, Boston (E.M.H.); Gildhøj Private Hospital, Copenhagen (M.R.L.); Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA (K.W.M.); International Trial Expertise Advisory and Services, Amsterdam (A.S.); and Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City (G.E.R.).

Background: Factor XIa inhibitors for the prevention and treatment of venous and arterial thromboembolism may be more effective and result in less bleeding than conventional anticoagulants. Additional data are needed regarding the efficacy and safety of milvexian, an oral factor XIa inhibitor.

Methods: In this parallel-group, phase 2 trial, we randomly assigned 1242 patients undergoing knee arthroplasty to receive one of seven postoperative regimens of milvexian (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily) or enoxaparin (40 mg once daily). The primary efficacy outcome was venous thromboembolism (which was a composite of asymptomatic deep-vein thrombosis, confirmed symptomatic venous thromboembolism, or death from any cause). The principal safety outcome was bleeding.

Results: Among the patients receiving milvexian twice daily, venous thromboembolism developed in 27 of 129 (21%) taking 25 mg, in 14 of 124 (11%) taking 50 mg, in 12 of 134 (9%) taking 100 mg, and in 10 of 131 (8%) taking 200 mg. Among those receiving milvexian once daily, venous thromboembolism developed in 7 of 28 (25%) taking 25 mg, in 30 of 127 (24%) taking 50 mg, and in 8 of 123 (7%) taking 200 mg, as compared with 54 of 252 patients (21%) taking enoxaparin. The dose-response relationship with twice-daily milvexian was significant (one-sided P<0.001), and the 12% incidence of venous thromboembolism with twice-daily milvexian was significantly lower than the prespecified benchmark of 30% (one-sided P<0.001). Bleeding of any severity occurred in 38 of 923 patients (4%) taking milvexian and in 12 of 296 patients (4%) taking enoxaparin; major or clinically relevant nonmajor bleeding occurred in 1% and 2%, respectively; and serious adverse events were reported in 2% and 4%, respectively.

Conclusions: Postoperative factor XIa inhibition with oral milvexian in patients undergoing knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Bristol Myers Squibb and Janssen Research and Development; AXIOMATIC-TKR ClinicalTrials.gov number, NCT03891524.).
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http://dx.doi.org/10.1056/NEJMoa2113194DOI Listing
November 2021

Management strategies and clinical outcomes in patients with inferior vena cava thrombosis: Data from GARFIELD-VTE.

J Thromb Haemost 2021 Oct 29. Epub 2021 Oct 29.

Thrombosis Research Institute, London, UK.

Background: Inferior vena cava (IVC) thrombosis is a rare form of venous thromboembolism (VTE). The optimal treatment strategies and outcomes are unclear in patients with this presentation.

Objective: We aimed to compare baseline characteristics, treatment patterns and 24-month outcomes in IVC thrombosis patients (n = 100) with lower extremity deep vein thrombosis (LEDVT) patients (n = 7629).

Methods: GARFIELD-VTE is a prospective, observational registry of 10 868 patients with objectively diagnosed VTE from 415 sites in 28 countries.

Results: IVC thrombosis patients were younger (51.9 vs. 59.8 years), more frequently had active cancer (26.0% vs. 8.9%) or history of cancer (21.0% vs. 12.2%), and less frequently had recent trauma or surgery than LEDVT patients. IVC thrombosis was more frequently treated with parenteral anticoagulants alone (35.1% vs. 15.9%), whereas patients with LEDVT more commonly received vitamin K antagonists (32.0% vs. 25.8%) or direct oral anticoagulants (49.0% vs. 35.1%). Thrombolysis (11.0% vs. 3.6%) and surgical/mechanical interventions (4.0% vs. 1.4%) were more frequent in IVC thrombosis. At 24-months, the rate per 100 person-years (95% confidence interval) of all-cause mortality was higher in patients with IVC thrombosis than LEDVT (13.28 [8.57-20.58] vs. 4.91 [4.55-5.3]); the incidence of cancer-associated mortality was comparable as was the incidence of VTE recurrence (4.11 [1.85-9.15] vs. 4.18 [3.84-4.55]). Major bleeding was slightly higher in IVC thrombosis (2.03 [0.66-6.31] vs. 1.66 [1.45-1.89]).

Conclusion: In summary, IVC thrombosis patients have higher all-cause mortality rates than those with LEDVT, a finding only partly attributable to malignancy.
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http://dx.doi.org/10.1111/jth.15574DOI Listing
October 2021

Association between body mass index, waist circumference, and relative fat mass with the risk of first unprovoked venous thromboembolism.

Nutr Metab Cardiovasc Dis 2021 10 30;31(11):3122-3130. Epub 2021 Jul 30.

Department of Medicine and Surgery, University of Insubria, Varese, Italy; Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy.

Background And Aims: Obesity defined by body mass index (BMI) is independently associated with venous thromboembolism (VTE). Abdominal obesity, defined by waist circumference, is a predictor of cardiovascular events. Recently, relative fat mass (RFM) was proposed as a marker of cardiovascular risk. We assessed the role of three different measures of obesity to predict unprovoked VTE in a longitudinal study.

Methods And Results: Moli-sani is a prospective cohort study carried out in the general population of the Molise region, Italy. A total of 23,538 individuals (48% men, age 55.4 years) enrolled between 2005 and 2010 were eligible. Patients on anticoagulant treatment were excluded. BMI ≥30 kg/m defined obesity, waist circumference >102 cm for men or 88 cm for women defined abdominal obesity, tertiles of RFM were compared. The long-term incidence of first unprovoked VTE during follow-up was assessed. Overall, 29.6% individuals were obese and 44.2% had abdominal obesity. A total of 66 first unprovoked VTE events were diagnosed during a median follow-up of 8.2 years. After multivariable Cox regression analysis, the risk of unprovoked VTE was significantly higher in obese participants (HR 1.89, 95% CI 1.16-3.07) than in participants with BMI <30; in subjects with abdominal obesity than with normal waist circumference (HR 2.19, 1.26-3.81); and in subjects with third vs first RFM tertile index (HR 2.46, 1.15-5.28). The areas under the curves for the models including the three obesity indexes were comparable.

Conclusions: Three indexes of obesity based on BMI, waist circumference or RFM similarly predict first occurrence of unprovoked VTE.
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http://dx.doi.org/10.1016/j.numecd.2021.07.018DOI Listing
October 2021

Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial.

Thromb Haemost 2021 Sep 24. Epub 2021 Sep 24.

AP-HP, hôpital européen Georges-Pompidou, Service de Pneumologie et de Soins Intensifs, APHP.Centre - Université de Paris, Paris, France.

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.
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http://dx.doi.org/10.1055/a-1653-4699DOI Listing
September 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

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

Ann Intern Med 2021 10 14;174(10):1420-1429. Epub 2021 Sep 14.

Bayer, Wuppertal, Germany (A.W.L., M.G.).

Background: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain.

Purpose: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups.

Data Sources: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021.

Study Selection: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment.

Data Extraction: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies.

Data Synthesis: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs.

Limitation: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs.

Conclusion: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE.

Primary Funding Source: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).
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http://dx.doi.org/10.7326/M21-1094DOI Listing
October 2021

Influence of body mass index on clinical outcomes in venous thromboembolism: Insights from GARFIELD-VTE.

J Thromb Haemost 2021 12 16;19(12):3031-3043. Epub 2021 Sep 16.

Thrombosis Research Institute, London, UK.

Background: There is limited information on the influence of body mass index (BMI) on clinical outcomes in patients with venous thromboembolism (VTE).

Objectives: Investigate the influence of BMI on baseline characteristics, treatment patterns, and 24-month outcomes in VTE patients.

Methods: GARFIELD-VTE is a prospective, non-interventional study of 10 869 patients with objectively confirmed VTE. Patients were grouped according to BMI: <18.5 (underweight; n = 214); 18.5-24.9 (normal; n = 2866); 25.0-29.9 (overweight; n = 3326); ≥30 (obese; n = 3073).

Results: Compared with patients with a normal BMI, obese patients were more frequently Caucasian (77.4% vs. 57.9%), treated in the outpatient setting (30.4% vs. 23.1%), and had previous VTE (17.5% vs. 11.7%). Active cancer was associated with lower BMI (underweight: 30.4%, normal: 13.5%, overweight: 9.4%, obese: 7.0%). At baseline, overweight and obese patients less often received parenteral therapy alone (16.7% and 14.4%) compared with those with an underweight or normal BMI (30.8% and 21.6%). Obese patients more commonly remained on anticoagulants for ≥2-years compared to those with a normal BMI (52.3% vs. 37.7%). After 24-months, the risk of all-cause mortality was lower in overweight and obese patients than in those with normal BMI (adjusted hazard ratio [95% CI]; 0.75 [0.63-0.89] and 0.59 [0.49-0.72], respectively). Underweight patients more often experienced major bleeding (2.45 [1.41-4.26]) and all-cause mortality (1.90 [1.43-2.53]) than patients with a normal BMI. Recurrent VTE was comparable among groups.

Conclusion: Underweight VTE patients have the highest risk of mortality and major bleeding. The risk of mortality in obese VTE patients is lower than that in VTE patients with a normal BMI.
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http://dx.doi.org/10.1111/jth.15520DOI Listing
December 2021

Safety and effectiveness of dabigatran in routine clinical practice: the RE-COVERY DVT/PE study.

J Thromb Thrombolysis 2021 Aug 28. Epub 2021 Aug 28.

Thrombosis and Atherosclerosis Research Institute and McMaster University, Hamilton, ON, Canada.

RE-COVERY DVT/PE is a two-phase, international, observational study of anticoagulant therapy in patients with deep vein thrombosis and/or pulmonary embolism (DVT/PE). The objective of the second phase was to compare the safety and effectiveness of dabigatran versus a vitamin K antagonist (VKA) over 1 year of follow-up. Primary safety and effectiveness outcomes were major or clinically relevant nonmajor bleeding events (MBE/CRNMBEs) and symptomatic recurrent venous thromboembolism (VTE) (including deaths related to recurrent VTE). To minimize bias due to unbalanced patient characteristics, only patients in an overlapping range of estimated propensity scores were included (analytic set), and propensity score weighting was applied to compare outcomes. Outcome analysis used an as-treated approach, censoring patients after they stopped or switched their initial anticoagulant. Overall, 3009 patients enrolled from 2016 to 2018 were eligible: 60% were diagnosed with DVT alone, 21% with PE alone, and 19% with DVT plus PE. The analytic set consisted of 2969 patients. The incidence rate in %/year (95% confidence interval [CI]) of MBE/CRNMBEs was 2.63 (1.79-3.74) with dabigatran versus 4.48 (3.23-6.06) with warfarin; hazard ratio 0.63 (95% CI 0.32-1.25). For symptomatic recurrent nonfatal or fatal VTE the incidence rate was 1.53 (0.91-2.42) with dabigatran versus 2.01 (1.21-3.14) with VKAs; hazard ratio 0.78 (95% CI 0.30-2.02). In conclusion, we found lower annualized rates of MBE/CRNMBEs with dabigatran than VKA, although the difference was not statistically significant. Annualized rates of symptomatic VTE or related mortality were similar with dabigatran and VKA. These observational results with 1 year of follow-up reflect those of the randomized clinical trials. Trial registration: ClinicalTrials.gov identifier NCT02596230, first registered November 4, 2015.
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http://dx.doi.org/10.1007/s11239-021-02463-xDOI Listing
August 2021

Long-term risk of recurrent venous thromboembolism among patients receiving extended oral anticoagulant therapy for first unprovoked venous thromboembolism: A systematic review and meta-analysis.

J Thromb Haemost 2021 11 22;19(11):2801-2813. Epub 2021 Aug 22.

Bayer AG, Wuppertal, Germany.

Background: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain.

Objectives: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5 years in patients with a first unprovoked VTE.

Methods: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3 months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results.

Results: Twenty-six studies and 15 603 patients were included in the analysis. During 11 631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03-1.84) and 0.09 (0.04-0.16), with 5-year cumulative incidences of 7.1% (3.0%-13.2%) and 1.2% (0.4%-4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77-1.44) with direct oral anticoagulants and 1.55 (1.01-2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%-8.7%).

Conclusions: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE.
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http://dx.doi.org/10.1111/jth.15491DOI Listing
November 2021

Incidence Rates and Case-Fatality Rates of Cerebral Vein Thrombosis: A Population-Based Study.

Stroke 2021 Nov 10;52(11):3578-3585. Epub 2021 Aug 10.

Department of Medicine and Surgery (W.A., F.D.), University of Insubria, Varese/Como, Italy.

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.121.034202DOI Listing
November 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

Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering.

J Healthc Eng 2021 25;2021:5556207. Epub 2021 Jun 25.

UOC Malattie Infettive, Ospedale San Gerardo, ASST Monza, Monza, Italy.

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February-May 2020). Patients' characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction ( < 0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment.
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http://dx.doi.org/10.1155/2021/5556207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238578PMC
August 2021

Recurrent bleeding and thrombotic events after resumption of oral anticoagulants following gastrointestinal bleeding: Communication from the ISTH SSC Subcommittee on Control of Anticoagulation.

J Thromb Haemost 2021 10 8;19(10):2618-2628. Epub 2021 Aug 8.

Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands.

Background: Gastrointestinal bleeding frequently complicates anticoagulant therapy causing treatment discontinuation. Data to guide the decision regarding whether and when to resume anticoagulation based on the risks of thromboembolism and recurrent bleeding are scarce.

Objectives: We aimed to retrospectively evaluate the incidence of these events after anticoagulant-related gastrointestinal bleeding and assess their relationship with timing of anticoagulation resumption.

Methods: Patients hospitalized because of gastrointestinal bleeding during oral anticoagulation for any indication were eligible. All patients were followed up to 2 years after the index bleeding for recurrent major or clinically relevant non-major bleeding, venous or arterial thromboembolism, and mortality.

Results: We included 948 patients hospitalized for gastrointestinal bleeding occurring during treatment with vitamin K antagonists (n = 531) or direct oral anticoagulants (n = 417). In time-dependent analysis, anticoagulant treatment was associated with a higher risk of recurrent clinically relevant bleeding (hazard ratio [HR] 1.55; 95% confidence interval [CI] 1.08-2.22), but lower risk of thromboembolism (HR 0.34; 95% CI 0.21-0.55), and death (HR 0.50; 95% CI 0.36-0.68). Previous bleeding, index major bleeding, and lower glomerular filtration rate were associated with a higher risk of recurrent bleeding. The incidence of recurrent bleeding increased after anticoagulation restart independently of timing of resumption.

Conclusions: Anticoagulant treatment after gastrointestinal bleeding is associated with a lower risk of thromboembolism and death, but higher risk of recurrent bleeding. The latter seemed to be influenced by patient characteristics and less impacted by time of anticoagulation resumption.
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http://dx.doi.org/10.1111/jth.15476DOI Listing
October 2021

Rivaroxaban for extended thromboprophylaxis in acutely ill medical patients 75 years of age or older.

J Thromb Haemost 2021 11 17;19(11):2772-2780. Epub 2021 Aug 17.

Department of Medicine, Anticoagulation and Clinical Thrombosis Services Northwell Health at Lenox Hill Hospital, The Feinstein Institute for Medical Research and Zucker School of Medicine at Hofstra/Northwell, New York, NY, USA.

Background: Although older patients are at increased risk for venous thromboembolism (VTE), thromboprophylaxis is underused because of bleeding concerns. The MARINER trial evaluated whether rivaroxaban reduced symptomatic postdischarge VTE in acutely ill medical patients.

Objectives: We hypothesized that rivaroxaban would have a favorable benefit/risk profile in patients ≥75 years of age.

Methods: Patients were randomized in a double-blind manner at hospital discharge to rivaroxaban (10 mg/day for creatinine clearance ≥50 ml/min; 7.5 mg/day for ≥30-<50 ml/min) or placebo for 45 days. Using a Cox proportional hazard model including treatment as a covariate, we compared the risk of the primary efficacy outcome (symptomatic VTE plus VTE-related death in the intention-to-treat population) and safety outcome (International Society on Thrombosis and Haemostasis major bleeding in the safety population) in the prespecified subgroups of patients ≥ and <75 years of age.

Results: The primary event rate in patients ≥75 years of age was 2-fold higher than that in those <75 years. The incidence of the primary efficacy outcomes in both age groups was numerically lower with rivaroxaban than with placebo (≥75: 1.2% and 1.6%, HR 0.73, 95% CI 0.43-1.22; <75 0.6% and 0.8%, HR 0.78, 95% CI 0.46-1.32; interaction p-value for age group = .85). The incidence of major bleeding was low and similar in the two age and treatment groups (interaction p value for age group = .35).

Conclusion: Symptomatic VTE and VTE-related death occur frequently in older patients with acute medical illness. The benefit/risk profile of rivaroxaban in patients ≥75 years of age appears consistent with that observed in the general population.
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http://dx.doi.org/10.1111/jth.15477DOI Listing
November 2021

Illustrated State-of-the-Art Capsules of the ISTH 2020 Congress.

Res Pract Thromb Haemost 2021 Jul 16;5(5):e12532. Epub 2021 Jul 16.

Transfusion Medicine NHS Blood and Transplant (London) and Barts Health NHS Trust London UK.

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) was hosted virtually from Philadelphia July 17-21, 2021. The conference, now held annually, highlighted cutting-edge advances in basic, population and clinical sciences of relevance to the Society. Despite being held virtually, the 2021 congress was of the same scope and quality as an annual meeting held in person. An added feature of the program is that talks streamed at the designated times will then be available on-line for asynchronous viewing. The program included 77 State of the Art (SOA) talks, thematically grouped in 28 sessions, given by internationally recognized leaders in the field. The SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. The topics, across the main scientific themes of the congress, include Arterial Thromboembolism, Coagulation and Natural Anticoagulants, COVID-19 and Coagulation, Diagnostics and Omics, Fibrinogen, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostasis in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Angiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the congress.
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http://dx.doi.org/10.1002/rth2.12532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285574PMC
July 2021

Management and Outcomes of Isolated Distal Deep Vein Thromboses: A Questionable Trend toward Long-Lasting Anticoagulation Treatment. Results from the START-Register.

TH Open 2021 Jul 8;5(3):e239-e250. Epub 2021 Jul 8.

Dipartimento di Emergenza e Accettazione, Centro Trombosi ed Emostasi, Ospedale di Circolo, Università dell'Insubria, Varese, Italy.

 Isolated distal deep vein thromboses (IDDVT) are frequently diagnosed; however, their natural history and real risk of complications are still uncertain. Though treatment is still not well standardized, international guidelines recommend no more than 3 months of anticoagulation therapy. We investigated how Italian clinicians treat IDDVT patients in their real life in our country.  Baseline characteristics and clinical history of the patients enrolled in the prospective, observational, multicenter START-Register for a first IDDVT or proximal DVT (PDVT) were analyzed.  Overall, 412 IDDVT patients were significantly younger, with better renal function, and more frequent major transient risk factors, when compared with 1,173 PDVT patients. The anticoagulation duration was >180 days in 52.7% of IDDVT patients (70.7% in PDVT). During treatment, bleeding occurred in 5.6 and 2.8% patient-years in IDDVT and PDVT, respectively (  = 0082). Bleeding was more frequent in IDDVT than PDVT patients treated with warfarin (6.8 vs. 3.2 patient-years,  = 0.0228, respectively). Thrombotic complications occurred in 1.1 and 2.4% patient-years in IDDVT and PDVT patients, respectively. Analyzing together the two groups, 66.1% of bleeds and 86.1% thrombotic complications occurred after 90 days anticoagulation treatment.  The large majority of IDDVT patients received anticoagulation for more than 3 months. Most bleeding and thrombotic complications occurred after the first 90 days of anticoagulation therapy. These results indicate that an extended anticoagulation beyond 90 days in IDDVT patients is associated with increased risk of complications. Whether an extended treatment may lower recurrences after anticoagulation withdrawal should be assessed by specifically designed studies.
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http://dx.doi.org/10.1055/s-0041-1730038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266420PMC
July 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

Second consensus document on diagnosis and management of acute deep vein thrombosis: updated document elaborated by the ESC Working Group on aorta and peripheral vascular diseases and the ESC Working Group on pulmonary circulation and right ventricular function.

Eur J Prev Cardiol 2021 Jul 13. Epub 2021 Jul 13.

Department of Cardiology, Dupuytren University Hospital and Inserm 1094, Tropical Neuroepidemiology, School of Medicine, 2 avenue martin Luther-King 87042 Limoges, France.

This consensus document is proposed to clinicians to provide the whole spectrum of deep vein thrombosis management as an update to the 2017 consensus document. New data guiding clinicians in indicating extended anticoagulation, management of patients with cancer, and prevention and management of post-thrombotic syndrome are presented. More data on benefit and safety of non-vitamin K antagonists oral anticoagulants are highlighted, along with the arrival of new antidotes for severe bleeding management.
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http://dx.doi.org/10.1093/eurjpc/zwab088DOI Listing
July 2021

Difficult challenges in vascular medicine.

Authors:
Walter Ageno

Minerva Med 2021 Jul 8. Epub 2021 Jul 8.

Department of Medicine and Surgery, University of Insubria, Varese, Italy -

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http://dx.doi.org/10.23736/S0026-4806.21.07702-8DOI Listing
July 2021

Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study.

Front Med (Lausanne) 2021 9;8:639970. Epub 2021 Jun 9.

Ospedale del Mare, ASL Napoli 1, Napoli, Italy.

Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients.
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http://dx.doi.org/10.3389/fmed.2021.639970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221239PMC
June 2021

Outcomes among patients with cancer and incidental or symptomatic venous thromboembolism: A systematic review and meta-analysis.

J Thromb Haemost 2021 10 12;19(10):2468-2479. Epub 2021 Jul 12.

Department of Medicine, University of Ottawa at The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Background: Patients with cancer have an increased risk of venous thromboembolism (VTE) and it is commonly detected incidentally. The outcomes and optimal management for patients with cancer and incidental VTE remain debated.

Objectives: We conducted a systematic review and meta-analysis to evaluate the outcomes in patients with cancer and incidentally detected VTE compared to those with symptomatic events.

Patients/methods: We searched the electronic databases and included randomized controlled trials (RCTs) and observational studies reporting recurrent VTE, major bleeding events, and mortality in patients with cancer and incidental VTE compared to symptomatic VTE.

Results: We included 23 studies for the systematic review: 3 RCTs and 20 observational studies. The meta-analysis of the 3 RCTs showed a significantly lower rate of VTE recurrence at 6 months in patients with incidental VTE compared to those with symptomatic VTE (relative risk [RR] 0.62, 95% confidence interval [CI] 0.44-0.87). The risk of major bleeding events at 6 months was numerically higher with incidental VTE compared to symptomatic VTE (RR 1.47, 95% CI 0.99-2.20). There was no difference in overall mortality.

Conclusions: Among patients with cancer, incidental VTE was associated with a lower rate of VTE recurrence compared to symptomatic VTE, with a trend in increased major bleeding events. The risk-benefit ratio of anticoagulation may differ between incidental and symptomatic events and should be considered in patient management.
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http://dx.doi.org/10.1111/jth.15435DOI Listing
October 2021

Cancer-Associated Splanchnic Vein Thrombosis.

Semin Thromb Hemost 2021 Nov 11;47(8):931-941. Epub 2021 Jun 11.

Department of Medicine and Surgery, University of Insubria, Varese, Italy.

Splanchnic vein thrombosis (SVT), which includes portal, mesenteric, and splenic vein thrombosis and the Budd-Chiari syndrome, is an infrequent manifestation of venous thromboembolism (VTE). Like typical site VTE, SVT is also frequently associated with cancer, particularly intra-abdominal solid malignancies and myeloproliferative neoplasms (MPNs). The clinical presentation of SVT is nonspecific. Symptoms may be related to the underlying malignancy, and thrombosis is incidentally diagnosed by imaging studies for cancer staging or follow-up in a substantial proportion of cases. The occurrence of SVT predicts worse prognosis in patients with liver or pancreatic cancer and, not uncommonly, SVT may precede the diagnosis of cancer. Therefore, the occurrence of an apparently unprovoked SVT should prompt careful patient evaluation for the presence of an underlying malignancy or MPN. Cancer patients carry a high risk of VTE extension and recurrence and long-term anticoagulant treatment is suggested in the absence of high risk of bleeding. Either LMWH or direct oral anticoagulants (DOACs) are suggested for the treatment of patients with cancer-related SVT, although limited experience is available on the use of DOACs in these settings. Vitamin K antagonists (VKAs) are suggested for the short and long-term treatment of SVT associated with MPN. This review outlines the epidemiological aspects, pathogenesis, risk factors, and diagnosis of cancer-associated SVT, and addresses questions regarding the management of this challenging condition.
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http://dx.doi.org/10.1055/s-0040-1722607DOI Listing
November 2021

Current management of cancer-associated venous thromboembolism in patients with thrombocytopenia: a retrospective cohort study.

Intern Emerg Med 2021 Jun 10. Epub 2021 Jun 10.

Thrombosis and Hemorragic Diseases Unit, IRCCS Humanitas Clinical and Research Hospital, Milan, Italy.

Optimal management of venous thromboembolism (VTE) in cancer patients with thrombocytopenia is uncertain. We described current management and clinical outcomes of these patients. We retrospectively included a cohort of cancer patients with acute VTE and concomitant mild (platelet count 100,000-150,000/mm), moderate (50,000-99,000/mm), or severe thrombocytopenia (< 50,000/mm). Univariate and multivariate logistic regression analyses explored the association between different therapeutic strategies and thrombocytopenia. The incidence of VTE and bleeding complications was collected at a 3-month follow-up. A total of 194 patients of whom 122 (62.89%) had mild, 51 (26.29%) moderate, and 22 (11.34%) severe thrombocytopenia were involved. At VTE diagnosis, a full therapeutic dose of LMWH was administered in 79.3, 62.8 and 4.6% of patients, respectively. Moderate (OR 0.30; 95% CI 0.12-0.75), severe thrombocytopenia (OR 0.01; 95% CI 0.00-0.08), and the presence of cerebral metastasis (OR 0.06; 95% CI 0.01-0.30) were independently associated with the prescription of subtherapeutic LMWH doses. Symptomatic VTE (OR 4.46; 95% CI 1.85-10.80) and pulmonary embolism (OR 2.76; 95% CI 1.09-6.94) were associated with the prescription of full therapeutic LMWH doses. Three-month incidence of VTE was 3.9% (95% CI 1.3-10.1), 8.5% (95% CI 2.8-21.3), 0% (95% CI 0.0-20.0) in patients with mild, moderate, and severe thrombocytopenia, respectively. The corresponding values for major bleeding and mortality were 1.9% (95% CI 0.3-7.4), 6.4% (95% CI 1.7-18.6), 0% (95% CI 0.0-20.0) and 9.6% (95% CI 5.0-17.4), 48.2% (95% CI 16.1-42.9), 20% (95% CI 6.6-44.3). In the absence of sound evidence, anticoagulation strategy of VTE in cancer patients with thrombocytopenia was tailored on an individual basis, taking into account not only the platelet count but also VTE presentation and the presence of cerebral metastasis.
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http://dx.doi.org/10.1007/s11739-021-02771-3DOI Listing
June 2021

Association of thromboelastography profile with severity of liver cirrhosis and portal venous system thrombosis.

BMC Gastroenterol 2021 Jun 7;21(1):253. Epub 2021 Jun 7.

Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), No. 83 Wenhua Road, Shenyang, 110840, Liaoning Province, China.

Background And Aim: Hemostasis profile is often complicated in liver cirrhosis. Thromboelastography is a global viscoelastic test recommended by the current practice guideline and consensus. This cross-sectional study aimed to evaluate the association of thromboelastography profile with severity of liver cirrhosis and presence of portal venous system thrombosis (PVST).

Methods: Overall, 116 and 50 cirrhotic patients were included in the Shenyang and Xi'an cohorts, respectively. Thromboelastography parameters were compared between cirrhotic patients with Child-Pugh class A and B/C, those with and without decompensated events, and those with and without PVST. Hypercoagulability would be considered if at least two of the following thromboelastography parameters were met: shortened reactive time (R), shortened coagulation time (K), increased angle, and increased maximum amplitude (MA).

Results: In the Shenyang cohort, 16 patients had shortened R, of whom seven (43.75%) had prolonged K and 11 (68.75%) decreased MA. In the Xi'an cohort, 24 patients had shortened R, of whom seven (29.17%) had prolonged K and 15 (62.50%) decreased MA. In the Shenyang cohort, the prevalence of hypercoagulability was not significantly different between cirrhotic patients with Child-Pugh class A and B/C (3.85% vs. 6.25%, P = 0.873), those with and without decompensated events (5.49% vs. 4.00%, P = 1.000), and those with and without PVST (4.17% vs. 5.88%, P = 1.000), which were similar to the results obtained in the Xi'an cohort.

Conclusion: There is a high rate of discordance between R and other thromboelastography parameters. In addition, hypercoagulability may not be related to more advanced stage of liver cirrhosis or presence of PVST.
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http://dx.doi.org/10.1186/s12876-021-01832-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185912PMC
June 2021
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